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Bruce Neal, MD; Neil Chapman, MD
Institute for International Health, University
Newtown, Sydney, Australia
By the mid 1990's, systematic overviews (meta-analyses) of unconfounded randomised controlled trials of blood pressure lowering had demonstrated that reductions in blood pressure of about 10-12 mmHg systolic and 5-6 mmHg diastolic conferred relative reductions in stroke risk of about 38% and in coronary heart disease risk of about 16% [1-3]. The sizes of these effects were broadly consistent with those anticipated from observational studies of the long-term associations of blood pressure with stroke and coronary heart disease risk [4-6]. However, the trials included in these overviews were of blood pressure-lowering regimens based mainly on diuretics and beta-blockers. Since large-scale randomised trials of the effects of ACE inhibitors compared to placebo among hypertensive patients had not been completed, the overviews provided no direct evidence about their effects. At the time, evidence about the effects of ACE inhibitors on major cardiovascular outcomes was restricted to indirect data from two randomised controlled trials that compared the effects of ACE inhibitor-based regimens with diuretic- or beta-blocker-based regimens [7, 8]. These two trials identified no differences in the effects of the regimens on stroke or coronary heart disease risk but even in combination were too small to exclude anything but very large differences. Evidence about the clinical effects of ACE inhibitors in hypertensive patients was therefore largely restricted to information about intermediate outcomes such as blood pressure [7, 8] and surrogate endpoints such as renal function [9, 10] and left ventricular hypertrophy , although clear benefits had been demonstrated on major cardiovascular outcomes in patients with heart failure  and acute myocardial infarction .
With the recent completion of some large-scale randomised trials, direct evidence about the effects on major cardiovascular outcomes of antihypertensive regimens based on ACE inhibitors has now become available. The findings of these studies are summarized in the recent overviews conducted by the Blood Pressure Lowering Treatment Trialists' Collaboration . These prospectively planned overviews  include meta-analyses of ACE-inhibitor-based regimens compared both to placebo and to other active blood pressure lowering regimens. Since each comparison was based on larger numbers of cause-specific outcomes, estimates of differences between regimens derived from these overviews should be subject to less random error than those from any individual trial . In addition, the prospective determination of the trials to be included, the hypotheses to be addressed and the outcomes to be studied should mean that estimates from these overviews are subject to few biases . The first cycle of analyses was performed in 2000 and was based on data from a total of 15 trials and almost 75,000 subjects . This report summarises the overview methods and the findings of the overviews that included a comparison of ACE inhibitor-based therapy with either placebo or another active agent.
Trial inclusion criteria
Eligible trials were randomised comparisons of blood pressure lowering drugs with placebo or another active blood pressure lowering regimen. In addition, each trial had a planned minimum of 1000 patient-years of follow-up in each treatment arm, had not reported main results prior to July 1995 but had made results available to the Trialists' Collaboration by June 2000.
The pre-specified comparisons included in this report were of ACE inhibitor-based regimens versus placebo, ACE inhibitors-based regimens versus diuretic- or beta-blocker-based regimens and ACE inhibitor-based regimens versus calcium antagonist-based regimens.
There were six pre-specified primary outcome measures, defined according to the International Classification of Disease (ninth revision): (1) stroke defined as non-fatal stroke or death from cerebrovascular disease; (2) coronary heart disease (CHD) defined as non-fatal myocardial infarction, death from CHD or sudden death; (3) heart failure causing death or requiring hospitalisation; (4) death from any cardiovascular cause; (5) major cardiovascular events including stroke, myocardial infarction, heart failure or any cardiovascular death (all as defined above) and (6) total mortality.
Data from individual trials were provided in tabular form by the collaborating Trialists or calculated from individual participant data sets held by the coordinating centre, and were distributed for confirmation by the Trialists on at least two occasions. The overviews were conducted using standard statistical methods for overview analyses that have been described in detail elsewhere . For each outcome, relative risks (RR) and 95% confidence intervals (CI) were calculated separately for each trial according to the principle of intention to treat. Pooled estimates of effect were calculated using a fixed-effect method and chi-squared tests were used to test the assumption of homogeneity of treatment effect among different trials.
Overviews of trials comparing ACE inhibitor-based regimens with placebo
Four trials, involving 12,124 subjects, compared ACE inhibitors with placebo () [17-20]. For every study, an elevated risk of cardiovascular disease was a requirement for entry. In 2 studies [19, 20] all participants had established coronary heart disease, in one study all participants had either coronary heart disease or other cardiovascular disease  and in the fourth and largest study, all participants had coronary heart disease, other cardiovascular disease or diabetes and an additional cardiovascular risk factor . Hypertension was not a requirement for entry into any of the studies but overall approximately half of all participants were hypertensive. Placebo-controlled falls in blood pressure during follow up were generally small, ranging from 3/1 mmHg in HOPE  to 6/4 mmHg in PART-2 . Approximately three-quarters of subjects in each of the randomised arms remained on their assigned medication at the end of the follow up period.
Overall, 1,860 major cardiovascular events and 1,165 deaths occurred in the 4 studies, most of them (88% and 90% respectively) among participants in the HOPE study  (). Patients assigned ACE inhibitor therapy had significant reductions of 20-30% in the risks of stroke, coronary heart disease, major cardiovascular events and cardiovascular death, as well as a reduction in total mortality ( ). There was no significant reduction in risk of heart failure (relative risk 0.84) although the 95% confidence intervals (0.68 - 1.04) did not exclude a possible moderate benefit of ACE inhibitor therapy. There was no evidence of heterogeneity between the studies for any of the outcomes tested.
Overviews of trials comparing
ACE inhibitor-based regimens with diuretic or beta-blocker- based regimens
Three trials, involving 16,161 patients, compared ACE-inhibitor-based regimens with regimens based on diuretics and/or beta-blockers ( ) [21-23]. In two studies [21, 22] subjects in the control group were assigned to either a diuretic or a beta-blocker and in the third, all were assigned a beta-blocker . All subjects had hypertension at baseline and all participants in the UKPDS-HDS study were diabetic . Between two-thirds and three-quarters of patients remained on randomised therapy throughout the scheduled follow-up period.
Differences in blood pressure between randomised groups at trial entry were small in two of the studies, but in the CAPPP study  blood pressure at entry was 2/2 mmHg higher in the group assigned to ACE-inhibitors than it was in the group assigned diuretics or beta-blockers. This raises the possibility of some non-random assignment of study treatment. Differences in measured BP between randomised groups during follow-up were small. However, the largest difference (3/1 mmHg higher BP seen among those assigned to the ACE-inhibitor-based regimen) was again observed in the CAPPP trial; this is likely to reflect the difference observed at baseline rather than differential effects of study treatment. For this reason, in these overviews, separate analyses were performed for each outcome: one including CAPPP and one excluding it.
Overall, a total of 2022 major cardiovascular events and 1257 deaths from all causes were observed. There were no detectable differences between randomised groups in the risks of any of the outcomes studied (). However, for most of the comparisons, the 95% confidence intervals were too wide to exclude small-moderate differences in cause-specific outcomes (e.g. a 10% difference in the relative risk of coronary heart disease). There was borderline significant evidence of heterogeneity between the results of individual trials for stroke (p=0.05) ( ). This is due to an apparent difference between the results of CAPPP and the other trials - a difference that is consistent with the higher baseline and follow-up blood pressure of patients assigned ACE inhibitor-based therapy in CAPPP. Exclusion of CAPPP from the overview analyses reduced the evidence of heterogeneity but did not materially alter the overall results for stroke or any other outcome.
Overviews of trials comparing
ACE inhibitor-based regimens with calcium antagonist- based regimens
Only 2 trials, involving 4,871 patients, compared ACE-inhibitor-based regimens with calcium antagonist-based regimens () [22, 24]. One trial, ABCD , included only diabetics and the analyses reported here include only the subgroup of participants with hypertension at baseline. For both studies, blood pressures levels at baseline were balanced and differences between follow-up blood pressure levels in the randomised groups were small.
Most of the outcome data were provided by one trial: of the 1178 major cardiovascular events and 774 deaths from all causes in these two trials, 92% and 96%, respectively, were observed in STOP-2  (). In ABCD, randomised treatments were discontinued before the scheduled end of follow-up because of an apparently extreme difference in coronary heart disease in favour of patients assigned the ACE inhibitor (RR 0.35 [0.19 - 0.66]). For this outcome and for major cardiovascular events there was significant heterogeneity (p=0.01 and p=0.04, respectively) between the results of the two trials ( ). While the 95% confidence intervals for coronary heart disease in STOP-2 did not exclude possible moderate advantages for ACE-inhibitor-based therapy (RR 0.87 [0.73 - 1.05]), those for major cardiovascular events excluded all but small differences between randomised groups (RR 0.94 [0.85 - 1.04]). In the combined analysis for coronary heart disease, the 95% confidence intervals did not overlap with unity (RR 0.81 [0.68 - 0.97]). However, as ABCD was stopped early, and in view of the heterogeneity of the trials with regard to this endpoint, it is difficult to interpret this finding. In neither trial, nor in the combined analyses, was there any clear evidence of differences between randomised groups in the risks of stroke, cardiovascular death or total mortality, nor was there any evidence of statistically significant heterogeneity between trials for these outcomes (all p>0.2). For heart failure, there was a borderline significant trend towards reduced risk among those assigned ACE inhibitor-based therapy (RR 0.82 [0.67-1.00]); while most of this difference was observed in STOP-2, there was no evidence of statistically significant heterogeneity between the two individuals studies (p=0.35).
The results of these overviews provide clear evidence that ACE inhibitor based blood pressure lowering regimens have beneficial effects on the risks of major cardiovascular outcomes. The overview of placebo-controlled trials of ACE inhibitors showed that, with only a modest reduction in blood pressure, these agents reduce the risks of stroke, coronary heart disease and major cardiovascular events by 20-30% among high-risk patients selected on the basis of a history of cardiovascular disease or diabetes mellitus. While patients in these trials were not selected on the basis of high blood pressure, a large number of individuals with treated hypertension were included and in the largest of the studies  there were similar proportional benefits of ACE inhibitors among those with or without hypertension at baseline. The demonstration of benefits of ACE inhibitors for stroke and coronary heart disease risk in the heterogeneous high-risk patient populations included in this overview extend the evidence of benefits beyond those reported by other overviews of randomised controlled trials of ACE inhibitors among patients with left ventricular dysfunction  or acute myocardial infarction . While there was no clear evidence in these analyses of a reduction in the risk of heart failure, the 95% confidence intervals did not exclude possible benefits of moderate magnitude among those assigned ACE inhibitor therapy. Both the small number of endpoints and the widespread pre-hospital use of ACE inhibitors in patients with any manifestation of heart failure  would have limited the ability of these overviews to detect any true benefits of treatment. Several other randomised trials have provided clear evidence that ACE inhibitors prevent heart failure in other high-risk situations  and in the largest of the studies included in this overview  there was evidence of a benefit of ACE inhibitors for heart failure when a wider definition of this outcome was used.
In the overview comparing ACE inhibitor-based regimens with diuretic- or beta blocker-based regimens, no differences between the regimens were observed. However, the 95% confidence intervals were frequently wide and while all but small differences in major cardiovascular events are unlikely, moderate differences in the effects of the regimens on cause-specific outcomes, such as heart failure, could not be reliably excluded.
In the overview comparing ACE inhibitor-based regimens with calcium antagonist-based regimens, a reduced risk of CHD was observed among the participants assigned to ACE inhibitor-based therapy. However, extreme reductions in the risk of coronary heart disease among patients assigned ACE inhibitor-based therapy in the small ABCD trial,  resulted in the trial being stopped early, and its results may therefore provide an inflated estimate of any real treatment difference . Additionally, no such difference was detected in the other much larger study (STOP-2)  and there was highly significant heterogeneity between the findings of the two studies for this outcome. For these reasons, the combined analysis of coronary heart disease events does not provide reliable evidence of a difference between ACE inhibitor- and calcium antagonist-based regimens in their effects on this outcome. In this overview, there was also some evidence of a reduced risk of heart failure among those patients assigned to ACE inhibitor-based regimens. On this occasion all of the evidence was provided by STOP-2 and the differences between the findings of the two studies were less marked. However, once again the 95% confidence intervals were wide and the true size of any difference between regimens could not be determined reliably.
In these overviews, the combination of results from different trials addressing the same question should have minimised random errors . In addition, the pre-specification of the studies to be included, hypotheses to be addressed and outcomes to be studied should have minimised biases . As a consequence, the evidence about ACE inhibitors that is provided by these overviews should be the most reliable possible. However, the true differences between the effects of ACE inhibitors and placebo and the true differences between the effects of ACE inhibitors and other active regimens are likely to have been underestimated. The true differences are those that would have been observed if all participants had fully adhered to randomised treatments throughout follow-up. In most of the trials included in these overviews, between one quarter and one half of participants discontinued their assigned treatment prior to the end of the scheduled follow-up period. In the presence of such non-adherence, analyses conducted according to the principle of intention-to-treat, while minimising important biases, will result in systematic underestimation of the differences between treatment regimens . For the same reason, if the real difference between the regimens was small or the rate of non-adherence was particularly high, non-adherence may have resulted in a failure to detect a difference between regimens .
The most recent international guidelines for the management of high blood pressure provide for the initiation of therapy with any of the major classes of blood pressure lowering drugs . These guidelines also suggest that the choice of first-line agent should be determined by qualifying factors such as socio-economic conditions, cardiovascular risk profile, the presence of co-existing target organ damage or disease, individual responses to different drugs, possible interactions with concomitant therapies and the strength of the evidence of benefit for each blood pressure lowering agent . In particular the guidelines suggest that ACE inhibitor-based therapy may be especially beneficial among hypertensive individuals with heart failure, diabetic nephropathy or left ventricular dysfunction following acute myocardial infarction [9, 10, 12, 13].
The current evidence clearly supports the use of ACE inhibitor-based blood pressure lowering regimens in the first-line management of hypertension. However, reliable evidence of differences between the effects of ACE inhibitors and other active blood pressure lowering regimens is not available for any outcome or any patient subgroup. Informed recommendations about the preferential selection of a specific class of agent, on the basis of differential effects on mortality and major morbidity cannot therefore be made. Further evidence about the effects of ACE inhibitor-based blood pressure lowering regimens will become available with the completion of ongoing large-scale trials () and from future rounds of overviews by the Blood Pressure Lowering Treatment Trialists Collaboration. These new data should provide more precise estimates of the effects of ACE inhibitor-based regimens already reported as well as new evidence about the effects of ACE inhibitor-based regimens in particular patient subgroups, such as the elderly, those with diabetes and those at high risk of stroke. If differences in the effects of ACE inhibitors and other drug classes on cause-specific outcomes or among particular patient subgroups are proved, then it may become possible to tailor blood pressure lowering regimens to the specific risks of the individual patient.
The effects of antihypertensive therapy based upon diuretics or beta-blockers on major cardiovascular outcomes have been clearly established for some years. Evidence about the effects of ACE inhibitors on these same outcomes among hypertensive subjects has only recently become available. The Blood Pressure Lowering Treatment Trialists' Collaboration performed a series of prospectively designed overviews of randomised trials to determine the effects of ACE inhibitor-based blood pressure lowering regimens compared with placebo or blood pressure lowering regimens based on other drug classes. The overviews clearly demonstrated that ACE inhibitors have beneficial effects compared to placebo in high-risk patients both with and without hypertension. The overviews provided no reliable evidence of differences between the effects of regimens based on ACE inhibitors and those based on other drug classes for any outcome. However, small differences between the effects of different regimens could not reliably be excluded. The results of ongoing trials and future overview analyses should substantially increase the evidence about the effects of different blood pressure lowering regimens on mortality and major cardiovascular morbidity.
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