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Study flow diagram.
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Figure 1

Study flow diagram.

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

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.
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Analysis 1.1

Comparison 1 Combination therapy versus monotherapy, Outcome 1 Total mortality.

Comparison 1 Combination therapy versus monotherapy, Outcome 2 Cardiovascular mortality.
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Analysis 1.2

Comparison 1 Combination therapy versus monotherapy, Outcome 2 Cardiovascular mortality.

Comparison 1 Combination therapy versus monotherapy, Outcome 3 Cardiovascular events.
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Analysis 1.3

Comparison 1 Combination therapy versus monotherapy, Outcome 3 Cardiovascular events.

Comparison 1 Combination therapy versus monotherapy, Outcome 4 Serious adverse events.
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Analysis 1.4

Comparison 1 Combination therapy versus monotherapy, Outcome 4 Serious adverse events.

Comparison 1 Combination therapy versus monotherapy, Outcome 5 Withdrawals due to adverse effects.
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Analysis 1.5

Comparison 1 Combination therapy versus monotherapy, Outcome 5 Withdrawals due to adverse effects.

Comparison 1 Combination therapy versus monotherapy, Outcome 6 Reaching target blood pressure at 1 year.
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Analysis 1.6

Comparison 1 Combination therapy versus monotherapy, Outcome 6 Reaching target blood pressure at 1 year.

Comparison 1 Combination therapy versus monotherapy, Outcome 7 Systolic blood pressure change from baseline at end of 1 year.
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Analysis 1.7

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.
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Analysis 1.8

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.
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Analysis 2.1

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.
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Analysis 2.2

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.
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Analysis 2.3

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.
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Analysis 2.4

Comparison 2 Combination therapy versus monotherapy (men versus women), Outcome 4 Diastolic blood pressure change from baseline at end of 1 year.

Summary of findings for the main comparison. Combination therapy versus monotherapy for primary hypertension

Combination therapy versus monotherapy for primary hypertension

Patient or population: people with primary hypertension
Settings: outpatients mostly in Europe
Intervention: combination therapy
Comparison: monotherapy

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Monotherapy

Combination therapy

Total mortality
Follow‐up: 12 to 36 months

3 per 1000

4 per 1000
(0 to 65)

RR 1.35
(0.08 to 21.72)

568
(3 studies)

⊕⊝⊝⊝
Very low1,2,3

Cardiovascular mortality
Follow‐up: 12 to 36 months

See footnote4

See footnote4

Not estimable

568
(3 studies)

⊕⊝⊝⊝
Very low1,2,4

Cardiovascular events
Follow‐up: 12 to 36 months

9 per 1000

9 per 1000
(2 to 39)

RR 0.98
(0.22 to 4.41)

568
(3 studies)

⊕⊝⊝⊝
Very low1,2,3

Serious adverse events
Follow‐up: 12 to 36 months

176 per 1000

136 per 1000
(55 to 338)

RR 0.77
(0.31 to 1.92)

568
(3 studies)

⊕⊝⊝⊝
Very low1,2,5

Withdrawals due to adverse effects
Follow‐up: 12 to 36 months

128 per 1000

109 per 1000
(68 to 173)

RR 0.85
(0.53 to 1.35)

568
(3 studies)

⊕⊝⊝⊝
Very low1,2,5

*The basis for the assumed is the mean monotherapy group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the combination group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio.

GRADE Working Group grades of evidence
High certainty: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low certainty: 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 certainty: We are very uncertain about the estimate.

1 All data come from subgroups of participants not predefined in the original studies. Outcomes of our review were not the primary outcome in any included trial.
2 Two trials included only people with type 2 diabetes, whereas the other excluded participants treated with drugs for diabetes, hypocholesterolaemia or cardiovascular disease. So none of them was fully representative of the general hypertensive population.
3 There were very few events and confidence intervals were extremely wide.
4 There were no events for this outcome.
5 Confidence intervals were wide and included both appreciable harm and appreciable benefit.

Figures and Tables -
Summary of findings for the main comparison. Combination therapy versus monotherapy for primary hypertension
Table 1. Baseline characteristics of included participants (without previous antihypertensive treatment)

Characteristic

Treatment

Mean (standard deviation)

BENEDICT‐A 2004

PREMIER 2003

REASON 2001

Number of participants

Combination

115

55

63

Monotherapy

215

54

66

Total participants included in the trial (%)

Combination

38.08%

22.78%

28.09%

Monotherapy

35.54%

22.54%

25.82%

Age (years)

Combination

60.98 (7.62)

57.27 (8.53)

52.49 (12.68)

Monotherapy

60.62 (8.36)

59.93 (8.75)

50.38 (10.57)

Sex (% men)

Combination

67.83%

74.55%

71.43%

Monotherapy

69.30%

77.78%

62.12%

Ethnicity (% white people)

Combination

100.00%

96.36%

98.41%

Monotherapy

100.00%

88.89%

93.94%

Body mass index (kg/m2)

Combination

28.68 (5.19)

28.23 (3.18)

26.85 (3.11)

Monotherapy

28.34 (4.42)

29.22 (3.51)

26.99 (2.38)

Systolic blood pressure (mm Hg)

Combination

151.61 (9.70)

154.56 (9.86)

162.56 (11.24)

Monotherapy

152.11 (11.57)

154.04 (11.67)

158.74 (12.84)

Diastolic blood pressure (mm Hg)

Combination

88.72 (7.17)

90.98 (8.43)

97.65 (6.89)

Monotherapy

89.54 (6.32)

91.00 (8.26)

98.94 (5.07)

Figures and Tables -
Table 1. Baseline characteristics of included participants (without previous antihypertensive treatment)
Comparison 1. Combination therapy versus monotherapy

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total mortality Show forest plot

3

568

Risk Ratio (M‐H, Random, 95% CI)

1.35 [0.08, 21.72]

1.1 People with diabetes

2

439

Risk Ratio (M‐H, Random, 95% CI)

1.35 [0.08, 21.72]

1.2 People without diabetes

1

129

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2 Cardiovascular mortality Show forest plot

3

568

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.1 People with diabetes

2

439

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.2 People without diabetes

1

129

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Cardiovascular events Show forest plot

3

568

Risk Ratio (M‐H, Fixed, 95% CI)

0.98 [0.22, 4.41]

3.1 People with diabetes

2

439

Risk Ratio (M‐H, Fixed, 95% CI)

0.62 [0.10, 3.95]

3.2 People without diabetes

1

129

Risk Ratio (M‐H, Fixed, 95% CI)

3.14 [0.13, 75.69]

4 Serious adverse events Show forest plot

3

568

Risk Ratio (M‐H, Random, 95% CI)

0.77 [0.31, 1.92]

4.1 People with diabetes

2

439

Risk Ratio (M‐H, Random, 95% CI)

0.62 [0.24, 1.64]

4.2 People without diabetes

1

129

Risk Ratio (M‐H, Random, 95% CI)

3.14 [0.34, 29.42]

5 Withdrawals due to adverse effects Show forest plot

3

568

Risk Ratio (M‐H, Fixed, 95% CI)

0.85 [0.53, 1.35]

5.1 People with diabetes

2

439

Risk Ratio (M‐H, Fixed, 95% CI)

0.81 [0.49, 1.35]

5.2 People without diabetes

1

129

Risk Ratio (M‐H, Fixed, 95% CI)

1.05 [0.32, 3.45]

6 Reaching target blood pressure at 1 year Show forest plot

3

548

Risk Ratio (M‐H, Random, 95% CI)

1.15 [0.52, 2.54]

6.1 People with diabetes, target ≤ 120/80 mmHg

1

314

Risk Ratio (M‐H, Random, 95% CI)

0.18 [0.01, 3.18]

6.2 People with diabetes, target ≤ 140/90 mmHg

1

105

Risk Ratio (M‐H, Random, 95% CI)

2.0 [1.24, 3.22]

6.3 People without diabetes, target ≤ 140/90 mmHg

1

129

Risk Ratio (M‐H, Random, 95% CI)

0.89 [0.62, 1.28]

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]

7.1 People with diabetes

2

419

Mean Difference (IV, Random, 95% CI)

‐2.54 [‐8.27, 3.19]

7.2 People without diabetes

1

129

Mean Difference (IV, Random, 95% CI)

‐2.33 [‐7.28, 2.62]

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]

8.1 People with diabetes

1

314

Mean Difference (IV, Fixed, 95% CI)

‐0.39 [‐1.56, 0.78]

8.2 People without diabetes

1

129

Mean Difference (IV, Fixed, 95% CI)

1.45 [‐1.40, 4.30]

Figures and Tables -
Comparison 1. Combination therapy versus monotherapy
Comparison 2. Combination therapy versus monotherapy (men versus women)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Serious adverse events Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.1 Women

1

103

Risk Ratio (M‐H, Fixed, 95% CI)

1.25 [0.52, 3.00]

1.2 Men

1

227

Risk Ratio (M‐H, Fixed, 95% CI)

0.75 [0.45, 1.24]

2 Withdrawals due to adverse effects Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.1 Women

1

103

Risk Ratio (M‐H, Fixed, 95% CI)

1.27 [0.43, 3.73]

2.2 Men

1

227

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.42, 1.66]

3 Systolic blood pressure change from baseline at end of 1 year Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

3.1 Women

1

97

Mean Difference (IV, Fixed, 95% CI)

1.74 [‐2.10, 5.58]

3.2 Men

1

217

Mean Difference (IV, Fixed, 95% CI)

‐1.03 [‐3.25, 1.19]

4 Diastolic blood pressure change from baseline at end of 1 year Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

4.1 Women

1

97

Mean Difference (IV, Fixed, 95% CI)

0.47 [‐1.96, 2.90]

4.2 Men

1

217

Mean Difference (IV, Fixed, 95% CI)

‐0.77 [‐2.08, 0.54]

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Comparison 2. Combination therapy versus monotherapy (men versus women)