Risk of Sudden Death With Some Hypertension Drug-Antibiotic Combinations

Two classes of medication used to treat hypertension (high blood pressure) — angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) — are among the most widely prescribed drugs in the U.S. In 2011 alone, 250 million prescriptions for these drugs were dispensed.[1]

For many patients, these drugs provide safe and effective options for managing hypertension, heart failure and chronic kidney disease. However, physicians and patients need to be aware that combining an ACE inhibitor or an ARB with certain other commonly used drugs can cause serious, even fatal, consequences.

A recent study in the British Medical Journal (BMJ) reinforces this important lesson: The study showed that for patients already using an ACE inhibitor or an ARB, also taking a widely prescribed antibiotic that can raise blood potassium levels increased the risk of sudden death, most likely due to abnormal heart rhythms.

Potassium danger

An electrolyte (type of salt) found in the blood and inside all cells of the body, potassium is essential for life. Most people do not consume enough potassium, and maintaining adequate intake can actually reduce blood pressure (see "More Dietary Potassium Can Reduce Occurrence of Hypertension, Amount of Drugs Needed for Its Treatment" for more). However, when blood potassium levels rise significantly above normal — a condition known as hyperkalemia — life-threatening heart problems may occur.

One well-recognized effect of ACE inhibitors and ARBs is that they can raise blood potassium levels. They do so by interfering with the kidneys’ ability to remove excess potassium from the body.

Some degree of hyperkalemia develops in about 10 to 20 percent of patients taking ACE inhibitors and in up to 30 percent of patients taking ARBs.[2],[3] For most of these patients, the rise in blood potassium levels is mild and unlikely to cause life-threatening cardiac effects.

However, as many as 1 to 2 percent of patients on ACE inhibitors and 3 percent of patients on ARBs develop severe hyperkalemia, which can lead to fatal abnormal heart rhythms.[4],[5] People over 70 years old or who have kidney failure have an even higher risk of developing severe hyperkalemia while taking these drugs.[6]

Because of the hyperkalemia risk, patients treated with ACE inhibitors and ARBs need to undergo periodic blood tests to monitor potassium levels. Those with risk factors for severe hyperkalemia require more frequent monitoring.

Many other drugs, on their own, can cause hyperkalemia, among them the combination antibiotic trimethoprim-sulfamethoxazole (BACTRIM, SEPTRA, SULFATRIM PEDIATRIC).[7],[8] This antibiotic is most commonly prescribed for urinary tract infections (UTIs). Trimethoprim, like ACE inhibitors and ARBs, can block removal of excess potassium from blood by the kidneys. Severe hyperkalemia can develop within four to five days of starting trimethoprim-sulfamethoxazole.[9]

Combining ACE inhibitors or ARBs with other drugs known to cause hyperkalemia, such as trimethoprim-sulfamethoxazole, thus magnifies the risk of developing severe hyperkalemia. In 2011, a research team with the Canadian Drug Safety and Effectiveness Research Network found that among patients older than age 65 who were taking an ACE inhibitor or an ARB, use of trimethoprim-sulfamethoxazole was associated with a nearly sevenfold increased risk of hospitalization for hyperkalemia compared with similar patients prescribed amoxicillin (AMOXIL, LAROTID, MOXATAG), an antibiotic that does not affect potassium blood levels.[10]

The BMJ study[11]

The same research team subsequently examined whether combining ACE inhibitors or ARBs with trimethoprim-sulfamethoxazole was associated with an increased risk of sudden death and published their findings in the BMJ in October 2014.

In this study the researchers analyzed prescription drug, medical and health insurance records, as well as death certificate data, for elderly people in Ontario, Canada.

They first identified all patients older than age 65 who were prescribed either an ACE inhibitor or an ARB from April 1, 1994, to Jan. 1, 2012 (approximately 1.6 million patients). From this large group, they selected all patients who had died suddenly. They then examined the cases of sudden death within seven days of an outpatient prescription for trimethoprim-sulfamethoxazole or for any one of four other antibiotics that also are commonly used to treat UTIs: amoxicillin, ciprofloxacin (CIPRO), nitrofurantoin (FURADANTIN, MACROBID, MACRODANTIN) or norfloxacin. Except for trimethoprim-sulfamethoxazole, none of these antibiotics causes hyperkalemia.

Of the approximately 40,000 cases of sudden death that occurred in patients treated with an ACE inhibitor or ARB during the 17-year study period, 1,110 occurred within seven days of a prescription for one of the five antibiotics. After accounting for differences in patients’ ages and risk factors for hyperkalemia and for sudden death, the researchers found that prescription of trimethoprim-sulfamethoxazole in patients already taking an ACE inhibitor or an ARB was associated with a 38 percent increased risk of sudden death within seven days compared to treatment with amoxicillin. Treatment with ciprofloxacin also was associated with a 29 percent increased risk of sudden death. No increased risk was seen with norfloxacin, but nitrofurantoin was associated with a significantly lower risk of sudden death.

The investigators suggested that the increased risk of sudden death in patients treated with trimethoprim-sulfamethoxazole was related to fatal abnormal heart rhythms induced by hyperkalemia. In contrast, the increased sudden-death risk seen with ciprofloxacin treatment may have been related to the antibiotic’s ability, in rare cases, to cause QT prolongation, a change in the electrical activity of the heart that can lead to a fatal heart rhythm disturbance called torsades de pointes.

The investigators concluded:

The importance of our findings is underscored by the fact that [trimethoprim-sulfamethoxazole] is prescribed to millions of patients taking angiotensin converting enzyme inhibitors or angiotensin receptor blockers. Sudden death in these patients is likely to be misattributed to underlying cardiovascular disease, rather than hyperkalemia.

What You Can Do

If you are an elderly patient taking an ACE inhibitor or an ARB and develop a UTI or other bacterial infection requiring antibiotics, adhere to the following safeguards:

• Ask your doctor to prescribe an antibiotic other than trimethoprim-sulfamethoxazole.
• If another antibiotic is not a good option for treating your infection, take the lowest antibiotic dose for the shortest time period necessary.
• Before starting trimethoprim-sulfamethoxazole, your doctor should check your blood potassium level to confirm that it is in the normal range. The potassium level then should be monitored closely while you are on treatment.
• If you develop severe hyperkalemia while taking trimethoprim-sulfamethoxazole, you should discontinue the antibiotic and receive treatment to lower your blood potassium level.

References

[1] IMS Institute for Healthcare Informatics. The use of medicines in the United States: Review of 2011. Slide 37: Top therapeutic classes by prescriptions. http://www.imshealth.com/ims/Global/Content/Insights/IMS%20Institute%20for%20Healthcare%20Informatics/IHII_Medicines_in_U.S_Report_2011.pdf. Accessed March 25, 2015.

[2] Reardon LC, Macpherson DS. Hyperkalemia in outpatients using angiotensin-converting enzyme inhibitors: How much should we worry? Arch Intern Med. 1998;158(1):26-32.

[3] Sadjadi SA, McMillan J, Jaipaul N, et al. A comparative study of the prevalence of hyperkalemia with the use of angiotensin-converting enzyme inhibitors versus angiotensin receptor blockers. Ther Clin Risk Manag. 2009;5: 547–552.

[4] Reardon LC, Macpherson DS. Hyperkalemia in outpatients using angiotensin-converting enzyme inhibitors: How much should we worry? Arch Intern Med. 1998;158(1):26-32.

[5] Sadjadi SA, McMillan J, Jaipaul N, et al. A comparative study of the prevalence of hyperkalemia with the use of angiotensin-converting enzyme inhibitors versus angiotensin receptor blockers. Ther Clin Risk Manag. 2009;5: 547–552.

[6] Reardon LC, Macpherson DS. Hyperkalemia in outpatients using angiotensin-converting enzyme inhibitors: How much should we worry? Arch Intern Med. 1998;158(1):26-32.

[7] Marinella MA. Trimethoprim-induced hyperkalemia: An analysis of reported cases. Gerontology. 1999;45(4):209-212.

[8] Lam N, Weir MA, Juurlink DN, et al. Hospital admissions for hyperkalemia with trimethoprim-sulfamethoxazole: A cohort study using health care database codes for 393,039 older women with urinary tract infections. Am J Kidney Dis. 2011;57(3):521-525.

[9] Marinella MA. Trimethoprim-induced hyperkalemia: An analysis of reported cases. Gerontology. 1999;45(4):209-212

[10] Antoniou T, Gomes T, Juurlink DN, et al. Trimethoprim-sulfamethoxazole-induced hyperkalemia in patients receiving inhibitors of the renin-angiotensin system: A population-based study. Arch Intern Med. 2010;170(12):1045-1049.

[11] Fralick M, Macdonald EM, Gomes T, et al. Co-trimazole and sudden death in patients receiving inhibitors of renin-angiotensin system: Population based study. BMJ. 2014;349:g6196. doi: 10.1136/bmj.g6196.;