Thiazides, beta-blockers suspected in deaths

Deaths increased with dosages

They’re cheap, they’re effective, and for many they remain the mainstay of antihypertensive therapy. But a new report suggests that thiazide diuretics, on the market since 1957, may be killers.

Researchers at the Academic Hospital in Utrecht, The Netherlands, say that two case-control studies show that hypertensive patients taking thiazide diuretics have twice the risk of sudden cardiac death in comparison to patients taking potassium-sparing diuretics. Even more surprising, the researchers found that beta-blockers also may increase the risk of sudden death in hypertensives. Death is considered "sudden" if it occurs within one hour after onset of symptoms.

More study is needed

How might thiazides kill? Electrolyte depletion is one theory: Loss of potassium and magnesium could trigger a fatal arrhythmia.

But there’s conflicting evidence on that score. Some studies have found no correlation between thiazide- induced electrolyte depletion and arrhythmias.The researchers admit their findings seem to fly in the face of all the recent good news about thiazides — that they actually prevent stroke and deterioration of the heart — but they suggest that’s because the concept of "sudden cardiac death" hasn’t been studied adequately.

When the researchers looked at data from seven previous clinical trials of thiazides, for example, they found an unusually high incidence of sudden death among patients taking the drugs — an incidence that frequently was higher than that of a non-drug control group. That’s surprising, given that a lower blood pressure should decrease the risk of sudden death.

The researchers also analyzed two old sets of data — one American, one Dutch — which specifically addressed the question of thiazides and sudden death. Both studies found thiazides increased the risk of sudden death, especially with higher doses. The American data, collected between 1977 and 1990, showed a nearly four-fold increase in the risk of sudden death among patients taking 100 mg of thiazide a day vs. 25 mg.

Even the results from the most famous cardiac study of all may prove their point, the researchers suggest. The Framingham Heart Study’s 30-year follow-up report found that hypertensives taking medication had a twofold increase in risk of sudden death vs. those who went untreated. Specific drugs aren’t addressed in the report, but given that thiazides were in wide use during the Framingham study era, it’s a fair bet that many patients were using the drugs. (The Dutch researchers do acknowledge, however, that a more recent analysis of the Framingham study showed that people with untreated hypertension had a much greater chance of dying from heart disease than those who used medication.)

Even more surprising is the news that beta-blockers may cause sudden death — the exact opposite of what they’ve been touted to prevent, at least in heart attack patients. The key may be in the reason for beta-blocker use. In heart attack victims, beta-blockers work to prevent sudden cardiac death by preventing ischemia and arrhythmias.

But in hypertensives, the drugs may have toxic effects on the heart, the researchers say, and poor compliance may be one reason. As most pharmacists know, sudden withdrawal of a beta-blocker is associated with fatal arrhythmias. But one study shows that even patients who are 80% to 90% compliant with beta-blocker use are at risk of developing cardiac complications.

Scant evidence supports claim

Another possible reason for sudden death is that highly selective beta-1 blockers may exaggerate the sensitivity of cardiac beta-2 receptors. A rush of adrenaline therefore could trigger a fatal arrhythmia. There’s scant evidence to support this claim, but one study found a difference in fatal events between patients taking a selective beta-blocker vs. a non-selective one.

One study found that elderly hypertensive patients using atenolol, a selective beta-blocker, showed no decrease in the number of fatal events vs. patients taking placebo. However in mild hypertensives, propranolol, a non-selective beta-blocker, decreased the incidence of sudden death when compared with patients taking placebo.

And the biggest drop in the incidence of sudden cardiac death? The study found it came from the use of a potassium-sparing diuretic.