Aspirin, Statins, or Both Drugs for the Primary Prevention of Coronary Heart Disease Events in Men: A CostUtility Analysis Cost-Effectiveness and Population Impact of Statins for Primary Prevention in Adults Aged 75 Years or Older in the United States Interactions between the single nucleotide polymorphisms in the homocysteine pathway (MTHFR 677C>T, MTHFR 1298 A>C, and CBSins) and the efficacy of HMG-CoA reductase inhibitors in preventing cardiovascular disease in high-risk patients of hypertension: the GenHAT study A cardiovascular disease policy model that predicts life expectancy taking into account socioeconomic deprivation Genetic variation at the LDL receptor and HMG-CoA reductase gene loci, lipid levels, statin response, and cardiovascular disease incidence in PROSPER. Cost-Effectiveness of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor Therapy in Older Patients with Myocardial Infarction The effect of nine common polymorphisms in coagulation factor genes (F2, F5, F7, F12 and F13) on the effectiveness of statins: the GenHAT study Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). A coronary primary intervention study of Japanese men: study design, implementation and baseline data. The Kyushu Lipid Intervention Study Group. Comparisons of effects of statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) on fasting and postprandial lipoproteins in patients with coronary heart disease versus control subjects. Risk Factors and Secondary Prevention in Women with Heart Disease: The Heart and Estrogen/progestin Replacement Study Continuation of statin treatment and all-cause mortality: a population-based cohort study. Beneficial impact of Xuezhikang on cardiovascular events and mortality in elderly hypertensive patients with previous myocardial infarction from the China Coronary Secondary Prevention Study (CCSPS). Cost-effectiveness of pravastatin in secondary prevention of coronary heart disease: comparison between Belgium and the United States of a projected risk model. Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study). HMG-coenzyme a reductase inhibitor use is associated with mortality reduction in hemodialysis patients. The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek atorvastatin and coronary heart disease evaluation (GREACE) study Association of Genetic Variants Related to CETP Inhibitors and Statins With Lipoprotein Levels and Cardiovascular Risk Benefit versus risk in statin treatment. Management of Dyslipidemia in Adults With Diabetes Shared decision-making following disclosure of coronary heart disease genetic risk: results from a randomized clinical trial Incorporating a Genetic Risk Score Into Coronary Heart Disease Risk Estimates: Effect on Low-Density Lipoprotein Cholesterol Levels (the MI-GENES Clinical Trial) Treatment with Atorvastatin to the National Cholesterol Educational Program Goal Versus 'Usual' Care in Secondary Coronary Heart Disease Prevention
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 Editors ' Notes Context Clinical guidelines provide conflicting recommendations about whether to prescribe statins in persons aged 75 years or older for primary prevention of unwanted cardiovascular outcomes . Contribution This study used information from clinical trials to model the tradeoffs between benefits and harms and found that using  statins  in all persons aged 75 to 94 years would prevent new myocardial infa rct ions and deaths from coronary heart disease at an acceptable cost . Caution Small increases in the frequency or severity of harms would negate the benefits . Implication Additional research is warranted to better underst and the tradeoffs between benefits and harms in this age group . Statins are commonly used in adults aged 75 years or older ( 1 ) . Despite their widespread use , evidence for their effectiveness for primary prevention in elderly adults is unclear , and guidelines for their use in this population are inconsistent . The recently published American College of Cardiology/American Heart Association ( ACC/AHA ) Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults gave limited recommendations for statin use for primary prevention in adults aged 75 years or older ( 2 ) , noting that few data were available to indicate an atherosclerotic cardiovascular disease event reduction benefit in primary prevention among individuals > 75 years of age who do not have clinical year atherosclerotic cardiovascular disease , and suggesting that comorbid conditions , safety , and priorities of care are recommended for joint provider and patient decision making . The American Medical Directors Association , a professional group of long-term care providers , recommended that statins not be routinely prescribed in adults aged 70 years or older as part of the American Board of Internal Medicine Choosing Wisely campaign ( 3 ) . This recommendation was based on the lack of an association between high cholesterol levels and outcomes in older adults as well as the potential for an increased risk for statin-related adverse events , including cognitive impairment , falls , neuropathy , and muscle damage ( 3 ) . The variation in these treatment recommendations reflects uncertainty about the balance between the benefits and risks of statin use in older adults compared with younger adults as well as the more limited evidence base in this population . Adults aged 75 years or older have been underrepresented in trials of statins for primary prevention , so the effectiveness of statins is less clear in this population . Results from observational studies suggest that the associations between low-density lipoprotein ( LDL ) cholesterol levels and outcomes are attenuated in older adults ( 47 ) . Although the baseline risk for cardiovascular disease is increased in older adults , their life expectancy is shorter and their risks for competing mortality are greater . Finally , there has been concern about geriatric-specific adverse effects , especially functional limitation due to muscle pain , weakness , and mild cognitive impairment ( 816 ) . In the presence of uncertainty about the riskbenefit tradeoff , computer simulations can provide estimates of the potential benefits of various treatment strategies as well as the costs and potential risk for harms . We evaluated the population benefit and cost-effectiveness of statins in persons aged 75 years or older without a history of cardiovascular disease in the United States . This investigation was conducted using the Cardiovascular Disease Policy Model ( CVDPM ) , a Markov model of the U.S. population ( 17 ) . We simulated the impact of statins for primary prevention based on treatment of the high-risk groups identified by the ACC/AHA guidelines , the associated costs , and potential harms that could offset the potential cardiovascular benefits in the U.S. population of adults aged 75 to 94 years over the next 10 years . Methods The Model The CVDPM is an established state-transition ( Markov ) model of the incidence , prevalence , mortality , and cost of CHD and stroke in U.S. residents aged 35 to 94 years ( 17 ) . The present study was limited to adults aged 75 to 94 years . The model comprises 3 components . First , the demographic-epidemiologic submodel estimates the incidence of coronary heart disease ( CHD ) ( cardiac arrest , myocardial infa rct ion [ MI ] , angina , or CHD death ) , ischemic stroke , and death from other causes on the basis of age , sex , systolic blood pressure , smoking , high-density lipoprotein and LDL cholesterol levels , diabetes , body mass index , and statin use . Second , the bridge submodel characterizes the initial CHD or stroke event and related events in the subsequent 30 days . Third , the disease-history submodel predicts the number of subsequent CHD and stroke events , revascularization procedures , and deaths among patients with cardiovascular disease , stratified according to age , sex , and history of cardiovascular disease events . In addition , persons may exit the model at any stage through a non-CHD , nonstroke mortality function , allowing for competing risk . Modifiable components of the model include population distributions , risk factor levels , risk factor coefficients , event rates , case-fatality rates , costs , and disability adjustments ( 17 ) . Costs for stroke requiring hospitalization , CHD , and acute stroke rehabilitation were estimated using California hospital data ( 18 ) and were deflated using costcharge ratios and the ratio of the U.S. national average costs to the California average ( 19 , 20 ) . Age- and sex-specific background health care costs were estimated using national data ( 21 ) . All model costs were inflated to 2014 costs by using the medical component of the Consumer Price Index ( 22 ) . All disability weights associated with the CHD and stroke event states were based on the Global Burden of Disease Study ( 23 , 24 ) . Additional details are provided in the Appendix . Simulation Inputs We modeled the effect of statins on LDL cholesterol level based on PROSPER ( Prospect i ve Study of Pravastatin in the Elderly at Risk of Vascular Disease ) , a r and omized , placebo-controlled trial of 5804 men and women aged 70 to 82 years ( 25 ) . In that trial , the mean reduction in LDL cholesterol level was 34 % for participants with an average initial level of 147 mg/dL , consistent with the estimated effect of a moderate-dose statin in the 2013 ACC/AHA guideline ( 2 ) . We included 3 estimates for the effectiveness of a decrease in LDL cholesterol level on events . The primary estimates were derived by extrapolating the age-stratified effect sizes of a 1.0-mmol/L reduction in LDL cholesterol level from the Cholesterol Treatment Trialists ' meta- analysis ( 26 ) . We fit a regression line to the 3 age strata reported in that analysis ( 60 years , > 60 to 70 years , and > 70 years ) to estimate the effect sizes at ages 80 and 90 years . In a sensitivity analysis , we used a high estimate based on the age-pooled estimate of effect of a 1.0-mmol/L reduction in LDL cholesterol level on major coronary events in the meta- analysis . We used a low estimate based on the effect size from PROSPER for primary prevention ( 25 ) . Statin costs were derived from the National Average Drug Acquisition Cost ( NADAC ) data base ( 27 ) . Our primary cost estimate ( $ 5.59 for a 30-day supply ) was the average of the NADAC costs for the 4 moderate-dose statins that are available in generic form : atorvastatin , 10 mg ; simvastatin , 20 mg ; pravastatin , 40 mg ; and lovastatin , 40 mg . This cost estimate was $ 5.00 when indexed to 2010 dollars based on the medical component of the Consumer Price Index ( 22 ) . In addition , we used a low cost estimate of $ 4 per month , based on the price of generic statins from multiple discount retailers ( such as Walmart , Target , and Walgreens ) . For a high cost estimate , we used $ 30 for a 30-day supply ; the low and high cost estimates have been used similarly in other contemporary cost-effectiveness analyses ( 28 , 29 ) . Adults aged 65 years or older use a median of 4 medications ; therefore , we estimated the cost of an additional 0.25 physician visit per year for statin use , assuming that medication management could be covered in 1 visit ( 30 , 31 ) . We estimated 1 lipid panel per year for monitoring ( 32 ) . Event rates for myopathy and hemorrhagic stroke were estimated as 0.001 per statin-year of use , based on the ACC/AHA guideline statement ( 2 ) . Although many major and minor adverse effects have been reported to be associated with statin use , we focused on 2 that are important to geriatric population s and that have generated concern in the scientific literature : functional limitation due to muscle pain and weakness , and mild cognitive impairment ( 816 ) . Both are prevalent in older adults and can have a substantial effect on quality of life and the ability to live independently . A recent review of late-life activity limitations in the United States reported data on participants in 5 nationally representative surveys . The prevalence of limitations in activities of daily living was 27 % in adults aged 75 to 84 years and 45 % in those aged 85 years or older ( 33 ) . The population -weighted average of these estimates is 32 % for adults aged 75 to 94 years . Widely varying prevalence estimates for mild cognitive impairment have been reported due to the differential measures of this condition and the differences between population s. A recent review reported prevalence of mild cognitive impairment of 19 % to 28 % in studies of older U.S. adults ; we used the average of the 4 U.S. studies , which was 25 % ( 34 ) . Disability-adjusted life-years for the corresponding states were calculated as 1 minus the disability weights reported in the Global Burden of Disease Study ( 24 ) . Because the statin-associated relative risk for these adverse effects is uncertain , we assumed no elevated risk for these adverse effects in our base-case scenario . The goal of this investigation was not to evaluate the strength of the literature regarding the presence of these adverse Background High homocysteine blood concentrations predispose to coronary artery disease and  statins influence homocysteine levels . Aim To study whether genes that regulate homocysteine metabolism interact with statins to modify the risk of coronary heart disease ( CHD ) and other cardiovascular outcomes . Methods The Genetics of Hypertension Associated Treatment is an ancillary study of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) . The genotyped population in the Lipid-Lowering Trial of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial included 9624 participants r and omly assigned to pravastatin or to usual care . The efficacy of pravastatin in reducing risk of all-cause mortality and CHD was compared among genotype strata ( MTHFR 677 CC , CT , and TT , MTHFR 1298 AA , AC , and CC , CBSins DD and I+ ) by examining an interaction term in a proportional hazards model . Results No evidence existed of a pharmacogenetic effect on statins with the MTHFR 1298 A > C genotype for CHD risk . However , in persons with the CC variant for the MTHFR 677 C > T genotype , a significantly protective effect against CHD [ 0.71 ( 95 % CI 0.58–0.87 ) ] was shown , although in the CT [ 1.25 ( 95 % CI 0.97–1.61 ) ] and TT groups [ 0.80 ( 95 % CI 0.50–1.28 ) ] there were no such effects ( interaction hazard ratio P=0.004 ) . The CBSins , I+ variant was associated with a significantly reduced risk for CHD among those on statin treatment [ 0.58 ( 95 % CI 0.44–0.78 ) ] whereas the DD genotype showed no effect of statin therapy [ 1.01 ( 95 % CI 0.84–1.20 ; P=0.002 for interaction ] . For the endpoint all-cause mortality , no significant differences in efficacy were noted . Conclusion Polymorphisms in genes in the homocysteine pathway ( MTHFR 677 C > T and CBSins ) appear to modify the efficacy of pravastatin  in reducing risk of cardiovascular events Objectives A policy model is a model that can evaluate the effectiveness and cost-effectiveness of interventions and inform policy decisions . In this study , we introduce a cardiovascular disease ( CVD ) policy model which can be used to model remaining life expectancy including a measure of socioeconomic deprivation as an independent risk factor for CVD . Design A state transition model was developed using the Scottish Heart Health Extended Cohort ( SHHEC ) linked to Scottish morbidity and death records . Individuals start in a CVD-free state and can transit to three CVD event states plus a non-CVD death state . Individuals who have a non-fatal first event are then followed up until death . Taking a competing risk approach , the cause-specific hazards of a first event are modelled using parametric survival analysis . Survival following a first non-fatal event is also modelled parametrically . We assessed discrimination , validation and calibration of our model . Results Our model achieved a good level of discrimination in each component ( c-statistics for men (women)—non-fatal coronary heart disease ( CHD ) : 0.70 ( 0.74 ) , non-fatal cerebrovascular disease ( CBVD ) : 0.73 ( 0.76 ) , fatal CVD : 0.77 ( 0.80 ) , fatal non-CVD : 0.74 ( 0.72 ) , survival after non-fatal CHD : 0.68 ( 0.67 ) and survival after non-fatal CBVD : 0.65 ( 0.66 ) ) . In general , our model predictions were comparable with observed event rates for a Scottish r and omised statin trial population which has an overlapping follow-up period with SHHEC . After applying a calibration factor , our predictions of life expectancy closely match those published in recent national life tables . Conclusions Our model can be used to estimate the impact of primary prevention interventions on life expectancy and can assess the impact of interventions on inequalities Our purpose was to evaluate associations of single nucleotide polymorphisms ( SNPs ) at the low density lipoprotein ( LDL ) receptor ( LDLR C44857 T , minor allele frequency ( MAF ) 0.26 , and A44964 G , MAF 0.25 , both in the untranslated region ) and HMG-CoA reductase ( HMGCR i18 T > G , MAF 0.019 ) gene loci with baseline lipid values , statin-induced LDL-cholesterol ( C ) lowering response , and incident coronary heart disease ( CHD ) and cardiovascular disease ( CVD ) on trial . Our population consisted of 5804 elderly men and women with vascular disease or one or more vascular disease risk factors , who were r and omly allocated to pravastatin or placebo .  Other risk factors and apolipoprotein ( apo ) E phenotype were controlled for in the analysis . Despite a prior report , no relationships with the HMGCR SNP were noted . For the LDLR SNPs C44857 T and A44964 G we noted significant associations of the rare alleles with baseline LDL-C and triglyceride levels , a modest association of the C44857 T with LDL-C lowering to pravastatin in men , and significant associations with incident CHD and CVD of both SNPs , especially in men on pravastatin . Our data indicate that genetic variation at the LDLR locus can affect baseline lipids , response to pravastatin , and CVD risk in subjects placed on statin treatment Recent large-scale r and omized , controlled trials of 3-hydroxy-3-methylglutaryl coenzyme A ( HMG-CoA ) reductase inhibitors ( statins ) have shown statistically significant reductions in cardiovascular events , strokes , and total mortality among selected groups , including patients with risk factors for vascular disease or a history of vascular disease ( 1 - 5 ) . In addition , cost-effectiveness analyses of the Sc and inavian Simvastatin Survival Study and the West of Scotl and Coronary Prevention Study have shown favorable cost-effectiveness ratios ( 6 , 7 ) . A limitation of the r and omized , controlled trials of statin therapy published to date , however , has been their failure to enroll patients older than 75 years of age . Ongoing r and omized , controlled trials are including patients in this age category , but results will not be available for some time ( 8 , 9 ) . Meanwhile , analyses of data from two secondary prevention trials , the Sc and inavian Simvastatin Survival Study and the Cholesterol and Recurrent Events ( CARE ) trial , have found that participants 65 to 70 years of age and those 65 to 75 years of age , respectively , experienced statistically significant reductions in cardiac end points similar to those seen in trial participants as a whole ( 10 , 11 ) . These results raise the prospect of extending the use of statins to patients older than 75 years of age with established coronary heart disease ( 12 ) . Although the issue of efficacy in patients older than 75 years of age will not be resolved definitively until trials of patients in this age group are published , decision-analytic models can test various assumptions about efficacy to gauge the potential cost-effectiveness of statins in this context . We modeled the cost-effectiveness of  statin therapy in a hypothetical cohort of patients 75 to 84 years of age with a history of myocardial infa rct ion by extrapolating results from published r and omized , controlled trials and epidemiologic data . Methods Model We compared two strategies for patients 75 to 84 years of age with previous myocardial infa rct ion :  usual care and initiation of HMG-CoA reductase inhibitor therapy . We developed a Markov model ( 13 ) and conducted a cohort simulation to track costs and health outcomes for hypothetical patients r and omly assigned to one of these strategies . In this model , patients can occupy one of six health states : baseline ( history of at least one myocardial infa rct ion ) , recurrent myocardial infa rct ion , postrecurrent myocardial infa rct ion , stroke , post-stroke , or dead ( Figure 1 ) . The model was not configured to deal with multiple events ( such as recurrent myocardial infa rct ion after stroke ) because such sequences of events occur infrequently enough to have a small effect on the overall analysis . Other health states , such as congestive heart failure , were not modeled explicitly but were averaged into the mortality estimates and quality -of-life weights . The model was constructed by using DATA 3.5 software ( TreeAge Software , Williamstown , Massachusetts ) . We adopted the societal perspective in all analyses . Figure 1 . Markov model . MI Transition Probabilities Each state of the model has an associated mortality rate that specifies the probability of dying in any given cycle ( Table 1 ) . These mortality rates were determined by using mortality risk ratios relative to all-cause mortality for an age-matched unselected population ; all-cause mortality rates were obtained from vital statistics data ( 14 ) . We chose to use mortality risk ratios ( multiplicative model ) rather than excess mortality ( additive model ) because a multiplicative model better captures how the risk for death from coronary heart disease changes with age ( 15 , 16 ) . Table 1 . Variables Governing Transition Probabilities for the Markov Model For purpose s of calibration , we initially created a two-state ( alive or dead ) Markov model , with mortality rates based on the 10-year survival curve after acute myocardial infa rct ion for patients 75 to 84 years of age ( 17 ) . The life expectancy of patients in the calibration model was then used as a benchmark to calibrate life expectancy for patients in the usual care strategy of the full six-state model . In the six-state model , we differentiated between death after recurrent myocardial infa rct ion or stroke and death from nonmyocardial infa rct ion or nonstroke causes because statins , by preventing both myocardial infa rct ion and stroke ( 2 ) , also prevent death after these events . Because patients with a history of myocardial infa rct ion have a higher chance of dying of coronary heart disease that is unrelated to recurrent myocardial infa rct ion ( for example , arrhythmia ) , this cohort has a higher risk for death from causes other than myocardial infa rct ion or stroke than does an unselected population . Long-term mortality after recurrent myocardial infa rct ion was adjusted upward to account for the additional risk for death after a recurrent event , on the basis of hazard ratios for coronary heart disease death as a function of nonfatal reinfa rct ion ( 18 ) . We converted these ratios into a hazard ratio for total mortality on the basis of data from the same trial indicating that coronary heart disease caused 76 % of deaths ( 19 ) and on the assumption of no excess risk for noncoronary heart disease death in patients with reinfa rct ion . Mortality rates after stroke were based on published data from the Oxfordshire Community Stroke Project ( 20 ) . Transition probabilities to recurrent myocardial infa rct ion or stroke from the baseline state are based on data describing reinfa rct ion rates ( 21 ) and stroke rates ( 22 , 23 ) . All of the data used to determine transition probabilities are population -based and specific to patients older than 75 years of age , with the exception of data from a clinical trial of patients up to 75 years of age ( 18 , 19 ) . We used data from a follow-up study of patients 65 to 75 years of age in the CARE trial to estimate the relative risk reduction conferred by statin therapy for the end points of myocardial infa rct ion ( fatal and nonfatal combined ) and stroke ( 11 ) . This study stratified patients in the CARE trial into those younger than 65 years of age and those 65 to 75 years of age and found that the latter group experienced statistically significant and clinical ly important reductions in cardiac and cerebrovascular events . Our base-case analysis used the mean estimates of relative risk reduction published in this study for patients 65 to 75 years of age , and the sensitivity analysis used the 95 % confidence limits . We applied risk reductions due to statin therapy to only two transitions out of the baseline state : recurrent myocardial infa rct ion and stroke . Because we did not explicitly model multiple strokes or recurrent myocardial infa rct ion , the model is based on the assumption that patients discontinue statin therapy after their first stroke or recurrent myocardial infa rct ion and no longer experience any additional costs or benefits of statin therapy . We also assumed that patients in the baseline state who are receiving statin therapy continue to accrue the benefits and costs associated with this therapy for the duration of their time in the baseline state . In a sensitivity analysis , we limited benefits of statin therapy to the first 5 years in the baseline state ; this time frame is similar to the duration of follow-up for the large r and omized , controlled trials of statin therapy ( 1 - 5 ) . Under this scenario , after 5 years , patients experience the same event rates and mortality rates as those not using statin therapy but continue to accrue the costs of drug while in the baseline state . This conservative analysis was conducted to examine the consequences of continuing to take a drug that in fact provides no additional benefit beyond the period for which it has been studied . Health-Related Quality of Life The model measured health effects in terms of quality -adjusted life expectancy . The health-related quality -of-life weights for the health states ( Table 2 ) were derived from time-tradeoff scores collected from patients with myocardial infa rct ion in the quality -of-life sub study of Global Use of Strategies to Open Occluded Coronary Arteries ( GUSTO-I ) ( 24 ) , which included patients older than 75 years of age . That study reported quality -of-life scores in patients who experienced various levels of disability from in-hospital stroke after myocardial infa rct ion and in patients who did not have a stroke . The quality -of-life weight ( utility ) for stroke was derived from the mean time-tradeoff utility for patients with ischemic stroke in GUSTO-I because these represent most nonfatal strokes . Bounds for sensitivity analysis were based on quality -of-life estimates approximately 1 SD from the mean . We also conducted a sensitivity analysis in which health states were not adjusted for quality -of-life differences . Table 2 . Utilities , Costs , and Discount Rate The base-case model assumed no disutility associated with statin use . This assumption was based on two studies of pravastatin that included patients older than 75 years of age and showed that pravastatin was well tolerated , with an incidence of adverse events similar to that of placebo ( 25 , 26 ) . However , because we know of no published studies of utilities in patients receiving statins , we performed a sensitivity analysis using a utility decrement of 0.013 in patients taking statins  . This number represents the utility decrement related to taking warfarin , a drug associated with considerably more inconvenience ( monthly laboratory monitoring ) , lifestyle modification , and risk than statins ( 27 ) . Costs In the base-case model , we included the following direct medical costs for both strategies : hospitalizations for nonfatal and fatal myocardial infa rct ion , hospitalizations for stroke , and post-stroke institutional care ( nursing home and rehabilitation ) . Patients in the  statin  group also experienced yearly drug costs and the cost of two additional office visits and two hepatic function Background Pharmacogenetic research has shown that genetic variation may influence statin responsiveness . Statins exert a variety of beneficial effects beyond lipid lowering , including antithrombotic effects , which contribute to the risk reduction of cardiovascular disease . Statins have been shown to influence the expression of coagulation factors II , V , VII , XII and XIII . Aim Data from a large r and omized clinical trial of pravastatin , design ed to show efficacy relative to usual care , were used to investigate whether a pharmacogenetic effect of polymorphisms in genes coding for coagulation factors II , V , VII , XII and XIII is associated with reduced fatal coronary heart disease ( CHD ) and nonfatal myocardial infa rct ion , combined CHD and all-cause mortality . Methods The Genetics of Hypertension Associated Treatment is an ancillary study of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial . The genotyped population in the lipid-lowering trial of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial included 9624 participants r and omly assigned to pravastatin or to usual care .  The efficacy of pravastatin in reducing risk of all-cause mortality , CHD and nonfatal myocardial infa rct ion and combined CHD , was compared among genotype strata by examining an interaction term in a proportional hazards model . Results None of the polymorphisms were associated with the clinical outcomes . For the F7 ( –323 ) ins/del polymorphism there was no interaction with pravastatin for either outcome . For both the F5 Arg506Gln G > A ( rs6025 ) polymorphism and F7 Arg353Gln G > A ( rs6046 ) polymorphism there were no interactions with pravastatin in relation to all-cause mortality , but there were significant interactions with combined CHD [ interaction hazard ratio = 1.33 , 95 % confidence interval ( 1.01–1.76 ) and interaction hazard ratio = 1.92 , 95 % confidence interval ( 1.00–3.65 ) , respectively ] . There were no interactions between the polymorphisms in the other coagulation genes and pravastatin in relation to any outcome . Conclusion Polymorphisms in anticoagulation genes ( F5 and F7 ) seem to modify the efficacy of  pravastatin in reducing risk of cardiovascular events CONTEXT Studies have demonstrated that statins administered to individuals with risk factors for coronary heart disease ( CHD ) reduce CHD events . However , many of these studies were too small to assess all-cause mortality or outcomes in important subgroups . OBJECTIVE To determine whether pravastatin compared with usual care reduces all-cause mortality in older , moderately hypercholesterolemic , hypertensive participants with at least 1 additional CHD risk factor . DESIGN AND SETTING Multicenter ( 513 primarily community-based North American clinical centers ) , r and omized , nonblinded trial conducted from 1994 through March 2002 in a subset of participants from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) . PARTICIPANTS Ambulatory persons ( n = 10 355 ) , aged 55 years or older , with low-density lipoprotein cholesterol ( LDL-C ) of 120 to 189 mg/dL ( 100 to 129 mg/dL if known CHD ) and triglycerides lower than 350 mg/dL , were r and omized to  pravastatin  ( n = 5170 ) or to  usual care  ( n = 5185 ) . Baseline mean total cholesterol was 224 mg/dL ; LDL-C , 146 mg/dL ; high-density lipoprotein cholesterol , 48 mg/dL ; and triglycerides , 152 mg/dL. Mean age was 66 years , 49 % were women , 38 % black and 23 % Hispanic , 14 % had a history of CHD , and 35 % had type 2 diabetes . INTERVENTION Pravastatin , 40 mg/d , vs usual care . MAIN OUTCOME MEASURES The primary outcome was all-cause mortality , with follow-up for up to 8 years . Secondary outcomes included nonfatal myocardial infa rct ion or fatal CHD ( CHD events ) combined , cause-specific mortality , and cancer . RESULTS Mean follow-up was 4.8 years . During the trial , 32 % of usual care participants with and 29 % without CHD started taking lipid-lowering drugs . At year 4 , total cholesterol levels were reduced by 17 % with pravastatin vs 8 % with usual care ; among the r and om sample who had LDL-C levels assessed , levels were reduced by 28 % with pravastatin vs 11 % with usual care .  All-cause mortality was similar for the 2 groups ( relative risk [ RR ] , 0.99 ; 95 % confidence interval [ CI ] , 0.89 - 1.11 ; P = .88 ) , with 6-year mortality rates of 14.9 % for pravastatin vs 15.3 % with usual care .  CHD event rates were not significantly different between the groups ( RR , 0.91 ; 95 % CI , 0.79 - 1.04 ; P = .16 ) , with 6-year CHD event rates of 9.3 % for pravastatin and 10.4 % for usual care . CONCLUSIONS Pravastatin did not reduce either all-cause mortality or CHD significantly when compared with usual care in older participants with well-controlled hypertension and moderately elevated LDL-C. The results may be due to the modest differential in total cholesterol ( 9.6 % ) and LDL-C ( 16.7 % ) between pravastatin and usual care compared with prior statin trials supporting cardiovascular disease prevention This report describes the design and baseline results of the Kyushu Lipid Intervention Study ( KLIS ) . The study aims to test the hypothesis that the long term reduction of serum total cholesterol by pravastatin will lead to a decrease in coronary heart disease ( CHD ) events . The trial was design ed to include a r and om 6,000 male patients aged 45 - 74 years with serum total cholesterol of 220 mg/dl ( 5.69 mmol/l ) or greater and without a history of myocardial infa rct ion , coronary surgery or angioplasty , to undertake either pravastatin or conventional treatment ( including hypolipidemic drugs other than HMG CoA reductase inhibitors , probucol and bezafibrate ) , and to follow up each patient for 5 years . Primary endpoints are fatal and nonfatal myocardial infa rct ion , coronary bypass surgery and angioplasty , cardiac death , and sudden and unexpected death . During the period from May 1990 to September 1993 , a total of 5,640 male patients aged 45 - 74 were recruited by 902 participating physicians throughout Kyushu . R and omization was , however , neglected by study physicians ; the numbers of patients enrolled were 3,061 in the pravastatin group and 2,579 in the conventional treatment group . Patients allocated to the pravastatin treatment were generally unfavorable regarding coronary risk factors . Baseline mean levels of serum total cholesterol were 259 mg/dl ( 6.70 mmol/l ) in the pravastatin group and 246 mg/dl ( 6.36 mmol/l ) in the conventional treatment group ( p < 0.001 ) . Although the trial was regarded as a prospect i ve observational study , the KLIS provides valuable quantitative data regarding cholesterol lowering and reduction in CHD events as well as safety data of the long-term use of a statin in Japanese men with hypercholesterolemia The effects of atorvastatin at 20 , 40 , and 80 mg/day on plasma lipoprotein subspecies were examined in a r and omized , placebo-controlled fashion over 36 weeks in 97 patients with coronary heart disease ( CHD ) with low-density lipoprotein ( LDL ) cholesterol levels of > 130 mg/dl and compared directly with the effects of fluvastatin ( n = 28 ) , pravastatin ( n = 22 ) , lovastatin ( n = 24 ) , and simvastatin ( n = 25 ) . The effects of placebo and 40 mg/day of each statin were also examined in subjects with CHD with subjects in the fasting state and in the fed state 4 hours after a meal rich in saturated fat and cholesterol and compared with results in age- and gender-matched control subjects . At all doses tested in the fasting and fed states , atorvastatin was significantly ( p < 0.01 ) more effective in lowering LDL cholesterol and non-high-density lipoprotein ( HDL ) cholesterol than all other statins , and significantly ( p < 0.05 ) more effective than all statins , except for simvastatin , in lowering triglyceride and remnant lipoprotein ( RLP ) cholesterol . At 40 mg/day in the fasting state , atorvastatin was significantly ( p < 0.01 ) more effective than all statins , except for lovastatin and simvastatin , in lowering cholesterol levels in small LDL , and was significantly ( p < 0.05 ) more effective than all statins , except for simvastatin , in increasing cholesterol in large HDL and in lowering LDL particle numbers . Our data indicate that atorvastatin was the most effective statin tested in lowering cholesterol in LDL , non-HDL , and RLP in the fasting and fed states , and getting patients with CHD to established goals , with fluvastatin , pravastatin , lovastatin , and simvastatin having about 33 % , 50 % , 60 % , and 85 % of the efficacy of atorvastatin , respectively , at the same dose in the same patients Context Risk factors for recurrent events among women with known coronary disease and whether these women commonly receive secondary prevention treatments are mostly unknown . Contribution This large cohort study showed that 11 different factors , including several previous infa rct ions , renal dysfunction , diabetes , angina , heart failure , and uncontrolled hypertension , predicted up to a sixfold increased rate of coronary disease events in postmenopausal women with preexisting coronary disblockers , angiotensin-converting enzyme inhibitors , or cholesterol-lowering drugs . Implication s Clinicians can identify women who have high risks for recurrent coronary events and should promote greater use of secondary prevention treatments for them . The Editors Coronary heart disease ( CHD ) is the leading cause of death in women . The major independent risk factors that predict CHD onset in healthy women are similar to those identified by epidemiologic studies of healthy men ( 1 - 7 ) . A recent report described six independent risk factorsage , low-density lipoprotein ( LDL ) and high-density lipoprotein ( HDL ) cholesterol levels , high blood pressure , diabetes mellitus , and smokingthat were strongly associated with risk for a first CHD event in both men and women ( 8) . However , the strength of the association of certain risk factors with CHD events may vary by sex ( 9 ) as well as age . Diabetes may be a stronger risk factor in women than in men ( 7 ) ; among older women , HDL cholesterol level may be a relatively strong risk factor and LDL cholesterol level a relatively weak one ( 6 ) . In the period immediately after myocardial infa rct ion ( MI ) , studies of mostly male sample s have found that persistent ischemia , impaired left ventricular systolic function , and ventricular arrhythmias are the major determinants of subsequent MI and death ( 10 - 13 ) . In the Coronary Drug Project study of men with a history of heart attack , electrocardiographic abnormalities and heart failure  were stronger predictors than the atherosclerosis risk factors identified in primary prevention setting s ( 14 ) . However , the risk factors for coronary events among women with recognized but stable coronary disease are mostly unknown . Better underst and ing of these factors could improve secondary prevention in this large and high-risk group . The Heart and Estrogen/progestin Replacement Study ( HERS ) was a r and omized clinical trial of estrogen plus progestin for prevention of CHD events in women with coronary disease ( 15 ) . Overall , no significant differences were noted between the hormone and placebo groups in CHD events ; trends of more CHD events with therapy in year 1 were offset by fewer such outcomes during years 4 and 5 . The trial collected extensive data on CHD risk factors and medication use and performed exhaustive outcome ascertainment procedures , with complete mortality follow-up . Therefore , HERS offers a unique opportunity to assess the long-term effect of coronary risk factors and use of recommended treatments in women with established coronary disease . Methods Participants Participants in HERS were postmenopausal women who were younger than 80 years of age , had not had a hysterectomy , and had known coronary artery disease ( MI , coronary artery bypass surgery , percutaneous transluminal coronary angioplasty , or angiographic evidence of 50 % narrowing of one or more major coronary arteries ) . Women were excluded if they had had a coronary event within the 6 months before r and omization , had a serum triglyceride level greater than 3.39 mmol/L ( 300 mg/dL ) , had used hormones within 3 months , or had a history of conditions that would contraindicate estrogen therapy ( 16 ) . Participants in HERS were r and omly assigned within clinical centers to 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate in one tablet daily ( n = 1380 ) or a placebo of identical appearance ( n = 1383 ) . The institutional review boards at the coordinating center and each of the 20 HERS clinical centers approved the protocol , and all participants provided written informed consent . Predictors In the baseline interview , information was obtained by self-report on demographic characteristics , behavioral risk factors , and medical history . Among women who reported ever having smoked at least 100 cigarettes , years of smoking , average cigarettes per day , and current smoking were ascertained . Alcohol use in the past 30 days was assessed for frequency and usual numbers of drinks per occasion .  Exercise  was measured as participation in a regular exercise program such as cardiac rehabilitation or aerobics or walking at least occasionally for exercise more than 10 minutes at a time . Use of  aspirin , -blockers , lipid-lowering medications ( statins , niacin , fibrates , bile acidbinding resins , and probucol ) , angiotensin-converting enzyme ( ACE ) inhibitors , calcium antagonists , and folate or vitamin B was assessed by self-report . In the baseline physical examination , blood pressure , waist-to-hip ratio , and body mass index were measured . A physician assessed history and symptoms of heart failure ( jugular venous distention , third heart sound , significant murmurs , pulmonary rales , and peripheral edema ) . High blood pressure was defined as systolic blood pressure greater than or equal to 140 mm Hg or diastolic blood pressure greater than or equal to 90 mm Hg , according to the Sixth Report of the Joint National Committee on Prevention , Detection , Evaluation and Treatment of High Blood Pressure ( 17 ) . Angina was defined as self-report of chest discomfort in the previous 4 weeks during exercise , emotion , or sexual activity . Serum specimens were obtained , and a central ized laboratory measured fasting levels of LDL cholesterol , HDL cholesterol , lipoprotein(a ) , triglycerides , glucose , and creatinine ( 15 , 16 ) . Creatinine clearance was estimated by using the CockcroftGault equation ( 18 , 19 ) . Outcomes The primary HERS outcome was CHD events , defined as nonfatal MI or CHD death . Suspected outcome events were reported within 24 hours to the coordinating center and were systematic ally assessed every 4 months at the follow-up contacts . An independent morbidity and mortality subcommittee that was blinded to treatment assignment adjudicated all deaths and suspected outcome events . Nonfatal MI was diagnosed by using an algorithm based on ischemic symptoms , electrocardiographic abnormalities , and elevated cardiac enzyme levels ( 16 ) . Death from CHD included fatal documented MI , sudden death within 1 hour of symptom onset , unobserved death that occurred out of the hospital in the absence of other known causes , or death due to a coronary revascularization procedure or congestive heart failure . The date of each event was determined from the documentation obtained by the clinical centers . The total number of events reported here is slightly larger than that published in the primary HERS results ( 15 ) because of subsequent adjudications ( 20 ) . Statistical Analyses We used multivariable Cox proportional-hazards models to assess the associations between risk factors and CHD events . These models were stratified by clinical center to account for potential clustering . Waist-to-hip ratio and LDL and HDL cholesterol levels were modeled as continuous variables , but lipoprotein(a ) level was dichotomized at the median and creatinine clearance was dichotomized at 0.66 mL/s ( 40 mL/min ) to reflect the nonlinear responses we have reported elsewhere ( 19 , 21 ) . We used an indicator for any alcohol use , since almost all of the 39 % of HERS women who reported alcohol use were light or moderate drinkers . Exercise was modeled by an indicator for participation in an exercise program or walking for exercise for more than 10 minutes . The multivariable model includes previously identified risk factors that were significant ( P 0.20 ) in unadjusted models and were not judged redundant on substantive grounds . Body mass index was excluded because it was clearly nonsignificant after adjustment ( P > 0.2 ) and was also highly correlated with waist-to-hip ratio , which was the stronger predictor in unadjusted analysis . Similarly , triglyceride levels were excluded because of their strong negative correlation with HDL cholesterol levels , which in our judgment were more likely to be causal . We also controlled for use of aspirin , statins , other lipid-lowering medications , diuretics , -blockers , ACE inhibitors , calcium antagonists , and folate or vitamin B. The effect of assignment to hormone therapy was modeled separately for each year of follow-up , as in the post hoc analysis of HERS ( 15 ) . Interactions between risk factors and relevant treatments were also examined . Specifically , we compared hazard rates among patients with diagnosed diabetes who reported use of insulin or oral hypoglycemic agents  with rates in the combined group of diabetic persons not using these medications and women with fasting glucose levels greater than 6.94 mmol/L ( > 125 mg/dL ) but no history of diabetes diagnosis . Likewise , we compared estimates for LDL and HDL cholesterol levels stratified by use of any lipid-lowering medication or assignment to hormone therapy ; for lipoprotein(a ) level , stratified by assignment to hormone therapy ; for high blood pressure on examination , stratified by use of at least one antihypertensive medication ; for heart failure and creatinine clearance less than or equal to 0.66 mL/s ( 40 mL/min ) , stratified by use of ACE inhibitors ; and for more than one previous MI and angina , stratified by use of any indicated medications . The final model includes interactions that were significant at a P value less than or equal to 0.2 . We used residuals to assess overall model fit , validity of the proportional hazards assumption , and linearity of associations with continuous predictors . The study lacked power to examine interactions between clinical center and potential risk factors . We tested the assumption of noninformative censoring by considering the two extremes of the possible outcomes BACKGROUND The beneficial effects of statins on cardiovascular mortality in secondary prevention have been established in several long-term , placebo-controlled trials . However , the value of statin therapy in reduction of overall mortality in patients without coronary heart disease ( CHD ) is question able . This study evaluated the effect of statin therapy in subjects with no indication of cardiovascular disease ( primary prevention ) and patients with known CHD ( secondary prevention ) . METHODS This retrospective cohort study included 229 918 adult enrollees in a health maintenance organization in Israel who initiated statin treatment from 1998 through 2006 ( mean age , 57.6 years ; 50.8 % female ) .  Proportion of days covered ( PDC ) with  statins  was measured by the number of dispensed  statin prescriptions during the interval between the date of the first statin prescription and the end of follow-up . RESULTS During a mean of 4.0 and 5.0 years of follow-up , there were 4259 and 8906 deaths among the primary prevention and secondary prevention cohorts , respectively . In both cohorts , continuity of treatment with statins ( PDC , > or = 90 % ) conferred at least a 45 % reduction in risk of death compared with patients with a PDC of less than 10 % . A stronger risk reduction was calculated among patients with high baseline low-density lipoprotein cholesterol level and patients initially treated with high-efficacy statins . CONCLUSIONS Better continuity of statin treatment provided an ongoing reduction in mortality among patients with and without a known history of CHD . The observed benefits from statins were greater than expected from r and omized clinical trials Coronary heart disease , hypertension , and dyslipidemia are highly prevalent and commonly coexist in people who are middle-aged and older . Previous data suggested that lowering cholesterol concentrations in individuals at high risk of cardiovascular disease improved clinical outcomes . Xuezhikang , a partial extract of red yeast rice containing statin , has a marked impact on lipids . The purpose of this study , therefore , was to evaluate the impact of Xuezhikang on reducing cardiovascular events and mortality in elderly Chinese hypertensive patients with a history of myocardial infa rct ion ( MI ) enrolled in the Chinese Coronary Secondary Prevention Study . In this r and omized trial , 1530 elderly hypertensive patients ( > or = 65-years-old ) with previous MI were assigned either to placebo ( n = 758 ) or to Xuezhikang ( n = 772 ) daily for an average of 4.5 years . The primary endpoint was recurrent coronary events ; the secondary endpoint was all-cause mortality and other clinical events , including adverse effects . There were 68 cases of coronary events ( 8.8 % ) detected in the Xuezhikang group and 108 cases ( 14.3 % ) in the placebo group ( 38.2 % risk reduction by Xuezhikang therapy ) . Death from coronary heart disease ( CHD ) totaled 49 cases in the Xuezhikang group ( 6.4 % ) and 68 cases in the placebo group ( 9.0 % ) , indicating that Xuezhikang significantly decreased the risk of CHD death by 29.2 % . Our study demonstrated that Xuezhikang therapy could effectively and safely reduce cardiovascular events and all-cause death in Chinese elderly hypertensive patients with previous MI . This finding may have an important implication for the treatment of elderly hypertensive patients with CHD Method ological differences and variations in health care regulations among countries often preclude direct comparisons of cost-effectiveness studies . A projected risk model was applied , design ed to determine the economic value in the United States of pravastatin in the secondary prevention of coronary heart disease ( CHD ) , to Belgium using local health care costs . A Markov process was used to model the effectiveness of treatment for 3 years with pravastatin versus placebo in 1000 male CHD patients aged 60 years and clinical ly similar to those in the pravastatin limitation of atherosclerosis in the coronary arteries ( PLAC I ) and pravastatin , lipids and atherosclerosis in the carotid arteries ( PLAC II ) studies . The PLAC I and II trials have shown that pravastatin treatment for 3 years at a weighted mean dose of 36.64 mg daily significantly reduced the incidence of non-fatal myocardial infa rct ion in patients with CHD . Framingham data were used to project the risk of mortality 10 years post-myocardial infa rct ion . The incremental cost per life year gained ( LYG ) , after discounting costs and benefits by 5 % annually , in the setting of Belgian health care regulations , was Belgian francs ( BEF ) 720794 ( US$ 24359 ) for CHD patients with one additional risk factor ; BEF 526464 ( US$ 17792 ) for those with two additional risk factors ; and BEF 392765 ( US$ 13274 ) for those with three or more additional risk factors . The cost per LYG in Belgium appeared to be more sensitive to drug acquisition cost than to costs of medical interventions . The cost-effectiveness ratios of pravastatin monotherapy for 3 years in secondary prevention of CHD , obtained with the same projected risk model , are from 86 to 92 % higher in Belgium than in the United States , due to differences in medical patterns of practice and in intervention costs International guidelines recommend lower target cholesterol levels and treatment of low high-density lipoprotein cholesterol ( HDL-C ) and elevated triglycerides for patients at moderately high to high coronary heart disease ( CHD ) risk . Combination therapy is often required to achieve multiple lipid treatment goals , and > or = 50 % reduction in low-density lipoprotein cholesterol ( LDL-C ) is needed in some patients to achieve aggressive LDL-C targets . In this context , we evaluated comparative effects on lipid levels of combination therapy at low to moderate doses with a statin plus extended-release niacin ( niacin ER ) , a statin plus ezetimibe , and a highly potent statin alone . This was an open-label , multicenter , 12-week study in 292 patients ( 50 % women ) who qualified for drug therapy based on number of CHD risk factors . Patients were r and omized to four parallel arms , titrated from low to moderate or high doses : atorvastatin/niacin ER , rosuvastatin/niacin ER , simvastatin/ezetimibe , or rosuvastatin alone . Baseline mean values were , for LDL-C 197 mg/dL ( 5.1 mmol/L ) , HDL-C 49 mg/dL ( 1.3 mmol/L ) , triglycerides 168 mg/dL ( 1.9 mmol/L ) . There were no significant differences among treatment groups in the change from baseline in LDL-C at pre-specified timepoints during treatment . All groups lowered LDL-C by approximately 50 % or more ( range -49 to -57 % ) , achieving mean levels of 82 - 98 mg/dL ( 2.1 - 2.5 mmol/L ) . Changes in non-HDL-C ( range -46 to -55 % ) mirrored those for LDL-C and did not differ among treatment groups . Statin/niacin ER combination regimens also increased HDL-C and large HDL ( HDL2 ) and lowered triglycerides and lipoprotein ( a ) significantly more than other regimens . No drug-related myopathy or hepatotoxicity was observed . In this study , low to moderate dose combination therapy with a statin and niacin ER provided broad control of lipids and lipoproteins independently associated with CHD BACKGROUND Cardiovascular disease is the most common cause of mortality in patients with end-stage renal disease . Cardiovascular benefits of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ( statins ) have been clearly established in the general population , but not in dialysis patients . This study examined statin prescription patterns and assessed the relationship between statin prescription and clinical outcomes in hemodialysis ( HD ) patients . METHODS Data were analyzed from the Dialysis Outcomes and Practice Patterns Study , a prospect i ve observational study of HD patients r and omly selected from representative dialysis facilities in France , Germany , Italy , Spain , the United Kingdom , Japan , and the United States . Predictors of statin prescription were investigated by means of logistic regression . Cox regression models tested the association between statin prescription and risk for mortality and cardiac events , with adjustments for common demographic factors and comorbid conditions . RESULTS Statins were prescribed for 11.8 % of HD patients overall . Most facilities ( 81.2 % ) prescribed statins to less than 20 % of their patients . Patients prescribed statins had a 31 % lower relative risk for death compared with those not prescribed statins ( P < 0.0001 ) . Statins were associated with a 23 % lower cardiac mortality risk ( P = 0.03 ) and a 44 % lower noncardiac mortality risk ( P < 0.0001 ) . At a facility level , prescribing statins was associated with lower overall mortality rate , with a 5 % lower risk for every 10 % increase in number of patients prescribed statins within the facility ( P = 0.02 ) . CONCLUSION Statin prescription is associated with reduced mortality in HD patients , providing additional support for the value of statin therapy in this patient group Background : Little is known about statins in the prevention of  dyslipidaemia induced renal function decline . The secondary coronary heart disease ( CHD ) prevention GREACE study suggested that dose titration with atorvastatin ( 10–80 mg/day , mean dose 24 mg/day ) achieves the national cholesterol educational programme treatment goals and significantly reduces morbidity and mortality , compared with usual care . Aims : To report the effect of statin on renal function compared with untreated dyslipidaemia in both treatment groups . Methods / Results : All patients had plasma creatinine values within the reference range < 115 µmol/litre ( 13 mg/litre ) .  The on study creatinine clearance ( CrCl ) , as estimated ( for up to 48 months ) by the Cockroft-Gault formula , was compared within and between treatment groups using analysis of variance to assess differences over time . Patients from both groups not treated with statins ( 704 ) showed a 5.2 % decrease in CrCl ( p < 0.0001 ) . Usual care patients on various statins ( 97 ) had a 4.9 % increase in CrCl ( p = 0.003 ) . Structured care patients on atorvastatin ( 783 ) had a 12 % increase in CrCl ( p < 0.0001 ) . This effect was more prominent in the lower two quartiles of baseline CrCl and with higher atorvastatin doses . After adjustment for 25 predictors of all CHD related events , multivariate analysis revealed a hazards ratio of 0.84 ( confidence interval 0.73 to 0.95 ; p = 0.003 ) with every 5 % increase in CrCl . Conclusions : In untreated dyslipidaemic patients with CHD and normal renal function at baseline , CrCl declines over a period of three years . Statin treatment prevents this decline and significantly improves renal function , potentially off setting an additional factor associated with CHD risk Importance Some cholesteryl ester transfer protein ( CETP ) inhibitors lower low-density lipoprotein cholesterol ( LDL-C ) levels without reducing cardiovascular events , suggesting that the clinical benefit of lowering LDL-C may depend on how LDL-C is lowered . Objective To estimate the association between changes in levels of LDL-C ( and other lipoproteins ) and the risk of cardiovascular events related to variants in the CETP gene , both alone and in combination with variants in the 3-hydroxy-3-methylglutaryl-CoA reductase ( HMGCR ) gene . Design , Setting , and Participants Mendelian r and omization analyses evaluating the association between CETP and HMGCR scores , changes in lipid and lipoprotein levels , and the risk of cardiovascular events involving 102 837 participants from 14 cohort or case-control studies conducted in North America or the United Kingdom between 1948 and 2012 . The associations with cardiovascular events were externally vali date d in 189 539 participants from 48 studies conducted between 2011 and 2015 . Exposures Differences in mean high-density lipoprotein cholesterol ( HDL-C ) , LDL-C , and apolipoprotein B ( apoB ) levels in participants with CETP scores at or above vs below the median . Main Outcomes and Measures Odds ratio ( OR ) for major cardiovascular events . Results The primary analysis included 102 837 participants ( mean age , 59.9 years ; 58 % women ) who experienced 13 821 major cardiovascular events . The validation analyses included 189 539 participants ( mean age , 58.5 years ; 39 % women ) with 62 240 cases of coronary heart disease ( CHD ) . Considered alone , the CETP score was associated with higher levels of HDL-C , lower LDL-C , concordantly lower apoB , and a corresponding lower risk of major vascular events ( OR , 0.946 [ 95 % CI , 0.921 - 0.972 ] ) that was similar in magnitude to the association between the HMGCR score and risk of major cardiovascular events per unit change in levels of LDL-C ( and apoB ) . When combined with the HMGCR score , the CETP score was associated with the same reduction in LDL-C levels but an attenuated reduction in apoB levels and a corresponding attenuated nonsignificant risk of major cardiovascular events ( OR , 0.985 [ 95 % CI , 0.955 - 1.015 ] ) . In external validation analyses , a genetic score consisting of variants with naturally occurring discordance between levels of LDL-C and apoB was associated with a similar risk of CHD per unit change in apoB level ( OR , 0.782 [ 95 % CI , 0.720 - 0.845 ] vs 0.793 [ 95 % CI , 0.774 - 0.812 ] ; P = .79 for difference ) , but a significantly attenuated risk of CHD per unit change in LDL-C level ( OR , 0.916 [ 95 % CI , 0.890 - 0.943 ] vs 0.831 [ 95 % CI , 0.816 - 0.847 ] ; P < .001 ) compared with a genetic score associated with concordant changes in levels of LDL-C and apoB. Conclusions and Relevance Combined exposure to variants in the genes that encode the targets of CETP inhibitors and statins was associated with discordant reductions in LDL-C and apoB levels and a corresponding risk of cardiovascular events that was proportional to the attenuated reduction in apoB but significantly less than expected per unit change in LDL-C. The clinical benefit of lowering LDL-C levels may therefore depend on the corresponding reduction in apoB-containing lipoprotein particles The Statin Safety Assessment Conference of the National Lipid Association ( NLA ) , reported in this supplement to The American Journal of Cardiology , provides a comprehensive evaluation of old and new experience on adverse events associated with the 3-hydroxy-3-methylglutaryl coenzyme A ( HMG-CoA ) reductase inhibitors , or statins . To place these in context , one can express both the risk of side effects and the benefits for cardiovascular disease in terms of events per person-year of statin treatment . The mortality risk from fatal rhabdomyolysis is approximately 0.3 per 100,000 person-years , and the risks of nonfatal rhabdomyolysis and of putative statin-attributable peripheral neuropathy are approximately 3 and 12 events , respectively , per 100,000 person-years . Reports of acute liver failure and acute or chronic kidney disease give lower rate estimates that , even when corrected for underreporting , are approximately equal to the background rates of these conditions in the general population , lending scant support for statin-attributable etiology . In contrast , the benefit of statin use is to avert several hundred deaths and several hundred cases each of heart and brain infa rct ion per 100,000 person-years in appropriately treated high-risk patients . Although population estimates such as these are useful , they must be translated repeatedly to individual patient-provider encounters , where clinical skill and art must combine with scientific evidence . The continued publication of individual case reports and small r and omized trials among groups of patients with potential side effects should be encouraged . Statins should not be used in situations where minimal benefit is expected , as safety data and risk-benefit analysis must be meshed with guidelines that help the clinician decide whom to treat and how aggressively to treat Subjects with diabetes have a greatly increased risk of CHD , which is only partially related to their elevated glucose . Other factors such as insulin resistance and dyslipidemia are likely to be important . The type of dyslipidemia that is most characteristic of type 2 diabetic subjects is elevated triglycerides and decreased HDL cholesterol levels , although all lipoproteins have compositional abnormalities . Surprisingly few good prospect i ve studies of lipoprotein levels in relation to CHD have been done in diabetic subjects . Available studies suggest that low HDL cholesterol may be the most important risk factor for CHD in observational studies . In studies in which total cholesterol and triglyceride were done , cholesterol and triglycerides were risk factors for CHD , although triglycerides were often a stronger predictor . However , the strength of triglyceride as a risk factor for CHD may depend partially on its association with other variables ( e.g. , hypertension , plasminogen activator inhibitor 1 [ PAI-1 ] , etc . ) . In clinical trials in diabetic subjects , LDL reduction with statins has led to significant reductions in CHD incidence . In addition , overall mortality was reduced with statin therapy , although the results were not statistically significant . Gemfibrozil has led to reductions in CHD incidence in diabetic subjects , although the results were not statistically significant perhaps because of low sample size . Regarding lipoproteins and CHD risk in diabetic patients , the very positive results of statin trials point to LDL cholesterol being more important than previous realized . Apparently , having a borderline high LDL cholesterol ( between 130 and 160 mg/dl ) in a diabetic patient is equivalent to a much higher LDL cholesterol in terms of CHD risk for a nondiabetic subject . Therefore , the primary target of therapy in diabetic patients is lowering LDL cholesterol ( or possibly , non-HDL cholesterol ) .  Statins are the preferred pharmacological agent in this situation . Once LDL cholesterol levels have been lowered , attention can be given to treatment of residual hypertriglyceridemia and low HDL . The goal here is weight reduction and increased exercise . However , for selected patients , combining a fibric acid ( or low-dose nicotinic acid ) with a statin also can be considered . Reduction of LDL levels should take priority over reduction of triglycerides in combined hyperlipidemia because of the proven safety of the statin class of drugs as well as greater reduction in CHD incidence Whether disclosure of genetic risk for coronary heart disease ( CHD ) influences shared decision-making ( SDM ) regarding use of statins to reduce CHD risk is unknown . We r and omized 207 patients , age 45–65 years , at intermediate CHD risk , and not on statins , to receive the 10-year risk of CHD based on conventional risk factors alone ( n=103 ) or in combination with a genetic risk score ( n=104 ) . A genetic counselor disclosed this information followed by a physician visit for SDM regarding statin therapy . A novel decision aid was used in both encounters to disclose the CHD risk estimates and facilitate SDM regarding statin use . Patients reported their decision quality and physician visit satisfaction using vali date d surveys . There were no statistically significant differences between the two groups in the SDM score , satisfaction with the clinical encounter , perception of the quality of the discussion or of participation in decision-making and physician visit satisfaction scores . Quantitative analyses of a r and om subset of 80 video-recorded encounters using the OPTION5 scale also showed no significant difference in SDM between the two groups . Disclosure of CHD genetic risk using an electronic health record-linked decision aid did not adversely affect SDM or patients ’ satisfaction with the clinical encounter . Trial registration number NCT01936675 ; Results Background — Whether knowledge of genetic risk for coronary heart disease ( CHD ) affects health-related outcomes is unknown . We investigated whether incorporating a genetic risk score ( GRS ) in CHD risk estimates lowers low-density lipoprotein cholesterol ( LDL-C ) levels . Methods and Results — Participants ( n=203 , 45–65 years of age , at intermediate risk for CHD , and not on statins ) were r and omly assigned to receive their 10-year probability of CHD based either on a conventional risk score ( CRS ) or CRS + GRS ( + GRS ) . Participants in the + GRS group were stratified as having high or average/low GRS . Risk was disclosed by a genetic counselor followed by shared decision making regarding statin therapy with a physician . We compared the primary end point of LDL-C levels at 6 months and assessed whether any differences were attributable to changes in dietary fat intake , physical activity levels , or statin use . Participants ( mean age , 59.4±5 years ; 48 % men ; mean 10-year CHD risk , 8.5±4.1 % ) were allocated to receive either CRS ( n=100 ) or + GRS ( n=103 ) . At the end of the study period , the + GRS group had a lower LDL-C than the CRS group ( 96.5±32.7 versus 105.9±33.3 mg/dL ; P=0.04 ) . Participants with high GRS had lower LDL-C levels ( 92.3±32.9 mg/dL ) than CRS participants ( P=0.02 ) but not participants with low GRS ( 100.9±32.2 mg/dL ; P=0.18 ) . Statins  were initiated more often in the + GRS group than in the CRS group ( 39 % versus 22 % , P<0.01 ) . No significant differences in dietary fat intake and physical activity levels were noted . Conclusions — Disclosure of CHD risk estimates that incorporated genetic risk information led to lower LDL-C levels than disclosure of CHD risk based on conventional risk factors alone . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT01936675 Summary Background : Atorvastatin is very effective in reducing plasma low-density lipoprotein cholesterol ( LDL-C ) levels . However , there is no long-term survival study that evaluated this statin . Patients − Methods : To assess the effect of atorvastatin on morbidity and mortality ( total and coronary ) of patients with established coronary heart disease ( CHD ) , 1600 consecutive patients were r and omised either to  atorvastatin  or to  ' usual ' medical care . The dose of atorvastatin was titrated from 10 to 80mg/day , in order to reach the National Cholesterol Education Program ( NCEP ) goal of LDL-C < 100mg/dl ( 2.6mmol/l ) . All patients were followed up for a mean period of 3 years . Main Outcome Measures : Primary endpoints of the study were defined as death , non-fatal myocardial infa rct ion , unstable angina , congestive heart failure , revascularisation ( coronary morbidity ) and stroke . Secondary endpoints were the safety and efficacy of the hypolipidaemic drugs as well as the cost-effectiveness of atorvastatin . Results : The mean dosage of atorvastatin was 24 mg/day . This statin reduced total cholesterol by 36 % , LDL-C by 46 % , triglycerides by 31 % , and non-high-density lipoprotein cholesterol ( non-HDL-C ) by 44 % , while it increased HDL-C by 7 % ; all these changes were significant . The NCEP LDL-C and non-HDL-C treatment goals were reached by 95 % ( n = 759 ) and 97 % ( n = 776 ) , respectively , of patients on atorvastatin . Only 14 % of the ' usual ' care patients received any hypolipidaemic drugs throughout the study and 3 % of them reached the NCEP LDL-C treatment goal . The cost per quality -adjusted life-year gained with atorvastatin was estimated at $ US 8350 . During this study 196 ( 24.5 % ) CHD patients on ' usual ' care had a CHD recurrent event or died vs. 96 ( 12 % ) CHD patients on atorvastatin ; risk ratio ( RR ) 0.49 , confidence interval ( CI ) 0.27 - 0.73 , p < 0.0001 . In detail , atorvastatin reduced , in comparison to ' usual ' care , total mortality ( RR 0.57 , CI 0.39 - 0.78 , p = 0.0021 ) , coronary mortality ( RR 0.53 , CI 0.29 - 0.74 , p = 0.0017 ) , coronary morbidity ( RR 0.46 , CI 0.25 - 0.71 , p < 0.0001 ) , and stroke ( RR 0.53 , CI 0.30 - 0.82 , p = 0.034 ) . All subgroups of patients ( women , those with diabetes mellitus , arterial hypertension , age 60 to 75 years , congestive heart failure , recent unstable angina or prior revascularisation ) benefited from treatment with atorvastatin . Withdrawal of patients because of side-effects from the atorvastatin group was low ( 0.75 % ) and similar to that of the ' usual ' care group ( 0.4 % ) . Conclusions : Long-term treatment of CHD patients with atorvastatin  to achieve NCEP lipid targets significantly reduces total and coronary mortality , coronary morbidity and stroke , in comparison to patients receiving ' usual ' medical care . Treatment with atorvastatin is well tolerated and cost-effective
At costs lower than $ 0.10 per pill , treating all persons with LDL cholesterol levels greater than 3.4 mmol/L ( > 130 mg/dL ) could be a better strategy .
Previous cost-effectiveness analyses ( 719 ) show that statin therapy is generally cost-effective for secondary prevention and for high-risk primary prevention but do not focus on population -level impact or average cost-effectiveness across the heterogeneous U.S. population , including such subgroups of patients as those with low risk but very high cholesterol levels .
Also , it is unclear whether the ATP III approach to risk stratification , in which risk is formally assessed only for patients with 2 or more established risk factors , is the simplest and most cost-effective way of targeting statin therapy .
The 2004 up date to ATP III ( 3 ) notes that treatment of high-risk subgroups may be useful even when cholesterol levels are low , which suggests that a more purely risk-based approach may be simpler and more cost-effective than the ATP III approach .
Context Which lipid-lowering policies with statins are cost-effective ?
Implication Optimum policies for lipid lowering with statins are highly dependent on statin costs .
The Editors Coronary heart disease ( CHD ) is the leading cause of death in the United States ( 1 ) .
Inhibitors of HMG-CoA reductase , known as statins , lower cholesterol and prevent CHD events and mortality ( 2 , 3 ) .
However , statins are expensive and sometimes cause side effects , which makes it difficult for patients , physicians , and policymakers to decide who should receive them .
The CHD Policy Model is a mathematical state-transition model of CHD in the United States that can be used to project event rates and costs related to CHD .