PrimeCuts: This Week in the Journals

February 15, 2010

Rachel Bond, MD

Faculty peer reviewed

August 12, 2003. Rosuvastatin aka Crestor becomes FDA approved in combination with diet and exercise to increase HDL cholesterol (HDL-C), reduce total cholesterol (TC), LDL cholesterol (LDL-C), apolipoprotein B, non-HDL cholesterol and triglycerides in patients with known hyperlipidemia and mixed dyslipidemia. [1] Additionally, guidelines propose the use of statins in patients with hyperlipidemia and diabetes and/or established vascular disease.[2] These effects have been shown to slow down the progression of atherosclerosis and ultimately reduce the risk of cardiovascular disease (CVD) such as myocardial infarction (MI), stroke and/or death from CVD.

All of this sounded great; however, recent research has shown that nearly half of all MI’s and strokes occur amongst apparently healthy men and women with levels of LDL-C that are below currently recommended thresholds for treatment with statins.[3] What are we to do now? Fast-forward to six years, five months and twenty seven days later…

February 8, 2010. The FDA approves a new indication, making Rosuvastatin the first and only statin to receive the additional indication for primary prevention of CVD in healthy adult patients with normal LDL-C levels, an increased risk for CVD based on age, elevated high-sensitivity C-reactive protein (hsCRP) levels and the presence of one additional CVD risk factor,[4] such as hypertension, low HDL-C, smoking or family history of premature heart disease.

As reported by Reuter’s in The NY Times Business Section “this clears the way for the drug to be used by millions of people who are not typically prescribed the drug now…likely increasing sales of the drug .”[5] This statement leads one to think: does this new approval help in the advancement of preventive medical research for the betterment of our patient population or is this just another way for pharmaceutical companies to make a whopping profit? Hmmm, maybe it’s a little bit of both.

After all, this novel approval stems from a clinical trial presented for the first time in 2008 at the American Heart Association’s Annual Scientific Sessions in New Orleans, sponsored by the actual makers of Crestor, AstraZeneca Pharmaceutical Company. The trial is referred to as the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER). In JUPITER, which was a randomly controlled, double-blinded, placebo-controlled, multi-center trial, the use of Crestor was examined in approximately 18,000 older patients who did not have elevated LDL cholesterol levels but illustrated other risk factors for heart disease, such as an elevated hsCRP (3). All patients examined in the trial were men and women of at least 50 and 60 years of age respectively. All lacked clinical evidence of heart disease and high LDL cholesterol levels (inclusion criteria of LDL<130 mg/dL), but all had levels of hsCRP ≥ 2 mg/L.

HsCRP is a protein/inflammatory marker found in the blood stream. Inflammation has been shown to play a major role in the initiation and progression of cardiovascular disease at the cellular level. In studies involving large numbers of patients, CRP levels have been shown to correlate with levels of cardiac risk. In fact, CRP seems to be at least as predictive, if not more predictive, of cardiac risk when compared to cholesterol levels. The Physicians Health Study,[6] a clinical trial involving 18,000 apparently healthy men, was the first large scale study to show that elevated levels of CRP were associated with a threefold increase in the risk of MI. In accordance, the Harvard Women’s Health Study [7] showed that the CRP test was more accurate than cholesterol levels in predicting coronary problems and was the strongest predictor of risk. As such, women in the group with the highest CRP levels were more than four times as likely to have died from coronary disease, suffered a nonfatal MI or stroke or to have required a cardiac procedure.

In the current study, Ridker et al. selected a treatment population according to their hsCRP level, based on the logic explained above and that statins have been shown to reduce levels of both hsCRP and LDL-C. [8,9] The investigators proposed that the main benefit of Crestor in individuals with normal levels of LDL, but elevated levels of hsCRP would be a reduced risk of non-fatal MI, non-fatal stroke and arterial revascularization (iii). In fact, patients in the study who were randomly assigned to take Crestor at a dose of 20 mg daily experienced a 44% reduction in the trial primary end point of all vascular events (P<0.00001), a 54% reduction in myocardial infarction (P=0.0002), a 48% reduction in stroke (P=0.002), a 46% reduction in need for arterial revascularization (P<0.001), and a 20% reduction in all cause mortality (P=0.02) compared to patients given the placebo. Clearly, true clinical benefit. Treatment with Crestor did not have a significant effect on secondary endpoints, such as cardiovascular death or hospitalization for unstable angina.

The percentage of patients who suffered MI, stroke, revascularization, hospitalization for unstable angina or died from cardiovascular causes was 1.6% in the Rosuvastatin arm and 2.8% in the placebo arm (iii), an absolute risk reduction of 1.2%. The proportion of participants with hard cardiac events in JUPITER was reduced from 1.8% (157 of 8901 subjects) in the placebo group to 0.9% (83 of the 8901 subjects) in the Rosuvastatin group; thus, 120 participants were treated for 1.9 years (actual duration of the study) to prevent one event.[10]

Side effects associated with Crestor in the JUPITER trial were generally similar to those previously associated with the statin class of medication and comparable in the Rosuvastatin and placebo group, with myalgia being one of the most frequently experienced adverse reactions. Of note, in the study, patients taking Crestor had higher rates of physician-reported diabetes than those taking placebo, including a higher increase in glycosylated hemoglobin (5.9% and 5.8%, respectively; P=0.001); however, it is important to note that an analysis of individuals in the JUPITER trial who had impaired fasting glucose at baseline did show a 34% reduction in major cardiovascular events with the use of Crestor. Once again, showing it to be of some clinical benefit.

Despite the positive findings, the question still prevails: patient beneficial, pharmaceutical moneymaker or a little of both? After all, there are many limiting factors that should be taken in to account in this trial. For one, scientists are still unsure whether the positive results of the trial are due to further reduction in LDL-C, hsCRP or both, since Crestor has been clinically shown to reduce both. As evaluated in the trial at twelve months there was a 50% lower median LDL-C and 37% lower median hsCRP in the Rosuvastatin group when compared to placebo (iii). This question cannot be answered in this study; however, it suggests that future studies should look specifically at the role of other anti-inflammatory medications as vascular therapeutic agents. Importantly, the absolute risk difference, a more clinically important factor, was found to be less impressive than the relative difference. Unfortunately, this point was overlooked in the discussion section of the trial. The study may also be limited due to its inability to adequately assess the potential risks of prolonged Crestor therapy in this population. The study was designed to last approximately four-years, but was stopped after only 1.9-years by an independent data monitoring board due to “meeting” predefined efficacy goals for the patients treated with Rosuvastatin. This short follow-up period raises concern of possible longer-term effects that could not be evaluated due to the shorter duration. In addition, lack of comparison of patients with low hsCRP levels (less than 2 mg/L) is a huge study limitation as there is not a pre-defined level goal. Further, since CRP is a nonspecific protein, elevated by a number of acute inflammatory conditions, it may not be reasonable to use it as a surrogate in the decision to initiate treatment with an expensive medication with associated adverse effects. Rosuvastatin, which roughly costs $3.45 per day, is much more expensive than that of generic statins (x). With this new FDA approval it should only be a matter of time before other pharmaceutical companies promote future studies comparing similar uses of other statins.

Based on these limitations, the FDA placed restrictions on their approval of Crestor for this indication. They state that physicians should take into account the clinical context of asymptomatic individuals who have evidence of clinical risk factors. As such, the FDA maintains Crestor should only be used as a preventative measure in individuals who have no clinical evidence of heart disease, but are at increased risk due to combined effect of older age (Men≥50, Women≥60), high hsCRP levels (≥2mg/L) and patient’s who illustrate one additional risk factor such as hypertension, low HDL-C, smoking or family history of premature heart disease. This makes the approval more conservative than may have been desired by the pharmaceutical company.

Regardless, debate will continue and AstraZeneca will continue to promote this medical breakthrough that has already increased its revenue. Crestor was AstraZeneca’s third-best selling product with estimated sales of $3.6 billion early last year. Since the publication of the JUPITER study in 2008, Crestor has increasingly been taking share away from competitors, including Pfizer’s Lipitor [11] which is expected to go generic in 2011. In fact, in the last quarter, revenue rose 29% to $4.5 billion, and now the FDA has cleared the way for an estimated six million more people in the US to buy the drug. Clearly, a true money maker.

In spite of the controversy, the study did succeed in its attempt to solve one piece of a vexing problem: not everyone who suffers a cardiovascular event has high cholesterol, and it’s next to impossible to predict who’s most likely to suffer from one imminently, even among people with some risks. Maybe hsCRP is the answer. Now with the new findings, a new question to ponder: to check hsCRP levels or not? I can only say physician discretion is advised.

Dr. Bond is a first year resident in internal medicine at NYU Medical Center.

Peer reviewed by Michael Poles MD, NYU Division of Gastroenterology

1. AstraZeneca Pharmaceuticals LP. Prescribing Information. Crestor: Rusuvastatin Calcium. Retrieved February 11, 2010 from http://www.crestor.com/c/home.aspx.

2.  Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110: 227-239.

3. Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto A, Kastelein JJP, Koenig W, Libby P, Lorenzatti AJ, MacFayden JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. New Engl J M 2008. 359: 2195-2207.

4. FDA US. Food and Drug Administration. Questions and Answers for Healthcare Professionals: CRESTOR and the JUPITER Trial. Retrieved February 11, 2010 from http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm199891.htm

5. Reuters. Crestor Wins Approval as a Drug to Prevent Heart Disease. The New York Times: Business Section. February 8, 2010.

6. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973-979.

7. Ridker PM, Hennekens CH Buring JE, Rifai N. C reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000;342:836-43.

8. Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation 1999;100:230-5.

9. Albert MA, Danielson E, Rifai N, Ridker PM. Effect of statin therapy on C-reactive protein levels: the Pravastatin Inflammation/CRP Evaluation (PRINCE): a randomized trial and cohort study. JAMA 2001;286:64-70.

10. Hlatky M. Expanding the Orbit of Primary Prevention- Moving beyond Jupiter. N Engl J Med 2008. 359: 2280-2282.

11. AP. FDA Panel say Astra Zeneca’s Cholesterol Pill Crestor Can Curb Heart Problems. Health News. Retrieved February 11, 2010 from http://blog.taragana.com/health/2009/12/15/fda-panel-says-astrazenecas-cholesterol-pill-crestor-can-curb-heart-problems-17104/.

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