Presentation on theme: "Lipid Guideline Controversies in 2014: The Decision is Yours"— Presentation transcript:
1Lipid Guideline Controversies in 2014: The Decision is Yours Carl E. Orringer, MD, FACC, FNLA
2ObjectivesTo provide an overview of the American College of Cardiology/American Heart Association and the National Lipid Association lipid management approaches for ASCVD preventionTo identify the similarities and differences between the two approachesTo provide the information needed to decide which approach to use and when
3Two Different Perspectives Two ASCVD Prevention ApproachesTwo Different PerspectivesExternal reviewerAuthor
5Mean age-adjusted LDL-C trends 2001–2011 in the United States: Analysis of 105 million patient recordsfrom a single national diagnostic laboratory/journal.pone
6Is There a Need for a Dramatic Change in Approach to ASCVD Prevention? ACC/AHACCSIASEAS/ESCJASNICENLAChanges in:Evidence baseCentral focusLipid goalsUse of non-statinsRisk calculator
7The Rules The topic will be identified Common ground and differences will be notedAppropriate supporting evidence will be introducedSummary will be providedYou make the decision
8Evidence Base ACC/AHA NLA Randomized controlled trials (RCT) of statin therapyMeta-analyses of RCTRCT of statins and non-statin drug therapyMeta-analyses of RCTObservational epidemiologic studiesGenetic studiesMetabolic studiesMechanistic studies
9Randomized Controlled Trials (RCT) Systematically test effect(s) of an intervention on pre-specified outcomes in defined populationsTheir use minimizes confoundingStudy populations are often not diverse and exclusion criteria may hamper physician’s ability to apply results to real-world patientsMost are designed to gain regulatory registration for pharmaceutical agents; lifestyle trials, studies of generic drugs or of those produced by smaller companies may be under-represented in RCT due to inadequate financial support
10Observational Epidemiologic Studies Worldwide in scope and may assess ASCVD risk across populationsCohort studies evaluate mortality and morbidity within populationsConfounding may occur even after matching, stratification, and multivariate adjustment because of measurement error or unmeasured or unknown risk factors
11Observational Epidemiologic Cohort Study of 2146 Patients with FH and no CHD at Baseline Versmissen J, et al BMJ 2008; 337: a2423
12Genetic StudiesGenetic epidemiology reduces the likelihood of confounding by focusing on single variables: genetic mutationsIdentification of specific mutations may serve to generate hypotheses for other types of trialsOften limited in patient selection and costly
13Data Demonstrating Genetic Variants Affecting ASCVD Risk Sequence variants in the gene encoding for PCSK9 resulting in loss of function mutations are associated with 28% reduction in LDL-C, an 88% reduction in CHD risk and provide support for the value of long term low LDL-C in promoting CHD risk reductionJ Cohen et al. N Engl J Med 2006;354:
14Evidence Base: Summary ACC/AHABy limiting the scope to RCT of statins and meta-analyses of RCT, only the highest level of evidence on statins in defined populations is employed to assess ASCVD outcomesNLABy including evidence from RCT and other sources, a broader evidence base for clinical decision making is employed . This approach is consistent with the perspective of previous NCEP ATP’s and the international community
15Central Focus of Guideline ACC/AHANLAIdentification of statin benefit groupsInitiation and maintenance of high or moderate intensity statin therapyAbandonment of lipid goalsAvoidance of non-statin therapy because of “unfavorable risk/benefit ratio.”Identification of an individual patient’s ASCVD risk based on clinical parameters and risk factorsInitiation of ASCVD risk-based lipid-lowering therapyMaintenance of lipid goals to assess effective reduction of atherogenic lipoproteins and enhace adherenceUse of high or moderate dose statins, ±non-statins, if necessary, to achieve goals
16ACC/AHA Statin Benefit Groups H=High intensity statin; M=Moderate intensity statinIndividuals with clinical ASCVD without New York Heart Association class II-IV heart failure or receiving hemodialysis (H preferred; M if age >75 or if not candidate for H).Individuals with primary elevations of LDL-C ≥190 mg/dl (H preferred; M if not candidate for H).Individuals age years with diabetes, and LDL-C mg/dl without clinical ASCVD (M if 10 yr risk <7.5%; H if ≥7.5%).Individuals without clinical ASCVD or diabetes, who are age years with LDL-C mg/dl, and have an estimated 10-year ASCVD risk of ≥ 7.5% using Pooled Cohort Equations (M or H).
17High- and Moderate-Intensity Daily Statin Therapy High Intensity (Lowers LDL-C ≥ 50%)Atorvastatin mgRosuvastatin mgModerate Intensity (Lowers LDL-C 30-50%)Atorvastatin 10 (20) mgRosuvastatin (5) 10 mgSimvastatin 20–40 mgSimvastatin 80 mg*Pravastatin 40 (80) mgLovastatin 40 mgFluvastatin XL 80 mgFluvastatin 40 mg 2x/dayPitavastatin 2–4 mgBold = Tested in RCT andreviewed by Expert PanelYellow= Not tested in RCT
18Efficacy of Intensive Lowering of LDL-C in Subjects with Low Baseline LDL-C Meta-analysis of RCT’s of >1000 participants and ≥2 years treatment duration of more versus less intense statin trials involving 169,138 subjectsThe major vascular event reduction, among in those with baseline LDL-C <77mg/dL per further 39 mg/dL reduction was 29% (99% CI 2-48, p=0.007); in those with baseline LDL-C <70 mg/dl, similar reduction in LDL-C continued to demonstrate MVE reduction (RR 0.63, 99% CI , p=0.004).Cholesterol Treatment Trialists Collaboration. Lancet 2010;376:
19ACC/AHA Perspective on Statin Therapy Statin intensity trials showed clear benefit for high intensity versus moderate intensity statinsBecause fixed doses, not dosage titrations, were employed, one should not assume that a dosage titration strategy is correct or that addition of non-statins to achieve low LDL-C is indicated
20ACC/AHA Perspective on Non-Statin Lipid Drug Therapy Non-statin drugs without demonstrated ASCVD risk reduction may favorably alter lipids but have an unfavorable risk/benefit ratioNiacin in AIM-HIGH and HPS-2 THRIVEFibrates in ACCORD-Lipid, FIELDLack of ASCVD event end-point data on ezetimibeCETP inhibitors torcetrapib and dalcetrapibThe use of non-statin drugs should generally be avoided
21Overview of the NLA Recommendations All preventive therapy begins with risk assessment and a provider-patient discussion of the pros and cons of therapyLifestyle therapy is at the basis of all ASCVD preventive recommendations, regardless of baseline riskJudicious use of evidence-based drug therapy, particularly moderate and high-dose statins, is associated with optimal ASCVD risk reductionWhen excessive circulating atherogenic cholesterol (non-HDL-cholesterol and LDL cholesterol) persists after appropriate lifestyle and statin therapy, the use of non-statin therapy may be consideredLong-term follow-up fostered by provider-patient communication is essential for optimal ASCVD preventionThis slide provides an overview of the NLA Recommendations for the Patient-Centered Management of Dyslipidemia. You will note that it begins with and ends with provider patient interaction.
22NLA ASCVD Risk Category Criteria Very HighASCVDDiabetes mellitus (type 1 or 2)≥2 other major ASCVD risk factors; orEvidence of end-organ damageHigh≥3 major ASCVD risk factors0-1 other major ASCVD risk factor, andno evidence of end-organ damageChronic kidney disease Stage 3B or 4LDL-C ≥190 or non-HDL-C ≥220 mg/dLModerate2 major ASCVD risk factorsFor specific clinical features, high quantitative risk score or specific biomarker levels, consider reclassification to high riskLow0-1 major ASCVD risk factorFor specific clinical features, consider reclassification to moderate riskThe NLA Recommendations advocate risk categorization, beginning with very-high and moving to progressively lower risk groups. Specific criteria are used for each risk category. Once the clinician defines the highest risk category applicable to a patient, the next step is discussion with the patient about risk-appropriate atherogenic cholesterol lowering therapy.
23NLA ASCVD Risk Categories, Levels for Consideration of Drug Therapy and Treatment Goals Risk CategoryConsider Drug TherapyTreatment GoalNon-HDL-C /LDL-C Goal (mg/dL)Non-HDL-C/LDL-C Goal (mg/dL)Very-high≥100≥70<100<70High≥130<130Moderate≥160Low≥190Recognizing that lifestyle therapy is always advocated as the basis for ASCVD prevention, this slide provides the NLA perspective on non-HDL-C and LDL-C thresholds for considering drug therapy and treatment goals. The non-HDL-C and LDL-C levels at which drug therapy should be considered vary in accordance with the absolute risk of the patient. However, the treatment goals are all <130 for non-HDL-C and <100 mg/dL for LDL-C, except in the very high risk patient in whom the non-HDL-C goal is <100 and LDL-C goal <70 mg/dL.For patients with ASCVD or diabetes mellitus, consider use of moderate or high intensitystatins, irrespective of baseline atherogenic cholesterol levels.
24NLA Perspective on Statin Therapy Statin therapy is the most potent and evidence-based approach to lowering atherogenic lipoproteins (non-HDL-C and LDL-C)Statin intensity trials showed clear benefit for high-intensity versus moderate-intensity statinsBroad-based evidence supports “lower is better” concept, and provides an opportunity for clinicians to address residual risk above that addressed by appropriately-dosed statin therapy
25NLA Perspective on Non-Statin Lipid Drug Therapy If non-HDL-C and LDL-C goals are not achieved with maximal tolerated statin therapy, the addition of non-statin therapy should be considered to lower atherogenic cholesterol levels and to achieve goalsDoctors can be instructed not to use niacin in patients on aggressive statin regimensAs ezetimibe is safe and lowers atherogenic cholesterol, its use may be considered in selected patients with elevated non-HDL-C and/or LDL-CResins may be considered in selected patientsMeta-analyses of fibrate therapy in subgroups with atherogenic dyslipidemia suggest ASCVD risk reduction
26Is High-Dose Statin Therapy the End of the Line?
27Variability of Achieved LDL-C With High-Intensity Statin Therapy Boekholdt SM et al. J Am Coll Cardiol 2014;64:Meta analysis of 8 statin RCT involving 38, 153 subjects of whom 5,387 had 6,286 major CV events and had baseline and 1 year lipids and lipoproteinsWaterfall plot ofIndividual valuesFrom TNT,SPARCL, IDEAL andJUPITERdemonstratingvariability ofLDL-C lowering.>40% did not achieveLDL-C <70 mg/dl onatorvastatin 80 orrosuvastatin 20 mgdailyBoekholdt’s meta-analysis of 8 statin RCT’s involving 38,153 subjects focused on 5,387 subjects who had 6,286 major CV events and had baseline and 1-year lipids and lipoproteins. In those receiving atorvastatin 80 mg daily or rosuvastatin 20 mg daily more than 40 % did not achieve LDL-C <70 mg/dl.
28Very Low LDL-C and Non-HDL-C in Statin Trials and Major CVD Event Risk On Treatment LDL- C, Non-HDL-C mg/dLBoekholdt et al. JACC 2014;64:
29Central Focus of Guidelines: Summary ACC/AHA: define statin benefit groups; risk/benefit discussion; use moderate or high-intensity statin therapy with lifestyle change as background therapy; generally avoid non-statin drug therapy; no lipid goalsNLA: identify ASCVD risk level; risk/benefit discussion; emphasize healthy lifestyle and use moderate or high-intensity statin therapy, and if necessary, adjunctive non-statin therapy, to lower atherogenic cholesterol; maintain lipid goals (non-HDL-C is favored lipoprotein target)
30Risk Calculators ACC/AHA NLA Use Pooled Cohort Risk calculator in non-Hispanic Whites and non-Hispanic African Americans age without ASCVD and not on statin therapy; may be considered in other populationsAssessment of lifetime risk may be considered in those aged with no ASCVD and not at high short-term riskConsider 10-year FRS, ACC/AHA Pooled Cohort Risk calculator, or 30-year risk in those with 2 major ASCVD risk factors; re-classify to higher risk those with ≥10% 10-year FRS, ≥15% ACC/AHA risk, or ≥45% long-term riskOne of the most contentious controversies between the ACC/AHA Guideline and the NLA Recommendations relates to the use of risk calculators. The ACC/AHA Guideline advocates the use of the Pooled Cohort Risk calculator in non-Hispanic Whites and non-Hipsanic African Americans age without ASCVD and not on stain therapy, and suggested that it could reasonably be used in other populations. The use of the lifetime risk calculator was suggested for those individuals age not found to be a high risk. The NLA Recommendations advises consideration of any of three risk calculators, including Framingham 10-year risk, Lifetime or 30 year risk, or the 10-year Pooled Cohort Risk in those with 2 major risk factors.
31This is a screen shot of the ACC/AHA risk calculator used to demonstrate 10 year ASCVD risk using the Pooled Cohort Risk Equations calculator available on the Cardiosource.org website. The variables employed include gender, age, HDL-C, systolic blood pressure, treatment for hypertension, cigarette smoking status and diabetes mellitus. When all of these variable are entered the 10 year calculated risk appears at the top on the left. Below it there is a box that estimates the patient’s risk level if all of those risk factors were optimal. To the right of those numbers there are boxes that estimate lifetime or 30-year ASCVD risk, a calculation that is recommended for consideration for individuals between the age of 20 and 59 with 10-year risk <7.5%. The Risk Assessment Working Group of the ACC/AHA does not use lifetime risk to advise the initiation of drug therapy, but suggests that such information may be of value when counseling individuals on the value of initiating lifestyle therapy for ASCVD prevention.
32Key Disclaimer of the ACC/AHA Pooled Cohort Risk Calculator It does not definitively recommend statin therapy for individuals with 10-year risk ≥7.5%It advises that for such individuals before initiating statin therapy “it is reasonable for clinicians and patients to engage in a discussion which considers the potential for ASCVD risk reduction benefits and for adverse effects, for drug-drug interactions and patient preferences for treatment.”The ACC/AHA Expert Panel emphasizes that the finding of a 7.5% 10 year risk is not an automatic recommendation for statin therapy, but represents a level at which joint patient provider discussion should be undertaken, explaining to the patient the benefit of starting statin therapy.
33Pooled Cohort Equations: Criticism Early criticism of the Pooled Risk calculator centered around lack of long-term prospective validation and possible overestimation of riskWhen the Pooled Risk Equation calculator was applied to 3 large, more recent primary prevention cohorts, the Women’s Health Study, the Physician’s Health Study and the Women’s Health Initiative Observational Study, it systematically overestimated observed risk by %, roughly doubling the actual observed riskAs the Pooled Cohort Equations lacked prospective long-term validation, debate ensued on the advisability of using this tool for clinical risk assessment and management reccommendations.Ridker PM, Cook NR. Statins: new American guidelines for prevention of cardiovascular disease.Lancet /S (13) published Nov 20. PubMedCopyright NLA 2014
34Pooled Cohort Equations: Defense Validation was more extensive than any other previous risk equationsThe primary prevention cohorts of WHS, PHS and WHI were likely significantly healthier than the general populationIn WHS and PHS some risk factors were self-reported in ranges rather than directly measured, resulting in imprecisionAll 3 cohorts might have been subject to some downstream initiation of statinsThe response to these criticisms were centered on potential selection of usually healthy subjects in the Women’s Health Study, Physician’s Health Study and Women’s Health Initiative populations; on the potential inaccuracy of self-reported rather than measured risk factors; and on the possibility that downstream initiation of statins may have been responsible for overestimation of risk.Lloyd-Jones DM, Goff D and Stone N. The Lancet, Early OnlinePublication, 4 December 2013 doi: /S (13)62348-XCopyright NLA 2014
35Pooled Cohort Equations: Criticism An analysis of the Women’s Health Study examined data from 632 women who had an ASCVD event over a median follow-up of 10 yearsAfter adjustment for the intervention effects of statins, revascularization and hypothetical confounding by indication the ratios of predicted to observed events were 1.8 in those with 0-<5% and 5-7.4% estimated 10-year risk and 1.3 in the groups with % and >10% estimated 10 year risk groupsA more recent analysis adjusted for intervention of statins, revascularization and hypothetical confounding and still found that the risk calculator over-estimated risk in the Women’s Health Study.Cook NR, Ridker PM. JAMA Intern Med Published Online October 6, 2014
36Pooled Cohort Equations: Defense 10,997 adults, ages 45-79, in the Reasons for Geographic Distribution and Racial Differences in Stroke study, without ASCVD or diabetes, with total cholesterol mg/dl and not taking statins were examined for incident ASCVD at 5 years, and additional analysis in 3,333 Medicare beneficiaries added additional ASCVD events as defined in Medicare Claims data.There was a high degree of correlation between observed and predicted ASCVD incidence per 1,000 person-years in groups with <5%, 5-<7.5%, 7.5-<10% and ≥10% (calibration) and moderate to good ability to accurately rank-order individuals (discrimination) (C-statistic ~0.7).Further validation of the Pooled Risk Equations was provided in this 2014 study, which demonstrated a high degree of correlation between observed and predicted ASCVD incidence in low, intermediate and high risk groups.Muntner P et al. JAMA 2014;311:Copyright NLA 2014
37Pooled Cohort Equations: Criticism Application to elderly populationsWhen the risk calculator was applied to 4,854 Rotterdam Heart Study participants with a mean age of 65 years, 96.4% of men and 65.8% of women would be recommended statinsThe average predicted versus observed cumulative incidence of hard ASCVD events was 21.5 vs % for men and 11.6 vs. 7.9% for women (poor calibration)There is continuing concern that the Pooled Cohort Equations recommend statin use in too many elderly patients. One example of this was noted when the Pooled Cohort Equations were applied to men and women participating in the Rotterdam Heart Study.Kavousi M et al. JAMA 2014: 311(14):
38ACC/AHA Risk Calculator: Possible Overtreatment in Older Patients? AgeTotal cholesterolHDL cholesterolSystolic BPTreatment for HBPDiabetesSmoker10-year ASCVD risk60 AA♂17050125No7.5%65 AA♀17813060 C ♂47Examining US populations, the individuals for who the Pooled Cohort Equations were designed, this slide provides 3 examples of patients for whom clinicians might not normally consider statin therapy.
39NLA Perspective on Risk Calculators Although any of 3 risk calculators are suggested for consideration (10 year Framingham risk, lifetime Framingham risk, ACC/AHA Pooled Cohort Risk Calculator), risk calculators measure diverse endpoints and have limited application in various ethnic and age groupsThe interpretation of a particular risk level using any risk calculator in a given patient must be done using careful clinical judgmentThe NLA Expert Panel provides a more conservative approach to the use of risk calculators, suggesting consideration of their use only in intermediate risk individuals for whom the clinician feels that more information is required to make preventive lipid therapy management decisions. It recognizes that each risk calculator examines different endpoints, has its strengths and weaknesses in any given patient and that careful clinical judgment must be used in applying the results to the management of a specific patient.
40Risk Calculators ACC/AHA NLA Consider 10-year FRS, ACC/AHA Pooled Cohort Risk calculator, or 30-year risk in those with 2 major ASCVD risk factors; re-classify to higher risk those with ≥10% 10-year FRS, ≥15% ACC/AHA risk, or ≥45%% long-term riskUse Pooled Cohort Risk calculator in non-Hispanic whites and non-Hispanic African Americans age without ASCVD and not on statin therapy; may be considered in other populationsAssessment of lifetime risk may be considered in those aged with no ASCVD and not at high short-term risk
41Lipid Guideline Controversies: Common Threads Between ACC/AHA and NLA Lifestyle therapy is warranted for ASCVD risk reduction, whether or not drug therapy is usedPatients with ASCVD, FH and diabetes are candidates for moderate or high-dose statinsRisk calculators aid in, but do not take the place of clinical judgmentWhether or not lipid goals are set, regular lipid follow-up is warranted to assess adherencePatient engagement in preventive care decision making aids in long-term adherence
42What’s Ahead in Guidelines? A new app for the NLA Recommendations Part 1New ACC/AHA performance measures related to the 2013 Blood Cholesterol Guideline and another app related to the GuidelineNLA Recommendations Part 2 on special populations (women, elderly, HIV, south Asian Indians, Hispanic, CKD, heart failure, rheumatoid arthritis)A new NLA Self-Assessment Program on Guidelines