Abstract

Activation of the renin–angiotensin system (RAS) plays an important role in the promotion of cardiovascular disease and target-organ damage, mediated in part by hypertension. Combination therapy targeting RAS activation may reduce target-organ damage and provide superior blood pressure (BP) control; combining angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) represents one possible approach. In monotherapy studies, both ACE inhibitors and ARBs have demonstrated similar positive effects on BP and on RAS-related target-organ damage, including nephropathy and congestive heart failure. Studies of combination therapy, most of which involved addition of an ARB to existing ACE inhibitor therapy, have demonstrated benefits among patients with congestive heart failure and renal disease. However, variances in study design and populations, dosing and titration methods, and clinical end points, in addition to inherent differences between agents, limit the ability to reach clinically meaningful conclusions about the value of dual RAS inhibition. Trials designed to document such efficacy are currently underway.

Activation of the renin–angiotensin system (RAS) is a primary driver of multiple adverse cardiovascular effects across a range of disease states. These effects, including hypertension, vascular remodeling, and endothelial dysfunction, are attributable in part to increased levels of the highly active neurohormone—angiotensin II—and are associated with profound damage to the cardiovascular system as a whole and to specific target organs, especially the heart, brain, kidneys, and retinas. Blood pressure (BP) elevation from RAS activation may damage the target organs but RAS-mediated effects may contribute independently to adverse outcomes.1,2

Two classes of pharmacologic agents with mechanisms of action that directly inhibit RAS pathways are currently available and in widespread use: angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). Although these agents were initially approved for treatment of hypertension, it should be emphasized that BP reduction in established targets is only a means to an end. The aim of antihypertensive therapy is to prevent and/or limit damage to the cardiovascular system and target organs. Moreover, as the pleiotropic effects of RAS activation have become more fully understood, it has become apparent that although BP reduction is the most easily measured outcome of RAS-directed therapy, the impact of such therapy may extend beyond hypertension.3,4,5

On the basis of clinical observations and clinical studies of antihypertensive agents, current consensus guidelines have concluded that antihypertensive monotherapy, regardless of the agent used, is insufficient to enable most hypertensive patients to reach BP targets.3,4 This review discusses the theoretical basis and clinical evidence suggesting that dual RAS inhibition with an ACE inhibitor plus an ARB results in additive benefit compared to monotherapy with regard to BP reduction, target-organ damage, and poor outcomes.

RAS Activation and Target-Organ Damage

Overview of the RAS

Key components and pathways of the RAS are depicted schematically in Figure 1, which illustrates the conversion of the progenitor angiotensinogen by renin to inactive angiotensin I, followed by conversion by ACE to angiotensin II. Increased expression and activity of angiotensin II is one factor involved in promoting hypertension, and ultimately target-organ damage. In addition to its action as a potent vasoconstrictor (the primary source of its hypertensive effects), angiotensin II also stimulates increased expression and release of aldosterone and the antidiuretic hormone (or vasopressin), both of which induce fluid retention that further contributes to hypertension.

Schematic depiction of the components (boxes), pathways (bold arrows), and receptors (ovals) involved in the RAS, along with potential points of inhibition (broken lines). ARB, angiotensin II receptor blocker; ACE, angiotensin-converting enzyme; RAS, renin–angiotensin system.

Figure 1 also illustrates possible targets for pharmacologic intervention directed at excessive or inappropriate RAS activity (shown schematically by broken lines). ACE inhibitors limit the conversion of inactive angiotensin I to angiotensin II; ARBs prevent angiotensin II from activating the AT-1 receptor, which appears to be the principal effector of RAS-induced adverse cardiovascular and renal outcomes.

In addition to ACE inhibition and AT-1 receptor blockade, two additional points in the RAS offer the potential for therapeutic intervention, although a detailed consideration of these is beyond the scope of this article. Aldosterone, which is in part under the influence of RAS activation, may be especially important in the development of vascular inflammation; two aldosterone blockers, spironolactone and eplerenone, are currently available in the United States.6 Spironolactone has reduced mortality and hospitalization in patients with severe congestive heart failure (CHF) already receiving ACE inhibitor plus diuretic therapy; similarly, addition of eplerenone, a selective aldosterone blocker, to optimal medical therapy reduced cardiovascular and overall mortality among patients with left ventricular dysfunction secondary to myocardial infarction.7,8

Inhibition of renin, which is responsible for the initial rate-limiting step in RAS activation, is also a logical target for RAS blockade.9 β-blockers inhibit renin secretion through the renal β-receptor, an effect that contributes to their antihypertensive efficacy. Aliskiren, a direct renin inhibitor that was approved by the US Food and Drug Administration in March 2007, has demonstrated the ability to provide dose-dependent BP reductions comparable to those provided by the ARB, losartan. Direct renin inhibition blocks the formation of angiotensin II at the rate-limiting step in this process, and it also has the potential to prevent the formation of angiotensin I and II via alternative pathways that may occur during long-term ACE inhibitor treatment.10,11,12

Effects of RAS activation

There are multiple pathways by which angiotensin II may contribute to both hypertension and target-organ damage. It modulates vasomotor tone and promotes cell growth and migration and extracellular matrix deposition. It also has proinflammatory effects that involve stimulation of both growth factors and other vasoactive agents. The signaling pathways that mediate the actions of angiotensin include stimulation of the phospholipase C–inositol 1,4,5-trisphosphate-1,2-diacylglycerol cascade, mitogen-activated protein kinases, tyrosine kinases, and RhoA/Rho kinase.13 It has also been shown that angiotensin II stimulates the formation of reactive oxygen species via activation of vascular nicotinamide adenine dinucleotide phosphate oxidase.13 Activation of these pathways may result in multiple deleterious effects, including aggravation of hypertension and the metabolic syndrome, negative effects on glucose/lipid metabolism, impairment of endothelial function via alteration in the redox status of endothelial cells, and exacerbation of atherosclerosis. Atherogenic effects of angiotensin II include promotion of local uptake, synthesis, and oxidation of lipids; stimulating migration and proliferation of inflammatory cells; destabilization of atherosclerotic plaques; enhancing activity of thrombocytes and coagulation; and adverse effects on renal function.1,14,15,16,17

Studies of endothelial function using both isolated arterioles and in vivo functional assays have shown that ARB treatment restores normal function, including response to the endogenous vasodilator nitric oxide and nitric oxide inhibitors.18,19 Endothelial dysfunction, involving reduced nitric oxide synthesis and availability and impaired response, further exacerbates hypertension; it also plays a central role in cardiovascular pathology, promoting atherosclerosis and atherothrombosis.20

Recent evidence suggests that the transduction of RAS activation into target-organ damage may be initiated through the remodeling of small arteries and arterioles. The precapillary microcirculation (arterial diameter <350 μm) is the point at which the greatest control over BP and flow is exerted and, consequently, the point at which even relatively minimal changes in arterial structure and function may have a marked effect on BP.21

Target-organ damage can perhaps be best assessed using changes in renal function. The risk for both cardiovascular disease and chronic kidney disease correlate strongly and independently with the presence and severity of microalbuminuria across a wide range of patients, including those both with and without diabetes.4,22,23,24 This early stage of renal dysfunction (preceding frank dipstick-positive proteinuria) can be non-invasively assessed and tracked using the albumin/creatinine ratio; in patients with and without diabetes, the albumin/creatinine ratio has a continuous progressive relationship with cardiovascular events, mortality, and hospitalization for CHF.23 Other forms of target-organ damage, such as left ventricular hypertrophy (LVH) and vascular remodeling, are usually asymptomatic in their early stages and are generally impractical for routine assessment.

RAS Inhibition by ACE Inhibitors and ARBs

Combination therapy is usually based on attacking different pathophysiologic pathways or different points in the same pathway that lead to adverse outcomes. A key concern with ACE inhibitor (and possibly ARB) monotherapy is a reactive increase in the level of renin (the rate-limiting effector in the RAS cascade), leading in turn to reactive increases in angiotensin I and angiotensin II levels with continued therapy over time.9,25 This potential “escape” makes combination therapy using an ACE inhibitor plus an ARB particularly attractive as a way to further suppress RAS activation, because each class targets different steps in this cascade. The phenomenon of ACE escape also supports the use of a renin inhibitor for RAS blockade.

In studies of monotherapy, ACE inhibitors have generally provided BP reduction consistent with that provided by older antihypertensive agents (including diuretics and β-blockers), along with similar improvements with regard to cardiovascular outcomes.4,26 Beyond direct BP effects, meta-analyses of ACE inhibitor studies have shown the ability to induce regression of LVH, an important marker of progressive remodeling and independent risk factor for morbidity, mortality, and cardiovascular events.27,28,29 Similarly, a number of recent studies have documented the ability of ARBs to reverse or attenuate the progression of LVH.30,31,32,33,34,35

As yet, no large-scale study has directly compared an ARB with a diuretic; however, the Losartan Intervention For Endpoint Reduction in Hypertension study compared the ARB losartan with the β-blocker atenolol among patients with essential hypertension and electrocardiographic evidence of LVH. The Losartan Intervention For Endpoint Reduction in Hypertension study showed that despite nearly identical reductions in BP with losartan and atenolol, losartan-treated patients were significantly less likely to experience a cardiovascular event, primarily because of significant reduction of stroke risk; in addition, losartan treatment was associated with reduced risk of new-onset diabetes.36 The reduction in stroke risk in the Losartan Intervention For Endpoint Reduction in Hypertension study led to the granting of a stroke indication for losartan. AT-1 receptor blockade may lower stroke risk (beyond effects attributable to BP reduction) via a number of possible mechanisms, including reduced incidence of atrial fibrillation, antiproliferative effects, or direct action on cerebrovascular AT-1 receptors.37

With regard to nephropathy, ACE inhibitors reduce urinary protein excretion and progression to end-stage renal disease among patients both with and without diabetes. In both patient classes, the beneficial effects of ACE inhibitor therapy could not be fully accounted for based solely on BP-lowering effects.38,39,40

Although a large-scale study of ARBs in the context of non-diabetic nephropathy has not yet been conducted, studies in patients with diabetes have shown that irbesartan reduces the risk of progression to frank nephropathy among patients with microalbuminuria.41 In addition, irbesartan and losartan reduce the risk of a composite renal outcome (end-stage renal disease, doubling of serum creatinine level, or mortality from any cause) among diabetic patients with extant nephropathy.42,43 As with ACE inhibitor therapy, reductions in BP with ARBs are not sufficient to explain the improvement in renal outcomes.

The Diabetics Exposed to Telmisartan and Enalapril study provided the first direct comparison between an ACE inhibitor (enalapril) and an ARB (telmisartan) with regard to long-term renal protective outcomes in patients with type 2 diabetes (n = 250; primary endpoint was analyzed for 216 patients). With respect to the primary end point, change in glomerular filtration rate, both treatment groups demonstrated comparable mean annual declines (indicating disease progression) after 5 years (enalapril, −15.0 ml/min/1.73 m2; telmisartan, −17.5 ml/min/1.73 m2per year; P = NS). The pattern of decline was similar for each agent; 7.6, 5.6, and 3.6 ml/min/1.73 m2 in years 1, 2, and 3, respectively, and a negligible decline in years 4 and 5. Importantly, no patient in either group advanced to end-stage renal disease or dialysis during the study, and mortality was low and identical between groups (six deaths in each group).44

Perhaps the most important distinction between earlier antihypertensive agents and ACE inhibitors and ARBs is that the newer drugs appear to affect multiple pathophysiologic conditions and pathways associated with RAS activation, including LVH, CHF, and nephropathy, in addition to development of type 2 diabetes mellitus, to a degree greater than expected based on BP reduction alone. As a result, recent consensus statements on hypertension have variously suggested that diabetes, diabetic and non-diabetic nephropathy, CHF, and LVH/left ventricular dysfunction represent “compelling indications” for or “conditions favoring the use” of ACE inhibitors, ARBs, or both.3,4,5

While considering the results from the Losartan Intervention For Endpoint Reduction in Hypertension study as well as those of other trials that have suggested BP-independent effects of ARBs, it is also important to consider results from the Conduit Artery Function Evaluation substudy of the Anglo-Scandinavian Cardiac Outcomes Trial.45 This study investigated whether different BP-lowering drugs (amlodipine with or without perindopril vs. atenolol with or without a thiazide diuretic) could have different effects on central aortic pressures despite similar effects on brachial BP. Results from this evaluation indicated similar brachial artery systolic BPs with the two treatments but substantial reductions in calculated central aortic pressures with amlodipine-based vs. atenolol-based treatment. Although the method for computing aortic pressures from radial pressure waveforms has been questioned,46 the results raise the possibility that some of the putative non-brachial BP effects of drugs may be mediated through reductions in central pressure. Nonetheless, it must be recognized that differences in wave reflection influencing central aortic pressure result from differences in small-artery effects that may be dependent on RAS activation. Since ARB therapy improves small-artery compliance,47 it is likely that wave reflections and central pressure would be reduced by RAS blockade. Thus the specific vascular effects of amlodipine and RAS inhibitors apparently lower central pressure, and it cannot be concluded whether the lower central pressure or the favorable vascular effects improved the outcome in the Anglo-Scandinavian Cardiac Outcomes Trial.

Clinical Studies: ACE Inhibitor Plus ARB Combination Therapy

Most studies of ACE inhibitor plus ARB combination therapy have involved patients with either CHF or nephropathy; reflecting the temporal order of their availability, most have used an active-comparator design in which an ARB was added to existing ACE inhibitor treatment. Although both drug classes are in general well tolerated, the incidence of adverse effects is lower with ARBs, leading some to suggest that the optimal approach to combination therapy might be to first maximize the dose of an ARB agent, followed by titration of an ACE inhibitor.9 Results from studies that have evaluated the effects of combination ACE inhibitor plus ARB therapy are summarized in Table 1.46,47,48,49,50,51,52,53,54,55,56

Table 1

Effects of combination therapy with an ACE inhibitor and an ARB

Study Number of patients Patient characteristics BP results Clinical/other results Comment 
Doulton48 434 Essential hypertension Combination therapy was significantly superior to ACE inhibitor or ARB alone in lowering BP None Advantage of combination therapy was lost with long-acting ACE inhibitors or when short-acting ACE inhibitors were administered in high doses 
Petrovic50 44 Moderate-to-severe hypertension BP reductions with telmisartan, ramipril, and the combination were not significantly different Telmisartan plus ramipril was significantly superior to either agent alone in improving LVMI, IMT, and CSA  
ValHeFT51 5,010 Class II–IV CHF Addition of valsartan to ACE inhibitor was superior to placebo in lowering BP Addition of valsartan to ACE inhibitor significantly decreased mortality and morbidity  
RESOLVD53 426 Class II–IV CHF Trend toward lower systolic BP with candesartan plus enalapril Combination of candesartan plus enalapril was significantly superior to either drug alone in improving cardiac ejection fraction  
CHARM-added54 2,548 Class II–IV CHF and ejection fraction ≰40% Addition of candesartan to ACE inhibitor resulted in significantly greater BP reductions than addition of placebo Combination of candesartan plus an ACE inhibitor significantly decreased risk versus placebo plus an ACE inhibitor for primary composite outcome of cardiovascular death or hospitalization for HF  
CHARM-overall55 7,601 Class II–IV CHF and ejection fraction ≰40% Not reported Combination of candesartan plus an ACE inhibitor significantly decreased all-cause mortality  
Cice56 80 CHF and ejection fraction <40% Not reported Addition of telmisartan to ACE inhibitor significantly decreased the risks for CHF hospitalization, all-cause mortality, and cardiovascular death  
VALIANT57 4,909 Recent myocardial infarction Addition of valsartan to captopril was significantly superior to placebo in lowering BP No significant differences between treatment groups with regard to the primary outcome measure, death from any cause  
CALM58 199 Diabetes mellitus, hypertension, and proteinuria Combination of lisinopril and candesartan was significantly superior to either drug alone in lowering BP Combination of lisinopril and candesartan was significantly superior to either drug alone in decreasing the albumin/creatinine ratio  
CALM II59 75 Diabetes mellitus plus hypertension Combination of candesartan and low-dose lisinopril was not significantly superior to high-dose lisinopril in lowering BP Combination of candesartan and low-dose lisinopril was not significantly superior to high-dose lisinopril placebo in lowering the albumin/creatinine ratio  
COOPERATE61 263 Chronic non-diabetic nephropathy Reductions in BP similar to losartan, trandolapril, and the combination Losartan plus trandolapril was significantly superior to either drug alone for decreasing risk for the composite endpoint of doubling of serum creatinine level or progression to end-stage renal disease  
Study Number of patients Patient characteristics BP results Clinical/other results Comment 
Doulton48 434 Essential hypertension Combination therapy was significantly superior to ACE inhibitor or ARB alone in lowering BP None Advantage of combination therapy was lost with long-acting ACE inhibitors or when short-acting ACE inhibitors were administered in high doses 
Petrovic50 44 Moderate-to-severe hypertension BP reductions with telmisartan, ramipril, and the combination were not significantly different Telmisartan plus ramipril was significantly superior to either agent alone in improving LVMI, IMT, and CSA  
ValHeFT51 5,010 Class II–IV CHF Addition of valsartan to ACE inhibitor was superior to placebo in lowering BP Addition of valsartan to ACE inhibitor significantly decreased mortality and morbidity  
RESOLVD53 426 Class II–IV CHF Trend toward lower systolic BP with candesartan plus enalapril Combination of candesartan plus enalapril was significantly superior to either drug alone in improving cardiac ejection fraction  
CHARM-added54 2,548 Class II–IV CHF and ejection fraction ≰40% Addition of candesartan to ACE inhibitor resulted in significantly greater BP reductions than addition of placebo Combination of candesartan plus an ACE inhibitor significantly decreased risk versus placebo plus an ACE inhibitor for primary composite outcome of cardiovascular death or hospitalization for HF  
CHARM-overall55 7,601 Class II–IV CHF and ejection fraction ≰40% Not reported Combination of candesartan plus an ACE inhibitor significantly decreased all-cause mortality  
Cice56 80 CHF and ejection fraction <40% Not reported Addition of telmisartan to ACE inhibitor significantly decreased the risks for CHF hospitalization, all-cause mortality, and cardiovascular death  
VALIANT57 4,909 Recent myocardial infarction Addition of valsartan to captopril was significantly superior to placebo in lowering BP No significant differences between treatment groups with regard to the primary outcome measure, death from any cause  
CALM58 199 Diabetes mellitus, hypertension, and proteinuria Combination of lisinopril and candesartan was significantly superior to either drug alone in lowering BP Combination of lisinopril and candesartan was significantly superior to either drug alone in decreasing the albumin/creatinine ratio  
CALM II59 75 Diabetes mellitus plus hypertension Combination of candesartan and low-dose lisinopril was not significantly superior to high-dose lisinopril in lowering BP Combination of candesartan and low-dose lisinopril was not significantly superior to high-dose lisinopril placebo in lowering the albumin/creatinine ratio  
COOPERATE61 263 Chronic non-diabetic nephropathy Reductions in BP similar to losartan, trandolapril, and the combination Losartan plus trandolapril was significantly superior to either drug alone for decreasing risk for the composite endpoint of doubling of serum creatinine level or progression to end-stage renal disease  

ARB, angiotensin II receptor blocker; ACE, angiotensin-converting enzyme; BP, blood pressure; CALM, Candesartan and Lisinopril Microalbuminuria; CHARM, Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity; CHF, congestive heart failure; COOPERATE, Combination Treatment of Angiotensin II Receptor Blocker and Angiotensin-converting Enzyme Inhibitor in Nondiabetic Renal Disease; CSA, cross-sectional intima-media area; HF, heart failure; IMT, intima-media thickness; LVMI, left ventricular mass index; RESOLVD, Randomized Evaluation of Strategies for Left Ventricular Dysfunction Pilot Study; Val-HeFT, Valsartan Heart Failure Trial; VALIANT; Valsartan in Acute Myocardial Infarction.

Studies in patients with hypertension

The benefits of combining an ACE inhibitor and an ARB in patients with hypertension have been evaluated in a meta-analysis that included information from 14 studies.48 Overall, ACE inhibitor plus ARB combinations reduced ambulatory BP by 4.7/3.0 mm Hg vs. ACE inhibitor monotherapy and 3.8/2.9 mm Hg vs. ARBs alone. The respective decreases in clinic BP were 3.8/2.7 and 3.7/2.3 mm Hg. However, it is important to note that submaximal doses or once-daily dosing of shorter-acting ACE inhibitors were employed in most of the trials reviewed and that when a larger dose of shorter-acting ACE inhibitor was given or a longer-acting ACE inhibitor was used, there was generally no additive effect of the ARBs on BP in patients receiving ACE inhibitors.48

The combination of aliskiren and valsartan has also been evaluated in a double-blind study that included 1,797 patients with hypertension. At the week 8 endpoint, the combination of aliskiren 300 mg and valsartan 320 mg lowered mean sitting diastolic BP from baseline by 12.2 mm Hg, significantly more than either monotherapy or placebo.49

In a smaller open-label study, monotherapy using the ARB telmisartan or the ACE inhibitor ramipril was compared with combination telmisartan plus ramipril therapy in 75 previously untreated patients with moderate-to-severe hypertension. This 6-month study focused on cardiovascular remodeling outcomes, using left ventricular mass index, carotid intima-media thickness, and carotid cross-sectional intima-media area as endpoints. These remodeling endpoints demonstrated significant improvement with both ARB and ACE inhibitor monotherapy, with somewhat greater improvement observed with telmisartan than with ramipril (left ventricular mass index reduction: telmisartan 11.4%, ramipril 9.9%; intima-media thickness reduction: telmisartan 14.6%, ramipril 12.0%; cross-sectional intima-media area reduction: telmisartan 7.8%, ramipril 4.3%). However, all three endpoints demonstrated consistently greater improvement with the combination (reductions of 15.6, 18.2, and 11.5% in left ventricular mass index, intima-media thickness, and cross-sectional intima-media area, respectively). Importantly, these differences were observed despite comparable BP reductions with all three regimens.50

Studies in patients with CHF

The Valsartan Heart Failure Trial compared the ARB, valsartan, with a placebo as an adjunct to existing therapy in patients with New York Heart Association functional class II–IV CHF. Because ACE inhibitor therapy was the accepted standard of care, 93% of the 5,010 enrolled patients were receiving an ACE inhibitor at baseline. Although not designed as a combination study, and despite the low proportion of patients not receiving ACE inhibitors, the study size permitted statistical subgroup comparisons based on the presence or absence of ACE inhibitor baseline treatment. The reductions in the primary end points of mortality and mortality plus morbidity associated with valsartan therapy were larger among patients not receiving an ACE inhibitor at baseline than among those receiving an ACE inhibitor. However, the addition of valsartan to existing ACE inhibitor therapy still produced significant improvement in mortality plus morbidity versus placebo (P = 0.02), primarily as a result of a reduction in hospitalization for heart failure. Valsartan also demonstrated an improvement in the cardiac ejection fraction, regarded as a marker for regression of RAS-associated remodeling. In the Valsartan Heart Failure Trial, the addition of valsartan to the treatment of patients receiving both an ACE inhibitor and a β-blocker at baseline surprisingly worsened mortality versus placebo. The Valsartan Heart Failure Trial study did not include BP reduction as an end point.51 In a post-hoc analysis of patients not receiving a β-blocker, the dosage of the ACE inhibitor appeared to influence morbidity. Reduction in hospitalization for heart failure was significantly improved regardless of the ACE inhibitor dose.52

In the Randomized Evaluation of Strategies for Left Ventricular Dysfunction Pilot Study, 426 patients with New York Heart Association functional class II–IV CHF were randomized to treatment with the ACE inhibitor enalapril, the ARB candesartan, or combination enalapril plus candesartan; in addition, patients in each arm were randomized to the addition of either the β-blocker metoprolol or the placebo. After 43 weeks, patients receiving enalapril plus candesartan plus metoprolol had significantly greater improvement in the primary end point, or the cardiac ejection fraction, than patients receiving enalapril plus candesartan (P ≤ 0.01) or enalapril or candesartan monotherapy (P ≤ 0.001), although the effect was modest. Similar patterns were found for end-systolic volume and end-diastolic volume; thus, with regard to these remodeling outcomes, triple-agent therapy was found to be beneficial relative to ACE inhibitor plus ARB therapy. There were no significant between-group differences in systolic or diastolic BP reduction; however, the candesartan plus enalapril group showed a trend toward greater systolic BP reduction than other groups. Both dual ACE inhibitor plus ARB therapy and triple ACE inhibitor plus ARB plus β-blocker therapy were well tolerated.53 These data suggest that triple-agent therapy is beneficial in patients with heart failure; however, the study was too small to evaluate whether the changes observed in cardiac volumes translate into an improvement in the rate of clinical events.

The Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity (CHARM-Added) study compared candesartan with a placebo as adjunctive therapy in 2,548 patients with New York Heart Association functional class II–IV CHF and an ejection fraction ≤40% and already receiving ACE inhibitors. After a median follow-up of 41 months, patients receiving candesartan plus an ACE inhibitor were significantly less likely than patients receiving the placebo plus an ACE inhibitor to experience the primary composite outcome, cardiovascular death or hospitalization for heart failure (hazard ratio, 0.85 (95% confidence interval, 0.75–0.96); P = 0.011). In addition, candesartan was associated with significantly greater reductions than the placebo in systolic BP (4.6 mm Hg vs. placebo, P = 0.007) and diastolic BP (3.0 mm Hg vs. placebo, P = 0.004) after 6 months of therapy. Candesartan therapy produced comparable benefit with regard to multiple secondary outcomes (various combinations of CHF events), and benefit was similar between patients receiving or not receiving β-blockers at baseline.54

In addition to CHARM-Added, the CHARM study program incorporated studies of candesartan in patients with CHF who were intolerant of ACE inhibitors (CHARM-Alternative) and in those with a left ventricular ejection fraction >40% (CHARM-Preserved). Pooled results across all three studies (CHARM-Overall) support the conclusion that the addition of an ARB provides added benefit in patients already receiving ACE inhibitors.55 Across the entire CHARM program, candesartan provided comparable benefit to patients with New York Heart Association functional class II–IV heart failure with regard to the primary composite end point of cardiovascular death or hospitalization for heart failure, regardless of ACE inhibitor use at baseline. Candesartan was also associated with significantly greater BP reductions than the placebo (systolic, 5.2 mm Hg vs. placebo; diastolic, 3.0 mm Hg vs. placebo; P < 0.001 for both comparisons) after 6 months of therapy.55

A double-blind study compared an ARB (telmisartan at 80 mg/day or maximal tolerated dose) with a placebo in hemodialysis patients with CHF (cardiac ejection fraction <40%) who were already receiving baseline ACE inhibitor therapy. After 35 months of follow-up, telmisartan therapy was associated with significant reduction versus placebo in CHF hospitalization (37.7% vs. 68.4%, P < 0.0001), an indicator of worsening heart function. In addition, ARB therapy significantly reduced the risk of all-cause mortality (58.3% vs. 73.1%, P < 0.001) and cardiovascular death (39% vs. 49.3%, P < 0.001).56

The Valsartan in Acute Myocardial Infarction study compared combination therapy with the ACE inhibitor, captopril, plus the ARB, valsartan, to monotherapy with each agent in patients with recent myocardial infarction (within 10 days). Mean systolic and diastolic BP increased in all groups after 1 year of treatment; however, there were significant differences favoring the combination therapy group over the captopril group with regard to systolic and diastolic BP (P < 0.001 for both comparisons). After a median follow-up of 24.7 months, there were no significant differences between treatment groups with regard to the primary outcome measure, death from any cause, or multiple secondary outcomes involving various combinations of death from cardiovascular events. In addition, the combination of valsartan plus captopril was associated with higher rates of adverse events and discontinuation than was either monotherapy arm. To some extent, these results appear to conflict with those from the Valsartan Heart Failure Trial and CHARM studies, which demonstrated added benefit when an ARB was added to ACE inhibitor therapy; however, the Valsartan in Acute Myocardial Infarction study initiated patients on combination therapy, rather than adding a new therapy onto preexisting background therapy.57

Studies in patients with nephropathy

With regard to renal disease outcomes, the Candesartan and Lisinopril Microalbuminuria study compared the combination of candesartan plus the ACE inhibitor lisinopril with candesartan and lisinopril monotherapy in 199 patients with type 2 diabetes mellitus complicated by hypertension (diastolic BP 90–110 mm Hg) and microalbuminuria. After 24 weeks of treatment, patients in all treatment groups experienced significant reductions in BP and albumin/creatinine ratio. However, patients receiving combination therapy achieved significantly greater reductions than either monotherapy regimen in BP, averaging about 8 mm Hg lower than both lisinopril and candesartan (mean reduction in BP from baseline with combination: systolic, 25.3 mm Hg; diastolic, 16.3 mm Hg). Combination therapy was also associated with greater reduction from baseline in albumin/creatinine ratio (50%) than either of the monotherapies (lisinopril 39% (P = 0.04 vs. combination); candesartan 24% (P > 0.20 vs. combination)). In addition, combination therapy was as well tolerated as either of the monotherapies.58

In the Candesartan and Lisinopril Microalbuminuria II study, however, the combination of candesartan plus low-dose lisinopril (20 mg/day) did not produce greater BP reductions than high-dose lisinopril (40 mg/day) monotherapy after 1 year of treatment in patients with type 1 or type 2 diabetes mellitus and hypertension.59 Ambulatory systolic BP in this study tended to favor combination therapy at end point (mean difference, 3.9 mm Hg) but this difference was not significant (P = 0.16). The investigators suggest that incremental benefit of dual RAS inhibition may not be realized unless the ACE inhibitor component is titrated to maximal dosage.59 This concept is supported by results of a small-scale cross-over study (20 patients with type 2 diabetes mellitus and chronic nephropathy) in which the addition of candesartan to maximal doses of lisinopril, enalapril, or captopril produced a significant incremental reduction in albuminuria.60

Among non-diabetic patients, renal outcomes were evaluated in the Combination Treatment of Angiotensin II Receptor Blocker and Angiotensin-converting Enzyme Inhibitor in the Non-diabetic Renal Disease study, which randomized 263 patients with chronic nephropathy to the combination of the ACE inhibitor, trandolapril, plus the ARB, losartan, or monotherapy with either agent. After 3 years of treatment and follow-up, 11% of the patients receiving losartan plus trandolapril experienced the primary composite end point (doubling of serum creatinine level or progression to end-stage renal disease) compared to 23% in both the losartan and trandolapril monotherapy groups (vs. losartan: hazard ratio 0.40 (95% confidence interval, 0.17–0.69), P = 0.016; vs. trandolapril: hazard ratio 0.38 (95% confidence interval 0.18–0.63), P = 0.018). These differences were sufficient to lead to premature discontinuation of the study at 3 years rather than the planned 5 years. Importantly, the impact of combination therapy on renal outcomes appears to be mediated by mechanisms independent of BP, because BP reductions from baseline were similar across all groups (∼5 mm Hg for systolic and 3 mm Hg for diastolic).61

It is challenging to reach generalized conclusions based on this survey of existing studies of dual RAS blockade. In addition to addressing different manifestations of RAS activation (e.g., CHF vs. nephropathy), these studies vary enormously with respect to study design and duration, end points, size of study population, and baseline disease attributes. Based on the available data, however, several points emerge with regard to combination ACE inhibitor plus ARB therapy. First, there is some evidence of added benefit relative to monotherapy with either agent class used in standard doses. Second, despite some exceptions, the safety and tolerability of combination therapy appears to be comparable to monotherapy with either class. Third, the added benefits of combination therapy with regard to target-organ damage are observed in both the presence and absence of additive effects on BP reduction. The results from the meta-analysis of ACE inhibitor and ARB combination in patients with hypertension also underscore the importance of dosing issues in these studies. Furthermore, it is important to keep in mind data from the Conduit Artery Function Evaluation study, which suggest that brachial BP may not be an adequate guide to antihypertensive efficacy.

Although the reasons that combination therapy enhances target-organ benefits in the absence of apparent incremental BP reduction remain unclear, a possible mechanism may involve aldosterone, which is recognized as a particularly important driver of cardiovascular remodeling. Recent evidence suggests that dual ACE inhibitor–ARB therapy induces synergistic reductions in aldosterone levels.62

Before any conclusion regarding the efficacy and safety of combination ACE inhibitor plus ARB therapy can be made, more clinical evidence is needed. A large, ongoing study may provide additional information with regard to the effectiveness of combination therapies. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial study has randomized 23,400 high-risk patients to monotherapy with the ARB telmisartan, the ACE inhibitor ramipril, or combination therapy. The primary end point is a composite of cardiovascular mortality, stroke, acute myocardial infarction, and hospitalization for CHF, with a maximum follow-up of 5.5 years; the results are expected to be reported in 2008 (ref. 63).

Conclusions

Based on the evidence described here, dual RAS inhibition with ACE inhibitors and ARBs appears to be a promising, but not yet fully tested, approach to the treatment of patients at high risk for adverse cardiovascular and target-organ outcomes resulting from RAS activation. Studies involving patients with CHF and with nephropathy have generally suggested incremental benefits for dual RAS inhibition over ACE inhibitor or ARB monotherapy, and these benefits may extend to regression, attenuation, and/or prevention of target-organ damage.

Critical unanswered questions remain with regard to treatment sequencing (initiation with a fixed-dose combination vs. ARB initiation prior to or following ACE inhibitor initiation), optimal dosing of both ACE inhibitor and ARB, and within-class differences between agents. From a mechanistic point of view, additional research is also required to further clarify the nature and extent of target-organ treatment effects that are attributable to or independent of BP reduction.

Disclosure:

J.N.C. received consulting fees, research grants, or honoraria from Boehringer Ingelheim, GlaxoSmithKline, Medtronic, and Novartis. J.M.G. received research support from Novartis, Boehringer Ingelheim, Amgen, Genentech, and Novo-Nordisk.

Acknowledgements

Editorial assistance for the development of this manuscript was provided by Steve Collins, Boehringer Ingelheim Pharmaceuticals. This work was supported by Boehringer Ingelheim Pharmaceuticals.

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