A drug that was shown in a landmark clinical trial five years ago to save the lives of patients with heart failure may have taken lives instead.
In 1999, researchers showed that a little-used, 40-year-old drug significantly reduced death and hospitalization for patients with congestive heart failure. Those results were so compelling that the trial was halted ahead of schedule. Now Canadian researchers are reporting that spironolactone (Mylan Labs) might have had a much different effect. (The brand-name drug, generic Aldactone®, is made by Pfizer.)
The publication of the 1999 study resulted in a greater than fourfold increase in prescriptions for the generic drug over an 18-month period. That surge in use was accompanied by a tripling of hospital admissions and of deaths resulting from dangerous elevations of potassium (hyperkalemia), a known side effect of spironolactone. Highly elevated potassium levels can cause severe muscle pain and can disrupt electrical conduction in the heart, causing sudden death.
Canadian researchers noted that, among heart patients after 1999, the number of prescriptions for spironolac-tone, the number of hospital admissions for hyperkalemia, and the death rate attributed to hyperkalemia all increased.
Researchers said that the culprit was not the drug itself but, rather, the willingness of doctors to prescribe it for patients who were already at an increased risk for the potassium problem. Furthermore, these patients were not carefully monitored for hyperkalemia. Before the 1999 study, the drug had been used mainly as a diuretic and for liver patients.
The new findings offer a provocative look at the difference between clinical trial results and real-world medicine— and the potential dangers of applying trial results too widely. Patients in clinical studies are usually carefully selected to maximize the chance of showing a benefit and to minimize side effects. Trial patients represent only a subset of the types of patients whom doctors treat in their offices.
In the new study, researchers found that patients taking spironolactone in the aftermath of the 1999 study were, on average, 13 years older than participants in the original trial and were more likely to have diabetes. Older patients and those with diabetes are at higher risk for elevated potassium levels. The average dose in actual practice was 30 mg, whereas the study dose was 25 mg, perhaps reflecting how doctors tend to prescribe higher doses if an initial lower dose is ineffective.
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Pfizer is now marketing eplerenone (Inspra™), a second-generation version of spironolactone, for patients with heart failure after a heart attack.
The study is not iron-clad proof of cause and effect, in part because researchers did not specifically match individual patients taking the drug with poor outcomes. The lead author emphasized that spironolactone can be beneficial to appropriate patients and that risks can be managed by selecting patients carefully, monitoring potassium levels, and adjusting medications to minimize adverse effects.