Orbit of JUPITER extends to stroke prevention

Medical Tribune April 2009 P12
David Brill

The benefits of rosuvastatin for patients with elevated high sensitivity C-reactive protein (hsCRP) could include a reduction in the risk of stroke, according to new data from the JUPITER* trial.

The relative risk of any stroke was reduced by 48 percent among patients taking the drug, the study’s investigators reported recently at the International Stroke Conference in San Diego, US.

This finding appears to have been driven largely by a reduction in ischemic stroke rates – just 23 of the 8,901 patients in the treatment group experienced this outcome compared to 47 in the equally-sized placebo group (hazard ratio 0.49; P=0.004). Rates of hemorrhagic stroke, conversely, were not significantly different – six events occurred in the intervention group and nine in the placebo group (hazard ratio 0.67; P=0.44).

The new stroke data bring fresh fuel to the debate about the role of hsCRP in risk stratification and the use of statins for primary prevention – questions that have risen to prominence since the presentation of the original JUPITER study at the American Heart Association’s annual Scientific Sessions in November last year. [N Engl J Med 2008 Nov 20;359(21):2195-207]

“The bottom line is that we now have conclusive evidence for the efficacy of statins specifically for primary prevention of stroke,” said Dr. Robert Glynn of Brigham and Women’s Hospital in Boston, US, one of the JUPITER investigators who presented the latest findings.

LDL cholesterol is not typically considered as a risk factor for stroke in patients without established vascular disease, said Glynn, noting that CRP, however, has been shown to be a valid predictor of stroke risk. Statin therapy, which lowers levels of both biomarkers, could therefore be particularly beneficial for stroke prevention in patients with elevated CRP, he added.

The ARIC** study implicated hsCRP as a risk marker for stroke. The study, which involved 12,762 middle-aged men and women followed up for around 6 years, showed that those with an hsCRP level above 3 mg/L had an adjusted hazard ratio for ischemic stroke of 2.7 when compared to those with an hsCRP level below 1 mg/L. [Arch Intern Med 2005 Nov 28;165(21):2479-84]

The SPARCL*** study, meanwhile, demonstrated the benefits of atorvastatin (80 mg daily) for secondary stroke prevention in a population of 4,731 patients with a recent history of stroke or transient ischemic attack. After a median follow up of 4.9 years, overall stroke risk was reduced by 16 percent in the statin group compared to placebo (adjusted hazard ratio 0.84; P=0.03) with comparable mortality between the two groups. There was, however, an increase in the number of hemorrhagic strokes: 55 events occurred in the atorvastatin group and 33 in the placebo group. [N Engl J Med 2006 Aug 10;355(6):549-59]

The original JUPITER trial found that after a median of 1.9 years of follow up rosuvastatin (20 mg daily), as compared to placebo, reduced the relative risk of major cardiovascular events by 44 percent in a cohort of 17,802 overtly healthy subjects with baseline hsCRP levels above 2 mg/L and LDL cholesterol levels below 130 mg/dL (hazard ratio 0.56; P<0.00001). Over the course of the study hsCRP levels were reduced by 37 percent and LDL cholesterol levels by 50 percent. *JUPITER: Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin **ARIC: Atherosclerosis Risk in Communities *** SPARCL: Stroke Prevention by Aggressive Reduction in Cholesterol Levels

Southeast Asia aligns with JUPITER

Medical Tribune February 2009 P9
(Indonesia / Philippines edition only)
David Brill

Experts in Southeast Asia are responding with cautious optimism to the landmark JUPITER* study, which dominated headlines at the recent American Heart Association conference in the US.

While there are several important messages to draw from the study doctors should not rush to incorporate the findings into routine practice, specialists from the region told Medical Tribune.

Local guidelines are not anticipated to change in the immediate future, they said.

JUPITER – a randomized controlled trial of 17,802 participants – demonstrated that rosuvastatin, as compared to placebo, significantly reduced major cardiovascular event rates in overtly healthy people with normal LDL-cholesterol but elevated high-sensitivity C-reactive protein (hsCRP) levels. [N Engl J Med 2008 Nov 20;359(21):2195-207] The study has moved hsCRP into the limelight and prompted some international experts to call for the biomarker to take a more prominent role in cardiovascular risk stratification.

Professor Cheuk-Man Yu, head of the division of cardiology at the Chinese University of Hong Kong, said that the reduction of cardiovascular events in the study was “highly encouraging” for both physicians and patients but noted that more research is still needed into the pathophysiological mechanisms that underlie the effect.

“It will be difficult to generalize this into routine practice without further understanding the relationship between lipid lowering, reduction of vascular inflammation and reducing atherosclerosis,” he said.

“I don’t think we fully understand the hsCRP story. From this study it does seem to be a very important mediator for underlying vascular disease but we still haven’t got the definite answer as to whether it is a stand-alone risk factor or just a manifestation of the accumulated conventional risk factors.”

hsCRP levels can be altered by a number of factors and may not be solely a marker of inflammation in vascular plaques, said Yu, noting that bacterial and viral infections, rheumatoid arthritis, tuberculosis and lupus erythematosus can all increase levels of the biomarker. These potential explanations would all need to be ruled out, and all conventional risk factors worked upon, before considering intervention on the basis of an elevated hsCRP alone, he said.

Associate Professor Terrance Chua, chairman of the Singapore Heart Foundation, said that he expects hsCRP testing to “take on a bigger role” in risk assessment, in light of the data from JUPITER.

“It would be useful in a situation where a patient is at intermediate risk and one is trying to make a decision whether or not to initiate lipid-lowering therapy. hsCRP may help to further refine the risk and cast the deciding vote on whether or not to start treatment in these patients. We will have to wait and see how the guidelines committee absorbs this information,” he said.

Chua also noted that the JUPITER results are consistent with those of previous statin trials and provide further reassurance as to the benefits of cholesterol-lowering therapy. He added, however, that it is important not to lose sight of the importance of non-pharmaceutical interventions such as diet.

“The great challenge is really to try to change lifestyle,” he said. “It’s a bigger challenge than taking a tablet but if we want to have a truly cost-effective way of dealing with the growing problem then changing lifestyle would obviously be more effective.”

Dato’ Seri Dr. Robaayah Zambahari, senior consultant cardiologist at the National Heart Institute in Kuala Lumpur, Malaysia, said that she believes strongly in the benefits of statins for secondary prevention but that the risk-to-benefit ratio will need to be reviewed before adopting a primary prevention strategy.

She added that JUPITER did not address the long-term safety of rosuvastatin since the trial was stopped after just 1.9 years.

-------------------------------------------------
*Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin

hsCRP: A new player on the cardiovascular risk stratification stage

Medical Tribune January 2009 P2&3

Dr. Jacques Genest, director of cardiology and Novartis Chair in Medicine at McGill University, Montreal, Canada, addresses the emerging role of high-sensitivity C-reactive protein in predicting cardiovascular risk.

High-sensitivity C-reactive protein (hsCRP) represents a new paradigm in the assessment of cardiovascular risk. It is set to become the first new biomarker for 30 years to be incorporated into routine clinical practice alongside traditional tests such as blood pressure and cholesterol. Guidelines across the world are under review, and it is only a matter of time before hsCRP becomes an integral tool in the risk stratification armory of the primary care physician.

The recent Justification for the Use of Statins in Prevention (JUPITER) trial showed that treating patients who had elevated hsCRP in the absence of other risk factors could significantly reduce the incidence of major cardiovascular events. After a median of 1.9 years of follow-up, the occurrence of cardiovascular death, myocardial infarction, stroke, arterial revascularization or hospitalization for angina was reduced by 44 percent in those treated with rosuvastatin (20mg daily). [N Engl J Med 2008 Nov 20;359(21):2195-207]

These results do not justify testing everyone for hsCRP, but rather suggest that the test will be of great benefit for patients who occupy the grey area between low and high risk. A high hsCRP score can push a debatable case over the treatment threshold while a low score, conversely, can confirm that the patient does not require treatment. Those already deemed to be at high-risk should receive treatment regardless of hsCRP, so the test will add little prognostic value in these patients, while at the other end of the scale there is not sufficient evidence to support routine hsCRP testing in young, healthy people with no other risk factors.

Physicians should begin, therefore, by performing a full and complete cardiovascular risk stratification including sex (until menopause in women), age, physical activity levels, diet, diabetic status, blood pressure and LDL, HDL and total cholesterol levels. For patients who are not obviously at high or very low risk, the physician should now routinely include an hsCRP test. Present evidence suggests that this strategy should be adopted in all men aged over 50 and women aged over 60 – the population that was successfully targeted for treatment in JUPITER. In my opinion, hsCRP will ultimately prove to be of use in men aged over 40 and all postmenopausal women, since these years often herald an increasingly sedentary lifestyle whereby the long-term outcome is likely to be heart disease or cancer. We await the support of local guidelines on this point, however, and at present physicians should exercise their own judgment as to the appropriate age for introducing hsCRP testing.

JUPITER treated patients with hsCRP levels of 2.0 mg/l or higher, and physicians may wish to adopt this level as their cut-point for deciding whether to initiate treatment. There is, however, strong epidemiological data and an ongoing argument in support of adopting a threshold of 3.0 mg/l or higher. This, again, will prove a matter for the guideline makers to decide and is likely to vary from country to country. For those with socialized medicine the cost implications of adopting the lower threshold will be considerable, and will prove an important factor in this decision.

Introducing routine hsCRP testing will undoubtedly increase the number of patients being treated with statins. We must not lose sight, however, of the continued importance of diet and lifestyle interventions, for which there is incontrovertible evidence in favor. Physicians should continue to press the message on five fronts: smoking cessation, quality of diet, quantity of diet, daily exercise, and serenity. The latter encompasses both stress management and levels of social interaction – both important prognostic factors in long-term mortality outcomes. Addressing these issues in a single consultation can be difficult – particularly when seeing the patient only once every 6 to 9 months – and I would recommend that GPs refer certain cases to a dietician and kinesiologist in order to improve motivation through more regular advice and feedback.

Many biomarkers have come and gone over the past 20 years of my research career but very few have proven to be clinically useful. Homocysteine, inflammatory factors, cell adhesion molecules, matrix metalloproteinases, and enzymes such as lipoprotein-associated phospholipase A2 have all failed or are still not ready for primetime use. These markers may predict disease but that does not mean that targeting them will automatically yield a reduction in hard clinical trial endpoints.

The journey towards hsCRP testing has been a long one but the marker has finally matched our ability to predict with our ability to prevent, while also asserting its independence from other risk factors. Guidelines will change in time, but in the face of the evidence from JUPITER physicians may decide not to wait. The time is right, in my opinion, to begin measuring hsCRP and implementing the appropriate strategies in the JUPITER-like patient while we await further international guidance. Unlike other biomarkers, hsCRP testing is here for good.

Dr. Genest is one of the investigators of the JUPITER trial and reports receiving consulting fees from AstraZeneca, Merck, Merck Frosst, Schering-Plough, Pfizer, Novartis, Resverlogix and Sanofi-Aventis.

JUPITER shows statin benefits for low-risk patients

Medical Tribune December 2008 P1 & 13

David Brill

Rosuvastatin can dramatically reduce the risk of death and major cardiovascular events among apparently healthy people, the highly-anticipated results of the JUPITER* study show.

The findings raise important questions about the indications of statins for primary prevention and should prompt a reassessment of current guidelines on risk assessment, one expert said.

JUPITER comprised 17,802 overtly healthy people with normal LDL cholesterol but elevated levels of high sensitivity C-reactive protein (hsCRP) – a group not currently indicated for statin treatment.

A 44 percent reduction in the incidence of the primary endpoint – comprising myocardial infarction (MI), stroke, cardiovascular death, arterial revascularization or unstable angina – was seen among those taking the drug compared to those on placebo (hazard ratio 0.56; P less than 0.00001).

Just 25 people would need to be treated with rosuvastatin to prevent one vascular event over a 5-year period, the researchers said.

The benefits of treatment were such that the trial was stopped a median of 1.9 years into the intended 4 year follow-up period.

"Despite evaluating a population with lipid levels widely considered to be optimal in almost all of our current guidelines, the relative benefit observed in JUPITER was greater than in almost all prior statin trials," said Professor Paul Ridker, the study’s principal investigator who presented the findings at a press conference during the recent annual Scientific Sessions of the American Heart Association.

"I think this is extremely reassuring for the statins as a class, and hopefully for the public at large who have been concerned about mortality benefits in this setting," he said.

Rosuvastatin reduced all-cause mortality risk by 20 percent and MI, stroke or cardiovascular death risk by 47 percent compared to placebo (hazard ratios 0.80 and 0.53; P=0.02 and P less than 0.00001, p=0.01).

The risk reductions were consistent across all subgroups regardless of gender, age, ethnicity, smoking status, BMI and Framingham risk score.

Statin therapy appears to have been safe, with no significant difference in serious adverse event rates between the groups. There was, however, an increase in the rate of physician-reported diabetes: 270 cases were recorded in the statin group and 216 in the placebo group (P=0.01).

Professor Andrew Tonkin, head of the cardiovascular research unit at Monash University, Melbourne, Australia, described the reduction in cardiovascular events in JUPITER as “extremely important.”

“I think that there will need to be a review of the guidelines for where CRP sits in risk assessment,” he said, adding that more information, such as the absolute risk reductions in subgroups and the cost effectiveness of treatment, is critically needed in order to establish the role of the marker as a screening tool for primary prevention.

Dr. Timothy Gardner, president of the American Heart Association, noted that the mechanisms for the risk reductions seen in JUPITER remain unclear.

“Statins lower both LDL cholesterol and hsCRP. Thus the findings presented today cannot determine whether lowering cholesterol, reducing inflammation, or a combination of both is responsible for the effects seen in this paper,” he said.

JUPITER, which was concurrently published in The New England Journal of Medicine, included men aged 50 or older and women aged 60 or older who had LDL cholesterol levels below 130mg/dl and hsCRP levels of 2.0mg/l or higher. Participants were non-diabetics with no history of cardiovascular disease. [2008 Nov 9; Epub ahead of print]

Rosuvastatin treatment (20mg daily) reduced LDL cholesterol levels by 50 percent and hsCRP by 37 percent.

Ridker, of Harvard Medical School, Boston, US, acknowledged that the study was too short to fully assess long-term safety, but noted that there is a large amount of data on statins as a whole and that they have been found to be “remarkably safe.” Despite the early conclusion, over 1,000 people in JUPITER were followed up for more than 4 years, he added.

“These drugs as a class are extraordinary. We want to give out a message that we want to continue with diet, exercise and smoking cessation but now we have very overwhelming evidence that this class of drugs, this method of lowering these surrogates [LDL cholesterol and hsCRP], fixes hard endpoints,” he said.

The JUPITER trial was supported by AstraZeneca.

*Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin