The Headline

Spironolactone saves lives in heart failure patients

The Facts

The Big Idea:
Spironolactone reduces mobidity and mortality among heart failure patients

Study Design:
Multicenter, double-blind, randomized, placebo-controlled trial (intention to treat)

Outcomes
Death from any cause, hospitalization for cardiac problems, and a change in NYHA heart failure class

Number of Patients
1663 randomized patients, 822 patients received sprionolactone 25 mg QD, 841 patients in placebo arm

Type of Patients
Patients who have severe heart failure (NYHA III-IV class) with a left ejection fraction less than 35 percent who were being treated with an angiotensin-converting–enzyme inhibitor (ACEI), a loop diuretic, and in most cases digoxin.

Important ExclusionsPatients were excluded if they had primary operable valvular heart disease (other than mitral or tricuspid regurgitation with clinical symptoms due to left ventricular systolic heart failure), congenital heart disease, unstable angina, primary hepatic failure, active cancer, or any life-threatening disease (other than heart failure). Patients who had undergone heart transplantation or were awaiting the procedure were also ineligible. Other criteria for exclusion were a serum creatinine concentration of more than 2.5 mg per deciliter (221 µmol per liter) and a serum potassium concentration of more than 5.0 mmol per liter

Interventions
Spironolactone 25 mg daily and my be increased to 50 mg, or placebo once daily

Duration
24 months, the trial was terminated early because an interim analysis determined that spironolactone was efficacious.

Statistics
Kaplan–Meier, log-rank test, Cox proportional-hazards regression models,

Funding

Supported by a grant from Searle, Skokie, Ill

Results

There were 386 deaths in the placebo group (46%) compared to 284 (35%) in the spironolactone group (CI 0.60-0.82, P < 0.001). The frequency of hospitalization for worsening heart failure (NYHA heart failure class) was 35% lower in the spironolactone group than in the placebo grou. Gynecomastia or breast pain was reported in 10% of men who were treated with spironolactone, as compared with 1% of men in the placebo group (P<0.001).

Spironolacotone 25-50 mg a day with an ACEI, and loop diuretic reduces mobidity and mortality among heart failure (NYHA III-IV class) patients

Reference

Pitt, B, Zannad, F et al. The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure. N Eng J Med1999;341:709

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The Headline

Patients with CHF taking carvedilol have significantly less mortatility than patients taking metoprolol

The Facts

The Big Idea:
This study looked to show which beta-blocker was superior, carvedilol or metoprolol.

Study Design:
Multicenter (341 centers in 15 European countries), randomized, double blind, parallel-group

Outcomes
All cause mortatility and all cause mortatility and all cause admission

Number of Patients
3029 randomized: 1511 in carvedilol arm and 1518 in metoprolol arm

Type of Patients
Symptomatic heart failure (NYHA Class II-IV), one cardio admission in past 2 years, being treated with ACEI’s and diuretics unless contraindications, LVEF of < or = 0.35 withink previous 3 months.

Important ExclusionsRecent change in therapy or recent use of beta or alpha blockers in past 2 weeks; being treated with CCBs, amiodarone, class-I antiarrhythmics or investigational drugs in past 30 days; patients with MI, unstable angina or stroke in last 2 months; uncontrolled HTN (>170/105); pregnancy; autmatic defibrillator, known drug or alcohol issues

Interventions
3.125 mg carvedilol BID or 5 mg metoprolol tartrate BID (both titrated up to goals of 25 mg carvedilol and 50 mg BID metoprolol tartrate)

Duration
58 Months

Statistics
Cox’s proportional hazard, log rank test

Funding

Roche and GlaxoSmithKline

Results

All cause mortality: Carvedilol – 34%; Metoprolol – 40% (HR 0.83 [0.74 - 0.93] p = 0.002) All cause mortality and all cause admission: Carvedilol – 74%; Metoprolol – 76% (HR 0.94 [0.86 - 1.02] p = 0.122) For the Cynic
Once major concern with this study was the use of metoprolol tartrate when compared to carvedilol. The extended release succincate salt is most often used and studied in CHF. It is possible the results may have changed someone based on the different drug formulations. Also some of the funding comes from Roche – who makes carvedilol (Coreg). Whether the formulation of metoprolol succinate would fare better, is an interesting question. Another interesting question is whethere the alpha action from the carvedilol contributes to its increased efficacy.

Carvedilol shows increased benefit in CHF patients compared to metoprolol tartrate.

Reference

Poole-Wilson PA, Swedberg K, Cleland JGF, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet 2003 Jul 5; 362: 7-13

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Lipitor prevents cardiovascular events in people with normal cholesterol

The Facts

The Big Idea: Major cardiovascular events can be reduced with atorvastatin in patients who are not dyslipidemic

Study Design: Multicenter, randomized, placebo-controlled trial

Outcomes Nonfatal MI and fatal CHD

Number of Patients 19342 randomized, 10,305 in lipid-lowering arm, 5168 atorvaststin, 5137 placebo

Type of Patients 40-79 yo with hypertension and total cholesterol less than 250. At least 3 of following risk factors: LVH, abnormalities on ECG,Diabetes, Peripheral Artery Disease, previous stroke or TIA, male, 55 or older, microalbuminuria or proteinuria, smoking, ratio of TC to HDL of >6, family history of premature CHD

Important ExclusionsCoronary artery disease, recent stroke, TG >400 gm/dl, heart failure, uncontrolled arrhythmias Interventions 10mg atorvastatin or placebo once daily

Duration 3.3 years

Statistics Kaplan-Meier & Cox’s proportional hazard

The Results

Outcomes in 3.3 years

Note that mortality difference is not statistically sigificant

For The Cynic

Funding Funded by Pfizer. The absolute risks in our fact box are not as impressive as the 36% reduction reported in the abstract. Note that you have to be very high risk to get the benefits listed. Even in this high risk group, you have a 97% chance of not having the primary outcome in 3 years. This improves to a 98.1% chance if you take atorvastatin. This is a real improvement however.

Atorvastatin 10mg/day reduces cardiovascular risk in high risk patients with normal cholesterol.

Reference

Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. The Lancet, Volume 361, Issue 9364, Pages 1149 – 1158, 5 April 2003

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