First‐line combination therapy versus first‐line monotherapy for primary hypertension

Javier Garjón; Luis Carlos Saiz; Ana Azparren; José J Elizondo; Idoia Gaminde; Mª José Ariz; Juan Erviti

doi:10.1002/14651858.CD010316.pub2

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Figure 1

Study flow diagram.

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Figure 2

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

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Analysis 1.1

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

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Analysis 1.2

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

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Analysis 1.3

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

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Analysis 1.4

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

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Analysis 1.5

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

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Analysis 1.6

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

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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.

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Analysis 2.1

Comparison 2 Combination therapy versus monotherapy (men versus women), Outcome 1 Serious adverse events.

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Analysis 2.2

Comparison 2 Combination therapy versus monotherapy (men versus women), Outcome 2 Withdrawals due to adverse effects.

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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.

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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.

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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 low^1,2,3	‐
Cardiovascular mortality Follow‐up: 12 to 36 months	See footnote⁴	See footnote⁴	Not estimable	568 (3 studies)	⊕⊝⊝⊝ Very low^1,2,4	‐
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 low^1,2,3	‐
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 low^1,2,5	‐
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 low^1,2,5	‐
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.

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

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Table 1. Baseline characteristics of included participants (without previous antihypertensive treatment)

Characteristic	Treatment	Mean (standard deviation)
Characteristic	Treatment	BENEDICT‐A 2004	PREMIER 2003	REASON 2001
Number of participants	Combination	115	55	63
Number of participants	Monotherapy	215	54	66
Total participants included in the trial (%)	Combination	38.08%	22.78%	28.09%
Total participants included in the trial (%)	Monotherapy	35.54%	22.54%	25.82%
Age (years)	Combination	60.98 (7.62)	57.27 (8.53)	52.49 (12.68)
Age (years)	Monotherapy	60.62 (8.36)	59.93 (8.75)	50.38 (10.57)
Sex (% men)	Combination	67.83%	74.55%	71.43%
Sex (% men)	Monotherapy	69.30%	77.78%	62.12%
Ethnicity (% white people)	Combination	100.00%	96.36%	98.41%
Ethnicity (% white people)	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)
Body mass index (kg/m²)	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)
Systolic blood pressure (mm Hg)	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)
Diastolic blood pressure (mm Hg)	Monotherapy	89.54 (6.32)	91.00 (8.26)	98.94 (5.07)

Table 1. Baseline characteristics of included participants (without previous antihypertensive treatment)

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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]

Comparison 1. Combination therapy versus monotherapy

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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]

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

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