First‐line drugs inhibiting the renin angiotensin system versus other first‐line antihypertensive drug classes for hypertension

Yu Jie Chen; Liang Jin Li; Wen Lu Tang; Jia Yang Song; Ru Qiu; Qian Li; Hao Xue; James M Wright

doi:10.1002/14651858.CD008170.pub3

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Figure 1

PRISMA 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 citations

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Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included citations

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Analysis 1.1

Comparison 1 RAS inhibitors vs CCBs, Outcome 1 All‐cause death.

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Analysis 1.2

Comparison 1 RAS inhibitors vs CCBs, Outcome 2 Total CV events.

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Analysis 1.3

Comparison 1 RAS inhibitors vs CCBs, Outcome 3 Total HF.

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Analysis 1.4

Comparison 1 RAS inhibitors vs CCBs, Outcome 4 Total MI.

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Analysis 1.5

Comparison 1 RAS inhibitors vs CCBs, Outcome 5 Total stroke.

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Analysis 1.6

Comparison 1 RAS inhibitors vs CCBs, Outcome 6 ESRF.

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Analysis 1.7

Comparison 1 RAS inhibitors vs CCBs, Outcome 7 SBP.

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Analysis 1.8

Comparison 1 RAS inhibitors vs CCBs, Outcome 8 DBP.

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Analysis 1.9

Comparison 1 RAS inhibitors vs CCBs, Outcome 9 HR.

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Analysis 2.1

Comparison 2 RAS inhibitors vs thiazides, Outcome 1 All‐cause death.

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Analysis 2.2

Comparison 2 RAS inhibitors vs thiazides, Outcome 2 Total CV events.

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Analysis 2.3

Comparison 2 RAS inhibitors vs thiazides, Outcome 3 Total HF.

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Analysis 2.4

Comparison 2 RAS inhibitors vs thiazides, Outcome 4 Total MI.

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Analysis 2.5

Comparison 2 RAS inhibitors vs thiazides, Outcome 5 Total stroke.

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Analysis 2.6

Comparison 2 RAS inhibitors vs thiazides, Outcome 6 ESRF.

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Analysis 2.7

Comparison 2 RAS inhibitors vs thiazides, Outcome 7 SBP.

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Analysis 2.8

Comparison 2 RAS inhibitors vs thiazides, Outcome 8 DBP.

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Analysis 2.9

Comparison 2 RAS inhibitors vs thiazides, Outcome 9 HR.

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Analysis 3.1

Comparison 3 RAS inhibitors vs beta‐blockers (β‐blockers), Outcome 1 All‐cause death.

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Analysis 3.2

Comparison 3 RAS inhibitors vs beta‐blockers (β‐blockers), Outcome 2 Total CV events.

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Analysis 3.3

Comparison 3 RAS inhibitors vs beta‐blockers (β‐blockers), Outcome 3 Total HF.

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Analysis 3.4

Comparison 3 RAS inhibitors vs beta‐blockers (β‐blockers), Outcome 4 Total MI.

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Analysis 3.5

Comparison 3 RAS inhibitors vs beta‐blockers (β‐blockers), Outcome 5 Total stroke.

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Analysis 3.6

Comparison 3 RAS inhibitors vs beta‐blockers (β‐blockers), Outcome 6 ESRF.

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Analysis 3.7

Comparison 3 RAS inhibitors vs beta‐blockers (β‐blockers), Outcome 7 SBP.

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Analysis 3.8

Comparison 3 RAS inhibitors vs beta‐blockers (β‐blockers), Outcome 8 DBP.

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Analysis 3.9

Comparison 3 RAS inhibitors vs beta‐blockers (β‐blockers), Outcome 9 HR.

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Analysis 4.1

Comparison 4 RAS inhibitors vs alpha‐blockers (α‐blockers), Outcome 1 SBP.

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Analysis 4.2

Comparison 4 RAS inhibitors vs alpha‐blockers (α‐blockers), Outcome 2 DBP.

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Analysis 4.3

Comparison 4 RAS inhibitors vs alpha‐blockers (α‐blockers), Outcome 3 HR.

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Analysis 5.1

Comparison 5 RAS inhibitors vs CNS active drug, Outcome 1 SBP.

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Analysis 5.2

Comparison 5 RAS inhibitors vs CNS active drug, Outcome 2 DBP.

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Analysis 5.3

Comparison 5 RAS inhibitors vs CNS active drug, Outcome 3 HR.

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Summary of findings for the main comparison. RAS inhibitors compared to CCBs for hypertension

First‐line RAS inhibitors compared to first‐line CCBs for hypertension
Patient or population: people with hypertension Settings: outpatients with mean follow‐up of 4.5 years Intervention: First‐line RAS inhibitors Comparison: First‐line CCBs
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	CCBs	RAS inhibitors
All‐cause death	124 per 1000	127 per 1000 (121 to 135)	RR 1.03 (0.98 to 1.09)	35,226 (5)	⊕⊕⊕⊝ moderate¹
Total cardiovascular events	178 per 1000	174 per 1000 (166 to 182)	RR 0.98 (0.93 to 1.02)	35,223 (6)	⊕⊕⊕⊝ moderate¹
Death or hospitalization for heart failure	72 per 1000	60 per 1000 (55 to 65)	RR 0.83 (0.77 to 0.90)	35,143 (5)	⊕⊕⊕⊝ moderate¹	ARR = 1.2% NNTB = 83
Total myocardial infarction	68 per 1000	69 per 1000 (63 to 74)	RR 1.01 (0.93 to 1.09)	35,043 (5)	⊕⊕⊕⊝ moderate¹
Total stroke	39 per 1000	46 per 1000 (42 to 51)	RR 1.19 (1.08 to 1.32)	34,673 (4)	⊕⊕⊕⊝ moderate¹	ARI = 0.7% NNTH = 143
End stage renal failure	25 per 1000	22 per 1000 (19 to 26)	RR 0.88 (0.74 to 1.05)	19,551 (4)	⊕⊕⊝⊝ low^{1, 2}
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; RR: risk ratio; ARR: absolute risk reduction; ARI: absolute risk increase; NNTB: number needed to treat to prevent one adverse outcome; NNTH: number needed to treat to cause one adverse outcome
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
¹Downgraded because we judged some of the included trials to be at high risk of bias. ²Downgraded because of wide confidence intervals which include a clinically important benefit.

Summary of findings for the main comparison. RAS inhibitors compared to CCBs for hypertension

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Summary of findings 2. RAS inhibitors compared to thiazides for hypertension

First‐line RAS inhibitors compared to first‐line thiazides for hypertension
Patient or population: people with hypertension Settings: outpatients with mean follow‐up of 4.9 years Intervention: First‐line RAS inhibitors Comparison: First‐line thiazides
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Thiazides	RAS inhibitors
All‐cause death	144 per 1000	144 per 1000 (135 to 154)	RR 1.00 (0.94 to 1.07)	24,309 (1)	⊕⊕⊕⊝ moderate¹
Total cardiovascular events	194 per 1000	204 per 1000 (194 to 215)	RR 1.05 (1.00 to 1.11)	24,379 (2)	⊕⊕⊕⊝ moderate¹
Death or hospitalization for heart failure	57 per 1000	68 per 1000 (61 to 75)	RR 1.19 (1.07 to 1.31)	24,309 (1)	⊕⊕⊕⊝ moderate¹	ARI = 1.1% NNTH = 91
Total myocardial infarction	93 per 1000	86 per 1000 (80 to 94)	RR 0.93 (0.86 to 1.01)	24,379 (2)	⊕⊕⊕⊝ moderate¹
Total stroke	44 per 1000	50 per 1000 (45 to 56)	RR 1.14 (1.02 to 1.28)	24,309 (1)	⊕⊕⊕⊝ moderate¹	ARI = 0.6% NNTH = 167
End stage renal failure Follow‐up: mean 4.9 years	13 per 1000	14 per 1000 (11 to 18)	RR 1.10 (0.88 to 1.37)	24,309 (1)	⊕⊕⊝⊝ low^{1, 2}
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; RR: risk ratio; ARI; absolute risk increase. NNTH: number needed to treat to cause one adverse outcome
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
¹Based on one large trial (ALLHAT 2002). ²Downgraded due to wide confidence intervals.

Summary of findings 2. RAS inhibitors compared to thiazides for hypertension

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Summary of findings 3. RAS inhibitors compared to beta‐blockers for hypertension

First‐line RAS inhibitors compared to first‐line beta‐blockers for hypertension
Patient or population: people with hypertension Settings: outpatients with mean follow‐up of 4.8 years Intervention: First‐line RAS inhibitors Comparison: First‐line beta‐blockers
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Β‐blockers	RAS inhibitors
All‐cause death	94 per 1000	84 per 1000 (73 to 95)	RR 0.89 (0.78 to 1.01)	9193 (1)	⊕⊕⊝⊝ low^{1, 2}
Total cardiovascular events	143 per 1000	126 per 1000 (114 to 140)	RR 0.88 (0.80 to 0.98)	9239 (2)	⊕⊕⊝⊝ low^{1, 2}	ARR = 1.7% NNTB = 59
Total heart failure	35 per 1000	33 per 1000 (27 to 41)	RR 0.95 (0.76 to 1.18)	9193 (1)	⊕⊕⊝⊝ low^{1, 2}
Total myocardial infarction	41 per 1000	43 per 1000 (35 to 52)	RR 1.05 (0.86 to 1.27)	9239 (2)	⊕⊕⊝⊝ low^{1, 2}
Total stroke	67 per 1000	50 per 1000 (42 to 59)	RR 0.75 (0.63 to 0.88)	9193 (1)	⊕⊕⊝⊝ low^{1, 2}	ARR = 1.7% NNTB = 59
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; RR: risk ratio; ARR: absolute risk reduction. NNTB: number needed to treat to prevent one adverse outcome
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
¹Based primarily on one moderate‐sized trial (LIFE 2002). ²Wide confidence intervals and moderate to high risk of bias.

Summary of findings 3. RAS inhibitors compared to beta‐blockers for hypertension

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Comparison 1. RAS inhibitors vs CCBs

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause death Show forest plot	5	35226	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.98, 1.09]

2 Total CV events Show forest plot	6	35223	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.93, 1.02]

3 Total HF Show forest plot	5	35143	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.77, 0.90]

4 Total MI Show forest plot	5	35043	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.93, 1.09]

5 Total stroke Show forest plot	4	34673	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [1.08, 1.32]

6 ESRF Show forest plot	4	19551	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.74, 1.05]

7 SBP Show forest plot	20	36437	Mean Difference (IV, Fixed, 95% CI)	1.23 [0.90, 1.56]

8 DBP Show forest plot	20	36437	Mean Difference (IV, Fixed, 95% CI)	0.98 [0.79, 1.18]

9 HR Show forest plot	5	540	Mean Difference (IV, Fixed, 95% CI)	0.30 [‐1.63, 2.22]

Comparison 1. RAS inhibitors vs CCBs

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Comparison 2. RAS inhibitors vs thiazides

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause death Show forest plot	1	24309	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.94, 1.07]

2 Total CV events Show forest plot	2	24379	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [1.00, 1.11]

3 Total HF Show forest plot	1	24309	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [1.07, 1.31]

4 Total MI Show forest plot	2	24379	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.86, 1.01]

5 Total stroke Show forest plot	1	24309	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [1.02, 1.28]

6 ESRF Show forest plot	1	24309	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.88, 1.37]

7 SBP Show forest plot	10	26382	Mean Difference (IV, Fixed, 95% CI)	1.60 [1.20, 1.99]

8 DBP Show forest plot	9	26335	Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐0.36, 0.13]

9 HR Show forest plot	2	84	Mean Difference (IV, Fixed, 95% CI)	0.66 [‐2.87, 4.19]

Comparison 2. RAS inhibitors vs thiazides

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Comparison 3. RAS inhibitors vs beta‐blockers (β‐blockers)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause death Show forest plot	1	9193	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.78, 1.01]

2 Total CV events Show forest plot	2	9239	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.80, 0.98]

3 Total HF Show forest plot	1	9193	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.76, 1.18]

4 Total MI Show forest plot	2	9239	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.86, 1.27]

5 Total stroke Show forest plot	1	9193	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.63, 0.88]

6 ESRF Show forest plot	1	46	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.78]

7 SBP Show forest plot	16	10905	Mean Difference (IV, Fixed, 95% CI)	‐0.55 [‐1.22, 0.11]

8 DBP Show forest plot	16	10905	Mean Difference (IV, Fixed, 95% CI)	0.48 [0.14, 0.83]

9 HR Show forest plot	10	9979	Mean Difference (IV, Fixed, 95% CI)	6.05 [5.59, 6.50]

Comparison 3. RAS inhibitors vs beta‐blockers (β‐blockers)

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Comparison 4. RAS inhibitors vs alpha‐blockers (α‐blockers)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 SBP Show forest plot	3	380	Mean Difference (IV, Fixed, 95% CI)	‐2.38 [‐3.98, ‐0.78]

2 DBP Show forest plot	3	380	Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐1.09, 0.85]

3 HR Show forest plot	1	44	Mean Difference (IV, Fixed, 95% CI)	3.1 [‐2.41, 8.61]

Comparison 4. RAS inhibitors vs alpha‐blockers (α‐blockers)

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Comparison 5. RAS inhibitors vs CNS active drug

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 SBP Show forest plot	1	56	Mean Difference (IV, Fixed, 95% CI)	1.30 [‐6.01, 8.61]

2 DBP Show forest plot	1	56	Mean Difference (IV, Fixed, 95% CI)	‐0.30 [‐1.85, 1.25]

3 HR Show forest plot	1	56	Mean Difference (IV, Fixed, 95% CI)	1.5 [‐4.13, 7.13]

Comparison 5. RAS inhibitors vs CNS active drug

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