Beyond Current Strategies: Focus on Angiotensin Receptors

ARBs: Evolution of protective benefits Initially, ARBs were developed as antihypertensive agents, but subsequently, a series of major trials have demonstrated the benefits of ARBs across the spectrum of CV and renal disease. In addition, results from recent clinical trials have suggested improved glycemic control with these agents. The upcoming slides will summarize clinical data from major trials of ARBs.

Clinical trials of the RAAS manipulation with ARBs Although it is now well established that ACEIs can reduce CV risk, attention is increasingly being focused on ARBs because of their mechanism of action, ie, obviating angiotensin II escape, and allowing continued activation of the protective AT2 receptor could theoretically provide more complete RAAS inhibition. ARBs have been studied for the treatment of hypertension, coronary artery disease (CAD) and MI, diabetes and renal disease, stroke, and CHF.

Meta-analysis of CV events with ARBs vs comparators The Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC) performed a meta-analysis of 29 hypertension trials that compared the effects of various antihypertensive regimens based on different drug classes. Four trials, involving 16,791 patients, compared ARBs with control regimens. ARB-based treatment reduced the risk of stroke by 21% (10% to 31%), heart failure by 16% (3% to 28%), and major CV events by 10% (4% to 17%).

ARB exhibits BP-lowering effects and some anti-inflammatory effects In the Valsartan-Managing BP Aggressively and Evaluation Reductions in hs-CRP (Val-MARC) study, valsartan reduced high sensitivity C-reactive protein (hs-CRP) in a manner independent of BP reduction. In this trial, 1668 patients with stage 2 hypertension were randomized to treatment with valsartan or valsartan/ hydrochlorothiazide (HCTZ) for 6 weeks The valsartan/HCTZ group had a significantly greater reduction in BP compared with the valsartan monotherapy group (-25/14 mm Hg vs -18/9 mm Hg, P < 0.01). By contrast, the median change in hsCRP was -0.12 mg/L in the valsartan monotherapy compared with +0.55 mg/L in the valsartan/HCTZ (P < 0.001). These results raise the hypothesis that ARBs may have anti-inflammatory effects in addition to BP-lowering effects.

TROPHY: Reduction in new-onset HTN The Framingham Heart Study, The Multiple Risk Factor Intervention Total (MRFIT), and other studies indicate that prehypertension is a strong predictor of excessive CV risk. The Trial of Preventing Hypertension (TROPHY) evaluated 2 years of treatment with candesartan in individuals with prehypertension. The primary objective to determine if the incidence of HTN can be reduced for up to 2 years after discontinuation of active treatment. Candesartan significantly delayed new-onset HTN vs placebo: Relative risk reduction: 66% (year 2); 16% (year 4) Absolute reduction of new-onset hypertension: 26.8% (year 2); 9.8% (year 4) New-onset hypertension at 2 years: 13.6% vs 40.4%

CHARM: ARB reduces death, CV deaths, and HF hospitalizations The Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) program consisted of 3 parallel, independent, integrated, randomized, double-blind, placebo-controlled, clinical trials comparing candesartan with placebo in 3 distinct but complementary populations of patients with symptomatic HF. Median follow-up was 37.7 months. The study included patients who had LV ejection fractions of 40% or less who were not receiving ACEIs because of previous intolerance, or who were currently receiving ACEIs; and patients with LV ejection fractions >40%. Overall, the time to CV death or hospital admission for HF, the primary outcome of each of the component trials, was reduced by 16% (P < 0.0001) The overall hazard ratio for all-cause mortality was 0.91 (P = 0.055).

VALIANT: ACEI and ARB show similar effects in post-MI patients with LV dysfunction The Valsartan in Acute Myocardial Infarction Trial (VALIANT) investigators compared the effects of the ARB valsartan, the ACEI captopril, and a combination of the 2 on mortality among patients with MI complicated by LV systolic dysfunction, HF, or both. The study enrolled 14,808 patients during a median follow-up of 24.7 months. Mortality from any cause and cause-specific mortality were similar in the 3 treatment groups. The rate of the secondary combined CV endpoint of death from CV causes, recurrent MI, or hospitalization for HF was also similar in the 3 groups. Thus, valsartan was as effective as captopril in reducing the rates of death and other adverse CV outcomes among patients at high risk for CV events after MI.

ARBs in CAD In summary, evidence from clinical trials of ARBs show a benefit in post-MI patients with LV dysfunction, but as yet no conclusive evidence on benefits in patients with chronic stable disease. Pooled data from major large-scale trials show no clear BP-independent benefit. Importantly, 2 separate meta-analyses show no evidence of adverse CV outcomes.

LIFE study: CV effects of ARBs are chiefly due to stroke reduction Despite a similar reduction in BP in the losartan and atenolol groups, the losartan group had a significant reduction in the primary endpoint, a composite of CV mortality, stroke, and MI. However, the reduction in the primary outcome was chiefly attributable to a reduction in the incidence of stroke.

MOSES: ARB surpasses CCB for secondary stroke prevention The Morbidity and Mortality After Stroke, Eprosartan Compared With Nitrendipine for Secondary Prevention (MOSES) study, tested the hypothesis that in hypertensive stroke patients, for the same level of BP control, an ARB (eprosartan)-based regimen is more effective than a calcium channel blocker (CCB; nitrendipine)-based regimen in reducing cerebrovascular and CV morbidity and mortality. In both treatment arms, 75.5% of the eprosartan group and 77.7% in the nitrendipine group reached the target BP of 140/90 mm Hg or lower, and they achieved nearly equal levels of BP control. The percentage of patients received only the study drugs was comparable in both groups, 34.4% and 33.1%, respectively. The primary endpoint, a composite of total mortality and all CV and cerebrovascular events, including recurrent events, was reduced significantly (21%) in the eprosartan group. The eprosartan group also had significant reductions of 25% in the secondary endpoints of fatal and nonfatal CV and cerebrovascular events.

SCOPE: Impact of ARBs on cognitive decline in hypertensive patients A post hoc analysis of the Study on Cognition and Prognosis in the Elderly (SCOPE), a blood-pressure-lowering trial, assessed cognitive outcomes in patients with lower versus higher cognitive function at baseline. The subgroup with baseline Mini Mental State Examination (MMSE) scores of 24 to 28 were categorized as having low cognitive function (LCF); patients with MMSE scores of 29 to 30 were categorized as having high cognitive function (HCF). Patients were randomly allocated to treatment with candesartan or placebo; open-label therapy was added as needed to control BP. Mean follow-up was 3.7 years. At the last visit, patients treated with candesartan exhibited significantly better BP control, the mean difference in adjusted BP reduction was 3.3/1.5 mm Hg in favor of candesartan in patients with HCF, and 2.5/1.9 mm Hg in favor of candesartan in patients with LCF. The results indicated that effective antihypertensive therapy may reduce cognitive decline in elderly patients with hypertension and LCF. By contrast, in patients with HCF, there was no difference in change in MMSE scores between the candesartan and control groups.

PRoFESS trial: Secondary stroke prevention–2  2 factorial design The ongoing PRoFESS (Prevention Regimen for Effectively Avoiding Second Strokes) trial is the largest secondary stroke prevention trial to date involving more than 20,000 patients from 695 sites in 35 countries or regions. Individuals eligible for randomization are aged 50 years or more who have had an ischemic stroke within <120 days, and are stable on entering the study. The 2 × 2 factorial design will directly compare 2 antithrombotic regimens, a fixed-dose combination of extended-release dipyridamole plus aspirin with clopidogrel, and telmisartan vs placebo. The primary outcome is recurrent stroke.

PRoFESS: Effect of angiotensin receptor blockade on recurrent stroke During a mean follow-up of 2.5 years, mean blood pressure was 3.8/2.0 mm Hg lower in the telmisartan group. The rate of recurrent stroke was 8.7% and 9.2% in the telmisartan and placebo groups, respectively (hazard ratio 0.95, 95% CI 0.86-1.04, P = 0.23).

ARBs decrease renal complications in T2DM The Irbesartan Diabetic Nephropathy Trial (IDNT) and the Reduction of Endpoints in Noninsulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan (RENAAL) trial demonstrated that ARBs reduce end-stage renal disease in hypertensive patients with T2DM. The Irbesartan in Patients With T2DM and Microalbuminuria (IRMA-2) and the Microalbuminuria Reduction With Valsartan (MARVAL) trials demonstrated that ARBs provide renoprotection in patients with T2DM and microalbuminuria. Results of these trials have led to the current recommendation of ARBs as first-line therapy for patients with diabetic nephropathy.

AMADEO: Comparative effect of telmisartan vs losartan on proteinuria The AMADEO study compared the effects of telmisartan vs losartan on proteinuria in patients with T2DM, overt nephropathy, and hypertension. One year of treatment with telmisartan provided greater reductions in proteinuria when compared with losartan, an ARB with an indication to slow diabetic nephropathy progression. Telmisartan was superior to losartan in reducing proteinuria in hypertensive patients with diabetic nephropathy despite similar BP control.