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OffLine Summer 2000

Volume 12 Number 4

Group Health Center for Health Studies (CHS) was founded in 1983 to conduct research relevant to the prevention and effective treatment of major health problems. To help accomplish this mission, CHS has maintained strong collaborative relationships with several institutions over the last 15 years, including the University of Washington (UW) and the Fred Hutchinson Cancer Research Center. One of the most fruitful collaborations has been with the Cardiovascular Health Research Unit (CHRU). Over the last 15 years, this group of UW-based scientists has worked with Group Health investigators and the Group Health "population laboratory" to study risk factors for heart attack, cardiac arrest, and stroke.

In recent years, the CHRU has focused on 2 major "exposures" that may be related (either positively or negatively) to heart attack or stroke: 1) the use of blood pressure-lowering medications among hypertensive persons; and 2) the use of hormone replacement therapy (HRT) among postmenopausal women. Results from these studies, often reported in high profile medical journals, have had a major influence on evidence-based guidelines, scientific policy debate and clinical practice at Group Health and nationwide. This issue of Off Line describes selected CHRU research over the last 5 years.

A Case Study
One CHRU research effort, in particular, will highlight the rewards and perils that come with conducting research in high profile, controversial subject areas. Blood pressure-lowering medications are used by 25 million people in the United States and represent a lucrative source of income for pharmaceutical companies. While the immediate goal of these medications is to reduce high blood pressure (often a symptomless condition), the ultimate aim is to prevent the serious consequences of hypertension—heart attacks and strokes.

CHRU physician and epidemiologist Bruce Psaty conducted a case-control study to examine the relationship between antihypertensive medications and myocardial infarction (MI). Cases were Group Health enrollees with pharmacologically treated hypertension who suffered a first-time fatal or non-fatal MI. Controls frequency-matched to cases on sex and age had pharmacologically treated hypertension but did not have an MI. Psaty found that short-acting calcium channel blockers, as compared to diuretics or beta-blockers, were associated with a 60 percent increase in the risk of MI. These observational results supported existing guidelines that recommended diuretics and beta-blockers as first-line agents for the treatment of hypertension.

Basically, this case-control study found that calcium channel blockers might cause the very problem they were meant to prevent—namely, MI. How could this be? "The FDA typically approves antihypertensive medications on the basis of whether they lower blood pressure among patients in small, short-term studies that compare the drug with a placebo," explains Psaty. "For the most part, the newer classes of drugs had not been put to a more stringent test to see if they reduced the risk of coronary heart disease. They had been approved on the basis of lowering blood pressure alone." According to Psaty, this phenomenon of evaluating medications based solely on "surrogate" or intermediate outcomes can be misleading. In a recent article in the Journal of the American Medical Association, he and his colleagues advocated large, long-term clinical trials designed to assess the effect of drug therapies on major disease endpoints over 3 to 5 years.

Indeed, Psaty’s findings regarding calcium channel blockers in part led experts to agree that longer-term randomized trials were needed to definitively gauge the relative safety of this class of medications. In the meantime, the National Heart, Lung, and Blood Institute warned that doctors should prescribe short-acting calcium channel blockers "with great caution, if at all." In response to this warning, Group Health’s Heart Care Roadmap intervened with physicians to transfer patients off nifedipine (a short-acting calcium channel blocker). Working with members of the Heart Care team, CHRU investigators found that within 6 months following the physician intervention, 80 percent of enrollees taking nifedipine had discontinued use.

The large impact of the calcium channel blocker study was not lost on the pharmaceutical companies. Smarting from their potential loss of revenue, the companies went on the offensive, attacking the investigators’ integrity and making unreasonable demands for data and new analyses. In response, the CHRU investigators described the harassment in an article published in the New England Journal of Medicine entitled "The Messenger Under Attack—Intimidation of Researchers by Special Interest Groups." The article cautions that important research may be inhibited if attacks on scientific results by powerful constituencies go unchecked.

More blood pressure related studies
In another Group Health-based study related to blood pressure-lowering medications, led by David Siscovick, CHRU investigators found that diuretic-based drug regimens were associated with a lower risk of stroke than drug regimens that did not include a diuretic. Results from this observational study, like those from the calcium channel blocker study, supported the use of diuretics as a first-line agent for the treatment of high blood pressure.

While these studies demonstrate that a provider’s choice of a first-line agent for the treatment of hypertension (HTN) is potentially critical, recent CHRU research underscores the importance of blood pressure control on a population level. Investigators found that, among Group Health enrollees with pharmacologically treated hypertension, only 38 percent had what could be termed as "controlled blood pressure." They estimated that this poor blood pressure control accounts for 15 percent of all first-time MI’s and 32 percent of all first-time strokes among patients with pharmacologically treated HTN. Poor patient compliance with antihypertensive drugs and lack of appropriate treatment are probably the biggest barriers to blood pressure control. The CHRU analyses provide a strong incentive to develop interventions that address these barriers. Interestingly, these analyses demonstrated that, among persons with treated HTN, control of blood pressure at Group Health (38 percent) is comparable to blood pressure control in the U.S. overall (41 percent).

Hormone Replacement Therapy and Cardiovascular Events
Another primary emphasis of the CHRU has been to examine the association between cardiovascular disease (CVD) and hormone replacement therapy (HRT) among postmenopausal women. To date, the weight of the evidence from observational studies suggests that long-term use of HRT is protective against a first-time MI, perhaps because estrogen helps maintain a normal cholesterol level. However, these studies did not assess whether the risk of incident MI continued to decline the longer the woman used HRT. A case-control study conducted by Susan Heckbert of the CHRU found that among postmenopausal women currently using estrogen, longer duration of HRT use was associated with a reduced risk of first MI. However, another CHRU case-control study found no association between the use of HRT and first-time stroke among women, regardless of duration of use.

The "Prognosis Study"
In another project begun in 1995, Heckbert and colleagues have continued their examination of the role of HRT in the prevention of cardiovascular disease. As part of the "Prognosis Study", the investigators identified all Group Health women who survived to hospital discharge following a first-time MI (heart attack) between 1986 and 1996. Follow-up data were collected on these women for a period ranging from 2 to 10 years after hospital discharge. The goal of the study is to identify risk factors for recurrent heart attack, death and stroke in post-MI patients. This project has the potential to shed light on a very controversial question regarding HRT—what is its role in women with established heart disease, typically called secondary prevention? Results from several observational studies suggest that HRT is associated with an improved CVD prognosis among women who had already had a cardiovascular event. However, a recent large randomized trial found no benefit over a four-year follow-up period.

While Heckbert has not yet reported results from the "Prognosis Study" regarding HRT’s role in the secondary prevention of cardiovascular disease, she has conducted analyses that might help explain the contradictory findings in this area. Among the cohort of postmenopausal women discharged from the hospital following an MI, she compared those prescribed estrogen upon discharge with those who were not. HRT use after MI increased over time, and other independent predictors of HRT use after MI included younger age, absence of diabetes, and being prescribed aspirin at hospital discharge. Heckbert concludes that the protective effect of estrogen found in observational studies among women with established CVD may be partly due to differences between users and non-users in cardiovascular health and medical treatment.

Heckbert and colleagues are currently analyzing data related to another primary focus of the "Prognosis Study"—the safety of calcium channel blockers in the secondary prevention of MI in women. Earlier clinical trials have shown that calcium channel blockers have no positive effect, and in some cases a negative effect, on future risk of reinfarction or death. The problem is that these trials were conducted primarily among men and thus, scientists and practitioners cannot be sure that the trials’ results are applicable to women. The "Prognosis Study" was designed to address this gap in knowledge regarding women’s cardiovascular health. This issue is particularly salient because calcium channel blockers have been prescribed with increasing frequency to women with established CVD.

Ongoing studies
Following up on surprising findings from a previous trial showing that two antiarrhythmic drug therapies increased mortality, an ongoing CHRU study led by David Siscovick is looking at the association between antiarrhythmic, anticonvulsant and antidepressant drug therapies and sudden cardiac arrest. In certain circumstances, these drugs may have the potential for proarrythmia, meaning that they may inadvertently cause heart arrythmias. The CHRU has also initiated several studies looking at the possibility of drug-gene interactions that may affect cardiovascular disease. For example, one study is designed to find out whether one of several genetic mutations that make certain postmenopausal women susceptible to developing blood clots in deep veins are at especially high risk of clots when they are taking HRT.

Group Health Center for Health Studies and the CHRU have a long history of successful collaboration. Former CHS Director Ed Wagner was one of Bruce Psaty’s mentors in the mid-1980’s during Psaty’s tenure as a Robert Wood Johnson Clinical Scholar. Since that time, CHRU scientists have worked closely with CHS administrative, technical and scientific staff, including Andrea LaCroix, Katherine Newton and Lisa Jackson, to carry out their research and, in turn, have been a valuable source of expertise for CHS investigators. Of course, the Group Health enrollee population is the common denominator in these collaborative efforts. The synergy among these groups—Group Health, CHS, and CHRU—has resulted in high quality science over the last 15 years and undoubtedly will produce research of equal caliber into the indefinite future.

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