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Current Vascular Pharmacology, 2010, 8, 742-746
Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in the Treatment of Hypertension: Should they be Used Together? Paolo Verdecchia1,*, Fabio Angeli2, Giovanni Mazzotta3, Giuseppe Ambrosio3 and Gianpaolo Reboldi4 1
Dipartimento di Medicina, Ospedale di Assisi, Assisi, Italy; 2Struttura Complessa di Cardiologia, Unità di Ricerca Clinica ‘Cardiologia Preventiva’, Ospedale S. Maria della, Misericordia, Perugia, Italy; 3Università degli Studi di Perugia, Struttura Complessa di Fisiopatologia Cardiovascolare, Perugia, Italy; 4Università degli Studi di Perugia, Dipartimento di Medicina Interna, Perugia, Italy Abstract: The combined use of angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) poses a dilemma to clinicians. On the one hand, indirect evidence from compelling, but still surrogate outcome measures such as blood pressure and proteinuria suggest some merits of this combination. On the other hand, the outcome benefits of the ACEIs+ARBs combination in morbidity/mortality trials remain confined to patients with severe congestive heart failure (CHF) and reduced ejection fraction. Incidentally, most of the benefit offered by the ACEIs+ARBs combination in these patients was not driven by mortality, but by fewer rehospitalizations for CHF. Even in patients with renal disease and proteinuria, the combined use of ACEIs and ARBs, although highly effective in reducing urinary protein excretion, has not yet been proven to significantly delay end-stage renal disease and the need for dialysis. In the Ongoing Telmisartan Alone and In Combination With Ramipril Global Endpoint Trial (ONTARGET), the dual blockade of the renin angiotensin system did not produce additional outcome benefit over that afforded by ACE inhibition alone. Notably, however, patients with BP >160/100 mmHg at entry were excluded from ONTARGET, thus limiting the applicability of these results to the treatment of hypertension. The European Society of Hypertension guidelines do not suggest large-scale use of the ACEIs+ARBs combination in patients with hypertension. However, patients with resistant hypertension, particularly if proteinuria coexists, could benefit from this combination, which however requires close monitoring for adverse events, including hyperkalemia and worsening renal function.
Keywords: Angiotensin converting enzyme inhibitors, angiotensin receptor blockers, hypertension, proteinuria, renal failure. INTRODUCTION The dual blockade of the renin-angiotensin system (RAS), achievable with the combination of an ACE-inhibitor (ACEI) and an angiotensin receptor blocker (ARB), has been considered an attractive therapeutic option for several years. Large trials conducted in patients with congestive heart failure (CHF) [1, 2], systematic overviews [3, 4] and a rather solid pharmacologic rationale [5, 6] supported the combination of ACEIs with ARBs. Studies in Heart Failure In the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM-ADDED) trial [1], 2548 patients with heart failure and left ventricular ejection fraction of 40% or less who were treated with a background therapy including ACEIs and other drugs (but excluding ARBs) were randomized to candesartan titrated to 32 mg daily or placebo and treated for a median of 41 months. Candesartan reduced the primary composite outcome (cardiovascular death or hospitalization for heart failure) by 15% (p=0.011). The rate of all-cause mortality did not differ*Address correspondence to this author at the Dipartimento di Medicina, Ospedale di Assisi, Assisi, Italy; Tel: +39-075-8139336; E-mail:
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(p=0.086) between candesartan (30%) and placebo (32%). In this study, the ACE-inhibitors more frequently used were enalapril, lisinopril, captopril and ramipril and the mean daily doses were 17 mg, 17 mg, 82 mg and 7 mg, respectively. Thus, although the dual blockade was achieved in the presence of a sub-maximal dose of ACEIs, and although the primary end-point was driven by hospitalization for CHF, the study suggested that a complete blockade of the reninangiotensin system achieved by adding candesartan to ACEinhibitors may be useful in patients with CHF and reduced ejection fraction. The Valsartan Heart Failure Trial (Val-HeFT) [2] was a randomized placebo-controlled, double-blind study between valsartan titrated to 160 mg twice daily and placebo in 5010 patients with heart failure and left ventricular ejection fraction of 40% or less. The most frequently used ACEIs were enalapril, lisinopril, captopril, ramipril and quinapril at a mean daily dose of 17 mg, 19 mg, 80 mg, 6 mg and 23 mg, respectively. The mean duration of follow-up was 23 months. The incidence of the primary composite end-point of mortality and morbidity (defined as resuscitated cardiac arrest or re-hospitalization for heart failure) was lower by 13.2% in the valsartan group compared to the placebo group (p=0.009). However, similarly to CHARM-added all-cause mortality did not differ significantly between the groups © 2010 Bentham Science Publishers Ltd.
Angiotensin Receptor Blockers in Hypertension
(19.7% vs. 19.4%). The Val-Heft study suggested that a dual blockade of the RAS by adding valsartan to ACEIs in patients with CHF and reduced ejection fraction reduces the combined end-point of morbidity and mortality. An unexpected finding from a post-hoc analysis of the Val-Heft study was a significant adverse effect of valsartan on outcome in the subset of patients who were being treated with both an ACEI and a -blocker at baseline. These findings, however, were not confirmed in the CHARM-ADDED trial, where the effect of candesartan was maintained in the subgroup of patients treated with beta-blockers [1]. The better cardiovascular protection afforded by the dual blockade of the RAS in the CHARM ADDED and ValHeft trials may be explained by the high degree of RAAS activation in these patients with generally severe CHF and reduced ejection fraction, thus requiring a dual blockade to be fully reversed. In support of this view, there is evidence that angiotensin II levels are still elevated in up to 45% of patients with CHF who are chronically treated with ACEIs [6]. Although one potential mechanism could be a sub-optimal dose of ACEI, with consequent insufficient suppression of ACE, another explanation may be the existence of alternative enzymes for the synthesis of angiotensin II [7]. It has been demonstrated that several tissue chymases may actively mediate angiotensin II formation, and that these chymases become activated when ACE activity is reduced by an ACEI [7]. Theoretically, the accumulation of renin and angiotensin I during treatment with ACE-inhibitors may overcome the capacity of an ACEI to effectively suppress ACE activity. CHF is therefore a clinical condition in which angiotensin II escape may exert biologically important effects, thus justifying the clinical role of the dual RAS blockade. However, it has also been noted that the ACEI+ARB combination in these patients may lead to an increased risk of hypotension, worsening renal function and hyperkalemia [8]. These side effects command close monitoring because of their potentially threatening consequences, and may be associated with higher likelihood of treatment discontinuation; yet, at the same time they might be taken as an indication that in fact dual blockade with ACEI+ARB combination affords a greater degree of suppression of angiotensin II activity in these patients. The positive results of the CHARM and ValHeft trials have not been confirmed in the Valsartan in Acute Myocardial Infarction (VALIANT) trial, a double-blind, randomized comparison between captopril titrated to 50 mg three times daily, valsartan titrated to 160 mg twice daily and their combination in 14703 patients with myocardial infarction complicated by left ventricular systolic dysfunction, heart failure, or both [9]. The primary end point was all-cause mortality. Duration of follow-up was 24.7 months. The trial was primarily designed as a non-inferiority trial of valsartan vs. captopril, with a pre-specified upper 97.5% confidence limit of 1.13. The hazard ratio in the valsartan group compared to the captopril group was 1.00 and its 97.5 percent confidence interval ranged between 0.90 and 1.11 (p=0.98). Therefore, since the achieved upper 97.5% confidence margin (1.11) was within the pre-specified margin of 1.13, the VALIANT study satisfied the pre-specified criteria for non-inferiority of valsartan vs. captopril (p=0.004). However, the valsartan
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plus captopril combination was not superior to captopril alone (p=0.73), and adverse events, particularly hypotension and renal dysfunction, were more frequent in the combination group [9]. BASIS FOR THE DUAL BLOCKADE OF RAS IN HYPERTENSION It is uncertain whether and to what extent standard doses of ACEIs may achieve only partial inhibition of the RAS in clinical conditions different from CHF, such as hypertension or nephropathy with proteinuria, thus generating the potential need for a more complete blockade of RAS. For example, there is evidence in healthy individuals that upon stimulation of the RAS, up to 40% of angiotensin II affecting the kidney is produced through pathways independent of ACE [5]. Effects on Collagen and Left Ventricular Hypertrophy There is experimental evidence that angiotensin II directly stimulates endothelin-1 production [10] and accumulation of collagen [11, 12] via AT-1 receptors independently of the rise in blood pressure. In an animal model of Dahl saltsensitive rats, the dual RAS blockade with benazepril and valsartan was more effective than each individual component in reducing some markers of collagen accumulation [13]. These results have been confirmed in another experiment in Dahl salt-sensitive rats, where the combination of olmesartan and temocapril was more effective that temocapril alone in reducing the progression of ventricular fibrosis [14]. In a human study conducted in hypertensive patients, Grandi and co-workers found that the combination of ramipril plus candesartan was more effective that the combination of ramipril plus lercanidipine in reducing left ventricular mass (-22% vs. -12.8%; p 160/100 mmHg at entry were excluded from ONTARGET [23], thus limiting the full applicability of these results to the treatment of hypertension. In a study which specifically addressed the renal findings of the ONTARGET study, Mann and co-corkers concluded that the dual blockade of RAS actually worsened major renal outcomes [17]. However, occurrence of chronic dialysis or doubling of serum creatinine were not more frequent in the combination group than in the ramipril group (HR 1.05; 95% CI 0.65-1.69; p=0.85 and 1.20; 95% CI 0.96-1.50; p=0.11, respectively). Most of the adverse outcome was driven by acute dialysis (HR 2.19; 95% CI 1.13-4.22; p=0.02), most likely an effect of acute exacerbations of hyperkalemia or occasional, but not chronic, deteriorations of renal function. The progressive rise in proteinuria from entry to study end was less in the combination group (+21%) than in the ramipril (+31%) and telmisartan (+24%) group (p=0.003 and 0.03, respectively). In parallel, the estimated glomerular filtration rate decreased more (p
