4 ACE Inhibitor Controversies

Chapter 4 / ACE Inhibitor Controversies 63

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From: Contemporary Cardiology: Cardiac Drug Therapy, Seventh Edition M. Gabriel Khan © Humana Press Inc., Totowa, NJ

4 ACE Inhibitor Controversies

ACE INHIBITORS VERSUS ARBs: DOES THE CHOICE MATTER?

• Angiotensin-converting enzyme (ACE) inhibitors have been shown in large randomized controlled trials (RCTs) to prevent cardiovascular disease (CVD) outcomes significantly in patients with hypertension and heart failure (HF) and in patients with acute myocardial infarction (MI) with left ventricular (LV) dysfunction. Several recent RCTs including Con- desartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM)

equivalence of ACE inhibitors and angiotensin II receptor blockers (ARBs). Their adverse effects, however, deserve careful scrutiny if we are to give patients medications that have a lower adverse effect profile.

• ACE inhibitors cause cough in more than 15% of treated individuals and, most important, produce a significantly higher incidence of angioedema versus ARBs; this incidence is much higher in patients of African origin. Deaths owing to angioedema have been reported in several hypertension RCTs.

Angioedema: In the well-run large Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (3), angioedema occurred in 8 of 15,255 (0.1%), 3 of 9048 (<0.1%), and 38 of 9054 (0.4%) persons in the chlorthalidone, amlodipine, and lisinopril treatment groups, respectively. Significant differences for angioedema were seen for the lisinopril versus chlorthalidone comparison overall ( p < 0.001):

• In blacks angioedema was seen in 2 of 5369 (<0.1%) for chlorthalidone and 23 of 3210 (0.7%) for lisinopril ( p < 0.001). Caution is urged in the use of ACE inhibitors in blacks;

it is preferable to use an ARB if cost is not a concern.

• In non-blacks (angioedema was seen in 6 of 9886 (0.1%) for chlorthalidone and 15 of 5844 for lisinopril (0.3%; p = 0.002).

• The only death from angioedema was in the lisinopril group.

Death should not occur in the treatment of healthy individuals; the patient with mild pri- mary hypertension is invariably healthy and asymptomatic. Importantly, most patients with angioedema caused by an ACE inhibitor require emergency room treatment. Because hypertensive patients are mostly asymptomatic, ARBs offer major advantages over ACE inhibitors with regard to safety profile. The clinician’s objective is to produce salutary effects for patients without causing harm.

ACE INHIBITORS/ARBs CAUSE RENOPROTECTION:

TRUE OR FALSE?

• It is said by experts and clinical teachers that ACE inhibitors and ARBs have specific reno-

protective effects. Guidelines indicate that these are the drugs of choice for the treatment

of hypertension in patients with renal disease with or without proteinuria.

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Casas et al. (4) assessed electronic databases for RCTs of antihypertensive drugs and progression of renal disease. Effects on primary discrete end points (doubling of crea- tinine and end-stage renal disease) and secondary continuous markers of renal outcomes (creatinine, albuminuria, and glomerular filtration rate) were calculated with random- effect models. Comparisons of ACE inhibitors or ARBs with other antihypertensive drugs yielded a relative risk of 0.71 (95% CI 0.49–1.04) for doubling of creatinine and a small benefit in end-stage renal disease (relative risk 0.87, 0.75–0.99). In patients with diabetic nephropathy, no benefit was seen in comparative trials of ACE inhibitors or ARBs on the doubling of creatinine (1.09, 0.55–2.15), end-stage renal disease (0.89, 0.74–1.07), glomerular filtration rate, or creatinine amounts. Placebo-controlled trials of ACE inhibitors or ARBs showed greater benefits than comparative trials on all renal out- comes but were accompanied by substantial reductions in blood pressure in favor of ACE inhibitors or ARBs. These investigators concluded that:

• The benefits of ACE inhibitors or ARBs on renal outcomes in placebo-controlled trials prob- ably result from a blood-pressure-lowering effect (4).

ACE INHIBITORS DECREASE THE INCIDENCE OF DIABETES:

TRUE OR FALSE?

In the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study (5), atenolol was compared with losartan. In a post hoc analysis it is claimed that there was a significant 15% excess of new-onset diabetes over 5 yr, but the absolute rise in glucose was not stated. A large number of patients in the beta-blocker group received diuretics, and the frequency of diuretic use in each study arm was not given. In most studies, including LIFE, post hoc analysis (6) suggested that increased risk of new-onset diabetes was confined to individuals with an elevated blood glucose at baseline and family pre- disposition to diabetes (6).

In the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial, new- onset type 2 diabetes was 25% more frequent in the patients on amlodipine than in those on valsartan (13.1% versus 16.4%; p < 0.0001) (7). Other RCTs combined ACE inhibi- tors with diuretics and calcium antagonists, and firm conclusions cannot be ascertained (see CONVINCE and PROGRESS trials in Chapters 8 and 9).

ACE inhibitors appear in RCTs to lower the incidence of new diabetes compared with beta-blockers and diuretics, but this effect might be owing to

1. Masking of latent diabetes, a situation that has long-term effects, because treatment of the diabetic process is delayed.

2. Reducing the incidence of benign reversible glucose intolerance (see Chapters 8 and 9).

COMBINATION OF ACE INHIBITOR AND ARB PROVEN EFFECTIVE:

TRUE OR FALSE?

The search for virtually complete renin-angiotensin-aldosterone system (RAAS) blockade appears to make good sense. The combination of ACE inhibitor and ARB, how- ever, did not result in satisfactory therapeutic goals in the valsartan RCT. Combination therapy did not result in significant reduction in primary outcomes in patients with HF.

Most important, the combination of valsartan with a beta-blocker needed for HF treat-

ment increased mortality (2).

Chapter 4 / ACE Inhibitor Controversies 65

In CHARM-Added, after 41 mo of follow-up patients receiving candesartan were 15%

less likely to experience the primary end point compared with those given placebo (42%

versus 37.9%; p = 0.0011). This result occurred regardless of whether or not patients were given a beta-blocker and independent of the dose of ACE inhibitor used (1). Addition of candesartan to an ACE inhibitor led to further clinically important reduction in cardio- vascular death and hospitalization for HF, but total mortality was not reduced. Caution is needed when a combination of ACE inhibitor and ARB is administered because hyper- kalemia may ensue, especially if renal dysfunction is present, a scenario that is common in the elderly. In CHARM, hyperkalemia occurred in 2.7%, and creatinine increased 3.7% above placebo.

It is preferable to add an aldosterone antagonist to an ACE inhibitor rather than adding an ARB. Caution is needed in HF patients treated with aldosterone antagonists because these agents may cause hyperkalemia, and the addition of an ARB would cause severe hyperkalemia. The strategy of complete RAAS blockade with the combination of ACE inhibitor and ARB remains controversial, particularly when the combination of an ACE inhibitor and an aldosterone antagonist has been proved successful in RCTs (spironolac- tone in RALES [8] and eplerenone in EPHESUS [9].)

ACE INHIBITORS FOR HF

WITH PRESERVED SYSTOLIC FUNCTION

ACE inhibitors have been shown conclusively to improve outcomes in patients with MI and HF. However, the evidence for significant benefit in MI patients with preserved LV systolic function is probably not conclusive. Al-Mallah et al. (10) analyzed 6 of 61 RCTs that met specified inclusion criteria. There were 16,772 patients randomized to an ACE inhibitor and 16,728 patients randomized to placebo. Treatment was associated with a decrease in cardiovascular mortality (relative risk [RR] 0.83, 95% CI 0.72–0.96;

p = 0.01), nonfatal MI (RR 0.84, 95% CI 0.75–0.94, p = 0.003), all-cause mortality (RR 0.87, 95% CI 0.81–0.94, p = 0.0003), and revascularization rates (RR 0.93, 95% CI 0.87–

1.00, p = 0.04). Treatment of 100 patients for an average duration of 4.4 yr prevents either one death, or one nonfatal MI, or one cardiovascular death. The cumulative evidence pro- vided by this meta-analysis showed a modest favorable effect of ACE inhibitors on the outcome of patients with CHD and preserved LV systolic function (10).

REFERENCES

1. Swedberg K, Granger CB, McMurray JJV, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors:

the CHARM-Added trial. Lancet 2003;362:767–771.

2. Pfeffer MA et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction or both. N Engl J Med 2003;349:1893–1906.

3. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major out- comes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981–2997.

4. Casas JP, Chau W, Loukogeorgakis S, et al. Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: Systematic review and meta-analysis. Lancet 2005;366:

2026–2033.

5. Dahlöf B, Devereux RB, Kjeldsen SE, et al. for the LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint Reduction in Hypertension study (LIFE): A ran- domised trial against atenolol. Lancet 2002;359:995–1003.

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6. Lindholm LH, Ibsen H, Borch-Johnsen K, et al. Risk of new-onset diabetes in the Losartan Interven- tion for Endpoint Reduction in Hypertension study. J Hypertens 2002;20:1879–1886.

7. Julius S, Kjeldsen SE, Weber M, et al. for the VALUE Trial Group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimes based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004;363:2002–2031.

8. Pitt B, Zannad F, Remme WJ, et al. for the Randomized Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:

709.

9. Pitt B, Remme W, Zannad F, et al. for the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309–1321.

10. Al-Mallah MH, Tleyjeh IM, Abdel-Latif AA, et al. Angiotensin-converting enzyme inhibitors in coro- nary artery disease and preserved left ventricular systolic function. A systematic review and meta-analysis of randomized controlled trials. J Am Coll Cardiol 2006;47:1576–1583.

SUGGESTED READING

Jhund P, McMurray JJV. Does aspirin reduce the benefit of an angiotensin-converting enzyme inhibitor?:

Choosing between the Scylla of observational studies and the Charybdis of subgroup analysis. Circulation 2006;113:2566–2568.