Impact of ACE Inhibition on Mortality in Hypertension Trials
Impact of ACE Inhibition on Mortality in Hypertension Trials
Each meta-analysis is influenced by the methodology used, and the methods of our meta-analysis are described in detail in the main results paper that appeared in the European Heart Journal. Briefly, a systematic search of PubMed (Ovid MEDLINE®) and ADIS Clinical Trials Insight (ISI Web of Science) using a wide range of keywords, such as 'antihypertensive agents', 'angiotensin-converting enzyme inhibitors', 'hypertension' and 'mortality', identified prospective randomized controlled ACE inhibitor and ARB morbidity–mortality trials published in English between 2000 and 2011.Post-hoc analyses and subanalyses were excluded, as well as trials in specific populations selected for criteria other than hypertension (heart failure, acute myocardial infarction [MI], stroke and so forth). For each trial, patient population, treatments, protocol and end points were critically and independently evaluated by two investigators. Of the publications identified, 20 were included in the meta-analysis. These 20 trials were included based on the following: >66% of patients having hypertension according to individual trial hypertension definitions; incidence of all-cause mortality being sufficiently high (n > 10); RAAS inhibitors not being used simultaneously in both arms; a relatively high number of participants (n > 100) and trials lasting ≥1 year.
The end points were all-cause mortality and cardiovascular mortality. All-cause mortality data were available for all 20 trials and cardiovascular mortality data were available for 16 trials. Our analysis was based on incidence of all-cause and cardiovascular mortality. For the active treatment and control arms, estimates of the incidences of all-cause mortality and cardiovascular mortality were calculated. Estimates of absolute and relative reductions in the incidence of end points in the active treatment arm were also determined. Reported hazard ratios (HRs) and confidence intervals or standard errors were used to determine estimates of relative treatment effects. HR data were available for 17 trials and calculated using incidence rates for three.
Trial characteristics are presented in Table 1 . In total, 158,998 patients were randomized to active (n = 71; 401) or control treatment (n = 87; 597). Most patients were hypertensive (91%), mean baseline systolic BP was 153 mmHg (range: 135–182 mmHg), mean age was 67 years (range: 59–84 years) and 58% of participants were male.
The authors noted a significant reduction in the relative risk (RR) of all-cause mortality of 5% (HR = 0.95; 95% CI: 0.91–1.00; p = 0.032) with RAAS inhibitors. A substantial part of this mortality reduction was due to the effect of ACE inhibitors, which produced a significant 10% reduction in the RR of all-cause mortality (HR = 0.90; 95% CI: 0.84–0.97; p = 0.004) (Figures 1 & 2). No significant reduction in the RR of all-cause mortality could be demonstrated with ARBs (HR = 0.99; 95% CI: 0.94–1.04; p = 0.68). The treatment–effect difference between ACE inhibitors and ARBs was significant (p = 0.036 for interaction).
(Enlarge Image)
Figure 1.
The effect of treatment on all-cause mortality in angiotensin-converting enzyme inhibitor and angiotensin receptor blocker hypertension trials. The effect of treatment on all-cause mortality was significant with ACE inhibitors (p = 0.004), but not with ARBs (p = 0.68).
ACE: Angiotensin-converting enzyme; ARB: Angiotensin receptor blocker; HR: Hazard ratio.
Reproduced with permission from [6].
(Enlarge Image)
Figure 2.
Impact of angiotensin-converting enzyme inhibitors on all-cause mortality.
Significant reduction in all-cause mortality in trial.
ACE: angiotensin-converting enzyme; HR: Hazard ratio.
Pooled analysis of RAAS inhibitor trials also demonstrated a significant reduction in the RR of cardiovascular mortality, by 7% (HR = 0.93; 95% CI: 0.88–0.99; p = 0.018) (Figure 3). Of the 13 ARB trials eligible for all-cause mortality analysis, four trials did not report cardiovascular mortality data. A pooled analysis of the rest (nine trials featuring 73,100 patients) showed that ARBs had no effect on cardiovascular mortality (HR = 0.96; 95% CI: 0.90–1.01; p = 0.14). As with all-cause mortality, cardiovascular mortality reduction with RAAS inhibitors was dominated by the effect of ACE inhibitors. With ACE inhibitors (seven trials featuring 76,615 patients), there was a clear trend toward a RR reduction in cardiovascular mortality of 12% (HR = 0.88; 95% CI: 0.77–1.00; p = 0.051) (Figure 4).
(Enlarge Image)
Figure 3.
Random-effects model comparison of cardiovascular mortality reduction in angiotensin-converting enzyme inhibitor and angiotensin receptor blocker trials.
ARB: angiotensin receptor blocker; HR: Hazard ratio; RAAS: Renin–angiotensin–aldosterone system.
Adapted with permission from [6].
(Enlarge Image)
Figure 4.
Impact of angiotensin-converting enzyme inhibitors on cardiovascular mortality.
Significant reduction in cardiovascular mortality in trial.
ACE: angiotensin-converting enzyme; HR: Hazard ratio.
Trial variation, in terms of hypertensive population, dosage and BP target, was a limiting factor. Other limitations included the unavailability of information about comorbidities and therapy, the use of estimated follow-up times and the disparity in follow-up length of some trials. More importantly, our results were based on good-quality data from randomized controlled trials in a large number of patients (n = 158,998) and thus may be considered reliable overall.
Meta-analysis of Contemporary Trials in Hypertension: All-Cause & Cardiovascular Mortality
Each meta-analysis is influenced by the methodology used, and the methods of our meta-analysis are described in detail in the main results paper that appeared in the European Heart Journal. Briefly, a systematic search of PubMed (Ovid MEDLINE®) and ADIS Clinical Trials Insight (ISI Web of Science) using a wide range of keywords, such as 'antihypertensive agents', 'angiotensin-converting enzyme inhibitors', 'hypertension' and 'mortality', identified prospective randomized controlled ACE inhibitor and ARB morbidity–mortality trials published in English between 2000 and 2011.Post-hoc analyses and subanalyses were excluded, as well as trials in specific populations selected for criteria other than hypertension (heart failure, acute myocardial infarction [MI], stroke and so forth). For each trial, patient population, treatments, protocol and end points were critically and independently evaluated by two investigators. Of the publications identified, 20 were included in the meta-analysis. These 20 trials were included based on the following: >66% of patients having hypertension according to individual trial hypertension definitions; incidence of all-cause mortality being sufficiently high (n > 10); RAAS inhibitors not being used simultaneously in both arms; a relatively high number of participants (n > 100) and trials lasting ≥1 year.
The end points were all-cause mortality and cardiovascular mortality. All-cause mortality data were available for all 20 trials and cardiovascular mortality data were available for 16 trials. Our analysis was based on incidence of all-cause and cardiovascular mortality. For the active treatment and control arms, estimates of the incidences of all-cause mortality and cardiovascular mortality were calculated. Estimates of absolute and relative reductions in the incidence of end points in the active treatment arm were also determined. Reported hazard ratios (HRs) and confidence intervals or standard errors were used to determine estimates of relative treatment effects. HR data were available for 17 trials and calculated using incidence rates for three.
Trial characteristics are presented in Table 1 . In total, 158,998 patients were randomized to active (n = 71; 401) or control treatment (n = 87; 597). Most patients were hypertensive (91%), mean baseline systolic BP was 153 mmHg (range: 135–182 mmHg), mean age was 67 years (range: 59–84 years) and 58% of participants were male.
The authors noted a significant reduction in the relative risk (RR) of all-cause mortality of 5% (HR = 0.95; 95% CI: 0.91–1.00; p = 0.032) with RAAS inhibitors. A substantial part of this mortality reduction was due to the effect of ACE inhibitors, which produced a significant 10% reduction in the RR of all-cause mortality (HR = 0.90; 95% CI: 0.84–0.97; p = 0.004) (Figures 1 & 2). No significant reduction in the RR of all-cause mortality could be demonstrated with ARBs (HR = 0.99; 95% CI: 0.94–1.04; p = 0.68). The treatment–effect difference between ACE inhibitors and ARBs was significant (p = 0.036 for interaction).
(Enlarge Image)
Figure 1.
The effect of treatment on all-cause mortality in angiotensin-converting enzyme inhibitor and angiotensin receptor blocker hypertension trials. The effect of treatment on all-cause mortality was significant with ACE inhibitors (p = 0.004), but not with ARBs (p = 0.68).
ACE: Angiotensin-converting enzyme; ARB: Angiotensin receptor blocker; HR: Hazard ratio.
Reproduced with permission from [6].
(Enlarge Image)
Figure 2.
Impact of angiotensin-converting enzyme inhibitors on all-cause mortality.
Significant reduction in all-cause mortality in trial.
ACE: angiotensin-converting enzyme; HR: Hazard ratio.
Pooled analysis of RAAS inhibitor trials also demonstrated a significant reduction in the RR of cardiovascular mortality, by 7% (HR = 0.93; 95% CI: 0.88–0.99; p = 0.018) (Figure 3). Of the 13 ARB trials eligible for all-cause mortality analysis, four trials did not report cardiovascular mortality data. A pooled analysis of the rest (nine trials featuring 73,100 patients) showed that ARBs had no effect on cardiovascular mortality (HR = 0.96; 95% CI: 0.90–1.01; p = 0.14). As with all-cause mortality, cardiovascular mortality reduction with RAAS inhibitors was dominated by the effect of ACE inhibitors. With ACE inhibitors (seven trials featuring 76,615 patients), there was a clear trend toward a RR reduction in cardiovascular mortality of 12% (HR = 0.88; 95% CI: 0.77–1.00; p = 0.051) (Figure 4).
(Enlarge Image)
Figure 3.
Random-effects model comparison of cardiovascular mortality reduction in angiotensin-converting enzyme inhibitor and angiotensin receptor blocker trials.
ARB: angiotensin receptor blocker; HR: Hazard ratio; RAAS: Renin–angiotensin–aldosterone system.
Adapted with permission from [6].
(Enlarge Image)
Figure 4.
Impact of angiotensin-converting enzyme inhibitors on cardiovascular mortality.
Significant reduction in cardiovascular mortality in trial.
ACE: angiotensin-converting enzyme; HR: Hazard ratio.
Trial variation, in terms of hypertensive population, dosage and BP target, was a limiting factor. Other limitations included the unavailability of information about comorbidities and therapy, the use of estimated follow-up times and the disparity in follow-up length of some trials. More importantly, our results were based on good-quality data from randomized controlled trials in a large number of patients (n = 158,998) and thus may be considered reliable overall.
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