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Home , ACE inhibitor, Enalapril, Lisinopril

Journal of Human (2001) 15, 89–92  2001 Nature Publishing Group All rights reserved 0950-9240/01 $15.00 www.nature.com/jhh COMMENTARY Blockade of the -- system with combination angiotensin receptor antagonist and ACE inhibitor therapy: Observations from Val-HeFT and CALM

BSP Chin and GYH Lip University Department of Medicine, City Hospital, Birmingham B18 7QH, UK

Keywords: angiotensin receptor antagonists; angiotensin-converting enzyme inhibition; failure; renal

The renin-angiotensin-aldosterone system (RAAS) includes vascular remodelling, glomerular hyper- appears to be at the root of most of evil (in this trophy, cardiomyocyte hypertrophy and angio- instance, cardiovascular disease). The RAAS is acti- genesis.7,8 Importantly, tissue-based RAAS is more vated in conditions as diverse as hypertension, dia- difficult to block than renal RAAS and require betes and . In the latter, the RAAS is higher doses of ACE-inhibitors. Certain types of initially activated as a compensatory mechanism in ACE-inhibitors (such as ) are more lipo- response to the failing heart, but in fact RAAS acti- philic and could potentially have better tissue pen- vation results in even greater fluid retention and etrance than others,9 although this property was not , worsening the clinical syndrome clinically evident in studies comparing different of heart failure.1 Administration of loop to types of ACE-inhibitors.10 Secondly, Ang II can be reduce fluid retention further activates the RAAS. generated independently of ACE, for example, via Thus, blockade of the RAAS with ACE inhibitors, the catalytic actions of serine proteases, such as chy- and more recently, the ‘aldosterone’ component of mase, in a variety of tissues, including cardiac, vas- the RAAS by the aldosterone antagonist, spironolac- cular and renal tissue11. The percentage of locally tone, are established for the treatment of heart fail- generated Ang II in cardiac tissues is about 70%, ure.2 With blockade of angiotensin converting while that in tissues is about 20%, rising to enzyme (ACE) by the ACE inhibitors and aldos- 40% in diabetics.12 terone with , it seemed we had near- Reducing the production of circulatory Ang II complete blockade of the RAAS, and we could do would remove the negative feedback upon renin and no more, or so we thought. result in higher levels of renin and angiotensin I.13,14 Blockade of angiotensin II (Ang II) formation with As renin levels rise, ACE-inhibition becomes less ACE-inhibitors is an effective means of reducing effective and higher doses of ACE-inhibitors become pressure. However, reduction necessary.15 Plasma Ang II ultimately returns to nor- alone could not account for the reduction in mor- mal with chronic use of recommended doses of ACE tality and morbidity seen with heart failure patients inhibitors.16 This ‘ACE escape’ phenomenon could 3,4 treated with ACE-inhibitors. Hence other related explain the additional benefit seen when increasing mechanism(s) must be at play. the doses of ACE inhibitors in heart failure and renal One such mechanism may be tissue-based RAAS, failure patients despite no further reductions to the effects of which are local and cellular, rather blood pressure.17,18 5,6 than circulatory and endocrine in nature. Its The availability of the angiotensin receptor block- mitogenic actions, possibly mediated via cytokines, ers (ARBs), has enabled us to block Ang II at the AT1 receptor, regardless of site of action. Indeed, if Ang II Correspondence: Dr GYH Lip. E-mail: g.y.h.lipȰbham.ac.uk which is generated independently of ACE is patho- Received 22 December 2000 physiologically of relevance, ARBs would have the Blockade of the RAAS BSP Chin and GYH Lip 90 upper hand in blocking the actions of ACE-inde- The CALM study was a prospective, randomised, pendent Ang II. The ‘ACE escape’ phenomenon parallel group, double-blind study of 199 patients described above also suggests that there would be aged 30–75 years, to assess and compare the effects potential benefits in adding an ARB to ACE-inhibi- of the ARB, 16 mg or the ACE inhibitor, tor. Thus, it came as no surprise that early surrogate 20 mg, or both, on blood pressure and uri- data indicated that the combination of an ACE nary albumin in patients with micro- inhibitor with a direct angiotensin II receptor albuminuria, hypertension, and type 2 .22 At blocker (ARB) improved left ventricular function 24 weeks the mean reduction in diastolic blood and reduced neurohormonal levels.19 In patients pressure with combination treatment (16.3 mm Hg, with , combination ARB and P Ͻ 0.001) was significantly greater than that with ACE inhibitor therapy succeeded only in modest candesartan (10.4 mm Hg, P Ͻ 0.001) or lisinopril systolic and diastolic blood pressure reduction as (mean 10.7 mm Hg, P Ͻ 0.001). Furthermore, the compared to monotherapy.20,21 Even then, these reduction in urinary albumin: ratio with trials have been criticised for using sub-optimal combination treatment (50%, 95% CI 36% to 61%, doses of ACE-inhibitors when employed as mono- P Ͻ 0.001) was greater than with candesartan (24%, therapy. Nevertheless, the early data on combination P = 0.05) and lisinopril (39%, P Ͻ 0.001). Thus can- ARB and ACE inhibitor therapy have been recently desartan 16 mg once daily was as effective as lisino- substantiated by two studies, the in Heart pril 20 mg once daily in reducing blood pressure Failure Trial (Val HeFT) and the Candersartan And and microalbuminuria in hypertensive patients with Lisinopril Microalbuminuria (CALM) study. . Combination treatment was well tol- In Val HeFT, presented by Dr Jay Cohn at the erated and more effective in reducing blood pressure American Heart Association scientific sessions in and the urinary albumin:creatinine ratio. New Orleans, in November 2000, 5010 patients Val-HeFT and CALM are only the latest of clinical (mean age 62 years) with symptomatic heart failure studies to push the case for combination therapy for (NYHA II-IV, with 62% NYHA II and 36% NYHA treatment; in the management of heart failure, com- III) and dilated left ventricles (left ventricular end- bination therapy has variously seen improvements diastolic diameter Ͼ2.9 cm/m2) with ejection frac- to NYHA functional class, left ventricular function, tion Ͻ40%, were randomly assigned to standard exercise tolerance and reductions in ventricular vol- therapy or standard therapy plus valsartan (force- umes and total peripheral resistance.23,24 However, titrated from 40 mg b.i.d. to 160 mg b.i.d.). The we are left with more questions than answers. On majority (57%) had coronary artery disease and at the one hand, the data from Val HeFT suggest a baseline, 85% were taking diuretics, 67% , reduction in hospitalisations with valsartan. Sub- 35% beta-blockers, and 93% ACE inhibitors. There group analysis, however, suggests a possible adverse was no significant difference or benefit in all-cause effect if valsartan is used in combination with a beta- mortality with valsartan (19.7% vs placebo 19.4%; blocker and an ACE inhibitor, which does raise the RR 1.02, 95% CI 0.90–1.15; P = 0.8). However, the question that perhaps when beta-blockers are used, combined end point of ‘all-cause mortality and mor- further inhibition of the RAAS may not be necessary bidity’ was significantly reduced in the valsartan or beneficial. The key question which will need to group (28.8% vs 32.1% in placebo; RR 0.87, 95% CI be answered in a prospective trial is, ‘which is bet- 0.79–0.96; P = 0.009, with a dramatic reduction in ter?’: an ACE inhibitor plus beta-blocker or an ACE hospitalisation rate. Importantly, the survival curves inhibitor plus an ARB: In Val-HeFT, adding an ARB began to separate very early and separation rose to standard therapy resulted in a further 13% throughout the follow-up period. In the valsartan reduction in hospitalisation and all-cause mortality group, 13.9% of patients had a first hospitalisation but only a third of these patients were on beta-block- for heart failure, compared with 18.5% in the pla- ers. By contrast, MERIT-HF and CIBIS-II have both cebo arm (RR 0.73, 95% CI 0.63–0.83; P = 0.00001). reported a clear 39% beneficial reduction in mor- Both NYHA class, subjective dyspnoea on exertion tality, when beta-blockers were added to standard and echocardiographic ejection fraction also therapy in heart failure patients; therefore, beta- improved in the valsartan group. Patients who were blockers must be the second added to an ACE not receiving an ACE inhibitor at the time of enrol- inhibitor while treating systolic heart failure.2,25,26 ment (7% of the population) appeared to have a Based on Val HeFT, an ARB could potentially be the benefit from valsartan (n = 185) over placebo second drug if beta-blockers are contraindicated or (n = 181), with a 44.5% risk reduction in the com- not tolerated. bined end point of all-cause mortality and mor- The fact that valsartan was substantially beneficial bidity. In patients taking an ACE inhibitor, a nonsig- in patients not taking an ACE inhibitor suggests that nificant trend toward an overall beneficial effect was ARBs may be a good substitute for ACE inhibitors if seen, but in the patients taking both an ACE inhibi- the latter are not tolerated. However, to date, no trial tor and a beta-blocker, there was a trend favouring has shown equivalence of ARBs and ACE inhibitors placebo (with wide 95% confidence intervals). How- in the treatment of heart failure. Despite initial ever, in the 65% of patients not taking a beta- hopes from ELITE-I, the recently published ELITE II blocker, a striking benefit of valsartan was seen. trial failed to show superiority of over cap-

Journal of Human Hypertension Blockade of the RAAS BSP Chin and GYH Lip 91 topril in outcome but was not powered as a non- Conflict of interest statement inferiority trial.19,27 ELITE-II has similar treatment arms to the ongoing OPTIMAAL trial comparing BSPC and GYHL are investigators for clinical trials, and losartan in patients post-myocardial including ELITE-II, OPTIMAAL and VALIANT. infarction with left ventricular dysfunction, and Both have received research funding and honoraria may again show non-superiority of losartan over for educational symposia, meetings, etc from various captopril. One also remembers the Randomized manufacturers. Evaluation of Strategies for Left Ventricular Dys- function (RESOLVD) Pilot Study,19 where mortality References was 6.1% for the group receiving candesartan alone, 8.7% for those receiving candesartan plus 1 Francis GS. Neurohumoral mechanisms involved in and 3.7% for those receiving enalapril alone congestive heart failure. Am J Cardiol 1985; 55: 15A– = 21A. (P 0.15), with heart failure hospitalisations of 2 Gibbs CR, Davies MR, Lip GYH (eds). ABC of Heart 10.7% with candesartan alone, 7.2% with candesar- Failure. BMJ Books: London, 2000. tan plus enalapril, and 3.7% with enalapril alone 3 The CONSENSUS Trial Study Group. Effects of enala- (P = 0.048). Importantly, the combined end point of pril on mortality in severe congestive heart failure. mortality plus hospitalisation rates were 14.6% for Results of the Cooperative North Scandinavian Enalap- candesartan alone, 15.1% for candesartan plus enal- ril Survival Study (CONSENSUS). N Engl J Med 1987; april, and 6.4% for enalapril alone (P = 0.058). 316: 1429–1435. Nevertheless, heart failure trials like RALES, 4 The SOLVD Investigators. Effects of enalapril on sur- vival in patients with reduced left ventricular ejection MERIT-HF and CIBIS-II have shown that much can fractions and congestive heart failure. N Engl J Med be gained from combining different strategies of 1991; 325: 293–302. blocking the RAAS.2,25,26,28 With CHARM, VALIANT 5 Dzau VJ. Short- and long-term determinants of cardio- and OPTIMAAL all in progress and waiting to report vascular function and therapy: contributions of circul- in a few years, this may indeed be the case.29 In ating and tissue renin-angiotensin systems. J Cardio- CHARM, the addition of candesartan to an ACE vasc Pharmacol 1989; 14 (Suppl 4): S1–S5. inhibitor will be tested in patients with heart failure, 6 Johnston CI. Renin-angiotensin system: a dual tissue in addition to a subgroup with heart failure due to and hormonal system for cardiovascular control. J Hypertens 1992; 10 (Suppl 7): S13–S26. diastolic dysfunction. The role of combination ARB ± 7 Dzau VJ, Re R. Tissue angiotensin system in cardio- and ACE inhibitor therapy in heart failure left ven- vascular medicine: a paradigm shift? Circulation 1994; tricular dysfunction early post-myocardial infarc- 89: 493–498. tion, is being tested in the VALIANT study. Time, 8 Rakugi H, Wang DS, Dzau VJ, Pratt RE. Potential data and P values will tell. importance of tissue angiotensin-converting enzyme What does this mean for the patient with heart inhibition in preventing neointima formation. Circu- failure? Not only do we treat the patient with lation 1994; 90: 449–455. 9 Pinto YM et al. Dosing of ACE inhibitors in left ven- , ACE inhibitor, spironolactone and a beta- tricular dysfunction: does current clinical dosing pro- blocker, if they are in atrial fibrillation we add vide optimal benefit? J Cardiovasc Pharmacol 1999; 34 digoxin, and consider and . (Suppl 1): S13–S17. Many will also be taking aspirin, despite the lack of 10 Cashin-Hemphill L et al. Angiotensin-converting evidence-based medicine for benefit and some enzyme inhibition as antiaterhosclerotic therapy: no analyses even suggesting some harm from aspirin in answer yet. QUIET Investigators. Quinalapril Ischemic view of an interaction with the ACE inhibitors and Event Trial. Am J Cardiol 1999, 83: 43–47. warfarin may be better.30 With Val-HeFT, we should 11 Liao Y, Husain A. The chymase-angiotensin system in humans: biochemistry molecular biology and potential add an ARB, especially if the patient is not taking a role in cardiobascular . Can J Cardiol 1995; 11 beta-blocker, which leaves the patient with a con- (Suppl F): 13F–19F. siderable pharmacological attack on the neurohor- 12 Hollenberg NK, Fisher NDL, Price DA. Pathways for monal axis in heart failure. In hypertension, we angiotensin II generation in intact human tissue. Evi- await more data with interest but CALM suggests dence from comparative pharmacological interruption that in diabetics at least, combination of ARBs and of the renin system. Hypertension 1998; 32: 387–392. an ACE inhibitor can only be advantageous, 13 Juillerat I et al. Determinants of angiotensin II gener- especially in light of the new recommended targets ation during converting enzyme inhibition. Hyperten- sion 1990; 16: 564–572. of blood pressure reduction in diabetics and the 14 Nussberger J, Brunner DB, Waeber B, Brunner HR. additional benefits in reducing diabetic . Plasma angiotensin under sustained converting Hopefully, we may avoid acronymmania with state- enzyme inhibition with enalapril in normal humans. J ments such as ‘what is the VALUE of OPTIMAAL Hypertens 1985; 3 (Suppl 3): S269–S270. blockade of the renin-angiotensin system, and 15 Jorde UP et al. Maximally recommended doses of should these ELITE patients remain CALM, feel angiotensin-converting enzyme (ACE) inhibitors do VALIANT or be RESOLVeD to ?’ not completely prevent ACE mediated formation of angiotensin II in chronic heart failure. Circulation 2000; 101: 844–846.

Journal of Human Hypertension Blockade of the RAAS BSP Chin and GYH Lip 92 16 Mooser V et al. Reactive hyperreninemia is a major 23 Carson PE. Rationale for the use of combination angio- determinant of plasma angiotensin II during ACE inhi- tensin-converting /angiotensin II bition. J Cardiovasc Pharmacol 1990; 15: 276–272. receptor blocker therapy in heart failure. Am Heart J 17 Brunner-La Rocca HP et al. Within-patients compari- 2000; 140: 361–366. son of effects of different dosages of enalapril on func- 24 Weinberg MS, Weinberg AJ, Zappe DH. Effectively tar- tional capacity and neurohormone levels in patients geting the renin-angiotensin-aldosterone system in car- with chronic heart failure. Am Heart J 1999; 138: diovascular and renal disease: rationale for using 654–662. angiotensin II receptor blockers in combination with 18 Packer M et al, for the ATLAS Study Group. Compara- angiotensin-converting enzyme inhibitors. J Renin tive effects of low and high doses of the antiotensin- Angiotens Aldos System 2000; 1: 217–233. converting enzyme inhibitor lisinopril on morbidity 25 CIBIS II Investigators and Committees. The Cardiac and mortality in chronic heart failure. Circulation Insufficiency Bisoprolol Study (CIBIS-II): a random- 1999; 100: 2312–2318. ised trial. Lancet 1999; 353: 9–13. 19 McKelvie RS et al. Comparison of candersartan, enala- 26 MERIT-HF Study Group. Effect of metoprolol CR/XL pril and their combination in congestive heart failure. in chronic heart failure: Metoprolol CR/XL Random- Randomised evaluation of strategies for left ventricular ised Intervention Trial in congestive heart failure dysfunction (RESOLVD) pilot study. Circulation 1999; (MERIT-HF). Lancet 1999; 353: 2001–2007. 100: 1056–1064. 27 Pitt B et al. Effect of losartan compared with captopril 20 Fogari R et al. Adding losartan to lisinopril therapy on mortality in patients with symptomatic heart fail- in patients with hypertension: assessment by 24-hour ure: randomised trial – the Losartan Heart Failure Sur- ambulatory blood pressure monitoring. Curr Therap vival Study ELITE II. Lancet 2000; 355: 1582–1587. Res 1999; 60: 326–334. 28 Pitt B, Zannard F, Remme WJ, Cody RJ. Spironolactone 21 Stergiou GS et al. Additive hypotensive effect of angio- appears to be beneficial regardless of ejection fraction: tensin-converting enzyme inhibition and angiotensin the RALES Trial. Circulation 1999; 100 (Suppl 1): I- receptor antagonism in essential hypetension. J Car- 298. diovas Pharmacol 2000; 35: 937–941. 29 Pfeffer MA. Enhancing cardiac protection after myo- 22 Mogensen CE et al, for the CALM Study Group. Ran- cardial infarction: rationale for newer clinical trials of domised controlled trial of dual blockade of renin- angiotensin receptor blockers. Am Heart J 2000; 139: angiotensin system in patients with hypertension, S23–S28. microalbuminuria, and non-insulin dependent dia- 30 Cleland JGF. and antiplatelet therapy in betes: the Candersartan and Lisinopril Microalbumin- heart failure. Curr Opinion in Cardiology 1997; 12: uria (CALM) study. BMJ 2000; 321: 1440–1444. 276–287.

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