AZ Guide u CLINICAL TRIAL
HEART

ALIVE

• ALIVE trial is evaluating the effect of Azimilide, an Class III antiarrhythmic agent, in reducing mortality in post myocardial infarction patients with depressed ejection fractions.
• Six thousands patients will be recruit. All patients will be randomised to Azimilide or placebo.

The Beta-Blocker Evaluation Survival Trial

Background and Rationale

Numerous studies suggest that beta-blockade improves ventricular function in congestive heart failure (CHF) and several mortality trials, as outlined below, suggest that beta-blockers may also reduce mortality.

n Beta-blocker Heart Attack Trial (BHAT)¹

In this study, patients after myocardial infarction (MI) were randomised to the non-selective beta-blocker Propranolol or placebo to determine the influence on mortality. The results showed that patients with a history of heart failure had a greater reduction of cardiac and sudden death mortality than those with no history of heart failure.

n Cardiac Arrhythmia Suppression Trial (CAST)²

The influence of beta-blockade on mortality was analysed in all enrolled CAST postmyocardial patients with an ejection fraction <40%. In these patients beta-blocker therapy significantly reduced mortality vs. patients who did not receive beta-blockade.

n The Metroprolol in Dilated Cardiomyopathy Trial (MDC)³

This trial evaluated the effect of the selective beta-blocker Metoprolol vs. placebo on mortality and the need for heart transplantation in patients with idiopathic cardiomyopathy. There was a trend toward reduction in this morbidity and mortality end point in Metoprolol treated patients, but this was due entirely to a reduction in the need for transplantation.
As outlined above, the concept that beta-blockers definitively reduce mortality in CHF patients, remains to be proven.

BEST aims to determine whether the addition of beta-blockade (Bucindolol) to standard CHF therapy will reduce total mortality in patients with moderate to severe heart failure (NYHA class III or IV)⁴

Why use a non-selective beta-blocker?⁴

n In cardiomyopathy trials, beta-1 selective agents did not reduce cardiac death.
n In secondary prevention trials, beta-1 selective agents also failed to show a reduction in sudden cardiac death.
n Non-selective beta-blockade has been shown to reduce sudden cardiac death in post MI patients, suggesting that non-selective beta-blockade may be more effective in reducing mortality than beta-1 selective therapy.

BEST is co-sponsored by the U.S. National Heart, Lung, and Blood Institute and the U.S. Department of Veterans Affairs.

Study design:

• Randomised, double-blind, placebo controlled, multicentre trial
• Evaluating 2800 patients from all CHF population (1400 per arm)
• Dose titration over a period of 6 weeks
• Followed-up for 18 (minimum) to 54 months

Primary Endpoint:

• Total mortality

Secondary Endpoint

• Cardiovascular mortality (total, due to worsening heart failure, due to sudden death)
• Quality of life
• Hospitalisations and costs
• Left ventricular ejection fraction at 3 and 12 months of therapy
• Incidence of myocardial infarction
• Combined transplant/mortality endpoint
• Changes in the need for co-therapy

Furthermore, the impact of aetiology; race, ejection fraction and gender on outcomes will be assessed.

Inclusion Criteria:

• Men and women over 18 years of age
• Compensated congestive heart failure due to idiopathic dilated cardiomyopathy or coronary artery disease
• NYHA functional class III or IV
• Left ventricular ejection fraction < 35%
• Patients taking standard congestive heart failure treatment (ACE inhibitor, digitalis and if needed, a diuretic)

Why Bucindolol?⁴

• Non-selective beta-blocker
• Well tolerated in moderate to severe heart failure
• Weak vasodilator (avoids difficulty in determining whether beta-blockade or vasodilatation is responsible for any treatment effects)

References:

1. Chadda K et al. Circulation 1986; 73; 503-510
2. Kennedy HL et al. Circulation 1992; 86 (suppl 1); I-403
3. Waagstein F et al. Lancet 1993; 342; 1141-1146
4. Design of the Beta-Blocker Evaluation Survival Trial (BEST), Am J Cardiol 1995; 75:1220-1223

CAPTURE

CAPTURE trial is a multicenter, randomised study which has demontrated that platelet inhibition with the glycoprotein IIb/IIIa antibody abcximab reduces risk for myocardial infarction in patients with refractory unstable angina prior and during coronary baloon angioplasty.

CARE trial is a 5-year study, involving 4159 patients, survived a myocardial infarct.
In the Pravastatin-treated group, there was a 25% reduction in relative risk of having another coronary event.
The relative risk of needing coronary artery bypass or angioplasty was reduced by 32%.

A post doc subgroup analysis shows that non-diabetic patients defined as glucose intolerant, who received Pravastatin had a lower rate of coronary events than patients given placebo.

[Sacks V et al. Circulation 1998; 98: 2513-2519]

• The CAST was designed to assess whether pharmacological suppression of asympomatic or mildly symptomatic ventricular arrhythmias in patients who had experienced an myocardial infarction (MI), would reduce the rate of arrhythmia- associated death.
• Patients were randomised to receive treatment with Encainide, Flecainide, Moracizine, or matching placebo.
• In April 1989, on the basis of interim results, Encainide and Flecainide were withdrawn from CAST because the drugs appeared to be harmful.
• The revised CAST (CAST II) continued with Moracizine.

[N Engl J Med 1991; 324: 781-788]

The trial has enrolled 3.000 patients.

Dofetilide is a selective potassium channel blocker.

GUSTO IIb

A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator for acute myocardial infarction.

N Engl J Med 1997; 336: 1621-1628

• Patients with acute ischemic syndromes present recurrent ischemic events despite the use of Aspirin.
• These recurrent ischemic events are a consequence of an ongoing thrombotic stimulus.
• OASIS Pilot Study has studied the effects of long-term Warfarin at 2 intensities in patients with acute ischemic syndromes (AIS) without ST elevation.
• Long-term treatment with moderate-intensity Warfarin (INR 2.0-2.5) plus Aspirin but not low-intensity Warfarin (INR 1.5) plus Aspirin appears to reduce the rate of recurrent ischemic events in patients with AIS without ST elevation

(Circulation 1998; 98: 1064-1070)

RALES Trial

Heart failure is a neurohormonal and a hemodynamic syndrome, involving the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system, and various neurohumoral substances.
Aldosterone produces a fluid retention and potassium and magnesium loss.

As Aldosterone is the end-product of the RAAS, an attempt was made inhibiting the conversion of the angiotensin I to angiotensin II by using ACE-inhibitors.
Morever also inhibiting the activity of ACE, there may be an "escape" of Aldosterone.
Escape of Aldosterone despite ACE inhibition could be due in part to non-ACE-dependent angiotensin II production.
In addition the control of Aldosterone production is also under the actions of atrial natriuretic factor (ANF), corticotropin or serum potassium concentrations.

The RALES trial was planned for assessing the role of Aldosterone receptor antagonist in the prevention of heart failure and mortality in patients with systolic left ventricular dysfunction.

The RALES trial, conducted in 15 countries, is a multicenter, randomized, double-blind, placebo controlled trial.
In this study were enrolled 1,663 patients, classified as NYHA Class III or IV.
The patients were assigned to two groups of treatment: placebo or Aldosterone receptor antagonist.
All patients were receiving a stable dose of an ACE inhibitor and loop diuretic.

The Data Safety Monitoring Board, analyzing the intermediate results, statistically and clinically significant, has halted the RALES trial, originally scheduled to conclude in December, 1999.

Among the 1,663 patients randomized, there were 372 deaths (44%) in the placebo group and 283 deaths (34%) in the Aldosterone antagonist group. The mortality was decreased by 27%, applying the Kaplan-Meier method.

During the trial 764 (91%) placebo-treated patients and 663 (81%) Aldosterone antagonist- treated patients had at least one non-fatal hospitalization, representing 1,317 hospitalizations for the placebo group, and 1,088 hospitalizations for the Aldosterone antagonist group.

The RALES trial indicates that:

Aldosterone antagonist when given in conjunction with an ACE inhibitor reduces the mortality by 27% in patients with severe chronic congestive heart failure.
In the group treated with Aldosterone antagonist has been seen an decrease by 22% in the combined endpoint of non-fatal hospitalizations and total mortality.

[RALES Trial was presented at the 71^st Meeting of the American Heart Association in Dallas (USA), November 11, 1998]

Reduction of restenosis after PTCA, early administration of Reviparin in a double-blind, unfractioned heparin and placebo controlled evaluation.