Pharmacology Watch

Women's Health Issue — Adverse Medication Effects

In this issue: Calcium supplements and MI; birth control pills and VTE; ACE inhibitors and breast cancer risk; spending on pharmaceuticals; and FDA actions.

Calcium supplements and MI risk

Do calcium supplements increase the risk of myocardial infarction (MI)? Researchers from New Zealand recently reanalyzed data from the Women's Health Initiative (WHI) in an attempt to answer this question. In 2008 the same group published a randomized, placebo-controlled trial of calcium supplements in nearly 1500 healthy postmenopausal women that showed upward trends in cardiovascular event rates with calcium use (BMJ 2008;336:262-266). The same group subsequently carried out a meta-analysis of cardiovascular events in randomized, placebo-controlled trials of women taking calcium supplementation without vitamin D. In that study, calcium supplementation significantly increased the risk of MI by about 30% (BMJ 2010;341:c3691). Although these studies garnered some interest, they were also viewed with skepticism, and most physicians, especially in this country, did not change their practice of recommending calcium supplementation for postmenopausal women. The New Zealand group then turned to the WHI data, a rather strange place to look considering that one of the main outcomes of WHI was the finding of no adverse effect of calcium and vitamin D on cardiovascular risk. However, the researchers found one major caveat: WHI did not consider whether women were taking calcium on their own prior to entry into the study. The New Zealand group got access to the original NIH data and were able to tease out women who were not using personal calcium supplements at randomization. They found nearly 17,000 women who fit that category. Women in this subgroup who were randomized to calcium and vitamin D had small but significant increased risk for cardiovascular events with hazard ratios that ranged from 1.13-1.22 (P = 0.05 for clinical MI or stroke, P = 0.04 for clinical MI or revascularization). When the WHI data were added to the previously done meta-analysis of three placebo-controlled trials, calcium and vitamin D were found to increase the risk of MI (relative risk [RR] 1.21 [95% confidence interval [CI] 1.01-1.44]; P = 0.04), stroke (1.20 [CI 1.00-1.43], P = 0.05), and the composite of MI or stroke (1.16 [CI 1.02-1.32], P = 0.02). Trial level data was available for more than 28,000 women who were randomly assigned to calcium plus vitamin D or placebo. Calcium or calcium plus vitamin D increased the risk of MI (RR 1.24 [CI 1.07-1.45], P = 0.004) and a composite of MI or stroke (1.15 [CI 1.03-1.27], P = 0.009). The authors conclude that calcium supplements with or without vitamin D modestly increase the risk of cardiovascular events, especially MI. They suggest that a reassessment of the role of calcium supplementation in osteoporosis management is warranted (BMJ 2011;342:d2040 doi:1136/BMJ.d2040, published April 19, 2011). This study has been hotly debated and was even criticized in an editorial in the same issue of BMJ. Nonetheless there is a bit of irony in using WHI data, which are largely responsible for millions of women stopping hormone replacement therapy, to show a relationship between calcium and cardiovascular disease disease. There is no suggestion in any of these data that dietary calcium leads to adverse events. It is postulated that the rapid increases in calcium that occur with calcium supplementation may somehow play a role in increased cardiovascular risk.

Birth control pills and VTE risk

A progestin commonly used in birth control pills may increase the risk of venous thromboembolism (VTE). A recent report suggests that women taking oral contraceptives containing drospirenone may be at increased risk of VTE compared to women taking contraceptives containing other progestins. Two studies were recently published in BMJ. The first was a case-controlled study of U.S. women that showed that women taking drospirenone-containing contraceptives were twice as likely to develop nonfatal VTE compared to women taking levonorgestrel (BMJ 2011;342:d2151). The other study, a case-controlled study of British women, showed a three-fold higher rate of VTE with drospirenone-containing contraceptives compared to levonorgestrel (BMJ 2011;342:d2139). Oral contraceptives containing drospirenone include Yaz, Yasmin, and Angeliq.

ACE inhibitors and breast cancer risk

Researchers at UCLA and Kaiser Permanente in northern California recently published data suggesting that angiotensin converting enzyme inhibitors (ACEi) may increase the risk of breast cancer recurrence in breast cancer survivors. Using a database of nearly 1800 women with a history of breast cancer, there were 292 recurrences, 174 breast cancer deaths, and 323 total deaths. Twenty-three percent of the women in the study were exposed to either a beta-blocker or an ACEi. ACEi exposure was associated with breast cancer recurrence 1.5 times baseline (HR 1.56, 95% CI 1.02-2.39, P = 0.04) but not increased cause-specific or overall mortality. Beta-blocker exposure was associated with lower hazard of recurrence and cause-specific mortality. There was no dose-response with either medication. When a beta-blocker was combined with an ACEi, there was a lower hazard ratio for recurrence than with ACEi alone. The authors suggest that ACEis may be associated with an increased risk of breast cancer recurrence; although beta-blockers may be somewhat protective, more research is needed (Breast Cancer Res Treat, published online, DOI: 1007/s10549-011-1503-3). Beta-blockers have been shown to be protective against breast cancer recurrence in other studies, but the ACEi findings were unexpected.

Spending on U.S. pharmaceuticals

Spending on pharmaceuticals in the United States grew at its smallest level in years in 2010, according to a report by the IMS Institute for Healthcare Informatics. Pharmaceutical spending increased 2.3% in 2010 compared to 5.1% in 2009. Generics dominated the pharmaceutical market in 2010 making up 78% of total market share compared to 63% in 2006. Of the top 25 drugs by volume, only three were brand-name products: atorvastatin (Lipitor), clopidogrel (Plavix), and montelukast (Singulair). By spending dollars, however, Lipitor was the top grossing product at $7.2 billion in 2010, down from $7.6 billion in 2009. Esomeprazole (Nexium) was second at $6.3 billion, while Plavix ranked third at $6.1 billion. The domination of generics is of major concern to the pharmaceutical industry since there are few new drugs in the development pipeline and several high-profile drugs are due to lose protection soon. Foremost among these is Pfizer's Lipitor. Pfizer has been battling to maintain its patent protection, but generic manufacturer Watson Pharmaceuticals is expected to introduce the first generic atorvastatin in November of this year. Likewise, Merck's Singulair will likely lose its patent protection next year. The economy also has played a role in the decrease in pharmaceutical spending as the total volume of medicines consumed decreased 0.5% in 2010 along with a decrease in the number of doctor office visits of 4.2%. This extends a decline that began in mid 2009 — likely due to higher unemployment and rising health care costs.

FDA actions

The FDA has approved rituximab (Rituxan) for the expanded indication to treat Wegener's granulomatosis and microscopic polyangiitis, two rare vasculitides. The effectiveness of rituximab was demonstrated in a single control trial in which 197 patients with either condition were randomized to rituximab plus glucocorticoids or oral cyclophosphamide plus glucocorticoids. After 6 months, 64% of the patients treated with rituximab had a complete remission compared to 53% of patients treated with cyclophosphamide. Rituximab is manufactured by Genentech.

The FDA has approved gabapentin enacarbil for the treatment of moderate-to-severe restless leg syndrome. The approval was based on two 12-week clinical trials in adults showing the effectiveness of the drug vs placebo. Gabapentin enacarbil is formulated as a once a day extended-release tablet. It is marketed by GlaxoSmithKline and Xenoport as Horizant.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5468. E-mail: