PREPARING FOR GUIDELINES IN 2013

Neil J. Stone MD, MACP, FAHA, FACC, FNLABonow Professor of Medicine Division of CardiologyFeinberg School of MedicineNorthwestern University Chicago Campus

DisclosuresNo relationships with industry to disclose.

I am chair of the ATP IV panel appointed by NHLBI. The official report is under review.

Views expressed in this talk are my own and not necessarily those of ATP IV.

This is not an official report of ATP IV and should not be reported as such

Why Guidelines for CVD from atherosclerosis? They are important!

• Atherosclerosis is global

• Costs of managing atherosclerosis are substantial

• Population is growing older – more in the ages where CVD from atherosclerosis is common

• Women get atherosclerosis and those with atherosclerosis benefit as much from statins as men

Estimated direct and indirect costs (in billions of dollars) of major cardiovascular diseases and stroke – in US. 2010. Source: NHLBI

177.1

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Prevalence of CVD in adults age 20 and older by age and sex (NHANES 2003-2006). Source: NCHS and NHLBI. These data include coronary heart disease, heart failure, stroke and hypertension.

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Annual rate of first heart attack by age, sex and race.ARIC Surveillance: 1987-2004Source: NHLBI.

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35-44 45-54 55-64 65-74

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Guidelines – What We Should ExpectFoundation for Clinical Management

• Authoritative and trustworthy

• Reflect established science

• Inclusive/Transparent

• IOM (Institute of Medicine). Clinical Practice Guidelines We Can Trust. Washington, DC: National Academies Press; 2011

Guidelines – Challenges A Foundation for Clinical Management

1) Which patients benefit 2) What therapy,3) What age 4) What Rx intensity

B) Keep it Simple

Guidelines – Challenges Authoritative/Trustworthy:

Deal with bias/conflicts of interest transparently-Diverse panel; appropriate recusal -Focus on RCTs whose value judged by independent

panel -Less emphasis on expert opinion

Reflect established science-Address critical questions; not a lipid primer

Inclusive/Transparent Important for patients, physicians, other stakeholders

How Have Guidelines Been Doing?

“Fewer than half the guidelines surveyed met more than 50% of the IOM standards”Arch Intern Med. 2012;172(21):1628-1633.

•

Arch Intern Med. 2012;T. Shaneyfelt

Guideline panel membership is a main determinant of trustworthiness of guidelines

Even more problematic for guideline consumers is determining the role of conflicts of interest (COI)

Majority have no COIChairs have no COI

Those with significant COI do not participate in voting on recommendations but may offer written input so their clinical and research expertise is maintainedA closely related topic if the single subspecialty panel....

Three Critical Questions• What is the evidence that treatment to LDL-Cholesterol and non HDL-C goals reduces outcomes in atherosclerotic cardiovascular disease in

• Primary Prevention• Secondary Prevention

• What is the evidence for efficacy and safety of each of the 5 lipid drug classes

Cautions/Benefits of RCTs, systematic reviews and meta-analyses to guide practiceLook for:

-Prospective definition of Inclusion/Exclusion criteria-Individual level meta-analysis

Cautions:-Avoid low quality RCT’s, systematic reviews and meta-analyses

Limitations: • For risk assessment: cohort trials more inclusive• For adverse effects of large effect

–observational often adequate:• By definition, RCTs by their selection, limit generalizability

Look for: -Prospective definition of Inclusion/Exclusion criteria-Individual level meta-analysis

Cautions:-Avoid low quality RCT’s, systematic reviews and meta-analyses

Limitations: • For risk assessment: cohort trials more inclusive• For adverse effects of large effect

–observational often adequate:• By definition, RCTs by their selection, limit generalizability

Cautions/Benefits of RCTs, systematic reviews and meta-analyses to guide practiceBenefits:

The advantage of inclusion/exclusion criteria for RCTs is that they define clearly

-the population that derives treatment benefit -the proportion that do not tolerate treatment, drop out or experience harms-allow number needed to treat to be compared tonumber needed to harm -assessment if the benefits are worth the risks

Importantly, in the field of ASCVD prevention, a robust database of RCTs has developed that looks at participants over a wide range of LDL-cholesterol, co-morbidities, and cardiovascular severity

Why use data from RCTs and meta-analyses of RCTS in clinical practice?

What about those who didn’t qualify for these trials?1. Should be a focus of ongoing research investigations

2. Patients need to know what decisions are based on data that is less “solid” so they can participate in shared

decision making

3. Guidelines can help address concerns of “maximizers” and minimizers”** among us**.

4. Can’t assume all “high CVD risk” patients benefit from statins:e.g. Heart failure, hemodialysis, and/or aortic stenosis

_________________________**From Groopman J, Hartzband P. “Your Medical Mind: How to

Lancet 2005; 366: 1267–78

This

We undertook meta-analyses of individual participant data from randomized trials involving at least 1000 participants and at least 2 years of treatment duration for more versus less intensive statin regimens

CTT Collaboration: Lancet 2010; 376: 1670-1681

CTT Collaboration: Lancet 2010; 376: 1670-1681

Further reduction in LDL cholesterol safely produce definite further reductions in the incidence of heart attack, of revascularization and of ischemic stroke with each 38.7 mg/dl (1 mmol/L) reducing reducing the annual rate of these MVE by just over 1/5th

No threshold effect seen within the range studied

Statins reduce relative risk of major CVD* in Secondary and Primary Prevention

• Major CVD = first occurrence of any major coronary event (nonfatal MI, coronary death) , coronary revascularization, or stroke

• 1 mmol/L = 39 mg/dL

Primary prevention

CTT Collaboration: Lancet 2010; 376: 1670-1681

CTT Collaboration 2010; 376: 1670-1681

Traits Events (%/yr) RR (CI) per 38.7 mg/dl Heterogeneity/

Statins/more control/less reduction in LDL-c trend test

High vs. lower dose statin comparative studies in secondary preventionStudy Acute/chronic CAD Intervention/

comparatorPROVE IT Acute atorva 80 vs prava 40TNT Chronic atorva 80 vs atorva 10IDEAL Chronic atorva 80 vs simva 20-40SEARCH Chronic simva 80 vs simva 20A-Z Acute simva 40-80 vs Placebo

then simva 20CTT Collaboration: Lancet 2010; 376: 1670-1681

Value of RCTs seen in this groupTwo of the trials showed reasons not to use simvastatin 80 mg daily

-Lack of increased efficacy in A-Z-Unacceptable myopathy (rhabdo) incidence in

SEARCHA. SLC01B1 genetic variant in more than 60%B. Drug-drug interactions – e.g. amiodarone

FDA Other cardiac drug-drug: diltiazem, amlodipine, verapamil

deLemos et al JAMA 2004;292:1307-1316 Study of the Eðectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative

Group:Lancet 2010; 376: 1658 1669

More Statin versus less

CTT Collaboration: Lancet 2010; 376: 1670-1681

Effects on major vascular events per 38.7 mg/dl (1 mmol/L) reduction in LDL-c by baseline LDL-C in less intensive or control rgimen

Baseline LDLc

Effects on Cause Specific Mortality per 38.7 mg/dl (1 mmol/L) reduction in LDL-C

Statin Rx Does Not Increase Risk for Cancer

Address Side-EffectsDiabetes

Muscle Aches and Pains

Cognitive Function

Liver function

Preiss D, Sattar N. Current Opinion in Lipidology2011:22:460-466

Incident diabetes

Incident CVD

Secondary prevention studies

Lessons from a primary prevention trial on statins and diabetes• Jupiter clinical trial: 17,603 men/women randomized to rosuvastatin 20 mg vs placebo• Primary prevention (Ridker et al N Engl J Med. 2008;359(21):2195-

2207.)

• Men 50 and older; hs CRP >2• Women 60 and older; hs CRP>2

• Four major risk factors for DM• Metabolic syndrome; BMI 30 or more• impaired fasting glucose, glycated Hb >6%Ridker PM et al. Lancet 2012: 380; 565 – 571

RCT evidence regarding preventing diabetes with lifestyle changes

• Finnish Diabetes Prevention & DPP Trials• NEJM 2001, 2002

• Populations• Both with adults with impaired glucose tolerance

• Intervention: Lifestyle Change to• Reduce saturated fat• Lose modest amounts of weight• Regular exercise

• Outcomes: Reduced new diabetes by ~60%

• Muscle problems, not liver problems are the major concern in the clinic

• Muscle issues not seen in most randomized trials because• Placebo or active drug wash-in phase • Eliminated those who didn’t tolerate the drug in the 1st 2 weeks

• Co-morbidity carefully controlled• Need randomized trials of those who are statin intolerant

Statin Safety

Statins and cognitive functionInformation about the potential for generally non-serious and reversible cognitive side effects (memory loss, confusion, etc) ...has been added to the statin labels.....

Data from the observational studies and clinical trials did not suggest that cognitive changes associated with statin use are common or lead to clinically significant cognitive decline.

RCTS examined cognitive function in two trialsHPS: (Simvastatin 40 v placebo): No differencePROSPER: (Pravastatin 40 v placebo): No difference

Administered a well validated modified Telephone Interview for Cognitive Status (TICS-m) questionnaire in HPS participants during their final follow-up(89% in clinic and 11% by telephone) after a mean of 5·3 years of scheduled treatment.

A TICS-m score below 22 out of 39 was prespecified as indicative of some cognitive impairment It was more common

1. older individuals2. those who had a previous stroke.

By allocation Simvastatin Placebo

Cognitively impaired 23.7% 24.2%Dementia noted 0.3% 0.3%Mean TICS-m score 24.08 24.06No significant changes seen in the scores of the 4 separate domains including memory

HPS Study Collaborative Group. Lancet 2004: 363; 757– 67.

Enhancing Medical AdherenceFrishman WH . Am J Med 2012: 125:841-42.

Adherence is responsibility shared by patient and healthcare provider

• Patient’s socio-demographics

• Characteristics of health care provider

• Medication characteristics

• Disease characteristics

In Conclusion: • Prevention of ASCVD is important• Guidelines must be trustworthy• Important features include:

-Transparency- Diversity of the panel interests- Focus on critical questions - RCTs must be rated for quality-Multiple levels of review including public

review

In Conclusion: • The clinician should be able to understand guidelines that focus on:

“Whom to treat, when, with what therapeutic regimens, and with what intensity”