Fewer women than men meet criteria for heart failure trials

Fewer women than men meet eligibility criteria for trials of heart failure medication, according to a study presented this week at Heart Failure 2018 and the World Congress on Acute Heart Failure.

The study investigated why just 21% of patients enrolled in the large-scale PARADIGM-HF trial — which had a total of 8399 participants across 47 countries — were women. The trial compared the effectiveness of an angiotensin receptor neprilysin inhibitor (ARNI) versus standard treatment with an angiotensin-converting enzyme (ACE) inhibitor in patients with heart failure and an ejection fraction (the proportion of blood the heart is capable of pumping out of the left ventricle) of 35% or less. To participate in the trial, patients had to first tolerate target doses of an ACE inhibitor or angiotensin receptor blocker (ARB).

To conduct the current study, Helena Norberg and her colleagues at Umeå University applied the trial criteria to 1924 community-based heart failure patients in Sweden, of whom 43% were women. When the requirement to have an ejection fraction of 35% or less was applied there were 401 patients remaining, of whom 28% were women. After applying the other participation criteria of the trial, 246 patients were excluded because they failed to reach the target dose of an ACE inhibitor or ARB and 60 were excluded for other reasons. That left 95 eligible patients, of which just 15 were women (16%).

The requirement to reach the target dose of an ACE inhibitor or ARB thus disproportionately excluded women, the researchers concluded. In the community-based heart failure population, just 26% of women with heart failure and a reduced ejection fraction could reach the target dose compared to 43% of men.

When the researchers compared the characteristics of women and men in the study with heart failure and reduced ejection fraction, they found that women were significantly older (81 versus 75 years on average), with lower body weight (69 versus 85 kg), worse kidney function (estimated glomerular filtration rate of 49 versus 70 mL/min) and higher systolic blood pressure (127 versus 123 mmHg). When they examined which of those variables were significantly associated with women’s failure to achieve the target dose of an ACE inhibitor or ARB, they found it was their older age and worse kidney function.

“One of the gold standard requirements for participating in a clinical trial of heart failure medication is that patients must first reach a fixed target dose of the currently recommended treatment,” explained Norberg, who was lead author of the new study. “This excludes many women, particularly older ones, meaning we don’t gain knowledge in this group.

“These target doses were calculated from trials conducted primarily in men with heart failure, who tend to be younger and have better kidney function. Future trials in heart failure should use achievement of maximum tolerated doses, rather than fixed target doses, as entry criteria to ensure that women are more represented.”

Norberg noted that the ARNI has been approved for clinical use by the US FDA and the European Medicines Agency. However, it is contraindicated in pregnant or breastfeeding women, and should be used cautiously in patients with severe renal impairment due to the risk of hyperkalaemia. It should not be used at the same time as an ACE inhibitor or ARB.

The news comes soon after Italian researchers proposed that a patient’s sex might impact on the efficacy of immunotherapy in cancer treatment, finding a higher survival benefit for men compared to women. Those researchers acknowledged that the underrepresentation of female patients in clinical trials is a widely recognised problem — with women comprising less than one-third of the total population in half of the trials in their study — and emphasised the need for sex-specific analyses to avoid erroneously extending to women results that are obtained mainly in male patients.

“Controlled clinical trials are widely regarded as the gold standard for evaluating the efficacy of a treatment,” said Carlos Aguiar, European Society of Cardiology (ESC) spokesperson on heart failure. “Yet when study design imposes rigorous criteria for participant eligibility, the findings may not generalise to other individuals. This analysis by Norberg and colleagues identifies factors that may help increase the representativeness of the results of heart failure trials in the large female population suffering from this condition.”

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