Effect of cocoa on blood pressure

  • Review
  • Intervention

Authors

  • Karin Ried,

    Corresponding author
    1. National Institute of Integrative Medicine, Melbourne, Victoria, Australia
    2. The University of Adelaide, Discipline of General Practice, Adelaide, South Australia, Australia
    • Karin Ried, National Institute of Integrative Medicine, 21 Burwood Rd, Hawthorn, Melbourne, Victoria, 3122, Australia. karinried@niim.com.au.

  • Peter Fakler,

    1. The University of Adelaide, Discipline of General Practice, Adelaide, South Australia, Australia
  • Nigel P Stocks

    1. The University of Adelaide, Discipline of General Practice, Adelaide, South Australia, Australia

Abstract

Background

High blood pressure is an important risk factor for cardiovascular disease, contributing to about 50% of cardiovascular events worldwide and 37% of cardiovascular-related deaths in Western populations. Epidemiological studies suggest that cocoa-rich products reduce the risk of cardiovascular disease. Flavanols found in cocoa have been shown to increase the formation of endothelial nitric oxide which promotes vasodilation and therefore blood pressure reduction. Here we update previous meta-analyses on the effect of cocoa on blood pressure.

Objectives

To assess the effects on blood pressure of chocolate or cocoa products versus low-flavanol products or placebo in adults with or without hypertension when consumed for two weeks or longer.

Search methods

This is an updated version of the review initially published in 2012. In this updated version, we searched the following electronic databases from inception to November 2016: Cochrane Hypertension Group Specialised Register, CENTRAL, MEDLINE and Embase. We also searched international trial registries, and the reference lists of review articles and included trials.

Selection criteria

Randomised controlled trials (RCTs) investigating the effects of chocolate or cocoa products on systolic and diastolic blood pressure in adults for a minimum of two weeks duration.

Data collection and analysis

Two review authors independently extracted data and assessed the risks of bias in each trial. We conducted random-effects meta-analyses on the included studies using Review Manager 5. We explored heterogeneity with subgroup analyses by baseline blood pressure, flavanol content of control group, blinding, age and duration. Sensitivity analyses explored the influence of unusual study design.

Main results

Thirty-five trials (including 40 treatment comparisons) met the inclusion criteria. Of these, we added 17 trials (20 treatment comparisons) to the 18 trials (20 treatment comparisons) in the previous version of this updated review.

Trials provided participants with 30 to 1218 mg of flavanols (mean = 670 mg) in 1.4 to 105 grams of cocoa products per day in the active intervention group. The control group received either a flavanol-free product (n = 26 treatment comparisons) or a low-flavanol-containing cocoa powder (range 6.4 to 88 mg flavanols (mean = 55 mg, 13 treatment comparisons; 259 mg, 1 trial).

Meta-analyses of the 40 treatment comparisons involving 1804 mainly healthy participants revealed a small but statistically significant blood pressure-reducing effect of flavanol-rich cocoa products compared with control in trials of two to 18 weeks duration (mean nine weeks):
Mean difference systolic blood pressure (SBP) (95% confidence interval (CI): -1.76 (-3.09 to -0.43) mmHg, P = 0.009, n = 40 treatment comparisons, 1804 participants;
Mean difference diastolic blood pressure (DBP) (95% CI): -1.76 (-2.57 to -0.94) mmHg, P < 0.001, n = 39 treatment comparisons, 1772 participants.

Baseline blood pressure may play a role in the effect of cocoa on blood pressure. While systolic blood pressure was reduced significantly by 4 mmHg in hypertensive people (n = 9 treatment comparisons, 401 participants), and tended to be lowered in prehypertensive people (n= 8 treatment comparisons, 340 participants), there was no significant difference in normotensive people (n = 23 treatment comparisons, 1063 participants); however, the test for subgroup differences was of borderline significance (P = 0.08; I2 = 60%), requiring further research to confirm the findings.

Subgroup meta-analysis by blinding suggested a trend towards greater blood pressure reduction in unblinded trials compared to double-blinded trials, albeit statistically not significant. Further research is needed to confirm whether participant expectation may influence blood pressure results. Subgroup analysis by type of control (flavanol-free versus low-flavanol control) did not reveal a significant difference.

Whether the age of participants plays a role in the effect of cocoa on blood pressure, with younger participants responding with greater blood pressure reduction, needs to be further investigated.

Sensitivity analysis excluding trials with authors employed by trials sponsoring industry (33 trials, 1482 participants) revealed a small reduction in effect size, indicating some reporting bias.

Due to the remaining heterogeneity, which we could not explain in terms of blinding, flavanol content of the control groups, age of participants, or study duration, we downgraded the quality of the evidence from high to moderate.

Results of subgroup analyses should be interpreted with caution and need to be confirmed or refuted in trials using direct randomised comparisons.

Generally, cocoa products were highly tolerable, with adverse effects including gastrointestinal complaints and nausea being reported by 1% of participants in the active cocoa intervention group and 0.4% of participants in the control groups (moderate-quality evidence).

Authors' conclusions

This review provides moderate-quality evidence that flavanol-rich chocolate and cocoa products cause a small (2 mmHg) blood pressure-lowering effect in mainly healthy adults in the short term.

These findings are limited by the heterogeneity between trials, which could not be explained by prespecified subgroup analyses, including blinding, flavanol content of the control groups, age of participants, or study duration. However, baseline blood pressure may play a role in the effect of cocoa on blood pressure; subgroup analysis of trials with (pre)hypertensive participants revealed a greater blood pressure-reducing effect of cocoa compared to normotensive participants with borderline significance.

Long-term trials investigating the effect of cocoa on clinical outcomes are also needed to assess whether cocoa has an effect on cardiovascular events and to assess potential adverse effects associated with chronic ingestion of cocoa products.

Résumé scientifique

Effet du cacao sur la tension artérielle

Objectifs

Déterminer l'effet des produits de chocolat ou de cacao riches en flavanol sur la tension artérielle des personnes avec ou sans hypertension.

Critères de sélection

Des essais contrôlés randomisés (ECR) examinant les effets des produits de chocolat ou de cacao sur la pression sanguine systolique et diastolique de l'adulte pendant une durée minimale de deux semaines.

Résultats principaux

Des effets indésirables, notamment des affections gastro-intestinales et du dégoût pour le produit de l'essai, ont été signalés par 5 % des patients dans les groupes d'intervention active au cacao et par 1 % des patients dans les groupes témoins.

Conclusions des auteurs

Les produits de chocolat et de cacao riches en flavanols pourraient avoir à court terme un effet hypotenseur modeste mais statistiquement significatif de 2-3 mm Hg.

アブストラクト

血圧に対するココアの効果

背景

高血圧は心血管疾患の重要なリスク因子の一つで、世界では心血管イベントの約50%、また西洋人集団では心血管関連死の37%を占めている。疫学的研究では、ココア高含有製品により心血管疾患リスクが低減することが示唆されている。ココアに含まれるフラバノールは、血管拡張を促進し血圧を下げる内皮一酸化窒素の生成を増加することが示されている。以下に、血圧に対するココアの効果について、過去のメタアナリシスをアップデートする。

目的

高血圧の有無にかかわらず、成人を対象として、チョコレートまたはココア製品を2週間以上摂取したときの血圧に対する効果を、フラバノール低含有製品またはプラセボと比較して評価する。

検索戦略

本レビューは、2012年に初めて公表したレビューのアップデート版である。今回のアップデート版では、以下の電子データベースを初版から2016年11月まで検索した。Cochrane Hypertension Group Specialised Register、CENTRAL、MEDLINEおよびEmbase。また、国際臨床試験登録ならびにレビュー論文および収載された試験の目録も検索した。

選択基準

成人を対象として、チョコレートまたはココア製品が収縮期血圧および拡張期血圧に及ぼす影響を2週間以上にわたり検討したランダム化比較試験(RCT)をレビュー対象とした。

データ収集と分析

2名のレビュー著者がそれぞれデータを抽出し、各試験についてバイアスのリスクを評価した。Review Manager 5を用い、選択基準を満たした研究のメタアナリシスをランダム効果モデルにより実施した。ベースライン血圧、対照群のフラバノール含有量、盲検化、年齢および摂取期間に基づくサブグループ解析で異質性を調べた。感度分析では、独自の研究デザインが及ぼす影響を調べた。

主な結果

35試験(治療比較 40件を含む)が組み入れ基準を満たした。このうち、17試験(治療比較20件)を、本アップデートレビューの旧版で対象としていた18試験(治療比較20件)に加えた。

試験では、実介入群において、1日1.4~105 gのココア製品中のフラバノール30~1218 mg(平均670 mg)を参加者に摂取させていた。対照群には、フラバノール無含有製品(治療比較26件)またはフラバノール低含有ココア粉末(フラバノール含有量6.4~88 mg[平均含有量55 mg、治療比較13件]および259 mg[1試験])を摂取させていた。

主として健康な参加者1804名を対象とした治療比較40件についてメタアナリシスを実施した結果、2~18週間(平均9週間)にわたる試験において、フラバノール高含有ココア製品は対照と比較して、わずかではあるが統計学的に有意な血圧低下作用を有することが示された。収縮期血圧(SBP)の平均差(95%信頼区間[CI]):-1.76(-3.09~-0.43)mmHg、P = 0.009、治療比較40件、参加者1804名。拡張期血圧(DBP)の平均差(95% CI):-1.76(-2.57~-0.94)mmHg、P < 0.001、治療比較39件、参加者1772名。

血圧に対するココアの効果に、ベースライン血圧が影響を及ぼしている可能性がある。高血圧の参加者では収縮期血圧4 mmHgの有意な低下(治療比較9件、参加者401名)が認められ、前高血圧状態の参加者では収縮期血圧の低下傾向(治療比較8件、参加者340名)が認められたものの、血圧正常者では有意な差は認められなかった(治療比較23件、参加者1063名)。しかし、サブグループ間の差に関する検定において、境界有意であった(P = 0.08、I2 = 60%)ため、今後の研究によりこの結果を確認する必要がある。

盲検化に基づくサブグループのメタアナリシスから、統計学的に有意ではないものの、非盲検試験では二重盲検試験に比べて血圧低下幅が大きい傾向が示唆された。参加者の期待が血圧測定値に及ぼす影響の有無を確認するため、今後の研究が求められる。対照の種類に基づくサブグループのメタアナリシス(フラバノール無含有と低含有)では、有意差は認められなかった。

血圧に対するココアの効果に参加者の年齢が影響を及ぼすか否かについては、血圧低下幅が大きい若年参加者を対象に、さらに検討を重ねる必要がある。

試験に資金援助する産業により雇用された者が執筆した試験を除いて感度分析を行った結果、若干の効果量の減少が認められ、多少の報告バイアスが存在することが示された(33試験、参加者1482名)。

遺残する異質性は、盲検化、対照群のフラバノール含有量、参加者の年齢または試験実施期間によって説明がつかず、エビデンスレベルの評価を高から中等度に引き下げた。

サブグループ解析の結果は慎重に解釈にするべきであり、直接ランダム化比較法を用いた試験では裏付けが必要な場合や、反証を示すべき場合もある。

概して、ココア製品は忍容性が極めて良好であり、消化管愁訴や悪心などの有害作用報告は、実介入群で1%、対照群で0.4%であった(エビデンスの質は中等度)。

著者の結論

主に健康成人において、フラバノール高含有チョコレートおよびココア製品は短期的に血圧をわずかに低下させる(2 mmHg)作用を有するとの中等度の質のエビデンスが、本レビューから得られた。

試験間には、盲検化、対照群のフラバノール含有量、参加者の年齢または試験実施期間などに基づく事前に定めたサブグループ解析では説明がつかない異質性が存在するため、上記の結果には限界が認められる。しかし、血圧に対するココアの効果には、ベースライン血圧が影響を及ぼしている可能性があり、試験のサブグループ解析から、高血圧および前高血圧状態の参加者では、境界有意を示した血圧正常者の結果と比較して、ココアの血圧低下作用は大きい ことが明らかになった。

ココアが心血管イベントに有効か否か、またココア製品を習慣的に摂取した場合の有害作用の可能性を評価するため、臨床アウトカムに対するココアの効果を検討する長期試験も必要である。

บทคัดย่อ

ผลของโกโก้ต่อความดันโลหิต

บทนำ

ความดันโลหิตสูงเป็นปัจจัยเสี่ยงสำคัญสำหรับโรคหัวใจและหลอดเลือด ซึ่งมีส่วนทำให้เกิดโรคหลอดเลือดหัวใจประมาณ 50% ทั่วโลกและ 37% ของผู้เสียชีวิตจากโรคหัวใจและหลอดเลือดเป็นประชากรชาวตะวันตก การศึกษาเชิงระบาดวิทยาแนะนำว่าผลิตภัณฑ์ที่มีส่วนประกอบของโกโก้ลดความเสี่ยงของโรคหัวใจและหลอดเลือด ฟลาวานอลที่พบในโกโก้แสดงการเพิ่มการก่อตัวของเอนโดธีเลียลไนตริกออกไซด์ (endothelial nitric oxide) ซึ่งส่งเสริมการขยายตัวของหลอดเลือดและลดความดันโลหิต ครั้งนี้เราได้ปรับปรุงการวิเคราะห์เมตต้าของผลของโกโก้ต่อความดันโลหิตก่อนหน้านี้

วัตถุประสงค์

เพื่อประเมินผลกระทบของช็อกโกแลตหรือผลิตภัณฑ์โกโก้ต่อความดันโลหิตเปรียบเทียบกับผลิตภัณฑ์ที่มีฟลาโวนอลต่ำหรือยาหลอกในผู้ใหญ่ที่มีหรือไม่มีความดันโลหิตสูงเมื่อบริโภคเป็นเวลาสองสัปดาห์หรือนานกว่านั้น

วิธีการสืบค้น

การศึกษานี้เป็นการปรับปรุงรายงานการทบทวนฯที่ตีพิมพ์ครั้งแรกในปี 2012 ในการปรับปรุงนี้เราได้ค้นหาในฐานข้อมูลอิเล็กทรอนิกส์ต่อไปนี้ Cochrane Hypertension Group Specialised Register, CENTRAL, MEDLINE และ Embase ตั้งแต่เริ่มก่อตั้งจนถึงเดือนพฤศจิกายน 2016 นอกจากนี้เรายังได้ค้นหาในทะเบียนการทดลองนานาชาติและรายการอ้างอิงของบทความการทบทวนและการทดลองที่นำเข้า

เกณฑ์การคัดเลือก

Randomised controlled trials (RCTs) ที่ทดสอบผลของช็อกโกแลตหรือผลิตภัณฑ์โกโก้ต่อความดัน systolic และความดัน diastolic ในผู้ใหญ่เป็นเวลาอย่างน้อยสองสัปดาห์

การรวบรวมและวิเคราะห์ข้อมูล

ผู้ทบทวนสองคน ดึงข้อมูลและประเมินความเสี่ยงของการมีอคติของแต่ละการศึกษาอย่างเป็นอิสระต่อกัน เราได้ทำการวิเคราะห์เมตต้าแบบ random-effect จากการศึกษาที่คัดเข้า โดยใช้ Review Manager 5 เราได้ตรวจสอบ heterogeneity ด้วยการวิเคราะห์กลุ่มย่อยตาม ค่าความดันโลหิต ณ เวลาเริ่มต้นการศึกษา ปริมาณฟลาโวนอลที่ให้ในกลุ่มควบคุม การปกปิด อายุ และระยะเวลาการศึกษา การวิเคราะห์ความไวเพื่อศึกษาอิทธิพลของรูปแบบการศึกษาที่ไม่ใช่แบบที่ใช้ปกติ

ผลการวิจัย

พบสามสิบห้าการทดลอง ( รวม 40 คู่เปรียบเทียบการรักษา) ที่เป็นไปตามเกณฑ์การคัดเลือก จากข้อมูลเหล่านี้ เราเพิ่ม 17 การทดลอง (20 คู่เปรียบเทียบการรักษา) เข้าไปใน 18 การทดลอง (20 คู่เปรียบเทียบการรักษา) จากการทบทวนฉบับก่อนหน้านี้

การทดลองให้ฟลาโวนอล 30 ถึง 1218 มก. (เฉลี่ย 670 มก.) ในผลิตภัณฑ์โกโก้ 1.4 ถึง 105 กรัมต่อวัน แก่ผู้เข้าร่วมการศึกษาในกลุ่มทดลอง กลุ่มควบคุมได้รับผลิตภัณฑ์ที่ไม่มีฟลาโวนอล (n = 26 คู่การเปรียบเทียบการรักษา) หรือผงโกโก้ที่มีฟลาโวนอลต่ำ (ปริมาณฟลาโวนอลอยู่ในช่วง 6.4 ถึง 88 มก. (เฉลี่ย 55 มก., 13 คู่เปรียบเทียบการรักษา; 259 มก., 1 การทดลอง)

การวิเคราะห์เมตต้าของ 40 คู่การเปรียบเทียบการรักษา มีผู้เข้าร่วมการศึกษา 1804 คน ซึ่งส่วนใหญ่มีสุขภาพดี แสดงให้เห็นการลดลงของความดันโลหิตที่เป็นผลจากผลิตภัณฑ์โกโก้ที่มีส่วนผสมของฟลาโวนอล เปรียบเทียบกับกลุ่มควบคุมเป็นระยะเวลาสองถึง 18 สัปดาห์ (เฉลี่ยเก้าสัปดาห์):
ค่าเฉลี่ยความแตกต่างของระดับความดันโลหิต systolic (SBP) (ช่วงเชื่อมั่น 95% (CI): -1.76 (-3.09 ถึง -0.43) มิลลิเมตรปรอท, P = 0.009, n = 40 คู่เปรียบเทียบการรักษา, ผู้เข้าร่วมการศึกษา 1804 คน;
ค่าเฉลี่ยความแตกต่างของความดันโลหิต diastolic (DBP) (95% CI): -1.76 (-2.57 ถึง -0.94) มิลลิเมตรปรอท, P < 0.001, n = 39 คู่เปรียบเทียบการรักษา, ผู้เข้าร่วมการศึกษา 1772 คน

ความดันโลหิต ณ เวลาเริ่มต้นการศึกษาอาจมีบทบาทต่อผลของโกโก้ต่อความดันโลหิต แม้ว่าความดันโลหิต systolic ลดลงอย่างมีนัยสำคัญ 4 มิลลิเมตรปรอท ในผู้ที่เป็นโรคความดันโลหิตสูง (n = 9 คู่เปรียบเทียบการรักษา, ผู้เข้าร่วมการศึกษา 401 คน) และมีแนวโน้มลดลงในผู้ที่มีภาวะเสี่ยงต่อความดันโลหิตสูง (prehypertensive) (n = 8 คู่เปรียบเทียบการรักษา, ผู้เข้าร่วมการศึกษา 340 คน) มีความแตกต่างอย่างไม่มีนัยสำคัญทางสถิติในผู้ป่วยที่มีระดับความดันโลหิตปกติ (n = 23 คู่เปรียบเทียบการรักษา, ผู้เข้าร่วมการศึกษา 1063 คน) อย่างไรก็ตาม การทดสอบความแตกต่างตามกลุ่มย่อยอยู่บนเส้นขอบเขตนัยสำคัญ (P = 0.08; I2 = 60%) จำเป็นต้องมีการวิจัยเพิ่มเติมเพื่อยืนยันผลการวิจัย

การวิเคราะห์เมตต้ากลุ่มย่อยตามการปกปิด แสดงให้เห็นแนวโน้มลดลงของความดันโลหิตอย่างมากในการทดลองที่ไม่มีการปกปิดเมื่อเทียบกับการทดลองแบบ double-blinded แม้ว่าจะไม่มีนัยสำคัญทางสถิติ จำเป็นต้องมีการวิจัยเพิ่มเติมเพื่อยืนยันว่าความคาดหวังของผู้เข้าร่วมการศึกษาส่งผลต่อความดันโลหิตได้หรือไม่ การวิเคราะห์กลุ่มย่อยตามชนิดของการควบคุม (ไม่มีฟลาโวนอล กับมีฟลาโวนอลต่ำ) ไม่พบความแตกต่างอย่างมีนัยสำคัญ

อายุผู้เข้าร่วมการศึกษามีบทบาทต่อผลของโกโก้ต่อความดันโลหิต ผู้เข้าร่วมการศึกษาที่มีอายุน้อยกว่าตอบสนองต่อการลดลงของความดันโลหิตได้ดีกว่าหรือไม่ จำเป็นต้องได้รับการตรวจสอบต่อไป

การวิเคราะห์ความไว (Sensitivity Analysis) โดยคัดการทดลองที่ผู้แต่งได้รับการสนับสนุนจากโรงงานอุตสาหกรรมออก (33 การทดลอง ผู้เข้าร่วมในการศึกษา 1482 คน) พบว่าขนาดของผลลดลงเล็กน้อย แสดงให้เห็นถึงอคติในการรายงาน

เนื่องจากมี heterogeneity ซึ่งเราไม่สามารถอธิบายในแง่ของการปกปิด ปริมาณฟลาโวนอลที่ให้ในกลุ่มควบคุม อายุของผู้เข้าร่วมการศึกษา ระยะเวลาการศึกษา เราจึงปรับลดคุณภาพของหลักฐานที่ได้จากสูงเป็นปานกลาง

ผลลัพธ์ของการวิเคราะห์กลุ่มย่อย (subgroup analyses) ควรจะต้องอธิบายด้วยความระมัดระวัง และจำเป็นต้องได้รับการยืนยัน หรือคัดค้านในการทดลองที่เป็นการเปรียบเทียบแบบ direct randomised

โดยทั่วไป ผลิตภัณฑ์โกโก้มีความทนต่อฤทธิ์ข้างเคียง รวมถึงผลต่อกระเพาะอาหารและลำไส้และคลื่นไส้ มีการรายงานไว้ 1% ของผู้เข้าร่วมการศึกษาในกลุ่มทดลอง และ 0.4% ของผู้เข้าร่วมการศึกษาในกลุ่มควบคุม (หลักฐานคุณภาพปานกลาง)

ข้อสรุปของผู้วิจัย

การทบทวนนี้มีคุณภาพของหลักฐานปานกลางว่า ช็อกโกแลตและผลิตภัณฑ์โกโก้ที่อุดมด้วยฟลาโวนอลทำให้ความดันโลหิตลดลงเล็กน้อย (2 มิลลิเมตรปรอท) ในระยะสั้น ในผู้ใหญ่ซึ่งส่วนใหญ่ที่มีสุขภาพดี

ผลการวิจัยนี้มีข้อจำกัดเกี่ยวกับ heterogeneity ระหว่างการทดลอง ซึ่งไม่สามารถอธิบายได้โดยการวิเคราะห์กลุ่มย่อยที่กำหนดไว้ล่วงหน้า ทั้งการปกปิด ปริมาณฟลาโวนอลที่ให้แก่กลุ่มควบคุม อายุของผู้เข้าร่วมการศึกษา หรือรูปแบบการศึกษา อย่างไรก็ตาม ความดันโลหิต ณ จุดเริ่มต้นการศึกษาอาจมีบทบาทในผลของโกโก้ที่ส่งผลต่อความดันโลหิต การวิเคราะห์กลุ่มย่อยตามการเป็นโรคความดันโลหิตสูงของผู้เข้าร่วมการศึกษา แสดงให้เห็นการลดลงของความดันโลหิตจากอิทธพลของโกโก้ที่ดีกว่ากลุ่มผู้เข้าร่วมการศึกษาที่มีความดันโลหิตปกติอย่างมีนัยสำคัญ

การทดลองระยะยาวเพื่อตรวจสอบผลของโกโก้ต่อผลลัพธ์ทางคลินิกเป็นสิ่งจำเป็นสำหรับการประเมินว่าโกโก้มีผลต่อการเกิดโรคหัวใจและหลอดเลือดหรือไม่ และเพื่อประเมินผลกระทบที่อาจเกิดขึ้นจากการบริโภคผลิตภัณฑ์โกโก้มาเป็นเวลานาน

Plain language summary

Effect of cocoa on blood pressure

Review question

We assessed the effect of cocoa products on blood pressure in adults when consumed daily for at least two weeks. We found 35 studies, covering 40 treatment comparisons.

Background

Dark chocolate and cocoa products are rich in chemical compounds called flavanols. Flavanols have attracted interest as they might help to reduce blood pressure, a known risk factor for cardiovascular disease (disorders of the heart and blood vessels). The blood pressure-lowering properties of flavanols are thought to be related to widening of the blood vessels, caused by nitric oxide.

Study characteristics

Studies were short, mostly between two and12 weeks, with only one of 18 weeks. The studies involved 1804 mainly healthy adults. They provided participants with 30 to 1218 mg of flavanols (average of 670 mg) in 1.4 to 105 grams of cocoa products per day in the active intervention group. Seven of the studies were funded by companies with a commercial interest in their results, and the reported effect was slightly larger in these studies, indicating possible bias. The evidence is current to November 2016.

Key results

Meta-analysis of 40 treatment comparisons revealed a small but statistically significant lowering of blood pressure (systolic and diastolic) of 1.8 mmHg. This small reduction in blood pressure might complement other treatment options and might contribute to reducing the risk of cardiovascular disease.

We investigated whether participants' blood pressure at the start of the study, their age, an awareness of group allocation (active or control), the flavanol content used in the control group, or how long the study lasted may explain variations between trials. While blood pressure status (high blood pressure or normal blood pressure) is a likely factor in the effect size of cocoa on blood pressure, the impact of other factors needs to be confirmed or rejected in further trials.

Side effects including digestive complaints and dislike of the trial product were reported by only 1% of people in the active cocoa intervention group and 0.4% of people in the control groups.

Longer-term trials are needed to establish whether regularly eating flavanol-rich cocoa products has a beneficial effect on blood pressure and cardiovascular health over time, and whether there are any side effects of long-term use of cocoa products on a daily basis.

Quality of evidence

The evidence is of moderate quality. We were unable to identify any randomised controlled trials that tested the effect of long-term daily use of cocoa products on blood pressure, and there were no trials that measured the health consequences of high blood pressure, such as heart attacks or strokes.

Résumé simplifié

Effet du cacao sur la tension artérielle

La méta-analyse de 20 études, impliquant 856 participants pour la plupart en bonne santé, a révélé un effet léger mais statistiquement significatif de réduction de la tension artérielle de -2,8 mm Hg pour la pression systolique et -2,2 mm Hg pour la diastolique.

Des effets indésirables, notamment des affections gastro-intestinales et du dégoût pour le produit de l'essai, ont été signalés par 5 % des patients dans les groupes d'intervention active au cacao et par 1 % des patients dans les groupes témoins.

Bien que nous ayons effectué d'autres analyses et recherché des effets dans d'autres sous-groupes (notamment par âge, indice de masse corporelle et tension artérielle initiale ; teneur en sucre du produit de cacao), les résultats de toutes les analyses de sous-groupes et toute association d'effet mesurée nécessitent d'être examinés, et confirmés ou infirmés, dans de nouveaux essais.

Laički sažetak

Kakao za snižavanje krvnog tlaka

Istraživačko pitanje

U ovom Cochrane sustavnom pregledu procijenjen je učinak proizvoda od kakaa na krvni tlak odraslih ljudi, koji su proizvode od kakaa konzumirali svakodnevno tijekom najmanje dva tjedna. Nakon pretraživanja literature uključeno je 35 istraživanja u kojima je analizirano 40 različitih usporedbi terapija.

Dosadašnje spoznaje

Crna čokolada i proizvodi od kakaa bogati su kemijskim spojevima koji se nazivaju flavanoli. Flavanoli su u zadnje vrijeme pobudili zanimanje javnosti jer se pretpostavlja da mogu smanjiti arterijski krvni tlak. Povišeni arterijski krvni tlak je poznati čimbenik rizika za srčano-žilne bolesti (kardiovaskularne bolesti). Smatra se da flavonoli mogu sniziti arterijski krvni tlak djelovanjem na širenje krvnih žila putem dušikovog oksida.

Obilježja uključenih istraživanja

Uključena istraživanja bila su kratka. Uglavnom su trajala između 2 i 12 tjedana. Samo jedna studija trajala je 18 tjedana. Istraživanja su uključila 1804 odraslih, uglavnom zdravih ispitanika. Ispitanici su dobijali 30-1218 mg flavanola (prosječno 670 mg) u 1,4 do 105 grama proizvoda kaka svaki dan u aktivnim intervencijskim skupinama. Sedam istraživanja financirale su tvrtke koje imaju Dokazi se temelje na literaturi objavljenoj do studenog 2016.

Ključni rezultati

Meta-analiza 40 terapijskih usporedbi pokazala je malen, ali statistički značajan učinak proizvoda od kakaa na snižavanje arterijskog krvog tlaka (sistoličkog i dijastoličnog) od 1,8 mm Hg. Taj mali učinak može pojačati učinak drugih mogućnosti liječenja i može doprinijeti smanjenju rizika od srčano-žilnih bolesti.

Istraženo je mogu li se razlike između istraživanja objasniti razlikama u razini arterijskog krvnog tlaka na početku istraživanja, dobi ispitanika, poznavanju kojoj skupini ispitanici pripadaju (aktivnoj ili kontrolnoj), sadržaju flavonola u kontrolnoj skupini ili trajanju istraživanja. Razina arterijskog krvnog tlaka na početku istraživanja (visok krvni tlak ili normalan krvni tlak) vjerojatno utječe na veličinu učinka kakaa. Utjecaj drugih čimbenika treba potvrditi ili odbaciti u budućim istraživanjima.

Nuspojave uključuju probavne tegobe i odbojnost prma pojedinim istraživanim proizvodima. Takve nuspojave opisalo je 1% osoba u aktivnoj intervencijskoj skupini koja je primala kakao, a 0,4% osoba u kontrolnim skupinama.

Potrebna su dugotrajna istraživanja koja će procijeniti može li dugoročno konzumiranje proizvoda kakaa koji su bogati flavonolina imati povoljan učinak na arterijski krvni tlak i zdravlje srca i krvnih žila tijeko duljeg vremena. Također je nužno ispitati nuspojave svakodnevnog konzumiranja proizvoda kakaa.

Kvaliteta dokaza

Dokazi su umjerene kvalitete. Nisu pronađeni klinički pokusi koji su istražili učinak dugotrajnog svakodnevnog konzumiranja proizvoda od kakaa na arterijski krvni tlak. Također nisu pronađena istraživanja koja su mjerila posljedice visokog krvnog tlaka, kao što su srčani ili moždani udari.

Bilješke prijevoda

Cochrane Hrvatska
Prevela: Livia Puljak
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

淺顯易懂的口語結論

可可對血壓的影響

文獻回顧問題

我們評估了為期至少兩周、每日食用可可對成人血壓的影響。我們找到35個研究,包含40種介入措施的比較。

背景

黑巧克力和可可產品富含「黃烷醇(Flavanol)」之化學物質。黃烷醇因可能有助於降低血壓,其為心血管疾病(心臟和血管疾病)的已知危險因素而令人感興趣。黃烷醇的降血壓特性被認為與一氧化氮引起的血管擴張有關。

研究特徵

研究期間短,大多介於2至12週間(只有一個研究是18週)。這些研究納入1804位大多健康的成人。他們提供介入組受試者每天攝取1.4到105克的可可產品(其中包含30~1218毫克、平均670毫克的黃烷醇)。有七個研究被對於其結果有商業利益的廠商贊助,並且這些被贊助的研究結果效益比起其他研究的結果略大,指出有偏誤的可能性。證據蒐集系至2016年11月。

主要結果

40個介入措施比較的統合分析發現,少量但具統計意義下降1.8毫米汞柱的血壓(收縮壓和舒張壓)。這少量的降血壓幅度或許可以輔助其他治療方法,並可能有助於降低心血管疾病的風險。

我們調查研究是否一開始受試者的血壓、年齡、知道自己被分派的組別(介入組或對照組)、對照組中使用黃烷醇的量,或研究為期多久可能可解釋不同試驗之間的差異。雖然血壓狀態(高血壓或正常血壓)是可可對血壓的影響的一個可能因素,其他因素的影響就需要經過更進一步研究而被確認或排除。

實驗組中有1%及控制組中0.4%的受試者被報告有像是消化不良的副作用或不喜歡試驗中的產品。

有關長期規律食用富含黃烷醇的可可產品,是否對血壓和心血管疾病有正面影響,或者長期每日食用是否會有任何副作用,需要更長時間的研究來確認。

證據品質

證據品質中等。我們無法找到任何測試長期食用可可產品對血壓的影響的隨機對照試驗,也沒有試驗測量高血壓的後續健康影響,像是心臟病或中風。

譯註

翻譯者:翁乙田
服務單位:高雄醫學大學學士後醫學系
職稱:醫學生

本翻譯計畫由臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行
聯絡E-mail:cochranetaiwan@tmu.edu.tw

平易な要約

血圧に対するココアの効果

レビューの論点

成人を対象に、2週間以上にわたり連日摂取した場合の血圧に対するココア製品の効果を評価した。治療比較40件を含む35試験を同定した。

背景

ブラックチョコレートやココア製品は、フラバノールと呼ばれる化合物を豊富に含んでいる。心血管疾患(心臓および血管の障害)のリスクファクターとして知られる血圧の低下に役立つ可能性があるため、フラバノールに対する関心が高まっている。血圧を下げるフラバノールの性質は、一酸化窒素によって生じる血管拡張に関連していると考えられる。

試験の特性

各研究の期間は短く、ほとんどが2~12週間であり、18週間はわずか1試験であった。研究は、主として健康成人1804名を対象としていた。試験では、実介入群において、1日1.4~105 gのココア製品中のフラバノール30~1218 mg(平均670 mg)を参加者に摂取させていた。7試験が試験結果に商業的利害を持つ企業からの資金援助を受けており、上記7試験では、報告された効果が若干大きかったため、バイアスの可能性が示唆された。エビデンスは、2016年11月現在のものである。

主な結果

治療比較40件のメタアナリシスでは、わずかではあるが統計学的に有意な1.8 mmHgの血圧低下(収縮期血圧および拡張期血圧)がみられた。このわずかな血圧低下は、他の治療選択肢を補完し、心血管疾患リスクの低減に役立つ可能性がある。

試験開始時の参加者の血圧、年齢、割付け群(実介入群または対照群)を認識していたか否か、対照群のフラバノール含有量あるいは試験実施期間によって、試験間のばらつきに説明がつくか否かを調査した。血圧状態(高血圧または正常血圧)が血圧に対するココアの効果量の因子である可能性が高いものの、今後の試験で、他の因子の影響を確認または否定する必要がある。

消化管愁訴や試験に用いた製品に対する嫌悪などの副作用は、ココア実介入群ではわずかに1%、対照群では0.4%にみられた。

フラバノール高含有ココア製品の習慣的な摂取が血圧および心血管の健康に長期にわたって有益な作用を有するか否か、また、日常的にココア製品を長期摂取することにより副作用が生じるか否かを明らかにするため、長期試験の実施が求められる。

エビデンスの質

エビデンスレベルは中等度である。長期にわたるココア製品の日常的な摂取がもたらす血圧への影響を検討したランダム化比較試験を同定することはできず、また、心臓発作または脳卒中などの高血圧による健康上の影響を評価した試験は存在しなかった。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2017.11.27]
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。
 CD008893 Pub3

Streszczenie prostym językiem

Wpływ kakao na ciśnienie krwi

Pytanie badawcze

W niniejszym przeglądzie oceniliśmy wpływ codziennego spożywania produktów zawierających kakao na ciśnienie krwi u dorosłych w okresie co najmniej dwóch tygodni. Znaleźliśmy 35 badań, obejmujących 40 porównań interwencji.

Wprowadzenie

Gorzka czekolada i wyroby z kakao są bogate w związki chemiczne zwane flawanolami. Flawanole są interesującymi związkami, ponieważ mogą przyczynić się do obniżenia ciśnienia krwi, znanego czynnika ryzyka chorób układu krążenia (choroby serca i naczyń krwionośnych). Uważa się, że te właściwości flawanoli są związane z rozszerzeniem naczyń krwionośnych wywołanym przez tlenek azotu.

Charakterystyka badania

Włączone badania były krótkie, trwające głównie od 2 do 12 tygodni, a tylko jedno trwało 18 tygodni. Obejmowały one 1804, głównie zdrowych, dorosłych uczestników. W grupie otrzymującej aktywną interwencję organizatorzy badań zapewniali uczestnikom od 30 do 1218 mg flawanoli (średnio 670 mg), w 1,4 do 105 gramach produktów kakaowych dziennie. Siedem badań zostało sfinansowanych przez firmy komercyjne, które były zainteresowane wynikami badań i raportowane tam wyniki były nieco większe, co wskazuje na możliwe przeszacowanie wyniku. Dane naukowe są aktualne do listopada 2016 r.

Główne wyniki

Wyniki metaanalizy dla 40 porównań terapii wykazały małe, ale statystycznie istotne obniżenie ciśnienia krwi (skurczowego i rozkurczowego) o 1,8 mm Hg. Ten niewielki spadek ciśnienia tętniczego krwi może uzupełniać inne formy leczenia i może przyczynić się do zmniejszenia ryzyka choroby sercowo-naczyniowej.

Oceniliśmy czy ciśnienie krwi uczestników na początku badania, ich wiek, świadomość przydzielenia do grupy (aktywna interwencja lub kontrola), zawartość flawanoli stosowanych w grupie kontrolnej lub długość badania mogłyby stanowić wytłumaczenie różnic pomiędzy badaniami. Choć wartość ciśnienia krwi (wysokie ciśnienie krwi lub normalne ciśnienie krwi) jest prawdopodobnym czynnikiem wpływającym na wielkość efektu wywieranego przez kakao na ciśnienie krwi, wpływ innych czynników musi zostać potwierdzony lub odrzucony w dalszych badaniach.

Działania niepożądane obejmujące dolegliwości ze strony przewodu pokarmowego i niechęć do produktu ocenianego w badaniu odnotowano jedynie u 1% pacjentów w grupie przyjmującej kakao, i u 0,4% pacjentów w grupach kontrolnych.

Ponadto, potrzebne są badania o dłuższym okresie obserwacji w celu wyjaśnienia, czy regularne spożywanie wyrobów kakaowych bogatych we flawonole ma korzystny wpływ na ciśnienie krwi i układ sercowo-naczyniowy w dłuższej perspektywie, a także czy istnieją jakiekolwiek potencjalnie działania niepożądane związane z długotrwałym, codziennym spożywaniem wyrobów kakaowych.

Jakość danych naukowych

Jakość danych naukowych w przedstawianym przeglądzie została oceniona jako umiarkowana. Nie odnaleźliśmy żadnych badań z randomizacją , w których oceniano długoterminowy wpływ codziennego spożywania produktów kakaowych na ciśnienie krwi, a ponadto brakowało badań, w których oceniano wpływ interwencji na konsekwencje zdrowotne związane z wysokim ciśnieniem krwi, takie jak zawał serca czy udar mózgu.

Uwagi do tłumaczenia

Tłumaczenie: Joanna Zając Redakcja: Magdalena Koperny

Resumo para leigos

Efeito do cacau sobre a pressão arterial

Pergunta de revisão

Avaliamos o efeito dos produtos de cacau sobre a pressão arterial em adultos quando consumidos diariamente por pelo menos duas semanas. Foram encontrados 35 estudos, abrangendo 40 comparações de tratamento.

Contexto

O chocolate negro e produtos de cacau são ricos em compostos químicos chamados flavanóides. Flavanoides têm atraído interesse como eles podem ajudar a reduzir a pressão arterial, um conhecido fator de risco para doenças cardiovasculares (distúrbios do coração e vasos sanguíneos). Pensa-se que as propriedades de redução da pressão sanguínea dos flavanóides estão relacionadas com o alargamento dos vasos sanguíneos, causado pelo óxido nítrico.

Características dos estudos

Os estudos foram de curta duração, maioritariamente entre duas e 12 semanas, com apenas um estudo de 18 semanas. Os estudos envolveram 1804 adultos maioritariamente saudáveis. Nos estudos forneceram participantes 30 a 1218 mg de flavanol (média de 670 mg) em 1,4 a 105 gramas de produtos de cacau por dia no grupo de intervenção ativa. Sete dos estudos foram financiados por empresas com interesse comercial em seus resultados, e o efeito relatado foi ligeiramente maior nesses estudos, indicando viés possível. A evidência é atualizada até novembro de 2016.

Principais resultados

Uma meta-análise de 40 comparações de tratamento revelou uma diminuição pequena mas estatisticamente significativa da pressão arterial (sistólica e diastólica) de 1,8 mmHg. Esta pequena redução da pressão arterial pode complementar outras opções de tratamento e pode contribuir para reduzir o risco de doença cardiovascular.

Investigamos se a pressão arterial dos participantes no início do estudo, sua idade, a perceção da alocação de grupo (ativa ou controle), o teor de flavanol usado no grupo controle ou quanto tempo o estudo durou pode explicar as variações entre os ensaios. Embora o nível de pressão arterial (elevada ou normal) seja um fator provável no tamanho do efeito do cacau na pressão arterial, o impacto de outros fatores precisa ser confirmado ou rejeitado em outros ensaios.

Os efeitos adversos, incluindo queixas digestivas e aversão ao produto experimental, foram relatados por apenas 1% das pessoas no grupo de intervenção do cacau ativo e 0,4% das pessoas nos grupos de controle.

São necessários estudos a longo prazo para determinar se a ingestão regular de produtos de cacau ricos em flavanol tem um efeito benéfico na pressão sanguínea e na saúde cardiovascular ao longo do tempo e se existem efeitos secundários do uso a longo prazo de produtos de cacau numa base diária.

Qualidade da evidência

A evidência é de qualidade moderada. Não foi possível identificar quaisquer ensaios aleatorizados que testassem o efeito do uso diário de produtos de cacau a longo prazo na pressão arterial e não houve estudos que medissem as consequências para a saúde da pressão arterial elevada, como enfartes ou acidentes vasculares cerebrais.

Notas de tradução

Tradução: Gonçalo S Duarte, Laboratório de Farmacologia Clínica e Terapêutica, Faculdade de Medicina de Lisboa, com o apoio de Cochrane Portugal

Резюме на простом языке

Влияние какао на артериальное давление

Вопрос обзора

Мы оценили влияние какао-продуктов на артериальное давление у взрослых при ежедневном употреблении на протяжении, по меньшей мере, двух недель. Мы нашли 35 исследований, включающих 40 сравнений лечения.

Актуальность

Темный шоколад и какао-продукты богаты химическими веществами под названием флавонолы. Интерес к флавонолам вызван тем, что они могут помочь снизить артериальное давление, которое является общеизвестным фактором риска сердечно-сосудистых заболеваний (заболеваний сердца и кровеносных сосудов). Считается, что способность флавонолов снижать артериальное давление связана с расширением кровеносных сосудов за счет оксида азота.

Характеристика исследований

Исследования были непродолжительными, в основном, от 2 до 12 недель; только одно исследование длилось 18 недель. В исследованиях принимали участие 1804 взрослых, преимущественно здоровых. Участники в группе активного вмешательства получали ежедневно от 30 до 1218 мг флавонолов (в среднем - 670 мг) в 1,4 - 105 г какао-продуктов. Семь исследований финансировались компаниями, для которых результаты представляли коммерческий интерес. В таких исследованиях отмеченный эффект был несколько больше, что говорит о возможном смещении (предвзятости). Эти доказательства актуальны на ноябрь 2016 года.

Основные результаты

Мета-анализ 40 сравнений лечения выявил небольшое, но статистически значимое снижение артериального давления (систолического и диастолического) - на 1,8 мм рт. ст. Это небольшое снижение артериального давления может служить дополнением к другим вариантам лечения и способствовать снижению риска развития сердечно-сосудистых заболеваний.

Мы проанализировали, можно ли вариативность в результатах исследований объяснять следующими факторами: артериальное давление участников в начале исследования, их возраст, осведомленность о принадлежности к группе (активной или группе контроля), содержание флавонола, используемого в контрольной группе, продолжительность исследования. В то время как уровень артериального давления (высокое или нормальное) является возможным фактором, влияющим на величину эффекта какао на артериальное давление, влияние других факторов требует подтверждения или опровержения в последующих испытаниях.

О побочных эффектах, включая нарушение пищеварения и неприятие исследуемого продукта, сообщили лишь 1% участников группе активного вмешательства и 0,4% в контрольной группе.

Чтобы установить, оказывает ли регулярное употребление в пищу какао-продуктов, богатых флавонолами, благоприятное воздействие на артериальное давление и сердечно-сосудистую систему, и есть ли какие-либо побочные эффекты при продолжительном ежедневном употреблении какао-продуктов, необходимы более длительные клинические испытания.

Качество доказательств

Качество доказательств среднее. Нам не удалось выявить какие-либо рандомизированные контролируемые испытания, в которых бы изучали влияние продолжительного ежедневного употребления какао-продуктов на артериальное давление. Также не было обнаружено испытаний, в которых бы оценивали последствия повышенного артериального давления для здоровья, например, инфаркты и инсульты.

Заметки по переводу

Перевод: Антонова Валерия Алексеевна. Редактирование: Юдина Екатерина Викторовна. Координация проекта по переводу на русский язык: Cochrane Russia - Кокрейн Россия (филиал Северного Кокрейновского Центра на базе Казанского федерального университета). По вопросам, связанным с этим переводом, пожалуйста, обращайтесь к нам по адресу: cochrane.russia.kpfu@gmail.com; cochranerussia@kpfu.ru

Laienverständliche Zusammenfassung

Wirkung von Kakao auf den Blutdruck

Fragestellung

Wir bewerteten die Wirkung von Kakao-Produkten auf den Blutdruck von Erwachsenen bei täglichem Konsum für mindestens zwei Wochen. Wir fanden 35 Studien mit 40 Behandlungsvergleichen.

Hintergrund

Dunkle Schokolade und Kakao-Produkte sind reich an Flavanol, einem chemischen Stoff. Man wurde auf Flavanole aufmerksam, da sie helfen können, den Blutdruck zu senken - ein bekannter Risikofaktor für kardiovaskuläre Erkrankungen (Erkrankungen des Herzens und der Blutgefäße). Die blutdrucksenkenden Eigenschaften von Flavanolen hängen vermutlich mit einer Erweiterung der Blutgefäße, ausgelöst durch Stickstoffmonoxid, zusammen.

Studienmerkmale

Die Studien waren kurz, meist zwischen zwei und zwölf Wochen, mit nur einer Studie von 18 Wochen Dauer. Die Studien umfassten 1804, hauptsächlich gesunde, Erwachsene. Die Probanden der aktiven Interventionsgruppe erhielten zwischen 30 und 1218 mg Flavanol (durchschnittlich 670 mg) in 1,4 bis 105 g Kakao-Produkten pro Tag. Sieben Studien wurden von Unternehmen, die ein kommerzielles Interesse an den Ergebnissen hatten, finanziert. Die berichtete Wirkung war in diesen Studien etwas stärker, was auf einen möglichen Bias hinweist. Die Evidenz ist auf dem Stand von November 2016.

Hauptergebnisse

Die Meta-Analyse der 40 Behandlungsvergleiche ergab eine kleine, aber statistisch signifikante Senkung des Blutdrucks (systolisch und diastolisch) um 1,8 mmHg. Diese kleine Senkung des Blutdrucks kann andere Behandlungsoptionen ergänzen und kann dazu beitragen, dass das Risiko für kardiovaskuläre Erkrankungen gesenkt wird.

Wir untersuchten, ob der Blutdruck der Probanden zu Beginn der Studie, ihr Alter, ihr Bewusstsein für die Gruppenzuteilung (Aktive- oder Kontrollgruppe), der Flavanolgehalt, der in der Kontrollgruppe verwendet wurde oder die Dauer der Studie die Unterschiede zwischen den Studien erklären können. Während der Status des Blutdrucks (Bluthochdruck oder normaler Blutdruck) ein wahrscheinlicher Faktor für die Wirkung des Kakaos auf den Blutdruck ist, müssen auch die Einflüsse von anderen Faktoren in zukünftigen Studien bestätigt oder abgelehnt werden.

Nebenwirkungen wie Verdauungsbeschwerden und Abneigung gegen das Untersuchungsprodukt wurden von nur 1 % der Probanden in der aktiven Interventionsgruppe und von 0,4 % der Probanden in den Kontrollgruppen gemeldet.

Langzeit-Studien sind erforderlich, um festzustellen, ob der regelmäßige Verzehr von flavanolreichen Kakao-Produkten vorteilhafte Wirkungen auf den Blutdruck und somit auch auf die Herzkreislauf-Gesundheit hat. Es muss ebenfalls untersucht werden, ob bei der Langzeitanwendung von Kakao-Produkten bei täglichem Verzehr irgendwelche Nebenwirkungen auftreten.

Qualität der Evidenz

Die Evidenz ist von moderater Qualität. Wir konnten keine randomisierten kontrollierten Studien identifizieren, die die Wirkung des langfristigen, täglichen Verzehrs von Kakao-Produkten auf den Blutdruck untersuchten. Außerdem gab es keine Studien, die die gesundheitlichen Folgen von hohem Blutdruck, wie Herzinfarkte oder Schlaganfälle untersuchte.

Anmerkungen zur Übersetzung

H. Schilling, freigegeben durch Cochrane Deutschland

Ringkasan bahasa mudah

Kesan koko keatas tekanan darah

Soalan ulasan

Kita menilai kesan produk-produk Koko atas tekanan darah pada orang dewasa apabila dimakan setiap hari untuk sekurang-kurangnya dua minggu. Kami mendapati 35 kajian yang meliputi 40 perbandingan rawatan.

Latar belakang

Coklat gelap dan produk koko kaya dengan sebatian kimia yang dikenali sebagai flavanols. Flavanols telah menarik minat kerana mereka mungkin boleh membantu untuk mengurangkan tekanan darah, faktor risiko yang diketahui bagi penyakit kardiovaskular (penyakit jantung dan saluran darah). Keupayaan flavonols bagi mengurangkan tekanan darah dianggap berkaitan dengan perluasan saluran darah yang disebabkan oleh nitrik oksida.

Ciri-ciri kajian

Kajian-kajian adalah pendek, kebanyakannya antara dua dan 12 minggu, dengan hanya satu selama 18 minggu. Kajian-kajian ini melibatkan 1804 orang dewasa yang sihat. Mereka membekalkan peserta dengan 30-1218mg flavanols (purata 670mg) dalam 1.4 ke 105 gram produk-produk koko setiap hari dalam kumpulan intervensi aktif. Tujuh daripada kajian-kajian ini dibiayai oleh syarikat yang mempunyai kepentingan komersil dalam keputusan mereka, dan kesan yang dilaporkan adalah sedikit lebih besar dalam kajian-kajian ini, menunjukkan kemungkinan berat sebelah. Bukti adalah terkini hingga November 2016.

Hasil utama

Meta-analisis yang membandingkan 40 rawatan menunjukkan penurunan tekanan darah (sistolik dan diastolik) yang kecil dari 1.8mmHg tetapi signifikan secara statistik. Pengurangan kecil darah ini mungkin melengkapi pilihan rawatan lain dan mungkin menyumbang kepada pengurangan risiko penyakit kardiovaskular.

Kami menyiasat sama ada tekanan darah peserta pada permulaan kajian, umur mereka, kesedaran tentang pembahagian kumpulan (aktif atau kawalan), kandungan flavanol yang digunakan di dalam Kumpulan kawalan, atau berapa lama kajian ini berlangsung boleh menerangkan perbezaan antara kajian. Walaupun status tekanan darah (tekanan darah tinggi atau tekanan darah normal) boleh menjadi faktor yang berkemungkinan atas saiz kesan koko pada tekanan darah, kesan faktor-faktor lain perlu disahkan atau ditolak dalam kajian selanjutnya.

Kesan-kesan sampingan termasuklah aduan penghadaman dan tidak suka pada produk percubaan tersebut telah dilaporkan oleh hanya 1% daripada orang-orang dalam Kumpulan intervensi yang aktif koko dan 0.4% daripada pesakit dalam kumpulan kawalan.

Ujian jangka panjang diperlukan untuk menentukan sama ada memakan dengan kerap produk-produk koko kaya dengan flavanol mempunyai kesan yang baik terhadap kesihatan kardiovaskular dan tekanan darah dari masa ke masa, dan sama ada terdapat sebarang kesan sampingan jangka panjang penggunaan produk-produk Koko pada setiap hari.

Kualiti bukti

Bukti adalah berkualiti sederhana. Kami tidak dapat mengenal pasti sebarang percubaan terkawal rawak yang menguji kesan jangka panjang penggunaan harian produk-produk koko pada tekanan darah, dan terdapat tiada ujian yang mengukur kesan kesihatan akibat tekanan darah tinggi, seperti serangan jantung atau strok.

Catatan terjemahan

Diterjemahkan oleh Khaw Loke Tim (International Medical University). Disunting oleh Tuan Hairulnizam Tuan Kamauzaman (Universiti Sains Malaysia). Untuk sebarang pertanyaan sila hubungi LokeTimKhaw@imu.edu.my.

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ดาร์กช็อกโกแลตและผลิตภัณฑ์โกโก้อุดมไปด้วยสารเคมีที่เรียกว่า ฟลาโวนอล ฟลาโวนอลได้รับความสนใจเนื่องจากอาจช่วยลดความดันโลหิตซึ่งเป็นปัจจัยเสี่ยงที่เป็นที่รู้จักสำหรับโรคหัวใจและหลอดเลือด (ความผิดปกติของหัวใจและหลอดเลือด) สรรพคุณของฟลาโวนอลในการลดความดันโลหิตคาดว่าเกี่ยวข้องกับการขยายหลอดเลือดที่เกิดจากไนตริกออกไซด์

ลักษณะของการศึกษา

การศึกษาเป็นการศึกษาในระยะสั้น ส่วนใหญ่อยู่ระหว่างสองถึง 12 สัปดาห์ มีเพียงหนึ่งการศึกษาที่ศึกษาเป็นระยะเวลา 18 สัปดาห์ การศึกษาเกี่ยวข้องกับผู้ใหญ่ 1804 คน ซึ่งส่วนใหญ่มีสุขภาพดี พวกเขาให้ฟลาโวนอล 30 ถึง 1218 มก. (เฉลี่ย 670 มก.) ในผลิตภัณฑ์โกโก้ 1.4 ถึง 105 กรัมต่อวันแก่ผู้เข้าร่วมการศึกษาในกลุ่มทดลอง พบเจ็ดการศึกษาได้รับการสนับสนุนจากบริษัท โดยมีผลประโยชน์ทางธุรกิจในผลการศึกษา และผลที่รายงานมีขนาดใหญ่กว่าเล็กน้อย ชี้ให้เห็นอคติที่อาจเกิดขึ้น หลักฐานที่มีอยู่เป็นปัจจุบันจนถึงเดือนพฤศจิกายน 2016

ผลการศึกษาที่สำคัญ

การวิเคราะห์เมตต้าของ 40 คู่เปรียบเทียบการรักษาพบว่าความดันโลหิต (systolic และ diastolic) ลดลงเล็กน้อยคือ 1.8 มิลลิเมตรปรอท แต่มีนัยสำคัญทางสถิติ การลดลงของความดันโลหิตเพียงเล็กน้อยนี้อาจเป็นส่วนประกอบในการรักษาอื่นๆ และอาจมีส่วนช่วยลดความเสี่ยงต่อโรคหัวใจและหลอดเลือดได้

เราพิจารณาค่าความดันโลหิตของผู้เข้าร่วมการศึกษาที่เวลาเริ่มต้นการศึกษา อายุ ความตระหนักในการจัดกลุ่ม (กลุ่มทดลองหรือกลุ่มควบคุม) ปริมาณฟลาโวนอลที่ใช้ในกลุ่มควบคุม หรือระยะเวลาการศึกษาซึ่งอาจอธิบายความแตกต่างระหว่างการทดลองได้ ในขณะที่ภาวะความดันโลหิต (ความดันโลหิตสูง หรือความดันโลหิตปกติ) เป็นปัจจัยที่มีผลต่อขนาดของผลของโกโก้ต่อความดันโลหิต ผลกระทบจากปัจจัยอื่นๆจำเป็นต้องได้รับการยืนยันหรือคัดค้านในการทดลองต่อไป

ผลข้างเคียงรวมถึงโรคเกี่ยวกับทางเดินอาหาร และไม่ชอบผลิตภัณฑ์ทดลอง มีเพียง 1% ของคนในกลุ่มทดลอง และ 0.4% ของคนในกลุ่มควบคุม

จำเป็นต้องมีการทดลองในระยะยาวเพื่อหาว่าการบริโภคผลิตภัณฑ์โกโก้ที่มีส่วนผสมของฟลาโวนอลเป็นประจำจะมีผลต่อความดันโลหิตและสุขภาพหัวใจและหลอดเลือดเมื่อเวลาผ่านไปหรือไม่ และมีผลข้างเคียงใดๆจากการใช้ผลิตภัณฑ์โกโก้ในแต่ละวันเป็นระยะเวลานานหรือไม่

คุณภาพของหลักฐาน

หลักฐานมีคุณภาพปานกลาง เราไม่พบ randomised controlled trials ใดๆที่ทดสอบผลของการใช้ผลิตภัณฑ์โกโก้ในชีวิตประจำวันในระยะยาวต่อความดันโลหิต และไม่มีการทดลองใดที่วัดผลลัพธ์ด้านสุขภาพซึ่งเป็นผลเนื่องมาจากความดันโลหิตสูง เช่น หัวใจล้มเหลว หรือโรคหลอดเลือดสมอง

หมายเหตุการแปล

แปลโดย นางสาวน้ำเพชร จำปาทอง และ ตรวจสอบการแปลโดย ศ.ดร. มาลินี เหล่าไพบูลย์ ภาควิชาวิทยาการระบาดและชีวสถิติ คณะสาธารณสุขศาสตร์ มหาวิทยาลัยขอนแก่น Cochrane ประเทศไทย แปลเมื่อวันที่ 7 กันยายน 2017

Summary of findings(Explanation)

Summary of findings for the main comparison. Flavanol-rich cocoa products for blood pressure
  1. 1.Downgraded to moderate quality due to high heterogeneity which cannot be explained by subgroup analyses. SBP/DBP: I2 = 87%/78%.

    2.Good quality across 40 treatment comparisons. Only 5 trials (12.5%) had 2 items at high risk of bias, 19 trials (47.5%) had 1 item at high risk of bias, and 16 trials (40%) had no items at high risk of bias. 17 trials were unblinded or single-blinded. 7 industry-sponsored trials had authors employed by industry. Only 4 trials (10%) had more than 20% attrition. We explored influence of trials with items at high risk of bias by subgroup and sensitivity analysis.
    3.Statistically significant SBP: P = 0.009; DBP: P < 0.001.
    4.Sensitivity analysis excluding treatment comparisons (n = 7) with authors employed by trials sponsoring industry revealed reduced effect size and statistical significance.

Flavanol-rich cocoa products for blood pressure
Patient or population: adults with or without hypertension
Settings: Primary healthcare practice, community
Intervention: flavanol-rich cocoa products versus control
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control Flavanol-rich cocoa products
Systolic blood pressure
clinical digital sphygmomanometer
Follow-up: mean 9 weeks
The mean systolic blood pressure ranged across control groups from 107 to 154 mm HgThe mean systolic blood pressure in the intervention groups was
1.76 mmHg lower
(3.09 to 0.43 lower)
 1804
(35 trials with 40 treatment comparisons)
⊕⊕⊕⊕
moderate 1,2,3,4
 
Diastolic blood pressure
clinical digital sphygmomanometer
Follow-up: mean 9 weeks
The mean diastolic blood pressure ranged across control groups from 66 to 92 mm HgThe mean diastolic blood pressure in the intervention groups was
1.76 mmHg lower
(2.57 to 0.94 lower)
 1772
(34 trials with 39 treatment comparisons)
⊕⊕⊕⊕
moderate 1,2,3,4
 
Withdrawals due to adverse effects8 trials reported no withdrawals and no adverse effects. 9 trials reported adverse effects, including gastrointestinal complaints (cocoa groups: n = 8/760 (1%), control groups: n = 3/754 (0.4%)); dislike of the trial product (cocoa: n = 4/760; control: n = 1/754), headache (cocoa: n = 2/760; control: n = 1/754), and jitteriness (cocoa: n = 1/760, control: n = 0/754).1514 (31 trials) reported on withdrawals and adverse effects⊕⊕⊕⊕
moderate 1,2,3,4
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Dark chocolate and flavanol-rich cocoa products have attracted interest as an alternative treatment option for hypertension, a known risk factor for cardiovascular disease. Even small reductions in blood pressure may substantially reduce cardiovascular risk. Current guidelines strongly recommend integration of lifestyle modification and complementary treatment with the use of conventional blood pressure medications.

The interest in the effect of cocoa on blood pressure (BP) started with the discovery that an island population in Central America, the Kuna Indians, had a distinctively low rate of hypertension coupled with a consistent healthy low blood pressure unaffected by age (Hollenberg 2006; Kean 1944). The majority of the Kuna Indians live on the San Blas Island off Panama (population approximately 35,000); those Kuna Indians who migrated to the mainland had a higher prevalence of hypertension as well as an age-dependent rise in blood pressure, implying that lifestyle factors such as diet rather than genetics play a protective role (McCullough 2006). Island-dwelling Kuna Indians consume about three to four cups of cocoa drinks on average per day, while the mainland-dwelling Kuna Indians consume up to 10 times less cocoa (McCullough 2006; Schroeter 2006). Average high salt intake was not associated with the differences in blood pressure (McCullough 2006). Mean blood pressure of the island-dwelling adult Kuna Indians hovers around 110 mmHg systolic and 70 mmHg diastolic, while on the mainland the observed age-related rise in blood pressure and prevalence of hypertension is comparable with that of Western populations (Hollenberg 2006).

Description of the condition

High blood pressure is a critically important risk factor for cardiovascular disease, attributable for 47% of ischaemic heart disease and 54% of stroke events worldwide (Lawes 2008). More than a third (37%) of cardiovascular deaths are attributed to hypertension in Western populations (Martiniuk 2007), and 13.5% globally (Lawes 2008). The association between cardiovascular risk and blood pressure levels is continuous (McInnes 2005) with the risk of ischaemic heart disease and stroke halved for every 20 mmHg reduction in systolic blood pressure (SBP) and 10 mmHg diastolic blood pressure (DBP) (Lewington 2002). Even small reductions in blood pressure may therefore reduce cardiovascular events at a population level.

However, a steady increase in SBP with age is expected, whereas DBP tends to fall after middle age, with studies in elderly and middle-aged populations suggesting a nonlinear J- or U-shaped relationship between blood pressure and mortality (Bangalore 2010; Denker 2013). Appropriate assessment of an individual’s BP status is important to guide whether antihypertension therapy is indicated or to avoid potential overtreatment.

Blood pressure levels are defined as:

Primary hypertension: SBP ≥ 140 mmHg or DBP ≥ 90 mm-Hg

Prehypertension: SBP 120 - 139 mmHg or DBP 80 - 89 mmHg

Normotension: SBP < 120 mmHg or DBP < 80 mmHg, secondary hypertension

Description of the intervention

Cocoa is extracted from cacao beans, the fatty seeds of the Theobroma cacao tree. Cocoa is rich in flavanols, particularly epicatechin, catechin and procyanidins, proposed to be responsible for the blood pressure-lowering effect (Corti 2009; Heiss 2010a). Flavanols are also found in other plant-derived produce, including beans, apricots, blackberries, apples and tea leaves, albeit in a lower concentration than in cocoa products (460 - 610 mg/kg of flavanol monomers; 4 - 5 g/kg of flavanol polymers) (Fernandez-Murga 2011; Hammerstone 2000). Flavanol intake is, however, also dependent on serving size, and flavanol content depends on the processing of the cacao beans and raw cocoa.

Traditionally cocoa was consumed as a cold unsweetened drink of raw dried cacao powder, often mixed with starch and spices by the native Latin-American Indians, but this was considered bitter and unpalatable by the early European explorers, including Christopher Columbus in 1502 and Hernando Cortes in 1519. The Spanish brought cocoa to Europe, added sugar to it and heated the drink (Dillinger 2000; Lippi 2009). Subsequent roasting (up to 120 °C), mixing (conching), alkalising (dutching), adding sugar, milk, vanilla and lecithin emulsifiers make chocolate as we know it today (Beckett 2008). Various chocolate manufacturers have fine-tuned the processing, leading to different flavours and smoothness of chocolates, but also to altered cocoa and flavanol content in various cocoa products.

Dark chocolate contains larger amounts of cocoa (50% - 85%) than milk chocolate (20% - 30%). Different processes influence the flavanol content of the cocoa in the chocolate; a 70% cocoa-containing chocolate bar from one company therefore might not contain the same amount of flavanols and flavanol composition as a 70% chocolate bar from another company. Content and composition of flavanols depend on the variety and ripeness of cocoa beans used, as well as the manufacturing steps.

Fresh and fermented cocoa beans contain about 10% of flavanols (100 mg/g). The cocoa powder consumed by the Kuna Indians contains about 3.6% of flavanols, and cocoa-rich dark chocolate on the market about 0.5% of flavanols (Chaitman 2006; Chevaux 2001). Moreover, heavy dutching (the alkalising of chocolate to pH 7 - 8) can reduce the flavanol content to less than 10 mg per 100 grams (0.001%).

Research suggests that the monomeric portion of cocoa flavanols, epicatechin and catechin and to a lesser extent the polymeric flavanols, the procyanidins, are linked to blood pressure and vasoactive effects (Schroeter 2006). Modern processing of cacao reduces the monomeric flavanol content and influences the epicatechin/catechin ratio (Payne 2010). Fresh and fermented cocoa beans contain between 2.5 and 16.5 mg of epicatechin per gram, depending on the variety, the growing region and harvesting practices (Kim 1984; Wollgast 2000), whereas processed cocoa retains only 2% - 18% of the original epicatechin, due to roasting and dutching (Payne 2010). Because of the large variation in flavanol content in chocolate and cocoa products, it is critical to compare the dosages of flavanols rather than simply the amounts of chocolate or administered cocoa products in clinical trials investigating the effect of cocoa on blood pressure.

How the intervention might work

The blood pressure-lowering properties of cocoa have been linked to the formation of endothelial nitric oxide (NO) which promotes vasodilation and consequently lowers blood pressure. Increased NO production might be triggered by upregulation of NO-synthase through the insulin-mediated signalling pathway (Addison 2008). Insulin sensitivity has been shown to be improved after cocoa intake in a number of trials (Davison 2008a; Faridi 2008; Grassi 2005a; Grassi 2008), although Muniyappa 2008 did not confirm this. Secondly, cocoa flavanols have been shown to inhibit angiotensin converting enzyme (ACE) activity, and hence reduce blood pressure (Actis-Goretta 2006; Persson 2011). Thirdly, there is evidence to suggest that cocoa flavanols have an indirect antioxidant effect within the cardiovascular system, upregulating NO-synthase activity and hence reducing blood pressure (Fraga 2011; Keen 2005).

Why it is important to do this review

In the last decade, several clinical trials have investigated the effect of chocolate and cocoa products on blood pressure. This systematic review updates previous meta-analyses by Taubert 2007a (including five trials), Desch 2010a (10 trials), Ried 2010 (15 trials), and updates a previous version of this Cochrane Review (20 treatment comparisons) (Ried 2012). In addition, we explore the influence of baseline blood pressure, type of control (flavanol dosage), age, duration, and trial quality, in particular blinding, on blood pressure outcomes.

Objectives

To assess the effects on blood pressure of chocolate or cocoa products versus low-flavanol products or placebo in adults with or without hypertension when consumed for two weeks or longer.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled parallel or cross-over, single-blind, double-blind or open-label trials of 14 days or longer duration that reported the clinical mean or median with or without standard deviation (SD) or standard error (SE) SBP or DBP at baseline, before and after intervention.

Types of participants

Adults, with no further restrictions.

Types of interventions

We included trials if the control group received an intervention, e.g. a placebo or a minimal dose of flavanol-containing cocoa product.

We excluded:

  1. Trials in which the control dose exceeds 25% cocoa polyphenols of the active dose

  2. Trials testing isolated flavanols on blood pressure

  3. Trials with a very high attrition rate (loss to follow-up greater than 50%)

Types of outcome measures

Primary outcomes

Difference between cocoa and control group in systolic and diastolic blood pressure at final follow-up, and adjusted for baseline differences.

Secondary outcomes

Number of participants who withdrew due to adverse effects or intolerance, and total adverse events.

Search methods for identification of studies

Electronic searches

We searched the following electronic databases on OVID for primary studies:

  1. Cochrane Hypertension Group Specialised Register (1948 - Nov 2016), Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 2), MEDLINE (1948 - Nov 2016), Embase (1980 - Nov 2016), and Food Science and Technology Abstracts (1969 - Nov 2016).

  2. International trial registries (clinicaltrials.gov; www.trialregister.nl; www.anzctr.org.au; www.controlled-trials.com; www.apps.who.int/trialsearch/WHO clinical trials) for unpublished but completed studies investigating chocolate/cocoa for blood pressure.

We searched the electronic databases using a strategy combining the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity-maximising version (2008 revision) with selected MeSH terms and free-text terms, including cocoa, chocolate, blood pressure, and hypertension, with no language restrictions. The MEDLINE search strategy (Appendix 1) was translated into the Hypertension Group Specialised Register (Appendix 2), CENTRAL (Appendix 3), Embase (Appendix 4), and Food Science and Technology Abstracts (Appendix 5), using the appropriate controlled vocabulary as applicable, and the Database of Abstracts of Reviews of Effectiveness (DARE) and the Cochrane Database of Systematic Reviews for related reviews.

Searching other resources

  1. We identified reference lists of all papers and relevant reviews.

  2. We contacted authors of relevant papers regarding any further published or unpublished work.

  3. We searched ISI Web of Science for papers which cite studies included in the review.

Data collection and analysis

Selection of studies

Two review authors independently assessed titles and abstracts of search results for relevant articles, and critically appraised the full text of relevant articles according to the inclusion criteria listed above. We resolved any discrepancies by discussion.

Data extraction and management

Two review authors independently extracted data using a standardised data extraction form and then cross-checked them.

Assessment of risk of bias in included studies

Two review authors assessed the risks of bias for each trial by using the Cochrane tool for assessing risk of bias. This covers random sequence generation (selection bias), allocation concealment (selection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), and source of funding (other bias).

Measures of treatment effect

Mean difference in SBP/DBP in mmHg at final follow-up, adjusted for baseline differences. We estimated the precision of mean differences as the standard deviation (SD) at final follow-up.

When blood pressure measurements were reported in more than one position, the order of preference was: 1) sitting; 2) standing; and 3) supine.

When both clinical and ambulatory blood pressure measurements were available, the order of preference was: 1) clinical; 2) ambulatory.

Unit of analysis issues

If results are reported for several periods of follow-up, we preferred the longest follow-up from each study for comparison with baseline.

We conducted meta-analysis of cross-over trials by the generic invariance method, using mean differences and standard errors between outcome measurements (blood pressure) of experimental (cocoa) versus control groups. We extracted the mean (SE) blood pressure before and after intervention from tables, graphs, and text from individual studies included in the meta-analysis.

In multiple-arm studies, we included only the intervention arms and their comparable control arms in the meta-analysis. Comparable intervention/control groups in multiple-arm studies may have been stratified by age, body mass index (BMI), or blood markers. We avoided double-counting of individual participants in the meta-analysis.

Dealing with missing data

We contacted the authors of studies with missing information on mean SBP/DBP or SD or both in intervention and control groups and asked them to provide the missing data.

If standard errors were given instead of standard deviations, we calculated standard deviations at one time point with the formula SD = SE x square root of n. We assumed a correlation of 0.68 between the final follow-up SBP/DBP results for the two treatment arms in a cross-over trial, similar to previous meta-analyses by Taubert 2007a and Desch 2010a.

If both standard deviations and standard errors were missing, we imputed standard deviations based on the information in the same trial or from other trials using the same intervention. We used the following hierarchy to impute standard deviation values:

  1. standard deviation of blood pressure at end of treatment taken in a different position from that of the blood pressure data used

  2. standard deviation of blood pressure at baseline

  3. mean standard deviation of blood pressure at end of treatment from other trials using the same intervention

Assessment of heterogeneity

We assessed heterogeneity by the I2 statistic (Higgins 2003). We tested the following variables by subgroup analyses: baseline SBP or DBP, dosage of flavanols in the control group, age, study duration, and blinding.

Assessment of reporting biases

We assessed small-study effects by funnel plots.

Data synthesis

For each study, we recorded the number of participants, mean difference, and the SE of intervention and control groups in Cochrane Review Manager 5 software. We used the generic inverse variance method to combine both parallel-group and cross-over trials, and the random-effects model to incorporate heterogeneity.

Subgroup analysis and investigation of heterogeneity

We required at least four studies to conduct subgroup analysis.

We performed the following subgroup analyses:

  1. Baseline SBP ≥ 140 mmHg versus SBP 130 - 140 versus SBP < 130 mmHg

  2. Baseline DBP ≥ 80 mmHg versus DBP < 80 mmHg

  3. Flavanol-free control versus low flavanol control

  4. Double-blind versus single-blind/unblinded trials

  5. Mean age < 50 years versus ≥ 50 years

  6. Trial duration two to four weeks versus more than four weeks

We considered evidence of the differences found between subgroups to be stronger when the variation of the mean effects in the different subgroups was higher, as measured by the I2statistic for subgroup differences (e.g. I2 = 90% was considered more significant than I2 = 70%).

Sensitivity analysis

We tested the robustness of the results using the following sensitivity analyses:

Exclusion of trials using a unique study design compared to other trials (e.g. high flavanol content in the control group (20% - 25%) compared to active group, close to threshold level for excluded trials (> 25% flavanol content in control group).

'Summary of findings' table

The Summary of findings for the main comparison summarises the magnitude of the effect of cocoa on systolic and diastolic blood pressure of the 35 RCTs including 40 treatment comparisons and 1804 adults, and rates the quality of the evidence using the GRADE system, by assessing potential within-study biases and between-study heterogeneity (Guyatt 2008).

Results

Description of studies

Results of the search

The updated Cochrane search strategy (inception to October 2015) using Scopus, PubMed and Embase, identified 254 potentially relevant publications which we assessed at the title/abstract level,in addition to the 136 articles in the previous review. Of 26 new potentially relevant trials (in 27 articles) assessed at the full-text level, 17 new trials (20 new treatment comparisons, active vs control) met the inclusion criteria for meta-analysis. Adding these to the 20 treatment comparisons in 18 trials from the previous version of this review (Ried 2012) gives a total of 40 treatment comparisons (from 35 trials) in the updated meta-analysis. (Figure 1).

Figure 1.

PRISMA Flow diagram

Included studies

We include 35 trials involving 1804 participants in this updated review.

Of the 35 trials, five contained two treatment arms with comparable non-overlapping control groups, resulting in 40 bringing the number of treatment comparisons in the updated review. Trials with multiple treatment arms provided results stratified on the basis of blood pressure (normotensive/hypertensive) (Grassi 2005a), exercise (treatment only or in addition to exercise) (Davison 2008a), BMI (< 25, > 25 kg/m2) (Almoosawi 2012a), cholesterol (high, normal) (Sarria 2014), or age (young, elderly) (Heiss 2015a).

Eleven trials used commercially available chocolate and 24 trials used flavanol-rich cocoa powder (tablet, bar, or powder mixed with water or milk) and compared the effect to a control group, which either took flavanol-free placebo (white chocolate, milk or placebo pill) or low-flavanol powder. The active intervention group received either dark chocolate of 3.6 to 105 grams (6 grams are equal to one piece of a 100-gram dark chocolate bar) containing 50% to 90% cocoa, milk chocolate-based confectionary (105 grams of < 10% cocoa) or flavanol-enriched cocoa powder, containing a dosage of 30 to 1218 mg (mean = 670 mg) of flavanols per day. Trials ran between two weeks and 12 weeks, with a single trial ran 18 weeks.

Excluded studies

We excluded 24 trials from our meta-analysis, because:

  1. Trials investigated the acute effects within two hours after cocoa ingestion (n = 2)

  2. The intervention period was less than two weeks (n = 7)

  3. Trials did not have a true control group (n = 6)

  4. The intervention was cocoa plus another active ingredient (n = 3)

  5. Data required for meta-analysis were not available (n = 5)

  6. The trial was of low quality (n = 1)

See Figure 1; Characteristics of excluded studies table.

Ongoing studies

Eleven unpublished trials were identified in trial registries, they were either not completed at time of meta-analysis or data were not yet available (Characteristics of ongoing studies).

Studies awaiting classification

Eight recent additional studies were found just before finalizing the updated review for publication (Characteristics of studies awaiting classification). These could potentially meet the inclusion criteria but in order to establish that it would require careful assessment. We chose not to include these studies in this update to avoid further delays in publication, but this will be done in a future update.

Risk of bias in included studies

'Risk of bias' assessments are summarised in Figure 2.

Figure 2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Random sequence generation

Sixteen trials adequately described random sequence generation (Bogaard 2010; Crews 2008; Davison 2010; Desideri 2012; Esser 2014; Ibero-Baraibar 2014; Massee 2015; Mogollon 2013; Muniyappa 2008; Neufingerl 2013; Njike 2011; Ried 2009; Rostami 2015; Rull 2015; Sansone 2015; Taubert 2007).

Random sequence generation was unclear in 19 trials (Al-Faris 2008; Almoosawi 2012a (two treatment comparisons); Davison 2008a (two treatment comparisons); Engler 2004; Fraga 2005; Grassi 2005a (two treatment comparisons); Grassi 2008; Heiss 2010; Heiss 2015a (two treatment comparisons); Khan 2012; Koli 2015; Mastroiacovo 2015; Monagas 2009; Murphy 2003; Nickols-Richardson 2014; Sarria 2014 (two treatment comparisons); Shiina 2009; Sorond 2013; Taubert 2003).

Allocation concealment

Eighteen trials described adequate allocation concealment (Bogaard 2010; Crews 2008; Davison 2010; Desideri 2012; Esser 2014; Fraga 2005; Grassi 2008; Heiss 2015a (two treatment comparisons); Massee 2015; Mogollon 2013; Monagas 2009; Muniyappa 2008; Neufingerl 2013; Ried 2009; Rostami 2015; Sansone 2015; Taubert 2007).

Seventeen trials provided insufficient information regarding allocation concealment (Al-Faris 2008; Almoosawi 2012a; Davison 2008a (two treatment comparisons); Engler 2004; Grassi 2005a (two treatment comparisons); Heiss 2010; Ibero-Baraibar 2014; Khan 2012; Mastroiacovo 2015; Murphy 2003; Nickols-Richardson 2014; Njike 2011; Rull 2015; Sarria 2014 (two treatment comparisons); Shiina 2009; Sorond 2013; Taubert 2003).

Allocation was unconcealed in one trial (Koli 2015).

Blinding

Performance bias

Unblinded/ single-blinded trials

Thirteen trials compared the cocoa group with unblinded controls using commercially available white chocolate, or only milk or water (Al-Faris 2008; Fraga 2005; Grassi 2005a (two treatment comparisons); Grassi 2008; Khan 2012; Koli 2015; Monagas 2009; Nickols-Richardson 2014; Rostami 2015; Sarria 2014 (two treatment comparisons); Shiina 2009; Taubert 2003; Taubert 2007).

One trial (Almoosawi 2012a; two treatment comparisons) reported a single-blind design, with participants but not investigators probably blinded, as the placebo dark chocolate was matched in taste, texture, colour and macronutrient composition.

Double-blinded trials

Thirteen trials used a low-flavanol cocoa product as the control aiming to facilitate ‘blinding’ or ‘masking’ of participants to minimise any expectation bias or placebo effect (Crews 2008; Davison 2008a (two treatment comparisons); Davison 2010; Desideri 2012; Esser 2014; Heiss 2010; Mastroiacovo 2015; Mogollon 2013; Muniyappa 2008; Murphy 2003; Njike 2011; Rull 2015; Sorond 2013).

Eight trials used a blinded design with flavanol-free control groups (Bogaard 2010; Engler 2004; Heiss 2015a (two treatment comparisons); Ibero-Baraibar 2014; Massee 2015; Neufingerl 2013; Ried 2009; Sansone 2015).

Blinding was achieved in seven of the eight trials by matching taste, colour, texture, energy and nutrient components of the cocoa and placebo products. In addition, one trial (Ried 2009) compared the effect on blood pressure of dark chocolate or tomato extract capsules with placebo capsules. In this trial, blinding of the control group but not the dark chocolate group was assured, as participants in the control group did not know if they were allocated into an active or placebo capsule group.

Detection bias

One trial (Almoosawi 2012a; two treatment comparisons) reported adequate outcome assessment (n = 21), or did not report details but used standard blood pressure monitoring procedures (n = 16).

Incomplete outcome data

All but three trials (Davison 2008a (two treatment comparisons); Muniyappa 2008; Rull 2015) had less than 20% attrition.

Selective reporting

None of the trials was biased due to selective reporting. However, industry-funding may have introduced a bias.

Other potential sources of bias

We found a small risk of publication bias, with slightly asymmetrical funnel plots, probably due to high heterogeneity of the 35 trials included in the meta-analysis.

Involvement of industry-sponsored studies may have influenced results. We therefore conducted a sensitivity analysis excluding trials (n = 6 trials) in which authors were employed by industry (Desideri 2012; Fraga 2005; Heiss 2010; Heiss 2015a (two comparisons); Mastroiacovo 2015; Sansone 2015) (see Analysis 7.1 and Analysis 7.2).

Effects of interventions

See: Summary of findings for the main comparison Flavanol-rich cocoa products for blood pressure

Meta-analysis of all 40 treatment comparisons revealed a significant blood pressure-reducing effect of flavanol-rich cocoa products compared with control.

Mean difference systolic blood pressure (SBP) (95% confidence interval (CI)): -1.76 (-3.09 to -0.43) mmHg, P = 0.009, 40 comparisons, 1804 participants;
Mean difference diastolic blood pressure (DBP) (95% CI): - 1.76 (-2.57 to -0.94) mmHg, P < 0.001, 39 comparisons, 1772 participants.

Analysis 1.1, (Figure 3); Analysis 1.2, (Figure 4)

Figure 3.

Forest plot of comparison: 1 Effect of cocoa on BP, outcome: 1.1 SBP.

Figure 4.

Forest plot of comparison: 1 Effect of cocoa on BP, outcome: 1.2 DBP.

Baseline blood pressure - hypertensive, prehypertensive, normotensive

The previous versions of our review had revealed a difference in effect of cocoa products on blood pressure, depending on hypertension status at baseline. While blood pressure was significantly lowered in people with systolic hypertension (≥ 140 mmHg) or diastolic prehypertension (≥ 80 mmHg), there was no significant effect of cocoa on people with normal blood pressure (120/80 mmHg) (Ried 2010; Ried 2012).

Systolic blood pressure

The updated meta-analysis (Analysis 2.1; Figure 5) shows a significant systolic blood pressure-reducing effect in the hypertensive subgroup, a trend towards blood pressure reduction in the prehypertensive subgroup, and a small non-significant effect in the normotensive subgroup:

Figure 5.

Forest plot of comparison: 2 Hypertensive or normotensive subjects, outcome: 2.1 SBP.

Hypertensive subgroup (baseline SBP > 140 mmHg): mean SBP difference (95% CI): -4.00 (-6.71 to -1.30) mmHg, P = 0.004, 9 comparisons, 401 participants;
Prehypertensive subgroup (baseline SBP > 130 mmHg): mean SBP difference (95% CI): -2.43 (-5.02 to 0.17) mmHg, P = 0.07, 8 comparisons, 340 participants;
Normotensive subgroup (baseline SBP < 130 mm Hg): mean SBP difference (95% CI): -0.65 (-2.13 to 0.84) mmHg, P = 0.39, 23 comparisons, 1063 participants.

The 'Test for subgroup differences' (hypertensive/prehypertensive/normotensive) provided a trend between the subgroups with borderline significance: SBP: I2 = 60%, P = 0.08.

Notably, effect sizes in the hypertensive and prehypertensive subgroups were larger than the effect size of the main meta-analysis including 40 trial comparisons (mean SBP differences (SE): -1.76 (1.3) mmHg).

Diastolic blood pressure

None of the trials in this meta-analysis involved participants with hypertensive diastolic blood pressure (DBP > 90 mm Hg), so we undertook subgroup analysis by prehypertensive (mean DBP > 80 mm Hg) versus normotensive participants (mean DBP < 80 mmHg) (Analysis 2.2; Figure 6).

Figure 6.

Forest plot of comparison: 2 Hypertensive or normotensive subjects, outcome: 2.2 DBP.

While a significant effect of cocoa on DBP was evident in both subgroups, there was no difference between the subgroups (I2 = 0%, P = 0.64).
Prehypertensive subgroup (baseline DBP > 80 mmHg): mean DBP difference (95% CI): -1.98 (-3.38 to -0.57) mmHg, P = 0.006, 16 comparisons, 735 participants;
Normotensive subgroup (baseline DBP < 80 mmHg): mean DBP difference (95% CI): -1.57 (-2.54 to -0.61) mmHg, P = 0.001, 23 comparisons, 1037 participants.

Dosage of flavanols and type of control group

Dosage of flavanol content was determined by two common standardised methods (Adamson 1999; Singleton 1965). We are reasonably confident that flavanol dosages are comparable.

Trials provided participants in the active group with 30 to 1218 mg of flavanols (mean = 670 mg) in 3.6 to 105 grams of cocoa products per day. The control group received either a flavanol-free product (n = 26 treatment comparisons) or a low-flavanol cocoa powder (n = 14 treatment comparisons). Flavanol dosage of low-flavanol products in the control group ranged between 6.4 and 88 mg (mean = 45 mg), with one trial (Esser 2014) providing 259 mg flavanols in the control group per day.

Meta-analysis 3.1.1 and 3.2.1 of trials with true (flavanol-free) control groups revealed a significant blood pressure-reducing effect:

Mean difference SBP (95% CI): -1.80 (-3.46 to -0.13) mmHg, P = 0.03, 26 comparisons, 1116 participants;
Mean difference DBP (95% CI): -1.82 (-2.95 to -0.68) mmHg, P = 0.002, 26 comparisons, 1116 participants.

Subgroup 3.1.2 and 3.2.2 analysis of trials with low-flavanol control groups provided similar effect sizes:
Mean difference SBP (95% CI): -1.67 (-4.03 to 0.69) mmHg, P = 0.17, 14 comparisons, 688 participants;
Mean difference DBP (95% CI): -1.62 (-2.56 to -0.68) mmHg, P < 0.001, 13 comparisons, 656 participants.

Similarity of subgroup findings was confirmed with the 'Test for subgroup differences' (flavanol-free trials compared with low flavanol trials):
I2 = 0%, P = 0.9 (no heterogeneity, no difference).

Sensitivity analysis of subgroup 2 (low-flavanol control group) excluding the trial with very high flavanol content in the control group (Esser 2014), 1078 mg (active) versus 259 mg (24% of flavanol in the active group), did not change results appreciably.

Mean difference SBP (95% CI): -1.73 (-4.35 to 0.90) mmHg, P = 0.20, 13 comparisons, 606 participants;
Mean difference DBP (95% CI): -1.71 (-2.77 to -0.65) mmHg, P = 0.002, 12 comparisons, 1690 participants.

Participants in nine of the 14 trials using low-flavanol control groups received higher or similar dosages of flavanols (33 - 259 mg flavanols) (Crews 2008; Davison 2008a; Davison 2010; Desideri 2012; Esser 2014; Mastroiacovo 2015; Mogollon 2013; Rull 2015) than the active intervention group in the trial by Taubert 2007 (30 mg flavanols; 0 mg flavanol control).

Blinding

We investigated whether blinding of participants and investigators may have played a role in the overall effect.

Subgroup analysis 4.1.1 and 4.2.1 of double-blind trials provided a small effect size:

Mean difference SBP (95% CI): -0.95 (-2.77 to 0.86) mm Hg, P = 0.30, 23 comparisons, 1059 participants;
Mean difference DBP (95% CI): -1.16 (-2.05 to -0.27) mm Hg, P = 0.01, 21 comparisons, 927 participants.

In contrast, subgroup analysis 4.1.2 and 4.2.2 of unblinded and single-blinded trials revealed a greater effect size:
Mean difference SBP (95% CI): -2.71 (-4.66 to -0.76) mmHg, P < 0.001, 17 comparisons, 745 participants;
Mean difference DBP (95% CI): -2.33 (-3.62 to -1.04) mmHg, P < 0.001, 18 comparisons, 845 participants.

Nine out of the 23 comparisons (39%) in the double-blind subgroup had flavanol-free (0 mg) control groups, so differences between the blinding subgroups cannot be explained only by the type of control group. Instead, small changes in blood pressure can easily be influenced by participant expectation, as well as outcome measurement by unblinded investigators.

However, the 'Test for subgroup differences' (double-blinded versus unblinded/single-blinded) did not provide sufficient evidence for a genuine difference between the subgroups of SBP: I2 = 40.4%, P = 0.20.

Age

Subgroup differences by age were not statistically significant (I2 = 0%, P = 0.6).

Subgroup analysis 5.1.1 and 5.2.1 of trials with younger participants (< 50 years):

Mean difference SBP (95% CI): -1.79 (-4.05 to 0.48) mmHg, P = 0.12, 18 comparisons, 726 participants;
Mean difference DBP (95% CI): -2.01 (-3.45 to -0.58) mmHg, P 0.006, 18 comparisons, 726 participants.

Subgroup analysis 5.2.1 and 5.2.2 of trials with older participants (≥ 50 years):

Mean difference SBP (95% CI): -0.98 (-2.87 to 0.90) mmHg, P = 0.30, 20 comparisons, 1036 participants;
Mean difference DBP (95% CI): -1.28 (-2.32 to -0.24) mmHg, P = 0.02, 19 comparisons, 962 participants.

One trial (Almoosawi 2012a; 2 treatment comparisons) did not provide participants' age details and was therefore excluded from this subgroup analysis.

Duration

24 treatment comparisons were of two to four weeks duration, while 16 treatment comparisons were of six to 18 weeks duration (mean = 9 weeks).

We found no statistically significant difference between the subgroups by duration (I2 = 0%, P = 0.5).

Subgroup analysis 6.1.1 and 6.2.1 of trials of two to four weeks duration:
Mean SBP difference (95% CI): -1.37 (-3.23 to 0.49) mmHg, P = 0.15, 24 comparisons, 1043 participants;
Mean DBP difference (95% CI): -1.55 (-2.71 to -0.39) mmHg, P = 0.009, 23 comparisons, 1011 participants.

Subgroup analysis 6.1.2 and 6.2.2 of trials of 6 to 18 weeks duration:
Mean SBP difference (95% CI): -2.37 (-4.30 to -0.44) mmHg, P = 0.02, 16 comparisons, 761 participants;
Mean DBP difference (95% CI): -2.04 (-3.18 to -0.91) mmHg, P < 0.001, 16 comparisons, 761 participants.

Analysis 6.1; Analysis 6.2

Sensitivity analyses of all trials excluding those in which authors were employed by industry (n = 6) revealed a marked difference in results, reducing effect sizes and statistical significance, in particular for systolic blood pressure.

Mean difference SBP (95% CI): -1.08 (-2.60 to 0.43) mmHg, P = 0.16, 33 comparisons, 1482 participants;
Mean difference DBP (95% CI): -1.37 (-2.31 to -0.43) mmHg, P = 0.004, 33 comparisons, 1482 participants.

Analysis 7.1; Analysis 7.2

Summary of secondary outcomes

We did not meta-analyse withdrawals and adverse effects across trials, but we summarise them in Table 1.

Table 1. Adverse events & withdrawals
  1. C:Cross-over
    P: Parallel

Study

Study design

 

Participants

Cocoa/ Control

Withdrawn

Cocoa/Control

Reasons for withdrawal including adverse effects

Cocoa/Control

Taubert 2003C13/130/0-
Murphy 2003P13/153 in total

Family illness (2)

Non-compliance in final week (1)

Engler 2004P11/100/0-
Fraga 2005C14/141/0No reason given
Grassi 2005aC15/150/0-
Grassi 2005bC20/200/0-
Taubert 2007P22/220/0-
Crews 2008P45/456/5

Gastrointestinal upset/headache/cold sweat (2/1)

Bronchitis (1/0)

Jitteriness/increased energy (1/0)

Atrial arrhythmia/medication change (1/0)

Dislike of study product (1/1)

Family illness (0/1)

Unspecified reason (0/1)

No adherence to trial regimen (0/1)

Grassi 2008C19/190/0-
Muniyappa 2008C20/205/4

Lost to follow-up (0/1)

Discontinued intervention  (4/2) due to

Intolerance to treatment, family emergencies, personal problems

excluded from analysis (1/1)

Davison 2008aP12/117 in total

Time restrictions, personal circumstances (14)

Non-compliance (exercise or diet) (2)

 

Davison 2008bP13/135 in total
Al-Faris 2008P30/290/0-
Shiina 2009P20/190/0-
Ried 2009P11/102/2

Study product unpalatable (2/0)

Gastrointestinal upset (0/1)

Illness unrelated to study (0/1)

Monagas 2009C42/420/0Constipation (resolved with fibre intake)
Bogaard 2010C41/413 in total

Nausea (1)

Headache (1)

Arrythmia  unrelated (1)
Laxative effect (12/2) – did not withdraw

 

Heiss 2010C16/163 in totalDid not come to first visit
Davison 2010P13/147 in total

Mild gastric symptoms (1)

Non-compliance with study protocol (1)

Withdrew due to personal circumstances (5)

Njike 2011C38/387 in total

Non-compliance with study  protocol (1)

Withdrew  for personal reasons (6)

 

Almoosawi 2012aC21/211/1Personal reasons unrelated to study
Desideri 2012P30/300/1Gastric discomfort (1)
Khan 2012C42/421/0Constipation
Mogollon 2013P22/201/1Unrelated to study (1)/headache (1)
Neufingerl 2013P10/101/1Nausea (1)/unrelated (1)
Sorond 2013P29/291/1No details provided
Esser 2014C41/413 in totalMedical reasons (1), disliked chocolate (1), poor compliance (1)
Ibero-Baraibar 2014P24/232/1Personal reason (2), poor compliance (1)
Nickols-Richardson 2014P30/300/0None
Sarria 2014 (a)C

24/24

20/20

?No information given
Heiss 2015 (a)P

11/11

10/10

0/0None
Massee 2015P19/191/1Personal reasons (1)
Rostami 2015P32/282/6No information given
Koli 2015C22/220/0No side effects reported
Mastroiacovo 2015P30/301/0

Personal reasons (1)

No side effects reported
(1 gastric discomfort in IF (intermediate flavanol) group not included in this meta-analysis)

Rull 2015C21/2111No details provided
Sansone 2015P50/50?No information given

Four trials did not provide any information on reasons for withdrawals or adverse effects (Rostami 2015; Rull 2015; Sansone 2015; Sarria 2014).

Out of 31 comparisons (1514 participants, cocoa groups: n = 760; control groups: n = 754) which provided information on withdrawals and adverse effects, eight trials reported no withdrawals and no adverse effects (Engler 2004; Grassi 2005a; Grassi 2008; Heiss 2015a; Koli 2015; Nickols-Richardson 2014; Taubert 2003; Taubert 2007).

In the remaining 23 comparisons, reasons for withdrawal included personal and trial-unrelated reasons or adverse effects.

Withdrawals due to adverse effects were reported in nine trials (Bogaard 2010; Crews 2008; Davison 2010; Desideri 2012; Esser 2014; Khan 2012; Mogollon 2013; Neufingerl 2013; Ried 2009), including gastrointestinal complaints (cocoa groups: n = 8/760 (1%), control groups: n = 3/754 (0.4%)); dislike of the trial product (cocoa: n = 4/760; control: n = 1/754), headache (cocoa: n = 2/760; control: n = 1/754), and jitteriness (cocoa: n = 1/760, control: n = 0/754).

The product with a high theobromine content in one trial (Bogaard 2010) had a laxative effect (cocoa: n = 12/41, control: n = 2/41), but the affected participants completed the trial. Interestingly, two additional study groups in Neufingerl 2013, not included in this review, tested high theobromine content (850 mg or 1000 mg) and reported a high incidence of nausea, vomiting, headache, and diarrhoea (n = 7/20 participants).

While the potential effect on blood pressure is rather small, cocoa may have other cardiovascular benefits, including improved endothelial function and reduced vascular stiffness (Davison 2008a; Engler 2004; Grassi 2005a; Grassi 2008; Heiss 2010; Heiss 2015a; Mogollon 2013; Sansone 2015; Shiina 2009), as well as improved glucose metabolism and reduced insulin resistance, in particular in overweight or obese individuals (Almoosawi 2012a; Desideri 2012; Grassi 2005a; Grassi 2008; Mastroiacovo 2015; Muniyappa 2008; Nickols-Richardson 2014). It may reduce triglyceride levels and oxidised LDL-cholesterol (Almoosawi 2012a; Ibero-Baraibar 2014; Khan 2012; Rostami 2015; Sarria 2014), decrease platelet aggregation (Murphy 2003; Rull 2015), reduce inflammation (Esser 2014; Monagas 2009), and improve cognitive function (Desideri 2012; Massee 2015; Mastroiacovo 2015; Sorond 2013).

Discussion

Summary of main results

Our updated meta-analysis of 35 short-term trials with 40 treatment comparisons involving 1804 mainly healthy individuals suggests flavanol-rich cocoa products (mean 670 mg flavanols) to have a small but statistically significant effect in reducing blood pressure compared with control by 1.8 mmHg.

Heterogeneity was generally high. We explored reasons for heterogeneity in subgroup and sensitivity analyses.

Whilst subgroup meta-analyses by baseline blood pressure indicated a larger average effect of cocoa in systolic hypertension compared with systolic prehypertension or normotension, the test for interaction was of borderline significance (Test for subgroups differences: I2 = 60%, P = 0.08). Further studies with hypertensive people are needed to confirm any significant interaction between baseline blood pressure and effect size.
A significant blood pressure-lowering effect of cocoa was evident in diastolic blood pressure, independent of status at baseline.

We investigated whether blinding may play a role. While meta-analysis of trials with unblinded/single-blinded trials revealed a greater systolic blood pressure-reducing effect, compared to double-blinded trials, the test for subgroup differences was statistically not significant. In addition, any differences cannot be explained by the type of control alone (flavanol-free versus low flavanol control ), and may suggest an influence of participant expectations when unblinded to the intervention.

We found the effect of cocoa to be slightly attenuated by age, so that blood pressure reduction tended to be greater in younger individuals (mean age range 18 to 49 yrs; 18 trials) compared with older individuals (mean age range 50 to 73 yrs; 20 trials). While there was no statistically significance difference between subgroups, an age-related difference in the effect of cocoa on blood pressure is biologically plausible. The age-related effect might be associated with structural and biochemical changes in the arterial wall associated with aging (O'Rourke 1990) and subsequent vascular reactivity to stimuli. Age-related changes include arterial stiffening together with decrease of elastin, and increase of collagen and glycosaminoglycans (O'Rourke 1990). In addition, endothelin-1, a potent vasoconstrictor protein, is elevated in older adults (Donato 2009) and endothelial oxidative stress compromising nitric oxide availability is more pronounced in the elderly (Taddei 2001). Cocoa flavanols have been shown to reduce vascular resistance and arterial stiffness, and are potent scavengers of free radicals (Loke 2008; Schroeter 2006), which may lead to improved vascular function. In the short-term studies included in our review the effect of cocoa on blood pressure might be more pronounced in younger individuals, due to the age-related decrease in vascular reactivity to physiological stimuli such as cocoa flavanols.

Trial duration slightly influenced results, with greater effect sizes observed in the longer trials of six to 18 weeks compared to the shorter trials of two to four weeks, albeit not a statistically significant difference.

In this review, we assessed the flavanol content of cocoa products. Cocoa also contains the stimulant theobromine, which has been suggested to affect vasoactivity and thus blood pressure reduction in cocoa products (Kelly 2005). Theobromine is the bitter alkaloid of the cacao plant, and is also found in other plants, such as tea and the cola nut. Other similar compounds, the methylxanthines, include caffeine in coffee. However, analysis of the effect of cocoa on blood pressure by theobromine content was hindered by the lack of reporting of the theobromine content in a number of trials. Instead, ingestion of higher concentrations of theobromine have been associated with a higher rate of adverse effects, in particular nausea, vomiting, dizziness, and diarrhoea, as reported in a number of trials.
It is also questionable whether chocolate and cocoa products are palatable if large amounts of theobromine are included. While some animals, such as dogs, might succumb to theobromine poisoning from as little as 50 grams of chocolate for a smaller dog and 400 grams for an average-sized dog due to slow metabolism of theobromine (Strachan 1994), it is estimated that a 60 kg human would need to consume about 4.5 kg of dark chocolate containing natural theobromine to be poisoned (Rusconi 2010).

Sensitivity analysis of 33 treatment comparisons, excluding those with at least one of the authors employed by the trial sponsoring industry and with a commercial interest in the test cocoa product, revealed a reduced effect size and reduced statistical significance, alerting to a potential bias in reporting of results, and may explain some of the heterogeneity.

Overall completeness and applicability of evidence

Data were available for the 35 identified trials with 40 treatment comparisons fitting the inclusion criteria. We excluded two trials due to lack of data (Balzer 2008; Farouque 2006). Most trials studied healthy people with or without elevated blood pressure, including one trial of healthy pregnant women (Mogollon 2013). One trial (Heiss 2010) included people with coronary artery disease, three trials assessed individuals with impaired glucose tolerance or diabetes (Grassi 2008; Khan 2012; Rostami 2015), and one trial studied elderly people with mild cognitive impairment (Desideri 2012). Our findings are therefore applicable largely to healthy adults with or without hypertension. Our review included all types of cocoa products.

Our meta-analysis contributes to the evidence for flavanol-rich cocoa products being beneficial to cardiovascular health, albeit a modest effect. No long-term trials investigating the effect of cocoa products on clinical outcomes are available to shed light on the effects of cocoa on cardiovascular events or long-term adverse effects.

Quality of the evidence

We found a sufficient number of trials (35, with 40 treatment comparisons) and a reasonably large sample size (1804 participants) to generate meaningful meta-analysis and to allow several subgroup analyses, exploring heterogeneity. Because of the large number of trials, many of high quality, and despite unexplained high heterogeneity, we consider the quality of the evidence to be moderate (Summary of findings for the main comparison). We explored heterogeneity in several subgroup analyses with a reasonable number of trials.

Potential biases in the review process

A strength of this updated review is the comprehensive literature search including several databases, trial registries and reference lists of included trials.

While we investigated heterogeneity in several subgroup analyses, we could not fully explain the variations in effect of cocoa on blood pressure. Continuing high levels of heterogeneity within subgroup analyses suggest that there may be a combination of factors, or additional ones beyond those we considered. It is possible that subgroups by age and hypertension status at baseline might be subject to ecological bias. The effect we found between studies might not hold within studies. However, analysis of individual patient data was not an approach that we adopted for this review.

Agreements and disagreements with other studies or reviews

While the effect on cocoa on systolic blood pressure is significant, noticeably, the effect sizes became smaller with the increasing number of studies compared to previous meta-analyses. It is likely that a larger sample size provided a more unbiased result by reducing the influence of individual studies.

  • Ried 2012 (20 treatment comparisons): mean difference SBP (95% CI): -2.77 (-4.72 to -0.82) mmHg, P = 0.005, 856 participants

  • Ried 2010 (15 treatment comparisons): mean difference SBP (95% CI): -3.16 (-5.08 to -1.23) mmHg, P = 0.001, 578 participants

  • Desch 2010a (10 treatment comparisons): mean difference SBP (95% CI): -4.52 (-5.87 to -3.16) mmHg, P < 001, 297 participants

  • Taubert 2007a (5 treatment comparisons): mean difference SBP (95% CI): -4.7 (-7.6 to -1.8) mm-Hg, P = 0.002, 97 participants

Overall reduction in diastolic blood pressure in our updated meta-analysis is also smaller than reported in earlier versions of this review and previous meta-analyses:

  • Ried 2012 (19 treatment comparisons): mean difference DBP (95% CI): -2.20 (-3.46 to -0.93) mmHg, P = 0.006, 824 participants

  • Ried 2010 (15 treatment comparisons): mean difference DBP (95% CI): -2.02 (-3.35 to 0.69) mmHg, P = 0.003, 578 participants

  • Desch 2010a (10 treatment comparisons): mean difference DBP (95% CI): -2.5 (-3.90 to 1.20) mmHg, P < 0.001, 297 participants

  • Taubert 2007a (5 treatment comparisons): mean difference DBP (95% CI): -2.8 (-4.80 to -0.80) mmHg, P = 0.006, 97 participants

Authors' conclusions

Implications for practice

Our updated review provides moderate-quality evidence that flavanol-rich chocolate and cocoa products lower both systolic and diastolic blood pressure in mainly healthy adults by an average of 1.8 mmHg in the short term.

Our findings are limited by the heterogeneity between trials, which could not be explained by prespecified subgroup analyses, including blinding, flavanol content of the control groups, age of participants, or study duration. However, baseline blood pressure may play a role in the effect of cocoa on blood pressure, with subgroup analysis of trials with (pre)hypertensive participants revealing a greater blood pressure-reducing effect of cocoa compared to normotensive participants.

Implications for research

More trials are needed, designed to directly compare the effect of cocoa on specific population groups (e.g. hypertensive versus normotensive) to test the findings of our subgroup analyses.

Long-term trials are needed investigating the effect of cocoa on clinical outcomes, to assess whether cocoa has an effect on cardiovascular events.

Acknowledgements

We are thankful for the assistance by N Funabashi (Shiina 2009), D Grassi (Grassi 2008), and B van den Bogaard (Bogaard 2010), who provided unpublished data for inclusion in our meta-analysis.

We would like to acknowledge the assistance and advice received from the Cochrane Hypertension Group.

Data and analyses

Download statistical data

Comparison 1. Effect of cocoa on BP
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 SBP401804Mean Difference (Random, 95% CI)-1.76 [-3.09, -0.43]
2 DBP391772Mean Difference (Random, 95% CI)-1.76 [-2.57, -0.94]
Analysis 1.1.

Comparison 1 Effect of cocoa on BP, Outcome 1 SBP.

Analysis 1.2.

Comparison 1 Effect of cocoa on BP, Outcome 2 DBP.

Comparison 2. Hypertensive or normotensive participants
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 SBP401804Mean Difference (Random, 95% CI)-1.76 [-3.09, -0.43]
1.1 Hypertensive (> 140 mmHg)9401Mean Difference (Random, 95% CI)-4.00 [-6.71, -1.30]
1.2 Prehypertensive (> 130 mmHg)8340Mean Difference (Random, 95% CI)-2.43 [-5.02, 0.17]
1.3 Normotensive231063Mean Difference (Random, 95% CI)-0.65 [-2.13, 0.84]
2 DBP391772Mean Difference (Random, 95% CI)-1.76 [-2.57, -0.94]
2.1 (Pre)hypertensive (> 80 mmHg)16735Mean Difference (Random, 95% CI)-1.98 [-3.38, -0.57]
2.2 Normotensive (< 80 mmHg)231037Mean Difference (Random, 95% CI)-1.57 [-2.54, -0.61]
Analysis 2.1.

Comparison 2 Hypertensive or normotensive participants, Outcome 1 SBP.

Analysis 2.2.

Comparison 2 Hypertensive or normotensive participants, Outcome 2 DBP.

Comparison 3. Flavanol-free or low flavanol control
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 SBP401804Mean Difference (Random, 95% CI)-1.76 [-3.09, -0.43]
1.1 Flavanol-free control261116Mean Difference (Random, 95% CI)-1.80 [-3.46, -0.13]
1.2 Low flavanol control14688Mean Difference (Random, 95% CI)-1.67 [-4.03, 0.69]
2 DBP391772Mean Difference (Random, 95% CI)-1.76 [-2.57, -0.94]
2.1 Flavanol-free control261116Mean Difference (Random, 95% CI)-1.82 [-2.95, -0.68]
2.2 Low flavanol control13656Mean Difference (Random, 95% CI)-1.62 [-2.56, -0.68]
Analysis 3.1.

Comparison 3 Flavanol-free or low flavanol control, Outcome 1 SBP.

Analysis 3.2.

Comparison 3 Flavanol-free or low flavanol control, Outcome 2 DBP.

Comparison 4. Double-blinded or unblinded/single-blinded
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 SBP401804Mean Difference (Random, 95% CI)-1.76 [-3.09, -0.43]
1.1 Double-blind231059Mean Difference (Random, 95% CI)-0.95 [-2.77, 0.86]
1.2 Unblinded, single-blinded17745Mean Difference (Random, 95% CI)-2.71 [-4.66, -0.76]
2 DBP391772Mean Difference (Random, 95% CI)-1.76 [-2.57, -0.94]
2.1 Double-blind21927Mean Difference (Random, 95% CI)-1.16 [-2.05, -0.27]
2.2 Unblinded, single-blinded18845Mean Difference (Random, 95% CI)-2.33 [-3.62, -1.04]
Analysis 4.1.

Comparison 4 Double-blinded or unblinded/single-blinded, Outcome 1 SBP.

Analysis 4.2.

Comparison 4 Double-blinded or unblinded/single-blinded, Outcome 2 DBP.

Comparison 5. Participants ≥50 or <50 years old
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 SBP381762Mean Difference (Random, 95% CI)-1.36 [-2.79, 0.06]
1.1 < 50 years18726Mean Difference (Random, 95% CI)-1.79 [-4.05, 0.48]
1.2 ≥ 50 years201036Mean Difference (Random, 95% CI)-0.98 [-2.87, 0.90]
2 DBP371688Mean Difference (Random, 95% CI)-1.62 [-2.49, -0.76]
2.1 < 50 years18726Mean Difference (Random, 95% CI)-2.01 [-3.45, -0.58]
2.2 ≥ 50 years19962Mean Difference (Random, 95% CI)-1.28 [-2.32, -0.24]
Analysis 5.1.

Comparison 5 Participants ≥50 or <50 years old, Outcome 1 SBP.

Analysis 5.2.

Comparison 5 Participants ≥50 or <50 years old, Outcome 2 DBP.

Comparison 6. Study duration 2 - 4 weeks or > 4 weeks
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 SBP401804Mean Difference (Random, 95% CI)-1.76 [-3.09, -0.43]
1.1 2 - 4 week duration241043Mean Difference (Random, 95% CI)-1.37 [-3.23, 0.49]
1.2 > 4 week duration16761Mean Difference (Random, 95% CI)-2.37 [-4.30, -0.44]
2 DBP391772Mean Difference (Random, 95% CI)-1.76 [-2.57, -0.94]
2.1 2 - 4 week duration231011Mean Difference (Random, 95% CI)-1.55 [-2.71, -0.39]
2.2 > 4 week duration16761Mean Difference (Random, 95% CI)-2.04 [-3.18, -0.91]
Analysis 6.1.

Comparison 6 Study duration 2 - 4 weeks or > 4 weeks, Outcome 1 SBP.

Analysis 6.2.

Comparison 6 Study duration 2 - 4 weeks or > 4 weeks, Outcome 2 DBP.

Comparison 7. Sensitivity analysis: excl studies with industry employed authors
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 SBP331482Mean Difference (Random, 95% CI)-1.08 [-2.60, 0.43]
2 DBP331482Mean Difference (Random, 95% CI)-1.37 [-2.31, -0.43]
Analysis 7.1.

Comparison 7 Sensitivity analysis: excl studies with industry employed authors, Outcome 1 SBP.

Analysis 7.2.

Comparison 7 Sensitivity analysis: excl studies with industry employed authors, Outcome 2 DBP.

Appendices

Appendix 1. MEDLINE search strategy

Database: Ovid MEDLINE(R) 1946 to Present with Daily Update

Search Date: 7 November 2016

--------------------------------------------------------------------------------

1 (cacao$ or cocao$ or cocoa$ or chocolat$).mp. (5917)

2 exp cardiovascular diseases/ (2119273)

3 exp cardiovascular system/ (1138797)

4 cardiovascular.mp. (428184)

5 exp hypertension/ (239452)

6 (antihypertens$ or hypertens$).tw. (357352)

7 exp blood pressure/ (274194)

8 ((arterial or blood or diastolic or systolic) adj2 pressur?).tw. (297630)

9 (bloodpressur? or bp or dbp or sbp).tw. (139226)

10 or/2-9 (3094934)

11 randomized controlled trial.pt. (434369)

12 controlled clinical trial.pt. (91859)

13 randomi?ed.ab. (398909)

14 placebo.ab. (166289)

15 clinical trials as topic/ (180579)

16 randomly.ab. (231524)

17 trial.ti. (144974)

18 or/11-17 (1014610)

19 animals/ not (humans/ and animals/) (4303730)

20 18 not 19 (929627)

21 1 and 10 and 20 (161)

22 remove duplicates from 21 (151)

Appendix 2. Hypertension Group Specialised Register search strategy

Database: Hypertension Group Specialised Register
Search Date: 8 November 2016
--------------------------------------------------------------------------------
#1(cacao* or cocao* cocoa* or chocolat*) 179

#2RCT:DE 24183
#3 (Review OR Meta-Analysis):MISC2 1164
#4 #1 AND (#2 OR #3) 129

***************************

Appendix 3. CENTRAL search strategy

Database: Cochrane Central Register of Controlled Trials (CENTRAL) 2016, Issue 11 via the Cochrane Register of Studies Online
Search Date: 7 November 2016

--------------------------------------------------------------------------------
#1(cacao* or cocao* or cocoa* or chocolat*)623

#2MESH DESCRIPTOR Cardiovascular Diseases EXPLODE ALL TREES73677

#3MESH DESCRIPTOR Cardiovascular System EXPLODE ALL TREES17870

#4cardiovascular*47208

#5MESH DESCRIPTOR Hypertension EXPLODE ALL TREES14248

#6(antihypertens* or hypertens*)42379

#7MESH DESCRIPTOR blood pressure EXPLODE ALL TREES24557

#8(arterial or blood or diastolic or systolic) NEAR2 pressur*59742

#9(bloodpressur* or bp or dbp or sbp)13514

#10#2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9155268

#11#1 AND #10174

Appendix 4. Embase search strategy

Database: Embase <1974 to 2016 November 07>

Search Date: 7 November 2016

--------------------------------------------------------------------------------

1 (cacao$ or cocao$ or cocoa$ or chocolat$).mp. (9312)

2 exp cardiovascular disease/ (3576873)

3 exp cardiovascular system/ (1690837)

4 cardiovascular.mp. (814809)

5 exp hypertension/ (618867)

6 (antihypertens$ or hypertens$).tw. (536416)

7 exp blood pressure/ (504873)

8 ((arterial or blood or diastolic or systolic) adj2 pressur?).tw. (418083)

9 (bloodpressur? or bp or dbp or sbp).tw. (195852)

10 or/2-9 (4650010)

11 randomized controlled trial/ (460216)

12 crossover procedure/ (53690)

13 double-blind procedure/ (137595)

14 (randomi?ed or randomly).tw. (925570)

15 (crossover$ or cross-over$).tw. (85589)

16 placebo.ab. (239247)

17 ((singl$ or doubl$) adj blind$).tw. (191478)

18 assign$.ab. (295579)

19 allocat$.ab. (107734)

20 or/11-19 (1383382)

21 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) (5827297)

22 20 not 21 (1214819)

23 1 and 10 and 22 (326)

24 remove duplicates from 23 (303)

Appendix 5. Clinical Trials Registries

Database: ClinicalTrials.gov
Search Date: 7 November 2016
--------------------------------------------------------------------------------

Search terms: randomized
Study type: Interventional Studies
Intervention: cocoa OR chocolate
Outcome Measures: blood pressure (40)

***************************

Database: WHO International Clinical Trials Registry Platform
Search Date: 8 November 2016
--------------------------------------------------------------------------------

#1 random* AND blood pressure AND cocoa 5
#2 random* AND blood pressure AND chocolate 5
#3 random* AND hypertens* AND cocoa 7
#4 random* AND hypertens* AND chocolate 6
#5 random* AND cardiovasc* AND cocoa 8
#6 random* AND cardiovasc* AND chocolate 4
#7 #1 OR #2 OR #3 OR #4 OR #5 OR #6 35
#8 remove duplicates from #7 19

***************************

What's new

DateEventDescription
2 May 2017Amendedfixed minor display error in forest plot for Analysis 1.1

History

DateEventDescription
20 April 2017New search has been performed20 new treatment comparisons included, total of 40 treatment comparisons.
20 April 2017New citation required but conclusions have not changedUpdated search

Contributions of authors

Search strategy, obtain copies of studies, study selection, extract data: KR, PF

Data entry into RevMan: KR

Analysis and interpretation: KR, PF

Draft of the review: KR with contributions from PF and NS

Declarations of interest

KR has been an investigator on two randomised controlled trials included in this review (Ried 2009, Massee 2015). KR has no other conflict of interest to declare.

NS has been an investigator on one randomised controlled trial included in this review (Ried 2009). NS has no other conflict of interest to declare.

PF has no conflict of interest to declare.

Sources of support

Internal sources

  • The University of Adelaide, Australia.

  • National Institute of Integrative Medicine, Australia.

    First author is employed as Director of Research at NIIM

External sources

  • No sources of support supplied

Differences between protocol and review

We added to the exclusion criteria: Trials of very low quality, specifically high losses to follow up of more than 50%, were excluded from meta-analysis.

For clarity, we provided more detail of the approach for data analysis.
We modified:

  1. Primary outcome measure: 'Difference in systolic and diastolic blood pressure at final follow-up between cocoa and control group, adjusted for baseline.' Previously, the protocol had read: 'Changes in systolic and diastolic blood pressure from baseline compared with control.'

  2. Measurement of treatment effect: 'Mean difference in SBP/DBP in mmHg from baseline to final follow-up, adjusted for baseline differences.' Previously, the protocol had read: 'Change of mean difference in SBP/DBP from baseline to follow-up in mmHg.'

  3. Dealing with missing data: '....We assumed a correlation of 0.68 between the final follow-up SBP/DBP results for the two treatment arms in a cross-over trial.' Previously, the protocol had read: 'We will assume a correlation of 0.68 for the standard deviation of the differences from baseline to follow-up.'

  4. We modified the imputation of standard deviations as follows:

    1. standard deviation of blood pressure at end of treatment taken in a different position from that of the blood pressure data used

    2. standard deviation of blood pressure at baseline

    3. mean standard deviation of blood pressure at end of treatment from other trials using the same intervention.

Differences in versions of this review

The Ried 2012 version of this review incorporated a meta-regression analysis which we have not conducted for this update, for practical reasons.

Characteristics of studies

Characteristics of included studies [author-defined order]

Murphy 2003

Methods

P

DB

Participants

Community setting, Melbourne, Australia

Eligibility: healthy

N = 28

Age: 43.5

Male: 53%

Normotensive (mean baseline BP = 117/77 mmHg)

Interventions

1. Cocoa tablets (234 mg flavanols/procyanidins)
2. Placebo tablets (< 6 mg cocoa flavanols/procyanidins); daily

Duration: 28 days

Outcomes

SBP and DBP measured after 28 days. (No description of position of participant or which arm)

Secondary outcome measure

NotesSupported in part by Mars Inc, USA who supplied active tablets (CocoaPro; Mars Inc, Hackettstown, NJ) and placebo tablets
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Participants were separated into 2 groups that were sex-matched and randomly assigned to consume either treatment.

Sequence generation not described

Allocation concealment (selection bias)Unclear riskInsufficient information provided
Incomplete outcome data (attrition bias)
All outcomes
Low risk12.5% (4/32) loss to follow-up: 1 did not to meet inclusion criteria, 2 withdrew because of family illnesses, and 1 failed to consume the specified number of tablets during the final week of the intervention. No other missing outcome data reported.
Selective reporting (reporting bias)Low riskBP reported at beginning and end of intervention
Other biasUnclear riskindustry-supported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blinded (active and placebo tablets)
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAdequate

Taubert 2003

Methods

C

SB

Participants

Community setting, Cologne, Germany

Eligibility: healthy

N = 13

Age: 55 - 64

Male: 54%

Hypertensive (Mean baseline BP = 153/84 mgHg)

Interventions

1. 100 g dark chocolate (500 mg flavanols)
2. 90 g white chocolate (0 mg flavanols); daily

Duration: 2 weeks

Outcomes

Seated SBP and DBP (left upper arm) measured daily

Primary outcome measure

NotesSponsor not involved in data collection or analysis
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskParticipants were randomly assigned to receive 14 consecutive daily doses of either treatment. Sequence generation not described
Allocation concealment (selection bias)Unclear riskInsufficient information provided
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up. No missing outcome data reported
Selective reporting (reporting bias)Low riskBP data were provided for all time points
Other biasLow risknone
Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding of participants
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBP was recorded "in a blinded fashion"

Engler 2004

Methods

P

DB

Participants

Community setting, San Francisco, USA

Eligibility: healthy

N = 21

Age: 38 (21 - 55)

Male: 52%

Normotensive (Mean baseline BP = 116/67 mmHg)

Interventions

1. 46 g dark high flavanoid (213 mg procyanidin/46 mg epicatechin) chocolate
2. 46 g dark low flavanoid (trace procyanidin/epicatechin) chocolate; daily

Duration: 2 weeks

Outcomes

Resting supine SBP and DBP after 2 weeks

Secondary outcome measure

NotesFunded by the University of California, San Francisco. Chocolate sourced from American Cocoa Research Institute, Vienna, VA. Sponsor not involved in data collection or analysis.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomized. Sequence generation not described
Allocation concealment (selection bias)Unclear riskInsufficient information provided
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up. Excellent compliance in all participants was documented by the return of all empty sample wrappers and by plasma epicatechin concentrations at 2 weeks
Selective reporting (reporting bias)Low riskBP reported at beginning and end of intervention
Other biasLow risknone
Blinding of participants and personnel (performance bias)
All outcomes
Low riskEach chocolate sample was provided in coded foil wrapped containers. Both high- and low-flavonol chocolate bars were similar in physical appearance and taste.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAdequate

Fraga 2005

Methods

C

SB

Participants

Study dates: 10/00-11/00

Community setting, Buenos Aires, Argentina

Eligibility: young male active soccer players

N = 28

Age: 18 (18 - 21)

Male: 100%

Normotensive (mean baseline BP = 123/72 mmHg)

Interventions

1. 105 g (168 mg flavanols) containing milk chocolate (M&M's)
2. 105 g cocoa butter chocolate (0 mg flavanols); daily

Duration: 2 weeks

Outcomes

SBP and DBP measured daily. No description of position of participant or which arm

Primary outcome measure

Notes3 authors from Mars. Funding supplied by the University of Buenos Aires and Argentinian government (ANPCYT).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Randomised

Sequence generation not described

Allocation concealment (selection bias)Low risk2 treatments were provided in 105 g-coded bags (1 daily dose) for 7-day periods
Incomplete outcome data (attrition bias)
All outcomes
Low risk3.6% (1/28) loss to follow-up; reason not reported
Selective reporting (reporting bias)Low riskBP reported at beginning and end of intervention
Other biasHigh riskIndustry-funded and authored
Blinding of participants and personnel (performance bias)
All outcomes
High riskNon-blinding of participants (dark/white chocolate)
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAdequate

Grassi 2005a

Methods

C

SB

Participants

Community setting, L'Aquila, Italy

Eligibility: hypertensive

N = 15

Age: 34 (SD = 7.6)

Male: 47%

Normotensive (mean baseline BP = 113/74 mgHg)

Interventions

1. 100 g dark chocolate (500 mg flavanols)
2. 90 g white chocolate (0 mg flavanols); daily

Duration: 15 days

Outcomes

Seated resting SBP and DBP after 15 days

Primary outcome measure

NotesNormotensive group; Influence of funding body unclear
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised
Sequence generation not described
Allocation concealment (selection bias)Unclear riskNo information given
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up
Selective reporting (reporting bias)Low riskBP at start and end of study reported
Other biasUnclear riskInfluence of funding body unclear
Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding of participants
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBP was measured always by the same physician who was unaware of the study design, results, and purpose

Grassi 2005b

Methods

C

SB

Participants

Community setting, L'Aquila, Italy

Eligibility: hypertensive

N = 15

Age: 34 (SD = 7.6)

Male: 47%

Normotensive (mean baseline BP = 113/74 mgHg)

Interventions

1. 100 g dark chocolate (500 mg flavanols)
2. 90 g white chocolate (0 mg flavanols); daily

Duration: 15 days

Outcomes

Seated resting SBP and DBP after 15 days

Primary outcome measure

NotesHypertensive subgroup; Influence of funding body unclear
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised
Sequence generation not described
Allocation concealment (selection bias)Unclear riskNo information given
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up
Selective reporting (reporting bias)Low riskBP at start and end of study reported
Other biasUnclear riskInfluence of funding body unclear
Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding of participants
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBP was measured always by the same physician who was unaware of the study design, results, and purpose

Taubert 2007

Methods

C

SB

Participants

Study dates: 1/05-12/16

Community setting, Cologne, Germany

Eligibility: (pre-)hypertensive

N = 44

Age: 55 - 75

Male: 45%

Hypertensive (mean baseline BP = 148/86 mmHg)

Interventions

1. 6.3 g dark chocolate (30 mg flavanols)
2. 5.6 g white chocolate (0 mg flavanols); daily

Duration: 18 weeks

Outcomes

Seated resting SBP and DBP (left upper arm) after 6, 12, and 18 weeks

Primary outcome

NotesFunded by the University Hospital of Cologne, Germany. Funding body not involved in study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskPermuted randomisation in sex-stratified blocks of 4 persons each, sequentially allocated to dark chocolate and white chocolate using a computer-generated random number sequence
Allocation concealment (selection bias)Low riskTo conceal allocation from investigators, instructed trained staff at a separate site not involved with the trial generated and maintained the randomization list and prepared the chocolate
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up
Selective reporting (reporting bias)Low riskBP data at start, during and end of study.
Other biasLow risknone
Blinding of participants and personnel (performance bias)
All outcomes
High risk

No blinding of participants (dark/white chocolate)

All clinical investigations, dietary assessments, laboratory tests, data collection, and data analysis were performed by physicians and trained staff who were blinded to group assignment.

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Participants received no information about their examination data and the exact objective of the study until trial completion. Participants were instructed that disclosing their group assignment to investigators would result in exclusion from the study. To further minimize the confounding influence of alerting reactions on BP, measurements were performed at a separate location outside the physician’s office and not associated with usual patient care."

Al-Faris 2008

Methods

P

SB

Participants

Community setting, Riyadh University for girls, Saudi Arabia

Eligibility: healthy

Intervention: N = 30; age: 21 (SD = 2.0); male: 0%

Control: N = 30; age: 22 (SD = 1.8); male: 0%

Normotensive (mean baseline BP = 115.5/73 mmHg)

Interventions

1. 100 g dark chocolate (50%; 500 mg flavanols)
2. 90 g white chocolate (0 mg flavanols); daily

Duration: 15 days

OutcomesResting SBP and DBP (position not stated) after 15 days;
Primary outcome measure
NotesFunding not reported
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised.
Sequence generation not described
Allocation concealment (selection bias)Unclear riskInsufficient information provided
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up
Selective reporting (reporting bias)Low riskBP reported at beginning and end of intervention
Other biasUnclear riskInfluence of funding body unclear
Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding of participants
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Crews 2008

Methods

P

DB

Participants

Community setting, Virginia, USA

Eligibility: healthy

N = 90

Age: 69 (SD = 8.3)

Male: 42%

Normotensive (mean baseline BP = 127.5/74.5 mmHg)

Interventions

1. High-flavanol dark chocolate bars (37.0 g; containing 60% cacao; 755 mg flavanols) and cocoa beverage (12 g cocoa)
2. Low-flavanol ( 41 mg flavanols) placebos matched for appearance, smell, taste, and caloric content; daily.

Duration: 6 weeks

OutcomesSeated resting SBP and DBP (left upper arm) after 3 and 6 weeks
NotesIndustry research grant. The authors declared no conflict of interest.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputerised randomisation of the products was conducted by an independent researcher
Allocation concealment (selection bias)Low risk"The boxes and containers containing the products (and their randomization numbers, 1–101) were subsequently issued to participants in an ascending and sequential order as they entered the study (at the time of their pretreatment baseline assessments)."
Incomplete outcome data (attrition bias)
All outcomes
Low risk11% (11 of 101) lost to follow-up. 10 withdrew, 1 was excluded from analysis due to non-compliance
Selective reporting (reporting bias)Low riskBP reported at start, middle, and end of study
Other biasUnclear riskIndustry-funded
Blinding of participants and personnel (performance bias)
All outcomes
Low riskPlacebos were matched for appearance (e.g. colour and quantity), smell, taste, and caloric content
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAdequate

Davison 2008a

Methods

P

DB

Participants

Study dates: 9/05-12/16

Community setting, Adelaide, Australia

Eligibility: sedentary, overweight

Intervention: N = 12; age: 45 (SD = 4.4); male: 33%

Control: N = 11; Age: 44 (SD = 4.4); male: 27%

Normotensive (mean baseline BP = 124/76.5 mmHg)

Interventions

1. HiFl drink (902 mg flavanols)
2. LoFl drink (36 mg flavanols); daily

Duration: 12 weeks

Outcomes

Resting supine SBP and DBP at 6 and 12 weeks

Primary outcome measure

Notesno exercise
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Volunteers were block-matched into 2 groups according to BMI, gender, age and BP. The groups were then randomised to the daily consumption.

Sequence generation not described

Allocation concealment (selection bias)Unclear riskInsufficient information provided
Incomplete outcome data (attrition bias)
All outcomes
High risk21% (14/65) lost to follow-up
Selective reporting (reporting bias)Low riskChange of BP from baseline reported
Other biasUnclear riskManufacturer (Mars Inc.) provided the cocoa drinks and financial support
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind. Cocoa beverages were matched for taste and appearance
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAdequate

Davison 2008b

Methods

P

DB

Participants

Study dates: 9/05-12/16

Community setting, Adelaide, Australia

Eligibility: sedentary, overweight

Intervention: N = 13; age: 45 (SD = 3.0); male: 31%

Control: N = 13; age: 46 (SD = 4.0); male: 46%

Normotensive (mean baseline BP = 124/76 mmHg)

Interventions

1. HiFl drinks (902 mg flavanols); in addition to physical exercise
2. LoFl drinks (36 mg flavanols); daily; in addition to physical exercise

Duration: 12 weeks

Outcomes

Resting supine SBP and DBP at 6 and 12 weeks

Primary outcome measure

NotesIntervention in addition to physical exercise; Manufacturer (Mars Inc.) provided the cocoa drinks and financial support.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Volunteers were block-matched into 2 groups according to BMI, gender, age and BP. The groups were then randomised to the daily consumption

Sequence generation not described.

Allocation concealment (selection bias)Unclear riskInsufficient information provided
Incomplete outcome data (attrition bias)
All outcomes
High risk21% (14/65) lost to follow-up
Selective reporting (reporting bias)Low riskChange of BP from baseline reported
Other biasUnclear riskIndustry-funded
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind. Cocoa beverages were matched for taste and appearance
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAdequate

Grassi 2008

Methods

C

SB

Participants

Hospital outpatients setting, L'Aquila, Italy

Eligibility: hypertensive, impaired glucose tolerance

N = 19

Age: 45 (SD = 8)

Male: 58%

Hypertensive (Mean baseline BP = 141/91 mmHg)

Interventions

1. 100 g flavanol-rich dark chocolate bars (1080 mg flavanols)
2. 100 g flavanol-free (0 mg) white chocolate bars; daily.

Duration: 15 days

Outcomes

24-hour automated ambulatory SBP and DBP, in addition to seated SBP and DBP; after 15 days.

Primary outcome measure

NotesSupported by the Italian government (Ministero della Universita´e della Ricerca Scientifica) and the US government (USDA Agricultural Research Service). The dark chocolate bars were donated by the manufacturer. The authors declared no conflict of interest.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Randomised.

Sequence generation not described

Allocation concealment (selection bias)Low risk"Chocolate doses for each subject were rolled in aluminium foil and administered in dated, sequentially numbered, nontransparent boxes not labelled with regard to content. Involved physicians and staff were unaware of the group assignment."
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up
Selective reporting (reporting bias)Low riskBP reported at beginning and end of intervention
Other biasLow risknone
Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding of participants, only of personnel. Participants did not receive information regarding the chocolate and were instructed not to disclose their assigned group to investigators
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAdequate

Muniyappa 2008

Methods

C

DB

Participants

Community setting, Bethesda, USA

Eligibility: hypertensive

N = 20

Age: 51 (SEM = 1.5)

Male: 40%

Hypertensive (mean baseline BP = 141/91 mmHg)

Interventions

1. 31 g cocoa drink powder mixed in 150 mL warm water (902 mg flavanols)
2. 31 g matching placebo drink powder mixed in 150 mL warm water (28 mg total flavanols); daily

Duration: 2 weeks

Outcomes

Resting (seated) SBP and DBP (on nondominant arm) measured 3 times a week

Primary outcome measure

NotesSupported by the US government (Intramural Research Program, NCCAM, NIH, and Office of Dietary Supplements, NIH). Cocoa and placebo preparations provided by manufacturer (Mars Inc.), not involved in research.The authors declared no conflict of interest.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskBlock randomisation by NIH Clinical Center Pharmacy
Allocation concealment (selection bias)Low riskAssignment codes were not available to investigators until 20 participants completed the entire study and the database had been completed and secured
Incomplete outcome data (attrition bias)
All outcomes
High risk31% (9/29) participants completed the study
Selective reporting (reporting bias)Unclear riskBP measured 3 times a week, but only outcomes at baseline and after 2 weeks treatment reported
Other biasLow risknone
Blinding of participants and personnel (performance bias)
All outcomes
Low risk"The cocoa and placebo drinks were similar in colour, taste, and packaging and participants were blinded to treatment assignment. Participant blinding was assessed by a questionnaire administered at the end of 6 wks that asked participants to indicate which treatment they believed they received during each of the 2 phases (cocoa, placebo, or uncertain)."
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskIn addition to monitoring BP in the outpatient clinic, participants were required to self-monitor their blood pressure at home using a portable BP device

Monagas 2009

Methods

C

SB

Participants

Hospital outpatients setting, Barcelona, Spain

Eligibility: diabetes, or >=3 CVD risk factors

N = 25

Age: 70

Male: 45%

Prehypertensive (mean baseline BP = 138/84 mmHg)

Interventions

1. 40 g cocoa powder (495 mg flavanols) in milk
2. Only milk (0 mg flavanols); daily

Duration: 4 weeks

OutcomesResting SBP and DBP (position not stated) after 4 weeks,
Secondary outcome measure
NotesSupported by grants from the Spanish Ministries of Education and Science and Innovation. Funding body not involved in the study. No conflict of interest
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Randomised

Sequence generation not described

Allocation concealment (selection bias)Low riskAllocation concealment achieved by using closed envelopes with correlative numbers by prespecified subgroups of sex and age
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up
Selective reporting (reporting bias)Low riskBP reported at beginning and end of intervention.
Other biasLow risknone
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo blinding of participants, but blinding of personnel: The clinical investigators and laboratory technicians were blinded to the interventions
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAdequate

Ried 2009

Methods

P

SB

Participants

Study dates: 6/07-12/07

Community setting, Adelaide, Australia

Eligibility: (pre-)hypertensive

Intervention: N = 11; age: 49 (SD = 12.2); male: 64%

Control: N = 10; age: 58 (SD = 13.4); male: 50%

Prehypertensive (mean baseline BP = 135.5/81 mmHg)

Interventions

1. 50 g dark chocolate (70%) (750 mg flavanols)
2. Placebo pill (0 mg flavanols); daily

Duration: 8 weeks

Outcomes

Resting supine SBP and DBP at 4 and 8 weeks

Primary outcome measure

NotesChocolate provided by manufacturer (Haigh's Chocolates, Adelaide). Manufacturer did not provide funding and were not involved in study design, data collection, analysis or preparation of the manuscript. The authors stated that they had no conflict of interest.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskParticipants were randomly allocated by permuted block randomisation using the SAS 9.1 software package.
Allocation concealment (selection bias)Low riskTo conceal allocation from investigators, trained staff not involved in trial design and analysis handed out intervention packs to participants
Incomplete outcome data (attrition bias)
All outcomes
Low risk8% (4/39) lost to follow-up/ withdrawal
Selective reporting (reporting bias)Low riskBP data reported comprehensively
Other biasLow risknone
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding of participants to chocolate was impractical, however blinding of participants in the capsule groups was achieved by identical packaging of active tomato extract and placebo capsules. Control group and personnel blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAdequate

Shiina 2009

Methods

P

SB

Participants

Community setting, Chiba, Japan

Eligibility: males

Intervention: N = 20; age: 29 (SD = 3.4); male: 100%

Control: N = 19; age: 30 (SD = 4.5); male: 100%

Normotensive (Mean baseline BP = 119/68.5 mm Hg)

Interventions

1. 45 g dark chocolate (80%) (550 mg flavanols)
2. 35 g white chocolate (0 mg flavanols); daily

Duration: 2 weeks

OutcomesResting SBP and DBP (position not stated) after 2 weeks;
Secondary outcome measure
NotesSponsor not involved in data collection and analysis. No conflict of interest
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Randomised

Sequence generation not described

Allocation concealment (selection bias)Unclear riskInsufficient information provided
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up
Selective reporting (reporting bias)Low riskBP reported at beginning and end of intervention
Other biasLow risknone
Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were not blinded (dark/white chocolate)
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAdequate

Bogaard 2010

Methods

C

DB

Participants

Study dates: 11/08-10/09

Community setting, Amsterdam, Netherlands

Eligibility: (pre-)hypertensive

n=41

Age: 62 (SD = 4.5)

Male: 76%

Hypertensive (mean baseline BP = 142/84 mmHg)

Interventions

1. High flavanol drink (529 mg flavanols)
2. Low flavanol drink (0 mg flavanols); daily

Duration: 3 weeks

OutcomesResting (seated) SBP and DBP (on nondominant arm) after 3 weeks; 24-hour automated ambulatory SBP and DBP (on nondominant arm) after 3 weeks;
Primary outcome measure
NotesMean of theobromine-enriched chocolate group (TEC) + natural dose theobromine chocolate group (NTC); Sponsored by manufacturer (Unilever); one co-author (but none of the investigators) employed by Unilever; The contractual agreement between the Academic Medical Center and Unilever allowed the sponsor to review and comment on the article, but the investigators remained responsible for its contents and decision to submit the results for publication.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskTest product allocation and order of treatment were determined by a computer- generated randomised schedule
Allocation concealment (selection bias)Low riskTest products were provided in sequentially-numbered sealed bottles
Incomplete outcome data (attrition bias)
All outcomes
Low risk4% (2/42) lost to follow-up
Selective reporting (reporting bias)Low riskBP reported at beginning and end of intervention
Other biasUnclear riskIndustry-funded and co-authored
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe different test products all had similar taste and appearance
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAll of the haemodynamic measurements were performed by a single investigator, blinded for treatment allocation

Davison 2010

Methods

P

DB

Participants

Community setting, San Franscisco, USA

Eligibility: coronary artery disease

Group 1 (33 mg flavanol): N = 14; age: 53 (SD = 6.7); male: 71%

Group 2 (372 mg flavanol): N = 12; age: 56 (SD = 14.2); male: 58%

Group 3 (712 mg flavanol) N = 13; age: 60 (SD = 13.7); male: 62%

Group 4 (1052 mg flavanol): N = 13; sage: 57 (SD = 9.7); male: 54%

Hypertensive (mean baseline BP = 144/85.5 mmHg)

Interventions

Cocoa drink containing 33 mg/372 mg flavanol/712 mg flavanol/1052 mg flavanol; daily

Duration: 6 weeks

Outcomes

Seated clinic DBP and SBP (non-dominant arm) after 3 and 6 weeks; 24-hour automated ambulatory SBP and DBP (non-dominant arm) after 3 and 6 weeks

Primary outcome measure

NotesTrial received funding from industry. The authors declared no conflict of interest
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation of groups was undertaken independently of group minimisation procedure by separate staff members of the research centre not otherwise involved with the trial
Allocation concealment (selection bias)Low riskTrial investigators remained blinded to treatment allocation until after the completion of data analysis
Incomplete outcome data (attrition bias)
All outcomes
Low risk12% (7/59) lost to follow-up: 5 withdrawals, 1 exclusion due to non-compliance (deliberate weight loss), 1 exclusion due to gastric complaints
Selective reporting (reporting bias)Low riskBP reported for each assessment point (baseline, week 3, week 6)
Other biasUnclear riskIndustry-funded
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe reconstituted cocoa beverages were matched for appearance and taste
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAdequate

Heiss 2010

MethodsC
DB
Participants

Community setting, San Franscisco, USA

Eligibility: coronary artery disease

N = 16

Age: 64 (SD = 3)

Male: 19%

Prehypertensive (mean baseline SBP = 131.5 mmHg; no DBP given)

Interventions

1. High flavanol drink (750 mg flavanols)
2. Low flavanol (18 mg flavanols) drink; daily

Duration: 4 weeks

Outcomes

Resting supine SBP and DBP after 30 days

Tertiary outcome measure

NotesThis study was supported by a grant from the American Heart Association, and an unrestricted research grant from Mars, Inc. Two authors received funding from industry, and one author is employed by Mars.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomisation and dispensing of cocoa drinks were performed by the Department of Pharmacology. Sequence generation not described.
Allocation concealment (selection bias)Unclear riskInsufficient information provided
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk6% (1/17) lost to follow-up
Selective reporting (reporting bias)Low riskBP reported at beginning and end of intervention
Other biasHigh riskIndustry-funded and co-authored
Blinding of participants and personnel (performance bias)
All outcomes
Low riskAll drinks were similar in taste. Participants and investigators were masked throughout the study with regard to flavanol content of the test drinks
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAdequate

Njike 2011

Methods

C

DB

Participants

Study dates: 08/05-06/06

Community setting, Derby, USA

Eligibility: overweight

N = 38

Age = 52.5 (SD = 10.4)

Male: 15%

Normotensive (mean baseline BP = 123/68 mmHg)

Interventions

1. High flavanol drink (805 mg flavanols)
2. Low flavanol (9 mg flavanols) drink; daily

Duration: 6 weeks

OutcomesResting supine SBP and DBP after 6 weeks;
Secondary outcome measure
NotesGrant funding from manufacturer Hershey. One author received speaker's fee.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk44 participants were randomly assigned using a computer-generated random number sequence
Allocation concealment (selection bias)Unclear riskInsufficient information provided
Incomplete outcome data (attrition bias)
All outcomes
Low risk16% (7/44) lost to follow-up
Selective reporting (reporting bias)Low riskBP reported at beginning and end of intervention
Other biasUnclear riskIndustry-funded
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAdequate

Almoosawi 2012a

Methods

C

SB

Participants

Community setting, Cambridge, UK

N=21

Age: not provided

Male: 0%

Normotensive (Mean baseline BP: 107/70 mm Hg)

Interventions

Polyphenol-rich dark chocolate (500 mg polyphenol)
Polyphenol-free /placebo dark chocolate

The placebo was a dark chocolate matched for taste, texture, colour and macronutrient composition to the polyphenol-rich DC, but which contained no polyphenols.

Duration: 8 weeks

Outcomes

A validated automated A&D Medical UA-767 BP monitor (A&D medical, San Jose, CA, USA) was used to measure BP after a rest of 10 min. Three values were taken at 2 min intervals

Secondary

NotesBMI < 25 (Subgroup 1); The authors declare no conflicts of interest. Funding source not given, except for a manufacturer supplying the chocolate products. The authors declare no conflicts of interest.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskFollowing a 1-week run-in phase, eligible people were randomly assigned
Allocation concealment (selection bias)Unclear riskNo information on allocation concealment given
Incomplete outcome data (attrition bias)
All outcomes
Low risk1/22 (5%) lost to follow-up
Selective reporting (reporting bias)Low riskBP reported at beginning and end of intervention
Other biasUnclear riskFunding unclear
Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk"Single-blinded", but unclear who was blinded. Judging from the elaborate placebo, the investigators appear to have been unblinded
Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk"Single-blinded", but unclear who was blinded. Judging from the elaborate placebo, the investigators appear to have been unblinded

Almoosawi 2012b

Methods

C

SB

Participants

Community setting, Cambridge, UK

N = 21

Age: not provided

Male: 0%

Normotensive (mean baseline BP = 119/76 mmHg)

Interventions

1. Polyphenol-rich dark chocolate (500 mg polyphenol)
2. Polyphenol-free /placebo dark chocolate, matched for taste, texture, colour and macronutrient composition to the polyphenol-rich DC, but which contained no polyphenols

The placebo was a dark chocolate

Duration: 8 weeks

OutcomesAs in Almoosawi 2012a
NotesBMI > 25 (Subgroup 2)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskFollowing a 1-week run-in phase, eligible people were randomly assigned
Allocation concealment (selection bias)Unclear riskNo information on allocation concealment given
Incomplete outcome data (attrition bias)
All outcomes
Low risk1/22 (5%) lost to follow-up
Selective reporting (reporting bias)Low riskBP reported at beginning and end of intervention
Other biasUnclear riskFunding unclear
Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk"Single-blinded", but unclear who was blinded. Judging from the elaborate placebo, the investigators appear to have been unblinded
Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk"Single-blinded", but unclear who was blinded. Judging from the elaborate placebo, the investigators appear to have been unblinded

Desideri 2012

Methods

P

DB

Participants

Hospital setting: Alzheimer unit, L'Aquila, Italy

Eligibility criteria: Mild cognitive impairment, Petersen criteria

Intervention: N = 30; age: 71.2 (SD = 4.9); male: 47%

Control: N = 30; age: 71.0 (SD = 4.5); male: 53%

Hypertensive (mean baseline BP = 141/85 mmHg)

Interventions

1. High flavanol drink (990 mg flavanols)
2. Very low flavanol drink (48 mg flavanols)

Duration: 8 weeks

Outcomes

Seated rested SBP and DBP after 8 weeks;

Secondary outcome measure

NotesStudy was supported by industry grant (Mars Inc), who supplied high/low flavanol powder. One of the authors is employed by Mars Inc
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputerised randomisation of the products was conducted by an independent researcher
Allocation concealment (selection bias)Low riskPersonnel not involved in the trial labelled identical boxes containing individual anonymised sachets. The boxes were subsequently issued to participants in an ascending and sequential order as they entered the study (at the time of their pre-treatment baseline assessments). Neither the treating physicians, nor the participants were aware of treatment allocation
Incomplete outcome data (attrition bias)
All outcomes
Low riskOnly 1 participant (1.1%) discontinued due to side effects
Selective reporting (reporting bias)Low riskBP reported at baseline and end of study
Other biasHigh riskIndustry-funded and co-authored
Blinding of participants and personnel (performance bias)
All outcomes
Low riskResearch staff, treating physicians, and the participants were blinded to treatment allocation. Drink powder was indistinguishable in taste and appearance
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information given

Khan 2012

Methods

C

Open-label, unblinded

Participants

Hospital setting, Barcelona, Spain

Eligibility criteria: >= 3 risk factors CVD

N = 42

Age: 69.7 (SD = 11.5)

Male: 45%

78% hypertensive; mean baseline BP = 138/84 mmHg (pre-hypertensive)

Interventions

1. 40 cocoa powder (495 mg polyphenol incl. 56.5 mg epicatechin) in 500 ml skimmed milk
2. 500 ml skimmed milk (0 mg flavanols)

Duration: 4 weeks

Outcomes

BP after 4 weeks

Secondary outcome measure

NotesStudy was supported by grants from the Spanish Ministries of Education and Science and Innovation.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, no further information given
Allocation concealment (selection bias)Unclear riskNo further information given
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to -follow-up
Selective reporting (reporting bias)Low riskBP reported at baseline and end of study periods
Other biasLow risknone
Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants unblinded. No information of blinding of research staff given
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information given

Mogollon 2013

Methods

P

DB

Participants

Study dates: 7/08-4/09

Hospital setting, Quebec, Canada

Eligibility: pregnancy

Intervention: N = 22; age: 28.7 (SD = 3.2); male: 0%, all pregnant women

Control: N = 20 ; age: 29.8 (SD = 3.6); male: 0%, all pregnant women

Normotensive (mean baseline BP = 109/69 mmHg)

Interventions

1. High-flavanol chocolate (400 mg flavanols)
2. Low-flavanol chocolate (60 mg flavanols)

Duration: 12 weeks

Outcomes

BP was measured by a trained, certified nurse blinded to treatment allocation, with an electronic monitor (Microlife 3 BTO-A) after 15 mins of rest, back supported, arm supported at the heart level, and cuff placed on the left upper arm

Primary outcome measure

NotesAll other authors declare that they have no conflicts of interest. Hospital employees
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskConcealed randomisation was generated using computer-aided block randomisation (block size was kept secret), under the responsibility of an independent statistician
Allocation concealment (selection bias)Low riskStatistician undertook treatment allocation independently of the trial team. All clinical investigations, laboratory analyses, data collection and assessment were blinded to the randomisation allocation
Incomplete outcome data (attrition bias)
All outcomes
Low risk2 women dropped out of the study for reasons not related to the intervention
Selective reporting (reporting bias)Low riskBP reported at beginning and end of intervention
Other biasLow risknone
Blinding of participants and personnel (performance bias)
All outcomes
Low riskChocolate placebo was identical to the experimental chocolate in its content for all other nutrients except for flavanols (including theobromine and caffeine contents), similar in taste and supplied in individual, opaque packaging
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAll clinical investigations, laboratory analyses, data collection and assessment were blinded to the randomisation allocation

Neufingerl 2013

Methods

P

DB

Participants

Study dates: 12/10-2/11

Community setting, Grenoble and Lyon, France

Eligibility: <10% CVD risk on European risk chart

Intervention: N = 10; age: 55.2 (SD = 8.2); male: 50%

Control: N = 10; age: 55.4 (SD = 8.7); male: 50%

Normotensive (mean baseline BP: 118/75 mmHg)

Interventions

1. 6 g cocoa as chocolate-flavoured (325 mg flavanoids) pasteurised acidified milk drink
2. Milk drink (0 mg flavanols)

Duration: 4 weeks

Outcomes24-hour ambulatory Mean BP
Notes4-group study, only cocoa and placebo group considered here, additional groups: theobromine only (850 mg), n = 10 and cocoa + theobromine (C+T) group, n = 10 (total theobromine 1000 mg); adverse events in n = 6 (C+T), N = 1 (T): nausea, vomiting, headache, diarrhoea, potentially related to high dose of theobromine. All authors were employed by Unilever R&D Vlaardingen at the time the research was conducted. Unilever has no products enriched with theobromine under development or on the market; however, it markets food products enriched with plant sterols to lower LDL cholesterol.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskPre-established blockwise randomisation schedule
Allocation concealment (selection bias)Low riskSequentially allocated by clinical investigator
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up
Selective reporting (reporting bias)Low riskBP reported at baseline and end of study
Other biasUnclear riskIndustry-supported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDrinks supplied in identical tinted bottles that were packed individually for each participant in a neutral box and labelled with the participant code; participants were instructed not to pour the drink into a glass but to consume it directly out of the tinted bottle.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information given

Sorond 2013

Methods

P

DB

Participants

Hospital setting, Neurology Research Unit, Boston, USA

Eligibility: Hypertension

N = 60

Age: 72.9 (SD = 5.4) yrs

Male: 48%

Normotensive (mean baseline BP = 125.5/69 mmHg)

Interventions

1. Flavanol-rich cocoa 1218 mg
2. Flavanol-poor cocoa 26 mg; daily

Duration: 4 weeks

OutcomesBP mean of 3 measurements with automated cuff
NotesControlled hypertensives (on BP medication); Supported by government grants from the National Institite on Aging and National Heart Lung and Blood Institute. Cocoa was provided by Mars Inc.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo details provided, unclear whether randomised
Allocation concealment (selection bias)High riskNo details provided
Incomplete outcome data (attrition bias)
All outcomes
Low riskLoss to follow-up: n = 2 (3%)
Selective reporting (reporting bias)Low riskBP at baseline, day 1 and end of the study
Other biasLow risknone
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble-blind, but no further details provided
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details provided

Esser 2014

Methods

C

DB

Participants

Community setting, Wageningen, Netherlands

Eligibility: overweight

N = 41

Age: 63 (SD = 5)

Male: 100%

Normotensive (mean baseline BP = 128/79 mmHg)

Interventions

1. High flavanol chocolate (1078mg flavanols)
2. Normal flavanol chocolate (259 mg flavanols), with a 4-week washout between consumption periods

Duration: 4 weeks

Outcomes

Brachial SBP, DBP, and heart rate (HR) were assessed automatically (Dinamap Pro 100; GE Healthcare, Little Chalfont, UK) for 10 mins with a 3-min interval;

Secondary outcome measure

NotesStudy was funded by Top Institute Food and Nutrition (Wageningen, The Netherlands). The chocolate used in this study was donated by Barry Callebaut (Lebbeke, Belgium). The authors declare no conflicts of interest.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Randomisation was performed by an independent research assistant using a computer-generated table. We constructed 25 blocks with a size of 2."
Allocation concealment (selection bias)Unclear riskNo information on allocation concealment given
Incomplete outcome data (attrition bias)
All outcomes
Low risk3/44 (7%) participants dropped out or were excluded, 1 due to medical reasons not related to the study, 1 due to dislike of the chocolate and 1 due to failure to adhere to the treatment
Selective reporting (reporting bias)Low riskBP reported at beginning and end of intervention
Other biasLow risknone
Blinding of participants and personnel (performance bias)
All outcomes
Low riskResearchers as well as participants were blinded to randomisation until after data analysis
Blinding of outcome assessment (detection bias)
All outcomes
Low riskResearchers as well as participants were blinded to randomisation until after data analysis.

Ibero-Baraibar 2014

Methods

P

DB

Participants

Study dates: 3/12-6/12

Community setting, Navarra, Spain

Eligibility: overweight

N = 47

Age: 57.3 (SD = 5.2)

Male: 46%

Normotensive (mean baseline BP: 120/80 mmHg)

Interventions

1. Meals supplemented with 1.4 g/day cocoa extract (645 mg total polyphenols/414mg total flavanols)
2. Control meals (0 mg polyphenols)

Duration: 4 weeks

Outcomes

BP was taken 3 times with automatic monitor (Intelli Sense. M6, OMRON Healthcare, Hoofddorp, Netherlands), to use the average value obtained from the last 2 measurements

Secondary outcome measure

NotesCo-funded by food industry and government. Conducted at seemingly independent research institutions.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe randomisation was performed using the “random between 1 and 2” function in the Microsoft Office Excel (Microsoft Iberica, Spain)
Allocation concealment (selection bias)Unclear riskNo information on allocation concealment given
Incomplete outcome data (attrition bias)
All outcomes
Low risk3/50 (6%) participants dropped out or were excluded, 1 due to personal reasons and 2 due to failure to adhere to the treatment
Selective reporting (reporting bias)Low riskBP reported at beginning and end of intervention
Other biasUnclear riskIndustry co-funded
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBoxes in which the meals were provided had the same appearance and differed only on the code label, ensuring the double-blind
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information on blinding of outcome assessment given

Nickols-Richardson 2014

Methods

P

Unblinded?

Participants

Study dates: 7/09-7/10

Community setting, Pennsylvannia, USA

Eligibility: overweight

N = 60

Age: 35.9 (SEM = 0.8)

Male: 0%

Normotensive (mean baseline BP = 118/73 mmHg)

Interventions

1. 236 mL natural cocoa beverage and 2.9 oz dark chocolate (270 mg flavanols)
2. 236 mL cocoa-free vanilla beverage and non-chocolate sweet snacks (0 mg flavanols)

Duration: 18 weeks

Outcomes

Seated systolic and diastolic BP;

Primary outcome measure

NotesCo-funded by food industry and public sources
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, but no further information given
Allocation concealment (selection bias)Unclear riskNo information on allocation concealment given
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk85% of the women completed the intervention with no difference between DC and NC groups in discontinuation rate
Selective reporting (reporting bias)Low riskBP reported at beginning and end of intervention
Other biasUnclear riskIndustry co-funded
Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants not blinded; no information on blinding of personnel given
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information on blinding of outcome assessment given

Sarria 2014a

Methods

C

unblinded

Participants

Community setting, Madrid, Spain

N = 24

Age: 27 (SD = 8.4)

Male: 46%

Normotensive (Mean baseline BP: 116/72 mmHg)

Interventions

1. Milk with cocoa (416 mg flavanols)
2. Milk only (0 mg flavanols)

Duration: 4 weeks

Outcomes

Seated systolic and diastolic BP

Secondary outcome measure

NotesSubgroup: Normal cholesterol; Funded by food industry. The authors stated that they had no conflict of interest.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, no further information
Allocation concealment (selection bias)Unclear riskNo further information on allocation concealment given
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk6/50 withdrew due to personal, health or professional reasons (numbers not provided by intervention groups)
Selective reporting (reporting bias)Low riskBP reported at beginning and end of intervention
Other biasUnclear riskIndustry funded
Blinding of participants and personnel (performance bias)
All outcomes
High riskLack of blinding of participants and investigators
Blinding of outcome assessment (detection bias)
All outcomes
High riskLack of blinding of participants and investigators

Sarria 2014b

Methods

C

Unblinded

Participants

Community setting, Madrid, Spain

N = 20

Age: 30 (SD = 9)

Male: 45%

Normotensive (mean baseline BP = 121/76 mmHg)

InterventionsAs in Sarria 2014a
OutcomesAs in Sarria 2014a
NotesSubgroup: High cholesterol; Funded by food industry. The authors stated that they had no conflict of interest.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, no further information
Allocation concealment (selection bias)Unclear riskNo further information on allocation concealment given
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk6/50 withdrew due to personal, health or professional reasons (numbers not provided by intervention groups)
Selective reporting (reporting bias)Low riskBP reported at beginning and end of intervention
Other biasUnclear riskIndustry funded
Blinding of participants and personnel (performance bias)
All outcomes
High riskLack of blinding of participants and investigators
Blinding of outcome assessment (detection bias)
All outcomes
High riskLack of blinding of participants and investigators

Heiss 2015a

Methods

P

DB

Participants

Community setting, Duesseldorf, Germany

Eligibility: healthy male

N = 22

Age: 26 (SEM = 1)

Male: 100%

Normotensive (mean baseline BP: 120/77 mmHg)

Interventions

1. Cocoa extract powder (900 mg flavanols) dissolved in water
2. Placebo powder (0 mg flavanols) dissolved in water

Duration: 2 weeks

Outcomes

Office blood pressure was measured 3 times after 10 mins of rest using an automated clinical digital sphygmomanometer (Dynamap, Tampa, FL, USA) with appropriately sized cuff placed around the upper arm at heart level

Primary outcome measure

NotesYoung subgroup; Co-funded by food industry and public sources. One author employed by the company that manufactures and markets the specific cocoa powder used in the study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskParticipants were randomly assigned, no further information
Allocation concealment (selection bias)Low riskAnonymised sachets in alphanumeric order
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants completed the study and all data were included in the analysis
Selective reporting (reporting bias)Low riskBP reported at beginning and end of intervention
Other biasHigh riskIndustry funded and co-authored
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe beverage mixes were provided in sachets labelled with an alphanumeric identifier to enable a double-masked study design
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information on blinding of outcome assessment given

Heiss 2015b

Methods

P

DB

Participants

Community setting, Duesseldorf, Germany

Eligibility: healthy male

N = 20

Age: 60 (SEM = 2)

Male: 100%

Prehypertensive (mean baseline BP = 131/82 mmHg)

Interventions

1. Cocoa extract powder (900 mg flavanols) dissolved in water
2. Placebo powder (0 mg flavanols) dissolved in water

Duration: 2 weeks

Outcomesas in Heiss 2015a
NotesElderly subgroup; Co-funded by food industry and public sources. One author employed by the company that manufactures and markets the specific cocoa powder used in the study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskParticipants were randomly assigned, no further information
Allocation concealment (selection bias)Low riskAnonymised sachets in alphanumeric order
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants completed the study and all data were included in the analysis
Selective reporting (reporting bias)Low riskBP reported at beginning and end of intervention
Other biasHigh riskIndustry funded and co-authored
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe beverage mixes were provided in sachets labelled with an alphanumeric identifier to enable a double-masked study design
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information on blinding of outcome assessment given

Koli 2015

Methods

C

Unblinded (no placebo, but reduced snack intake during study period)

Participants

Community setting, Helsinki, Finnland

Eligibility: hypertensive

N = 22

Age: 45.8 (SD = 8.3)

Male: 64%

Hypertensive (mean baseline BP = 142/89 mmHg)

Interventions

1. 49 g dark chocolate (70% cacao, 603 mg flavanols)
2. Reduced intake of habitual snacks only (no placebo) (0 mg flavanols)

Duration: 8 weeks

Outcomes

Clinical blood pressure and 24-hr ambulatory BP monitor measured, no details given on assessment of clinical BP;

Ambulatory 24-hour blood pressure was monitored on a day of standard physical activity, with an adequate cuff for the size of the participant’s arm. Welch Allyn ABPM 6100 (Welch Allyn Inc, USA) validated according to the protocol of the Finnish Hypertension Society

Primary outcome measure

NotesFunded by Finnish chocolate manufacturer Oy Karl Fazer
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe participants were randomly assigned to 1 of the 2 groups (denoting order of interventions) after stratification by sex and BMI. No details on random sequence generation provided
Allocation concealment (selection bias)High riskParticipants knew which group they were in before/after cross-over, not stated if researchers knew as well
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants completed the study and all data were included in the analysis
Selective reporting (reporting bias)Low riskBP reported at beginning and end of intervention
Other biasUnclear riskIndustry funded
Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were unblinded, no placebo; unclear if investigators were blinded
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information on blinding of outcome assessment given

Massee 2015

Methods

P

DB

Participants

Study dates: 8/13-9/14

Community setting, Melbourne, Australia

Eligibility: healthy

N = 38

Age: 24 (SD = 4.5)

Male: 33%

Normotensive (mean baseline BP = 119/71 mmHg)

Interventions

1. Active cocoa tablet (3058 mg cacao seed extract, 250 mg catechin polyphenols)
2. Placebo tablet, identical in appearance, size, texture and colour to cocoa tablet, containing inert cellulose powder (0 mg polyphenols)

Duration: 4 weeks

Outcomes

BP was assessed in a quiet, dedicated university laboratory following a 5-min rest period completed by participants in the supine position on an examination bed;

Secondary outcome measure

NotesFunded from public or charitable sources. Cocoa and placebo tablets provided by supplement company, not involved in study design, data collection, analysis and publication. Authors declare no conflict of interest.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskParticipants were randomly assigned to receive either active or placebo tablets using a computer-generated permuted block randomisation schedule
Allocation concealment (selection bias)Low riskIdentical bottles in alphanumerical order, packaged offsite by staff not involved in participant recruitment and testing
Incomplete outcome data (attrition bias)
All outcomes
Low risk5% (2/40) lost to follow-up, 1 each from intervention and control groups
Selective reporting (reporting bias)Low riskBP reported at beginning and end of intervention
Other biasLow risknone
Blinding of participants and personnel (performance bias)
All outcomes
Low riskPlacebo tablet (Identical in appearance, size, texture and colour to cocoa tablet, containing inert cellulose powder).
Blinding of outcome assessment (detection bias)
All outcomes
Low riskThe blinding code was only revealed after analysis of the main study

Mastroiacovo 2015

Methods

P

DB

Participants

Study dates: 12/06-7/08

Community setting, L'Aquila, Italy

Eligibility: cognitively intact, Mini-Mental-State-Examination Score < 27

N = 30 (high flavanol group), N = 30 (low flavanol group = control); (N = 30 intermediate flavanol group not included in this meta-analysis)

Age: 70 (SE = 0.8)

Male: 43%

Prehypertensive (mean baseline BP = 135/80 mmHg), incl. about 50% hypertensive

Interventions

1. Dry dairy-based beverage mixes with flavanol-rich cocoa powder (993 mg flavanols, Cocoapro processed cocoa powder; Mars Inc)
2. Highly processed, alkalised cocoa powder (48 mg flavanols)

Duration: 8 weeks

Outcomes

"Seated systolic and diastolic BP recorded in the morning with a validated oscillometric device with appropriately sized cuffs (Omron 705 CP; Omron Matsusaka) on the nondominant upper arm. These evaluations were performed by staff blinded to the study protocol. At each visit, participants rested 15 mins in a seated position, the first blood pressure measurement was taken but discarded, and the subsequent 3 consecutive blood pressure readings, taken at 3-min intervals, were recorded. The average of these latter measures was considered for statistical analysis."

Secondary outcome measure

NotesOne of the authors is employed by Mars Inc., a company with long-term research and commercial interests in cocoa flavanols.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo details on random sequence generation given
Allocation concealment (selection bias)Unclear riskNeither the treating physicians nor the participants were aware of treatment allocation. No further details provided
Incomplete outcome data (attrition bias)
All outcomes
Low risk1 discontinued trial, 0 lost to follow-up per group
Selective reporting (reporting bias)Low riskBP reported at beginning and end of intervention
Other biasHigh riskIndustry funded and co-authored
Blinding of participants and personnel (performance bias)
All outcomes
Low riskFood products were indistinguishable in appearance and had a flavanol content that was not obvious on the basis of flavour. Staff were blinded to the study protocol
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information on blinding of outcome assessment given

Rostami 2015

Methods

P

SB

Participants

Study dates: 3/11-2/12

Hospital setting, Tehran, Iran

Eligibility: type-2-diabetes, hypertension

Intervention: N = 32; age: 59 (SD = 9); male: 37.5%

Control: N = 28; age: 57 (SD = 8); male: 42.9%

Prehypertensive (Mean baseline BP = 137/86 mmHg)

Interventions

1. 25 g chocolate containing 83% cocoa solids
2. Iso-caloric white chocolate

no flavanol content given

Duration: 8 weeks

Outcomes

Systolic and diastolic blood pressure was reported on average of 2 properly measured in the right or left arm supported at the heart level of seated position after 10 mins of rest by a trained nurse using a mercury sphygmomanometer;

Primary outcome measure

NotesFunded by University. The authors stated that they had no conflict of interest.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskBlocked randomisation method
Allocation concealment (selection bias)Low riskThe participants were given chocolate bars containing either dark chocolate or white chocolate in the same package by blinded person to the same colour and shape
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk13% (8/60) lost to follow-up: intervention group: n = 2; control group: n = 6
Selective reporting (reporting bias)Low riskBP reported at beginning and end of intervention
Other biasLow risknone
Blinding of participants and personnel (performance bias)
All outcomes
High riskSB only personnel-blinded. The participants were given chocolate bars containing either dark chocolate or white chocolate in the same package by blinded person to the same colour and shape. Participants were aware unblinded to the intervention
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information on blinding of outcome assessment given

Rull 2015

Methods

C

DB

Participants

Community setting, London, UK

Eligibility: hypertension

N = 21

Age: 55 (SEM = 1.5)

Male: 100%

Prehypertensive (mean baseline BP = 135/85 mmHg)

Interventions

1. 50 g high flavanol (1064 mg) dark chocolate bars
2. 50 g low flavanol (88 mg) dark chocolate bars

Duration: 12 weeks

OutcomesAmbulatory blood pressure measurements (24-hour) were made during participant screening and at 6 and 12 weeks using a Spacelabs ABP monitor 90207 (Dolby UK, Stirling)
NotesThis study was supported by a grant from Barry Callebaut Belgium NV to one of the authors (R. Corder).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe randomisation schedule was sent as a password-protected file to Barry Callebaut, who prepared separate participant coded boxes for each phase of the study
Allocation concealment (selection bias)Unclear riskAll interventions were provided in anonymised sachets
Incomplete outcome data (attrition bias)
All outcomes
High riskHigh loss to follow-up; 11/32 participants (34%) due to failure to attend the clinic on the required day, or BP monitor recording failure at either 6 or 12 weeks
Selective reporting (reporting bias)Low riskBP reported at beginning and end of intervention
Other biasUnclear riskIndustry funded and co-authored
Blinding of participants and personnel (performance bias)
All outcomes
Low riskPlacebo-control chocolate specifically manufactured, suggested to be similar in appearance to intervention, both plain foil wrapped. The investigators were blinded to the randomisation schedule
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information on blinding of outcome assessment given

Sansone 2015

  1. a

    BMI: body mass index
    BP: blood pressure
    C: cross-over
    CVD: cardiovascular disease
    DB: double-blind
    DBP: diastolic blood pressure
    P: parallel
    SB: single-blind
    SBP: systolic blood pressure
    SD: standard deviation
    SEM: standard error of the mean

MethodsP
DB
Participants

Study dates: 2/13-8/14

Community / Hospital setting, Duesseldorf, Germany

Eligibility: healthy

N = 100

Age: 44.5 (SD = 8.5)

M: 52.4%

Normotensive (mean baseline BP = 123/77 mmHg)

Interventions

1. High flavanol (450 mg) drink
2. Low flavanol (0 mg) drink; daily

Duration: 4 weeks

Outcomes

Office BP was measured using an automated clinical digital sphygmomanometer (Dynamap) at the upper left arm in supine position, after 10 mins of rest in a quiet room with the arm at the heart level. 3 measurements were taken, the first discarded and the second and third averaged for further analysis.

Secondary outcome measure

NotesOne of the authors is employed by Mars Inc., a company engaged in flavanol research and flavanol-related commercial activities. None of the other authors has a conflict of interest to declare other than stated above.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskParticipants were randomly assigned to 1 of 2 parallel groups by block randomisation
Allocation concealment (selection bias)Low riskAll interventions were provided as drink powder in sachets to be freshly prepared by mixing with approximately 500 ml of water. The beverage mixes were provided in sachets (7 g = 1 serving) labelled with an alphanumeric identifier to enable a double-masked study design
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo information on compliance or dropouts reported
Selective reporting (reporting bias)Low riskBP reported at beginning and end of intervention
Other biasHigh riskIndustry funded and co-authored
Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants and investigators were masked throughout the study for flavanol content of the test drinks
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information on blinding of outcome assessment given

Characteristics of excluded studies [author-defined order]

StudyReason for exclusion
Farouque 2006Data for meta-analysis not available (mean SBP/DBP, SD)
Wang-Polagruto 2006Low quality (50% lost to follow-up, small sample size)
Flammer 2007Duration < 2 weeks, acute effects of cocoa, (heart transplant patients)
Balzer 2008Data for meta-analysis not available (mean SBP/DBP, SD)
Erdman 2008High cocoa dosage in control group, cocoa+plant sterols vs cocoa; same study as Allen 2008
Faridi 2008Duration < 2 weeks, acute effects of cocoa
Almoosawi 2010High cocoa dosage in control group
Berry 2010Duration < 2 weeks, acute effects of cocoa
Desch 2010Control group 25% flavanol content (6 g dark chocolate) vs intervention group (25 g dark chocolate)
Sudarma 2011No true control group: dark chocolate bar versus dark chocolate bar plus lycopene or dark chocolate bar plus lycosome
Curtis 2013Combination treatment of chocolate (850 mg flavanols) plus 100 mg isoflavones daily for 1 year in active group
D'Anna 2014Combination treatment of cocoa (30 mg) + isoflavanols (80 mg) + myo-inositol (2g) in active group
Pereira 2014No intervention in control group
Petyaev 2014No true control group: flavanol/polyphenol content in active group intervention not provided; dietary polyphenol intake similar in active and control groups
West 2014Acute BP after 2 hours
Wirtz 2014Acute BP
Grassi 20155-week cross-over trial of different cocoa dosages and placebo, each taken 1 week
Lee 2016conference abstract only, insufficient information
Leyva-Soto 2016conference abstract only, insufficient information
Suh 2014cohort study, not randomized, only conference abstract, insufficient information
Grassi 2016Duration < 2 weeks
Kuebler 2016Duration < 2 weeks
Sanguigni 2016Duration < 2 weeks
Sanchez-Aguadero 2016Duration < 2 weeks, no separate chocolate intervention

Characteristics of studies awaiting assessment [ordered by study ID]

Campbell 2016

Methods6-week clinical trial
Participantsnine panelists (age: 22.6 ± 1.7; BMI: 22.3 ± 2.1)
Interventionschocolate-protein beverages once per week, including placebo, whey protein isolate (WPI), low polyphenolic cocoa (LP), high polyphenolic cocoa (HP), LP-WPI, and HP-WPI
Outcomesblood glucose and adiponectin levels, and hunger ratings at baseline and 0.5–4.0 h following beverage consumption
Notes 

De Palma 2016

Methodssingle-centre randomized double-blind placebo-controlled investigation with a crossover design
ParticipantsThirty-two patients with chronic HF, stable on guideline-directed medical therapy, were randomized. Twenty-four patients completed the study
Interventions50 g/day of high-flavanol dark chocolate (HFDC; 1064 mg of flavanols/day) or low-flavanol dark chocolate (LFDC; 88 mg of flavanols/day) for 4 weeks and then crossed over to consume the alternative dark chocolate for a further 4 weeks
Outcomesreductions in N-terminal pro-B-type natriuretic peptide (NT-proBNP) as an index of improved cardiac function. Changes in blood pressure. Effect on platelet function.
Notessupported by a grant from Barry Callebaut Belgium NV

Flammer 2012

Methods4 week double-blind, randomized placebo-controlled trial
ParticipantsTwenty-two patients with stable CHF (NYHA ≥ II) and ejection fraction <50% have been randomized. Two patients dropped out during follow-up. Twenty patients were included into the final analysis.
Interventionstwo chocolate bars/day commercially available flavanol-rich chocolate compared with cocoa-liquor-free control chocolate
Outcomesendothelial function; platelet function; blood pressure; heart rate
Notes 

Noad 2016

Methods12-week randomised controlled, single-blinded dietary intervention design
Participants92 participants aged 40–65 years, with documented grade I (140–159/90–99 mm Hg) or grade II (160–179/100–109 mm Hg) hypertension
InterventionsThe study commenced with a four-week ‘run-in phase’ for all participants, during which they were asked to consume two portions or less of F&V, and to exclude berries and dark chocolate (low-polyphenol diet). At the end of this period, subjects were randomised to continue with the above low-polyphenol diet for a further 8-week ‘intervention period’ or to consume a high-polyphenol diet of six portions F&V (including one portion of berries per day) and 50 g of dark chocolate per day
OutcomesThe primary endpoint was between-group change in maximum FBF response to the endothelium-dependent vasodilator, ACh. Secondary endpoints included between-group change in self-reported polyphenol-rich food intake, between-group change in biochemical markers of nutritional status and between-group change in SBP and lipid profile
NotesNCT01319786

Ottaviani 2015

Methods

Part 1 was an open-label, intake-amount escalation study.

Part 2 was a controlled, randomized, double-masked, 2-parallel-arm dietary intervention study

Participants34 healthy adults aged 35-55 years
Interventions

Part 1: consume escalating amounts of cocoa flavanol, ranging from 1000 to 2000 mg/d over 6 wk

Part 2: consume for 12 consecutive weeks up to 2000 mg cocoa flavanol per day (n = 46) or a CF-free control (n = 28)

Outcomes

Primary outcomes were blood pressure and platelet function, select metabolic variables, and the occurrence and severity of AEs.

Secondary outcomes included plasma concentrations of CF-derived metabolites and methylxanthines

Notes 

Pearson 2016

Methods12-week randomised, controlled, parallel study
Participants102 non-obese participants
Interventions4 arms: ˜1100 kJ/day for each of hazelnuts (42 g), chocolate (50 g), potato crisps (50 g), or no added snack food
OutcomesDiet records, body composition, and physical activity were measured at baseline and week 12
Notes 

Petrilli 2016

Methodscross-over, placebo-controlled, double-blind, randomized clinical trial
Participants92 individuals on antiretroviral therapy for at least six months and at viral suppression
Interventions65 g of chocolate or chocolate-placebo or 3 g of yerba mate or mate-placebo for 15 days each, alternating by a washout period of 15 days
Outcomesdata regarding anthropometry, inflammatory, oxidative and immunological parameters were collected at baseline, and at the end of each intervention regimen. High-sensitivity C-reactive protein, fibrinogen, lipid profile, white blood cell profile and thiobarbituric acid reactive substances were assessed
Notes 

Rassaf 2016

Methodsrandomized, double-blind, placebo-controlled trial
ParticipantsFifty-seven participants with ESRD
Interventionsingested CF-rich beverages (900 mg CF per study day), compared with those ingesting CF-free placebo
Outcomeschanges in flow–mediated dilation and hemodynamics
Notesindependent investigator–initiated trial without any commercial interest

Characteristics of ongoing studies [ordered by study ID]

ACTRN12607000239460

Trial name or titleThe effect of long term intervention with cocoa flavanols on metabolic control and cardiovascular parameters in subjects with and without type 2 diabetes
MethodsRandomised controlled trial
ParticipantsRandomisation among groups with and without diabetes
InterventionsHigh flavanol supplement:low flavanol supplement
OutcomesSystolic and diastolic blood pressure
Starting date2007
Contact informationDr Anne Reutens, Baker IDI Heart and Diabetes Institute, 250 Kooyong Road Caulfield VIC 3162, anne.reutens@bakeridi.edu.au
NotesSponsor: Mars Symbioscience, a division of Mars Incorporated

Farhat 2012

Trial name or titleEffect of Polyphenol-rich Dark Chocolate on Insulin Sensitivity in Normal Weight and Overweight Adults
Methods

Duration: 4 weeks

Allocation: Randomized

Intervention Model: Parallel Assignment

Masking: Single Blind (Participant)

Participants

61 Adults with no history of hypertension, diabetes and cardiovascular diseases

  • BMI from 18-24.9 and BMI >25

  • Males and Females

  • Age: 18-65 years

Interventions

Experimental: Polyphenol-rich Dark chocolate: Participants will be asked to consume 20g of dark chocolate containing 500mg of polyphenols daily for a period of 4 weeks

Placebo Comparator: Placebo Dark chocolate: Participants will be asked to consume 20g of dark chocolate containing little or no polyphenols for a period of 4 weeks

OutcomesPrimary Outcome Measures: Determine if the consumption of DC rich in polyphenols can induce a change in insulin sensitivity [ Time Frame: Baseline and week 4 ]Insulin sensitivity will be determined by determined by HOMA-IR (Homeostasis Model of Assessment - Insulin Resistance)

Secondary Outcome Measures: Determine if the consumption of DC rich in polyphenols can induce a change in glucose levels [ Time Frame: Baseline and week 4 ]
Determine if the consumption of DC rich in polyphenols can induce a change in Lipid profile (TC, HDL, LDL & TG) [ Time Frame: Baseline and week 4 ]
Determine if the consumption of DC rich in polyphenols can induce a change in oxidized LDL levels [ Time Frame: Baseline and week 4 ]
Determine if the consumption of DC rich in polyphenols can induce a change in BMI and Waist circumference [ Time Frame: Baseline and week 4 ]
Determine if the consumption of DC rich in polyphenols can induce a change in blood pressure [ Time Frame: Baseline and week 4 ]
Determine if the consumption of DC rich in polyphenols can induce a change in salivary cortisol-to-cortisone ratio [ Time Frame: Baseline and week 4 ]
Determine if the consumption of DC rich in polyphenols can induce a change in high sensitivity CRP [ Time Frame: Baseline and Week 4 ]
Starting dateMarch 2012
Contact informationGrace Farhat, PhD research student, Queen Margaret University, Musselburgh, East Lothian, United Kingdom, EH21 6UU
Notes 

ISRCTN12092733

Trial name or titleImpact of High Energy Nutritional Supplement Drink (HENSD) consumed for five consecutive days on appetite, energy intake and cardiometabolic risk factors in underweight females
MethodsSingle-blinded randomised controlled crossover study
Participants22 Healthy women with body mass index of 17- 20 kg/m2
Interventions

1. HENSD (Scandishake, Chocolate, Nutricia) made up with 240 g of full fat milk, according to the manufacturer instructions (Nutricia, 2009)

2. Placebo (a low calorie drink prepared with 240 g of skimmed milk, 4 g of cocoa and two sweeteners)

Outcomes

Primary:

1. Fasting lipids, postprandial lipaemia, insulin resistance

2. Energy intake and body mass

Secondary:

1. Appetite measures

2. Metabolic rate

Starting date12/02/2014
Contact information

Dr Sadia Fatima

Human Nutrition Section
School of Medicine College of Medical
Veterinary and Life Sciences
(MVLS)
New Lister Building
Glasgow Royal Infirmary10-16 Alexandra Parade.
Glasgow
G31 2ER
United Kingdom
-
s.fatima.1@research.gla.ac.uk

Notes 

ISRCTN32888088

Trial name or titleAn investigation into the effects of chronic consumption of cocoa flavonoids on vascular function: a randomised controlled trial
MethodsRandomised controlled trial
Participants16 Non-smoking postmenopausal women aged between 48 and 65 years
Interventionscocoa powder
Outcomes

Primary:

Blood pressure taken at the beginning and end of each intervention period.

Secondary:

Arterial stiffness, flow mediated dilatation, plasma ICAM-1, VCAM-1, C-reactive protein, P-selectin, 8-isoprostane F2 α, lipids and urinary 8-isoprostane F2

Starting date24/08/2006
Contact information

Dr Ummezeinab Mulla

zeinab.mulla@imperial.ac.uk

Professor Thomas Sanders

tom.sanders@kcl.ac.uk

Notes 

NCT00125866

Trial name or titleThe effect of cocoa flavanoids on blood pressure
MethodsRCT double-blind parallel
ParticipantsChildren, adults, elderly people with hypertension, n = 50
InterventionsFlavonoid-rich cocoa drink vs low-flavanoid drink daily for 12 weeks
OutcomesPrimary: mean diff 24-hour AMBP;
Secondary: cholesterol, glucose, insulin, echocardiogram, PWV
Starting dateSep 2005
Contact informationNeil R Poulter, Imperial College London, Paddington, IK W21PG
NotesSponsor: MasterFoods

NCT01276951

Trial name or titleControlled clinical trial to determine the effective dose of cocoa in lowering blood pressure
MethodsRCT, double-blind, parallel
ParticipantsAdults 18 - 65 yrs, I-II hypertension
Interventions6.5 g, 12 g, 25 g, or 50 g (change of groups every 2 weeks) of chocolate for 18 weeks
OutcomesPrimary: blood pressure inpatient
Starting date12/2008
Contact informationMonica Lucia Giraldo Restrepo, Universidad de Antioquia, Colombia
NotesSponsor: Universidad de Antioquia

NCT01754662

Trial name or titleA Pilot Study Investigating the Effects of the Combined Effects of Cocoa and Soy Polyphenols in a Soy Protein Matrix on Insulin Resistance and Cardiovascular Disease Risk in Type 2 Diabetes
Methods8-week Randomised Placebo-Controlled Double-Blind Parallel Study
Participants84 Patients with type 2 diabetes controlled by diet or metformin only, Stable medication history for 3 months prior to screening visit, Age 45-80
Interventions

Soy protein with isoflavones and cocoa

Soy protein alone with cocoa

Soy protein with soy isoflavones

Soy protein alone

Placebo bar without soy protein, isoflavones or cocoa polyphenols

Outcomes

Primary: Insulin resistance, lipid profile

Secondary: Cardiovascular risk, Isoflavones, Endothelial function

Starting dateOctober 2011
Contact informationStephen L Atkin, University of Hull
Notes 

NCT01882881

Trial name or titleEffects of Polyphenolic-rich Dark Chocolate/Cocoa and Almonds on Cardiovascular Disease Risk Factors
Methods

Allocation: Randomized

Intervention Model: Crossover Assignment

Masking: Investigator

Primary Purpose: Prevention

Participants48 Overweight and obese adults (BMI ≥25, ≤40 kg/m2) with moderately elevated LDL-C between the 25-95th percentile from NHANES: 105-194 mg/dL for males; 98-190 mg/dL for females
Interventions

Experimental: Dark Chocolate/Cocoa + Almond Diet

Experimental: Almond Diet

Experimental: Dark Chocolate/Cocoa Diet

Active Comparator: Healthy American Control Diet

Outcomes

Primary Outcome Measures:

  • Lipid/lipoprotein change (standard panel) [ Time Frame: 0 wk, 4 wk, 10 wk, 16 wk, and 22 wk (at baseline and after each of the 4 diet periods) ]Total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides

  • 24-hour ambulatory blood pressure change [ Time Frame: 0 wk, 4 wk, 10 wk, 16 wk, and 22 wk (at baseline and after each of the 4 diet periods) ]

  • Flow-mediated dilation change [ Time Frame: 0 wk, 4 wk, 10 wk, 16 wk, and 22 wk (at baseline and after each of the 4 diet periods) ]

  • Lipoprotein class and subclass change [ Time Frame: 0 wk, 4 wk, 10 wk, 16 wk, and 22 wk (at baseline and after each of the 4 diet periods) ]The VAP© Test provides a direct measure of the following lipid and lipoprotein classes and subclasses: LDL, Lp(a), IDL, LDL1, LDL2, LDL3, LDL4, HDL, HDL2, HDL3, VLDL, VLDL1+2, VLDL3, TC, TG, Non-HDL, Remnant Lipoproteins, ApoB100, and ApoA1.

Secondary Outcome Measures:

  • Serum C-reactive protein change [ Time Frame: 0 wk, 4 wk, 10 wk, 16 wk, and 22 wk (at baseline and after each of the 4 diet periods) ]

  • Serum insulin change [ Time Frame: 0 wk, 4 wk, 10 wk, 16 wk, and 22 wk (at baseline and after each of the 4 diet periods) ]

  • Serum glucose change [ Time Frame: 0 wk, 4 wk, 10 wk, 16 wk, and 22 wk (at baseline and after each of the 4 diet periods) ]

  • Plasma flavonoid change [ Time Frame: 0 wk, 4 wk, 10 wk, 16 wk, and 22 wk (at baseline and after each of the 4 diet periods) ]

  • LDL oxidation potential change (plasma) [ Time Frame: 0 wk, 4 wk, 10 wk, 16 wk, and 22 wk (at baseline and after each of the 4 diet periods) ]The ex vivo resistance of LDL to Cu2+-mediated oxidation will be determined.

  • Urinary F2α-isoprostane change [ Time Frame: 0 wk, 4 wk, 10 wk, 16 wk, and 22 wk (at baseline and after each of the 4 diet periods) ]

  • Plasma tocopherol change [ Time Frame: 0 wk, 4 wk, 10 wk, 16 wk, and 22 wk (at baseline and after each of the 4 diet periods) ]

Other Outcome Measures:

  • PON1 activity change (serum) [ Time Frame: 0 wk, 4 wk, 10 wk, 16 wk, and 22 wk (at baseline and after each of the 4 diet periods) ]

  • Ex vivo cholesterol efflux change (serum) [ Time Frame: 0 wk, 4 wk, 10 wk, 16 wk, and 22 wk (at baseline and after each of the 4 diet periods) ]

Starting dateMarch 2012
Contact informationPenny Kris-Etherton, Penn State University
Notes 

NCT02789761

Trial name or titleThe Vascular and Cognitive Effects of Chronic High-flavanol Intake in Healthy Males
Methods

Allocation: Randomized

Intervention Model: Parallel Assignment

Masking: Double Blind (Participant, Investigator)

Primary Purpose: Prevention

Participants

34 male adults (18 to 40 years)

Body Mass Index 18.5-27.5 kg/m2

Normal Blood pressure (< 150/90)

Non-smoker

Regular exercise routine

Interventions

Active Comparator: High-flavanol milk chocolate

Placebo Comparator: Low-flavanol milk chocolate

Outcomes

Primary Outcome Measures:

  • Flow-mediated Dilation (FMD)

Secondary Outcome Measures:

  • Blood pressure (BP)

  • Executive Function

  • Endothelial progenitor cells and Microparticles

  • Plasma flavanol metabolite analysis

  • Plasma Nitrite & Nitrate analysis

  • Serum analysis of cardivascular-related blood marker(s) concentration

  • Serum analysis of insulin

Starting dateJanuary 2016
Contact informationJeremy Paul Edward Spencer, University of Reading
Notes 

NCT02802904

Trial name or titleMulticountry Studies on the Effect of Positional Distribution of Fatty Acids at Triglyceride Backbone on Serum Lipids, Lipoprotein(a) and LDL-subclasses in Healthy Malaysian Volunteers
Methods

4 weeks

Allocation: Randomized

Intervention Model: Crossover Assignment

Masking: Single Blind (Participant)

Participants42 Healthy adult male or female, aged 20-50 years, BMI 18.5- 24.9 kg/m2 as per WHO Classification (1998)
Interventions

Experimental: Palm olein IV 64

Experimental: Cocoa butter

Experimental: Virgin olive oil

Outcomes

Primary Outcome Measures:

  • Changes of Ratio of total cholesterol to HDL cholesterol (TC:HDL)

Secondary Outcome Measures:

  • changes of serum HDL cholesterol

  • changes of serum LDL cholesterol

  • changes of serum Triacylglycerol (TAG)

  • changes of serum non-esterified fatty acids (NEFA)

  • changes of serum LDL sub-fractions

  • changes of serum Lp(a)

  • changes of Blood pressure

  • Changes of body mass index (BMI)

  • changes of Waist circumference

Starting dateJanuary 2016
Contact informationMalaysia Palm Oil Board
Notes 

NCT02845622

  1. a

    AMBP: ambulatory measurement of blood pressure
    PWV: pulse wave velocity

Trial name or titleEffects of Hazelnuts and Cocoa on Metabolic Parameters and Vascular Reactivity
Methods

2 weeks

Allocation: Randomized

Intervention Model: Parallel Assignment

Masking: Open Label

Primary Purpose: Health Services Research

Participants61 adults (18 to 40 years) with BMI 18.5-24.9 kg/m2
Interventions

1. Experimental: 30g peeled hazelnuts cream

2. Experimental: 30g unpeeled hazelnuts cream

3. Experimental: snack w/ 30g peeled hazelnuts

4. Experimental: snack w/ 2.5g cocoa powder

5. Experimental: snack w/ 30g peeled hazelnuts+2.5g cocoa

6. Placebo Comparator: empty snack

Outcomes

Primary Outcome Measures:

  • Effects of a breakfast integration on vascular reactivity, assessed by the variation of peak systolic velocity of the brachial artery, in healthy subjects.

Secondary Outcome Measures:

  • Effects of a breakfast integration on total cholesterol (mg/dL) in healthy subjects.

  • Effects of a breakfast integration on high-density lipoprotein-cholesterol (mg/dL) in healthy subjects.

  • Effects of a breakfast integration on low-density lipoprotein-cholesterol (mg/dL) in healthy subjects.

  • Effects of a breakfast integration on triglycerides (mg/dL) in healthy subjects.

  • Effects of a breakfast integration on glucose (mg/dL) in healthy subjects.

  • Effects of a breakfast integration on insulin (uU/mL) in healthy subjects.

  • Effects of a breakfast integration on glucagon (pg/mL) in healthy subjects.

  • Effects of a breakfast integration on leptin (ng/mL) in healthy subjects.

  • Effects of a breakfast integration on ghrelin (ng/mL) in healthy subjects.

  • Effects of a breakfast integration on uric acid (mg/dL) in healthy subjects.

  • Effects of a breakfast integration on homocysteine (umol/L) in healthy subjects.

  • Effects of a breakfast integration on ESR (mm/h) in healthy subjects.

  • Effects of a breakfast integration on hs-CRP (mg/dL) in healthy subjects.

Starting dateJune 2014
Contact informationAnna Ferrulli, Ospedale San Donato, Italy
Notes 

Ancillary