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Women and Men Differ in Response to Some Heart Failure Therapies

Key findings

  • Because of the lack of robust, randomized trials, no sex-specific recommendations exist for any heart failure (HF) therapy
  • Beta-blockers have not demonstrated strong benefit in patients who have HF with preserved ejection fraction, the most common type among women
  • Potential sex differences in response to diuretics and renin–angiotensin–aldosterone system inhibitors have not been well studied
  • More studies and guidelines are needed to define the role of device therapies and heart transplantation in the treatment of women with HF

In general, women with heart failure (HF) gain as much benefit from guideline-directed medical therapy as men do, according to Nasrien E. Ibrahim, MD, associate director of the Resynchronization & Advanced Cardiac Therapeutics Program.

However, women are frequently undertreated, and there are sex differences in response to pharmacologic, device and advanced therapies for HF, which Dr. Ibrahim and colleagues recently reviewed in Current Treatment Options in Cardiovascular Medicine.

Pharmacologic Therapies


Beta-blockers are well established to be an effective treatment for both men and women with HF and reduced ejection fraction (HFrEF). However, beta-blocker use in HF patients with preserved ejection fraction (HFpEF), the more common type in women, has failed to demonstrate similar benefits. No strong data are available to support clinical decision-making in that group.

Renin–angiotensin–aldosterone System Inhibitors

  • Only limited data are available regarding sex-specific response to renin–angiotensin–aldosterone system inhibitors. Current guidelines do not distinguish between men and women when recommending the use of angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors
  • Three randomized trials of mineralocorticoid receptor antagonists did not demonstrate any sex differences in outcomes, but enrollment rates for women were low
  • The new angiotensin receptor–neprilysin inhibitors are recommended for patients with HFrEF who remain symptomatic despite use of other guideline-directed therapy. Only one major trial has explored sex differences: a pivotal trial of sacubitril/valsartan showed no difference between men and women on the combined primary endpoint (cardiovascular death or first HF hospitalization), but only men had significant improvement in cardiovascular death alone.


No clinical studies have investigated sex differences in response to diuretics, but pharmacology studies show that women tend to have higher rates of hyponatremia, hypokalemia and related arrhythmias than men do. The mechanism is unknown, but women seem to develop higher peak plasma levels and have reduced excretion compared with men.

Device Therapies

Implantable cardioverter Defibrillator (ICD)

ICD remain underused in women and ethnic minorities, according to the authors. It is true that women have a lower risk of sudden cardiac death than men do, along with more severe comorbidities, which introduce competing causes of death and may minimize the effectiveness of ICD.

Yet a review of the American Heart Association's Get With the Guidelines registry demonstrated, in general, that women with HF live significantly longer if they have an ICD. More studies are needed to define the risks and benefits of ICDs for women for both primary and secondary prevention.

Cardiac Resynchronization Therapy Defibrillator (CRT-D)

Women are more likely than men to receive a CRT-D because of their higher prevalence of non-ischemic cardiomyopathy, left bundle branch block and symptomatic HF. In a subgroup analysis of the MADIT-CRT trial, female gender was an independent predictor of a positive response to CRT-D.

Furthermore, a patient-level meta-analysis conducted by the FDA detected a greater survival benefit of CRT-D in women than in men at QRS of 130 to 149 ms. The researchers call for sex-specific guidelines about using CRT-D in patients with shorter QRS durations.

Advanced Therapies

Heart Transplantation

Women account for approximately one-quarter of heart transplants. Among patients with the highest United Network for Organ Sharing (UNOS) risk score, women have a 20% higher mortality rate than men while awaiting heart transplantation. Yet UNOS transplant criteria do not account for this disparity.

Left Ventricular Assist Device (LVAD)

Early pulsatile flow LVADs were not designed for women. The smaller, continuous-flow LVADs are now being implanted in women, but sex-specific outcomes data are still limited. What is known is that women are at increased risk of a first neurological event, as demonstrated in several retrospective studies.

Coping with Growing Complexity

Because of the lack of robust, randomized clinical trials, no sex-specific recommendations exist for any HF therapy, Dr. Ibrahim says.

They refer clinicians to the 2017 Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment, published by the American College of Cardiology. It contains practical, targeted recommendations for managing the increasingly diverse and complex patient population with HF.

Refer a patient to the Mass General Heart Center

Learn more about the Heart Failure and Cardiac Transplantation Program

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