Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease Risk in Adults: Synopsis of the 2013 American College of Cardiology/American Heart Association Cholesterol Guideline 2017 Focused Update of the 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. Effects of Intensive Lipid‐Lowering Therapy on the Coronary Arteries of Asymptomatic Subjects With Elevated Apolipoprotein B Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): comparison of ezetimbe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes. Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study). Efficacy and safety of K-877, a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα), in combination with statin treatment: Two randomised, double-blind, placebo-controlled clinical trials in patients with dyslipidaemia. Design and baseline characteristics of the Incremental Decrease in End Points through Aggressive Lipid Lowering study. Rosuvastatin alone or with extended-release niacin: a new therapeutic option for patients with combined hyperlipidemia. Effects of combination lipid therapy in type 2 diabetes mellitus. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. Long-term safety and efficacy of fenofibric acid in combination with statin therapy for the treatment of patients with mixed dyslipidemia. Effects of Fenofibric Acid on Carotid Intima-Media Thickness in Patients With Mixed Dyslipidemia on Atorvastatin Therapy: Randomized, Placebo-Controlled Study (FIRST) An analysis of calibration and discrimination among multiple cardiovascular risk scores in a modern multiethnic cohort. Aggressive Versus Moderate Lipid-Lowering Therapy in Hypercholesterolemic Postmenopausal Women: Beyond Endorsed Lipid Lowering With EBT Scanning (BELLES) Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. Design and baseline characteristics of the simvastatin and ezetimibe in aortic stenosis (SEAS) study.
Atherosclerotic cardiovascular disease ( ASCVD ) is the leading cause of death , decreased quality of life , and medical costs in the United States . Nearly 1 in 3 Americans die of heart disease and stroke ( 1 ) . Most ASCVD is preventable through a healthy lifestyle and effective treatment of cholesterol and blood pressure . The 2013 Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults from the American College of Cardiology and American Heart Association ( ACC/AHA ) provides an evidence -based approach to reducing ASCVD risk ( 2 ) . Guideline Development Process In 2008 , the National Heart , Lung , and Blood Institute ( NHLBI ) convened the Adult Treatment Panel ( ATP ) IV to up date the 2001 ATP-III cholesterol guidelines using a rigorous systematic process to identify and review r and omized , controlled trials ( RCTs ) with cardiovascular outcomes and meta-analyses of these RCTs . The panel comprised experts and clinicians from the fields of cardiology , epidemiology , primary care , and endocrinology ( 2 ) and received support from the Lifestyle Management and Risk Assessment Work Groups ( 3 , 4 ) . Systematic evidence review s conducted according to principles recommended by the Institute of Medicine ( 5 ) were performed to answer 3 questions relevant to clinical care . Two questions focused on the evidence supporting low-density lipoprotein cholesterol ( LDL-C ) and nonhigh-density lipoprotein cholesterol ( HDL-C ) levels as targets of treatment . One question examined the reduction in ASCVD events and adverse effects for each cholesterol-lowering drug class . The panel synthesized the evidence from these 3 review s as well as from Lifestyle Management and Risk Assessment Work Groups review s ( 3 , 4 ) that addressed 5 additional critical questions . Systematic electronic search es of relevant data bases of the peer- review ed English- language literature published from 1 January 1995 through 1 December 2009 for each critical question were conducted by an NHLBI-selected independent contractor and focused on RCTs and systematic review s and meta-analyses of RCTs assessed as fair to good quality . In addition , RCTs with ASCVD outcomes that included coronary heart disease , stroke , and cardiovascular deaths published after that date were eligible for consideration through July 2013 . Evidence tables were constructed , and the strength of evidence was rated according to the NHLBI ( Table 1 of the Supplement ) . Recommendations were grade d according to criteria from the NHLBI ( Table 2 of the Supplement ) and ACC/AHA ( Table 3 of the Supplement ) . Because of the inherent differences in grading systems and the clinical questions driving the recommendations , alignment between the NHLBI and ACC/AHA formats was imperfect . A complete description of the methods used and results of the evidence review are provided in the guideline ( 2 ) and the NHLBI evidence report ( www.nhlbi.nih.gov/ guidelines /cholesterol/ser/index.htm ) . Supplement . NHLBI and ACC/AHA Criteria for Rating Strength of Evidence To help clinicians estimate ASCVD risk , the risk assessment working group developed the Pooled Cohort Equations using data from 5 NHLBI-sponsored longitudinal , population -based cohorts of African American and non-Hispanic white men and women to estimate risk for a first myocardial infa rct ion , coronary heart disease death , or fatal or nonfatal stroke on the basis of age , sex , race , smoking status , total cholesterol level , HDL-C level , systolic blood pressure , antihypertensive therapy , and diabetes ( 4 , 6 ) . These equations significantly advance ASCVD risk estimation by providing sex- and race-specific estimates and including stroke as an outcome . The earlier Framingham equations calculated only coronary heart disease risk for non-Hispanic whites . The draft recommendations were review ed by 23 experts and representatives of federal agencies identified by the NHLBI . In September 2013 , the recommendations developed by the panel were transitioned to the ACC/AHA and had additional review by 4 experts nominated by the ACC Foundation and the AHA . The governing bodies of the ACC and AHA approved the guideline , which also received endorsement from the American Association of Cardiovascular and Pulmonary Rehabilitation , American Pharmacists Association , American Society for Preventive Cardiology , Association of Black Cardiologists , Preventive Cardiovascular Nurses Association , and WomenHeart : The National Coalition for Women with Heart Disease . Recommendations The guideline focuses on treatment of blood cholesterol to reduce ASCVD risk in adults . Major recommendations are summarized here and in Table 1 . The guideline report provides a complete listing of recommendations and supporting evidence behind each recommendation ( 2 ) . Table 1 . Major Recommendations for the Treatment of Blood Cholesterol to Reduce ASCVD Risk in Adults * 1 . Encourage Adherence to a Healthy Lifestyle A healthy lifestyle is the foundation for cardiovascular health . The panel endorsed the 2013 ACC/AHA Lifestyle Management Guideline ( 3 ) for a diet that is low in saturated fat , trans fat , and sodium ; emphasizes vegetables , fruits , whole grains , low-fat dairy products , poultry , fish , legumes , nontropical vegetable oils , and nuts ; and limits sweets , sugar-sweetened beverages , and red meats and engage in regular aerobic physical activity . Adults also should maintain a healthy body weight , avoid smoking , and control hypertension and diabetes when present . 2 . Statin Therapy Is Recommended for Adults in Groups Demonstrated to Benefit Strong RCT evidence shows that reduction in ASCVD events from statin therapy exceeds adverse events for 4 patient groups : those with clinical ASCVD ( acute coronary syndromes , myocardial infa rct ion , stable angina , coronary or other arterial revascularization , stroke , transient ischemic attack , or peripheral arterial disease of atherosclerotic origin ) when  statins are used for secondary prevention , and those with LDL-C levels 190 mg/dL ; those aged 40 to 75 years with diabetes and LDL-C levels 70 to 189 mg/dL ; and those aged 40 to 75 years without diabetes and with a 10-year ASCVD risk 7.5 % when statins are used for primary prevention . Moderate evidence supports consideration of statin therapy for primary prevention in individuals with a 10-year ASCVD risk of 5 % to < 7.5 % . Routine initiation of statin therapy is not recommended in adults with New York Heart Association heart failure class II to IV or those receiving maintenance hemodialysis . R and omized , controlled trials in these groups showed no reduction in ASCVD . 3 . Statins have an Acceptable Margin of Safety When Used in Properly Selected Individuals and Appropriately Monitored Strong RCT evidence supports safety of statins when they are used as directed in conjunction with regular follow-up assessment s in properly selected patients . Adjustment of statin intensity is recommended in individuals older than 75 years with a history of statin intolerance or other characteristics ( 2 ) or those receiving drug therapy that may increase statin adverse events . Routine monitoring of hepatic aminotransferase level or creatine kinase level is not recommended unless clinical ly indicated by symptoms suggesting hepatotoxicity or myopathy . Given the potential for decreasing ASCVD events and death , the relationship of muscle and other symptoms to statin treatment must be confirmed . Therefore , eliciting a history of muscle symptoms before statin initiation and carefully monitoring symptoms during statin discontinuation and rechallenge is recommended . Severe myopathy , rhabdomyolysis , and possibly hemorrhagic stroke are rare complications of statin therapy . Although statin therapy modestly increases the risk for type 2 diabetes , ASCVD risk reduction outweighs the excess risk for diabetes for high-intensity statins in secondary prevention or for 10-year ASCVD risk 7.5 % . Similarly , ASCVD risk reduction outweighs the excess risk for diabetes for moderate-intensity statin therapy in adults with a 10-year ASCVD risk 5 % . 4 . Engage in a ClinicianPatient Discussion Before Initiating Statin Therapy , Especially for Primary Prevention in Patients With Lower ASCVD Risk Decisions to initiate statin therapy in primary prevention should be based on clinical judgment and preferences of informed patients . In adults without clinical ASCVD or diabetes whose LDL-C level is < 190 mg/dL , calculating the estimated 10-year ASCVD risk should be the start of the clinicianpatient discussion and should not automatically lead to statin initiation . As the absolute risk for ASCVD events decreases , so does the net benefit of the intervention . Therefore , discussion of the potential for ASCVD event reduction , adverse effects , drugdrug interactions , and patient preferences is especially important for lower-risk primary prevention . The discussion provides the opportunity to encourage healthy lifestyle habits and control other risk factors . Additional factors may be considered when a risk-based decision is uncertain , including LDL-C levels 160 mg/dL , family history of premature ASCVD , elevated  lifetime ASCVD risk  , high-sensitivity C-reactive protein level 2.0 mg/L ,  coronary artery calcification score  > 300 Agatston units , and anklebrachial index < 0.9 . After age 75 years , comorbid conditions , anticipated longevity , safety considerations , and patient preferences should play a large role in decision making . 5 . Use the Newly Developed Pooled Cohort Equations for Estimating 10-Year ASCVD Risk The Pooled Cohort Equations are currently the best available method for estimating 10-year ASCVD risk to guide statin initiation ( 4 , 6 ) . Application of the inclusion and exclusion criteria from RCTs is cumbersome and results in underidentifying high-risk and overidentifying low-risk individuals for statin treatment . The Pooled Cohort Equations were developed using recent data from 5 NHLBI-sponsored , longitudinal , population -based cohorts of African American and white men and women ( ARIC [ In 2016 , the American College of Cardiology published the first expert consensus decision pathway ( ECDP ) on the role of non-statin therapies for low-density lipoprotein (LDL)-cholesterol lowering in the management of atherosclerotic cardiovascular disease ( ASCVD ) risk . Since the publication of that document , additional evidence and perspectives have emerged from r and omized clinical trials and other sources , particularly considering the longer-term efficacy and safety of proprotein convertase subtilisin/kexin 9 ( PCSK9 ) inhibitors in secondary prevention of ASCVD . Most notably , the FOURIER ( Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk ) trial and SPIRE-1 and -2 ( Studies of PCSK9 Inhibition and the Reduction of Vascular Events ) , assessing evolocumab and bococizumab , respectively , have published final results of cardiovascular outcomes trials in patients with clinical ASCVD and in a smaller number of high-risk primary prevention patients . In addition , further evidence on the types of patients most likely to benefit from the use of ezetimibe in addition to statin therapy after acute coronary syndrome has been published . Based on results from these important analyses , the ECDP writing committee judged that it would be desirable to provide a focused up date to help guide clinicians more clearly on decision making regarding the use of ezetimibe and PCSK9 inhibitors in patients with clinical ASCVD with or without comorbidities . In the following summary table , changes from the 2016 ECDP to the 2017 ECDP Focused Up date are highlighted , and a brief rationale is provided . The content of the full document has been changed accordingly , with more extensive and detailed guidance regarding decision making provided both in the text and in the up date d algorithms . Revised recommendations are provided for patients with clinical ASCVD with or without comorbidities  on statin therapy for secondary prevention . The ECDP writing committee judged that these new data did not warrant changes to the decision pathways and algorithms regarding the use of ezetimibe or PCSK9 inhibitors in primary prevention patients with LDL-C < 190 mg/dL with or without diabetes mellitus or patients without ASCVD and LDL-C ≥190 mg/dL not due to secondary causes . Based on feedback and further deliberation , the ECDP writing committee down- grade d recommendations regarding bile acid sequestrant use , recommending bile acid sequestrants only as optional secondary agents for consideration in patients intolerant to ezetimibe . For clarification , the writing committee has also included new information on diagnostic categories of heterozygous and homozygous familial hypercholesterolemia , based on clinical criteria with and without genetic testing . Other changes to the original document were kept to a minimum to provide consistent guidance to clinicians , unless there was a compelling reason or new evidence , in which case justification is provided BACKGROUND AND METHODS The effect of intensive lipid-lowering therapy on coronary atherosclerosis among men at high risk for cardiovascular events was assessed by quantitative arteriography . Of 146 men no more than 62 years of age who had apolipoprotein B levels greater than or equal to 125 mg per deciliter , documented coronary artery disease , and a family history of vascular disease , 120 completed the 2 1/2-year double-blind study , which included arteriography at base line and after treatment . Patients were given dietary counseling and were r and omly assigned to one of three treatments : lovastatin ( 20 mg twice a day ) and colestipol ( 10 g three times a day ) ; niacin ( 1 g four times a day ) and colestipol ( 10 g three times a day ) ; or conventional therapy with placebo ( or colestipol if the low-density lipoprotein [ LDL ] cholesterol level was elevated ) . RESULTS The levels of LDL and high-density lipoprotein ( HDL ) cholesterol changed only slightly in the conventional-therapy group ( mean changes , -7 and + 5 percent , respectively ) , but more substantially among patients treated with lovastatin and colestipol ( -46 and + 15 percent ) or niacin and colestipol ( -32 and + 43 percent ) . In the conventional-therapy group , 46 percent of the patients had definite lesion progression ( and no regression ) in at least one of nine proximal coronary segments ; regression was the only change in 11 percent . By comparison , progression ( as the only change ) was less frequent among patients who received lovastatin and colestipol ( 21 percent ) and those who received niacin and colestipol ( 25 percent ) , and regression was more frequent ( lovastatin and colestipol , 32 percent ; niacin and colestipol , 39 percent ; P less than 0.005 ) . Multivariate analysis indicated that a reduction in the level of apolipoprotein B ( or LDL cholesterol ) and in systolic blood pressure , and an increase in HDL cholesterol correlated independently with regression of coronary lesions . Clinical events ( death , myocardial infa rct ion , or revascularization for worsening symptoms ) occurred in 10 of 52 patients assigned to conventional therapy , as compared with 3 of 46 assigned to receive lovastatin and colestipol and 2 of 48 assigned to receive niacin and colestipol ( relative risk of an event during intensive treatment , 0.27 ; 95 percent confidence interval , 0.10 to 0.77 ) . CONCLUSIONS In men with coronary artery disease who were at high risk for cardiovascular events , intensive lipid-lowering therapy reduced the frequency of progression of coronary lesions , increased the frequency of regression , and reduced the incidence of cardiovascular events Background Do the benefits of intensive lipid-lowering therapy seen in symptomatic patients extend to high-risk subjects who have never had symptoms ? Methods and ResulsOf 120 men completing the FATS trial , 91 were symptomatic and 29 asymptomatic . All had apolipoprotein B 2125 mg/dL , a positive family history , and coronary atherosclerosis . All were counseled in diet and r and omized to intensive therapy : colestipol 10 g TID plus either niacin 1 g QID or lovastatin 20 mg BID or to conventional therapy : placebos , or colestipol if low-density lipoprotein cholesterol was elevated . End points included quantitative arteriographic disease change and clinical events over a 2.5-year interval . At baseline , symptomatic and asymptomatic patients had comparable risk profiles , but proximal stenosis severity averaged 36 % for symptomatic and 23 % for asymptomatic patients ( P<.001 ) . Among the 91 symptomatic patients , those in the intensive group experienced definite ( .101%S ) proximal lesion progression less frequently than conventional ( 24 % of intensive versus 48 % of conventional ) and definite regression more frequently ( 36 % of intensive versus 15 % of conventional ) ( P=.009 ) . Similarly , among the 29 asymptomatic patients , 19 % of intensive versus 38 % of conventional had progression and 31 % of intensive versus 0%1 of conventional , regression ( P=.04 ) . Ischemia on baseline exercise tolerance testing was associated with significantly greater proximal disease progression among the asymptomatic patients . Clinical cardiovascular events ( death , infa rct ion , or revascularization ) occurred in 10 of 38 symptomatic patients originally assigned to conventional therapy , compared with 5 of 76 symptomatic patients assigned to intensive ( P<.01 ) ; no asymptomatic patient had an event . ConcluionsAsymptomatic subjects with this high-risk profile have less coronary disease at baseline than comparable symptomatic patients , and they have an excellent short-term clinical prognosis . However , asymptomatic subjects are indistinguishable from symptomatic patients in terms of their arterial disease progression with conventional therapy and their regression with intensive . These findings may justify an active treatment strategy in such subjects , particularly those with provokable ischemia BACKGROUND Reduction in low-density lipoprotein cholesterol ( LDL-C ) improves clinical outcomes in patients with chronic coronary artery disease and acute coronary syndromes ( ACSs ) . The combination of ezetimibe/simvastatin produces greater reductions in LDL-C compared to simvastatin monotherapy . The IMProved Reduction of Outcomes : Vytorin Efficacy International Trial ( IMPROVE-IT ) is a multicenter , r and omized , double-blind , active-control trial design ed to test the hypothesis that the addition of ezetimibe to statin therapy , using ezetimibe/simvastatin , will translate into increased clinical benefit on cardiovascular outcomes relative to simvastatin monotherapy in patients with ACS . STUDY DESIGN The study will recruit up to 18,000 moderate- to high-risk patients stabilized after ACS . Patients are r and omized in a 1:1 ratio to once-daily doses of either ezetimibe/simvastatin 10/40 mg or simvastatin monotherapy 40 mg . Follow-up visits are at 1 and 4 months , and every 4 months thereafter . If consecutive measures of LDL-C are > 79 mg/dL at follow-up visits , the simvastatin dose will be increased to 80 mg in a double-blind manner . The primary end point is the first occurrence of cardiovascular death , nonfatal myocardial infa rct ion , rehospitalization for unstable angina , coronary revascularization ( occurring at least 30 days after r and omization ) , or stroke . Patients will be followed for a minimum of 2.5 years and until at least 5,250 patients experience a primary end point . SUMMARY IMPROVE-IT will determine whether the addition of ezetimibe to statin therapy , using ezetimibe/simvastatin , improves cardiovascular outcomes compared with simvastatin monotherapy in patients after ACS . In addition , the difference in achieved LDL-C levels between the groups will provide data on whether the target for LDL-C lowering should be reduced further 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 AND AIMS Substantial residual cardiovascular risks remain despite intensive statin treatment . Residual risks with high triglyceride and low high-density lipoprotein cholesterol are not the primary targets of statins . K-877 ( pemafibrate ) demonstrated robust efficacy on triglycerides and high-density lipoprotein cholesterol and a good safety profile as a monotherapy . The aim of these studies was to evaluate the efficacy and safety of K-877 add-on therapy to treat residual hypertriglyceridaemia during statin treatment . METHODS The objectives were investigated in two , multicentre , r and omised , double-blind ,  placebo-controlled  , parallel group comparison clinical trials : ( A ) K-877 0.1 , 0.2 , and 0.4 mg/day in combination with pitavastatin for 12 weeks in 188 patients , ( B ) K-877 0.2 ( fixed dose ) and 0.2 ( 0.4 ) ( conditional up-titration ) mg/day in combination with any statin for 24 weeks in 423 patients . RESULTS In both studies , we found a robust reduction in fasting triglyceride levels by approximately 50 % in all combination therapy groups , which was significant compared to the statin-monotherapy ( placebo ) groups ( p < 0.001 ) . High-performance liquid chromatography analysis for lipoprotein subfractions revealed that atherogenic lipoprotein profiles were ameliorated by K-877 add-on therapy , i.e. small low-density lipoproteins decreased whereas larger ones increased , and larger high-density lipoproteins decreased whereas smaller ones increased . The incidence rates of adverse events and adverse drug reactions in K-877 combination therapy groups were comparable to those in statin-monotherapy groups without any noteworthy event in both studies . CONCLUSIONS These results strongly support the favourable benefit-to-risk ratio of K-877 add-on therapy in combination with statin treatment The Incremental Decrease in End Points through Aggressive Lipid Lowering ( IDEAL ) study is an investigator-initiated trial design ed to determine whether additional clinical benefit might be gained through a strategy that decreases levels of low-density lipoprotein cholesterol levels better than those currently achieved with established statin therapy in patients who have coronary heart disease . IDEAL is a multicenter prospect i ve , r and omized , open-label , blinded , end point classification study . Patients who had myocardial infa rct ion were r and omized to prescription treatment with 80 mg/day of atorvastatin or 20 mg/day of simvastatin ( the dose was increased to 40 mg/day at week 24 in those patients whose plasma total cholesterol remained > 5.0 mmol/L , or 190 mg/dl , or whose low-density lipoprotein cholesterol remained > 3.0 mmol/L , or 115 mg/dl ) . The primary clinical outcome variable is the time to initial occurrence of a major coronary event , which is defined as nonfatal acute myocardial infa rct ion , coronary death , or resuscitated cardiac arrest . The study is design ed to have a power of 90 % to detect a relative decrease of 20 % in the atorvastatin-group compared with the simvastatin-group in the number of major events caused by coronary heart disease over approximately 5.5 years . The 8,888 r and omized patients had the following characteristics : mean age 61.7 + /- 9.5 years , 19.1 % women ( mean age 64.0 + /- 9.5 years ) , baseline total cholesterol 5.1 + /- 1.0 mmol/L ( 197 mg/dl ) , low-density lipoprotein cholesterol 3.2 + /- 0.9 mmol/L ( 124 mg/dl ) , and high-density lipoprotein cholesterol 1.2 + /- 0.3 mmol/L ( 46 mg/dl ) . Drug treatment before r and omization consisted of statins in 77 % of patients , aspirin in 78.9 % , beta blockers in 75.1 % , and angiotensin-converting enzyme inhibitors in 30 % Combination therapy with a statin and niacin may provide optimal therapy for patients with combined hyperlipidemia and low levels of high-density lipoprotein ( HDL ) cholesterol . The authors assessed the efficacy and safety of rosuvastatin monotherapy , extended-release ( ER ) niacin monotherapy , or rosuvastatin and ER niacin combined therapy in patients with atherogenic dyslipidemia . In a 24-week , open-label , multicenter trial , men and women aged > or = 18 years with fasting levels of total cholesterol > or = 200 mg/dL , HDL cholesterol > or = 45 mg/dL , triglycerides 200 - 800 mg/dL , and apolipoprotein B > or = 110 mg/dL were r and omly assigned to one of four treatment groups : rosuvastatin 10 - 40 mg , ER niacin 0.5 - 2 g , rosuvastatin 40 mg plus ER niacin 0.5 - 1 g , or rosuvastatin 10 mg plus ER niacin 0.5 - 2 g. Daily doses of rosuvastatin 40 mg monotherapy reduced low-density lipoprotein ( LDL ) cholesterol and non-HDL cholesterol levels significantly more than did either ER niacin 2 g monotherapy or rosuvastatin 10 mg combined with ER niacin 2 g. Addition of ER niacin 1 g to rosuvastatin 40 mg did not further reduce total or non-HDL cholesterol . Triglyceride reductions were similar among the four treatment groups . ER niacin mono- and combined therapy produced significantly greater rises in HDL cholesterol and apolipoprotein A-1 than did rosuvastatin monotherapy . Rosuvastatin monotherapy was better tolerated than ER niacin taken either alone or with rosuvastatin . In this study , rosuvastatin very effectively improved the three major lipoprotein-lipid abnormalities of combined hyperlipidemia BACKGROUND We investigated whether combination therapy with a statin plus a fibrate , as compared with statin monotherapy , would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease . METHODS We r and omly assigned 5518 patients with type 2 diabetes who were being treated with open-label simvastatin to receive either masked fenofibrate or placebo .  The primary outcome was the first occurrence of nonfatal myocardial infa rct ion , nonfatal stroke , or death from cardiovascular causes . The mean follow-up was 4.7 years . RESULTS The annual rate of the primary outcome was 2.2 % in the fenofibrate group and 2.4 % in the placebo group ( hazard ratio in the fenofibrate group , 0.92 ; 95 % confidence interval [ CI ] , 0.79 to 1.08 ; P=0.32 ) . There were also no significant differences between the two study groups with respect to any secondary outcome . Annual rates of death were 1.5 % in the fenofibrate group and 1.6 % in the placebo group ( hazard ratio , 0.91 ; 95 % CI , 0.75 to 1.10 ; P=0.33 ) . Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex , with a benefit for men and possible harm for women ( P=0.01 for interaction ) , and a possible interaction according to lipid subgroup , with a possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high-density lipoprotein cholesterol ( P=0.057 for interaction ) . CONCLUSIONS The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events , nonfatal myocardial infa rct ion , or nonfatal stroke , as compared with simvastatin alone . These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes . ( Clinical Trials.gov number , NCT00000620 . CONTEXT Prior intravascular ultrasound ( IVUS ) trials have demonstrated slowing or halting of atherosclerosis progression with statin therapy but have not shown convincing evidence of regression using percent atheroma volume ( PAV ) , the most rigorous IVUS measure of disease progression and regression . OBJECTIVE To assess whether very intensive statin therapy could regress coronary atherosclerosis as determined by IVUS imaging . DESIGN AND SETTING Prospect i ve , open-label blinded end-points trial ( A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden [ ASTEROID ] ) was performed at 53 community and tertiary care centers in the United States , Canada , Europe , and Australia . A motorized IVUS pullback was used to assess coronary atheroma burden at baseline and after 24 months of treatment . Each pair of baseline and follow-up IVUS assessment s was analyzed in a blinded fashion . PATIENTS Between November 2002 and October 2003 , 507 patients had a baseline IVUS examination and received at least 1 dose of study drug . After 24 months , 349 patients had evaluable serial IVUS examinations . INTERVENTION All patients received intensive statin therapy with rosuvastatin , 40 mg/d . MAIN OUTCOME MEASURES Two primary efficacy parameters were prespecified : the change in PAV and the change in nominal atheroma volume in the 10-mm subsegment with the greatest disease severity at baseline . A secondary efficacy variable , change in normalized total atheroma volume for the entire artery , was also prespecified . RESULTS The mean ( SD ) baseline low-density lipoprotein cholesterol ( LDL-C ) level of 130.4 ( 34.3 ) mg/dL declined to 60.8 ( 20.0 ) mg/dL , a mean reduction of 53.2 % ( P<.001 ) . Mean ( SD ) high-density lipoprotein cholesterol ( HDL-C ) level at baseline was 43.1 ( 11.1 ) mg/dL , increasing to 49.0 ( 12.6 ) mg/dL , an increase of 14.7 % ( P<.001 ) . The mean ( SD ) change in PAV for the entire vessel was -0.98 % ( 3.15 % ) , with a median of -0.79 % ( 97.5 % CI , -1.21 % to -0.53 % ) ( P<.001 vs baseline ) . The mean ( SD ) change in atheroma volume in the most diseased 10-mm subsegment was -6.1 ( 10.1 ) mm3 , with a median of -5.6 mm3 ( 97.5 % CI , -6.8 to -4.0 mm3 ) ( P<.001 vs baseline ) . Change in total atheroma volume showed a 6.8 % median reduction ; with a mean ( SD ) reduction of -14.7 ( 25.7 ) mm3 , with a median of -12.5 mm3 ( 95 % CI , -15.1 to -10.5 mm3 ) ( P<.001 vs baseline ) . Adverse events were infrequent and similar to other statin trials . CONCLUSIONS Very high-intensity statin therapy using rosuvastatin 40 mg/d achieved an average LDL-C of 60.8 mg/dL and increased HDL-C by 14.7 % , result ing in significant regression of atherosclerosis for all 3 prespecified IVUS measures of disease burden . Treatment to LDL-C levels below currently accepted guidelines , when accompanied by significant HDL-C increases , can regress atherosclerosis in coronary disease patients . Further studies are needed to determine the effect of the observed changes on clinical outcome . TRIAL REGISTRATION Clinical Trials.gov Identifier : NCT00240318 BACKGROUND Co-administration of a fibrate and statin is an effective treatment option for patients with multiple lipid abnormalities , yet adequate long-term safety and efficacy data are lacking . OBJECTIVE To evaluate the long-term safety and efficacy of fenofibric acid combined with statins in adults with mixed dyslipidemia . METHODS Three large , 12-week , phase three , double-blind , r and omized , controlled trials evaluated fenofibric acid 135 mg combined with a low- or moderate-dose statin compared to fenofibric acid or statin monotherapy , and a subsequent 52-week open-label extension study evaluated fenofibric acid 135 mg combined with moderate-dose statin ( rosuvastatin 20 mg , simvastatin 40 mg , or atorvastatin 40 mg ) . This prespecified analysis integrated results from these studies to assess the long-term safety and efficacy of combination therapy . RESULTS Across the controlled studies and the extension study , 2201 patients received at least one dose of fenofibric acid + statin  for a median duration of 364 days . The most common adverse events were headache , upper respiratory tract infection , nasopharyngitis , and back pain , with the incidence of all adverse events being similar across all combination therapy treatment groups . Rhabdomyolysis or treatment-related death was not reported in any group . Combination therapy result ed in sustained improvements in multiple lipid parameters , including triglycerides , high-density lipoprotein cholesterol , low-density lipoprotein cholesterol , non-high-density lipoprotein cholesterol , very low-density lipoprotein cholesterol , total cholesterol , apolipoprotein B , and high-sensitivity C-reactive protein . CONCLUSION Long-term fenofibric acid + statin combination therapy was generally well tolerated and result ed in comprehensive and sustained improvements in multiple lipid parameters in adults with mixed dyslipidemia Objective —To assess whether adding a fibrate to statin therapy reduces residual cardiovascular risk associated with elevated triglycerides and low high-density lipoprotein cholesterol , The Evaluation of Choline Fenofibrate ( ABT-335 ) on Carotid Intima-Media Thickness ( cIMT ) in Subjects with Type IIb Dyslipidemia with Residual Risk in Addition to Atorvastatin Therapy ( FIRST ) trial evaluated the effects of fenofibric acid ( FA ) treatment on cIMT in patients with mixed dyslipidemia on atorvastatin . Approach and Results —This multicenter , double-blind , placebo-controlled study was performed in patients with mixed dyslipidemia ( fasting triglycerides , ≥150 mg/dL ; high-density lipoprotein cholesterol , ⩽45 [ men ] or 55 mg/dL [ women ] ; low-density lipoprotein cholesterol , ⩽100 mg/dL once and averaging ⩽105 mg/dL ) and a history of coronary heart disease or risk equivalent . Patients on background atorvastatin ( continued on starting dose or titrated to 40 mg , if needed ) were r and omized to FA 135 mg or placebo . The primary end point was rate of change from baseline through week 104 of the mean posterior-wall cIMT , measured by ultrasound . In patients with controlled low-density lipoprotein cholesterol while on atorvastatin background therapy , rate of change in posterior-wall cIMT was similar with FA plus atorvastatin ( −0.006 mm/y ) versus atorvastatin monotherapy ( 0.000 mm/y ; P=0.22 ) . FA plus atorvastatin was favored ( P<0.05 ) in 5 of 24 prespecified subgroups : age ≥60 years , history of coronary artery disease , cIMT > 0.795 mm , triglycerides 170 to 235 mg/dL , and statin use at entry . Adverse events were consistent with the known safety profiles of both drugs ; however , FA plus atorvastatin was associated with a greater incidence of renal-related adverse events compared with atorvastatin monotherapy ( 6.5 % versus 0.9 % ) . Conclusions —Compared with atorvastatin monotherapy , FA plus atorvastatin did not further decrease cIMT progression in high-risk patients with mixed dyslipidemia BACKGROUND Accurate risk assessment of atherosclerotic cardiovascular disease ( ASCVD ) is essential to effectively balance the risks and benefits of therapy for primary prevention . OBJECTIVE To compare the calibration and discrimination of the new American Heart Association ( AHA ) and American College of Cardiology ( ACC ) ASCVD risk score with alternative risk scores and to explore preventive therapy as a cause of the reported risk overestimation using the AHA-ACC-ASCVD score . DESIGN Prospect i ve epidemiologic study of ASCVD . SETTING MESA ( Multi-Ethnic Study of Atherosclerosis ) , a community-based , sex-balanced , multiethnic cohort . PATIENTS 4227 MESA participants aged 50 to 74 years and without diabetes at baseline . MEASUREMENTS Observed and expected events for the AHA-ACC-ASCVD score were compared with 4 commonly used risk scores- and their respective end points-in MESA after a 10.2-year follow-up . RESULTS The new AHA-ACC-ASCVD and 3 older Framingham-based risk scores overestimated cardiovascular events by 37 % to 154 % in men and 8 % to 67 % in women . Overestimation was noted throughout the continuum of risk . In contrast , the Reynolds Risk Score overestimated risk by 9 % in men but underestimated risk by 21 % in women .  Aspirin , lipid-lowering or antihypertensive therapy  , and  interim revascularization  did not explain the overestimation . LIMITATION Comparability of MESA with target population s for primary prevention and possibility of missed events in MESA . CONCLUSION Of the 5 risk scores , 4 , including the new AHA-ACC-ASCVD score , showed overestimation of risk ( 25 % to 115 % ) in a modern , multiethnic cohort without baseline clinical ASCVD . If vali date d , overestimation of ASCVD risk may have substantial implication s for individual patients and the health care system . PRIMARY FUNDING SOURCE National Heart , Lung , and Blood Institute Background —Women have been underrepresented in statin trials , and few data exist on the effectiveness and safety of statins in this gender . We used sequential electron-beam tomography ( EBT ) scanning to quantify changes in coronary artery calcium ( CAC ) as a measure of atherosclerosis burden in patients treated with statins . Methods and Results —In a double-blind , multicenter trial , we r and omized 615 hyperlipidemic , postmenopausal women to intensive ( atorvastatin 80 mg/d ) and moderate ( pravastatin 40 mg/d ) lipid-lowering therapy .  Patients also su bmi tted to 2 EBT scans at a 12-month interval ( mean interval 344±55 days ) to measure percent change in total and single-artery calcium volume score ( CVS ) from baseline . Of the 615 r and omized women , 475 completed the study . Mean±SD percent LDL reductions were 46.6%±19.9 % and 24.5%±18.5 in the intensive and moderate treatment arms , respectively ( P<0.0001 ) , and National Cholesterol Education Program Adult Treatment Panel III LDL goal was reached in 85.3 % and 58.8 % of women , respectively ( P<0.0001 ) . The total CVS% change was similar in the 2 treatment groups ( median 15.1 % and 14.3 % , respectively ; P = NS ) , and single-artery CVS% changes and absolute changes were also similar ( P = NS ) . In both arms , there was a trend toward a greater CVS progression in patients with prior cardiovascular disease , diabetes mellitus , and hypertension , whereas hormone replacement therapy had no effect on progression . Conclusions —In postmenopausal women , intensive statin therapy for 1 year caused a greater LDL reduction than moderate therapy but did not result in less progression of coronary calcification . The limitations of this study ( too short a follow-up period and the absence of a placebo group ) precluded determination of whether progression of CVS was slowed in both arms or neither arm compared with the natural history of the disease CONTEXT Statin drugs reduce both atherogenic lipoproteins and cardiovascular morbidity and mortality . However , the optimal strategy and target level for lipid reduction remain uncertain . OBJECTIVE To compare the effect of regimens design ed to produce intensive lipid lowering or moderate lipid lowering on coronary artery atheroma burden and progression . DESIGN , SETTING , AND PATIENTS Double-blind , r and omized active control multicenter trial ( Reversal of Atherosclerosis with Aggressive Lipid Lowering [ REVERSAL ] ) performed at 34 community and tertiary care centers in the United States comparing the effects of 2 different statins administered for 18 months . Intravascular ultrasound was used to measure progression of atherosclerosis .  Between June 1999 and September 2001 , 654 patients were r and omized and received study drug ; 502 had evaluable intravascular ultrasound examinations at baseline and after 18 months of treatment . INTERVENTIONS Patients were r and omly assigned to receive a moderate lipid-lowering regimen consisting of 40 mg of pravastatin or an intensive lipid-lowering regimen consisting of 80 mg of atorvastatin . MAIN OUTCOME MEASURES The primary efficacy parameter was the percentage change in atheroma volume ( follow-up minus baseline ) . RESULTS Baseline low-density lipoprotein cholesterol level ( mean , 150.2 mg/dL [ 3.89 mmol/L ] in both treatment groups ) was reduced to 110 mg/dL ( 2.85 mmol/L ) in the pravastatin group and to 79 mg/dL ( 2.05 mmol/L ) in the atorvastatin group ( P<.001 ) . C-reactive protein decreased 5.2 % with pravastatin and 36.4 % with atorvastatin ( P<.001 ) . The primary end point ( percentage change in atheroma volume ) showed a significantly lower progression rate in the atorvastatin ( intensive ) group ( P = .02 ) . Similar differences between groups were observed for secondary efficacy parameters , including change in total atheroma volume ( P = .02 ) , change in percentage atheroma volume ( P<.001 ) , and change in atheroma volume in the most severely diseased 10-mm vessel subsegment ( P<.01 ) . For the primary end point , progression of coronary atherosclerosis occurred in the pravastatin group ( 2.7 % ; 95 % confidence interval [ CI ] , 0.2 % to 4.7 % ; P = .001 ) compared with baseline . Progression did not occur in the atorvastatin group ( -0.4 % ; CI -2.4 % to 1.5 % ; P = .98 ) compared with baseline . CONCLUSIONS For patients with coronary heart disease , intensive lipid-lowering treatment with atorvastatin reduced progression of coronary atherosclerosis compared with pravastatin . Compared with baseline values , patients treated with atorvastatin had no change in atheroma burden , whereas patients treated with pravastatin showed progression of coronary atherosclerosis . These differences may be related to the greater reduction in atherogenic lipoproteins and C- reactive protein in patients treated with atorvastatin Aortic valve stenosis and atherosclerotic disease have several risk factors in common , in particular , hypercholesterolemia . Histologically , the diseased valves appear to have areas of inflammation much like atherosclerotic plaques . The effect of lipid-lowering therapy on the progression of aortic stenosis ( AS ) is unclear , and there are no r and omized treatment trials evaluating cardiovascular morbidity and mortality in such patients . The Simvastatin and Ezetimibe in Aortic Stenosis ( SEAS ) Study is a r and omized , double-blind , placebo-controlled , multicenter study of a minimum 4 years ' duration investigating the effect of lipid lowering with ezetimibe/simvastatin 10/40 mg/day in patients with asymptomatic AS with peak transvalvular jet velocity 2.5 to 4.0 m/s . Primary efficacy variables include aortic valve surgery and ischemic vascular events , including cardiovascular mortality , and second , the effect on echocardiographically evaluated progression of AS . The SEAS Study r and omly assigned 1,873 patients ( age 68+/-10 years , 39 % women , mean transaortic maximum velocity 3.1+/-0.5 m/s ) from 173 sites . Other baseline characteristics were mean blood pressure of 145+/-20/82+/-10 mm Hg ( 51 % hypertensive ) ; 55 % were current or previous smokers ; and most were overweight ( mean body mass index 26.9 kg/m2 ) . At baseline , mean total cholesterol was 5.7+/-1.0 mmol/L ( 222 mg/dl ) , low-density lipoprotein cholesterol was 3.6+/-0.9 mmol/L ( 139 mg/dl ) , high-density lipoprotein cholesterol was 1.5+/-0.4 mmol/L ( 58 mg/dl ) , and triglycerides were 1.4+/-0.7 mmol/L ( 126 mg/dl ) . The SEAS Study is the largest r and omized trial to date in patients with AS and will allow determination of the prognostic value of aggressive lipid lowering in such patients
Population Characteristics and Study Quality of Included Trials , by Combination Therapy Agent and Potency Comparison Long-Term Clinical Outcomes We found insufficient evidence to compare long-term clinical outcomes ( mortality , acute coronary events , cerebrovascular events , and revascularization procedures ) for all combination therapy and statin intensity comparisons .
Figure 1 presents an evidence map of studies that evaluated these
Atherosclerotic cardiovascular disease ( ASCVD ) affects more than 15 million Americans ( 1 ) and is the leading cause of death for both men and women in the United States ( 2 ) .
Trials have demonstrated reductions in low-density lipoprotein ( LDL ) cholesterol levels ( 3 ) and decreased ASCVD risk with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor ( statin ) monotherapy ( 4 ) .
Over the past decade , statins have often been used in combination with other lipid-modifying agents .
Recently , several high-profile r and omized , controlled trials ( RCTs ) have evaluated add-on therapy ( 57 ) , wherein statin monotherapy is compared with the combination of the same statin dose and another lipid-modifying agent .
Add-on combination therapy can lead to superior lipid outcomes , but studies have not shown decreased rates of cardiovascular death , myocardial infa rct ion , revascularization , or stroke ( 57 ) .
Therefore , the 2013 American College of Cardiology ( ACC ) and American Heart Association ( AHA ) guidelines recommend moderate- or high-intensity statin monotherapy as the first-line strategy for ASCVD risk reduction among patients with LDL cholesterol levels of 4.91 mmol/L or greater ( 190 mg/dL ) , preexisting ASCVD , diabetes mellitus ( DM ) , or estimated 10-year ASCVD risk of 7.5 % or greater ( 8) .
Adverse effects are more common with higher-intensity statin regimens ( 9 ) , and musculoskeletal adverse events occur frequently among patients with the C variant in the SLCO1B1 gene ( 10 ) .
The 2013 ACC/AHA guidelines suggest that clinicians consider moderated combination therapy with a lower-intensity statin and another lipid-modifying medication among high-risk patients ( LDL cholesterol level 4.91 mmol/L [ 190 mg/dL ] , preexisting ASCVD , or DM ) who are intolerant of or unresponsive to statins ( evidence grade E : expert opinion ) ( 8) .
Yet , it is unclear whether this strategy results in similar ASCVD risk reductions and fewer adverse effects compared with higher-intensity statin monotherapy .
A 2009 systematic review that examined these questions found insufficient evidence to weigh benefits and risks of moderated combination therapy ( 12 ) .
We aim ed to compare the effectiveness , safety , and tolerability of moderated combination therapy of statin with another lipid-modifying medication ( bile acid sequestrant , ezetimibe , fibrate , niacin , or -3 fatty acid ) with those of higher-intensity statin monotherapy among high-risk patients .
We sought to compare the long-term clinical benefits and short-term lipid effects of moderated combination therapy with those of higher-intensity statin monotherapy , as well as to determine whether these regimens differ in rates of adherence and harms .
Given the recent release of the 2013 ACC/AHA guidelines ( 8) , we narrowed the scope of this manuscript to focus on evidence most relevant to high-risk population s for whom combination therapy might be considered .
Prior studies have suggested schemes to group statins on the basis of their reported LDL cholesterol reduction ( 17 , 18 ) , which are similar to the strategy used by the ACC/AHA committee ( 8) .