The Differences Between ACE Inhibitor‐Treated and Calcium Channel Blocker‐Treated Hypertensive Patients

Abstract

Large‐scale outcome trials have demonstrated that blood pressure reduction with angiotensin‐converting enzyme (ACE) inhibitors or calcium channel blockers (CCBs) is associated with reduced cardiovascular complications in hypertension. Comparative trials against conventional drugs and between ACE inhibitors and CCBs have failed to reveal conclusive differences in cause‐specific outcomes. Studies in high‐risk patients suggest that ACE inhibitors are superior to CCBs and other drugs in protection against cardiovascular events and renal disease. Very long‐term prospectively collected observational data from the Glasgow Blood Pressure Clinic and the UK General Practice Research Database strongly support an advantage of ACE inhibitors over CCBs for cardiovascular morbidity and mortality. Considering all the available information, it can be concluded that the use of CCBs in the routine therapy of hypertension cannot be recommended while wider use of ACE inhibitors, along with low‐dose diuretics and β blockers, appears justified.

Angiotensin‐converting enzyme (ACE) inhibitors and calcium channel blockers (CCBs) have been used in the management of hypertension for more than 20 years. These drugs have similar efficacy to that of other antihypertensive agents ¹ , ² and overall tolerability is no different than that of thiazide diuretics and β blockers. ¹ , ² However, it has been widely speculated that ACE inhibitors and CCBs might have advantages over conventional drugs. Metabolic complications, which may be responsible for the shortfall in coronary heart disease (CHD) prevention that was observed in early trials, ³ are avoided. Furthermore, ACE inhibitors and CCBs have potential vascular protective properties independent of blood pressure reduction, and advantages for surrogate end points have been claimed. As a consequence, these drugs have been widely employed as first choice agents in hypertension, although the results of large outcome trials in hypertension did not appear until nearly two decades after their introduction.

OUTCOME TRIALS IN HYPERTENSION

In placebo‐controlled comparisons, ACE inhibitors, ⁴ , ⁵ , ⁶ , ⁷ and CCBs ⁸ , ⁹ , ¹⁰ reduce the risk of stroke, coronary heart disease, heart failure, major cardiovascular events, cardiovascular deaths, and all‐cause morality. Only one randomized study ¹⁰ was conducted in an exclusively hypertensive population, but the results across individual trials are consistent. The Heart Outcomes Prevention Evaluation (HOPE) study ⁵ has been interpreted as showing an advantage of ACE inhibition beyond that to be expected from blood pressure reduction since the magnitude of the reductions in cardiovascular end points was greater than that predicted from epidemiologic data for the small differences in blood pressure observed. However, HOPE enrolled patients on the basis of high cardiovascular risk and the reduction in cardiovascular events per mm Hg difference in blood pressure was no greater than that seen in other high‐risk populations, such as diabetes, treated with other forms of antihypertensive therapy. ¹¹ , ¹² In the absence of a positive control group, treated with another agent providing equivalent blood pressure control, no definitive conclusions can be reached. A better acronym for HOPE might be “HYPE.”

The results of large outcome trials comparing ACE inhibitors or CCBs with conventional therapy (diuretics or β blockers) were slow to appear. ¹³ , ¹⁴ , ¹⁵ , ¹⁶ The wait was hardly worthwhile. Although none detected a clear difference in cardiovascular events between therapy based on newer drugs and that based on conventional agents, the precision of comparisons in individual trials was weak, with wide 95% confidence intervals (CIs) for differences. Since clinically useful differences between therapies could not be excluded in any of the trials, individually the trials were not informative.

Individual trials had other shortcomings that cloud their interpretation. In the Captopril Prevention Project (CAPPP), ¹⁶ blood pressure at randomization and persistently throughout the trial was higher in patients treated with captopril compared with those given conventional therapy. It is almost certain that there was failure in the randomization procedure ¹⁷ rendering the results unreliable. This extends to the findings in the subset with diabetes mellitus where there appeared to be an advantage of ACE inhibition. ¹⁶ In the Swedish Trial in Old Patients With Hypertension‐2 study (STOP‐2) ¹⁵ —ACE inhibitors or CCBs vs. β blockers or diuretics—and the International Nifedipine GITS study: Interactions as a Goal in Hypertension Treatment (INSIGHT) ¹³ —CCBs vs. diuretics—withdrawal rates from randomized therapy were unacceptably high (34%–39% and 33%–40%, respectively). Where less than 70% of all randomized patients remained on assigned therapy at the end of follow‐up, intention‐to‐treat analysis will underestimate differences in treatment that would have been seen had there been full adherence to the randomized regimens. Significantly fewer fatal and nonfatal cardiac events were observed in the ACE inhibitor‐treated patients than in CCB‐treated patients in STOP‐2. ¹⁵ However, this was only one of 48 statistical comparisons and interpretation must be treated with caution.

Three direct comparisons of ACE inhibitors and CCBs have been reported. The Appropriate Blood Pressure Control in Diabetes (ABCD) trial ¹⁸ was discontinued prematurely because of apparent outcome differences in CHD and major cardiovascular events in favor of ACE inhibitors. No significant differences for these end points were observed in the even smaller Fosinopril versus Amlodipine Cardiovascular Events Trial (FACET) ¹⁹ and the much larger STOP‐2 study, ¹⁵ although trends were similar. FACET ¹⁹ reported an advantage for ACE inhibitors for a composite end point, and STOP‐2 ¹⁵ suggested a similar advantage in prevention of heart failure.

The recent trials of newer drugs have failed us because they were too small, the event rate was low, and almost 50% of deaths were not cardiovascular. Insufficient power and the large proportion of nonvascular mortality made it difficult to detect differences between treatment for cause‐specific outcomes.

Meta‐Analyses

In the face of uncertainty from individual trials it has become fashionable to resort to meta‐analysis. The Blood Pressure Lowering Treatment (BPLT) Trialists' Collaboration, ²⁰ which is collecting prospective data from over 30 trials, should provide adequate power to more reliably compare different antihypertensive regimens with respect to particular events. However, the recently published preliminary analysis ²⁰ has not taken the matter of differential protection much further forward.

The overview of placebo‐controlled trials of ACE inhibitors (four trials, 12,124 high‐risk patients mostly with coronary heart disease) revealed significant reductions in stroke (30%), CHD (20%), and major cardiovascular events (21%) for only a modest reduction in blood pressure. One study provided most of the data: of the 1860 cardiovascular events and the 1165 deaths from all causes, 88% and 90%, respectively, were seen in the HOPE study, ⁵ in which patients were selected on the basis of a history of cardiovascular disease or diabetes mellitus rather than blood pressure.

Placebo‐controlled trials of CCBs (two trials, 5520 patients mostly with hypertension) showed reductions in stroke (39%) and major cardiovascular events (28%). The larger of these, Systolic Hypertension‐Europe (Syst‐Eur) ¹⁰ was conducted among patients with isolated systolic hypertension, and the smaller Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) ⁹ was carried out in those selected on the basis of coronary heart disease. Of the 388 major cardiovascular events and 296 deaths from all causes, 86% and 95% respectively, were seen in Syst‐Eur. Thus, CCBs reduced the risks of stroke and major cardiovascular events by about 30%–40%, mainly among elderly patients with isolated systolic hypertension among whom study treatment reduced blood pressure by much the same amount as that observed in earlier trials of diuretic‐based or β blocker‐based therapy. There was no clear evidence of reductions in CHD or heart failure.

The results of this first cycle of analyses from this program of prospectively designed overviews show that benefits of blood pressure‐lowering drugs are not limited to regimens based on diuretics or β blockers. However, differences in cause‐specific effects between active therapies were of borderline significance. No differences were detected in comparisons of ACE inhibitors and conventional therapy but this analysis was heavily dependent on the unreliable CAPPP ¹⁶ and STOP‐2. ¹⁵ There were no detectable differences between randomized groups in the risks of any of the outcomes studied (all p>0.1), but for most of the comparisons, moderate differences in cause‐specific outcome (e.g., 10% difference in the relative risk of CHD) were not excluded by the 95% CIs. There was borderline significant evidence of heterogeneity between the results of individual studies for stroke (p=0.05), because of an apparent excess of strokes among patients assigned ACE inhibitor‐based treatment in CAPPP ¹⁶ —a difference that could be explained largely by the higher initial and on‐treatment blood pressure of patients assigned ACE‐inhibitor‐based therapy in this study. Exclusion of CAPPP from the overview analyses decreased the evidence of heterogeneity for this outcome, but did not materially alter the overall results for any outcome.

Compared with conventional therapy, CCB‐based therapy was associated with a 13% reduction in strokes and an increase of similar magnitude (12%) in CHD events, with no difference between CCB types. Since these trends were similar in trials of dihydropyridine and nondihydropyridine CCBs, the results provide no clear support for the hypothesis that there may be qualitatively different effects of these agents on coronary risks. For both outcomes, 95% CIs were wide and the sizes of any true differences could not be determined reliably.

Direct comparison of ACE inhibitor and calcium channel blocker‐based therapies depended on only two trials (STOP‐2 ¹⁵ and ABCD ¹⁸ ), between which there was significant heterogeneity; over 90% of events occurred in a single study (STOP‐2). The combined analysis suggested a reduced risk of CHD events among the patients assigned ACE inhibitor‐based therapy. Extreme reductions in the risk of CHD among patients assigned ACE inhibitor‐based therapy were seen in one small trial (ABCD) ¹⁸ with very few events, but no such difference was detected in the other much larger study with many more events (STOP‐2). ¹⁵ The small trial was stopped early on the basis of an apparent difference in fatal or non‐fatal myocardial infarction, and so its results could provide an inflated estimate of any real treatment difference, which might explain the heterogeneity. It does not provide reliable evidence of a difference between ACE inhibitor and CCB‐based regimens.

Another simultaneously published meta‐analysis ²¹ of trials comparing intermediate‐acting or long‐acting CCBs and other antihypertensive therapies suggested a highly significant 26% excess risk of CHD events with CCB‐based therapy. CCBs were also associated with a significantly higher risk of other major complications of hypertension, including congestive heart failure and combined major cardiovascular events, but not stroke or all‐cause mortality. This analysis used data on 27,743 patients from nine trials, while the BPLT Trialist' review ²⁰ was based on 23,454 patients from six of these trials. It had fewer CHD events and more strokes than the BPLT Trialists' (ratio 0.86 vs. 1.09), emphasizing differences in the populations included. Nevertheless, there was no real difference between the meta‐analyses—the clinically relevant message is that there remains uncertainty.

Both meta‐analyses had limited statistical power to detect differences in cause‐specific outcomes. There are insufficient data to suggest that ACE inhibitors are superior to diuretics and β blockers and insufficient power to provide a definitive comparison of the efficacy of CCBs against that of diuretics, β blockers, and ACE inhibitors for CHD events. The quality of a meta‐analysis depends on the quality of the studies included; in both of these examples, the studies included had major shortcomings.

HIGH‐RISK PATIENTS

Current management guidelines recommend that high‐risk patients should be the focus of therapeutic attention since such individuals gain the greatest benefit of treatment. ²² Although differences between ACE inhibitors and CCBs have been difficult to substantiate in outcome trials in relatively low‐risk hypertensive patients, differential benefits may be apparent in high‐risk populations.

Large‐scale outcome trials have demonstrated that treatment with ACE inhibitors reduces morbidity and mortality in patients with left ventricular systolic dysfunction ²³ and after acute myocardial infarction. ²⁴ Recent evidence indicates that the benefit of ACE inhibition extends to a broad range of high‐risk patients without left ventricular dysfunction or heart failure. ⁵

In contrast, CCBs offer no particular advantage in heart failure and may be associated with a significantly increased risk of myocardial infarction in such patients. ²⁵ No trial with a dihydropyridine has shown outcome benefit in patients post myocardial infarction or with CHD. ²⁶ , ²⁷ Large intervention trials in patients treated with nondihydropyridines after myocardial infarction indicated a reduction in coronary mortality in those without evidence of heart failure. ²⁷ , ²⁸ However, in patients with clinical or echocardiographic systolic dysfunction, diltiazem is associated with a poorer outcome ²⁷ and verapamil has no benefit. ²⁷ , ²⁸

Relatively small‐scale angiographic studies have suggested that calcium channel blocking agents may prevent new coronary artery disease and/or the progression of minimal coronary lesions. ²⁹ , ³⁰ In a much larger trial (PREVENT), ⁹ however, amlodipine had no demonstrable effect on angiographic progression of coronary atherosclerosis or risk of major cardiovascular events.

Recent data in patients with nondiabetic kidney disease have suggested significant benefits with ACE inhibitors compared with other antihypertensive agents. ³¹ , ³² In contrast, the CCB amlodipine performed poorly for equivalent blood pressure reduction. ³¹

DIABETES MELLITUS

Patients with diabetes mellitus represent a group with very high risk of cardiovascular and other complications. ACE inhibitors delay or prevent cardiovascular outcomes after acute myocardial infarction, ³³ in the presence of low ejection fraction or heart failure, ³⁴ and in the absence of evidence of impaired cardiac function. ³⁵ Similarly, in the diabetic subgroup of CAPPP, ¹⁶ cardiovascular outcomes were significantly better in captopril‐treated patients compared with those randomized to β blockers or diuretics. However, no such advantage for ACE inhibitors over conventional drugs was found in STOP‐2 ³⁶ or the United Kingdom Prospective Diabetes Study (UKPDS). ³⁷

ACE inhibitors also prevent overt nephropathy and other microvascular outcomes in patients with type 1 ³⁸ , ³⁹ and type 2 diabetes. ³⁵ , ⁴⁰ The benefits are seen in patients with and without hypertension ³⁵ and the cardiovascular benefit appears greater than that attributable to the decrease in blood pressure. ⁴¹ For equivalent reduction in blood pressure, ACE inhibitor‐based therapy is superior to treatment based on conventional drugs in retarding the progression of diabetic nephropathy.

Subgroup analysis of the Syst‐Eur trial ¹³ has suggested that nitrendipine‐based treatment of systolic hypertension in elderly diabetic subjects is beneficial compared with placebo in reducing total mortality, and cardiovascular morbidity and mortality. Percentage reduction in end points with the long‐acting dihydropyridine was much greater in diabetic than in nondiabetic subjects. Qualitatively similar results were found in diabetic subjects in the Hypertension Optimal Treatment (HOT) study ¹¹ where felodipine was first‐line therapy. Certainly, intention‐to‐treat analyses of data from these trials clearly show that CCBs did no harm. However, CCB treatment with dihydropyridines ¹³ , ³⁶ or diltiazem ¹⁴ was no different from conventional therapy in prevention of cardiovascular events in diabetic hypertensives. In diabetic patients with nephropathy, a distinction needs to be drawn between dihydropyridine CCBs, which have shown little benefit, and nondihydropyridines such as verapamil and diltiazem, which have been shown to reduce cardiovascular and renal events. ⁴²

Direct comparisons have suggested a significant advantage of ACE inhibitors over dihydropyridine CCBs in prevention of cardiovascular events in hypertensive patients with type 2 diabetes mellitus. ¹⁸ , ¹⁹ , ³⁶ These findings have been criticized on the basis of small numbers of events, ¹⁸ , ¹⁹ premature discontinuation, ¹⁸ and multiple statistical comparisons in subgroup analyses ³² but the consistency of the observations cannot be ignored.

The pooled findings of studies on patients with diabetes ⁴³ suggest that ACE inhibitors are more effective than other drugs in reducing the risk of acute myocardial infarction and cardiovascular events, but not stroke. In contrast, CCBs seem inferior to ACE inhibitors ⁴⁴ and other drugs ²¹ in protecting against cardiovascular outcomes. CCBs should not be assumed to have an adverse effect on cardiovascular outcomes since addition to ACE inhibitors further reduces events. ¹⁹ The most plausible explanation is that ACE inhibitors, but not CCBs, have advantages beyond blood pressure reduction.

OTHER EVIDENCE

By their nature, controlled trials are time limited whereas antihypertensive therapy is often life‐long. Very long‐term data may be derived from carefully designed prospective observational data.

Observational studies are generally frowned upon since the introduction of chance bias may confound interpretation. However, recently published metaanalyses ⁴⁵ , ⁴⁶ have indicated that well‐conducted studies of this type can provide estimates of treatment effects which are qualitatively and quantitatively similar to those from randomized controlled trials.

The Glasgow Blood Pressure Clinic provides a convenient environment to observe the long‐term effects of antihypertensive drug therapy. The clinic was established in 1968 and now has a computerized database of almost 11,000 patients. This provides standardized records of clinical findings, drug treatment, and investigations. Patients are record‐linked with the Registrar General (Scotland) and the West of Scotland Cancer Registry; this provides information on dates and cause of death, and fatal and nonfatal cancer. The database has several attributes, including: prolonged follow‐up, large number of subjects, structured clinical records, accurate data on outcome, and high mortality rate.

The potential value of this resource is illustrated in the findings of a recent analysis of over 5000 patients prescribed antihypertensive medication at the Clinic from January 1, 1980 to December 31, 1995. This population was selected to examine the influence of newer antihypertensive drugs on outcome. Both dihydropyridine CCBs and ACE inhibitors were introduced into clinical practice in 1980. Of the patients included, 2295 received CCBs, 1599 received ACE inhibitors, 3679 received β blockers, and 3297 received diuretics. As expected, most patients received more than one drug during the 16‐year observation period.

The first objective was to address the question of whether CCBs predispose to cancer. No such association was found but an unexpected observation was that incident (fatal and nonfatal) and fatal cancers were reduced in patients who had received ACE inhibitors. ⁴⁷ Survival curves indicated that benefit was apparent only after 3–4 years of therapy, providing plausibility for this finding.

By the end of 1995, over 850 patients had died, and all‐cause mortality was significantly lower in patients who had received ACE inhibitors compared with the rest. In observational studies, a possible explanation for such a finding is bias, which might arise if, by chance, ACE inhibitors had been prescribed for low‐risk patients. No such bias was identified and an analysis using a Cox proportional hazard model to adjust for confounding factors (age, gender, year of entry, smoking status, blood pressure, blood sugar, serum cholesterol, blood urea, serum creatinine, diabetic, lipid‐lowering and anti‐platelet medication), confirmed the survival advantage in ACE inhibitor‐treated subjects. All‐cause, cardiovascular, and CHD mortality were significantly lower by 26%, 24%, and 27%, respectively, in patients who had received ACE inhibitors compared with those who had never received ACE inhibitors.

Observational studies are subject to potential confounding influences, which may introduce bias. The problems associated with observational studies can be reduced by limiting the analysis to comparison between drugs with similar patterns of usage, i.e., second‐line agents. In the context of the Glasgow Blood Pressure Clinic database, this means comparison of patients treated with ACE inhibitors or CCBs, drugs which were used conventionally as add‐on therapy in patients already receiving diuretics and/or β blockers during the period of study.

In the Glasgow Blood Pressure Clinic study, over 90% of CCB‐treated patients received dihydropyridines (more than 50% long‐acting preparations, nifedipine GITS, or amlodipine). The comparisons were between patients who had received an ACE inhibitor but never a CCB (n=680); CCB but never ACE inhibitor (n=1416); ACE inhibitor and also CCB (n=879), and those who had received neither an ACE inhibitor nor CCB (n=2232). After adjustment for patient characteristics (age, gender, epoch, smoking, blood pressure, creatinine, urea, antidiabetic, lipid‐lowering and antiplatelet medication) all cause mortality was significantly lower in patients who had received an ACE inhibitor (but never a CCB) and was significantly higher in patients who were prescribed a CCB (but never an ACE inhibitor) compared with those who had received neither. Patients who had received both classes had intermediate risk of death. Qualitatively similar differences, but of greater magnitude, were seen for all vascular mortality and CHD mortality.

Differences between treatment groups were particularly extreme for CHD mortality, where survival curves separated early, unlike the findings for cancer, and continued to separate over 10 years of follow‐up (Figure 1). This suggests that relatively short‐term prospective randomized trials may underestimate long‐term differences between treatments.

Figure 1.

Survival curves for coronary heart disease (CHD) mortality in patients who bad received angiotensin‐converting enzyme inhibitors (ACEIs) but never calcium channel blockers (CCBs) (ACEI group), CCBs but never ACE inhibitors (CCB group) and neither (ACEI — CCB‐group).

The high CHD mortality in CCB‐treated patients might be explained if these drugs were given preferentially to patients with CHD and who might be expected to have high CHD mortality. CCBs are used to treat symptomatic CHD but treatment with the most frequently used antianginal drugs, β blockers, was not associated with excess CHD mortality, suggesting that the results were not confounded by indication.

Short‐acting CCBs (such as nifedipine capsules) have been reported to increase CHD risk, ⁴⁸ and were used widely during the early period of observation. This could have influenced the results. However, when CHD mortality was examined in 4‐year epochs between 1980 and 1995, the excess risk associated with CCB treatment did not decline with time. Thus, increased CHD mortality seems to have persisted even after the widespread introduction of long‐acting dihydropyridines.

These findings may have substantial health implications. Based on 857 deaths over 34,519 patient‐years, it can be estimated that use of ACE inhibitors might spare 35 deaths per 1000 patients treated for 5 years. In contrast, use of CCBs might lead to the loss of 45 lives that would otherwise be spared (Figure 2). These calculations offer no support for the widespread use of CCBs and the relative underuse of ACE inhibitors in hypertension.

Figure 2.

Outcome difference between angiotensin‐converting enzyme inhibitors (ACEIs) and calcium channel blockers (CCBs). Lives spared or lives lost per 1000 patients treated for 5 years. Data for ACE inhibitor‐treated patients and CCB treated‐patients relative to patients who received neither of these drug classes, based on 857 deaths (564 vascular and 349 coronary artery disease) over 34,519 patient‐years. CHD=coronary heart disease

The findings from the Glasgow Blood Pressure Clinic relate to mortality data in patients referred to a secondary/tertiary referral center. To assess whether these findings can be extrapolated to morbidity data in patients managed in primary care, we have utilized information from the UK General Practice Research Database. ⁴⁹

The General Practice Research Database ⁴⁹ contains standardized morbidity and treatment data on several million patients. In a preliminary analysis, 117,965 hypertensive patients treated between 1988 and 1997 were identified. Of these, 105,759 had received treatment. To avoid potential confounding by indication, only those with no evidence of cardiovascular disease (n=80,364) were included. Among these patients, 7046 had subsequent cardiovascular events.

Compared with those who had received CCBs but never ACE inhibitors (n=17,981), patients who had received ACE inhibitors but never CCBs (n=15,004) had a significantly lower hazard ratio (0.64) for CHD morbidity. Findings were similar in those patients who received ACE inhibitors (n=l1,249) or CCBs (n=12,494) as first‐line therapy. For cerebrovascular events, the trends were again significantly in favor of ACE inhibitor‐treated patients.

Thus, the findings from the General Practice Research Database support those from the Glasgow Blood Pressure Clinic. However, the preliminary General Practice Research Database analysis is adjusted, using the Cox proportional hazard model, only for age, gender, and year of entry. Further adjustment is necessary to confirm the conclusions. Also, in the comparison of ACE inhibitors and CCBs as first‐line therapy, about 25% of each group subsequently received a drug from the other class. Nevertheless, the generalizability of the findings is supported.

CONCLUSIONS

Findings from clinical trials and other studies emphasize the importance of basing treatment decisions in hypertension on real outcome measures. The huge volume of data on surrogate end points, always unreliable allies of doubtful validity, can now be dispensed with because the challenge has shifted to differential efficacy in the true sense: the ability of different drug classes to prevent complications of hypertension such as CHD, stroke, heart failure, and renal failure.

The accumulated evidence suggests important differences between ACE inhibitors and CCBs in preventing hypertensive complications. ACE inhibitors appear to have an impressive protective effect additional to that due to blood pressure reduction, while CCBs have a relatively adverse effect on CHD. When compared with the other main classes of antihypertensive drugs, CCBs have a smaller impact on CHD prevention and are associated with increased heart failure incidence. On the other hand, CCB regimens have a larger effect in preventing stroke compared with conventional drugs, although not ACE inhibitors.

What does the differential effect of ACE inhibitors and CCBs mean in practice? That will depend on the balance between myocardial infarction and stroke in the population or individual treated. In Europe and North America, the ratio of myocardial infarction to stroke in mild to moderate hypertension is about 3:1. ²² Preference for CCBs over ACE inhibitors in such populations would reduce the relative risk reduction for combined effects in heart attacks and strokes by about 50%. The conclusion must be that CCBs are not suitable for populations or patients where the coronary risk equals or exceeds the risk of stroke. Even in populations at high risk of stroke and low risk of CHD, CCBs offer no important overall advantage over conventional drugs and are inferior to ACE inhibitors. ⁵⁰

Some patients have compelling indications or contraindications for one drug class or another ²² but the vast majority do not. For these patients, the accumulated evidence does not support the use of CCBs as routine therapy. ACE inhibitors, together with low‐dose diuretics and β blockers, are the preferred treatment for patients with hypertension while CCBs should be employed only as add‐on therapy. This represents a major change in practice since CCBs are currently the most widely used class of antihypertensive agents while ACE inhibitors are underprescribed.