Which patients should benefit from ACE inhibitor–b-blocker therapy?

Kateryna AMOSOVA,MD, PhD
Department of Internal Medicine
O. Bogomolets National Medical
University, Kyiv, UKRAINE

Which patients should benefit from ACE inhibitor–β-blocker therapy?

by K. Amosova, Ukraine

Candidates that will best benefit from the combination of an angiotensinconverting enzyme (ACE) inhibitor (first line) and a β-blocker are hypertensive patients with concomitant coronary artery disease. Patients with a relatively recent myocardial infarction and those with chronic heart failure and low ejection fraction are likely to obtain beneficial outcomes with this combination—predominantly independent of blood pressure lowering— while patients with angina will gain symptomatic benefits on top of the blood pressure–dependent improvement in prognosis. The improvement in prognosis, however, is likely to be inferior to that achieved with the use of an ACE inhibitor– dihydropyridine calcium channel blocker combination, due to the inferior central blood pressure reduction that is inherent with heart rate lowering. Although the combination of an ACE inhibitor and a β-blocker appears pathophysiologically to be a sound choice for use in a subset of younger patients with uncomplicated hypertension, hyperkinetic circulation, and probable hyperreninemia, its hemodynamic effectiveness in such patients is questionable. Moreover, the probability of obtaining a modification in outcomes that is comparable to that achieved in the ASCOT trial (Anglo-Scandinavian Cardiac Outcomes Trial) does not appear very high with the use of this combination because of the heart rate reduction that is inherent with its use. This particular combination approach is only likely to be preferable in hypertensive patients with palpitations and certain arrhythmias who will gain a symptomatic benefit, and heart rate should not be considered as a therapeutic goal. The optimal choice of ACE inhibitor– β-blocker combination is likely to rely on perindopril, which has the largest body of evidence showing outcome benefits in hypertensive and coronary artery disease patients, and long-acting β-blockers such as bisoprolol and nebivolol.

Medicographia. 2013;35:433-440 (see French abstract on page 440)

More than 50% of patients with uncomplicated hypertension require more than one drug to achieve adequate blood pressure (BP) control.1 This is because of the limited antihypertensive effect of monotherapy, which, on average, results in reductions of 9.1 mm Hg for systolic BP, and 5.5 mm Hg for diastolic BP.2 Multiple randomized controlled trials using placebo and active controls, and the majority of meta-analyses, have shown no significant differences in BP lowering and clinical efficacy between the five main classes of antihypertensive drugs when used at adequate doses. For this reason, the European Society of Hypertension (ESH)/European Society of Cardiology (ESC) 2007 guidelines stressed that the effect of BP-lowering drugs in reducing the risk of serious cardiovascular events and all-cause death is virtually entirely due to BP reduction, and diuretics, β-blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) should all be considered as equivalent first-line choices for monotherapy and add-on therapy.3

Are all combinations of first-line drugs equal in their effectiveness?

In contrast with the arbitrary choices made in many earlier randomized controlled trials using a varied assortment of add on drugs, the design of more recent trials has strictly specified the add-on treatment regimens in all treatment arms. Such an approach has allowed evidence to be obtained that can be used to make claims about the comparable efficacy of particular drug combinations. The results of these trials have enabled the ESH and ESC in the 2009 reappraisal of their guidelines to recommend specific combinations for priority use and to specify certain undesirable or unacceptable combinations (Figure 1).4 The former includes combinations of renin-angiotensin system (RAS) inhibitors (ACE inhibitors and ARBs) with a dihydropyridine CCB or diuretic, or a CCB with diuretic, and the latter would be combination of a β-blocker with diuretic (undesirable) or an ACE inhibitor with an ARB (unacceptable). Importantly, the inferiority of the β-blocker/diuretic and ACE inhibitor/ARB combinations in the landmark trials (LIFE [Losartan Intervention For Endpoint reduction in hypertension study],5 ASCOT [Anglo-Scandinavian Cardiac Outcomes Trial],6 and ONTARGET [ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial]) was marked not only by an increased frequency of serious side effects (for the β-blocker/ diuretic combination this was mainly new-onset diabetes and sexual dysfunction; for the ACE inhibitor–ARB combination it was hard renal end points), but also suboptimal clinical efficacy regarding particular BP reduction targets. In LIFE, combined therapy with a β-blocker and diuretic in high-risk hypertensive patients was associated with a higher incidence of stroke compared with an ARB–diuretic combination, despite identical BP control. ASCOT was stopped prematurely because of significantly higher all-cause mortality in the group of uncomplicated high-risk hypertension patients treated with the atenolol–diuretic combination compared with the amlodipine– perindopril combination. This was associated with a higher incidence of coronary events, stroke, and cardiovascular mortality, which, according to the results of the multivariate analysis, could only partly be explained by the small average difference in BP reduction of 2.7/1.9 mm Hg.7

Figure 1
Figure 1. Recommendations of the 2009 reappraisal of the European
Society of Hypertension (ESH) and European Society of
Cardiology (ESC) regarding optimal drug combinations in patients
with uncomplicated hypertension.

Abbreviations: ACE, angiotensin-converting enzyme; AT1, angiotensin II type 1;
CCB, calcium channel blocker.
After data from reference 4: Mancia G et al. J Hypertens. 2009;27:2121-2158.

Inferior cardiovascular protection with β-blockers in hypertension: evidence and reasons

The results of LIFE and ASCOT correspond with the results of several meta-analyses that have reassessed the cardiovascular protection and safety of β-blockers as a first-line therapy for hypertension.8-10 These have demonstrated that despite antihypertensive therapy based on a -blocker (mainly atenolol) achieving effective BP reduction compared with placebo, the β-blocker has no impact on all-cause mortality, coronary events, and stroke. beta;-Blocker therapy was also shown to be inferior to therapy with other first-line drugs when taken together, including diuretics, for all-cause mortality and stroke prevention.8-9 One meta-analysis comparing specific drug classes found that β-blockers were inferior to CCBs for all-cause mortality, stroke, and total cardiovascular events, and inferior to RAS inhibitors for stroke.10

According to the results of a meta-analysis by Khan and McAlister that took into account patient age, β-blockers reduced major cardiovascular outcomes in placebo controlled trials in younger patients but not in older patients.11 The observed benefits, however, were less than might be expected given the results of epidemiological studies.12 In active comparator trials, β-blockers were inferior to other therapies for the composite outcome of stroke, myocardial infarction, and death, and particularly inferior for stroke in elderly patients, although not in younger patients.

The principal explanation for the suboptimal cardiovascular protection afforded by β-blockers compared with other drug classes is the inferiority of their BP-lowering effect on central systolic BP despite producing a similar reduction in brachial BP to other antihypertensive drug classes; this has been shown in several small studies and was confirmed in the large CAFE trial (Conduit Artery Function Evaluation) (Figure 2).13,14 According to the results of the multifactorial analysis of the CAFE data, this inferiority is mainly due to their heart rate–reducing effect, which enables reflected pulse waves to return to the thoracic aorta well before the end of left ventricular systole. Such pulse wave dyssynchrony is facilitated by a proximal shift of its reflection sites in small resistance arteries, absolute or relative to other therapies. The lack of a positive effect of β-blockers on artery compliance, and the structural remodeling of small arteries that β-blockers produce—in contrast with treatment with dihydro-pyridine CCBs and RAS inhibitors with the same brachial BP-lowering effect—has been demonstrated in several studies.15,16 An important factor influencing the timing of the retrograde pulse wave return to the thoracic aorta and central BP is pulse wave velocity, which increases with aortic wall stiffening in the course of both physiological and premature vascular aging (eg, in hypertension and diabetes). This forms the theoretical background for the inferior clinical effectiveness of β-blockers in older hypertensive patients compared with younger ones.

Figure 2
Figure 2. Differences in brachial (peripheral) and aortic (central) systolic blood pressure
with use of atenolol/bendroflumethiazide and amlodipine/perindopril combinations
in the CAFE substudy of the ASCOT trial.

Abbreviations: ASCOT, Anglo-Scandinavian Cardiac Outcomes Trial; AUC, area under the curve;
CAFE, Conduit Artery Function Evaluation; SBP, systolic blood pressure.
After reference 14: Williams B et al. Circulation. 2006;113:1213-1225. © 2006, Wolters Kluwer Health.

Position of the guidelines on the use of β-blockers in uncomplicated hypertension

Taking into account the suboptimal cardiovascular protection afforded by β-blockers shown in the aforementioned randomized controlled trials and meta-analyses, as well as the physiological background, the UK National Institute for Health and Care Excellence (NICE) and British Hypertension Society disregarded the 2007 EHS/ESC recommendations3 and downgraded β-blockers from first-line to fourth-line drugs; eg, for use as add-on drugs in patients requiring multiple therapies.17 Similar recommendations were issued by the South African and Australian national hypertension societies,18,19 while the Canadian Hypertension Society excluded β-blockers from the list of first-line drugs for patients with diastolic or systolo-diastolic hypertension aged less than 60 years and for all patients with isolated systolic hypertension.20 These discrepancies between the opinions of leading experts regarding the role of β-blockers in therapy for uncomplicated hypertension highlight their disagreement on how to interpret the available data and the need for new, specially planned, randomized controlled trials.

Combination of ACE inhibitors and β-blockers in uncomplicated hypertension: expected benefits and risks

Are there grounds for speculating that combining β-blockers with drug classes other than diuretics (primarily ACE inhibitors) as a cornerstone of cardiovascular prevention may have potential benefits, at least in certain subgroups of patients, eg, younger patients? The combination of β-blocker with ACE inhibitor is very often used empirically in clinical practice for younger patients with a tendency toward a higher heart rate; eg, obese patients with the metabolic syndrome.

The pathophysiology of hypertension in younger people, especially those with short anamnesis, is different from that in older people. Sympathetic activation plays an important role in its development, causing high cardiac output and hyperdynamic circulation, as well as mediation of higher renin release via β receptors on the kidney juxtaglomerular cells. It is reasonable to speculate that treating such a subset of patients who have hyperkinetic circulation (and probably also normokinetic circulation) with an ACE inhibitor–β-blocker combination could produce additive antihypertensive effects: the lowering of cardiac output and inhibition of renin release produced by the β-blocker would combine with the ACE inhibitor neutralization of the undesirable vasoconstrictive effects and insulin resistance amplification produced by the β-blocker. Yoneda et al21 and Holmer et al22 demonstrated that the reactive increase in renin blood concentrations in hypertensive patients starting treatment with ACE inhibitors was largely prevented by concomitant treatment with β-blockers. The hemodynamic effectiveness and clinical implications of such an interaction remain to be demonstrated.

One small prospective study in patients with mild to severe hypertension found that the combination of a β-blocker with an ACE inhibitor lowered diastolic BP significantly more than monotherapy (–20 mm Hg versus –10 mm Hg), while the lowering of cardiac output and elevation of vascular resistance produced by the β-blockers was attenuated by addition of the ACE inhibitor.23 A more recent retrospective database analysis by Bisognano et al24 in patients treated with β-blockers who were matched for baseline characteristics (n=660; mean age 66 years; basal BP 156/88 mm Hg) showed that add-on therapy with ACE inhibitors produced a more-or-less similar reduction in systolic BP to that of CCBs (–16 mm Hg versus –18.5 mm Hg), and tended to be more effective than therapy with ARBs. However, diastolic BP reduction with ACE inhibitors was inferior to that with CCBs (–4.9 mm Hg versus –9.3 mm Hg; P<0.05) and similar to that with ARBs. The small sample size did not allow for analysis of the results in subpopulations; eg, younger or older patients. Thus, the question of the existence of additive antihypertensive effects with the ACE inhibitor–β-blocker combination in younger hypertensive patients remains open to debate. A separate comment deserves to be made on the appropriateness of heart rate control as one of the possible therapeutic goals of add-on treatment with β-blockers in younger patients with uncomplicated hypertension. It has become a clinical convention to consider heart rate as a universal risk factor, whose pharmacological slowing, eg, with β-blockers, invariably produces an improvement in outcome. Yet, in contrast with post–myocardial infarction or chronic heart failure patients (ejection fraction <40%),25,26 this contention appears to be wrong for the hypertensive patient; this is despite a multitude of observational data showing a tight association between heart rate and the cardiovascular and all-cause mortality rate in this patient population, similar to that observed in patients with coronary artery disease or chronic heart failure27,28 However, the fallacy of this contention can be seen in the results of ASCOT, wherein amlodipine–perindopril treatment was superior to atenolol–diuretic therapy for modification of outcomes, despite a higher mean on-treatment heart rate in the amlodipine–perindopril group. The magnitude of this positive effect did not differ in the subgroups with a basal heart rate ranging from <60 beats per minute to >90 beats per minute (Figure 3).29

Figure 3
Figure 3. Relationship between cardiovascular events and baseline heart rate in the
ASCOT trial.

Abbreviations: ASCOT, Anglo-Scandinavian Cardiac Outcomes Trial; bpm, beats per minute; CI, confidence
After reference 29: Poulter NR et al. J Am Coll Cardiol. 2009;54:1154-1161. © 2009, Elsevier.

The negative impact on the prognosis of hypertensive patients of heart rate reduction with β-blockers used as first line therapy was convincingly shown by the results of a meta-regression analysis performed by Bangalore et al.30 Exclusion criteria were previous acute myocardial infarction and chronic heart failure, but not chronic coronary artery disease. Paradoxically, the heart rate lowering attained in the β-blocker group at study end was associated with a proportionate rise in all-cause mortality (r=–0.51), cardiovascular mortality (r=–0.61) (Figure 4), and myocardial infarction rates (r=–0.85; all P<0.0001) (Figure 5). The same was true when the difference in heart rate at study end between the two treatment modalities was compared with the relative risk reduction for these events. Importantly, the average age of the patients was 58 years and the mean basal diastolic BP was 100 mm Hg. One can thus conclude that contrary to the situation in post–myocardial infarction and chronic heart failure patients with low ejection fraction, in hypertensive patients, heart rate elevation can be considered a risk marker but not a risk factor.

This finding can be explained by the important negative impact of central systolic and pulse BP elevation that occurs with pharmacological heart rate lowering, even in patients younger than age 60 years with systolo- diastolic hypertension, and probably in the absence of significant aorta stiffening. Thus, in hypertensive patients without recent myocardial infarction or chronic heart failure with low ejection fraction, even in younger patients, heart rate control should not be considered a therapeutic goal.

Based on this reasoning, I consider it inappropriate to use an ACE inhibitor–β-blocker combination in older patients with uncontrolled uncomplicated hypertension, and think that we should be careful when adding β-blockers to ACE inhibitors (particularly regarding dosing) in younger patients (in whom it would probably be for hyperreninemia correction). In my opinion, the safest candidates are patients with concomitant symptomatic tachycardia, and on-treatment resting heart rate should be as high as tolerated, in no case less than 70 beats per minute (better, 75 beats per minute). The use of nonpharmacological approaches should strongly be recommended as a priority for heart rate reduction in such patients with inappropriate tachycardia; ie, regular aerobic training and correction of excessive body mass.

Figure 4
Figure 4. Cardiovascular mortality risk as a function of heart rate.

Relative risk of cardiovascular mortality as a function of heart rate achieved at the end of the study in
the β-blocker group. The diameter of the circles represents the weight of each individual trial.
Abbreviations: ASCOT, Anglo-Scandinavian Cardiac Outcomes Trial; bpm, beats per minute; ELSA,
European Lacidipine Study on Atherosclerosis; HAPPHY, Heart Attack Primary Prevention in Hypertension;
INVEST, International Verapamil SR and Trandolapril study; IPPSH, International Prospective Primary
Prevention Study in Hypertension; LIFE, Losartan Intervention for End point Reduction trial.
After reference 30: Bangalore S et al. J Am Coll Cardiol. 2008;52:1482-1489. © 2008, Elsevier.

Figure 5
Figure 5. Risk of nonfatal myocardial
infarction as a function of heart rate.

Relative risk of nonfatal myocardial infarction as a function
of heart rate achieved at the end of the study in the
β-blocker group. The diameter of the circles represents
the weight of each individual trial.
Abbreviations: ASCOT, Anglo-Scandinavian Cardiac Outcomes
Trial; bpm, beats per minute; ELSA, European
Lacidipine Study on Atherosclerosis; HAPPHY, Heart
Attack Primary Prevention in Hypertension; INVEST, International
Verapamil SR and Trandolapril study; IPPSH,
International Prospective Primary Prevention Study in
Hypertension; LIFE, Losartan Intervention for End point
Reduction trial; VACS, Veterans Administration
Cooperative Study Group on Antihypertensive Agents.
After reference 30: Bangalore S et al. J Am Coll Cardiol.
2008;52:1482-1489. © 2008, Elsevier

Clinical situations favoring ACE inhibitor–β-blocker combination therapy

In hypertensive patients, the principal indication for combined ACE inhibitor–β-blocker therapy is concomitant coronary artery disease. According to the results of a recent meta-analysis by Law et al,2 compared with placebo or no treatment, β-blocker–based antihypertensive therapy was highly effective in reducing coronary events, chiefly when given within 4 months of an acute myocardial infarction (29% relative risk reduction; P<0.001). However, in hypertensive coronary artery disease patients without recent myocardial infarction or any myocardial infarction, it was only associated with a tendency toward risk reduction compared with placebo (relative risk 0.87; 95% confidence interval, 0.71-1.06) and did not show any benefits in terms of coronary event prevention compared with the other drug classes. Clearly, the pronounced relatively short-term preventive effect of β-blockers in hypertensive patients with recent myocardial infarction (up to 2 years after myocardial infarction) goes mostly beyond BP lowering and is due to their post-infarction protective effect, because in this particular clinical situation, the very high cardiovascular risk is mainly associated with the recent myocardial infarction. The same presumably holds true for the modification of prognosis seen in hypertensive patients with concomitant chronic heart failure and low ejection fraction who are treated with β-blockers. Aside from these situations, it is appropriate to consider the ACE inhibitor–β-blocker combination as the combination of choice for hypertensive patients with angina, or certain arrhythmias, for symptomatic improvement, if not modification of prognosis.31 However, for patients with angina, dihydropyridine CCB add-on therapy would be a better alternative for improvement of outcomes.

Choosing ACE inhibitors and β-blockers

Let us elaborate on which particular ACE inhibitor and β-blocker molecules might be considered as the optimal choices in a fixed-dose combination that could be a useful addition to the existing arsenal of fixed-dose combination antihypertensive drugs.

Trial-based evidence of improvement in outcomes
with certain drugs in certain clinical situations (possible
“drug effects”)

In the ACE inhibitor drug class, perindopril has the largest body of evidence for prognosis modification in hypertensive patients, both from randomized placebo-controlled trials (ADVANCE [Action in Diabetes and VAscular disease: Preterax and DiamicroN MR Controlled Evaluation], HYVET [HYpertension in the Very Elderly Trial], etc) and active comparator trials (ASCOT).

Perindopril and ramipril are the only ACE inhibitors to have demonstrated a cardioprotective effect, in the landmark placebo- controlled EUROPA (EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease) and HOPE trials (Heart Outcomes Prevention Evaluation). Participants in these trials were chronic coronary artery disease patients, including those post–myocardial infarction, more than half of whom had concomitant hypertension with satisfactory, but not optimal, BP control.

In the modern reperfusion era, the evidence-based β-blockers for the post–myocardial infarction patient are carvedilol (CAPRICORN [CArvedilol Post-infaRct survIval COntrol in left ventRicular dysfuNction]) and metoprolol succinate XL (COMMIT [ClOpidogrel and Metoprolol in Myocardial Infarction Trial]). For patients with chronic heart failure with low ejection fraction, in addition to carvedilol and metoprolol XL (COPERNICUS [CarvedilOl ProspEctive RaNdomIzed CUmulative Survival] and MERIT HF [MEtoprolol CR/XL Randomised Intervention Trial in congestive Heart Failure]), there is also bisoprolol (CIBIS-II [Cardiac Insufficiency BIsoprolol Study]). Nebivolol demonstrated a benefit versus placebo in the SENIORS study (Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with heart failure),32 which recruited elderly chronic heart failure patients with any level of ejection fraction—low as well as preserved— but nebivolol did not reduce mortality. For patients with uncomplicated coronary artery disease, we do not yet have evidence that any β-blocker treatment can improve prognosis. Although claims have been made that the pharmacodynamic advantages of the third-generation β-blockers (carvedilol and nebivolol) might transform into certain benefits in outcomes,9 as occurred for carvedilol versus metoprolol tartrate in chronic heart failure patients in the COMET trial (Carvedilol Or Metoprolol European Trial),33 this is not very likely. The CAMIS trial (Carvedilol Acute Myocardial Infarction Study)34 did not show any superiority for carvedilol over atenolol in patients with acute coronary syndrome and a mean ejection fraction of 54%; moreover, the aforementioned COMET trial was subjected to serious criticism.

Evidence of pharmacodynamic advantages
Considering the importance of optimal dual RAS inhibition and nitric oxide production for an ACE inhibitor, at least in terms of coronary event prevention, perindopril might be considered a drug of choice owing to it having the highest selectivity for bradykinin versus angiotensin I binding sites in its drug class.35

In terms of β-blockers, two small studies in hypertensive patients found that, for an equivalent lowering of brachial BP, therapy with nebivolol was associated with a greater reduction in aortic pulse pressure and a superior impact on the augmentation index than atenolol treatment. This was probably due to the reduction of wave reflection with nebivolol as a result of vasodilation of resistant arteries, as well as higher on-treatment heart rates.36,37 One might expect the same from carvedilol. I share the opinion of Sever and Messerli,38 however, that this complimentary effect of the newer β-blockers is unlikely to significantly improve clinical outcomes with fulldose β-blocker therapy in hypertensive patients, because heart rate reduction per se is the cornerstone of the suboptimal effect of β-blockers on central BP, as well as on BP variability.39 The latter, in addition to central BP, is considered to be a strong predictor of both stroke and myocardial infarction in hypertensive patients,40 and there is no evidence that the newer generation of β-blockers improves BP variability.41

Evidence of advantages in tolerability
In hypertensive patients with diabetes, the GEMINI trial (Glycemic Effects in diabetes Mellitus: carvedIlol-metoprolol comparisoN In hypertensives) showed a decrease in insulin resistance after treatment with carvedilol, but not metoprolol.42

The latter produced an increase in glycosylated hemoglobin levels from baseline, whereas the levels did not change over the course of therapy with carvedilol.4243 This can be at least partly explained by the peripheral vasodilatory properties that are unique to both of these third-generation β-blockers.

Evidence of pharmacokinetic advantages
In terms of pharmacokinetic advantages, perindopril is preferable to several other ACE inhibitors, including ramipril, and bisoprolol and nebivolol are preferable to carvedilol.

In conclusion, the optimal choice of drugs is likely to be: (i) perindopril, as it has the largest body of evidence showing beneficial outcomes in hypertensive and coronary artery disease patients; and (ii) long-acting β-blockers such as bisoprolol that have evidence of mortality reduction in post–myocardial infarction and heart failure patients. Nebivolol could also be considered due to its advantages in terms of metabolic control and pulse wave reflection, which is associated with relatively mild heart rate lowering and peripheral vasodilation.

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Keywords: ACE inhibitor; β-blocker; cardiovascular outcome; combination therapy; hypertension