Time for a primary stroke prevention trial in the elderly?

Susan Jeffrey

January 19, 2007

Iowa City, IA - In a new report, researchers set out their rationale and a preliminary design for a trial of primary stroke prevention in the elderly, specifically comparing statin therapy with placebo against a background of good blood-pressure control [1].

Statins certainly reduce the risk of cardiovascular events in those with clinical cardiovascular disease or diabetes, the authors note, but few data are currently available on how or whether to use statins in patients over 70 years old and what the best blood-pressure targets are for those who have reached their 70s or 80s without either CVD or diabetes—a growing group among health-conscious baby boomers.

"We've missed the vast burden of disease in the trials that have been done to date," first author Dr Jennifer G Robinson (University of Iowa, Iowa City) said, as most studies excluded these older age groups. "People say, Yes, it's important, but it's so hard to do a study in the elderly where there's competing mortality. . . . But it doesn't get you off the hook because it's hard to recruit for them."

Their report, which includes a review of the available evidence and a proposed design for the new trial, appears online December 28, 2006 in Stroke.

Questions Remain After PROSPER

Robinson points out that as a lipidologist, this question of how to approach lipid and blood-pressure management in those older than 70 years is typical of what she often hears, particularly from physicians in general practice. The main source of data to address this issue comes from results of the Prospective Study of Pravastatin in the Elderly at Risk of Vascular Disease (PROSPER) trial [2], which did show a benefit with statins in patients between 70 and 82 years of age with or at a high risk of developing cardiovascular disease or stroke, but there were issues with that study, she says.

Although there was a benefit seen with statin treatment, it was confined to death and nonfatal MI, and no effect was seen for stroke prevention in this population. Of concern with the trial was the fact that blood pressure did not appear to be adequately controlled, Robinson noted.

In the current paper, she said, "We reviewed the evidence, looking at where the gaps in the evidence were, and on the basis of that, roughly outlined how we thought this question would be addressed." They propose a placebo-controlled statin trial because, she noted, "We really need to prove that treating older people with statins is beneficial and safe."

There is more evidence to support blood-pressure reduction in this group to reduce both cardiovascular and renal events, although the optimal target for elderly individuals is not clear at this point.

Specifically, they advocate a five-year study with a 2x2 factorial design, enrolling at least 5000 patients older than 70 years who are free at baseline of cardiovascular disease, diabetes, or comorbidities likely to limit their survival to less than five years. Patients would be randomized to receive a statin or placebo. "Treatment choice and dose would depend on an established record of safety in those older than 70 years as well as the LDL treatment target (<100 mg/dL)."

Subjects would then be rerandomized to one of two antihypertensive regimens to achieve a systolic blood pressure of <140 mm Hg, "or, in those with wide pulse pressure, ie, >80, to try to achieve a level of <140 mm Hg if tolerated by the patient, with the goal of a systolic blood pressure of <160 mm Hg in all participants." The choice of treatment regimen would depend on the most recent data, they note, and multiple agents would be needed for a significant number of participants.

Coauthors on the paper include specialists from a number of disciplines, including hypertension expert Dr George Bakris (University of Chicago, IL); lipidologist Dr Neil Stone (Northwestern University, Evanston, IL); Dr James Torner (University of Iowa), a stroke epidemiologist; and Dr Robert Wallace (University of Iowa), an expert on aging. "We're really trying to make this a cross-cutting proposal," Robinson said.

Along with this primary focus, the study population would allow examination of a number of other questions, such as the effects of treatment on dementia, heart failure, kidney function, and overall functionality, she noted.

The group is already planning to meet with the National Institutes of Health to discuss the feasibility of such a trial, and several pharmaceutical sponsors have expressed interest in supporting it, Robinson said. "It takes a few years to get the ball rolling, but I think it's a trial that's going to happen."

A state of equipoise

In an editorial accompanying the paper [3], Dr Philip B Gorelick (Center for Stroke Research Chicago, IL), who has made primary stroke prevention the focus of some of his own research, writes that a cardiovascular primary-prevention trial such as that proposed by Robinson and colleagues "holds promise to provide important answers in relation to the safety and benefit of statin therapy in the elderly and the proper blood-pressure-lowering regimen and blood-pressure target."

"The clinical argument is strong" for such a trial, Gorelick said. "We don't know what to do, for example, in terms of the target for blood-pressure lowering." Elderly patients begin to have some cognitive impairment, he pointed out, and although it seems clear that lowering blood pressure prevents cognitive impairment before it begins, it may be detrimental to those who already have some challenge to brain perfusion.

"So I'm a big supporter of this," Gorelick said. "I deal a lot with the elderly, and I think this study is going to answer a lot of important questions."

He is sufficiently enthusiastic that he has accepted an invitation from Robinson to participate in the trial, he added. "I'm looking forward to working with the Iowa group as well as many investigators around the country in getting this off the ground."

Robinson discloses that she has received grants from the National Institutes of Health, Abbott, Andrx Labs, AstraZeneca, Atherogenics, Bristol-Myers Squibb, GlaxoSmithKline, Hoffman La Roche, Merck, Pfizer, Procter & Gamble, Schering-Plough, Sankyo, Takeda, and Wyeth Ayerst; having received speaker honoraria for educational programs from Merck and Pfizer; and having served on consultant/advisory boards for Merck, Pfizer, Proliant, and Wellmark. Disclosures for coauthors appear in the paper. Gorelick discloses that in the past 12 months he has been a consultant to Boehringer Ingelheim, Pfizer, and the Discovery Institute of Medical Education and has received honoraria for serving on a speaker's bureau for Boehringer Ingelheim.

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