AUSTRALIAN experts are divided on a call for sex- and gender-specific medicine following new research that shows women may be missing out on life-saving cardiac resynchronisation therapy because guidelines are based on research in men, who can benefit less from the devices.
The meta-analysis, published in JAMA Internal Medicine, pooled individual data from 4076 patients, predominantly with mild heart failure, in three trials comparing cardiac resynchronisation therapy defibrillators (CRT-D) with implantable cardioverter defibrillators (ICD), who were followed for up to 3 years. (1)
They wrote that 78% of trial participants were men. However, women benefited from CRT-D more than men, with the main difference seen in patients with left bundle branch block (LBBB) and a QRS of 130‒149 milliseconds. Women in this group had a 76% reduction in heart failure or death (absolute CRT-D to ICD difference, 23%) and a 76% reduction in death alone (absolute difference, 9%) — findings unaltered by adjustments for ischaemic aetiology, atrial fibrillation and flutter, and cardiac medications. In men there was no significant benefit in heart failure or death (absolute difference, 4%) or death alone (absolute difference, 2%).
The findings suggested that while men with LBBB should receive CRT-D when the QRS interval is ≥ 150 milliseconds, as guidelines state, women can benefit from treatment at shorter durations.
“Considering that women receive CRT-D less often than men, we believe that the current findings are important to communicate”, the study authors wrote.
“Overall, this study highlights the importance of sex-specific analysis in medical device clinical studies.”
The authors of an accompanying commentary said the study shed light on “a major contributor to the misdiagnosis and suboptimal treatment of [cardiovascular disease] in women”. (2)
Calling for sex- and gender-specific medicine, the editorial authors wrote guidelines were “typically based on a male standard and do not address important differences in women.”
Women, for instance, had a higher prevalence of coronary microvascular dysfunction and heart failure with preserved ejection fraction compared with men, as well as greater sensitivity to QT-prolonging medications, and higher heart failure mortality with digoxin.
Professor John Beltrame, cardiology academic lead in the Central Adelaide Local Health Network, strongly supported the editorial, describing one of the authors — Dr Noel Bairey Merz of the Barbra Streisand Women’s Heart Centre in California, who was recently in Australia for the World Cardiology Congress — as a “world authority on women’s cardiovascular health”.
“[The] editorial highlights how the biology of cardiovascular disease in women differs to men and therefore may manifest as different clinical phenotypes, often requiring different therapeutic approaches”, Professor Beltrame said.
However, Professor Andrew Sindone, director of the Heart Failure Unit and Department of Cardiac Rehabilitation at Sydney’s Concord Hospital, said the latest findings should be considered “hypothesis generating”.
“This study gives a strong signal but we need prospective trials”, he said.
Professor Sindone said it was unreasonable to suggest the current guidelines were “biased toward men” or likely to lead to undertreatment of women.
Heart failure typically occurred later in life for women than men, along with other comorbidities. He said for this reason women were less likely to be included in trials, which preferred younger patients with fewer comorbidities so that treatment effects were not diluted by underlying illnesses.
Patients with QRS durations of > 150 milliseconds were most likely to derive a benefit from CRT. While those with QRS durations of 120‒149 milliseconds might still benefit, the presence of dyssynchrony should be confirmed by echocardiography, Professor Sindone said.
“We may update the next issue of the [Australian] guidelines to say that in women the criteria for consideration of CRT may be at a lower QRS duration, based on a post-hoc analysis, but this would be at a fairly low level of evidence”, he said. (3)
Dr Robert Grenfell, national director of cardiovascular health at the Heart Foundation, said it was hard to know if women were being undertreated for chronic heart failure in Australia because there was no national register of cardiac devices or procedures.
However, Dr Grenfell said that based on the study “gender should be considered when a course of treatment is being decided upon, specifically among heart failure patients with LBBB”.
He added that more needed to be done to address the underrepresentation of women in clinical trials, to enable equitable care.