First‐line combination therapy versus first‐line monotherapy for primary hypertension
Information
- DOI:
- https://doi.org/10.1002/14651858.CD010316.pub3Copy DOI
- Database:
-
- Cochrane Database of Systematic Reviews
- Version published:
-
- 06 February 2020see what's new
- Type:
-
- Intervention
- Stage:
-
- Review
- Cochrane Editorial Group:
-
Cochrane Hypertension Group
- Copyright:
-
- Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Article metrics
Altmetric:
Cited by:
Authors
Contributions of authors
JG, the lead author of the review, entered the text of the review into Review Manager 5, appraised inclusion criteria and quality, and extracted and analysed data.
LCS co‐ordinated the review, conducted the external correspondence, appraised inclusion criteria and quality, and extracted and analysed data.
AA appraised inclusion criteria and quality of studies, and drafted the final review.
IG appraised inclusion criteria and quality of studies, and interpreted the analysis from a methodological and policy perspective.
MJA appraised inclusion criteria and quality of studies, and interpreted the analysis from a clinical perspective.
JE appraised inclusion criteria and quality of studies, and drafted the final review.
All authors participated in the writing of the Discussion and Authors' conclusions.
Sources of support
Internal sources
-
Navarre Health Service and Health Department of the Government of Navarre, Spain
Working time of authors (employees of the Government of Navarre). Facilities. Library services.
External sources
-
University of British Columbia, Vancouver, Canada
Bibliographic searches. Methodological support.
-
European Social Fund Operational Programme 2007 to 2013, Other
50% of the full research project, as salary from September 2012 to December 2015 for the Pharmacotherapy Research Coordinator in the Navarre Health Service (LCS).
Declarations of interest
Javier Garjón: None known.
Luis Carlos Saiz: None known.
Ana Azparren: None known.
Idoia Gaminde: None known.
M José Ariz: None known.
Juan Erviti: None known.
Acknowledgements
We are grateful to Dr James M Wright and the Cochrane Hypertension Group for their encouragement, support, and assistance.
Annalisa Perna, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy, provided protocol and individual participant data for three studies (BENEDICT‐A 2004; BENEDICT‐B 2011; DEMAND 2011).
Institut de Recherches Internationales Servier, Courbevoie, France, and Prof Roland Asmar, Foundation ‐ Medical Research Institutes, Geneva, Switzerland, provided aggregate results of participants without previous antihypertensive treatment for three studies (REASON 2001; PREMIER 2003; PICXEL 2005).
Flávio Danni Fuchs and Sandra Costa Fuchs, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Rio Grande do Sul, provided aggregate results of participants without previous antihypertensive treatment for the study PREVER‐treatment 2016.
Yuan Jinqiu, School of Public Health and Primary Care, The Chinese University of Hong Kong, checked the inclusion criteria of an article written in Chinese.
Kateryna Kuzmytska Kalayda, general practitioner, Navarre Health Service, Tafalla, Spain, checked the inclusion criteria of an article written in Russian.
Agustín Ciapponi and Demian Glujovsky, Institute of Clinical Effectiveness and Health Policy, Buenos Aires, Argentina, provided access to EROS.
Miguel Angel Imízcoz, retired cardiologist at Navarre Health Service, Pamplona, Spain, helped with the assessment of cardiovascular events reported in studies.
José J Elizondo, hospital pharmacist at CHN‐B, Navarre Health Service, Pamplona, Spain, contributed as author to a previous version of this systematic review.
Version history
| Published | Title | Stage | Authors | Version |
| 2020 Feb 06 | First‐line combination therapy versus first‐line monotherapy for primary hypertension | Review | Javier Garjón, Luis Carlos Saiz, Ana Azparren, Idoia Gaminde, Mª José Ariz, Juan Erviti | |
| 2017 Jan 13 | First‐line combination therapy versus first‐line monotherapy for primary hypertension | Review | Javier Garjón, Luis Carlos Saiz, Ana Azparren, José J Elizondo, Idoia Gaminde, Mª José Ariz, Juan Erviti | |
| 2013 Jan 31 | Monotherapy versus combination therapy used as first‐line therapy for primary hypertension | Protocol | Javier Garjón, Ana Azparren, José J Elizondo, Idoia Gaminde, Mª José Ariz, Juan Erviti, Luis Carlos Saiz | |
Differences between protocol and review
We have improved the wording of the title of the review from "Monotherapy versus combination therapy used as first‐line therapy for primary hypertension" to "First‐line combination therapy versus first‐line monotherapy for primary hypertension".
We have corrected the unit of analysis from "individual trials" to "individual participants".
We did not perform the subgroup analysis with people aged 75 years or over, due to insufficient data.
Keywords
MeSH
Medical Subject Headings (MeSH) Keywords
Medical Subject Headings Check Words
Humans;
PICOs
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1: Combination therapy versus monotherapy, Outcome 1: Total mortality
Comparison 1: Combination therapy versus monotherapy, Outcome 2: Serious adverse events
Comparison 1: Combination therapy versus monotherapy, Outcome 3: Cardiovascular events
Comparison 1: Combination therapy versus monotherapy, Outcome 4: Cardiovascular mortality
Comparison 1: Combination therapy versus monotherapy, Outcome 5: Withdrawals due to adverse effects
Comparison 1: Combination therapy versus monotherapy, Outcome 6: Reaching blood pressure control
Comparison 1: Combination therapy versus monotherapy, Outcome 7: Systolic blood pressure change from baseline at end of 1 year
Comparison 1: Combination therapy versus monotherapy, Outcome 8: Diastolic blood pressure change from baseline at end of 1 year
Comparison 2: Combination therapy versus monotherapy (men versus women), Outcome 1: Serious adverse events
Comparison 2: Combination therapy versus monotherapy (men versus women), Outcome 2: Withdrawals due to adverse effects
Comparison 2: Combination therapy versus monotherapy (men versus women), Outcome 3: Systolic blood pressure change from baseline at end of 1 year
Comparison 2: Combination therapy versus monotherapy (men versus women), Outcome 4: Diastolic blood pressure change from baseline at end of 1 year
Comparison 3: Combination with potassium‐sparing diuretics versus monotherapy, Outcome 1: Total mortality
Comparison 3: Combination with potassium‐sparing diuretics versus monotherapy, Outcome 2: Serious adverse events
Comparison 3: Combination with potassium‐sparing diuretics versus monotherapy, Outcome 3: Cardiovascular events
Comparison 3: Combination with potassium‐sparing diuretics versus monotherapy, Outcome 4: Cardiovascular mortality
Comparison 3: Combination with potassium‐sparing diuretics versus monotherapy, Outcome 5: Withdrawals due to adverse effects
Comparison 3: Combination with potassium‐sparing diuretics versus monotherapy, Outcome 6: Reaching blood pressure control
| Combination therapy compared to monotherapy for primary hypertension | |||||
| Patient or population: people with primary hypertension | |||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | |
|---|---|---|---|---|---|
| Risk with monotherapy | Risk with combination therapy | ||||
| Total mortality Follow‐up: 12 to 36 months | 3 per 1000 | 4 per 1000 | RR 1.35 | 568 | ⊕⊝⊝⊝ |
| Cardiovascular mortality Follow‐up: 12 to 36 months | 0 per 1000 | 0 per 1000 | Not estimable | 568 | ⊕⊝⊝⊝ |
| Cardiovascular events Follow‐up: 12 to 36 months | 9 per 1000 | 9 per 1000 | RR 0.98 | 568 | ⊕⊝⊝⊝ |
| Serious adverse events Follow‐up: 12 to 36 months | 176 per 1000 | 136 per 1000 | RR 0.77 | 568 | ⊕⊝⊝⊝ |
| Withdrawals due to adverse effects Follow‐up: 12 to 36 months | 128 per 1000 | 109 per 1000 | RR 0.85 | 568 | ⊕⊝⊝⊝ |
| *The risk in the intervention group (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). | |||||
| GRADE Working Group grades of evidence | |||||
| aWe downgraded by one level for serious risk of bias because all data came from subgroups of participants not predefined in the original studies, and the outcomes of our review were not the primary outcome in any included trial. | |||||
| Combination with potassium‐sparing diuretics versus monotherapy for primary hypertension | |||||
| Patient or population: people with primary hypertension | |||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | |
|---|---|---|---|---|---|
| Risk with monotherapy | Risk with combination with potassium‐sparing diuretics | ||||
| Total mortality Follow‐up: 18 months | 12 per 1000 | 3 per 1000 | RR 0.24 | 200 | ⊕⊝⊝⊝ |
| Cardiovascular mortality Follow‐up: 18 months | 0 per 1000 | 0 per 1000 | Not estimable | 200 | ⊕⊝⊝⊝ |
| Cardiovascular events Follow‐up: 18 months | 12 per 1000 | 17 per 1000 | RR 1.45 | 200 | ⊕⊝⊝⊝ |
| Serious adverse events Follow‐up: 18 months | 24 per 1000 | 17 per 1000 | RR 0.72 | 200 | ⊕⊝⊝⊝ |
| Withdrawals due to adverse effects Follow‐up: 18 months | 0 per 1000 | 0 per 1000 | Not estimable | 200 | ⊕⊝⊝⊝ |
| *The risk in the intervention group (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). | |||||
| GRADE Working Group grades of evidence | |||||
| aWe downgraded by one level for serious risk of bias because all data came from a subgroup of participants not predefined in the original study, and outcomes of our review were not the primary outcome in the trial. | |||||
| Characteristic | Treatment | Mean (standard deviation) | |||
|---|---|---|---|---|---|
| Number of participants | Combination | 115 | 55 | 63 | 116 |
| Monotherapy | 215 | 54 | 66 | 84 | |
| Total participants included in the trial (%) | Combination | 38.08% | 22.78% | 28.09% | 34.83% |
| Monotherapy | 35.54% | 22.54% | 25.82% | 26.09% | |
| Age (years) | Combination | 60.98 (7.62) | 57.27 (8.53) | 52.49 (12.68) | 51.8 (8.2) |
| Monotherapy | 60.62 (8.36) | 59.93 (8.75) | 50.38 (10.57) | 54.0 (9.0) | |
| Sex (% men) | Combination | 67.83% | 74.55% | 71.43% | 56.90% |
| Monotherapy | 69.30% | 77.78% | 62.12% | 61.90% | |
| Ethnicity (% white people) | Combination | 100.00% | 96.36% | 98.41% | 62.1% |
| Monotherapy | 100.00% | 88.89% | 93.94% | 64.3% | |
| Body mass index (kg/m2) | Combination | 28.68 (5.19) | 28.23 (3.18) | 26.85 (3.11) | 29.1 (5.0) |
| Monotherapy | 28.34 (4.42) | 29.22 (3.51) | 26.99 (2.38) | 28.8 (4.7) | |
| Systolic blood pressure (mmHg) | Combination | 151.61 (9.70) | 154.56 (9.86) | 162.56 (11.24) | 140.4 (8.8) |
| Monotherapy | 152.11 (11.57) | 154.04 (11.67) | 158.74 (12.84) | 142.0 (8.4) | |
| Diastolic blood pressure (mmHg) | Combination | 88.72 (7.17) | 90.98 (8.43) | 97.65 (6.89) | 91.7 (7.4) |
| Monotherapy | 89.54 (6.32) | 91.00 (8.26) | 98.94 (5.07) | 90.3 (7.0) | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Total mortality Show forest plot | 3 | 568 | Risk Ratio (M‐H, Random, 95% CI) | 1.35 [0.08, 21.72] |
| 1.1.1 People with diabetes | 2 | 439 | Risk Ratio (M‐H, Random, 95% CI) | 1.35 [0.08, 21.72] |
| 1.1.2 People without diabetes | 1 | 129 | Risk Ratio (M‐H, Random, 95% CI) | Not estimable |
| 1.2 Serious adverse events Show forest plot | 3 | 568 | Risk Ratio (M‐H, Random, 95% CI) | 0.77 [0.31, 1.92] |
| 1.2.1 People with diabetes | 2 | 439 | Risk Ratio (M‐H, Random, 95% CI) | 0.62 [0.24, 1.64] |
| 1.2.2 People without diabetes | 1 | 129 | Risk Ratio (M‐H, Random, 95% CI) | 3.14 [0.34, 29.42] |
| 1.3 Cardiovascular events Show forest plot | 3 | 568 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.22, 4.41] |
| 1.3.1 People with diabetes | 2 | 439 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.62 [0.10, 3.95] |
| 1.3.2 People without diabetes | 1 | 129 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.14 [0.13, 75.69] |
| 1.4 Cardiovascular mortality Show forest plot | 3 | 568 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 1.4.1 People with diabetes | 2 | 439 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 1.4.2 People without diabetes | 1 | 129 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 1.5 Withdrawals due to adverse effects Show forest plot | 3 | 568 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.85 [0.53, 1.35] |
| 1.5.1 People with diabetes | 2 | 439 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.81 [0.49, 1.35] |
| 1.5.2 People without diabetes | 1 | 129 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.32, 3.45] |
| 1.6 Reaching blood pressure control Show forest plot | 3 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.6.1 People with diabetes, target ≤ 120/80 mmHg | 1 | 314 | Risk Ratio (M‐H, Random, 95% CI) | 0.18 [0.01, 3.18] |
| 1.6.2 People with diabetes, target ≤ 140/90 mmHg | 1 | 105 | Risk Ratio (M‐H, Random, 95% CI) | 2.00 [1.24, 3.22] |
| 1.6.3 People without diabetes, target ≤ 140/90 mmHg | 1 | 129 | Risk Ratio (M‐H, Random, 95% CI) | 0.89 [0.62, 1.28] |
| 1.7 Systolic blood pressure change from baseline at end of 1 year Show forest plot | 3 | 548 | Mean Difference (IV, Random, 95% CI) | ‐2.06 [‐5.39, 1.27] |
| 1.7.1 People with diabetes | 2 | 419 | Mean Difference (IV, Random, 95% CI) | ‐2.54 [‐8.27, 3.19] |
| 1.7.2 People without diabetes | 1 | 129 | Mean Difference (IV, Random, 95% CI) | ‐2.33 [‐7.28, 2.62] |
| 1.8 Diastolic blood pressure change from baseline at end of 1 year Show forest plot | 2 | 443 | Mean Difference (IV, Fixed, 95% CI) | ‐0.12 [‐1.21, 0.96] |
| 1.8.1 People with diabetes | 1 | 314 | Mean Difference (IV, Fixed, 95% CI) | ‐0.39 [‐1.56, 0.78] |
| 1.8.2 People without diabetes | 1 | 129 | Mean Difference (IV, Fixed, 95% CI) | 1.45 [‐1.40, 4.30] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Serious adverse events Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1.1 Women | 1 | 103 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.25 [0.52, 3.00] |
| 2.1.2 Men | 1 | 227 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.45, 1.24] |
| 2.2 Withdrawals due to adverse effects Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.2.1 Women | 1 | 103 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.27 [0.43, 3.73] |
| 2.2.2 Men | 1 | 227 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.83 [0.42, 1.66] |
| 2.3 Systolic blood pressure change from baseline at end of 1 year Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.3.1 Women | 1 | 97 | Mean Difference (IV, Fixed, 95% CI) | 1.74 [‐2.10, 5.58] |
| 2.3.2 Men | 1 | 217 | Mean Difference (IV, Fixed, 95% CI) | ‐1.03 [‐3.25, 1.19] |
| 2.4 Diastolic blood pressure change from baseline at end of 1 year Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.4.1 Women | 1 | 97 | Mean Difference (IV, Fixed, 95% CI) | 0.47 [‐1.96, 2.90] |
| 2.4.2 Men | 1 | 217 | Mean Difference (IV, Fixed, 95% CI) | ‐0.77 [‐2.08, 0.54] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 Total mortality Show forest plot | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.24 [0.01, 5.87] |
| 3.2 Serious adverse events Show forest plot | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.72 [0.10, 5.04] |
| 3.3 Cardiovascular events Show forest plot | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.45 [0.13, 15.71] |
| 3.4 Cardiovascular mortality Show forest plot | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 3.5 Withdrawals due to adverse effects Show forest plot | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 3.6 Reaching blood pressure control Show forest plot | 1 | 200 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.15 [0.93, 1.42] |
