Women’s health 2015: An update for the internist
ABSTRACTThe field of women’s health is varied and dynamic. Major studies in 2014 and the first half of 2015 suggest that selective serotonin reuptake inhibitors are not strongly associated with congenital heart defects, that paroxetine 7.5 mg is effective for treating menopausal symptoms, and that women with heart failure may benefit more from cardiac resynchronization therapy than men.
KEY POINTS
- Earlier trials had raised concerns about possible teratogenic effects of selective serotonin reuptake inhibitors, but more recent trials have found no strong association between these drugs and congenital heart defects, and no association with miscarriage or autism spectrum disorder, though there may be a risk of attention deficit hyperactivity disorder in offspring.
- Paroxetine is approved for treating vasomotor symptoms of menopause, but in a lower dose (7.5 mg) than those used for depression and other psychiatric indications. Clinical trials have also shown good results with other antidepressants for treating hot flashes, but the drugs are not yet approved for this indication.
- Women with heart failure and left bundle-branch block can decrease their risk of death with cardiac resynchronization therapy more than men with the same condition. Moreover, women may benefit from this therapy even if their QRS duration is somewhat shorter than the established cutoff, ie, if it is in the range of 130 to 149 ms.
HEART DISEASE IN WOMEN: CARDIAC RESYNCHRONIZATION THERAPY
A 68-year-old woman with a history of nonischemic cardiomyopathy presents for routine follow-up in your office. Despite maximal medical therapy on a beta-blocker, an angiotensin II receptor blocker, and a diuretic, she has New York Heart Association (NYHA) class III symptoms. Her most recent studies showed an ejection fraction of 30% by echocardiography and left bundle-branch block on electrocardiography, with a QRS duration of 140 ms. She recently saw her cardiologist, who recommended cardiac resynchronization therapy, and she wants your opinion as to whether or not to proceed with this recommendation. How should you counsel her?
Which patients are candidates for cardiac resynchronization therapy?
Heart disease continues to be the number one cause of death in the United States for both men and women, and almost the same number of women and men die from heart disease every year.19 Though coronary artery disease accounts for most cases of cardiovascular disease in the United States, heart failure is a significant and growing contributor. Approximately 6.6 million adults had heart failure in 2010 in the United States, and an additional 3 million are projected to have heart failure by 2030.20 The burden of disease on our health system is high, with about 1 million hospitalizations and more than 3 million outpatient office visits attributable to heart failure yearly.20
Patients with heart failure may have symptoms of dyspnea, fatigue, orthopnea, and peripheral edema; laboratory and radiologic findings of pulmonary edema, renal insufficiency, and hyponatremia; and electrocardiographic findings of atrial fibrillation or prolonged QRS.21 Intraventricular conduction delay (QRS duration > 120 ms) is associated with dyssynchronous ventricular contraction and impaired pump function and is present in almost one-third of patients who have advanced heart failure.21
Cardiac resynchronization therapy, or biventricular pacing, can improve symptoms and pump function and has been shown to decrease rates of hospitalization and death in these patients.22 According to the joint 2012 guidelines of the American College of Cardiology Foundation, American Heart Association, and Heart Rhythm Society,22 it is indicated for patients with an ejection fraction of 35% or less, left bundle-branch block with QRS duration of 150 ms or more, and NYHA class II to IV symptoms who are in sinus rhythm (class I recommendation, level of evidence A).
Studies of cardiac resynchronization therapy in women
Recently published studies have suggested that women may derive greater benefit than men from cardiac resynchronization therapy.
Zusterzeel et al23 (2014) evaluated sex-specific data from the National Cardiovascular Data Registry, which contains data on all biventricular pacemaker and implantable cardioverter-defibrillator implantations from 80% of US hospitals.23 Of the 21,152 patients who had left bundle-branch block and received cardiac resynchronization therapy, women derived greater benefit in terms of death than men did, with a 21% lower risk of death than men (adjusted hazard ratio 0.79, 95% CI 0.74–0.84, P < .001). This study was also notable in that 36% of the patients were women, whereas in most earlier studies of cardiac resynchronization therapy women accounted for only 22% to 30% of the study population.22
Goldenberg et al24 (2014) performed a follow-up analysis of the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy. Subgroup analysis showed that although both men and women had a lower risk of death if they received cardiac resynchronization therapy compared with an implantable cardioverter-defibrillator only, the magnitude of benefit may be greater for women (hazard ratio 0.48, 95% CI 0.25–0.91, P = .03) than for men (hazard ratio 0.69, 95% CI 0.50–0.95, P = .02).
In addition to deriving greater mortality benefit, women may actually benefit from cardiac resynchronization therapy at shorter QRS durations than what is currently recommended. Women have a shorter baseline QRS than men, and a smaller left ventricular cavity.25 In an FDA meta-analysis published in August 2014, pooled data from more than 4,000 patients in three studies suggested that women with left bundle-branch block benefited from cardiac resynchronization therapy more than men with left bundle-branch block.26 Neither men nor women with left bundle-branch block benefited from it if their QRS duration was less than 130 ms, and both sexes benefited from it if they had left bundle-branch block and a QRS duration longer than 150 ms. However, women who received it who had left bundle-branch block and a QRS duration of 130 to 149 ms had a significant 76% reduction in the primary composite outcome of a heart failure event or death (hazard ratio 0.24, 95% CI 0.11–0.53, P < .001), while men in the same group did not derive significant benefit (hazard ratio 0.85, 95% CI 0.60–1.21, P = .38).
Despite the increasing evidence that there are sex-specific differences in the benefit from cardiac resynchronization therapy, what we know is limited by the low rates of female enrollment in most of the studies of this treatment. In a systematic review published in 2015, Herz et al27 found that 90% of the 183 studies they reviewed enrolled 35% women or less, and half of the studies enrolled less than 23% women. Furthermore, only 20 of the 183 studies reported baseline characteristics by sex.
Recognizing this lack of adequate data, in August 2014 the FDA issued an official guidance statement outlining its expectations regarding sex-specific patient recruitment, data analysis, and data reporting in future medical device studies.28 Hopefully, with this support for sex-specific research by the FDA, future studies will be able to identify therapeutic outcome differences that may exist between male and female patients.
Should our patient receive cardiac resynchronization therapy?
Regarding our patient with heart failure, the above studies suggest she will likely have a lower risk of death if she receives cardiac resynchronization therapy, even though her QRS interval is shorter than 150 ms. Providers who are aware of the emerging data regarding sex differences and treatment response can be powerful advocates for their patients, even in subspecialty areas, as highlighted by this case. We recommend counseling this patient to proceed with cardiac resynchronization therapy.
