The benefits of statin therapy in patients at all levels of cardiovascular risk

Weill Cornell Medical College, New York, NY

The goal of primary prevention in cardiovascular care is to prevent the development of atherosclerosis leading to coronary heart disease (CHD) before a clinical event such as a myocardial infarction (MI) can occur. Primary prevention through improved control of risk factors and therapeutic lifestyle changes (including dietary modification, aerobic exercise, and smoking cessation) is a central public health strategy advocated by the National Cholesterol Education Program, which issued the Adult Treatment Panel III (ATP III) guidelines for cholesterol testing and clinical management. According to ATP III and a 2004 update regarding the treatment of very high-risk patients, 1 aim of primary prevention is to reduce both long-term (>10 years) and short-term (≤10 years) risk.^1-2 Therapeutic lifestyle changes are the first recommended strategy for helping patients attain their low-density lipoprotein cholesterol (LDL-C) goals, but lipid-lowering drugs, and statins in particular, are appropriate options for many patients in primary prevention who are estimated to have a higher lifetime risk. Clinical trials show that such patients may also benefit from statin therapy in the short term.

Preventing coronary events before they occur is a strategy that could significantly benefit the public. A recent study calculated that full adherence to existing ATP III primary prevention guidelines in the United States could prevent an estimated 20,000 MIs and 10,000 CHD deaths per year.³ However, physicians typically focus treatment efforts on higher-risk patients who may have already begun developing symptoms, while lower-risk patients are often undertreated or not treated at all. For example, the Study to Help Improve Early Evaluation and Management of Risk Factors Leading to Diabetes (SHIELD), a US population-based longitudinal survey in individuals with or at risk for developing diabetes, attempted to assess whether the diagnosis of heart disease was being made while patients were still asymptomatic, as recommended by ATP III guidelines.⁴ Of 1573 respondents with heart disease, only 19% were diagnosed during routine screening. Approximately one-half of respondents were diagnosed after they had developed cardiovascular symptoms, and approximately 20% were diagnosed while being treated for another health problem, such as diabetes. These results suggest that strategies for primary prevention are not being fully implemented during routine screening and treatment for other health conditions.

The 2004 update of the ATP III treatment guidelines describes 4 categories of risk that should guide clinicians in determining the nature and intensity of lipid-lowering therapy, based on major risk factors and Framingham risk scoring.² These categories are high-risk, moderately high risk, moderate risk, and low risk. A consensus statement from the American Diabetes Association and the American College of Cardiology (ADA/ACC) largely endorses the updated ATP III recommendations with some modifications.⁵ The 5 major risk factors for CHD are shown in the Table. A Framingham risk calculator is available online at http://hp2010.nhlbihin.net/atpiii/calculator.asp.

High-risk. Patients with CHD or CHD risk equivalents (non-coronary atherosclerotic disease, diabetes, or at least 2 major risk factors) and who have a 10-year Framingham risk score >20% are placed in the high-risk category, according to ATP III. These patients should have an LDL-C level <100 mg/dL, with an optional target of <70 mg/dL for those considered to be at very high risk, based on physician judgment. The ADA/ACC statement modifies this categorization slightly and considers individuals with CHD or diabetes, plus 1 other major risk factor, to be at very high risk, with a recommended LDL-C <70 mg/dL. Individuals who have CHD or CHD risk equivalents and a 10-year risk >20% (but no other major risk factors) are considered to be at high risk, with a recommended LDL-C <100 mg/dL.^2,5

Moderately high risk. Individuals with at least 2 risk factors and a 10-year risk of 10% to 20% are considered to be at moderately high risk, and they have a recommended LDL-C target <130 mg/dL, according to ATP III. Prompt initiation of drug therapy to achieve this level is advisable. A lower LDL-C goal of <100 mg/dL is also a therapeutic option, based on physician judgment.

Moderate risk. Patients are at moderate risk when they have at least 2 risk factors and a 10-year risk <10%; their LDL-C should be <130 mg/dL, but drug therapy should be considered only if LDL-C remains ≥160 mg/dL after a trial of lifestyle therapy, according to ATP III.

Low risk. Finally, individuals are deemed to be at low risk, according to ATP III, if they have less than 2 major risk factors. Low-risk individuals should have LDL-C levels <160 mg/dL, and initiation of drug therapy may be considered if levels remain above this range after a trial of lifestyle modification.^2,5

Major Risk Factors (Exclusive of LDL-C) That Modify LDL-C Goals

  What the research tells us about primary and secondary prevention

In both primary and secondary prevention, a wealth of clinical trial evidence has demonstrated that statin therapy is effective in reducing LDL-C levels and in lowering the risk of coronary events and mortality. Shortly after the introduction of the first statin, lovastatin, in 1987 and the second, simvastatin, in 1988, the Scandinavian Simvastatin Survival Study (4S) showed that a 36% reduction in LDL-C in the intervention group, compared with placebo, was associated with a 30% reduction in all-cause mortality over a period of 5.4 years.⁶ The Heart Protection Study, which enrolled more than 20,000 patients with coronary or noncoronary atherosclerotic disease, diabetes, or hypertension, confirmed these findings of improved survival in a wider population, including women, the elderly, and people with “average” LDL-C levels.⁷

More recent secondary prevention trials have compared the effects of treatment with intensive vs standard statin therapy on recurrent events. In the Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial, which involved patients recently hospitalized for acute coronary syndromes, atorvastatin 80 mg/day was associated with a 16% greater reduction in the risk of cardiovascular events, compared with pravastatin 40 mg/day.⁸ The Treating to New Targets (TNT) study tested the efficacy of lowering LDL-C levels to below the recommended target of 100 mg/dL in CHD patients.⁹ The intensive atorvastatin group achieved a mean LDL-C level of 77 mg/dL, compared with 101 mg/dL in the standard therapy group, which translated into a 22% relative reduction in the risk of a first major cardiovascular event.

Numerous trials in primary prevention have demonstrated that statin therapy reduces the risk of developing a first cardiovascular event in various patient populations at moderate to moderately high risk. For example, the West of Scotland Coronary Prevention Study (WOSCOPS) was conducted in patients with very high LDL-C levels; the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) enrolled individuals with average LDL-C levels and low HDL-C; and the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm (ASCOT-LLA) included patients with type 2 diabetes, hypertension, and other cardiovascular risk factors.^10-12 All 3 trials demonstrated significant improvements in clinical outcomes with statin therapy.

In AFCAPS/TexCAPS, treatment with lovastatin over a mean 5.2 years led to a mean reduction in LDL-C levels of 25% from baseline and a mean increase in HDL-C of 6%.¹¹ Compared with placebo, statin therapy was associated with a 37% reduction in first acute major coronary events. Women constituted 15% of the 6605 patients enrolled in the study, and very few individuals in this subgroup experienced an acute major coronary event. Consequently, the 5-year number needed to treat (NNT) to prevent 1 event in this trial was 88 for women and 46 for men.¹³ The overall 5-year NNT for AFCAPS/TexCAPS was approximately 50 and similar to the estimated NNT for WOSCOPS.

Recent results from the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) suggest that the benefits of intensive statin therapy might extend to individuals with low LDL-C but elevated levels of the inflammatory marker C-reactive protein (CRP).¹⁴ The JUPITER population was at intermediate risk of CV events, as the placebo group experienced the primary end point at a rate of 1.36 per 100 person-years of follow-up. This trial was stopped by the Data and Safety Monitoring Board after a median 1.9 years of follow-up due to early evidence of efficacy. Compared with placebo, rosuvastatin at 20 mg/day reduced LDL-C levels by 50% to a median of 55 mg/dL and decreased CRP levels by 37%, which corresponded to a 44% reduction in the primary end point of major cardiovascular events and a 20% reduction in the secondary end point of all-cause mortality (Figures 1 and 2). Individuals who achieved LDL-C levels <70 mg/dL and CRP levels <1 mg/L experienced the greatest benefit, with a 79% relative reduction in cardiovascular events.¹⁵

The JUPITER study population contained approximately 38% women, and both women and men experienced similar benefit, as did every subgroup evaluated in the trial, including nonwhites. The 5-year NNT to prevent a cardiovascular event for the study overall was 25, which is considerably lower than that observed in AFCAPS/TexCAPS and WOSCOPS.¹⁴ It remains to be seen whether CRP levels and targets will be incorporated into future ATP guidelines, but the JUPITER results suggest that for individuals initiating statin therapy at increased risk for CV events, reductions in both LDL-C and CRP may result in the greatest cardiovascular benefit.

  Comparative efficacy of statins

Initial efforts to reduce elevated levels of LDL-C should include dietary modification, aerobic exercise, and smoking cessation. If pharmacologic intervention is warranted, treatment with statins is a safe and effective means of controlling LDL-C levels and reducing cardiovascular risk. The primary effect of statin therapy is LDL-C reduction. The statins share a common mechanism of action (inhibition of the rate-limiting enzyme in cholesterol synthesis, HMG CoA reductase), but they differ in terms of chemical structures and efficacy of lipid reduction. The response to statin therapy is variable and in part genetically determined, but LDL-C reductions can be expected to range from 20% to 63%. Elevations in HDL-C are typically more modest, with an approximate 5% to 15% increase. Triglycerides can be reduced by 10% to 37%.¹⁶

The available statins include atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, and simvastatin. In the 6-week Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin (STELLAR) trial, 2431 adults with hypercholesterolemia were randomized to 1 of the 4 most commonly prescribed statins at varying doses.¹⁷ At a dose of 20 mg/day, treatment with rosuvastatin resulted in significantly greater reductions in LDL-C (52%), as compared with atorvastatin (43%), simvastatin (35%), and pravastatin (24%) (Figure 3). These 4 statins also had varying effects on HDL-C and triglyceride levels. Recommended therapeutic doses, which typically reduce LDL-C by 30% to 45%, are atorvastatin 10 to 20 mg, fluvastatin 40 to 80 mg, lovastatin 40 mg, pitavastatin 1 to 4 mg, pravastatin 40 mg, rosuvastatin 10 mg, and simvastatin 20-40 mg.^18-19

All of the statins are well tolerated and have a similar safety profile, with standard doses occasionally causing myopathy and transient, reversible increases in liver enzymes; these risks increase at higher doses, but still remain very low.¹⁸ Choosing a statin and a dosage that can correct each aspect of the patient’s dyslipidemia is imperative to achieving optimal outcomes.

The Cholesterol Treatment Trialists’ meta-analysis of 14 randomized trials involving 90,056 participants confirms the efficacy and safety of lipid-lowering with statins.²⁰ This meta-analysis found that each 1 mmol/L (39 mg/dL) reduction in LDL-C reduces all-cause mortality by 12%, with corresponding reductions in nonfatal myocardial infarction (26%), major coronary events (23%), revascularization (24%), and stroke (17%). Furthermore, there was no evidence of increased risk of cancer or rhabdomyolysis with statin therapy. In general, adverse effects are extremely rare, with myopathy occurring in approximately 1 in 1000 patients and rhabdomyolysis in 1 in 10,000.²¹

The safety and efficacy of lipid lowering with statins has resulted in improved control of dyslipidemia across populations. The results of the Lipid Treatment Assessment Project (L-TAP) 2, a multinational survey of lipid goal attainment in individuals being treated for dyslipidemia, indicate that a larger proportion of patients are reaching their lipid targets compared with a decade ago.²² Success rates were highest in low-risk individuals, compared with high-risk individuals, with only 30% of patients at very high cardiovascular risk reaching an LDL-C target of <70 mg/dL. In general, these results suggest that efforts at cardiovascular prevention are improving, although there is still substantial unmet need, especially in higher-risk individuals.

  Implications for physicians

• Patients should be routinely assigned to risk categories based on major cardiovascular risk factors and Framingham scoring, and they should be treated to the appropriate LDL-C target based on their level of risk.

• Statin therapy has been shown to improve clinical outcomes and reduce mortality in both primary and secondary prevention.

• The positive results from the recent JUPITER trial underscore the benefits associated with intensive statin therapy in the reduction of cardiovascular risk.

• Choosing a statin and a dosage that can address each aspect of the patient’s dyslipidemia is imperative to achieving optimal outcomes.

·Acknowledgments·

The author would like to acknowledge the editorial and medical illustration assistance of Jennifer Moon, PhD, and the Editorial Office of the Dean, Weill Cornell Medical College, which received funding from AstraZeneca to help in the preparation of this e-newsletter.

Disclosures

Dr Gotto is a current consultant for AstraZeneca, KOWA Pharmaceuticals, Merck, and Roche Pharmaceuticals, and he is on advisory boards for DuPont and Novartis. He serves on corporate boards for Aegerion Pharmaceuticals, Arisaph Pharmaceuticals, and Vatera Capital.

References

1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486–2497.
2. Grundy SM, Cleeman JI, Merz CNB, et al, For the Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227–239.
3. Pletcher MJ, Lazar L, Bibbins-Domingo K, et al. Comparing impact and cost-effectiveness of primary prevention strategies for lipid-lowering. Ann Intern Med. 2009;150:243–254.
4. Lewis SJ, Fox KM, Grandy S. For the SHIELD Study Group. Self-reported diagnosis of heart disease: results from the SHIELD study. Int J Clin Pract. 2009;63:726–734.
5. Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol. 2008;51:1512–1524.
6. Scandinavian Simvastatin Survival Study Investigators. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–1389.
7. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial. Lancet. 2002;360:7–22.
8. Cannon CP, Braunwald E, McCabe CH, et al, For the Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495–1504.
9. LaRosa JC, Grundy SM, Waters DD, et al, For the Treating to New Targets (TNT) investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425–1435.
10. Shepherd J, Cobbe SM, Ford I, et al, For the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995;333:1301–1307.
11. Downs JR, Clearfield M, Weis S, et al, For the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results of AFCAPS/TexCAPS. JAMA. 1998;279:1615–1622.
12. Sever PS, Dahlöf B, Poulter NR, et al, For the ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomized controlled trial. Lancet. 2003;361:1149–1158.
13. Clearfield MJ, Downs JR, Weis S, et al. Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS): efficacy and tolerability of long-term treatment with lovastatin in women. J Women’s Health. 2001;10:971–981.
14. Ridker PM, Danielson E, Fonseca FAH, et al, For the 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.
15. Ridker PM, Danielson E, Fonseca FAH, et al, On behalf of the JUPITER Trial Study Group. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet. 2009;373:1175–1182.
16. Gotto AM. Contemporary Diagnosis and Management of Lipid Disorders. 4th ed. Newtown, PA: Handbooks in Health Care, 2008.
17. Jones PH, Davidson MH, Stein EA, et al. Comparison of the efficacy of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR trial). Am J Cardiol. 2003;92:152–160.
18. Armitage J. The safety of statins in clinical practice. Lancet. 2007;370:1781–1790.
19. Lee SH, Chung N, Kwan J, et al. Comparison of the efficacy and tolerability of pitavastatin and atorvastatin: an 8-week, multicenter, randomized, open-label, dose-titration study in Korean patients with hypercholesterolemia. Clin Ther. 2007;29:2365–2373.
20. Cholesterol Treatment Trialists’ Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267–1278.
21. Jacobson TA. Statin safety: lessons from new drug applications for marketed statins. Am J Cardiol. 2006;97(suppl):44C–51C.
22. Waters DD, Brotons C, Chiang Cheng-Wen, et al. Lipid Treatment Assessment Project 2: A multinational survey to evaluate the proportion of patients achieving low-density lipoprotein cholesterol goals. Circulation. 2009;120:28–34.

The Journal of Family Practice ©2009 Quadrant HealthCom Inc.