Maria-Rosa was a robust woman in her late forties with a loud voice and an infectious laugh. She was a project manager at a local contracting firm, a grandmother, and a born nurturer. During her multiple visits to the emergency department, she got to know some of the staff and was constantly asking after their little ones and offering them her brand of “take-no-prisoners” life advice.

Every time we saw Maria-Rosa, it seemed to be for a different concern. The first few times, she came in with acute back pain. No matter what she did, the pain kept getting worse. Her diagnoses were inconclusive. Her surgery for spinal stenosis was not effective. The only solution we and her other doctors could offer was to keep ramping up her pain medication and recommend that she incorporate lifestyle adjustments like a healthy diet and gentle yoga.

Eventually, the pain was so bad that she was prescribed oxycodone supplemented with ibuprofen between doses. Even then, she continued to visit the ED when the pain overwhelmed her and she couldn’t safely take any more painkillers. We were able to arrange steroid injections and offer short-term IV pain medication but ultimately had to send her home without a lasting solution.

Understandably, Maria-Rosa’s sleep was affected by her back pain. She couldn’t get comfortable and woke up multiple times per night. Her constant fatigue began to affect her work. Her primary physician gave her Benadryl and Ambien to help her sleep.

Living with that level of pain and the resulting sleep disruptions also affected Maria-Rosa’s mental state. She reported feeling anxious. Her therapist recommended anti-anxiety medication.
Then Maria-Rosa came into the Emergency Department with a raging urinary tract infection (UTI). The attending physician gave her Cipro, a powerful antibiotic, to kill the infection before it spread to her kidneys and made things even worse.

The last time I saw Maria-Rosa, she was on a stretcher, surrounded by frantic nurses and interns who were trying, without success, to restart her heart through CPR. According to her daughter, who’d made the call to 911, Maria-Rosa had been feeling 'a little off all day, but it’s nothing to worry about'—and then, while cooking dinner for her daughter and grandkids, she collapsed.

What happened to Maria-Rosa? How had idiopathic back pain—however excruciating—led to sudden cardiac death?

What went wrong?

Maria-Rosa experienced, and ultimately died as a result of, an issue that is more common than we would like to admit.

This issue isn’t talked about much, but it is widespread. In my book, Sex Matters: How Male-Centric Medicine Endangers Women's Health and What We Can Do About It, I show that the average American adult takes four or more different prescriptions. Women are statistically more likely to be prescribed medications than men and are more likely to have prescriptions from multiple providers, who may or may not be aware of what other drugs the patient is taking, since most of this information is self-reported.(1) Furthermore, women are more likely to have adverse reactions or interactions since most drugs are tested primarily (or even exclusively) in men.



In Maria-Rosa’s case, it’s almost certain that her prescriptions, in combination, caused her ventricular tachycardia and ultimate sudden cardiac death.

Unfortunately, cases like hers happen often. Arrhythmia (when the heart does not beat normally) is often a direct result of drug interactions. When women’s QT intervals (aka, the “resting time” between a person’s heartbeats) (2) are affected by various prescription drugs, the results can range from simple arrhythmia, to ventricular tachycardia (torsades de pointes), to asystole (flatline) and sudden cardiac death.

Why sex matters in clinical trials

Before Maria-Rosa’s back pain sent her into a “treatment spiral,” her heart appeared perfectly healthy. So how could this happen? Shouldn’t her doctors have worried that the combination of her pain medications, anti-anxiety pills, steroids, and antibiotics were creating a deadly cocktail?
Perhaps. But they didn't have a reason for concern because if Maria- Rosa had been a man, such a combination would likely not have produced the same effect—or even been dangerous at all.

The key to understanding this deadly disparity lies in the QT interval. Men have shorter QT intervals than women; this is a result of the surge in testosterone that occurs during male puberty.

In short, men’s hearts need less time to recover between contractions (i.e., heartbeats) than women’s do. Many prescription drugs—such as painkillers, anti-inflammatory drugs, steroids, sleep aids, antibiotics, antihistamines, and antidepressants, to name a few—have the effect of incrementally increasing a person’s QT interval.

Multiple Drugs Multiply Risk

When such drugs are taken alone, this isn’t cause for concern, as the effect is minimal. However, when such drugs are taken in combination over a period, the QT interval is increased to the point where the heart doesn’t beat correctly after its elongated rest period.

When this tipping point is reached, the heart just . . . sputters out. This is called “drug-induced torsades de pointes,” and it’s more common in women than in men—precisely because women lack the testosterone-protective effect and end up taking more prescription medications then men.

A German study found that, between 2008 and 2011, the majority (66 percent) of “long QT syndrome” patients were female and that 60 percent of those female cases were confirmed as drug-related according to World Health Organization criteria.(3)

In Maria-Rosa’s case, it was the antibiotics that put her over that QT interval tipping point. But for millions of other women around the country, it could be that new antidepressant, that new immunosuppressant for fibromyalgia, or even an extra daily dose of over-the-counter antacid.

Because her doctors outside the ED may have been unaware of female sex as an independent risk factor for serious drug interactions, because women are more likely to have multiple or over- lapping providers and prescribers (with each provider potentially unaware of existing prescriptions unless the patient reports them), and because our current system isn’t set up to take QT interval into account when prescribing new drugs, Maria-Rosa wasn’t offered the tests and alternatives that could have prevented her death.

Even though my emergency department is at the cutting edge of sex and gender medicine, it isn’t a routine part of our protocol to check a woman’s QT interval before prescribing a simple round of antibiotics for a UTI. 

We need to do better.

References:

(1) 1. M. Manteuffel et al., “Influence of Patient Sex and Gender on Medication Use, Adherence, and Prescribing Alignment with Guidelines,” Journal of Women’s Health 23, no. 2 (2014): 112–199.doi: 10.1089/jwh.2012.3972.

(2) An electrocardiogram measure which quantifies how long it takes cardiac ventricles to start contracting and finish relaxing - the start of the Q wave to the end of the T wave. 

(3) 2. Giselle Sarganas, “Epidemiology of Symptomatic Drug-Induced Long QT Syndrome and Torsade de Pointes in Germany,” EP Europace 16, no. 1 (2014): 101–108. doi: 10.1093/europace/eut214.