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University of Ottawa The Ottawa Hospital, Ottawa, ON, Canada
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 particularly in patients with LV dysfunction caused by acute myocardial infarction (MI).
The results are not as good for angiotensin receptor blockers [ARBs] that are unfortunately now more widely used than ACE inhibitors.
In Val-HeFT (2001): mainly classes II and III were randomly assigned to receive 160 mg of valsartan or placebo twice daily. There was no reduction in all-cause mortality. The incidence of the combined end point was a modest 13.2 % lower with valsartan than with placebo, predominantly because of a lower number of patients hospitalized for heart failure: 455 (18.2 %) in the placebo group and 346 (13.8 %) in the valsartan group (P < 0.001). This result is similar for that observed for digoxin. Yet digoxin is rarely used for HF.
In Val-HeFT, valsartan when combined with a beta-blocker caused significantly more cardiac events. A total of 5,010 patients with HF class II, III, or IV were randomly assigned to receive 160 mg of valsartan or placebo twice daily. There was no reduction in all causes of mortality. The incidence of the combined end point, however, was a modest 13.2 % lower with valsartan than with placebo (P = 0.009), predominantly because of a lower number of patients hospitalized for heart failure: 455 (18.2 %) in the placebo group and 346 (13.8 %) in the valsartan group (P < 0.001). Overall mortality was not reduced by valsartan administration (Cohn and Tognoni 2001).
Unfortunately less than 36 % of subjects received a beta-blocker and ~68 % received digoxin.
Often in patients with HF, a beta-blocker is needed as proven therapy. Thus, an ACE inhibitor must be used, not an ARB; telmisartan also failed in HF trials [TRANSCEND].
Caution: valsartan must not be combined with a beta-blocker.
In VALIANT ( 2003 ): a clinical trial of valsartan, captopril, or both in MI complicated by HF, left ventricular dysfunction, or both, during a median follow-up of 24.7 months, total mortality was not reduced by valsartan: 979 patients in the valsartan group died, as did 941 patients in the valsartan-and-captopril group and 958 patients in the captopril group. There was no placebo group.
Caution: Valsartan is not advisable in HF patients because in this large number of patients, a beta-blocker is the needed therapy.
Significant mortality reduction remains unknown for ARBs.
CHARM-Overall program (2003) compared candesartan with placebo in three distinct populations: patients with left ventricular ejection fraction (LVEF) 40 % or less who were not receiving ACE inhibitors because of previous intolerance or who were currently receiving ACE inhibitors and patients with LVEF higher than 40 %. Overall, 7,601 patients (7,599 with data) were randomly assigned candesartan (n = 3,803, titrated to 32 mg once daily) or matching placebo (n = 3,796); median follow-up was 37.7 months. The primary outcome of the overall program was all-cause mortality.
Total mortality was not reduced; 886 (23 %) patients in the candesartan and 945 (25 %) in the placebo group died p = 0.055.
CHARM-Alternative trial (2003) enrolled 2,028 patients with symptomatic heart failure and left ventricular ejection fraction 40 % or less who were not receiving ACE inhibitors because of previous intolerance. Patients were randomly assigned candesartan (target dose 32 mg once daily) or matching placebo.
There was no reduction in total mortality; 265 deaths occurred in the candesartan group and 296 in the placebo group p = 0.11. But 334 (33 %) of 1,013 patients in the candesartan group and 406 (40 %) of 1,015 in the placebo group had cardiovascular death or hospital admission for CHF p = 0.0004. Hospital admission for HF was modestly reduced. Only by combining events do these trials show positive results.
TRANSCEND (2008) investigators studied the effects of telmisartan on cardiovascular events in high-risk patients intolerant to ACE inhibitors. Telmisartan therapy for 56 months, although shown in ONTARGET to be equivalent to ramipril surprisingly:
Failed to decrease total mortality and had no significant effect on the primary outcome and hospitalizations for HF. Thus, telmisartan use should be avoided.
In the large well-run PRoFESS RCT, telmisartan failed to decrease recurrent stroke (Yusuf et al. 2008).
ARBs appear to be associated with a modestly increased risk for cancer, according to a meta-analysis published in the Lancet Oncology (Sipahi et al. 2010). Researchers, examining data from five randomized trials comprising nearly 62,000 patients, found that those taking ARBs (85 % were using telmisartan) had a significantly greater risk for new cancer than did controls (7.2 % vs. 6 %). Should we be concerned about all ARBs or a single drug, telmisartan?
Angioedema: ACE inhibitors cause cough in more than 20 % of treated individuals and produce a significantly higher incidence of angioedema vs. ARBs. This incidence is much higher in patients of African origin. Deaths owing to angioedema have been reported in several hypertension RCTs. In the well-run large Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT 2002), significant differences for angioedema were seen for the lisinopril vs. chlorthalidone comparison overall (p < 0.001). In blacks angioedema was seen in 2 of 5,369 (<0.1 %) for chlorthalidone and 23 of 3,210 (0.7 %) for lisinopril (p < 0.001). In non-blacks angioedema was seen in 6 of 9,886 (0.1 %) for chlorthalidone and 15 of 5,844 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 primary hypertension is invariably healthy and asymptomatic. Importantly, most patients with angioedema caused by an ACE inhibitor require emergency room treatment.
Conclusion: ACE inhibitors should be the first choice in all patients with a CVD problem. ARBs are indicated only if there is intolerance to ACE inhibitor use.
ACE Inhibitors/ARBs Cause Renoprotection: True or False?
Experts and clinical teachers believe that ACE inhibitors and ARBs have specific renoprotective effects. Guidelines indicate that these are the drugs of choice for the treatment of hypertension in patients with renal disease with or without proteinuria. Casas et al. (2005) assessed electronic databases for RCTs of antihypertensive drugs and progression of renal disease. Effects on primary discrete end points (doubling of creatinine 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) or end-stage renal disease (0.89, 0.74–1.07), glomerular filtration rate, or creatinine amounts. These investigators concluded that:
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