ISC 2009: JUPITER Stroke Results Show Significant Reduction in Stroke Risk

Susan Jeffrey

February 20, 2009

February 20, 2009 (San Diego, California) — A new analysis from the Justification for Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) that showed benefit from rosuvastatin (Crestor, AstraZeneca) treatment in patients with normal cholesterol levels but elevated C-reactive protein (CRP) shows a 48% relative risk reduction for total stroke, with no increase in hemorrhagic stroke.

Dr. Robert Glynn

"Despite evaluating a population with lipid levels widely considered to be optimal in almost all current prevention algorithms, the relative benefit on stroke observed in JUPITER was greater than in almost all prior statin trials," Robert Glynn, PhD, ScD, from the Harvard School of Public Health and Brigham and Women's Hospital, in Boston, Massachusetts, concluded.

The results, from the previously reported JUPITER trial, were presented here at the American Stroke Association International Stroke Conference 2009.

Primary Prevention

Low-density lipoprotein (LDL) cholesterol is not considered a major risk factor for stroke, and randomized trials conducted in hyperlipidemic patients without vascular disease have not shown a reduction in stroke risk, Dr. Glynn told the meeting here. However, for patients with established vascular disease or diabetes, statin therapy "has proven remarkably effective, reducing the risk for stroke by 19% to 48%," he said.

High-sensitivity (hs) CRP is an inflammatory biomarker that independently predicts future stroke, and elevated levels are markedly reduced by statin therapy, he said. Reduction of stroke risk by statin therapy therefore might be "particularly notable" in individuals with elevated hs-CRP, Dr. Glynn said. Evidence that CRP is a better predictor of stroke than lipids has been shown in a variety of populations.

JUPITER was a large, multinational, double-blind, placebo-controlled trial that randomized 17,802 men and women to 20 mg/day rosuvastatin or placebo. The hypothesis was that statin therapy, given to apparently healthy individuals with normal LDL-cholesterol levels (< 130 mg/dL) but elevated CRP levels (>2.0 mg/L), would reduce a composite primary end point, including nonfatal myocardial infarction (MI), nonfatal stroke, arterial revascularization, hospitalization for unstable angina, or cardiovascular death.

The primary JUPITER analysis was presented last fall at the American Heart Association's Scientific Sessions and published at the same time in the New England Journal of Medicine. (Ridker PM et al. N Engl J Med. 2008;359:2195-2207.)

Among patients treated with rosuvastatin, LDL-cholesterol levels were cut in half, decreasing from a median 108 mg/dL at baseline to 55 mg/dL at 12 months. CRP levels were also significantly reduced, declining from 4.2 mg/L at baseline to 2.2 mg/L at 12 months. Triglyceride levels were reduced 17% from baseline among those treated with statin therapy. These effects persisted over the course of the study.

After 1.9 years of follow-up, treatment with rosuvastatin significantly reduced the primary composite end point 44% compared with placebo. This reduction was observed among nearly all of the individual end points, including a 55% reduction in nonfatal MI, a 48% reduction in the risk for nonfatal stroke, and a 47% reduction in the risk for hard cardiac events (a composite of MI, stroke, and death from cardiovascular causes).

In terms of absolute benefits, the proportion of patients who had an MI, stroke, revascularization, or hospitalization for unstable angina or died from cardiovascular causes was 1.6% in the rosuvastatin group and 2.8% in the placebo group, an absolute risk reduction of 1.2%. Similarly, the proportion of patients with hard cardiac events — cardiovascular death, MI, and stroke — was reduced from 1.8% in the placebo group to 0.9% in the rosuvastatin group, an absolute reduction of 0.9%.

In the analysis presented here, the researchers looked more closely at stroke end points in particular. "The finding for any stroke was identical to the finding for nonfatal stroke," Dr. Glynn said, with only 9 immediately fatal strokes.

"The finding for ischemic stroke was a slightly stronger benefit, nearly spot-on the finding for myocardial infarction, a 51% reduction," he noted.

Unlike results from the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial with atorvastatin (Lipitor, Pfizer) for secondary stroke prevention, there was no signal of an increase in hemorrhagic stroke with treatment, although the numbers were small.

JUPITER: Stroke Outcomes with Rosuvastatin vs Placebo

End Point Rosuvastatin, n Placebo, n Hazard Ratio (95% CI) P
Any stroke 33 64 0.52 (0.34 – 0.79) .002
Nonfatal stroke 30 58 0.52 (0.33 – 0.80) .003
Fatal stroke 3 6
Stroke type
   Ischemic 23 47 0.49 (0.30 – 0.81) .004
   Hemorrhagic 6 9 0.67 (0.24 – 1.88) .44
   Unknown 4 8

Kaplan-Meier curves showed the effects of treatment were seen "almost immediately and widened with time," he noted. At the end of 5 years, the absolute difference was 1% in the occurrence of stroke between the active treatment and placebo groups.

The results were consistent across subgroups, with no significant heterogeneity, he said. High-risk groups, including older patients, those with hypertension, smokers, and those with Framingham risk scores above 10, had a "substantial and individual benefit" associated with treatment, Dr. Glynn said. Those with a baseline CRP of higher than 5 mg/L also had an increased risk for stroke and had significant benefit, he noted.

LDL-cholesterol levels showed little association with stroke risk. Those with low high-density lipoprotein (HDL) cholesterol were at increased risk, and rosuvastatin therapy was of benefit for this subgroup. Total mortality was reduced by 20% by treatment.

Serious adverse events were not significantly different between groups, including muscle weakness or myopathy, Dr. Glynn said. Significantly more patients on rosuvastatin developed new diabetes, but they had a significantly reduced rate of cancer deaths; glycated hemoglobin levels were higher with treatment at 24 months, but there was a significant benefit on glomerular filtration rate (GFR) at 12 months.

Absolute Risk

During the question period, Lewis B. Morgenstern, MD, from the University of Michigan, in Ann Arbor, asked Dr. Glynn about the number-needed-to-treat (NNT) calculation to prevent stroke based on these results. "You mentioned a lot of the relative risks, but then you said there was really only a 1% reduction over 5 years, which means you'd have to treat 100 patients for 5 years to show a reduction," Dr. Morgenstern pointed out.

Median systolic blood pressures in the trial were higher than 130 mm Hg, he added. "Wouldn't it be a little more cost-effective to use a little bit more hydrochlorothiazide and bring the blood pressures down?"

Dr. Glynn responded that this point was well-taken if the focus is just the prevention of stroke. "But any treatment needs to be considered in the context of the totality of treatment targets, and stroke was 1 part of it, certainly, yes." The number needed to treat would be around 100 to prevent a stroke, "but we're not talking about just preventing stroke; we're talking about preventing myocardial infarction, cardiovascular death, revascularization, and unstable angina."

The NNTs are substantially smaller for the target of total cardiovascular disease for statin therapy than for all the prior blood-pressure-reduction trials, he added.

Compelling Results

Dr. Cheryl Bushnell

Cheryl Bushnell, MD, from Wake Forest University Health Sciences, in Winston-Salem, North Carolina, moderated a press conference here where these results were presented. She called the JUPITER results compelling. "I think it was brilliantly designed, and they got results that are valid and believable," Dr. Bushnell told Medscape Neurology & Neurosurgery. "They even stopped the trial early, which is amazing in a primary-prevention trial."

However, she said, "I'll be honest that I have no idea what to do with my patients. I used to measure C-reactive proteins, and I guess the main difference is that I might consider initiating a statin in that situation, but it's still not clear to me if that's really going to be a cost-effective way of preventing stroke.

"There is going to be a lot of debate about how to frame a guideline given these results," she said. "I know people who are on both sides of the fence. I can't wait to hear what they finally decide."

Mark Alberts, MD, professor of neurology at Northwestern University Feinberg School of Medicine, in Chicago, Illinois, also raised the issue of numbers needed to treat. "While the relative risk reduction was fairly impressive, the absolute risk reduction, because the event rates were very low, is obviously more modest," he told Medscape Neurology & Neurosurgery. "So I think the challenge for clinicians and researchers is to figure out what characteristics put those roughly 100 people at increased risk for having stroke so you can better target therapy."

One possibility is another test of inflammation called Lp-PLA2 (PLAC Test, diaDexus), which appears to be more specific for vascular rather than systemic inflammation, he noted. "Vascular inflammation is really what drives a lot of these cardiac and cerebral events. It would be interesting to take a population like this and, besides taking people with elevated CRP, do Lp-PLA2 levels to see if that could further help identify those populations who are really at high risk for going on to have cerebral or cardiac events."

The test has already been used in populations such as the Atherosclerosis Risk in Communities (ARIC) study and found to be "fairly predictive,"Dr. Alberts added.

The study was funded by AstraZeneca US. Dr. Glynn and JUPITER lead investigator Paul Ridker, MD, from Brigham and Women's Hospital, report they have received grant support and/or consultation fees from 1 or more statin manufacturers, including AstraZeneca. Dr. Ridker is coinventor on patents held by the Brigham and Women's Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease that have been licensed to Dade-Behring and AstraZeneca.

International Stroke Conference 2009: Abstract 140. Presented February 19, 2009.

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