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Efecto del cacao sobre la presión arterial

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

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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)

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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

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PRISMA Flow diagram
Figures and Tables -
Figure 1

PRISMA Flow diagram

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 2

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

Forest plot of comparison: 1 Effect of cocoa on BP, outcome: 1.1 SBP.
Figures and Tables -
Figure 3

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

Forest plot of comparison: 1 Effect of cocoa on BP, outcome: 1.2 DBP.
Figures and Tables -
Figure 4

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

Forest plot of comparison: 2 Hypertensive or normotensive subjects, outcome: 2.1 SBP.
Figures and Tables -
Figure 5

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

Forest plot of comparison: 2 Hypertensive or normotensive subjects, outcome: 2.2 DBP.
Figures and Tables -
Figure 6

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

Comparison 1 Effect of cocoa on BP, Outcome 1 SBP.
Figures and Tables -
Analysis 1.1

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

Comparison 1 Effect of cocoa on BP, Outcome 2 DBP.
Figures and Tables -
Analysis 1.2

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

Comparison 2 Hypertensive or normotensive participants, Outcome 1 SBP.
Figures and Tables -
Analysis 2.1

Comparison 2 Hypertensive or normotensive participants, Outcome 1 SBP.

Comparison 2 Hypertensive or normotensive participants, Outcome 2 DBP.
Figures and Tables -
Analysis 2.2

Comparison 2 Hypertensive or normotensive participants, Outcome 2 DBP.

Comparison 3 Flavanol‐free or low flavanol control, Outcome 1 SBP.
Figures and Tables -
Analysis 3.1

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

Comparison 3 Flavanol‐free or low flavanol control, Outcome 2 DBP.
Figures and Tables -
Analysis 3.2

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

Comparison 4 Double‐blinded or unblinded/single‐blinded, Outcome 1 SBP.
Figures and Tables -
Analysis 4.1

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

Comparison 4 Double‐blinded or unblinded/single‐blinded, Outcome 2 DBP.
Figures and Tables -
Analysis 4.2

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

Comparison 5 Participants ≥50 or <50 years old, Outcome 1 SBP.
Figures and Tables -
Analysis 5.1

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

Comparison 5 Participants ≥50 or <50 years old, Outcome 2 DBP.
Figures and Tables -
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 1 SBP.
Figures and Tables -
Analysis 6.1

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

Comparison 6 Study duration 2 ‐ 4 weeks or > 4 weeks, Outcome 2 DBP.
Figures and Tables -
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 1 SBP.
Figures and Tables -
Analysis 7.1

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

Comparison 7 Sensitivity analysis: excl studies with industry employed authors, Outcome 2 DBP.
Figures and Tables -
Analysis 7.2

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

Summary of findings for the main comparison. Flavanol‐rich cocoa products for blood pressure

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

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding 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 Hg

The 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)

⊕⊕⊕⊕
moderate1,2,3,4

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 Hg

The 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)

⊕⊕⊕⊕
moderate1,2,3,4

Withdrawals due to adverse effects

8 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

⊕⊕⊕⊕
moderate1,2,3,4

*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.

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.

Figures and Tables -
Summary of findings for the main comparison. Flavanol‐rich cocoa products for blood pressure
Table 1. Adverse events & withdrawals

Study

Study design

 

Participants

Cocoa/ Control

Withdrawn

Cocoa/Control

Reasons for withdrawal including adverse effects

Cocoa/Control

Taubert 2003

C

13/13

0/0

Murphy 2003

P

13/15

3 in total

Family illness (2)

Non‐compliance in final week (1)

Engler 2004

P

11/10

0/0

Fraga 2005

C

14/14

1/0

No reason given

Grassi 2005a

C

15/15

0/0

Grassi 2005b

C

20/20

0/0

Taubert 2007

P

22/22

0/0

Crews 2008

P

45/45

6/5

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 2008

C

19/19

0/0

Muniyappa 2008

C

20/20

5/4

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 2008a

P

12/11

7 in total

Time restrictions, personal circumstances (14)

Non‐compliance (exercise or diet) (2)

 

Davison 2008b

P

13/13

5 in total

Al‐Faris 2008

P

30/29

0/0

Shiina 2009

P

20/19

0/0

Ried 2009

P

11/10

2/2

Study product unpalatable (2/0)

Gastrointestinal upset (0/1)

Illness unrelated to study (0/1)

Monagas 2009

C

42/42

0/0

Constipation (resolved with fibre intake)

Bogaard 2010

C

41/41

3 in total

Nausea (1)

Headache (1)

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

 

Heiss 2010

C

16/16

3 in total

Did not come to first visit

Davison 2010

P

13/14

7 in total

Mild gastric symptoms (1)

Non‐compliance with study protocol (1)

Withdrew due to personal circumstances (5)

Njike 2011

C

38/38

7 in total

Non‐compliance with study  protocol (1)

Withdrew  for personal reasons (6)

 

Almoosawi 2012a

C

21/21

1/1

Personal reasons unrelated to study

Desideri 2012

P

30/30

0/1

Gastric discomfort (1)

Khan 2012

C

42/42

1/0

Constipation

Mogollon 2013

P

22/20

1/1

Unrelated to study (1)/headache (1)

Neufingerl 2013

P

10/10

1/1

Nausea (1)/unrelated (1)

Sorond 2013

P

29/29

1/1

No details provided

Esser 2014

C

41/41

3 in total

Medical reasons (1), disliked chocolate (1), poor compliance (1)

Ibero‐Baraibar 2014

P

24/23

2/1

Personal reason (2), poor compliance (1)

Nickols‐Richardson 2014

P

30/30

0/0

None

Sarria 2014 (a)

C

24/24

20/20

?

No information given

Heiss 2015 (a)

P

11/11

10/10

0/0

None

Massee 2015

P

19/19

1/1

Personal reasons (1)

Rostami 2015

P

32/28

2/6

No information given

Koli 2015

C

22/22

0/0

No side effects reported

Mastroiacovo 2015

P

30/30

1/0

Personal reasons (1)

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

Rull 2015

C

21/21

11

No details provided

Sansone 2015

P

50/50

?

No information given

C:Cross‐over
P: Parallel

Figures and Tables -
Table 1. Adverse events & withdrawals
Comparison 1. Effect of cocoa on BP

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 SBP Show forest plot

40

1804

Mean Difference (Random, 95% CI)

‐1.76 [‐3.09, ‐0.43]

2 DBP Show forest plot

39

1772

Mean Difference (Random, 95% CI)

‐1.76 [‐2.57, ‐0.94]

Figures and Tables -
Comparison 1. Effect of cocoa on BP
Comparison 2. Hypertensive or normotensive participants

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 SBP Show forest plot

40

1804

Mean Difference (Random, 95% CI)

‐1.76 [‐3.09, ‐0.43]

1.1 Hypertensive (> 140 mmHg)

9

401

Mean Difference (Random, 95% CI)

‐4.00 [‐6.71, ‐1.30]

1.2 Prehypertensive (> 130 mmHg)

8

340

Mean Difference (Random, 95% CI)

‐2.43 [‐5.02, 0.17]

1.3 Normotensive

23

1063

Mean Difference (Random, 95% CI)

‐0.65 [‐2.13, 0.84]

2 DBP Show forest plot

39

1772

Mean Difference (Random, 95% CI)

‐1.76 [‐2.57, ‐0.94]

2.1 (Pre)hypertensive (> 80 mmHg)

16

735

Mean Difference (Random, 95% CI)

‐1.98 [‐3.38, ‐0.57]

2.2 Normotensive (< 80 mmHg)

23

1037

Mean Difference (Random, 95% CI)

‐1.57 [‐2.54, ‐0.61]

Figures and Tables -
Comparison 2. Hypertensive or normotensive participants
Comparison 3. Flavanol‐free or low flavanol control

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 SBP Show forest plot

40

1804

Mean Difference (Random, 95% CI)

‐1.76 [‐3.09, ‐0.43]

1.1 Flavanol‐free control

26

1116

Mean Difference (Random, 95% CI)

‐1.80 [‐3.46, ‐0.13]

1.2 Low flavanol control

14

688

Mean Difference (Random, 95% CI)

‐1.67 [‐4.03, 0.69]

2 DBP Show forest plot

39

1772

Mean Difference (Random, 95% CI)

‐1.76 [‐2.57, ‐0.94]

2.1 Flavanol‐free control

26

1116

Mean Difference (Random, 95% CI)

‐1.82 [‐2.95, ‐0.68]

2.2 Low flavanol control

13

656

Mean Difference (Random, 95% CI)

‐1.62 [‐2.56, ‐0.68]

Figures and Tables -
Comparison 3. Flavanol‐free or low flavanol control
Comparison 4. Double‐blinded or unblinded/single‐blinded

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 SBP Show forest plot

40

1804

Mean Difference (Random, 95% CI)

‐1.76 [‐3.09, ‐0.43]

1.1 Double‐blind

23

1059

Mean Difference (Random, 95% CI)

‐0.95 [‐2.77, 0.86]

1.2 Unblinded, single‐blinded

17

745

Mean Difference (Random, 95% CI)

‐2.71 [‐4.66, ‐0.76]

2 DBP Show forest plot

39

1772

Mean Difference (Random, 95% CI)

‐1.76 [‐2.57, ‐0.94]

2.1 Double‐blind

21

927

Mean Difference (Random, 95% CI)

‐1.16 [‐2.05, ‐0.27]

2.2 Unblinded, single‐blinded

18

845

Mean Difference (Random, 95% CI)

‐2.33 [‐3.62, ‐1.04]

Figures and Tables -
Comparison 4. Double‐blinded or unblinded/single‐blinded
Comparison 5. Participants ≥50 or <50 years old

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 SBP Show forest plot

38

1762

Mean Difference (Random, 95% CI)

‐1.36 [‐2.79, 0.06]

1.1 < 50 years

18

726

Mean Difference (Random, 95% CI)

‐1.79 [‐4.05, 0.48]

1.2 ≥ 50 years

20

1036

Mean Difference (Random, 95% CI)

‐0.98 [‐2.87, 0.90]

2 DBP Show forest plot

37

1688

Mean Difference (Random, 95% CI)

‐1.62 [‐2.49, ‐0.76]

2.1 < 50 years

18

726

Mean Difference (Random, 95% CI)

‐2.01 [‐3.45, ‐0.58]

2.2 ≥ 50 years

19

962

Mean Difference (Random, 95% CI)

‐1.28 [‐2.32, ‐0.24]

Figures and Tables -
Comparison 5. Participants ≥50 or <50 years old
Comparison 6. Study duration 2 ‐ 4 weeks or > 4 weeks

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 SBP Show forest plot

40

1804

Mean Difference (Random, 95% CI)

‐1.76 [‐3.09, ‐0.43]

1.1 2 ‐ 4 week duration

24

1043

Mean Difference (Random, 95% CI)

‐1.37 [‐3.23, 0.49]

1.2 > 4 week duration

16

761

Mean Difference (Random, 95% CI)

‐2.37 [‐4.30, ‐0.44]

2 DBP Show forest plot

39

1772

Mean Difference (Random, 95% CI)

‐1.76 [‐2.57, ‐0.94]

2.1 2 ‐ 4 week duration

23

1011

Mean Difference (Random, 95% CI)

‐1.55 [‐2.71, ‐0.39]

2.2 > 4 week duration

16

761

Mean Difference (Random, 95% CI)

‐2.04 [‐3.18, ‐0.91]

Figures and Tables -
Comparison 6. Study duration 2 ‐ 4 weeks or > 4 weeks
Comparison 7. Sensitivity analysis: excl studies with industry employed authors

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 SBP Show forest plot

33

1482

Mean Difference (Random, 95% CI)

‐1.08 [‐2.60, 0.43]

2 DBP Show forest plot

33

1482

Mean Difference (Random, 95% CI)

‐1.37 [‐2.31, ‐0.43]

Figures and Tables -
Comparison 7. Sensitivity analysis: excl studies with industry employed authors