Transcript
Page 1: Review of the New ACC/AHA Cholesterol Guidelines

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

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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

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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

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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

BIASES &VALUES

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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

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o No LDL target

o Statins only

o Only considered high quality RCT data

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4 statin benefit groups

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o ACS, h/o MI, angina, revascularization, TIA, stroke, peripheral arterial disease

o No RCTs identified that titrated drug therapy to specific LDL goals to improve ASCVD outcomes

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o Often genetic (family screening)

o Consider secondary causes– Drugs (diuretics, cyclosporin, glucocorticoids,

amiodarone)– Biliary obstruction, nephrotic syndrome– Hypothyroidism, pregnancy*

* Statins contraindicated in pregnancy & lactation

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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)

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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)]

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Primary Prevention

o Healthy individuals aged 40-75 yrs., without serious comorbidities and who were not taking drugs with potential for statin interaction

JAMA 11/25/13

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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

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

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o Conflicts of interest in most panel members

o Increased in statin utilization (“statinization”)?

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Conflicts of Interesto 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.

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Conflicts of Interesto COI should be disclosed

• Disclosure should reflect all current and planned commercial (including services from which a clinician derives a substantial proportion of income), non- commercial, 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

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“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!

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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

What effect did COIs have?

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Increased in statin utilization (“statinization”)?

o Risk calculator overestimates risko 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)

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

Health Affairs 2012

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o Risk prediction tool overestimates risk

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Clinical prediction rule development

Step 1. DerivationIdentification of factors with predictive power

Step 2. ValidationEvidence of reproducible accuracy

Narrow Validation Broad Validation

Application of a rule Application of a rule in a similar clinical in multiple clinical setting and population settings with varying as in Step 1 prevalence of disease

Step 3. Impact Analysis

Evidence that rule changes physician behavior and improves patient outcomes

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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

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Development of the Pooled Cohort Risk Assessment Equations

o Derivation– 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 (HDL-C), current smoking (Y/N), and diabetes (Y/N).

o Validation– Calculated area under the

receiver operating curve (C-statistic) 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.

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Validation

o Discrimination– Accurately determine if a person has or doesn’t

have disease– C-statistic or AUC

o Calibration– How well do predicted risk estimates match

observed risk in external populations

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Validation Women Men

Algorithm Derivation

Cohort

Validation Cohorts Algorithm Derivation

Cohort

Validation Cohorts

Contemporary (4)

MESA (5)

REGARDS (6)

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

C-statistic 0.8058 0.7377 0.7109 0.6599 0.7462 0.6843 0.7044 0.5950

Calib. Chi-sq 6.43 45.50 14.56 44.93 4.86 84.45 21.43 66.71

African American

Total N 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

C-statistic 0.8182 0.7068 0.7684 0.6625 0.7130 0.7109 0.6689 0.5564

Calib. Chi-sq 7.25 15.96 18.51 48.22 6.71 12.62 24.40 46.23

C statistic: range 0.5 – 1.0 (“reasonable” > 0.7, “strong” > 0.8)

(http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437741.48606.98/suppl/DC1 )

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Calibration

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External Validation

o How many of the 33 million expected to have risk >7.5% actually have risk that is much lower?

The Lancet, Volume 382, Issue 9907, Pages 1762 - 1765

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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

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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)

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Other recommendations from the guidelines

o CK should not be routinely measuredo Measure baseline ALT and only remeasure if

symptoms suggest hepatotoxicityo Screen for diabetes following current diabetes

screening guidelineso 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

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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

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Suggested Answerso 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.

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By Brian McFadden at DailyKos.com


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