Update on the New ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults Terry Shaneyfelt, MD, MPH Gen Med Noon Conf. December 10, 2013

Disclosures o > 5yrs ago speaker for unrestricted educational grant to Johns Hopkins School of Medicine on cholesterol mgmt and EBM Funded by AstraZeneca (Rosuvastatin) o VA P&T Committee member

Objectives o Apply the new guidelines to the care of adults at increased risk for ASCVD o Understand limitations of new pooled cohort risk prediction tool o Learn a little something about guideline limitations and prediction rules

Clinical practice guidelines are statements that include recommendations intended to optimize patient care that are informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options -- Institute of Medicine 2011

To be trustworthy guidelines must: o Be based on a systematic review of the existing evidence; o Be developed by a knowledgeable, multidisciplinary panel of experts and representatives from key affected groups; o Consider important patient subgroups and patient preferences, as appropriate; o Be based on an explicit and transparent process that minimizes distortions, biases, and conflicts of interest; o Provide a clear explanation of the logical relationships between alternative care options and health outcomes, o Provide ratings of both the quality of evidence and the strength of the recommendations; and o Be reconsidered and revised as appropriate when important new evidence warrants modifications of recommendations. IOM 2011

o No LDL target o Statins only o Only considered high quality RCT data

o ACS, h/o MI, angina, revascularization, TIA, stroke, peri pheral arterial disease o No RCTs identified that titrated drug therapy to specific LDL goals to improve ASCVD outcomes

o Often genetic (family screening) o Consider secondary causes Drugs (diuretics, cyclosporin, glucocorticoids, amiodaron e) Biliary obstruction, nephrotic syndrome Hypothyroidism, pregnancy* * Statins contraindicated in pregnancy & lactation

o Extrapolation of data for primary prevention in high risk ( 7.5% 10 yr risk) who did not have diabetes Expert opinion, some conflicting data (IIa, B) o < 40 or > 75 yrs the decision to initiate statin therapy should be individualized Expert opinion, divergent opinions (IIa, C)

o Most controversial area of guideline because of risk equations & lower cut off o Reasonable to offer statin therapy to those with risk of 5-7.5% [conflicting evidence (IIa, B)]

Primary Prevention JAMA 11/25/13 o Healthy individuals aged 40-75 yrs., without serious comorbidities and who were not taking drugs with potential for statin interaction

Primary Prevention o CTT metaanalysis (Lancet 2012;380:581) Similar efficacy findings found increased risk of myopathy (NNH 2000), diabetes (NNH 200) and hemorrhagic stroke (NNH 2000) No reduction in CVD events in patients with Heart failure Maintenance hemodialysis

Lancet 2012;380:581 1 mmol/l = 38.6 mg/dl

o Conflicts of interest in most panel members o Increased in statin utilization (statinization)?

Conflicts of Interest o 2 main types Financial Intellectual o Per IOM 2011: Whenever possible GDG members should not have COIs. Members with COIs should represent not more than a minority of the GDG. The chair or co-chairs should not be a person(s) with COIs. Funders should have no role in CPG development.

Conflicts of Interest o COI should be disclosed Disclosure should reflect all current and planned commercial (including services from which a clinician derives a substantial proportion of income), noncommercial, intellectual, institutional, and patient public activities pertinent to the potential scope of the CPG. o Members of the GDG should divest themselves of financial investments they or their family members have in, and not participate in marketing activities or advisory boards of, entities whose interests could be affected by CPG recommendations

Majority of panelists on controversial new cholesterol guideline have current or recent ties to drug manufacturers - BMJ 2013;347:16989 o Neil Stone, MD (chairman) Abbott, AstraZeneca, Merck, Pfizer, Sanofi-Aventis and Schering-Plough I will not take industry funding for 2 years after release of the guidelines o Jennifer Robinson, MD (Co-chair) Financial ties to several statin manufactures while on panel from 2008-2013 o 6 of 8 panelist with financial ties during service on the panel!

Conflicts of Interest o Members with conflicts were asked to recuse themselves from voting on any aspect of the guideline where a conflict might exist o Independent contractors performed the systematic review of evidence

Increased in statin utilization (statinization)? o Risk calculator overestimates risk o Lower thresholds to initiate statin therapy o 101 million people in US aged 40-79 yrs without cardiovascular disease 33 million expected to have 7.5% predicted risk 13 million expected to have 5-7.4% predicted risk US population 1/20th global population in this age range (33+13) x 20 = 920 million worldwide would be new statin candidates (JAMA 12/2/13)

Is this a bad thing? MI and stroke are leading causes of death in the US Health Affairs 2012

o Risk prediction tool overestimates risk

Clinical prediction rule development Step 2. Validation Evidence of reproducible accuracy Step 1. Derivation Identification of factors with predictive power Narrow Validation Application of a rule in a similar clinical setting and population as in Step 1 Broad Validation Application of a rule in multiple clinical settings with varying prevalence of disease Step 3. Impact Analysis Evidence that rule changes physician behavior and improves patient outcomes

Why a new risk predictor? o Previously used Framingham risk score was not felt to be adequate because of its derivation in an exclusively White sample population and the limited scope of the outcome (in determining CHD alone). o Other risk scores also suffered from nonrepresentative or historically dated populations, limited ethnic diversity, narrowly defined endpoints, endpoints influenced by provider preferences (e.g., revascularizations), and endpoints with poor reliability (e.g., angina and heart failure [HF]). o Broader outcomes of interest ASCVD: first occurrence of nonfatal myocardial infarction or CHD death, or fatal or nonfatal stroke

Development of the Pooled Cohort Risk Assessment Equations Used several large, racially and geographically diverse, modern NHLBI-sponsored cohort studies, including the ARIC study, Cardiovascular Health Study, and the CARDIA study, combined with applicable data from the Framingham Original and Offspring Study cohorts Sex-and race-specific proportional hazards models that included the covariates of age, treated or untreated systolic blood pressure (SBP), total cholesterol, high-density lipoprotein cholesterol (HDLC), current smoking (Y/N), and diabetes (Y/N). Calculated area under the receiver operating curve (Cstatistic) for discrimination and the calibration chi-squared statistic External validation done in external cohorts consisting of Whites and African Americans from the Multi-Ethnic Study of Atherosclerosis (MESA) and the REasons for Geographic And Racial Differences in Stroke study (REGARDS) and contemporary cohorts from ARIC and Framingham.

Validation o Discrimination Accurately determine if a person has or doesnt have disease C-statistic or AUC o Calibration How well do predicted risk estimates match observed risk in external populations

Validation (http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437741.48606.98/suppl/DC1 ) Wom en Algorithm Derivation Cohort Men Validation Cohorts Contemporary (4) MESA (5) Validation Cohorts Algorithm REGARDS (6) Derivation Cohort Contemporary (4) MESA (5) REGARDS (6) White Total N 11,240 6,509 1,273 6,333 9,098 5,041 1,184 5,296 Events(1) 683 400 37 101 1,032 539 57 218 Events(2) 722.9 426.7 38.4 120.7 1,095.2 580.9 59.7 250.2 Exp Events(3) 723.5 549.4 49.9 153.9 1,098.5 798.9 94.9 306.4 0.8058 0.7377 0.7109 0.6599 0.7462 0.6843 0.7044 0.5950 6.43 45.50 14.56 44.93 4.86 84.45 21.43 66.71 2,641 1,367 978 5,275 1,647 735 799 2,969 Events(1) 235 127 28 126 194 107 36 136 Events(2) 248.7 131.3 30.1 147.1 213.8 114.0 38.3 162.5 Exp Events(3) 250.6 173.5 59.4 217.5 212.5 120.8 72.3 180.7 0.8182 0.7068 0.7684 0.6625 0.7130 0.7109 0.6689 0.5564 7.25 15.96 18.51 48.22 6.71 12.62 24.40 46.23 Cstatistic Calib. Chi-sq African Am erican Total N Cstatistic Calib. Chi-sq C statistic: range 0.5 1.0 (reasonable > 0.7, strong > 0.8)

Calibration

External Validation The Lancet, Volume 382, Issue 9907, Pages 1762 - 1765 o How many of the 33 million expected to have risk >7.5% actually have risk that is much lower?

What should you do about risk assessment? o Use the pooled risk estimation equations o Use other risk scores (eg Framingham, QRISK, etc) o Ignore any risk assessment and consider that almost everyone benefits from primary prevention o Use eligibility criteria of the primary prevention trials

Other recommendations from the guidelines o In lower risk patients (5-7.5%, < 40 or > 75 yrs) clinicians should discuss with patients: ASCVD risk reduction benefits (30% RRR MIS, 45% HIS) Adverse effects (diabetes NNH 200) Drug-drug interactions Patient preferences o In lower risk individuals also consider: FH of premature CAD (< 55yo M, < 65yo F) hsCRP > 2 CAC score >300 Agatston units (or >75 percentile for age)

Other recommendations from the guidelines o CK should not be routinely measured o Measure baseline ALT and only remeasure if symptoms suggest hepatotoxicity o Screen for diabetes following current diabetes screening guidelines o Muscle symptoms: Temporarily d/c statin and assess for rhabdo if severe & other conditions that cause muscle symptoms Rechallenge with lower or same dose of statin If statin causative then give lower dose of different statin

Other recommendations from the guidelines o No recommendations for add-on therapy to lower LDL after optimal statin dosing o Separate guideline on triglycerides (Circul 2012) No gemfibrozil Fenofibrate only if TG > 500 mg/dl and benefits judged to outweigh risks o Consider rechecking lipid panel 4-12 wks after initiation to assess for adherence but not to adjust therapy

Suggested Answers o Case 1: B Pt has ASCVD and should be on high intensity statin o Case 2: A or B Risk is estimated at 7.2% which is below absolute recommended cutoff to initiate statin therapy for primary prevention o Case 3: E (if not tolerated then D) Risk is estimated at 9.1% (driven by age) which is above the 7.5% threshold.

By Brian McFadden at DailyKos.com