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Statins in Primary Prevention of Cardiovascular Disease Are We Ready?
Abstract & Commentary
By Rahul Gupta, MD, MPH, FACP, Assistant Professor, Department of Internal Medicine, Meharry Medical College Nashville, TN; Assistant Clinical Professor, Division of General Internal Medicine and Public Health, Vanderbilt University Medical School, Nashville, TN. Dr. Gupta reports no financial relationship to this field of study.
Synopsis: Use of statins as primary prevention in healthy people with elevated high-sensitivity C-reactive protein without hyperlipidemia may reduce the incidence of major cardiovascular events.
Source: Ridker P, et al; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-2207.
An estimated 80,700,000 american adults (1 in 3) have 1 or more types of cardiovascular disease (CVD), of whom about 38 million are estimated to be age 60 or older.1 Data from the Framingham Heart Study indicate that the lifetime risk for CVD is 2 in 3 for men and more than 1 in 2 for women at age 40.2 Additionally, in every year since 1900, except 1918, CVD accounted for more deaths than any other single cause or group of causes of death in the United States.3 Each year an estimated 770,000 Americans will have a new coronary attack and about 430,000 will have a recurrent attack. It is also estimated that an additional 190,000 silent first heart attacks occur each year. The average age of a person having a first heart attack is 64.5 years for men and 70.4 years for women.
There is developing evidence to support the notion that several inflammatory proteins may interact with endothelium and hemostatic factors to cause plaque formation and rupture.4 C-reactive protein (CRP) is one such protein. In the current study by Ridker et al, the authors contend that, since half of all myocardial infarctions and strokes occur among healthy populations who have LDL-cholesterol below that recommended for therapy, treating elevated CRP would prevent such processes.
This study was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 26 countries to assess the effect of rosuvastatin 20 mg daily on the levels of CRP and patients were followed for occurrence of combined primary endpoint of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from CVD. Healthy men > 50 years and women > 60 years were eligible if they had elevated CRP (> 2.0 mg/L) without elevated LDL or history of cardiovascular disease. A history of lipid-lowering therapy, current use of hormone replacement therapy, hepatic or renal dysfunction, diabetes, uncontrolled hypertension or hypothyroidism, recent history of cancers, alcohol/drug abuse, or any other known inflammatory state precluded individuals from enrollment. A total of 89,890 individuals were screened and 17,802 participated. The populations were well-matched with CRP levels of 4.2 mg/L and 4.3 mg/L in the treatment and placebo groups, respectively.
The study was terminated early, after a median follow-up of 1.9 years (maximum, 5.0). The rates of primary endpoint were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin 0.56; 95% confidence interval, 0.46-0.69; P < 0.00001). At 12 months, the median CRP levels were 2.2 mg/L and 3.5 mg/L in the treatment and placebo groups, respectively. A total of 95 patients were needed to treat with rosuvastatin for 2 years to prevent the occurrence of one primary endpoint. Physician-reported onset of diabetes was statistically more frequent in the rosuvastatin group than in the placebo group.
Several studies have debunked the falsely held belief that individual major risk factors for coronary heart disease (CHD) are absent in many patients (> 50%) with CHD.5,6 Greenland et al conducted a review of three prospective cohort studies to determine the frequency of exposure to major CHD risk factors.7 They found that about 90% of CHD patients have prior exposure to at least one of the following major risk factors: high total blood cholesterol levels, or current medication with cholesterol-lowering drugs; hypertension, or current medication with blood pressure-lowering drugs; current cigarette use; and clinical report of diabetes.
In an international study, spanning more than 52 countries, Yusuf et al found that 9 easily measured and potentially modifiable risk factors accounted for more than 90% of the risk of an initial acute MI.8 These are cigarette smoking, abnormal blood lipid levels, hypertension, diabetes, abdominal obesity, a lack of physical activity, low daily fruit and vegetable consumption, alcohol overconsumption, and psychosocial index.
Finally, when Vasan et al studied the occurrence of first CHD events according to 5 major (conventional) CHD risk factors blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol levels, glucose intolerance, and smoking they found that more than 90% of CHD events will occur in individuals with at least 1 risk factor and approximately 8% will occur in people with only borderline levels of multiple risk factors.9
In light of the above existing data, here are my concerns with the study in question. The healthy study population was not "real-life." In other words, I am not expected to see a majority of this low-risk population in my office on any given day. As a primary care physician, I am much more likely to see those that already meet the criteria for lipid-lowering therapy. Furthermore, there may be several such biomarkers that could be implicated in CHD in the future. Compared with the strength of data existing in favor of treating traditional risk factors in CHD like hyperlipidemia, smoking, hypertension, and hyperglycemia, an evidence-based case for long-term utility of such a targeted therapy for solely elevated CRP in the population at-large has not yet been presented. Finally, there was evidence that rosuvastatin may lead to increased incidence of diabetes. This is a real concern in primary care.
My question to the investigators is: Why was this trial stopped early after just 1.9 years? I agree there was a statistically significant difference between the two arms; however, was the placebo group prescribed statins afterwards? If so, based on what recommendations? And if not, why was this trial not continued?
What would I do? As stated, at this time, there is insufficient evidence to treat a healthy target population with statins solely for elevation of CRP. Perhaps I would prescribe lifestyle modification including exercise, which has proven positive effects on CRP. Additionally, I would encourage my primary care clinician colleagues not to lose focus on efforts to modify the traditional risk factors, which have a proven track record in lowering the burden of CHD. Hopefully, our health care system will also learn to encourage clinicians to give more priority to primary prevention in this manner. A primary care clinician can play an important role in the application of nondrug therapy in prevention, thereby not equating clinical management with pharmacological therapy.
1. American Heart Association Statistics, 2008. Available at: www.americanheart.org/downloadable/heart/1200078608862HS_Stats%202008.final.pdf. Accessed Jan. 12, 2009.
2. Hurst W. The Heart, Arteries and Veins. 10th ed. New York, NY: McGraw-Hill; 2002.
3. National Center for Health Statistics. Available at: www.nhlbi.nih.gov/resources/docs/shs_db.pdf. Accessed Jan. 12, 2009.
4. Ikonomidis I, et al. Atherosclerosis. Inflammatory and non-invasive vascular markers: The multimarker approach for risk stratification in coronary artery disease. Atherosclerosis 2008;199:3-11.
5. Khot UN, et al. Prevalence of conventional risk factors in patients with coronary heart disease. JAMA 2003; 290:898-904.
6. Grundy SM. Primary prevention of coronary heart disease: Integrating risk assessment with intervention. Circulation 1999;100:988-998.
7. Greenland P, et al. Major risk factors as antecedents of fatal and nonfatal coronary heart disease events. JAMA 2003;290:891-897.
8. Yusuf S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): Case-control study. Lancet 2004;364:937-952.
9. Vasan RS, et al. Relative importance of borderline and elevated levels of coronary heart disease risk factors. Ann Intern Med 2005;142:393-402.