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Pharmacotherapy for CVD in women: Focus on microvascular coronary dysfunction
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Humanistic and economic outcomes of heart disease in women continue to affect health care systems around the world.
With sponsorship from the NHLBI, the Women’s Ischemia Syndrome Evaluation (WISE) began more than a decade ago with the goal of understanding the underlying mechanisms of ischemic heart disease in women and to enhance diagnostic techniques of heart disease for use in women. To date, WISE has identified disease in the small vessels of a woman’s heart, or the microcirculation, as an important factor.
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Compared with women without symptoms of heart disease, microvascular dysfunction has been associated with an increased risk for stroke, congestive HF, MI and death. This represents an important component of overall heart disease that requires ongoing investigation by WISE and other investigators to provide the most comprehensive understanding of optimal diagnostic and treatment modalities for women with heart disease.
Pharmacotherapy
Invasive coronary reactivity testing represents the gold standard for assessing microvascular function. Testing typically utilizes acetylcholine, adenosine and nitroglycerin to identify diagnostic features of blood flow and coronary function. It has been shown that women who have microvascular dysfunction, or symptoms of angina in the absence of obstructive coronary disease, also have a high prevalence of important modifiable risk factors, including hypertension, obesity, diabetes and a history of smoking.
Recognition and aggressive use of pharmacotherapy treatment options aimed at improving endothelial function, as well as other risk factors, is important in the overall care of these women. Pharmacotherapy options include ACE inhibitors, statins, beta-blockers, nitrates, calcium channel blockers and ranolazine, all of which have been shown to successfully manage angina and myocardial ischemia symptoms and risk factors in women.
In a recent double blind, randomized trial, 78 women with microvascular dysfunction (defined as a coronary flow reserve <3 following adenosine and no obstructive CAD) were randomly assigned to an ACE inhibitor (quinapril 80 mg/day) or placebo for 16 weeks. Quinapril was selected based on its high tissue penetration and previously documented benefit in vascular function in ischemic heart diseases. The primary endpoint was coronary flow reserve (CFR) at 16 weeks, adjusted for baseline CFR, study site and clinical variables. Besides lower systolic BP, at 16 weeks the primary outcome of CFR improved more with the ACE inhibitor vs. placebo (P<.02), documenting that risk factor improvement with an ACE inhibitor is also associated with improved microvascular function. This beneficial effect was concentrated among women with more severe baseline CFR impairment. In this study, women treated with quinapril also had improved angina symptoms based on the Seattle Angina Questionnaire (SAQ) vs. women who received placebo (P=.037).
Another recent study explored the possibility that phosphodiesterase type 5 (PDE5) inhibition might be an effective drug for management of microvascular dysfunction in women. Twenty-three women had CFR measured before and 45 minutes after a single dose of sildenafil 100 mg. Baseline CFR ≤3 was required for study entry. Results showed that in these women with signs and symptoms of ischemia but no obstructed coronary arteries, PDE5 inhibition with sildenafil (Revatio and Viagra, Pfizer) was associated with acute improvement in CFR, and the effect was concentrated in those women with CFR ≤2.5. Whether this acute improvement in CFR would be sustained with chronic use is unclear, and additional investigation of this class of drugs in women with microvascular dysfunction is warranted.
Ranolazine (Ranexa, Gilead Sciences), a novel antianginal agent, was evaluated in a study of 20 women with microvascular dysfunction who also had abnormal cardiac magnetic imaging perfusion. In these women, just 4 weeks of ranolazine resulted in significant improvement in SAQ score and a trend toward improved myocardial perfusion. Data from this small pilot study are promising, and a larger trial of ranolazine in women with microvascular dysfunction is currently on going.
Effectiveness-based preventive guidelines
Besides considering the evidence provided in these small yet promising clinical trials, recent guidelines place the spotlight on effectiveness-based principles for prevention of CVD in women. Recommendations include nicotine replacement and other pharmacotherapy as indicated, combined with smoking cessation programs for women who smoke (Class I; Level Evidence B); consumption of omega-3 fatty acids in the form of fish or in capsule form may be considered for primary or secondary prevention (Class IIb; Level of Evidence B); and pharmacotherapy for major comorbidities, including hypertension (Class I; Level Evidence A), lipid lowering in high-risk women (Class I; Level Evidence A) and diabetes (Class IIa; Level Evidence B), is also recommended along with lifestyle adjustments as necessary.
Clarissa Havel, PharmD, BCPS, is a pharmacist for RPh on the go and is from Skokie, Ill.
Rhonda M. Cooper-DeHoff, PharmD, MS, is associate professor in the department of pharmacotherapy and translational research, College of Pharmacy, and division of cardiovascular medicine, College of Medicine, University of Florida, Gainesville. Dr. Cooper-DeHoff is Cardiology Today’s Pharmacology Consult column editor and a member of the CHD and Prevention section of the Cardiology Today Editorial Board. For suggestions for future topics in this column, contact her at dehoff@cop.ufl.edu.
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Disclosure: Dr. Havel reports no relevant financial disclosures.