707-4 The Randomized Aldactone Evaluation Study (RALES): Parallel Dose Finding Trial

Aldactone (AL), an aldosterone (A) receptor antagonist, causes diuresis and symptomatic improvement in patients with heart failure (HF) maintained on an angiotensin converting enzyme-inhibitor (ACE-I). The effective dose and safety of AL in patients with HF on an ACE-I and loop diuretic was determined in a multicenter, randomized, double-blind study of placebo (P) (n=40): AL 12.5 mg (n=41), 25 mg (n=45). 50 mg (n=47) and 75 mg (n=41) over 12 weeks. Left ventricular ejection fraction was ≤35%; 80% males; mean age 62 years; with 50% in NYHA Class II and 50% in III–IV. The mean dose of captopril was 62.0 mg, enalapril 14.3 mg and furosemide 73.9 mg Digitalis and Potassium (K) supplements were given in approximately 80% and 30% of patients, respectively. Efficacy was assessed by measuring changes in N-terminal plasma atrial natriuretic factor (ANF) pmol/L and systolic (S)/diastolic (D) blood pressure (BP) mmHg from baseline to 12 weeks (Δ). Safety by Δ in serum K mmol/L, creatinine (Cr) μmol/L and incidence of hyperkalemia (HK) ≥6.0 mmol/L.PAL12.5AL25AL50AL75pΔANF+55-287*-295-351*-371***ΔS/D BP+2.6/+1.9-14/-2.3-4.8/-32*-5.9/-5.3*-7.6/-5.3***ΔK-0.1+0.2*+0.4*+0.5*+0.6***ΔCr0+0.1*+0.1+0.2*+0.3***HK (%)0271112***p<0.05 vs. placebo;**significant treatment effect. p<0.05There were no deaths during the drug administration period of the study, and no significant changes in NYHA class among treatment groups. Thus, in patients with HF on an ACE-I and loop diuretic, AL at a dose ≥12.5mg is effective, with a dose response relationship to 75 mg. There was an increased incidence of HK with AL ≥50 mg. The effect of AL on hospitalization and death will be determined in the RALES-Survival Trial

Adverse events in HEAAL: when to hold and when to fold

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106139/1/ejhfhfs167.pd

Mineralocorticoid Receptor Antagonists in High‐Risk Heart Failure Patients With Diabetes Mellitus and/or Chronic Kidney Disease

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142475/1/jah32899.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142475/2/jah32899_am.pd

Future large‐scale clinical trials in cardiovascular medicine: challenges and uncertainties

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146871/1/ejhf1360_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146871/2/ejhf1360.pd

Withdrawal of cerivastatin from the world market

Cerivastatin was recently withdrawn from the market because of 52 deaths attributed to drug-related rhabdomyolysis that lead to kidney failure. The risk was found to be higher among patients who received the full dose (0.8 mg/day) and those who received gemfibrozil concomitantly. Rhabdomyolysis was 10 times more common with cerivastatin than the other five approved statins. We address three important questions raised by this withdrawal. Should we continue to approve drugs on surrogate efficacy? Are all statins interchangeable? Do the benefits outweigh the risks of statins? We conclude that decisions regarding the use of drugs should be based on direct evidence from long-term clinical outcome trials

Is hyperkalaemia in heart failure a risk factor or a risk marker? Implications for renin–angiotensin–aldosterone system inhibitor use

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143644/1/ejhf1175.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143644/2/ejhf1175_am.pd

Evaluation of the patient with congestive heart failure and ventricular arrhythmias

Although vasodilators and new inotropic agents have been shown to improve ventricular function and reduce symtoms, their effect on mortality is uncertain. In view of our failure to reduce mortality in patients with congestive heart failure (CHF), the identification and amelioration of potentially reversible factors that might alter survival are crucial before initiating therapy. The first step is to establish the diagnosis of CHF and the presence or absence of dilated congestive cardiomyopathy. The extent of myocardial dysfunction, both right and left, must also be evaluated. In post-myocardial infarction patients, left ventricular ejection fraction is an important indicator of prognosis during the first 1 to 2 years. However, in patients with chronic CHF and dilated cardiomyopathy, right ventricular ejection fraction may be a more effective predictor of survival. The presence, frequency and complexity of ventricular arrhythmias must be determined, because these arrhythmias may independently increase the risk of sudden cardiac death in patients with ischemic cardiomyopathy. Their role in patients with idiopathic cardiomyopathy is less certain. In addition, myocardial ischemia, left ventricular dyskinesis or aneurysm, occult myocarditis and neurothrombosis formation must be ruled out. Detection and correction of serum electrolyte and neurohumeral abnormalities are essential. Our failure to reduce mortality in patients with CHF may not entirely lie in the lack of effective therapeutic agents but rather in our failure to apply properly the diagnostic and therapeutic approaches now available.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26287/1/0000372.pd

Revisiting hyperkalaemia guidelines: rebuttal

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146358/1/ejhf1249_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146358/2/ejhf1249.pd

ACE Inhibitors in Heart Failure: Prospects and Limitations

ACE inhibitors have been shown to be effective in reducing the morbidity and mortality of patients with left ventricular systolic dysfunction, but their application to clinical practice in this situation is still limited. In part, the failure to prescribe an ACE inhibitor to a patient with left ventricular systolic dysfunction is due to perceptions regarding their side effects, such as cough and renal dysfunction. Relatively few patients with left ventricular systolic dysfunction and a serum creatinine ≥2 mg/dl receive an ACE inhibitor in clinical practice. In this situation one should consider an agent such as fosinopril, which is metabolized by the liver as well as secreted by the kidney. In patients with moderate renal dysfunction, fosinopril has been well tolerated without an increase in serum creatinine. In patients who develope cough due to an ACE inhibitor, consideration should be given to an angiotensin II type 1 receptor blocking agent, such as losartan. The relative safety and efficacy of an ACE inhibitor compared with an angiotensin II type 1 receptor blocking agent is being explored in a prospective randomized trial (Evaluation of Losartan In The Elderly [ELITE]), as well as the safety and pharmacological effectiveness of adding an angiotensin II receptor antagonist to an ACE inhibitor (Randomized Angiotensin receptor antagonists–ACE-inhibitor Study [RAAS]). There may also be a role for the combination of an aldosterone receptor antagonists and an ACE inhibitor in patients with left ventricular systolic dysfunction. Once an ACE inhibitor is administered to a patient with left ventricular systolic dysfunction it should be continued indefinitely. ACE inhibitors may be of value not only in preventing the progression of heart failure but also in reversing endothelial dysfunction and preventing the development of atherosclerosis and its consequences, such as myocardial infarction.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44553/1/10557_2004_Article_139131.pd