News and Views :Antibiotic Cotrimoxazole Combined With ACE Inhibitor or ARB Could Raise Risk of Sudden Death

October 31, 2014
TORONTO, ON — The risk of sudden death went up by more than a third in older patients taking ACE inhibitors or angiotensin-receptor blockers (ARBs) who were also put on the antibacterial agent cotrimoxazole, compared with those who were instead given amoxicillin, in a case-control study reported this week. The finding was independent of comorbidities, other medications, recent procedures, and other potential influencers of sudden-death risk, according to the authors.The elevated risk with cotrimoxazole, a combination of sulfamethoxazole and trimethoprim widely used for decades, was likely caused by its capacity for raising serum potassium, which became fatal on top of other medications known for causing hyperkalemia, speculate Dr Michael Fralick (University of Toronto, ON) and colleagues in their report, published October 30, 2014 in the BMJ. The same group had previously observed that combining cotrimoxazole with ACE inhibitors or ARBs similarly drove up the risk of hospitalization due to hyperkalemia.
"In patients who are on ACE inhibitors or ARBs, who are by definition at risk for hyperkalemia, the safest thing to do would be to use an antibiotic" other than cotrimoxazole, senior author Dr David N Juurlink (Institute for Clinical Evaluative Sciences and the University of Toronto, ON) told heartwire . "But that's not always going to be practical. Alternate strategies could be to use a lower dose or a shorter duration of the drug. Or, when you have to give trimethoprim-based antibiotics to somebody who's on an ACE inhibitor or an ARB, at a minimum being mindful of the potential for serious and even life-threatening hyperkalemia. That alone would go a long way toward reducing the dangers of this interaction."

That goes especially for some susceptible patient groups. "Patients with type 2 diabetes are sitting ducks for this," Juurlink said. "They have a tendency for hyperkalemia independent of anything else, because of what the diabetes does to their kidney function." And patients with heart failure may be on potassium-sparing spironolactone as well as ACE inhibitors or ARBs. "Someone who has reduced left ventricular function and has diabetes—there are millions of people like that in North America."
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The risk, he said, depends on the antibiotic's dosage and duration of use. It's not unusual for clinicians to prescribe 10 days of cotrimoxazole for ordinary, uncomplicated urinary-tract infections, "and that's just not necessary. If you gave 3 days' worth of the antibiotic, it should certainly suffice."

Tapping data from patients aged 66 or older who received ACE inhibitors or ARBs in Ontario from 1994 to 2012, the researchers identified outpatients who died of sudden death within 7 days of being prescribed cotrimoxazole, amoxicillin, ciprofloxacin, norfloxacin, or nitrofurantoin. Those 1027 cases were matched to 3733 controls alive within that time frame relative to the antibiotic prescriptions, based on, among other things, age, sex, chronic kidney disease, and diabetes.

The adjusted odds ratios (95% CI) for sudden death within 7 days of an antibiotic prescription on top of an ACE inhibitor or ARB, by antibiotic, relative to amoxicillin (which does not pose a hyperkalemia risk itself or prolong the QT interval) were:

• 1.38 (1.09–1.76) for cotrimoxazole.
• 1.29 (1.03–1.62) for ciprofloxacin.
• 0.74 (0.53–1.02) for norfloxacin.
• 0.64 (0.46–0.88) for nitrofurantoin.

"We included ciprofloxacin because of its clinical popularity, even though it is typically used for more complicated infections and can predispose to sudden death by prolonging the QT interval," the group writes.

When they looked at the adjusted odds of sudden death within 2 weeks of the antibiotic prescription, rather than 7 days, the OR with cotrimoxazole went up slightly to 1.54 (95% CI 1.29–1.84). But the elevated OR with ciprofloxacin seen over 7 days had attenuated over the longer time window to 1.18 (1.00–1.39).

"This distinction between cotrimoxazole and ciprofloxacin is, I think, really important. By rights, people who get ciprofloxacin are sicker and prone to sudden death by virtue of the effects of the drug on cardiac repolarization," Juurlink observed. "People who are going to die of ciprofloxacin-related arrhythmias are going to die in the first 5 to 7 days of therapy."

But hyperkalemia-related risks with other antibiotics are mediated by renal function and persist longer. That the risk with cotrimoxazole remained elevated over 2 weeks, unlike with ciprofloxacin, he said, strengthens the argument that the elevated sudden-death risk of the former agent seen in the current study was related to hyperkalemia.