Let's Review a Truly Positive Trial

The Study of the Week goes back to 1999. It was a great year for cardiology.

I spend a fair amount of time on Mondays showing problem trials. Such studies have great educational value. But so do hugely positive trials—experiments that truly advance the field.

One trial in 1999 transformed the care of patients with heart failure. Doctors were doubtful of the drug before the trial.

Heart failure due to a weak heart muscle was a terrible condition at that time. The failing heart would first compensate by dilating, but eventually patients would die because the heart couldn’t pump blood to the other organs.

This slow and inevitable progression has now changed. Uncommon is the patient that slowly dies of pump failure. The reason was the development of drugs that stop this progression.

The RALES trial studied the use of an old inexpensive drug called spironolactone—which primarily blocks the effect of aldosterone. Spironolactone was discovered in the 1950s. It is a very weak diuretic.

Aldosterone has a bunch of activity that affects heart failure. At the time, doctors did not feel that blockade of aldosterone was necessary because angiotensin-converting–enzyme (ACE) inhibitor suppressed aldosterone. Doctors also feared high potassium levels in patients who took both ACE-I and spironolactone.

In 15 countries, patients with heart failure were randomized to spironolactone 25 mg or placebo. A total of 1663 patients were randomized—about half in the active arm and half to placebo.

These were 65 year old, mostly male patients, who had severe left ventricular dysfunction (LVEF average 25%). All were on a loop diuretic, and 95% were taking ACE-I, which had been shown about 10 years before to improve mortality. Beta-blockers had yet to established—and only 10% of patients in RALES took beta-blockers.

The primary endpoint was simple and elegant: alive or dead. When I started cardiology, trials studied whether our therapies extended life. Back then we did not need surrogate or composite endpoints.

RALES was stopped early because the data safety monitoring committee noticed how effective the drug was. Trials have independent bodies to look at data to protect patients from getting ineffective treatments. (Though it is sometimes difficult to judge a treatment’s efficacy or futility when few events have occurred.)

When RALES was stopped, 46% of patients in the placebo arm had died but only 35% had died in the spironolactone group. That absolute risk reduction of a whopping 11% translated to a relative risk reduction of 30% (RR 0.70 95% CI 0.60-0.82).

This massive effect size was driven by lower rates of death from heart failure or sudden arrhythmic death—which were the two ways patients with heart failure used to die. (Now, most patients with heart failure die of something else.) The need for hospitalization for heart failure also fell by 35% in the spironolactone group.

There were some adverse effects. Contrary to what many doctors believed before the trial, the risk of seriously high potassium levels were similar. But spironolactone also has an anti-androgen effect, and 10% of patients (vs 1% on placebo) developed gynecomastia or breast pain.

In the discussion section of the paper in the NEJM, the authors speculated why this mild diuretic could have such large effects on mortality. Drugs that block the mineralocorticoid receptor likely have cardioprotective effects, such as the blockade of fibrosis, was their main thesis.

Here is the best part of evidence-based medicine: it doesn’t matter how or why the drug worked. It extended life. It worked.

While we need enough knowledge of biology to come up with theories to test, the ultimate answer of what works in Medicine comes from trials.

The RALES trial is one of the most unassailable trials in modern cardiology. Placebo-controlled, a once-daily tablet, huge effect size driven by plausible means, statistically persuasive and the drug was generic and inexpensive.

When you see a trial that promotes “positive” results, compare it to the RALES trial. I bet it falls short. JMM

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I wanted to write another note of thanks to our subscribers. Sensible Medicine continues to grow. We remain free of industry influence—and a place to express opinions and arguments that may not be welcome in the mainstream of modern medicine. Thank you x 1000. JMM