Relationship of dose of background angiotensin-converting enzyme inhibitor to the benefits of candesartan in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)–Added trial

McMurray, John J.V.; Young, James B.; Dunlap, Mark E.; Granger, Christopher B.; Hainer, James W.; Michelson, Eric L.; Earle, Steven; Olofsson, Bertil; Östergren, Jan; Yusuf, Salim; Swedberg, Karl; Pfeffer, Marc A.

doi:10.1016/j.ahj.2006.02.028

Cited by 68 publications

(32 citation statements)

References 11 publications

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“…Continuing with the prematurely terminated VA NEPHRON-D example, the hazard ratio for the primary endpoint was 0.78 CI (0.57-1.07) for those younger than 65 years CI (n = 667) and 0.78 (0.58-1.03) for white patients (n = 1051) for dual RAS blockade. Unfortunately, safety data for these predefined subpopulations are not available [McMurray et al 2006]. Thus, the possibility of a positive efficacy/safety ratio for white patients under 65 years with DKD cannot be ruled out and merits further trials.…”

Section: Is It Worth Trying To Improve the Safety Record Of Dual Ras mentioning

confidence: 99%

“…Indeed, some patient subpopulations may benefit from dual RAS blockade, including patients with heart failure, in whom cardiovascular mortality and hospitalizations were reduced by candesartan and ACEIs compared with candesartan alone [McMurray et al 2006]. Continuing with the prematurely terminated VA NEPHRON-D example, the hazard ratio for the primary endpoint was 0.78 CI (0.57-1.07) for those younger than 65 years CI (n = 667) and 0.78 (0.58-1.03) for white patients (n = 1051) for dual RAS blockade.…”

Section: Is It Worth Trying To Improve the Safety Record Of Dual Ras mentioning

confidence: 99%

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Combination use of medicines from two classes of renin–angiotensin system blocking agents: risk of hyperkalemia, hypotension, and impaired renal function

Esteras

Perez-Gomez

Rodríguez-Osorio

et al. 2015

Therapeutic Advances in Drug Safety

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European and United States regulatory agencies recently issued warnings against the use of dual renin–angiotensin system (RAS) blockade therapy through the combined use of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs) or aliskiren in any patient, based on absence of benefit for most patients and increased risk of hyperkalemia, hypotension, and renal failure. Special emphasis was made not to use these combinations in patients with diabetic nephropathy. The door was left open to therapy individualization, especially for patients with heart failure, when the combined use of an ARB and ACEI is considered absolutely essential, although renal function, electrolytes and blood pressure should be closely monitored. Mineralocorticoid receptor antagonists were not affected by this warning despite increased risk of hyperkalemia. We now critically review the risks associated with dual RAS blockade and answer the following questions: What safety issues are associated with dual RAS blockade? Can the safety record of dual RAS blockade be improved? Is it worth trying to improve the safety record of dual RAS blockade based on the potential benefits of the combination? Is dual RAS blockade dead? What is the role of mineralocorticoid antagonists in combination with other RAS blocking agents: RAAS blockade?

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Section: Is It Worth Trying To Improve the Safety Record Of Dual Ras mentioning

confidence: 99%

Section: Is It Worth Trying To Improve the Safety Record Of Dual Ras mentioning

confidence: 99%

Combination use of medicines from two classes of renin–angiotensin system blocking agents: risk of hyperkalemia, hypotension, and impaired renal function

Esteras

Perez-Gomez

Rodríguez-Osorio

et al. 2015

Therapeutic Advances in Drug Safety

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“…Our findings support those of a study adding an ARB to an evidence-based dose of enalapril (20 mg daily) in patients with heart failure in which favourable changes were seen in both neurohumoral activity and left ventricular ejection fraction, another surrogate generally predictive of improved clinical outcomes [13,14]. In addition to these mechanistic findings, a retrospective analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity-Added (CHARM-Added) trial showed that background dose of ACE inhibitor did not modify the effect of additional ARB treatment on death or heart failure hospitalisation [15]. However, these observations clearly seem to be at variance with two other large trials, one in patients with recent acute myocardial infarction and the other in patients with chronic arterial disease (or risk factors for arterial disease) [7,8].…”

Section: Discussionmentioning

confidence: 99%

Effect of Aliskiren in Patients with Heart Failure According to Background Dose of ACE Inhibitor: A Retrospective Analysis of the Aliskiren Observation of Heart Failure Treatment (ALOFT) Trial

Sidik

Solomon

Latini

et al. 2011

Cardiovasc Drugs Ther

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“…For example, the benefits of adding the ARB candesartan seemed to be preserved, irrespective of dose of ACEi background therapy in CHARM (Conduction in Heart Failure: Assessment of Reduction in Mortality and Morbidity)-Added. 9 In contrast, in Val-HeFT (Valsartan Heart Failure Trial), the beneficial effects of valsartan were progressively attenuated with increasing dose of background ACEi. 10 The data seem more clear-cut with MRA therapy; in both EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) 11 and now EMPHASIS-HF, the efficacy benefits of this strategy seem to be preserved in the setting of maximized background therapy.…”

Section: Discussionmentioning

confidence: 99%

Clinical Benefit of Eplerenone in Patients With Mild Symptoms of Systolic Heart Failure Already Receiving Optimal Best Practice Background Drug Therapy

Krum

Shi

Pitt

et al. 2013

Circ: Heart Failure

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Background— In EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure), eplerenone significantly reduced major cardiovascular events versus placebo in 2737 patients with mild symptoms of heart failure and an ejection fraction of <35%, in addition to recommended therapy. However, it is not known whether such benefits were preserved in patients receiving optimal background drug therapy, that is, high doses of angiotensin-converting enzyme inhibitor (ACEi, or angiotensin receptor blocker), β-blocker, or both drug classes. Methods and Results— We further analyzed EMPHASIS-HF according to the use and dose of these background drug classes. Patients receiving ≥50% of target dose were considered to be receiving high doses; patients on <50% or no drug comprised the low-dose group. The primary end point of the study (cardiovascular death/heart failure hospitalization), as well as all-cause mortality, was evaluated in this way. The beneficial clinical effects of eplerenone (as observed in the main study) were preserved for the EMPHASIS-HF primary end point in patients receiving higher doses of ACEi or angiotensin receptor blocker, β-blocker, or both (hazard ratio for eplerenone versus placebo, ACEi/angiotensin receptor blocker: high dose, 0.67; low dose, 0.65; β-blockers: high dose, 0.55; low dose, 0.72; both ACEi/angiotensin receptor blocker and β-blocker: high dose, 0.59; low dose, 0.68; P value for interaction 0.80, 0.15, and 0.53, respectively), as well as for all-cause mortality. There were no major safety issues, except a borderline increased risk of hypotension with eplerenone in those on high-dose ACEi or ACEi/β-blocker. Conclusions— Eplerenone provides substantial benefit on major events (with an acceptable safety profile) in patients with mild symptoms of systolic heart failure, even in those already receiving high doses of standard background therapies. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00232180.

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Relationship of dose of background angiotensin-converting enzyme inhibitor to the benefits of candesartan in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)–Added trial

Cited by 68 publications

References 11 publications

Combination use of medicines from two classes of renin–angiotensin system blocking agents: risk of hyperkalemia, hypotension, and impaired renal function

Combination use of medicines from two classes of renin–angiotensin system blocking agents: risk of hyperkalemia, hypotension, and impaired renal function

Effect of Aliskiren in Patients with Heart Failure According to Background Dose of ACE Inhibitor: A Retrospective Analysis of the Aliskiren Observation of Heart Failure Treatment (ALOFT) Trial

Clinical Benefit of Eplerenone in Patients With Mild Symptoms of Systolic Heart Failure Already Receiving Optimal Best Practice Background Drug Therapy

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