Cost-effectiveness of statin therapy for vascular event prevention in adults with elevated C-reactive protein: implications of JUPITER Cost-efficacy analysis of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors based on results of the STELLAR trial: clinical implications for therapeutic selection. Design and rationale of the ARBITER trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol)--a randomized trial comparing the effects of atorvastatin and pravastatin on carotid artery intima-media thickness. Continuation of statin therapy and primary prevention of nonfatal cardiovascular events. Cost-effectiveness of statins for primary prevention in patients newly diagnosed with type 2 diabetes in the Netherlands. Association of Statin Therapy with Outcomes of Acute Coronary Syndromes: The GRACE Study Automated outreach to increase primary adherence to cholesterol-lowering medications. Aspirin, Statins, or Both Drugs for the Primary Prevention of Coronary Heart Disease Events in Men: A CostUtility Analysis Effectiveness of an intervention designed to optimize statins use: a primary prevention randomized clinical trial Statins for Primary Prevention: The Debate Is Intense, but the Data Are Weak. An Economic Evaluation of Fluvastatin used for the Prevention of Cardiac Events Following Successful First Percutaneous Coronary Intervention in the UK Usefulness of statin drugs in protecting against atrial fibrillation in patients with coronary artery disease. A Pharmacoeconomic Evaluation of the Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study in the United Kingdom Improved fibrinolysis after 1-year treatment with HMG CoA reductase inhibitors in patients with coronary heart disease. An Economic Evaluation of Atorvastatin for Primary Prevention of Cardiovascular Events in Type 2 Diabetes Cost-effectiveness of rosuvastatin in the prevention of ischemic heart disease in Portugal. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial
Abstract Objectives : High-sensitivity C-reactive protein ( hs-CRP ) has been explored for use in predicting cardiovascular risk . The recent Justification for the Use of Statins in Primary Prevention : An Intervention Trial Evaluating Rosuvastatin ( JUPITER ) study found that statin therapy reduced cardiovascular events in those with low-density lipoprotein ( LDL ) cholesterol levels below current treatment thresholds ( ≤130 mg/dL , 3.4 mmol/L ) , but with elevated hs-CRP levels ( ≥2.0 mg/L ) . This study examines the cost-effectiveness of statin treatment for individuals with elevated hs-CRP but normal LDL cholesterol . Methods : A Markov decision-analytic model was conducted from the U.S. societal perspective . Data from JUPITER were used to estimate rates of myocardial infa rct ion , angina and stroke . Statin costs were based on generic simvastatin 80 mg , equipotent to the rosuvastatin 20 mg dose used in JUPITER . Primary prevention was the focus and secondary prevention was not modeled explicitly . Quality -adjusted life-years ( QALYs ) were calculated using nationally representative preference-based utility weights . One-way sensitivity analyses and multivariate probabilistic sensitivity analysis were used to explore uncertainty in model parameters as well as estimate the likelihood of cost-effectiveness when all event rates , costs and utilities were drawn r and omly from distributions reflecting uncertainty . Results : Statin therapy cost $ 10,889/QALY for vascular event prevention in this population . Results were sensitive to the cost of statin treatment . Based on 10,000 simulations , statin therapy was cost-effective in 99.5 % of simulations , using a willingness-to-pay threshold of $ 20,000/QALY , and 100 % of simulations using a threshold of $ 50,000/QALY . Conclusions : Treatment with statins in patients with elevated hs-CRP but normal cholesterol appears to be cost-effective . Limitations of this study include the assumption that an equipotent dose of simvastatin result ed in the same risk reduction  as rosuvastatin . Further , post-event states simulated the average experience of a patient . Continued statin use , subsequent events and /or heart failure were not explicitly modeled STUDY OBJECTIVE To compare the cost/1 % reduction in  low-density lipoprotein cholesterol ( LDL )  and the cost/patient achieving the National Cholesterol Education Program Adult Treatment Panel III ( NCEP ATP III ) LDL goal based on the results of the  Statin Therapies  for Elevated Lipid Levels Compared Across Doses to Rosuvastatin ( STELLAR ) trial . DESIGN Cost-efficacy analysis . INTERVENTION Investigators in the STELLAR trial evaluated percentage reductions in LDL and achievement of the ATP III LDL goal for various doses of atorvastatin , pravastatin , rosuvastatin , and simvastatin . We derived efficacy estimates for these four statins from the results of this trial . We also derived drug acquisition costs from the average wholesale prices to estimate the cost/1 % reduction in LDL levels and the cost/patient achieving the ATP III LDL goal . MEASUREMENTS AND MAIN RESULTS In the STELLAR trial , doses of rosuvastatin produced reductions in LDL significantly greater than those of equivalent milligram/milligram doses of atorvastatin , simvastatin , or pravastatin . The annual acquisition cost/percentage LDL reduction was lower with rosuvastatin at doses of 10 mg ( 20.92 dollars ) , 20 mg ( 18.28 dollars ) , and 40 mg ( 17.42 dollars ) than with the other statins analyzed . Rosuvastatin also had a lower average cost/patient achieving the ATP III LDL goal over 6 weeks than that of the other statins . CONCLUSION Although the long-term clinical benefits and safety data from the increased LDL reduction achieved with rosuvastatin remain uncertain , rosuvastatin may be the most cost-effective statin among those analyzed in terms of acquisition cost/1 % reduction in LDL levels and in terms of patients achieving ATP III LDL goals . On the basis of the efficacy estimates from the STELLAR trial in conjunction with acquisition cost , a potential cost savings could be realized from the use of rosuvastatin BACKGROUND As a class , statins are remarkably effective in reducing low-density lipoprotein ( LDL ) cholesterol , and several of these drugs have now been shown to reduce coronary heart disease morbidity and mortality . However , several important controversies in the use of statins remain to be answered by clinical trials . For example , it is controversial whether marked cholesterol reduction to levels below 100 mg/dL would further reduce the incidence of coronary heart disease . Furthermore , concerns about differences among statins for nonlipid effects has raised the concern that the assumption of a class effect is premature until head-to-head clinical trials are completed . METHODS Arterial Biology for the Investigation for the Treatment Effects of Reducing Cholesterol ( ARBITER ) is a single-center , r and omized , active-controlled study comparing the efficacy of high-dose atorvastatin ( 80 mg/d ) and pravastatin ( 40 mg/d ) in patients being treated for either the primary or secondary prevention of coronary heart disease . This trial will enroll up to 200 patients for the primary end point of the mean change in intima-media thickness of the common carotid artery . This effect will be evaluated over a treatment duration of 12 months . Secondary end points include the effects of statin therapy on inflammatory and hemostatic markers ( C-reactive protein and fibrinogen ) . CONCLUSION ARBITER will provide important data on the role of marked LDL reduction and the " class effect " theory of statin therapy in cardiovascular medicine Although the beneficial effect of statins in secondary prevention of cardiac events is well established , their effectiveness in primary prevention is question able when most evidence derives from r and omized controlled trials and not " real-life " data . To evaluate the association between persistent use of statins and risk of acute nonfatal cardiovascular events  in primary prevention patients in community setting s , we retrospectively analyzed a cohort of 171,535 adults 45 to 75 years old with no indication of cardiovascular disease who began statin therapy from 1998 to 2009 in a large health maintenance organization in Israel . Persistence with statins was measured by the proportion of days covered with dispensed prescriptions of statins during the follow-up period . Main outcome measurements were occurrence of myocardial infa rct ion or performance of a cardiac revascularization procedure . Incidence of acute cardiovascular events during the follow-up period ( 993,519 person-years ) was 10.22 per 1,000 person-years . Persistence with statins was associated with a lower risk of incident cardiac events ( p for trend < 0.01 ) . The most persistent users ( covered with statins for ≥80 % of their follow-up time ) had a hazard ratio of 0.58 ( 95 % confidence interval 0.55 to 0.62 ) compared to nonpersistent users ( proportion of days covered < 20 % ) . Similar results were found when analyses were limited to patients with > 5 years of follow-up . Treatment with high efficacy statins was associated with a lower risk of cardiac events . In conclusion , our large and unselected community-based study supports the results of r and omized controlled trials regarding the beneficial effect of statins in the primary prevention of acute cardiac events BACKGROUND Statins are lipid-lowering drugs that reduce the risk of cardiovascular events in patients with diabetes . OBJECTIVES The objective of this study was to determine whether statin treatment for primary prevention in newly diagnosed type 2 diabetes is cost-effective , taking nonadherence , baseline risk , and age into account . METHODS A cost-effectiveness analysis was performed by using a Markov model with a time horizon of 10 years . The baseline 10-year cardiovascular risk was estimated in a Dutch population of primary prevention patients with newly diagnosed diabetes from the Groningen Initiative to Analyse Type 2 Diabetes Treatment ( GIANTT ) data base , using the United Kingdom Prospect i ve Diabetes Study risk engine . Statin adherence was measured as pill days covered in the IADB.nl pharmacy research data base . Cost-effectiveness was measured in costs per quality -adjusted life-year ( QALY ) from the health care payers ' perspective . RESULTS For an average patient aged 60 years , the base case , statin treatment was highly cost-effective at € 2245 per QALY . Favorable cost-effectiveness was robust in sensitivity analysis . Differences in age and 10-year cardiovascular risk showed large differences in cost-effectiveness from almost € 100,000 per QALY to almost being cost saving . Treating all patients younger than 45 years at diabetes diagnosis was not cost-effective ( weighted cost-effectiveness of almost € 60,000 per QALY ) . CONCLUSIONS Despite the nonadherence levels observed in actual practice , statin treatment is cost-effective for primary prevention in patients newly diagnosed with type 2 diabetes . Because of large differences in cost-effectiveness according to different risk and age groups , the efficiency of the treatment could be increased by targeting patients with relatively higher cardiovascular risk and higher ages Context While the benefits of statins in the primary and secondary prevention of coronary artery disease are clear , the value of statin therapy in acute coronary syndromes is uncertain . Contribution Analyzing data from a large , international observational study of acute coronary syndromes , these investigators identified associations between statin use before and during acute coronary events and favorable outcomes . Caution s While these data suggest a potential benefit of statins during acute coronary events , trials are necessary to determine the most appropriate use of statins in the treatment of acute coronary events . The Editors Data from r and omized clinical trials support the efficacy of lipid-lowering medications , particularly statins , in the primary and secondary prevention of coronary artery disease ( 1 - 3 ) . The benefits of statins , however , were not readily apparent until after several months of therapy , suggesting that the drugs ' lipid-lowering capabilities were largely responsible . In vitro work has suggested that statins may have an abundance of pleiotropic effects ( 4 ) . These include modulation of inflammation , inhibition of platelet function and thrombosis , and enhancement of endothelial cell function . The demonstrated ability of statins to immediately affect basic pathophysiologic mechanisms has result ed in increased interest in their potential role in the setting of acute coronary syndromes . The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering ( MIRACL ) trial found that early treatment with high-dose atorvastatin modestly reduced event rates of recurrent ischemia in statin-naive patients presenting with an acute coronary syndrome ( 5 ) . These observations , while intriguing , did not conclusively establish the role of statins in patients with acute coronary syndromes . In the MIRACL trial , the failure of statins to significantly affect more concrete trial end points ( for example , death or recurrent myocardial infa rct ion [ MI ] ) was disappointing . Whether this reflected a true lack of physiologic impact of early statin treatment or merely indicated that the study was underpowered to detect differences in these end points remains unclear . In a sub study using data from the Platelet Receptor Inhibition for Ischemic Syndrome Management ( PRISM ) trial in patients with acute coronary syndromes , patients already taking statins  had better short-term outcomes ( decreased risk for death or nonfatal MI ) than those not previously receiving statin therapy , unless statin therapy was discontinued in the hospital ( 6 ) . Initiation of statin therapy after the onset of an acute coronary syndrome appeared to be less effective than treatment with statins before symptom onset . Using data from the Global Registry of Acute Coronary Events ( GRACE ) project , a large , multinational , observational study of patients with acute coronary syndromes , we examined the association between previous statin therapy  , presentation characteristics of acute coronary syndromes , and hospital outcomes . We also examined the effect of early in-hospital statin therapy ( or withdrawal of statins ) on important hospital outcomes , including death or the development of recurrent MI or stroke . Methods Full details of the GRACE rationale and methods have been published elsewhere and are outlined below ( 7 - 9 ) . Site Selection The GRACE project is design ed to reflect an unbiased population of patients with acute coronary syndromes , regardless of geographic region . Currently , 94 hospitals located in 14 countries ( Argentina , Australia , Austria , Belgium , Brazil , Canada , France , Germany , Italy , New Zeal and , Pol and , Spain , the United Kingdom , and the United States ) are participating in this observational study . Patients entered in the registry must be at least 18 years of age and alive at the time of hospital presentation ; be admitted with an acute coronary syndrome as a presumptive diagnosis ( that is , have symptoms consistent with acute ischemia ) ; and have at least 1 of the following : electrocardiographic changes consistent with an acute coronary syndrome , serial increases in serum biochemical markers of cardiac necrosis , or documentation of coronary artery disease ( 7 - 9 ) . The qualifying acute coronary syndrome must not be precipitated by a significant noncardiovascular comorbid condition ( for example , trauma or surgery ) . To ensure the enrollment of an unbiased sample , the first 10 to 20 consecutive patients ( depending on each site 's patient volume ) are recruited from each site on a monthly basis . Where required , study investigators received approval from their local hospital ethics or institutional review board . Data Collection At each site , a trained coordinator collected data using a st and ardized case-report form . Data on demographic characteristics , medical history , presenting symptoms , duration of prehospital delay , biochemical and electrocardiographic findings , treatment practice s , and hospital outcome were collected . St and ardized definitions of all patient-related variables and clinical diagnoses were used . All cases were assigned to 1 of the following categories : ST-segment elevation MI , nonST-segment elevation MI , unstable angina , and other cardiac or noncardiac diagnoses that have been previously described ( 7 - 9 ) . St and ardized definitions were also used for selected hospital complications and outcomes . Patient Sample For the current study , patients who were subsequently found to have noncardiac or other cardiac ( nonacute coronary syndrome ) primary diagnoses and those who transferred into or out of GRACE registry hospitals were excluded from further consideration . Treatments defined as previous use were those taken by the patient on a long-term basis at home and within 7 days of the presenting event , based on the review of information contained in medical records and abstract ed by trained study physicians and nurses . Treatments received in the hospital ( within the first 24 hours or thereafter ) were categorized as within hospital . Agents prescribed for use after discharge from participating hospitals were categorized as at discharge . Patient treatment categories were defined according to the following groupings : no previous treatment with statins and no treatment with statins during hospitalization , no previous therapy with statins but statin therapy  instituted during hospitalization , previous therapy with statins and statin therapy continued during hospitalization , and previous  therapy with statins but statin therapy not continued during the index hospitalization . Statistical Analysis We used the chi-square tests for discrete variables to analyze differences in demographic and clinical characteristics , treatment practice s , clinical presentation ( ST-segment elevation vs. nonST-segment elevation , large infa rct [ creatine phosphokinase level > 2 times the upper limit of normal ] vs. small infa rct ) , subsequent diagnosis ( ST-segment elevation MI , nonST-segment elevation MI , unstable angina ) , and hospital complications ( death , congestive heart failure or pulmonary edema , cardiogenic shock , stroke , ventricular tachycardia or ventricular fibrillation , and cardiac arrest ) in relation to statin use . The Wilcoxon rank-sum test was used to analyze differences between respective comparison groups for continuous variables . While controlling for potentially confounding variables , we performed multivariate regression analyses to examine the association between previous statin therapy and hospital presentation ( ST-segment elevation vs. no ST-segment elevation , creatine phosphokinase level 2 times normal vs. creatine phosphokinase level < 2 times the upper limit of normal ) , as well as any association between previous or in-hospital statin therapy and hospital outcomes ( death , recurrent MI or MI after 24 hours , and stroke ) or a composite end point of all 3 outcomes . C and i date variables for inclusion in the regression models evaluating previous statin use and hospital presentation included patient age , sex , smoking status , diabetes , history of vascular disease ( previous MI , stroke , positive angiogram , peripheral vascular disease , percutaneous coronary intervention , or coronary artery bypass graft surgery ) , hypertension , hyperlipidemia , and previous therapies ( aspirin , angiotensin-converting enzyme [ ACE ] inhibitors , -blockers , and other lipid-lowering agents ) . C and i date variables for regression models evaluating previous or in-hospital statin use and hospital outcomes included all of the previously listed characteristics plus characteristics present at the time of hospital admission ( heart rate , systolic blood pressure , Killip class , ST-segment elevation or left bundle-branch block pattern , and positive cardiac enzymes ) and receipt of in-hospital therapies ( aspirin and other antiplatelet agents , -blockers , unfractionated heparin , low-molecular-weight heparin , glycoprotein IIb/IIIa inhibitors , cardiac catheterization , percutaneous coronary intervention , or coronary artery bypass graft surgery ) . C and i date variables possibly associated with the outcomes of interest ( P < 0.25 after univariate analysis ) were included in the multivariate models . Variables for which the P value exceeded 0.05 were eliminated in a stepwise fashion so that only those that had a statistically significant association with the outcome of interest were included in the final regression models . Because of their clinical relevance and potential importance , age , sex , and history of hyperlipidemia were retained in the final multivariable models for clinical outcomes regardless of statistical significance . Final models were evaluated for goodness of fit by the HosmerLemeshow test . Because between-hospital variation in use of statin treatment could be considerable and potentially affect our study results , we adjusted for hospital r and om effects on the observed outcomes . We used a generalized estimating equation modeling technique , assuming patients were repeated measures within each hospital . Variable BACKGROUND Primary nonadherence occurs when new prescriptions are not dispensed . Little is known about how to reduce primary nonadherence . We performed a r and omized controlled trial to evaluate an automated system to decrease primary nonadherence to statins for lowering cholesterol . METHODS Adult members of Kaiser Permanente Southern California with no history of statin use within the past year who did not fill a statin prescription after 1 to 2 weeks were passively enrolled . The intervention group received automated telephone calls followed 1 week later by letters for continued nonadherence ; the control group received no outreach . The primary outcome was a statin dispensed up to 2 weeks after delivery of the letter . Secondary outcomes included refills at intervals up to 1 year . Intervention effectiveness was determined by intent-to-treat analysis and Fisher exact test . Subgroups were examined using logistic regression . RESULTS There were 2606 participants in the intervention group and 2610 in the control group .  Statins were dispensed to 42.3 % of intervention participants and 26.0 % of control participants ( absolute difference , 16.3 % ; P < .001 ) . The relative risk for the intervention vs control group was 1.63 ( 95 % CI , 1.50 - 1.76 ) . Intervention effectiveness varied slightly by age ( P = .045 ) but was effective across all age strata . Differences in the frequency of statin dispensations persisted up to 1 year ( P < .001 ) . CONCLUSIONS The intervention was effective in reducing primary nonadherence to statin medications . Because of low marginal costs for outreach , this strategy appears feasible for reducing primary nonadherence . This approach may generalize well to other medications and chronic conditions Context National guidelines recommend aspirin or statin drugs individually to reduce first coronary heart disease ( CHD )  events , but there are no guidelines about taking both . Contribution The authors used a Markov model to estimate the cost-effectiveness of aspirin , statins , both drugs , or neither in men . In patients with a 10-year risk for CHD of 7.5 % , aspirin alone reduced costs and lengthened life compared with no treatment . Adding a statin cost $ 56200 per additional quality -adjusted life-year at a 7.5 % risk but only $ 42500 at a 10 % risk . Caution s The authors ' analysis was limited to men . Implication s Therapy with aspirin alone is effective and cost-effective in men with an average level of risk for CHD . The addition of a statin is more cost-effective as risk increases . The Editors Aspirin and statin drugs have been shown to be effective for preventing first coronary heart disease ( CHD ) events ( 1 - 3 ) . Systematic review s and meta-analyses suggest that the relative risk reductions with both forms of therapy are similar in magnitude and seem to be independent and relatively constant across the range of underlying risk for CHD ( 2 - 5 ) . The absolute benefit from these treatments seems to be proportional to the patient 's underlying risk for CHD . National treatment guidelines recommend aspirin and statin drugs individually for the primary prevention of cardiovascular events in men who are at increased risk ( 4 , 6 , 7 ) . However , no U.S. guidelines have addressed how these drugs should be used together , and we are unaware of any previous analyses that have reported the cost-effectiveness of these drugs when used in combination for CHD prevention . To help inform clinical and policy decisions about primary CHD prevention , we performed a costutility analysis that examined the use of aspirin therapy , statin therapy , or combination therapy with both drugs in men with various underlying levels of risk for CHD . Methods To examine the cost and utility associated with aspirin and with statin use , we used Microsoft Excel 2002 for Windows ( Microsoft Corp. , Redmond , Washington ) to develop a Markov state-transition model . The model was design ed to simulate cohorts of initially healthy middle-aged men with no history of cardiovascular events and with various levels of 10-year risk for CHD ( Figure 1 ) . Figure 1 . General structure of the Markov model . Base-Case Scenario In our base-case scenario , we compared the effectiveness of 10 years of aspirin therapy , statin therapy , combination therapy with both drugs , and no therapy in 45-year-old men with a 10-year risk for CHD of 7.5 % . After 10 years , both groups adopted the treatment used in the intervention group . Although the differences in therapy were maintained for only 10 years , we examined the effects of these therapies over a lifetime . Model Assumptions All persons were initially healthy and progressed through the model in annual cycles . In each cycle , an individual remained healthy , had an initial cardiovascular event ( angina , myocardial infa rct ion , or stroke ) , experienced adverse effects from therapy ( gastrointestinal bleeding from aspirin or myopathy from statins ) , or died . We assumed that those who had cardiovascular events or adverse events stayed in the subacute state for the remainder of that cycle and then entered a postevent state . Adherence to treatment was assumed to be 100 % in the absence of adverse effects , although the treatment efficacy data were based on the actual rates of adherence in the clinical trials . Persons who had adverse effects from therapy stopped taking the offending medication ; their procession through the model was similar to that of healthy patients after the initial cycle . All costs and outcomes were discounted at 3 % in accordance with current consensus recommendations ( 8) . Model Parameters Model parameters , including base-case values , ranges , and references , are shown in Table 1 ( 1 - 3 , 9 - 29 ) . Table 1 . Base-Case Estimates and Ranges Used in Sensitivity Analyses Noncardiovascular Mortality Age-dependent noncardiovascular mortality rates were estimated from the National Vital Statistics life tables ( 31 ) . Rates were adjusted as the cohort aged over the time horizon of the analysis . Cardiovascular Event Rates Baseline risks for initial cardiovascular events ( myocardial infa rct ion , stroke , angina , and death from CHD ) were drawn from Framingham risk equations by using hypothetical scenarios of nonsmoking , nonhypertensive , nondiabetic men at different levels of risk for CHD ( Appendix Table ) ( 32 ) . Assuming an exponential distribution , we translated these 10-year risks into annual event-related transition probabilities . These probabilities were allowed to change over time to reflect increasing risk for CHD over the time horizon of the analysis . Appendix Table . Sample Baseline Characteristics of 45-Year-Old Men by Risk Level Because we were interested in primary prevention , we did not simulate or examine the details of a patient 's course after a primary , nonfatal event . Instead , we assigned them an increased risk for death , increased costs , and decreased utilities by using data from the literature regarding the average experience of patients after an initial event . The increased relative risk for death after an initial event ( Table 1 ) was drawn from population -based studies in the United Kingdom ( 12 , 16 ) and applied to the general mortality rates from the U.S. life tables to generate the estimated postevent mortality rates . We modified these event rates by assuming that all patients received optimal secondary prevention . Adverse Effects The excess risks for gastrointestinal bleeding with aspirin use and for myopathy with statin use were drawn from systematic review s of r and omized trials and a recent secondary data analysis ( 2 , 26 , 27 ) . Risks for gastrointestinal bleeding and myopathy in untreated patients were assumed to be zero so that only treatment-induced adverse events were counted . Because better data were not available , we estimated the risks for death from aspirin-related gastrointestinal bleeding and statin-induced myopathy and varied them in sensitivity analysis . Patients who had nonfatal adverse effects were not given therapy with alternate agents for primary prevention of CHD . Modeling Stroke Because many r and omized trials of aspirin prophylaxis did not distinguish by stroke type , we had difficulty estimating the precise effect of aspirin on ischemic and hemorrhagic strokes ( 30 ) . To account for this limitation , we used 2 approaches to model the effect of aspirin on stroke . In the base-case analysis , we followed the approach that was used in a recent meta- analysis ( 9 ) by including hemorrhagic stroke and ischemic stroke together in 1 estimate of the effect of aspirin on total stroke ( relative risk for stroke with aspirin , 1.06 ) . In an alternate scenario , we modeled hemorrhagic stroke and ischemic stroke as separate health states . We assumed that aspirin was associated with an excess annual risk of 20 hemorrhagic strokes per 100000 users on the basis of published meta-analyses and that one third of these hemorrhagic strokes would be fatal ( 19 , 30 , 33 ) . We conservatively assumed that aspirin had no effect on ischemic stroke ( 30 ) . The costs and utilities of ischemic stroke and hemorrhagic stroke were also considered separately . Treatment Efficacy We used summary relative risk estimates from existing meta-analyses or relative risks from individual trials to estimate the efficacy of aspirin and statin therapy , either alone or in combination , for preventing CHD events ( 3 , 24 , 29 ) . Where data were limited , we made conservative assumptions . The efficacy of the combined use of aspirin and statins was assumed to be independent on the basis of data from secondary prevention trials ( 5 ) . We did not model the effect of aspirin or statins on initial use of revascularization procedures in the absence of a cardiovascular event . All patients who survived an initial cardiovascular event were assumed to have received secondary preventive therapy with aspirin and a statin or with an alternate agent if  they could not tolerate  aspirin  or  statins . The effect of treatments on all-cause mortality was estimated from meta-analyses of secondary prevention trials ( 18 - 20 ) . Costs We conducted our analysis from the perspective of a third-party payer . State costs ( Table 1 ) , which were derived from data from the published literature and several recent national data bases , are expressed in 2003 dollars . To estimate the costs during the year in which an event occurred , we estimated acute care costs by drawing on data regarding hospital charges from the Healthcare Utilization Project data base and by converting these values to costs . To convert hospital charges to costs , we used the 1999 cost-to-charge ratio value of 0.4501 , which was derived from the Medicare Provider Analysis and Review of short-stay hospitals ( 28 ) . We then used the Medical Consumer Price Index to generate an inflation factor of 1.195 , which was applied to the 1999 cost figure to convert 1999 dollars to 2003 dollars ( 17 ) . In addition to the acute care costs , we assumed that each patient who survived an acute event would also incur one half of the estimated ongoing annual costs of care for the first year . Costs for subsequent years were based on ongoing costs of care that were drawn from the medical literature ( 22 - 25 ) . Drug costs were obtained from the 2003 Red Book average wholesale prices ( 21 ) . For our base-case analysis , we set the annual  statin cost to $ 730 by averaging the Red Book prices of simvastatin ( $ 922 for 10 mg/d ) and lovastatin ( $ 503 for 10 mg/d ) . The base-case cost of aspirin was based on an annual cost of $ 16 for Bayer aspirin ( Bayer Healthcare LLC , Morristown , New Jersey ) . The annual cost of generic aspirin  was estimated at approximately $ 6 ( 21 ) . We varied the costs of each drug over wide ranges in sensitivity analysis . To check our cost estimates , we compared our derived values with other cost estimates Background Although hypercholesterolemia is considered a cardiovascular risk factor , in isolation it is not necessarily sufficient cause for a cardiovascular event . To improve event prediction , cardiovascular risk calculators have been developed ; the REGICOR calculator has been vali date d for use in our population . The objective of this project is to develop an intervention with general practitioners ( GPs ) and evaluate its impact on prescription adequacy of cholesterol-lowering drugs in primary prevention of cardiovascular disease and in controlling the costs associated with this disease . Methods This nonblinded , cluster-r and omized clinical trial analyzes data from primary care electronic medical records ( ECAP ) and other data bases . Inclusion criteria are patients aged 35 to 74 years with no known cardiovascular disease and a new prescription for cholesterol-lowering drugs during the 2-year study period . Dependent variables include the following : RETIRA , defined as new cholesterol-lowering drugs initiated during the year preceding the intervention , considered inadequate , and withdrawn during the study period ; EVITA , defined as new cholesterol-lowering drugs initiated during the study period and considered inadequate ; COST , defined as the total cost of inadequate new treatments prescribed ; and REGISTER , defined as the recording of cardiovascular risk factors . Independent variables include the  GP ’s quality -of-care indicators and r and omly assigned study group ( intervention vs control )  , patient demographics , and clinical variables . Aggregated descriptive analysis will be done at the GP level and multilevel analysis will be performed to estimate the intervention effect , adjusted for individual and GP variables . Discussion The study objective is to generate evidence about the effectiveness of implementing feedback information programs directed to GPs in the context of Primary Care . The goal is to improve the prescription adequacy of lipid-lowering therapies for primary prevention . Trial registration Clinical Trials.gov Identifier : NCT01997671 . November 28 , 2013 This issue of JAMA contains the latest US Preventive Services Task Force ( USPSTF ) recommendation statement on statins for prevention of cardiovascular disease in adults,1 along with the accompanying evidence report and systematic review 2 on which the recommendations are based . The evidence report summarized data from 19 trials including a total of 71 344 patients and concluded that statin therapy was associated with reduced risk of all-cause and cardiovascular mortality and cardiovascular disease ( CVD ) events . Thus , the task force recommended “ initiating use of lowto moderate-dose statins in adults aged 40 to 75 years without a history of CVD who have 1 or more CVD risk factors and a calculated 10-year CVD event risk of 10 % or greater ( B recommendation ) ” or “ 7.5 % to 10 % ( C recommendation ) .”1 Although the task force did their usual careful job of review ing the evidence , the evidence for treating asymptomatic persons with statins does not appear to merit a grade B or even a grade C recommendation . The task force evidence report estimated an absolute benefit for use of statins of 0.40 % for all-cause mortality and 0.43 % for cardiovascular mortality and indicated that the absolute benefit was greater for patients at greater baseline risk.2 Notably , the evidence report did not exclude studies that included patients taking statins for secondary prevention , who have a higher baseline risk of cardiac events and death and thus are more likely to benefit from therapy that inflates the benefit attributed to a primary prevention population . The task force did perform a sensitivity analysis that excluded 3 trials with persons for whom there were prior “ hard ” cardiovascular events and obtained similar results of benefits ( eTable 5 in the article by Chou et al2 ) . This sensitivity analysis did not exclude WOSCOPS , which included patients receiving statins for secondary prevention—5 % had angina and 3 % had intermittent claudication,3 accounting for 15 % of the total weight in the meta- analysis . In contrast , a meta- analysis of 11 studies and 65 229 patients receiving statins for primary prevention , in which patients receiving statins for secondary prevention were excluded , found no benefit of statins for reducing all-cause mortality.4 The confidence intervals of these 2 analyses overlap , and the difference between these findings likely reflects differences in studies included . The USPSTF and authors of the evidence report did not have access to the primary data ( clinical study reports and anonymized patient-level data ) from the statin clinical trials . Rather , they had to rely on peer- review ed published reports as the basis for these recommendations . Exacerbating the potential bias , all of the trials included in the task force evidence report2 were industry-sponsored except 1 trial,5 and that trial contributed 0.2 % of the weight to the mortality calculation . Industry-sponsored studies have been shown to report greater benefit and lesser adverse effects than noncommercially sponsored trials of the same drugs.6 Whether this is true for statins and primary prevention of CVD is unknown . Among the 19 r and omized clinical trials of statins vs placebo or no statin included in the evidence report for the task force recommendations , only 15 reported all-cause mortality , 10 reported cardiovascular mortality , 12 reported fatal and nonfatal myocardial infa rct ion  , and 13 reported fatal and nonfatal stroke.2,7  Reliance on selective reporting of the most important outcomes , which are likely included in the clinical trial data , makes reporting bias possible . Furthermore , after allcause mortality , the comparative incidence of serious adverse events between treatment and control groups is arguably the second most important measure of the effect of active therapy in r and omized clinical trials . Underst and ing the evidence base in evaluating harms of statin therapy is also critically important . Although the benefits of any preventive therapy accrue according to risk of disease ( greater benefit in higher-risk patients ) , the harms of therapy usually distribute equally over all risk levels . Thus , persons at low risk have little chance of benefit but equal chance of harms and thus are more likely to have a net harm . The evidence base for harms of statins , despite the introduction of these drugs more than 20 years ago , is incomplete . Many of the trials did not ask about commonly reported statin effects , such as muscle pains and weakness , and only recorded myopathy , for which an increase in creatine kinase levels was required . Because most muscle problems do not involve an increase in creatine kinase levels , this leads to a significant underestimate of muscle problems . Other studies have estimated that closer to 20 % of statin users have muscle problems.8 Additionally , the actual trial data are largely held by the Cholesterol Treatment Trialists ’ Collaboration on behalf of the industry sponsor and have not been made available to other research ers , despite multiple requests over many years.9 Although reported rates of adverse events in clinical trials are low , this does not reflect the experience of clinicians who see patients who are taking statins . For instance , the experience of an NPR reporter with a calculated 2.9 % risk of heart disease over 10 years using the recommended American College of Cardiology/American Heart Association ( ACC/AHA ) risk calculator,10 but still prescribed a statin , and experiencing adverse effects from the medication , is typical of what many Related articles at jama.com Abstract Aims : To estimate the costs , benefits and cost effectiveness , from the UK NHS perspective , of fluvastatin ( relative to no HMG-CoA reductase inhibitor [ statin ] ) for the secondary prevention of major adverse cardiac events following a successful first percutaneous coronary intervention ( PCI ) . Methods : A cost-effectiveness analysis was undertaken using efficacy data from the Lescol ® Intervention Prevention Study ( LIPS ) . LIPS was a r and omised , double-blind , placebo-controlled trial undertaken in 77 centres ( predominantly in Europe ) . Patients included in the trial had moderate hypercholesterolaemia and had successfully undergone their first PCI .  Fluvastatin ( Lescol ® ) 40 mg twice daily plus dietary counselling was given to the intervention group for up to 4 years ; the control group received dietary counselling only . A Markov model was used to estimate the incremental costs per QALY gained over a 10-year period , with cost data drawn from the UK NHS ( 2002 values ) . Monte Carlo simulations and multivariate analysis were used to assess uncertainty . Costs were discounted at 6 % per annum , and health outcomes at 1.5 % per annum . Results : On average , treatment with fluvastatin cost an additional £ 300 ( SD £ 303 ) [ € 423 ; SD € 428 ] per patient and result ed in an additional 0.092 ( SD 0.06 ) QALYs per patient over 10 years compared with controls . The incremental cost per QALY gained with fluvastatin versus the control group was £ 3207 ( SD £ 5497 ) [ € 4527 ; SD € 7759 ] . Fluvastatin was dominant ( better outcomes and lower costs ) in 15.9 % of the simulations and was dominated in 2.9 % . The key determinants of cost effectiveness were : the effectiveness of fluvastatin in reducing acute myocardial infa rct ion , subsequent PCI , coronary artery bypass graft and cardiac deaths ; the utility weight associated with a subsequent post-PCI state ; the cost  of fluvastatin ; and the time horizon evaluated . Conclusions : Fluvastatin is the only statin which has proven effective in preventing major coronary adverse events in new PCI patients ; other statins lack this evidence . This Markov model , with its underlying assumptions and data , suggests that fluvastatin is a viable and economically efficient pharmaceutical ( relative to no statin ) to reduce heart disease in the UK when given routinely to all patients following PCI Atrial  fibrillation ( AF ) is prevalent in the elderly , in patients with hypertension , and in patients with coronary artery disease ( CAD ) . We hypothesized that statin therapy might be effective in preventing AF in patients with CAD and examined this hypothesis in a sample of patients with chronic stable CAD without AF , followed prospect ively at a large outpatient cardiology practice . The association between statin use and the risk of developing AF was examined univariately and then with adjustment for potential confounding factors . Four hundred forty-nine men and women between the ages of 40 and 87 years were followed for an average of 5 years . Fifty-two patients ( 12 % ) developed AF during follow-up . Statin therapy was used by 59 % of the patients during the study period and was associated with a significantly reduced risk of developing AF ( crude odds ratio , 0.48 , 95 % confidence interval 0.28 to 0.83 ) . This association remained significant after adjustment for potential confounders , including age , hypertension , left ventricular systolic function , occurrence of heart failure or acute ischemic events , and baseline cholesterol and changes in cholesterol levels ( adjusted odds ratio 0.37 , 95 % confidence interval 0.18 to 0.76 ) . Use of  statins in patients with chronic stable CAD appears to be protective against AF . The underlying mechanism for this effect is unknown but appears to be independent of the reduction in serum cholesterol levels Abstract Objective : To determine the short-term healthcare costs associated with intensive lipid lowering with atorvastatin initiated within 24–96 hours of the occurrence of acute coronary syndrome ( ACS ) in patients in the UK . Methods : Patient-level clinical outcome data from the Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering ( MIRACL ) trial and st and ard cost data were used to compare the total expected 16-week cost per patient on atorvastatin 80 mg/day  versus placebo . Clinical outcomes assessed included the following : death ; cardiac arrest with resuscitation ; nonfatal myocardial infa rct ion ; worsening angina pectoris with objective evidence of myocardial ischaemia requiring rehospitalisation ; surgical or percutaneous coronary revascularisation ; nonfatal stroke ; hospitalisation for angina without objective evidence of myocardial ischaemia ; and new or worsening congestive heart failure requiring rehospitalisation . All relevant direct medical costs from the perspective of the NHS were considered . Results : The total expected cost was £ 784.05 per patient in the placebo cohort and £ 851.59 per patient in the atorvastatin cohort , result ing in an incremental cost of £ 67.54 per patient in the atorvastatin group . The cost per event avoided was £ 1762.04 . A third of the cost of atorvastatin treatment was offset within 16 weeks by the cost savings result ing from the reduction in the number of events in the atorvastatin cohort compared with the placebo cohort . Conclusion : The clinical benefits of short-term intensive atorvastatin treatment administered after ACS is attainable through a marginal increase in ‘ upfront ’ The study was aim ed to investigate the effect of two different statins on the levels of haemostatic variables reflecting procoagulant and fibrinolytic activity in patients with coronary heart disease ( CHD ) , with the hypothesis that statins might beneficially modify these levels . Fifty-eight patients were r and omized to treatment with atorvastatin ( n=28 ) or simvastatin  ( n=30 ) for 1 year . The starting dose in both groups was 20 mg/day . Fasting blood sample s were collected before and after 12-month treatment for determinations of fibrinogen , prothrombin fragment 1 + 2 ( F1 + 2 ) , plasma D-dimer , soluble tissue factor , tissue plasminogen activator ( tPA ) antigen , tPA activity , plasminogen activator inhibitor type-1 activity ( PAI-1 activity ) and serum D-dimer as a global test of fibrinolytic activity . In the total population , improved fibrinolytic activity was observed after 1 year with increased levels of serum D-dimer ( P=.001 ) and tPA activity ( P=.024 ) and a reduction in tPA antigen ( P=.048 ) . No statistically significant changes were observed in any of the measured coagulation variables . Separately examined , an improved fibrinolytic profile was seen in the atorvastatin group with a significant increase in serum D-dimer ( P=.005 ) , a borderline increase in tPA activity ( P=.083 ) and a borderline reduction in tPA antigen ( P=.069 ) . Within the simvastatin group , a reduction in prothrombin F1 + 2 was observed ( P=.038 ) . The differences in changes between the groups were statistically significant only for global fibrinolysis ( serum D-dimer , P=.046 ) . In conclusion , an improved fibrinolytic profile was observed after statin treatment , most pronounced with atorvastatin . The results indicate that the drugs promote a profibrinolytic profile , and may in part explain the benefit of statin treatment rendered in the prevention of CHD Objective The CARDS trial , a multicentre , r and omized , controlled trial , found that atorvastatin 10 mg/day for patients with type 2 diabetes mellitus and normal low-density lipoprotein (LDL)-cholesterol significantly reduced cardiovascular ( CV ) events , including stroke . We estimated the cost effectiveness of atorvastatin as primary prevention against CV disease from the short-term and lifetime US payer perspectives . Research design and methods We constructed a decision analytic ( Markov ) model to evaluate long-term costs and outcomes for atorvastatin 10 mg/day versus no HMG-CoA reductase inhibitor ( statin ) therapy for patients with type 2 diabetes and no history of a CV event .  CV event rates and survival were based on risk equations calibrated to CARDS and applied to a US type 2 diabetes population ; the atorvastatin effect on CV events was based on hazard ratios from CARDS ; direct medical care costs were based on US treatment patterns and published costs analyses of patients with diabetes . Costs were valued in $ US , year 2005 values ; costs and benefits were discounted at 3 % per annum . Results Within the time horizon of the trial ( 5 years ) , the cost effectiveness of atorvastatin was $ US137 276 per QALY . At 10 years , the incremental cost per QALY improved to $ US3640 per QALY . At 25 years , overall costs were lower and QALYs higher in the atorvastatin arm . Costs of managing CV events were lower after 5 years for patients treated with atorvastatin . Conclusions For patients with type 2 diabetes and one additional risk factor for CV disease , normal LDL-cholesterol and no history of a CV event , primary prevention with atorvastatin appears to be cost saving and improve outcomes over 25 years , although it is costly from a short-term US payer perspective . From both a medical and an economic viewpoint , primary prevention is desirable in this patient population OBJECTIVE To assess the cost-effectiveness of rosuvastatin in the treatment of hypercholesterolemia and the prevention of ischemic heart disease ( IHD ) in Portugal . METHODS A probabilistic Markov model was constructed to analyze the costs and consequences of lifetime treatment with rosuvastatin , atorvastatin , pravastatin , and simvastatin . For this purpose , the results from r and omized head-to-head trials evaluating low-density lipoprotein ( LDL ) changes were combined with the results from a meta- analysis defining the relationship between LDL levels and fatal and nonfatal IHD events . The incidence of myocardial infa rct ion ( MI ) was derived from a 9-year Portuguese observational study . The eligible population was defined as untreated individuals aged more than 35 years with LDL levels above 115 mg/dl .  Death rates due to IHD and other causes were obtained from official data . Re source use in the treatment of MI was estimated by a Delphi panel of eight Portuguese cardiologists with at least 15 years of clinical practice . Costs were calculated from the payers ' perspective . RESULTS Rosuvastatin  increases life expectancy between 5.5 and 12.1 days per patient . It is cost-saving when compared to atorvastatin , but it increases costs when assessed against pravastatin and simvastatin ( euro1,004 and euro684 per patient , respectively ) . Therefore , rosuvastatin is a dominant alternative compared to atorvastatin , having an incremental cost-effectiveness ratio of euro30,350 to pravastatin and euro39,340 to simvastatin . In the probabilistic sensitivity analysis , performed rosuvastatin always dominates atorvastatin and is associated with a cost per life-year gained inferior to euro50,000 in 95.7 % of the cases when compared to pravastatin and in 67.0 % simulations when assessed against simvastatin . CONCLUSIONS Rosuvastatin is a cost-effective alternative in the prevention of IHD in Portugal BACKGROUND Statins lower high-sensitivity C-reactive protein ( hsCRP ) and cholesterol concentrations , and hypothesis generating analyses suggest that clinical outcomes improve in patients given statins who achieve hsCRP concentrations less than 2 mg/L in addition to LDL cholesterol less than 1.8 mmol/L ( < 70 mg/dL ) . However , the benefit of lowering both LDL cholesterol and hsCRP after the start of statin therapy is controversial . We prospect ively tested this hypothesis . METHODS In an analysis of 15 548 initially healthy men and women participating in the JUPITER trial ( 87 % of full cohort ) , we prospect ively assessed the effects of rosuvastatin 20 mg versus placebo on rates of non-fatal myocardial infa rct ion , non-fatal stroke , admission for unstable angina , arterial revascularisation , or cardiovascular death ( prespecified endpoints ) during a maximum follow-up of 5 years ( median 1.9 years ) , according to on-treatment concentrations of LDL cholesterol ( > /=1.8 mmol/L or < 1.8 mmol/L ) and hsCRP ( > /=2 mg/L or < 2 mg/L ) . We included all events occurring after r and omisation . This trial is registered with Clinical Trials.gov , number NCT00239681 . FINDINGS Compared with placebo , participants allocated to rosuvastatin who achieved LDL cholesterol less than 1.8 mmol/L had a 55 % reduction in vascular events ( event rate 1.11 vs 0.51 per 100 person-years ; hazard ratio [ HR ] 0.45 , 95 % CI 0.34 - 0.60 , p<0.0001 ) , and those achieving hsCRP less than 2 mg/L a 62 % reduction ( event rate 0.42 per 100 person-years ; HR 0.38 , 95 % CI 0.26 - 0.56 , p<0.0001 ) . Although LDL cholesterol and hsCRP reductions were only weakly correlated in individual patients ( r values < 0.15 ) , we recorded a 65 % reduction in vascular events in participants allocated to rosuvastatin who achieved both LDL cholesterol less than 1.8 mmol/L and hsCRP less than 2 mg/L ( event rate 0.38 per 100 person-years ; adjusted HR 0.35 , 95 % CI 0.23 - 0.54 ) , versus a 33 % reduction in those who achieved one or neither target ( event rate 0.74 per 100 person-years ; HR 0.67 , 95 % CI 0.52 - 0.87 ) ( p across treatment groups < 0.0001 ) . In participants who achieved LDL cholesterol less than 1.8 mmol/L and hsCRP less than 1 mg/L , we noted a 79 % reduction ( event rate 0.24 per 100 person-years ; HR 0.21 , 95 % CI 0.09 - 0.52 ) . Achieved hsCRP concentrations were predictive of event rates irrespective of the lipid endpoint used , including the apolipoprotein B to apolipoprotein AI ratio . INTERPRETATION For people choosing to start pharmacological prophylaxis , reduction in both LDL cholesterol and hsCRP are indicators of successful treatment with rosuvastatin
Considering a reasonable WTP threshold , intermediate dose statin therapy is economically attractive , and should be a priority intervention in prevention of cardiovascular events in Brazil
BACKGROUND Statins have proven efficacy in the reduction of cardiovascular events , but the financial impact of its widespread use can be substantial .
OBJECTIVE To conduct a cost-effectiveness analysis of three statin dosing schemes in the Brazilian Unified National Health System ( SUS ) perspective .