The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. The effect of nine common polymorphisms in coagulation factor genes (F2, F5, F7, F12 and F13) on the effectiveness of statins: the GenHAT study Aspirin, Statins, or Both Drugs for the Primary Prevention of Coronary Heart Disease Events in Men: A CostUtility Analysis Risk Factors and Secondary Prevention in Women with Heart Disease: The Heart and Estrogen/progestin Replacement Study Effect of pravastatin-induced LDL-cholesterol reduction on coronary heart disease and cerebrovascular disease in Japanese: Hokuriku lipid coronary heart disease study-pravastatin atherosclerosis trial (Holicos-PAT). Rationale and design for the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT Research Group. Implementation of case management to reduce cardiovascular disease risk in the Stanford and San Mateo Heart to Heart randomized controlled trial: study protocol and baseline characteristics HMG CoA reductase inhibition and endothelial function in children with chronic kidney disease (CKD) – a pilot study Management of Dyslipidemia in Adults With Diabetes 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 Coronary Angiographic Changes with Lovastatin Therapy: The Monitored Atherosclerosis Regression Study (MARS) Ten-year all-cause mortality in presumably healthy subjects on lipid-lowering drugs (from the Prospective Epidemiological Study of Myocardial Infarction [PRIME] prospective cohort). Effects of health advocacy, counseling, and activation among older coronary heart disease (CHD) patients 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 heart disease prediction model: the Korean Heart Study A coronary primary intervention study of Japanese men: study design, implementation and baseline data. The Kyushu Lipid Intervention Study Group. Effectiveness of an intervention designed to optimize statins use: a primary prevention randomized clinical trial
The Lipid Research Clinics Coronary Primary Prevention Trial ( LRC-CPPT ) , a multicenter , r and omized , double-blind study , tested the efficacy of cholesterol lowering in reducing risk of coronary heart disease ( CHD ) in 3,806 asymptomatic middle-aged men with primary hypercholesterolemia ( type II hyperlipoproteinemia ) . The treatment group received the bile acid sequestrant cholestyramine resin and the control group received a placebo for an average of 7.4 years . Both groups followed a moderate cholesterol-lowering diet . The cholestyramine group experienced average plasma total and low-density lipoprotein cholesterol ( LDL-C ) reductions of 13.4 % and 20.3 % , respectively , which were 8.5 % and 12.6 % greater reductions than those obtained in the placebo group . The cholestyramine group experienced a 19 % reduction in risk ( p less than .05 ) of the primary end point -- definite CHD death and /or definite nonfatal myocardial infa rct ion -- reflecting a 24 % reduction in definite CHD death and a 19 % reduction in nonfatal myocardial infa rct ion . The cumulative seven-year incidence of the primary end point was 7 % in the cholestyramine group v 8.6 % in the placebo group . In addition , the incidence rates for new positive exercise tests , angina , and coronary bypass surgery were reduced by 25 % , 20 % , and 21 % , respectively , in the cholestyramine group . The risk of death from all causes was only slightly and not significantly reduced in the cholestyramine group . The magnitude of this decrease ( 7 % ) was less than for CHD end points because of a greater number of violent and accidental deaths in the cholestyramine group . The LRC-CPPT findings show that reducing total cholesterol by lowering LDL-C levels can diminish the incidence of CHD morbidity and mortality in men at high risk for CHD because of raised LDL-C levels . This clinical trial provides strong evidence for a causal role for these lipids in the pathogenesis of CHD 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 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 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 The purpose of Holicos-PAT was to investigate the efficacy of serum lipid lowering by pravastatin against coronary heart disease ( CHD ) and cerebrovascular disease ( CVD ) in the Japanese population . Hypercholesterolemic men and women ( n = 2,232 ) , aged 40 - 70 years , were followed up for 5 years , while they were receiving pravastatin ( group P , n = 1,422 ) or only diet therapy ( group C , n = 810 ) . The primary endpoint was CHD ( a composite of onset or worsening of angina pectoris , performing CABG or PTCA , non-fatal myocardial infa rct ion , death from CHD including heart death or sudden death ) . The secondary endpoints were comprised of CVD , total mortality , variation of serum lipid and apoprotein levels , and a relationship between the LDL-C level and occurrence of CHD . For several reasons ( proving to meet the exclusion criteria after registration , etc . ) , 1,290 cases of group P and 749 cases of group C were used as subjects for the primary analysis . The mean follow-up period was 4.5 years in group P and 4.2 years in group C for events of CHD . The mean LDL-C level ( SD ) in group P was 176 ( 29 ) mg/dl and decreased to 134 ( 29 ) mg/dl one year later . This effect continued during the follow-up period . CHD events occurred in 9.2/1000 patient-years for men and 2.4/1000 patient-years for women without a history of CHD.CHD events occurred in 55.3/1000 patient-years for men and 23.6/1000 patient-years for women with a history of CHD , which was 6 times higher in men and 10 times higher in women than in those without a history of CHD , respectively . The adjusted relative risk ratio of group P to group C for CHD events was 0.74 ( 95%CI : 0.47 - 1.19 ) . In the patients with a history of CHD , the ratio was 0.55 ( 95%CI : 0.30 - 1.00 ) . The effect was apparent in the patients with a history of CHD . The incidence of myocardial infa rct ion in Japanese patients with hypercholesterolemia living in the Hokuriku district was apparently lower , than the worldwide incidence , indicative that pravastatin may have a tendency to inhibit the occurrence of events of arteriosclerotic disease Are newer types of antihypertensive agents , which are currently more costly to purchase on average , as good or better than diuretics in reducing coronary heart disease incidence and progression ? Will lowering LDL cholesterol in moderately hypercholesterolemic older individuals reduce the incidence of cardiovascular disease and total mortality ? These important medical practice and public health questions are to be addressed by the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) , a r and omized , double-blind trial in 40,000 high-risk hypertensive patients . ALLHAT is design ed to determine whether the combined incidence of fatal coronary heart disease ( CHD ) and nonfatal myocardial infa rct ion differs between persons r and omized to diuretic ( chlorthalidone ) treatment and each of three alternative treatments -- a calcium antagonist ( amlodipine ) , an angiotensin converting enzyme inhibitor ( lisinopril ) , and an alpha-adrenergic blocker ( doxazosin ) . ALLHAT also contains a r and omized , open-label , lipid-lowering trial design ed to determine whether lowering LDL cholesterol in 20,000 moderately hypercholesterolemic patients ( a subset of the 40,000 ) with a 3-hydroxymethylglutaryl coenzyme A ( HMG CoA ) reductase inhibitor , pravastatin  , will reduce all-cause mortality compared to a control group receiving  " usual care . "  ALLHAT 's main eligibility criteria are : 1 ) age 55 or older ; 2 ) systolic or diastolic hypertension ; and 3 ) one or more additional risk factors for heart attack ( eg , evidence of atherosclerotic disease or type II diabetes ) . For the lipid-lowering trial , participants must have an LDL cholesterol of 120 to 189 mg/dL ( 100 to 129 mg/dL for those with known CHD ) and a triglyceride level below 350 mg/dL. The mean duration of treatment and follow-up is planned to be 6 years . Further features of the rationale , design , objectives , treatment program , and study organization of ALLHAT are described in this article Background Case management has emerged as a promising alternative approach to supplement traditional one-on-one sessions between patients and doctors for improving the quality of care in chronic diseases such as coronary heart disease ( CHD ) . However , data are lacking in terms of its efficacy and cost-effectiveness when implemented in ethnic and low-income population s. Methods The Stanford and San Mateo Heart to Heart ( HTH ) project is a r and omized controlled clinical trial design ed to rigorously evaluate the efficacy and cost-effectiveness of a multi-risk cardiovascular case management program in low-income , primarily ethnic minority patients served by a local county health care system in California . R and omization occurred at the patient level . The primary outcome measure is the absolute CHD risk over 10 years . Secondary outcome measures include adherence to guidelines on CHD prevention practice . We documented the study design , methodology , and baseline sociodemographic , clinical and lifestyle characteristics of 419 participants . Results We achieved equal distributions of the sociodemographic , biophysical and lifestyle characteristics between the two r and omization groups . HTH participants had a mean age of 56 years , 63 % were Latinos/Hispanics , 65 % female , 61 % less educated , and 62 % were not employed . Twenty percent of participants reported having a prior  cardiovascular event . 10-year CHD risk averaged 18 % in men and 13 % in women despite a modest low-density lipoprotein cholesterol level and a high on-treatment percentage at baseline . Sixty-three percent of participants were diagnosed with diabetes and an additional 22 % had metabolic syndrome . In addition , many participants had depressed high-density lipoprotein ( HDL ) cholesterol levels and elevated values of total cholesterol-to-HDL ratio , triglycerides , triglyceride-to-HDL ratio , and blood pressure . Furthermore , nearly 70 % of participants were obese , 45 % had a family history of CHD or stroke , and 16 % were current smokers . Conclusion We have recruited an ethnically diverse , low-income cohort in which to implement a case management approach and test its efficacy and cost-effectiveness . HTH will advance the scientific underst and ing of better strategies for CHD prevention among these priority sub population s and aid in guiding future practice that will reduce health disparities Cardiovascular ( CVS ) death accounts for almost a quarter of paediatric and young adult end stage kidney disease deaths ( 1 ) and traditional CVS risk factors are often evident at an early age in children with chronic kidney disease ( CKD ) . Endothelial dysfunction is a precursor of atherosclerosis ( 2 ) and it has been documented to be present by the first decade of life in children with CKD . ( 3 ) . Given that endothelial dysfunction occurs very early in the timeline of atherosclerosis , it would seem to be an attractive target for therapeutic intervention ( 4 ) . There is some evidence that statins may improve endothelial dysfunction in nephrotic syndrome ( 5 ) , and in adults with raised ( 6,7 ) and borderline raised ( 8) lipid levels . We therefore design ed an intervention trial in children with CKD to determine whether we could improve endothelial dysfunction by using an HMG CoA reductase inhibitor ( statin ) .  Patients were included if lipid levels were ‡50th percentile ( rather than the more conventional 95th percentile ) because the risk of hyperlipidaemia seems to be continuous , evidence d by an almost linear correlation between increasing lipid levels and decreasing arterial distensibility in normal children ( 9 ) . The objective of this study was to assess the effect of statin-associated cholesterol lowering on endothelial function , lipoprotein levels , C reactive protein ( CRP ) , blood pressure ( BP ) and renal function in mildly hyperlipidaemic children with CKD stages 3–4 [ estimated glomerular filtration rate ( GFR ) ( 10 ) < 60 mL ⁄ min ⁄ 1.73 m ] . A prospect i ve , r and omized double-blinded placebo controlled , crossover trial of atorvastatin 10 mg daily for 8 weeks in children ( 5–17 years of age ; n = 8) with serum lipoprotein levels > 50th percentile was conducted ( i.e. each patient was studied before and after 8 weeks of placebo and atorvastatin with a 4-week washout period between treatment arms ) . Seven of eight children were taking Angiotensin Converting Enzyme Inhibitors ( ACE-inhibitors ) for renoprotection ( not hypertension ) . Endothelial function was measured non-invasively by study ing brachial artery reactivity by vascular ultrasound ( ATL HDI 5000 Phillips , Bothell , Washington , DC , USA ) ( 11 ) . Change in brachial artery endothelium-dependent flow-mediated dilatation ( FMD ) was the primary end-point . It was estimated that in a crossover design with scans before and after intervention , 10 patients would detect a significant change in FMD of 3.6 % ( 11 ) to provide 80 % power at the 5 % significance level . Unfortunately , placebo expiry and recruitment difficulty led to only eight patients participating in a pilot study . Patients were recruited from the renal clinic of Sydney Children ’s Hospital and South Eastern Area Health and Central Sydney Ethics Committees approved the study . Total cholesterol and LDL significantly decreased during treatment by a mean of 1.3 ± 0.3 mmol ⁄ L p < 0.0001 and 1.1 ± 0.3 mmol ⁄ L respectively p < 0.0001 ( paired student t test ) ( Table 1 ) . Baseline FMD was normal with a mean of 9.75 ± 0.39 % ( SEM ) and did not significantly alter after 8 weeks of atorvastatin ( 8.04 ± 1.02 % p = 0.18 ) ( Table 2 ) . No significant change was seen in creatinine , BP , CRP , liver function tests , or creatinine kinase levels  with atorvastatin . There was no significant correlation ( Pearson ) between vascular reactivity studies and serum creatinine or estimated GFR . There was no correlation between lipid concentrations , BP , BMI and FMD or glyceryl trinitrate ( GTN ) studies  . Atorvastatin therapy for 8 weeks did not alter endothelial function in children with CKD despite a dose which achieved a significant reduction in LDL cholesterol . We postulate this may be attributable to the FMD results that Acta Pædiatrica ISSN 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 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 The role of lipid-lowering therapy in primary and secondary prevention of ischemic heart disease continues to be debated [ 1 ] . Concerns include whether lowering lipid levels consistently inhibits or reverses the development of coronary artery lesions , influences cardiac and all-cause morbidity and mortality , and offers a prudent use of medical re sources . Because ischemic heart disease remains the leading cause of death in developed countries , these are important questions . Early trials that assessed various lipid-lowering therapies reported little or no angiographic evidence of efficacy , in large part because of modest changes in serum lipids and lipoprotein levels , small sample sizes , and other method ologic problems [ 2 - 4 ] . However , beginning with the Cholesterol Lowering Atherosclerosis Study ( CLAS ) , seven lipid-lowering studies with interventions ranging from multifactorial lifestyle modification , to diet and exercise or diet and either monotherapy or combination drug therapy , to ileal bypass surgery , have shown clear reductions in the progression of atherosclerotic disease or actual lesion regression [ 5 - 12 ] , or both . In three trials , clinical coronary events were significantly reduced [ 7 , 8 , 10 ] . The Program on the Surgical Control of the Hyperlipidemias ( POSCH ) , which showed that cholesterol lowering ( through partial iliac bypass surgery ) had a beneficial effect on coronary artery lesions [ 8 ] , recently found that the 3-year global change score , an overall consensus judgment of angiographic changes in coronary lesions determined by blinded panels of experts , was predictive of subsequent coronary events ( P < 0.0001 ) , fatal coronary events ( P = 0.003 ) , and all-cause mortality ( P = 0.01 ) over 3 to 10 years [ 13 ] . Although not in the context of a lipid-lowering trial , Waters and colleagues [ 14 ] found that patients with angiographic progression of disease at 2 years ( by quantitative coronary angiography ) also had a significantly increased risk for clinical coronary events during a 44-month follow-up period . In CLAS , we showed that diet in conjunction with colestipol and niacin therapy had a beneficial effect on coronary artery lesions at 2 and 4 years based on the global change score [ 5 , 15 ] and at 2 years based on quantitative coronary angiography [ 16 ] ; CLAS was the only angiographic trial to have used both the findings of quantitative coronary angiography and the global change score as end points . We present the results of a second angiographic trial using these two end points . The Monitored Atherosclerosis Regression Study ( MARS ) was a double-blind , placebo-controlled , r and omized trial that tested the reduction of low-density lipoprotein ( LDL ) cholesterol levels using lovastatin , an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A ( HMG CoA ) reductase . We compare our results regarding the effect of reducing lipid levels on coronary artery status with those of the CLAS and POSCH trials . Methods Patients were enrolled in the study if they were younger than 70 years and had coronary artery disease in at least two segments , with at least one segment showing diameter stenosis of 50 % or more ( but not total occlusion ) and unaltered by percutaneous transluminal coronary angioplasty .  Total cholesterol levels ranged from 4.92 to 7.64 mmol/L ( 190 to 295 mg/dL ) . Major exclusion criteria included hypertension ( diastolic blood pressure > 115 mm Hg or , if the patient was receiving treatment , > 100 mm Hg ) , diabetes mellitus , and the use of lipid-lowering drugs within 2 months of r and omization . Women were excluded if they were premenopausal , unless they had undergone surgical sterilization . C and i date s for coronary artery bypass graft surgery were excluded , but c and i date s for percutaneous transluminal coronary angioplasty were not . Between 1985 and 1989 , 270 patients were r and omly assigned within one of eight blocks , defined by sex , smoking status ( current smoker or nonsmoker ) , and plasma total cholesterol ( 6.22 mmol/L [ 240 mg/dL ] or > 6.22 mmol/L ) to receive either lovastatin , 40 mg twice a day , or placebo . Treatment groups had identical targets for cholesterol and fat intake ( daily cholesterol intake 250 mg ; 27 % of calories as fat , with saturated fat constituting 7 % of total fat calories and monounsaturated and polyunsaturated fats each accounting for 10 % of fat calories ) . In 58 % of cases , patients were recruited through cardiac catheterization laboratories and had undergone baseline coronary arteriography for clinical indications . The percutaneous femoral technique was used , and sufficient right and left anterior oblique views were obtained to show all lesions clearly [ 11 ] . During the trial , back-titration of the lovastatin dosage , which was necessary if two consecutive total cholesterol levels were less than 3.11 mmol/L ( 120 mg/dL ) or if one total cholesterol level was less than 2.85 mmol/L ( 110 mg/dL ) , was done once for 15 patients and twice for 3 patients . To maintain the blind , the dosage for a matched placebo recipient was also back-titrated . Lipid , lipoprotein , and apolipoprotein levels were measured using st and ardized laboratory procedures [ 11 ] ; safety laboratory tests were done ; concomitant medications , drug and diet compliance [ 11 ] , lenticular opacification [ 17 ] , and symptoms and adverse events were assessed during the trial . A follow-up angiogram ( n = 247 ) , done 2 years after r and omization , duplicated the protocol followed for the baseline angiogram , including nitroglycerin use , except in the 25 patients ( 8 receiving lovastatin and 17 receiving placebo )  for whom nitroglycerin was required only at follow-up because of angina . Lesions in patients with a nitroglycerin mismatch were excluded from the quantitative coronary analyses . Baseline films and procedure reports , review ed before follow-up angiography was done , ensured matching of all variables including the sequence of arteriographic projections , roentgenographic field , and catheter size . An optional double-blind 2-year extension of the original r and omized therapy ( MARS-II ) was accepted by 70 % of the patients ( 98 receiving lovastatin and 75 receiving placebo ) . Results of MARS-II have not yet been reported . Evaluation of Coronary Angiograms All evaluable film pairs ( n = 246 ) showing identical coronary artery views , with treatment allocation and temporal order masked , were evaluated by an expert panel of two angiographers and a moderator [ 11 , 18 ] . ( One placebo recipient did not have an evaluable angiogram by panel procedures . ) Using the first film , the panel reached a consensus on lesion identification and percent diameter stenosis , and these data were recorded by the moderator . Using the second film , the panel reached a consensus on the degree of change in each lesion and obtained a global change score ( 0 [ no demonstrable change ] to 3 [ extreme change ] ) that integrated panel-based visual changes . A direction for change ( - for regression , + for progression ) was subsequently assigned by the study statistician when the temporal blind was broken . Quantitative coronary angiography analyses were done by a single technician blinded to treatment but not to temporal ordering [ 11 , 19 ] . Film pairs ( n = 220 ) were processed in t and em using dual projectors to match frames for orientation and degree of contrast filling , and arterial segments were defined from branch to branch . Three sequential frames exposed during end-diastole were digitized when possible ; if such a sequence was unavailable , three sequential frames from other phases of the cardiac cycle were digitized . The right anterior oblique view was preferred for the quantitative coronary angiography analysis , but other views were substituted if they were superior . Percent diameter stenosis and minimum lumen diameter were measured in each lesion identified by the panel and in lesions identified by the quantitative coronary angiography analyst but not by the panel ; these latter lesions tended to be in smaller segments and were less severe . Edge coordinates were corrected for pin-cushion distortion ( artifactual coronary artery edge distortion seen in angiographic films ) measured from the image of a 1-cm anteroposterior grid filmed at the beginning of each angiogram . Each end point was averaged over three sequential frames . The primary end point was the average ( per-patient ) change from baseline in percent diameter stenosis in all lesions that showed 20 % stenosis at baseline or at follow-up as evaluated by quantitative coronary angiography . Power calculations based on this end point ( and st and ard deviations estimated to be in the range of 6 % to 8 % ) indicated that an effective sample size of 250 patients had at least an 80 % power to detect a treatment difference of 2 % to 3 % in diameter stenosis at the 0.05 significance level ( two-sided ) [ 11 ] . Three equally weighted secondary end points were average ( per-patient ) change in minimum lumen diameter ( assessed by quantitative coronary angiography ) , the global change score ( assessed by the panel ) , and the proportion of patients with progression or regression of disease ( assessed by quantitative coronary angiography ) . A patient defined as having progression or regression had lesion change of one type only , either progressing or regressing , but not both types ; a patient with a mixed lesion response ( that is , with both progressing and regressing lesions ) was considered unchanged . A progressing or regressing lesion was defined by a change in percent diameter stenosis of 12 % or greater . This cutoff is equal to twice the st and ard deviation ( 5.7 % ) elicited by analysis of repeated angiograms ( at the beginning and end of the same angiographic session ) of the same lesion in 17 patients ( 55 lesions ) in the MARS study .  New lesions and new total occlusions were not counted as progressing lesions ; recanalizations were not counted as regressing lesions . Analyses of change in both percent diameter stenosis and minimum lumen diameter were specified a priori for large ( 50 % at baseline ) lesions [ 11 ] . Lipid-lowering drugs are one of the most prescribed drugs worldwide . The aim was to compare 10-year all-cause mortality according to initial dyslipidemia status and lipid-lowering drug exposure . The PRIME study was a multicenter population -based prospect i ve cohort study of men recruited in 1991 to 1993 , aged 50 to 59 years at baseline , and followed up for 10 years . The 4 groups compared were  normolipidemic , untreated dyslipidemic , and dyslipidemic subjects on fibrate or statin therapy . Data were analyzed using multivariate Cox models . The cohort included 7,722 French men ( statin  group 4.0 % , fibrate group 7.9 % ,  untreated dyslipidemic  subjects 19.0 % , and normolipidemic subjects 69.1 % ) . After 10 years , 4.8 % of the sample was lost to follow-up and 416 deaths occurred ( cancers 53.1 % , cardiovascular diseases 17.1 % , and other 29.8 % ) . After adjustment for center , age , educational level , cardiovascular risk factors , lipids , alcohol intake , and history of cardiovascular and severe chronic diseases , hazard ratios ( HRs ) for all-cause mortality were 0.49 ( 95 % confidence interval [ CI ] 0.26 to 0.94 , p = 0.031 ) for subjects treated with a statin , 0.65 ( 95 % CI 0.42 to 0.99 , p = 0.046 ) for those on fibrate therapy , and 0.76 ( 95 % CI 0.56 to 1.03 , p = 0.080 ) for normolipidemic men compared with untreated dyslipidemic subjects . In the statin group , HRs for death from cardiovascular disease , cancer , and other causes were 0.55 ( p = 0.348 ) , 0.41 ( p = 0.067 ) , and 0.68 ( p = 0.546 ) compared with dyslipidemic subjects , respectively . In the fibrate group , HRs were 0.76 ( p = 0.499 ) , 0.52 ( p = 0.041 ) , and 0.87 ( p = 0.746 ) . In conclusion , in this cohort study carried out in a real-life setting , all-cause mortality was significantly lower in dyslipidemic subjects on fibrate or statin therapy than in untreated dyslipidemic patients . No excess risk of noncardiovascular death was observed Background and aims : Coronary heart disease ( CHD ) is common and the maprity of CHD patients are 65 years or older . There exist only a few r and omized , controlled intervention studies on secondary prevention of CHD among elderly CHD patients . Our study assessed the effects of health advocacy , counseling , and activation programs with outcome variables of changes in the use of fats , lipid-lowering medications , frequency of exercise , cigarette smoking , serum cholesterol and triglyceride concentrations , blood pressure , and symptoms of late-life CHD among CHD patients of the Lieto Study . Methods : R and omized , controlled intervention study . Late-life ( > 65 yrs ) CHD patients were r and omized into intervention group ( IG ) ( n=118 ) and control group ( CG ) ( n=109 ) . Intervention consisted of 16 lectures by experts , eight group discussion s , six group exercise sessions , and three social activity events . Results : The use of lipid-lowering medications became more common in IG than in CG among men ( p=0.041 ) , with a similar tendency among women . Among women , decreases in the means of total serum cholesterol ( p=0.009 ) and LDL-cholesterol ( p=0.049 ) were greater in IG than in CG . Conclusions : The program produced no positive effects on health behavior . Positive effects were gained by the increase in lipid-lowering medications , which reduced mean total serum cholesterol and LDL-cholesterol concentrations . More intensive counseling on health behavior should be planned , implemented , and evaluated 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 Objective The objectives of this study were to develop a coronary heart disease ( CHD ) risk model among the Korean Heart Study ( KHS ) population and compare it with the Framingham CHD risk score . Design A prospect i ve cohort study within a national insurance system . Setting 18 health promotion centres nationwide between 1996 and 2001 in Korea . Participants 268 315 Koreans between the ages of 30 and 74 years without CHD at baseline . Outcome measure Non-fatal or fatal CHD events between 1997 and 2011 . During an 11.6-year median follow-up , 2596 CHD events ( 1903 non-fatal and 693 fatal ) occurred in the cohort . The optimal CHD model was created by adding high-density lipoprotein (HDL)-cholesterol , low-density lipoprotein (LDL)-cholesterol and triglycerides to the basic CHD model , evaluating using the area under the receiver operating characteristic curve ( ROC ) and continuous net reclassification index ( NRI ) . Results The optimal CHD models for men and women included HDL-cholesterol ( NRI=0.284 ) and triglycerides ( NRI=0.207 ) from the basic CHD model , respectively . The discrimination using the CHD model in the Korean cohort was high : the areas under ROC were 0.764 ( 95 % CI 0.752 to 0.774 ) for men and 0.815 ( 95 % CI 0.795 to 0.835 ) for women . The Framingham risk function predicted 3–6 times as many CHD events than observed . Recalibration of the Framingham function using the mean values of risk factors and mean CHD incidence rates of the KHS cohort substantially improved the performance of the Framingham functions in the KHS cohort . Conclusions The present study provides the first evidence that the Framingham risk function overestimates the risk of CHD in the Korean population where CHD incidence is low . The Korean CHD risk model is well-calculated alternations which can be used to predict an individual 's risk of CHD and provides a useful guide to identify the groups at high risk for CHD among Koreans 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 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
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 .