C. Noel Bairey Merz
More women than men die annually of ischemic heart disease, which
represents a reversal of fortune from prior decades and places women firmly as
the new majority now affected. The adverse ischemic heart disease (HD) gender
gap is the widest in relatively young women, where MI mortality is twofold
higher in women younger than 50 years compared with age-matched men. Although
it is clear that there are many gender differences in ischemic HD outcomes,
including more frequent angina diagnosis, more office visits, more avoidable
hospitalizations, higher MI mortality, and higher rates of HF in women compared
with men, the contributing etiologies to these differences are unclear.
A number of contradictory findings are evident with regard to sex
differences in ischemic HD: Women have a higher prevalence of angina compared
with men, yet have an overall lower prevalence of obstructive CAD; symptomatic
women undergoing coronary angiography have less extensive and severe
obstructive CAD, despite being older with higher risk factor burden compared
with men; and despite relatively less obstructive CAD, women have a more
adverse prognosis compared with men. We have hypothesized an alternative,
female-specific pattern of ischemic HD due to the relatively high frequency of
microvascular coronary dysfunction in symptomatic women with and without
obstructive CAD, which we have linked with symptoms, ischemia and adverse
outcomes. This alternative “female-pattern” of ischemic HD is not
easily recognized, given our male-pattern strategies aimed at detection and
treatment of obstructive CAD.
What relevance does this have to the adverse gender gaps for ischemic HD
in women? The literature suggests that when women look like men (with
“male-pattern” obstructive CAD), they are more likely to be diagnosed
and treated as men are treated. As characterized by the “Yentl”
syndrome, depicted in the Barbra Streisand movie of the same name, Bernadine
Healy, MD, used this term in 2001 to call attention to the paradox of
adverse outcomes of women with ischemic HD, as well as the under-diagnosis and
under-treatment of women.
Ten years later, recent analyses published in the European Heart
Journal suggest that Yentl syndrome remains evident in 2011. Johnson and
colleagues compared diagnostic coronary angiography, medication usage, and
outcomes in 12,200 women and men with stable signs and symptoms of ischemic HD
and 2-year outcomes in Sweden between 2006 and 2008. Bugiardini and colleagues
summarized medication usage and outcomes in 6,558 women and men with ACS with
1-year outcomes from the Canadian ACS Registry I and II between 1999 and 2003.
Both studies demonstrate under-treatment of women with medication, including
lower rates of aspirin and ACE inhibitor use in stable women compared with men,
as well lower rates of ACE inhibitor, beta-blocker and statin medication in ACS
women compared with men. Both studies also show gender differences in use of
procedures, where interestingly, stable women undergo more repeat angiography,
whereas ACS women undergo fewer index angiograms, percutaneous coronary
interventions and CABG compared with their male counterparts. The adverse
outcomes described in these new works are consistent with prior literature.
Both studies demonstrate adverse gender differences for women; Stable women
have more MIs while ACS women have higher death rates compared with men.
The Swedish data report equivalent use of the four life-saving
medication strategies (ACE inhibitors, beta-blockers, aspirin and statins)
among stable women and men after angiographic diagnosis of obstructive CAD.
Importantly, appropriate medication utilization was accompanied by equivalent
mortality between the sexes, although event rates were predictably lower in
this stable lower-risk population. Prior work has shown an improvement of
ischemic HD prognosis in women over time. Nevertheless, other contemporary data
demonstrate persistently more adverse outcomes for women compared with men. The
Canadian Registry analysis adds to the accumulated literature that women with
ACS remain less likely than men to receive indicated diagnostic tests,
guideline-indicated medication and procedures and subsequently suffer
predictable higher rates of adverse outcomes.
Given the emphasis on guidelines therapy, why are women still
undertreated with appropriate ischemic HD guidelines therapy? Both of these new
studies provide similar clues. The Canadian Registry data demonstrate that
female sex, despite adjustment for multiple associated variables, independently
remains associated with under-utilization of guidelines therapy for ACS
patients. The Swedish data demonstrate that the relatively large differences in
medication between women and men before coronary angiography vanished following
demonstration of obstructive CAD at angiography. These findings, which are
consistent with prior literature, argue against cultural,
“gender-based” factors, including misogyny and sexism, as a driving
force for drug under-utilization in women, and suggest alternatively that
biological, “sex-based” differences are key contributors. We can
conclude from these studies and the prior literature that the presence or
absence of obstructive CAD (eg, “male-pattern” ischemic HD) remains a
key decision point in medication prescription for practicing physicians.
Because higher proportions of women with ischemic HD present without
obstructive CAD or undergo less coronary angiography, relatively fewer women
will be treated, including those with evident ACS (for which guideline
medication is not linked to angiography).
We have estimated the prevalence of signs and symptoms of ischemic HD in
the absence of obstructive CAD using the NCDR database to be between 2 and 3
million women, placing it as a larger health care threat to women than breast
cancer, and comparable to the highly prevalent 6 million women with clinically
documented obstructive CAD in the US alone. Accordingly, two guidelines now
specify strategies for women, including the AHA/ACC Prevention of
Cardiovascular Disease in Women, and the AHA/ACC Management of Patients with
Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction. Moreover,
ischemic HD strategies that provide guideline-driven infrastructure support to
physicians such as the AHA Get with the Guidelines and the ACC Guidelines
Applied in Practice initiatives appear to have the largest impact on closing
therapeutic gender-gaps that disadvantage women.
While increasing knowledge exists regarding pathophysiological
mechanistic pathways for “female-pattern” ischemic HD, translational
studies aimed at developing practical diagnosis and therapeutics with both
traditional and novel treatments are needed. Further closure of knowledge gaps
related to the paradox and the pathophysiology of ischemic HD in women is one
of our highest priorities to improve the health of the 51% of the population
that is female and who currently represent the majority of deaths.
C. Noel Bairey Merz, MD, is director of the Women’s Heart Center
at Cedars Sinai Medical Center in Los Angeles and a member of the Cardiology
Today Editorial Board.
For more information:
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Ischemia Syndrome Evaluation (WISE) study: protocol design, methodology and
feasibility report. J Am Coll Cardiol. May 1999;33(6):1453-1461.
- Bairey Merz CN, Shaw LJ, Reis SE, et al. Insights from the
NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study: Part
II: gender differences in presentation, diagnosis, and outcome with regard to
gender-based pathophysiology of atherosclerosis and macrovascular and
microvascular coronary disease. J Am Coll Cardiol. Feb 7 2006;47(3
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quality of care for women with cardiovascular disease: report of a DCRI Think
Tank, March 8 to 9, 2007. Am Heart J. Nov 2008;156(5):816-825, 825
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arteries: a changing philosophy. JAMA. Jan 26
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Underutilisation of Evidence Based Therapies in Women. European Heart
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gender differences in traditional and novel risk factors, symptom evaluation,
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Disclosure: Dr. Bairey Merz reports no relevant financial