These studies are needed to support formulary and drug-therapy selection decisions ..... in the Saskatchewan Health Databases. Pharmacoepidemiol Drug Saf ...
F e a t u r e
a r t i c l e
A Perspective on Principles of Comparative Cost-Effectiveness Studies for Pharmacotherapy of Chronic Diseases Pendar Farahani, MD, MSc
C
hronic diseases such as heart disease and diabetes are the leading causes of disability and death in the United States. Seventy percent of all deaths in the United States annually are the result of chronic diseases, and 25 million Americans live with a chronic disease that significantly limits their daily activity.1 Chronic diseases account for > 80% of health care spending in the United States annually.2 Elevated cholesterol is linked to three of the biggest killers in the United States: heart disease, stroke, and diabetes. The World Health Organization estimates that dyslipidemia is associated with more than half of the global cases of ischemic heart disease and more than 4 million deaths per year.3 Controlling this crucial health risk factor has a significant impact on these related diseases. For example, a 10% reduction in serum cholesterol levels can result in a 30% reduction in the incidence of coronary heart disease.4 The literature on the epidemiology and economics of dyslipidemia is extensive.5 Many articles have been written on dyslipidemia, considering the costs of dyslipidemia alongside stroke or diabetes. These studies analyze the prevalence and costs of dyslipidemia, with a focus on analyses related to stroke and diabetes.5 Comparative cost-effectiveness studies of therapeutics can accurately support decision-making in
54
health care resource allocation if principles of clinical pharmacology and pharmacoepidemiology are considered. The objective of this article is to review previous economic evaluations of statins and highlight methodological issues that can limit the applicability of their results. Several clinical and therapeutic factors are crucial to incorporate into comparative cost-effectiveness drug studies. Essential factors that affect the applicability of such studies include 1) bioequivalent doses of therapeutics, 2) escalating doses In Brief
Comparative cost-effectiveness drug studies can support decisionmaking for allocation of health care resources if principles of clinical pharmacology and pharmacoepidemiology are considered. Use of constant or milligramequivalent doses instead of bio-equivalent doses, reliance on placebo-controlled instead of head-to-head randomized trials, disparities in community-based distribution of disease burden, lack of clinically important endpoint data, and absence of adherence data can limit the applicability of such studies. This article highlights methodological issues that should be incorporated in comparative cost-effectiveness drug studies, using statins as an example.
(up-titration), 3) data from headto-head randomized clinical trials (RCTs), 4) community-based data of the target population, 5) evidencebased time horizon, 6) data on nonadherence and drug safety, and 7) use of hard endpoint outcomes. The following sections review each of these factors in detail. Bioequivalent Doses According to the American College of Clinical Pharmacy’s Guidelines for Therapeutic Interchanges, “therapeutically equivalent drugs are chemically dissimilar but produce essentially the same therapeutic outcome and have similar toxicity profiles. Usually, these drugs are within the same pharmacologic class.”6 For example, all 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (commonly referred to as “statins”) generally are not equivalent on a milligram-tomilligram basis. However, estimating equivalent doses based on efficacy and safety monitoring parameters proposes an approximate dosing equivalency of statins as follows: rosuvastatin, 5 mg = atorvastatin, 10 mg = simvastatin, 20 mg = pravastatin, 40 mg = lovastatin, 40 mg = fluvastatin, 80 mg.7 These equivalents can be used as a dosing conversion factor in therapeutic interchange programs in clinical practice.7 Economic evaluation of pharmacotherapies can accurately support decision-making in health care
Volume 30, Number 2, 2012 • Clinical Diabetes
F e a t u r e
resource allocation if therapeutically equivalent doses are incorporated into the economic analysis to reflect the clinical comparability of different agents. However, this important issue was not considered in most economic evaluations of statins. For example, the Surrogate Marker Cost-Efficacy (SMaC) study was undertaken to assess the economics of treatment with simvastatin, 10–20 mg/day, versus treatment with atorvastatin, 10–20 mg/day, in reducing LDL cholesterol in patients with hyperlipidemia, based on the results of a 1-year, double-blind, parallel-group clinical trial.8 However, 10–20 mg atorvastain is bioequivalent to 20–40 mg simvastatin. In another study, the Atorvastatin Comparative Cholesterol Efficacy and Safety Study (ACCESS), atorvastatin, 10–80 mg/day, was compared with fluvastatin, 20–40 mg/day or 40 mg twice daily; lovastatin, 20–40 mg/day or 40 mg twice daily; pravastatin, 10–40 mg/day; and simvastatin, 10–40 mg/day. Patients were started at the lowest available dose and titrated to higher doses at 6-week intervals until they achieved the National Cholesterol Education Program (NCEP)-II LDL cholesterol target or reached the highest available dose of medication.9,10 The studies did not take into consideration therapeutic bioequivalency. An economic-modeled analysis based on results of the Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL) trial was conducted to evaluate the long-term cost-effectiveness of high-dose atorvastatin compared to conventional-dose simvastatin, 20–40 mg/day) for secondary prevention.11 The IDEAL study, an RCT,12 demonstrated significant reductions in cardiovascular endpoints with high-dose atorvastatin (80 mg/day) compared to conventional-dose
Clinical Diabetes • Volume 30, Number 2, 2012
A r t i c l e
simvastatin in patients with stable coronary heart disease. A more meaningful comparison would have been between high-dose atorvastatin and high-dose simvastatin. Escalating Doses (Up-Titration) Management of hyperglycemia, hypertension, and hyperlipidemia often requires escalating doses of drugs to achieve predefined goals or clinical targets. Escalating doses (up-titration) reflects pharmacokinetics and pharmacodynamics of therapeutics that are applicable to the interpretation and economic evaluation of clinical protocols in practice settings. However, several pharmacoeconomic analyses incorporated fixed, constant-dose statins from RCTs. Examples include the West of Scotland Coronary Prevention Study (WOSCOPS),13,14 which measured the efficacy of a fixed and constant dose of pravastatin (40 mg/day),15 and a meta-analysis of RCTs of monotherapy with fixed doses of statins.16 In clinical practice, dose escalation is routinely used to achieve treatment goals. However, few economic evaluations have addressed the issue of up-titration in their models. One example in which uptitration was used is a study by Smith et al.,10 who conducted an economic evaluation using data from ACCESS. As mentioned earlier, in ACCESS, a 54-week RCT, patients were started at the lowest available dose of atorvastatin, fluvastatin, lovastatin, pravastatin, or simvastatin and titrated to higher doses at 6-week intervals until they achieved the NCEP II LDL cholesterol target or reached the highest available dose of medication.9 Using ACCESS data in this economic model reflects dose up-titration, which is applicable to clinical practice.
Head-to-Head Versus Placebo-Controlled RCTs In the development of a new drug, several studies must be completed before the drug wins approval by regulatory authorities for use in clinical practice.17 In phase 3 of this process, double-blind, placebo-controlled RCTs are conducted to evaluate the efficacy and safety of the drug.17 Head-to-head RCTs provide meaningful data by assessing a balanced distribution of the patient population among different arms of a trial with active therapeutics. However, for the economic evaluation of a class of drugs such as statins, for which several agents have already been marketed, placebocontrolled RCTs cannot accurately evaluate the superiority of one agent over another. Several economic evaluations of statins have used data from placebo-controlled RCTs such as the WOSCOPS, the Scandinavian Simvastatin Survival Study (4S), and the Collaborative Atorvastatin Diabetes Study (CARDS).13,14,18–22 These economic analyses are of limited use in guiding the drug therapy selection process. Therapeutic decisions should be based on the agent and dose that can lead to superior cost-effective outcomes. However, economic analyses of comparative studies for different agents of statins have not been extensively published. These studies are needed to support formulary and drug-therapy selection decisions regarding statins. Previous studies have compared the cost-effectiveness of different classes of lipid-lowering drugs. For example, the lifetime cost-effectiveness of statins was compared to that of fibrates for the treatment of hyperlipidemia. Estimates of lipid modification achieved because of drug therapy were based on published head-to-head comparisons of
55
F e a t u r e
specific statins and fibrates in randomized, double-blind studies.23 In other studies, the cost-effectiveness of simvastatin was compared to that of cholestyramine.24,25 These head-to-head RCTs can potentially be a better estimate of balanced assessments of therapeutics compared to placebo-controlled RCTs. Koren et al.26 used data from a randomized, 54-week, multicenter, head-to-head controlled trial to compare atorvastatin to simvastatin, lovastatin, and fluvastatin. Statin therapy was initiated at recommended starting doses and increased according to NCEP guidelines and drug package insert information. For patients who did not reach the goal at the highest recommended dose of each statin, the resin colestipol was added. These economic evaluations can reflect comparisons among medication classes and combination therapies in clinical practice. Community-Based Data of the Target Population RCTs assess drug efficacy in a controlled and somewhat artificial clinical environment. There are narrow inclusion criteria, and patients with comorbidities, children, elderly patients, and pregnant women are often excluded. The treatment strategies are fixed by study design, and drug doses and drug combinations are defined by protocol.27,28 In contrast, real life presents a wide spectrum of patients such that patient inclusion criteria are broad, and there are few, if any, exclusion criteria; combinations of drugs and drug doses are dynamic; and the treatment strategies are flexible and dependent on the course of the illness.27,28 Also, the treatment effect of a therapeutic agent may be different when it is used in an unselected population in clinical practice settings.29 These community-based
56
A r t i c l e
aspects of therapeutic evaluation can be associated with the population pharmacokinetics and pharmacodynamics of drugs and may reflect pharmacogenomics30,31 and pharmacoecology32 of therapeutics in the target population. The above-mentioned issues may also influence the outcomes of economic evaluation of therapeutics in community clinical practice when compared to RCTs.33,34 To achieve more meaningful results, cost-effectiveness studies should be conducted for a specific population to reflect medical patterns of practice, health care regulations, and intervention costs in the target population.35 Several pharmacoeconomic evaluations of statins incorporated a variety of community-based aspects of statin therapy in their models. In a U.K. economic evaluation, estimates of the distribution of patients receiving each dose of statin were derived from the U.K. national Doctors’ Independent Network database.36 In a Canadian economic assessment of statins, a model based on data from the Lipid Research Clinics cohort was used to estimate the benefits and cost-effectiveness of lipid modification with statins based on results from the 4S.37 Also, Ohsfeldt et al.38 assessed the effectiveness and cost-effectiveness of treatment with atorvastatin, rosuvastatin, and simvastatin in high-risk patients in routine clinical practice, involving patients 18–79 years of age with coronary heart disease or the equivalent who initiated statin therapy. These economic evaluations reflect the use of clinical data from community practices that is applicable for a target population. Evidence-Based Time Horizon Economic analyses based on RCTs often focus only on the results that are observed during the study. However, for many preventive interventions
such as cardiovascular risk reduction, associated costs and benefits will accumulate over patients’ remaining lifetime. Therefore, economic analyses beyond the duration of RCTs are required to fully evaluate the potential costs and benefits of long-term preventive therapies.39 When conducting cost-effectiveness studies, the choice of time horizon has a substantial effect on the calculated incremental costeffectiveness ratios.40 This has been illustrated in several simulation studies. For example, in a Canadian study,39 it was illustrated that the estimated efficacy and associated cost-effectiveness of ramipril is extremely sensitive to the selected time horizon. Consequently, care must be taken in choosing the time horizon in a cost-effectiveness analysis to minimize biases. Economic evaluations with a lifetime horizon commonly use Markov models, which simulate patients’ lifespan by dividing it into equal periods (cycles). At each cycle, the model exposes a hypothetical cohort to the competing hazards of normal aging and of the disease in question (disease-specific hazards), and the results are presented as years of life expectancy. However, because there are no readily available data on changes in disease-specific hazards over time, these hazards are often derived from short-term followup studies and are assumed to be constant over patients’ entire life.40 When the measurement of a longterm outcome is necessary, selecting evidence-based time horizons according to pharmacoepidemiology data over hypothetical models based on life-expectancy tables is crucial. Several pharmacoeconomics studies of statins incorporated long-term patterns in their models. For example, using data from CARDS, atorvastatin, 10 mg daily, was compared to placebo. Patients
Volume 30, Number 2, 2012 • Clinical Diabetes
F e a t u r e
were followed for a median period of 3.9 years and the cost per qualityadjusted life-year gained over a patient’s lifetime was calculated as one of the outcomes.20 In another study, it was estimated that 3–5.6 years (average 4.6 years) of statin treatment resulted in 0.15–0.41 years (average 0.3 years) saved over a lifetime time horizon.41 Conversely, using data from short-term RCTs for economic evaluation of interventions for chronic diseases is not clinically meaningful. For example, several pharmacoeconomic assessments of statin therapy incorporated data from short-term RCTs such as the Comparative Dose Efficacy Study of Atorvastatin Versus Simvastatin, Pravastatin, Lovastatin, and Fluvastatin in Patients with Hypercholesterolemia (CURVES)42 and the Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin (STELLAR) trial43 into their models. CURVES, a multicenter, randomized, parallel-group clinical trial, compared atorvastatin to fluvastatin, lovastatin, pravastatin, and simvastatin for a period of 8 weeks. STELLAR, a multicenter, randomized trial, consisted of a 6-week dietary lead-in period and a 6-week randomized treatment period. Patients who were compliant with the diet and met lipid criteria after the first 6 weeks were randomized for 6 weeks of statin therapy. Therefore, economic evaluation models should incorporate a time horizon that is long enough to be clinically meaningful. Adherence and Drug Safety Nonadherence with drug therapies not only limits their effectiveness, but in some instances is also associated with grave clinical sequelae44,45 and substantial economic burden.46 For example, Bouchard et al.47 evaluated the impact of adherence to statins
Clinical Diabetes • Volume 30, Number 2, 2012
A r t i c l e
on nonfatal coronary artery disease (CAD). Nonfatal CAD events were significantly lower among patients with adherence of > 90% compared to patients with adherence of < 90% after 1 year of follow-up (relative risk 0.81, 95% CI 0.67–0.97).47 Nonadherence always results in a reduction in efficacy, but its impact on cost varies substantially.46,48 First, in the RCT setting, withdrawals from studies are reported to be significantly lower than in postmarketing studies.49 Second, the rate of nonadherence and therapeutics discontinuation in clinical practice depends on the clinical and demographic characteristics of the patients in the target population. Sex, age, level of education, comorbidities, comedications, statin dose, and indication for statin therapy (primary versus secondary prevention) can influence adherence rates.50,51 Consequently, the overall nonadherence to statins obtained from clinical settings data demonstrates a wide range of divergence.33 For example, a cohort study52 using linked population-based administrative data from Ontario reported adherence to statins among patients > 65 years of age who received at least one statin prescription between January 1994 and December 1998. Two-year adherence rates in the cohorts were only 40.1% for patients with recent acute coronary syndrome, 36.1% for patients with chronic CAD, and 25.4% for patients without coronary disease (primary prevention). Another study53 was performed using data from the Régie de l’Assurance Maladie du Québec. Persistence and adherence to treatment were estimated separately. After 24 months, the persistence rate with the statins was 83%. The proportion of patients who switched from their initial statin varied across the statins (ranging from 7 to 34%).
The proportion of patients who were 80% adherent to statin therapy was 43%. Therefore, it is important to incorporate measures of adherence from real-world compliance data into pharmacoeconomic evaluations.54 Adverse events are one of the sources of nonadherence that can lead to discontinuation of therapeutics. Mild and severe adverse events occur for all therapeutics. Although statins are the first-line pharmacotherapy for hypercholesterolemia and have been shown to have a safe profile, in both RCTs and postmarketing observation studies,55 sporadic reports of serious adverse events such as hepatotoxicity and rabdomyolysis with statins should be considered in clinical effectiveness and cost-effectiveness studies.56–59 These adverse events may be associated with molecular properties, the dosage of statin, and its potential for drug-drug interactions.60 Average incidences per 10,000 person-years for monotherapy with rosuvastatin, atorvastatin, pravastatin, and simvastatin were reported as < 2% for myopathy, < 0.5% for rhabdomyolysis, and < 0.5% for acute liver toxicity.61–65 Although event rates are small, routine biochemical test monitoring is recommended for statin therapy in clinical practice to detect and prevent adverse drug reactions.55 Herman et al.66 included the cost of drug safety monitoring and adverse experiences into the calculation of the cost of simvastatin treatment. This monitoring process is associated with costs, which should be considered in costeffectiveness analysis. Hard Endpoints Versus Surrogate Endpoints Endpoints are the clinically important outcomes that are measured during
57
F e a t u r e
clinical studies, such as the impact of therapy on health-related quality of life, morbidity end points such as stroke or myocardial infarction, and mortality.67,68 The clinical outcomes measured in many pharmacoeconomic analyses of statin therapy have included death, cardiac arrest, nonfatal myocardial infarction, fatal myocardial infarction, angina pectoris, nonfatal stroke, congestive heart failure, surgical or percutaneous coronary revascularizations, and the incremental cost per clinical event avoided.69,70 However, measuring clinical (hard) endpoints in studies requires long-term follow-up of a large population (sample size). In these situations, use of surrogate endpoints is helpful. A surrogate endpoint or a biomarker is defined as “a characteristic that is objectively measured and evaluated as an indication of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.”71 Surrogate endpoints include a wide range of laboratory or physical measurements used in clinical studies as a substitute for meaningful clinical endpoints that directly assess the effects of the interventions tested on mortality or morbidity.72 Surrogate endpoints or biomarkers are often cheaper and easier to measure than hard endpoints. In clinical trials, the use of biomarkers allows for smaller sample sizes.67,68 Some economic evaluations considered biomarkers (surrogate endpoints) as outcome measures. For example, the SMaC study assessed the economics of hyperlipidemia treatment with simvastatin versus atorvastatin using LDL cholesterol as an outcome measure.8 In another study, a model-based economic evaluation was conducted to estimate the number of patients achieving the National Service Framework targets for LDL choles-
58
A r t i c l e
terol and triglycerides at each dose of statin and to calculate the average drug cost and incremental drug cost per patient achieving the target levels.36 However, although a surrogate endpoint (or biomarker) is a measure of the effect of a certain treatment that may correlate with a hard endpoint, it does not necessarily have a guaranteed relationship. Reliance on surrogate endpoints may be harmful and may lead to excess morbidity and mortality. Association studies using surrogate endpoints may demonstrate significant benefit for an intervention, but in fact the conclusion may not be reproducible for hard endpoints.68 For example, while dihydropyridine calcium channel blockers are efficacious in lowering blood pressure, their effects on clinically important outcomes such as stroke, myocardial infarction, and death are less certain.73,74 In another example, flecainide was believed to be beneficial because it reduced arrhythmias (a surrogate endpoint). However, the Cardiac Arrhythmia Suppression Trial found that flecainide increased the death rate (a clinically important endpoint).75 Summary Comparative cost-effectiveness studies of therapeutics for chronic diseases can accurately support decisionmaking in health care resource allocation if the principles of clinical pharmacology, therapeutics, and pharmacoepidemiology are considered. Economic evaluations of statins from numerous previous studies demonstrated several methodological limitations that diminish the applicability of these evaluations for clinical use and policy-making. To provide clinically meaningful results that can be applied to the real-world setting, costeffectiveness studies need to be designed to consider the principles
of clinical pharmacology and pharmacoepidemiology. Incorporating therapeutically equivalent doses into the economic analysis will reflect the clinical comparability of therapeutics. Using escalating doses, or up-titration, rather than fixed doses will result in evaluations that are applicable to clinical protocols in practice settings. Using head-to-head instead of placebocontrolled RCTs will provide a more meaningful economic comparison of therapeutics that assesses a balanced distribution of efficacy and safety of medication. Economic evaluations should be conducted on a target population rather than using data from RCTs. Evidence-based time horizons using available clinical data that are clinically meaningful can provide economic information that is applicable to the real-world clinical setting. Measures of adherence with drug therapies from real-world data as opposed to RCT settings should be incorporated into economic studies to provide a more accurate reflection of the clinical and demographic characteristics of the patients in the target population. Hard endpoints, which are clinically meaningful outcomes, should be used in economic evaluations of therapeutics instead of surrogate endpoints, which are cheaper and easier to measure but not always reliable for clinically significant outcomes. Inclusion of these factors in future comparative cost-effectiveness studies of therapeutics for chronic diseases will ensure applicability of the study results to real-world clinical settings. References 1
Council of State Governments: Costs of chronic diseases: what are states facing? [article online]. Available from http://www.healthystates.csg.org/NR/ rdonlyres/E42141D1-4D47-4119-BFF4A2E7FE81C698/0/Trends_Alert.pdf. Accessed 12 January 2012
Volume 30, Number 2, 2012 • Clinical Diabetes
F e a t u r e
2 Partnership for Solutions: Chronic conditions: making the case for ongoing care, September 2004 revision [article online]. Available from http://www.partnershipforsolutions.org/DMS/files/chronicbook2004.pdf. Accessed 12 January 2012 3 World Health Organization: Quantifying selected major risks to health. In The World Health Report 2002: Reducing Risks, Promoting Healthy Life. Geneva, Switzerland, World Health Organization, 2002, p. 47–97 4
Cohen JD: A population-based approach to cholesterol control. Am J Med 102:23–25, 1997 5
Smith DG: Epidemiology of dyslipidemia and economic burden on the healthcare system. Am J Manag Care 13:S68– S71, 2007 6
American College of Clinical Pharmacy: Guidelines for therapeutic interchange. Pharmacotherapy 13:252–256, 1993 7
Kendrach MG, Kelly-Freeman M: Approximate equivalent rosuvastatin doses for temporary statin interchange programs. Ann Pharmacother 38:1286–1292, 2004 8 Badia X, Russo P, Attanasio E: A comparative economic analysis of simvastatin versus atorvastatin: results of the Surrogate Marker Cost-Efficacy (SMaC) study. Clin Ther 21:1788–1796, 1999 9 Andrews TC, Ballantyne CM, Hsia JA, Kramer JH: Achieving and maintaining National Cholesterol Education Program low-density lipoprotein cholesterol goals with five statins. Am J Med 111:185–191, 2001 10 Smith DG, McBurney CR: An economic analysis of the Atorvastatin Comparative Cholesterol Efficacy and Safety Study (ACCESS). Pharmacoeconomics 21 (Suppl. 1):13–23, 2003 11 Lindgren P, Graff J, Olsson AG, Pedersen TJ, Jonsson B: Cost-effectiveness of high-dose atorvastatin compared with regular dose simvastatin. Eur Heart J 28:1448–1453, 2007 12 Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Larsen ML, Bendiksen FS, Lindahl C, Szarek M, Tsai J: High-dose atorvastatin vs. usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 294:2437–2445, 2005 13 Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, McKillop JH, Packard CJ: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 333:1301–1307, 1995 14
West of Scotland Coronary Prevention Study Group: A coronary primary prevention study of Scottish men aged 45–64 years: trial design. J Clin Epidemiol 45:849–860, 1992 15 Caro J, Klittich W, McGuire A, Ford I, Norrie J, McMurray J, Shepherd J: The West of Scotland Coronary Prevention Study: economic benefit analysis of primary prevention with pravastatin. BMJ 315:1577–1582, 1997 16 Perreault S, Levinton C, Le Lorier J: Efficacy and cost of HMG-CoA reduct-
Clinical Diabetes • Volume 30, Number 2, 2012
A r t i c l e
ase inhibitors in the treatment of patients with primary hyperlipidemia. Can J Clin Pharmacol 7:144–154, 2000 17 Spilker B: Guide to Clinical Trials. New York, Lippincott, Williams & Wilkins, 1991 18
Sever PS, Poulter NR, Dahlof B, Wedel H, Collins R, Beevers G, Caulfield M, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien E, Ostergren J: Reduction in cardiovascular events with atorvastatin in 2,532 patients with type 2 diabetes: Anglo-Scandinavian Cardiac Outcomes Trial Lipid-Lowering Arm (ASCOT-LLA). Diabetes Care 28:1151–1157, 2005 19
Lindgren P, Buxton M, Kahan T, Poulter NR, Dahlof B, Sever PS, Wedel H, Jönsson B: Cost-effectiveness of atorvastatin for the prevention of coronary and stroke events: an economic analysis of the AngloScandinavian Cardiac Outcomes Trial Lipid-Lowering Arm (ASCOT-LLA). Eur J Cardiovasc Prev Rehabil 12:29–36, 2005 20 Raikou M, McGuire A, Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Charlton-Menys V, Fuller JH: Cost-effectiveness of primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes: results from the Collaborative Atorvastatin Diabetes Study (CARDS). Diabetologia 50:733–740, 2007 21 Jonsson B, Johannesson M, Kjekshus J, Olsson AG, Pedersen TR, Wedel H: Costeffectiveness of cholesterol lowering: results from the Scandinavian Simvastatin Survival Study (4S). Eur Heart J 17:1001–1007, 1996 22 Johannesson M, Jonsson B, Kjekshus J, Olsson AG, Pedersen TR, Wedel H: Cost effectiveness of simvastatin treatment to lower cholesterol levels in patients with coronary heart disease. N Engl J Med 336:332–336, 1997 23 Perreault S, Hamilton VH, Lavoie F, Grover S: A head-to-head comparison of the cost effectiveness of HMG-CoA reductase inhibitors and fibrates in different types of primary hyperlipidemia. Cardiovasc Drugs Ther 10:787–794, 1997 24 Martens LL, Rutten FF, Erkelens DW, Ascoop CA: Cost effectiveness of cholesterol-lowering therapy in The Netherlands: simvastatin versus cholestyramine. Am J Med 87:54S–58S, 1989 25 Hjalte K, Lindgren B, Persson U: Cost-effectiveness of simvastatin versus cholestyramine: results for Sweden. Pharmacoeconomics 1:213–216, 1992 26
Koren MJ, Smith DG, Hunninghake DB, Davidson MH, Weiss SR, Schrott HG, Henley RW Jr, Tresh P, McLain RW, BakkerArkema RG, Black DM: The cost of reaching National Cholesterol Education Program (NCEP) goals in hypercholesterolaemic patients: a comparison of atorvastatin, simvastatin, lovastatin and fluvastatin. Pharmacoeconomics 14:59–70, 1998 27
Linden M: Controlled clinical trials and postmarketing experience. Psychopharmakotherapie 4:26–31, 1997
28 Linden M: Differences in adverse drug reactions in phase III and phase IV of the drug evaluation process. Psychopharmacol Bull 29:51–56, 1993 29 Farahani P, Levine M, Gaebel K, Thabane L: Clinical data gap between phase III clinical trials (pre-marketing) and phase IV (post-marketing) studies: evaluation of etanercept in rheumatoid arthritis. Can J Clin Pharmacol 12:e254–e263, 2005 30 Puccetti L, Acampa M, Auteri A: Pharmacogenetics of statins therapy: recent patents. Cardiovasc Drug Discov 2:228–236, 2007 31 Mangravite LM, Krauss RM: Pharmacogenomics of statin response. Curr Opin Lipidol 18:409–414, 2007 32 Flexner C: Pharmacoecology: a new name for an old science. Clin Pharmacol Ther 83:375–379, 2008 33 Sculpher MJ, Pang FS, Manca A, Drummond MF, Golder S, Urdahl H, Davies LM, Eastwood A: Generalisability in economic evaluation studies in healthcare: a review and case studies. Health Technol Assess 8:iii–192, 2004 34 Farahani P, Levine M, Goeree R: A comparison between integrating clinical practice setting and randomized controlled trial setting into economic evaluation models of therapeutics. J Eval Clin Pract 12:463–470, 2006 35 Muls E, Van Ganse E, Closon MC: Cost-effectiveness of pravastatin in secondary prevention of coronary heart disease: comparison between Belgium and the United States of a projected risk model. Atherosclerosis 137 (Suppl):S111–S116, 1998 36 Wilson K, Marriott J, Fuller S, Lacey L, Gillen D: A model to assess the cost effectiveness of statins in achieving the UK National Service Framework target cholesterol levels. Pharmacoeconomics 21 (Suppl. 1):1–11, 2003 37 Grover SA, Coupal L, Paquet S, Zowall H: Cost-effectiveness of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors in the secondary prevention of cardiovascular disease: forecasting the incremental benefits of preventing coronary and cerebrovascular events. Arch Intern Med 159:593–600, 1999 38 Ohsfeldt RL, Gandhi SK, Fox KM, Stacy TA, McKenney JM: Effectiveness and cost-effectiveness of rosuvastatin, atorvastatin, and simvastatin among high-risk patients in usual clinical practice. Am J Manag Care 12:S412–S423, 2006 39 Grover SA, Coupal L, Lowensteyn I: Determining the cost-effectiveness of preventing cardiovascular disease: are estimates calculated over the duration of a clinical trial adequate? Can J Cardiol 24:261–266, 2008 40 Benbassat J, Baumal R: The time horizons of formal decision analyses. Q J Med 100:383–388, 2007 41 Franco OH, Steyerberg EW, Peeters A, Bonneux L: Effectiveness calculation in economic analysis: the case of statins for cardiovascular disease prevention. J
59
F e a t u r e
A r t i c l e
Epidemiol Community Health 60:839–845, 2006
Regie de l’Assurance Maladie du Quebec data. Am Heart J 152:164–169, 2006
42 Hilleman DE, Heineman SM, Foral PA: Pharmacoeconomic assessment of HMG-CoA reductase inhibitor therapy: an analysis based on the CURVES study. Pharmacotherapy 20:819–822, 2000
54 Hughes DA, Bagust A, Haycox A, Walley T: The impact of non-compliance on the cost-effectiveness of pharmaceuticals: a review of the literature. Health Econ 10:601–615, 2001
43
Hirsch M, O’Donnell JC, Jones P: Rosuvastatin is cost-effective in treating patients to low-density lipoprotein-cholesterol goals compared with atorvastatin, pravastatin and simvastatin: analysis of the STELLAR trial. Eur J Cardiovasc Prev Rehabil 12:18–28, 2005 44 Blackburn DF, Dobson RT, Blackburn JL, Wilson TW: Cardiovascular morbidity associated with nonadherence to statin therapy. Pharmacotherapy 25:1035–1043, 2005 45 Ho PM, Magid DJ, Shetterly SM, Olson KL, Maddox TM, Peterson PN, Masoudi FA, Rumsfeld JS: Medication nonadherence is associated with a broad range of adverse outcomes in patients with coronary artery disease. Am Heart J 155:772–779, 2008 46 Peterson AM, McGhan WF: Pharmacoeconomic impact of non-compliance with statins. Pharmacoeconomics 23:13–25, 2005 47
Bouchard MH, Dragomir A, Blais L, Berard A, Pilon D, Perreault S: Impact of adherence to statins on coronary artery disease in primary prevention. Br J Clin Pharmacol 63:698–708, 2007 48
Cleemput I, Kesteloot K, DeGeest S: A review of the literature on the economics of noncompliance: room for methodological improvement. Health Policy 59:65–94, 2002 49
Riesen WF, Darioli R, Noll G: Lipidlowering therapy: strategies for improving compliance. Curr Med Res Opin 20:165–173, 2004 50 Kulkarni SP, Alexander KP, Lytle B, Heiss G, Peterson ED: Long-term adherence with cardiovascular drug regimens. Am Heart J 151:185–191, 2006 51 Schultz JS, O’Donnell JC, McDonough KL, Sasane R, Meyer J: Determinants of compliance with statin therapy and low-density lipoprotein cholesterol goal attainment in a managed care population. Am J Manag Care 11:306–312, 2005 52 Jackevicius CA, Mamdani M, Tu JV: Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA 288:462–467, 2002 53
Lachaine J, Rinfret S, Merikle EP, Tarride JE: Persistence and adherence to cholesterol lowering agents: evidence from
60
55
McKenney JM, Davidson MH, Jacobson TA, Guyton JR: Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol 97:89C–94C, 2006 56
Tenenbaum A, Fisman EZ, Motro M: Rhabdomyolysis and lipid-lowering drugs. JAMA 293:1448–1449, 2005 57 Cziraky MJ, Willey VJ, McKenney JM, Kamat SA, Fisher MD, Guyton JR, Jacobson TA, Davidson MH: Statin safety: an assessment using an administrative claims database. Am J Cardiol 97:61C–68C, 2006 58 Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L, Gurwitz JH, Chan KA, Goodman MJ, Platt R: Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 292:2585–2590, 2004 59 Shepherd J, Hunninghake DB, Stein EA, Kastelein JJ, Harris S, Pears J, Hutchinson HG: Safety of rosuvastatin. Am J Cardiol 94:882–888, 2004 60 Rosenson RS: Current overview of statin-induced myopathy. Am J Med 116:408–416, 2004 61 Newman CB, Palmer G, Silbershatz H, Szarek M: Safety of atorvastatin derived from analysis of 44 completed trials in 9,416 patients. Am J Cardiol 92:670–676, 2003 62 Silva MA, Swanson AC, Gandhi PJ, Tataronis GR: Statin-related adverse events: a meta-analysis. Clin Ther 28:26–35, 2006 63 Law M, Rudnicka AR: Statin safety: a systematic review. Am J Cardiol 97:52C–60C, 2006 64 McAfee AT, Ming EE, Seeger JD, Quinn SG, Ng EW, Danielson JD, Cutone JA, Fox JC, Walker AM: The comparative safety of rosuvastatin: a retrospective matched cohort study in over 48,000 initiators of statin therapy. Pharmacoepidemiol Drug Saf 15:444–453, 2006 65 Garcia-Rodriguez LA, Gonzalez-Perez A, Stang MR, Wallander MA, Johansson S: The safety of rosuvastatin in comparison with other statins in over 25 000 statin users in the Saskatchewan Health Databases. Pharmacoepidemiol Drug Saf 17:953–961, 2008
Herman WH, Alexander CM, Cook JR, Boccuzzi SJ, Musliner TA, Kjekshus 66
J, Pyörälä K: Effect of simvastatin treatment on cardiovascular resource utilization in impaired fasting glucose and diabetes: findings from the Scandinavian Simvastatin Survival Study. Diabetes Care 22:1771–1778, 1999 67 Cohn JN: Introduction to surrogate markers. Circulation 109:IV20–IV21, 2004 68 Aronson JK: Biomarkers and surrogate endpoints. Br J Clin Pharmacol 59:491–494, 2005 69 Olsson A, Casciano R, Stern L, Svangren P: A pharmacoeconomic evaluation of aggressive cholesterol lowering in Sweden. Int J Cardiol 96:51–57, 2004 70 Casciano R, Tarride JE, Breton MC, Stern L, Langer A: A pharmacoeconomic evaluation of the myocardial ischemia reduction with aggressive cholesterol lowering (MIRACL) study in Canada. Can J Clin Pharmacol 11:e179–e190, 2004 71 National Institutes of Health Definitions Working Group: Biomarkers and surrogate endpoints in clinical research: definitions and conceptual model. In Biomarkers and Surrogate Endpoints. 2nd ed. Downing GJ, Ed. Bethesda, Md., National Institutes of Health, 2000, p. 1–9 72 Psaty BM, Weiss NS, Furberg CD, Koepsell TD, Siscovick DS, Smith NL, Heckbert SR, Kaplan RC, Lin D, Fleming TR, Wagner EH: Surrogate end points, health outcomes, and the drug-approval process for the treatment of risk factors for cardiovascular disease. JAMA 282:786–790, 1999 73 Borhani NO, Mercuri M, Borhani PA, Buckalew VM, Canossa-Terris M, Carr AA, Kappagoda T, Rocco MV, Schnaper HW, Sowers JR, Bond MG: Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS): a randomized controlled trial. JAMA 276:785–791, 1996 74 Tatti P, Pahor M, Byington RP, Di Mauro P, Guarisco R, Strollo G, Strollo F: Outcome results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care 21:597–603, 1998 75 CAST Investigators: Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 321:406–412, 1989
Pendar Farahani, MD, MSc, is an endocrine fellow at Henry Ford Hospital in Detroit, Mich.
Volume 30, Number 2, 2012 • Clinical Diabetes