Statins and Adverse Cardiovascular Events in Moderate‐Risk Females: A Statistical and Legal Analysis with Implications for FDA Preemption Claims

Published date01 September 2008
Date01 September 2008
Statins and Adverse Cardiovascular
Events in Moderate-Risk Females:
A Statistical and Legal Analysis
with Implications for FDA
Preemption Claims
Theodore Eisenberg* and Martin T. Wells
This article presents: (1) meta-analyses of studies of cardioprotection of
women and men by statins, including Lipitor (atorvastatin), and (2) a legal
analysis of advertising promoting Lipitor as preventing heart attacks. The
meta-analyses of primary prevention clinical trials show statistically signifi-
cant benefits for men but not for women, and a statistically significant
difference between men and women. The analyses do not support (1)
statin use to reduce heart attacks in women based on extrapolation from
men, or (2) approving or advertising statins as reducing heart attacks
without qualification in a population that includes many women. The legal
analysis raises the question of whether Lipitor’s advertisements, which omit
that Lipitor’s clinical trial found slight increased risk for women, is consis-
tent with the Food, Drug, and Cosmetics Act and related Food and Drug
Administration (FDA) regulations. The analysis suggests that FDA regula-
tion should not preempt state law actions challenging advertising that is not
supported by FDA-approved labeling. Our findings suggesting inadequate
regulation of the world’s best-selling drug also counsel against courts
accepting the FDA’s claimed preemption of state law causes of action relat-
ing to warnings and safety. Courts evaluating preemption claims should
*Address correspondence to Theodore Eisenberg, Henry Allen Mark Professor of Law, Cornell
Law School, Myron Taylor Hall, Ithaca, NY 14853; email:
Wells is Charles A. Alexander Professor of Statistical Sciences, Cornell University, Professor of
Clinical Epidemiology and Health Services Research, Cornell University Weill Medical College,
and Elected Member of the Law Faculty, Cornell University.
We thank Kevin Clermont, Dr. Orli Etingin, Dr. Curt Furberg, Valerie Hans, Janey Peterson,
Dr. Michael Pignone, Norma Schwab, Stewart Schwab, and referees for comments. Michael
Heise served as the editor for this article. We served as consultants for plaintiffs’ counsel in
litigation relating to Vioxx.
Journal of Empirical Legal Studies
Volume 5, Issue 3, 507–550, September 2008
© 2008, Copyright the Authors
Journal compilation © 2008, Cornell Law School and Wiley Periodicals, Inc.
consider actual agency performance as well as theoretical institutional com-
petence. Billions of health-care dollars may be being wasted on statin use by
women but the current regulatory regime does not create incentives to
prevent such behavior.
I. Introduction
Lisa W, an active and healthy woman in her 50s, was told she had high
cholesterol. Her doctor recommended Lipitor (atorvastatin), a member of
the class of statin drugs. Lisa, reluctant to take a prescription medicine
when she felt fine, wanted to try to reduce her cholesterol through exer-
cise and diet. She reduced her total cholesterol by 35 points but her doctor
continued to recommend Lipitor because her total cholesterol still was
above present guidelines. Lisa reports knowing many female acquaintances
with similar stories.
Their experiences may be typical of millions of women. A 1996–1997
study found that women without coronary heart disease (CHD) constituted
23.1 percent of statin recipients, that 1.7 percent of women under age 70
without a history of CHD were prescribed statins, and that 9.1 percent of
women age 70 or over without a history of CHD were prescribed statins.1
Data through 2004 show 39.8 percent of statin users were at low risk for
cardiovascular disease (CVD).2As of 2004 in British Columbia, 20.9 percent
of those aged 65 to 85 years and 7.5 percent of those aged 45 to less than 65
years were using statins, with Lipitor by far the most widely used statin.3In
three Norwegian counties, over 20 percent of women aged 60 to 80 used
statins, with Lipitor again the most widely used.4By any reasonable measure,
1Isabelle Savoie & Arminée Kazanjian, Utilization of Lipid-Lowering Drugs in Men and Women:
A Reflection of the Research Evidence? 55 J. Clin. Epidem. 95, 97–98 (2002).
2Colette B. Raymond et al., A Population-Based Analysis of Statin Utilization in British
Columbia, 29 Clin. Therapeutics 2107, 2115 (2007).
3Id. at 2109.
4Ingeborg Hartz et al., Aspects of Statin Prescribing in Norwegian Counties with High, Average
and Low Statin Consumption—An Individual-Level Prescription Database Study, 7 BMC Clin.
Pharmacology 14 (2007).
508 Eisenberg and Wells
females without a history of CHD constitute a major segment of the statins
market. Lipitor has been the top-selling drug in the world5and has
accounted for over $12 billion in annual sales.6
This article reports meta-analyses that question Lipitor’s advertising.
Pfizer, Inc., the producer of Lipitor, claims that Lipitor is clinically estab-
lished to reduce heart attacks without any indication of qualification by
gender. Pfizer states:
LIPITOR is clinically proven to reduce the risk of heart attack, stroke, certain
kinds of heart surgeries, and chest pain in patients with several common risk
factors for heart disease.† [†Risk factors include family history, high blood
pressure, age, low HDL (“good” cholesterol), or smoking.]7
The words are presumably chosen carefully and one might reasonably con-
clude that age plus low HDL, for example, would count as “multiple risk
factors” for which clinical proof exists that Lipitor reduces heart attack risk.
We are unable to find high-quality clinical proof in the medical literature
documenting reduced heart attack risk for women. Furthermore, Pfizer’s
advertising omits label information relevant to women. In discussing the
clinical trial of Lipitor, Pfizer’s label states:
LIPITOR significantly reduced the rate of coronary events [either fatal coronary
heart disease ...ornonfatal MI]....Duetothesmallnumberofevents, results
for women were inconclusive.8
This express acknowledgment of “inconclusive” results for women contrasts
with the cardioprotective claims, not qualified by gender, in Pfizer’s adver-
tising. Nor does the label or the advertising disclose that the key clinical trial
5Marcia Angell, The Truth About Drug Companies 85 (2004).
6Stephanie Saul, Pfizer to End Lipitor Ads by Jarvik, N.Y. Times, Feb. 26, 2008 ($12.7 billion in
2007 sales of Lipitor); Peter Loftus, Pfizer’s Lipitor Patent Reissue Rejected, Wall St. J. Online,
Aug. 16, 2007 ($12.9 billion in 2006 sales of Liptor); Julie Schmit, Lipitor Sales on Track to Hit
Record Despite Arrival of Generic, USA Today, July 20, 2006.
jsp&setShowHighlightOn=../about-lipitor/benefits.jsp, accessed Mar. 22, 2008.
8Pfizer Label, LAB-0021-15.0, revised Mar. 2007, at 5.
Statins, Adverse Cardiovascular Events, and FDA Preemption Claims 509

To continue reading

Request your trial

VLEX uses login cookies to provide you with a better browsing experience. If you click on 'Accept' or continue browsing this site we consider that you accept our cookie policy. ACCEPT