Potential Clinical and Economic Impact of Statin Formulary Management

Potential Clinical and Economic Impact of Statin Formulary Management Karol E. Watson, MD Summary The evidence is clear that aggressive management of cardiac risk factors is beneficial and generally safe for the majority of patients. For the many patients who require medication to achieve their goals, drug selection should be based, first and foremost, on evidence of impact on morbidity and mortality outcomes. In addition to efficacy, safety, cost, and practical patient related concerns need to be considered. Key Points Early, sustained, goal-oriented optimization of cardiovascular risk factors is important. It s important to base drug selection on evidence of morbidity and mortality benefits. All costs, not just medications, must be considered when considering a formulary change. The impact of a change on patient compliance must also be considered. THE GOAL OF PREVENTIVE CARDIOLOGY is to maximize event reduction in patients with,or at risk for, heart disease.a wealth of epidemiologic evidence is available on risk factors, causes of heart disease, and interventions to prevent heart disease. Optimal management of cardiac risk factors includes early, sustained clinical goal optimization, compliance with medication,and non-pharmacological measures.clinical goal optimization is achieving nationally accepted guideline values for blood pressure, glucose, and lipids. Almost everyone in American society needs nonpharmacologic measures to reduce cardiac risk factors. When patients need additional help reaching their goals, drug therapy is important. Drug selection should be based, first and foremost, on evidence of impact on morbidity and mortality outcomes. In addition to efficacy, safety, cost, and practical patient related concerns need to be considered. Atherosclerosis begins silently in the teenage years. It starts with a thickening of the endothelial layer of the blood vessel.the process of ongoing changes and lipid accumulation within the blood vessel continues throughout a person s lifetime. By the third decade of life, a person may have perceptible thickening of the artery wall. As the process continues untreated, an advanced atherosclerotic lesion develops that may rupture, thereby forming a blood clot and obstructing blood flow that results in a heart attack or a stroke. Previously it was thought that patients could only be helped to survive a heart attack. With current evidence-based therapies, intervention can occur much earlier to slow the progression of atherosclerosis. Some data now suggest that the process can even be halted or reversed. Major Cardiovascular Risk Factors The four major risk factors for developing heart disease are hyperlipidemia, hypertension, cigarette smoking, and diabetes. Eighty-seven to 100 percent of patients in one study experiencing a fatal coronary event had at least one of these risk factors before dying. 1 About 80 percent of patients with coronary heart disease have at least one of these four major risk factors contributing to their development. 2 Most hypertensive patients have at least one additional risk factor and many have several other risk factors (Exhibit 1). 3 For men, hypertension, plus an additional risk factor, occurs in 2 percent of patients. Hypertension plus two risk factors occur in 25 percent of males. Hypertension and three risk factors occur in 22 percent. A small 18 Journal of Managed Care Medicine Vol. 9, No. 4 www.namcp.org

Exhibit 1: Most Hypertensive Patients Have Additional Risk Factors 2 Framingham Offspring (Ages 18 to 74 Years) with Hypertension Were Likely to Have Additional Risk Factors MEN WOMEN HTN +1 RF HTN +2 RFs HTN +1 RF HTN +2 RFs 2% 25% 27% 24% HTN only 19% 8% 22% HTN +3 RFs HTN only 17% 12% 20% HTN +3 RFs RF=risk factor HTN +4 or more RFs HTN +4 or more RFs Exhibit 2: Impact of Elevated Systolic BP and Total Cholesterol on CHD Mortality MRFIT 3 34 Age-Adjusted CHD Death Rates Per 10,000 Person-years 21 23 MRFIT N=202,19 17 13 12 8 10 245+ 221-244 203-220 Cholesterol Quintile (mg/dl) 182-202 MRFIT=Multiple Risk Factor Intervention Trial 12 9 11 8 4 3 3 <182 <118 18 8 17 14 5 142+ 132-141 125-131 118-124 Systolic BP Quintile (mm Hg) percentage of men have four risk factors. Multiple risk factors occur more often in women.thus, it is unusual for patients to have hypertension alone. It appears that risk conferred by each individual risk factor is not just additive, but probably multiplicative as illustrated by data from the MRFIT intervention trial (Exhibit 2). 3 Dyslipidemia is one of the cardiac risk factors for which much success in reducing cardiac events has been achieved. The lower low-density cholesterol (LDL-C) that is achieved, the lower the cardiovascular event rate, regardless of age, gender, history of heart attack, or starting cholesterol values. 4 This relationship between LDL-C lowering and cardiovascular event reduction from large, randomized, well-designed trials is shown in Exhibit 3. 5-1 Implications of Switching Statins As statins become widely available generically, many managed care plans have revised their lipid-lowering agent formularies. When these changes are made, several issues in addition to efficacy need to be addressed, including actual overall costs of switching thousands of patients therapy, compliance issues, and comparative safety of the various statins. Switching formulary agents results in more expense than just medication costs. A managed care plan must also consider the cost of additional medical visits and laboratory tests likely to occur as the result of any switch. Many clinicians will want to see a patient after a switch is made and run lipid profile and liver function tests to ensure the patient is effectively and safely www.namcp.org Vol. 9, No. 4 Journal of Managed Care Medicine 19

Exhibit 3: The Reduction in CHD Risk Is Proportional to the Percent of LDL-C Lowering 5-1 0.4 0.2 0-0.2-0.4-0. -0.8-1.0 0 5 10 15 20 25 30 35 40 ALLHAT-LLT LRC-CPPT A to Z TNT LIPID WOSCOPS CARE HPS LIPS ASCOT 4S Prove-It % Change in LDL- Cholesterol ALLHAT-LLT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial); LRC-CPPT (Lipid Research Clinics Coronary Primary Prevention Trial); A to Z (Aggrastat to Zocor); TNT (Treating to New Targets); LIPID (Long-term Intervention with Pravastatin in Ischemic Disease); WOSCOPS (West of Scotland Coronary Prevention Study); CARE (Cholesterol and Recurrent Events); HPS (Heart Protection Study); LIPS (Lescol Intervention Prevention Study); ASCOT (Anglo- Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm); 4S (Scandinavian Simvastatin Survival Study); PROVE-IT (Atorvastatin Evaluation and Infection Therapy) managed on the new agent.an example of estimates of switch-related costs are presented in Exhibit 4. This analysis used a national plan coverage policy as a basis for cost determination and a commercial payment rate (140 percent of the 200 Medicare Physician Fee Schedule). Based on six additional services occurring because of a switch (two physician visits, cholesterol panel, liver function test, and venipuncture), this analysis projects that for every 10,000 patients switched from one statin to another, the average cost would be greater than $800,000. These estimated initial medical costs have to be weighed against the potential cost savings of any statin change. Another issue to be addressed is the impact on compliance and persistence. One study conducted in a managed care setting attempted to determine the effect of switching medications on the compliance and persistence of new statin users. A retrospective analysis of a pharmacy claims database provided by a large PBM was conducted. 17 The study sample consisted of 38,000 new statin users age 18 to 5 receiving atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor), pravastatin (Pravachol), or simvastatin (Zocor). Rosuvastatin (Crestor) was not available at the time of this study. Compliance was assessed by the medication possession ratio, and persistence was measured by the time to discontinuation. The switching rates were derived from the proportion of patients filling a prescription other than the initial statin. Patients who were switched were less compliant by about 19 percent. 17 Statin switchers were less persistent by 20.9 percent to 48.3 percent (P<0.001), depending on the gap length used to define discontinuation. 17 Although derived from only one study in one type of setting, these data are of concern because of the small, but real incidence of statinwithdrawal effects. Acute coronary syndrome in the few months after stopping a statin abruptly has been reported. The authors of this study note that patients who change medications should be given special care to ensure compliance. 17 Another consideration in developing a statin formulary are safety and dosing restrictions.these issues tend to vary for each statin. Two adverse effects associated with statins, and of most concern, are liver dysfunction and muscle-related side effects. Both appear to be dose-related adverse effects and may occur more commonly with some statins than with others. Most studies have shown that as statin dosage is increased, particularly to the highest available dose, the incidence of adverse events increases. 18 The adverse event rates, although still low, are increased at the higher end of the dosage range. An important consideration is whether a statin chosen for formulary inclusion can be used safely at high doses to reach clinical goals. Because of the particular enzyme pathways used to metabolize certain statins, such as lovastatin and simvastatin, are more prone to be involved in significant drug interactions. Other agents are less prone to drug interactions. Metabolic drug interactions can lead to elevated statin levels in the body, which increase the risk of drug-related adverse effects. 20 Journal of Managed Care Medicine Vol. 9, No. 4 www.namcp.org

Exhibit 4: National Average Costs of Each Task and Aggregate Cost for the Health Plan Unit Cost/Unit No. of Patients Total (000s) Two Physician Visits $51. 10,000 $51,00 Cholesterol Panel $8.51 10,000 $85,120 ALT/AST $20.47 10,000 $204,80 Venipuncture $4.20 10,000 $42,000 TOTAL $848,400 Cost/Unit represents national average Every state has a specific Cost/Unit The 10,000 patient sample was arbitrarily chosen Commercial payment is calculated as a percentage of 200 Medicare physician and clinical laboratory fees. All Medicare date are derived from the 200 Medicare Physician Fee Schedule Final Rule published in the Federal Register on Sept. 30, 2005, and Nov. 21, 2005. All physician fees are based on services performed in the physician office (nonfacility) setting. Data on file. Pfizer Inc.; New York, N.Y. Conclusion For optimal management of dyslipidemia, goal optimization and compliance with medications and non-drug measures are critical. Drug selection should be primarily based on evidence of impact on morbidity and mortality outcomes in addition to safety, overall costs, and practical patient-related concerns.the evidence is clear that aggressive, early, sustained, goal- optimized management of cardiac risk factors is beneficial and generally safe for the majority of patients. From a formulary perspective, switching statins can create a need for more physician visits, more laboratory monitoring, and reduced compliance, leading to additional costs. JMCM Karol E. Watson, MD, is assistant professor of Medicine/Cardiology, codirector, UCLA Program in Preventive Cardiology at the Geffen School of Medicine at UCLA. References 1.Greenland P,Knoll MD,Stamler J et al.major Risk Factors as Antecedents of Fatal and Nonfatal Coronary Heart Disease Events. JAMA. 2003;290:891-897. 2. Khot UN, Khot MB, Bajzer CT et al. Prevalence of Conventional Risk Factors in Patients With Coronary Heart Disease. JAMA. 2003;290:898-904. 2. Kannel WB. Risk stratification in hypertension: new insights from the Framingham Study. Am J Hypertens. 2000 Jan;13(1 Pt 2):3S-10S. 3. Neaton JD, Blackburn H, Jacobs D et al. Serum cholesterol level and mortality findings for men screened in the Multiple Risk Factor Intervention Trial. Multiple Risk Factor Intervention Trial Research Group. Arch Intern Med. 1992 Jul;152(7):1490-500. 4. Cholesterol Treatment Trialists (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 05 participants in 14 randomised trials of statins. Lancet. 2005;3:127-78. 5.ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs. usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA. 2002;288(23):2998-3007.. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998; 339:1349 57. 7. Shepard J, Cobbe SM, Ford I. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995;333:1301-7. 8. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 53 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002; 30:7 22. 9. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 199;335:1001-09. 10. Serruys PW, de Feyter P, Macaya C et al. Lescol Intervention Prevention Study (LIPS) Investigators. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;287:3215-22. 11. Sever PS, Dahlof B, Poulter NR et al. 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 randomised controlled trial. Lancet. 2003;31(934):1149-58. 12. Pedersen TR, Olsson AG, Faergeman O et al. Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation. 1998;97(15):1453-0. 13. Scirica BM, Morrow DA, Cannon CP et al. PROVE IT-TIMI 22 investigators. Intensive statin therapy and the risk of hospitalization for heart failure after an acute coronary syndrome in the PROVE IT-TIMI 22 study. J Am Coll Cardiol. 200;47(11):232-31. 14. LaRosa JC, Grundy SM, Waters DD et al. Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352(14):1425-35. 15. de Lemos JA, Blazing MA,Wiviott SD et al.a to Z investigators. Early intensive vs. a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA. 2004;292(11):1307-1. 1. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease.jama. 1984;Jan 20;251(3):351-4. 17.Thiebaud P, Patel BV, Nichol MB, Berenbeim DM.The effect of switching on compliance and persistence: the case of statin treatment. Am J Manag Care. 2005;11(11):70-4. 18. Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA. 2003;181-90. www.namcp.org Vol. 9, No. 4 Journal of Managed Care Medicine 21