AHRQ’s Effective Health Care AHRQ’s Effective Health Care Program: Applying Existing Program: Applying Existing

Evidence to Guide Prescription Evidence to Guide Prescription Medication UseMedication Use

Monday, November 22, 2010Monday, November 22, 2010

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AgendaAgenda

Brief Overview of AHRQ’s Effective Health Care Brief Overview of AHRQ’s Effective Health Care Program-Program- Amanda Brodt, facilitator Amanda Brodt, facilitator

Comparative Effectiveness of ACE Inhibitors Comparative Effectiveness of ACE Inhibitors and/or ARBs Added to Standard Medical and/or ARBs Added to Standard Medical Therapy for Treating Patients With Stable Therapy for Treating Patients With Stable Ischemic Heart Disease and Preserved Left Ischemic Heart Disease and Preserved Left Ventricular Systolic Function-Ventricular Systolic Function- C. Michael White, C. Michael White, Pharm.D., FCP, FCCPPharm.D., FCP, FCCP

Q&A from Audience Q&A from Audience

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Patient-Centered Outcomes Patient-Centered Outcomes Research and AHRQ’s Effective Research and AHRQ’s Effective

Health Care ProgramHealth Care Program

Amanda Brodt, M.P.H. Amanda Brodt, M.P.H.

AHRQ’s Office of Communications and AHRQ’s Office of Communications and Knowledge TransferKnowledge Transfer

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Patient-Centered Patient-Centered Outcomes ResearchOutcomes Research

Benefits

Harms

Also known as comparative effectiveness researchAlso known as comparative effectiveness research

Unbiased and practical, evidence-based Unbiased and practical, evidence-based information information

Compares drugs, devices, tests and surgeries, and Compares drugs, devices, tests and surgeries, and approaches to health care approaches to health care – benefits and harms benefits and harms – what is known and what isn’twhat is known and what isn’t

Descriptive, not prescriptiveDescriptive, not prescriptive 66

Horizon Horizon ScanningScanning

EvidenceEvidence NeedNeed

IdentificationIdentification

Evidence Evidence SynthesisSynthesis

EvidenceEvidence GenerationGeneration

StrategiesStrategiesInterventionsInterventionsConditionsConditionsPopulationsPopulations

DisseminationDisseminationTranslationTranslation

ImprovementsImprovements inin

Health CareHealth Care

Research PlatformResearch PlatformInfrastructure – Methods Development – Training Infrastructure – Methods Development – Training

A Framework for A Framework for Patient-Centered Outcomes Patient-Centered Outcomes

ResearchResearch

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Research Focus: Research Focus: 14 Priority Conditions14 Priority Conditions

Arthritis and nontraumatic joint Arthritis and nontraumatic joint disordersdisorders

CancerCancer

Cardiovascular disease, Cardiovascular disease, including stroke and including stroke and hypertensionhypertension

Dementia, including Dementia, including Alzheimer’s diseaseAlzheimer’s disease

Depression and other mental Depression and other mental health disordershealth disorders

Developmental delays, ADHD Developmental delays, ADHD and autismand autism

Diabetes mellitusDiabetes mellitus

Functional limitations and Functional limitations and disabilitydisability

Infectious diseases, Infectious diseases, including HIV/AIDSincluding HIV/AIDS

ObesityObesity

Peptic ulcer disease and Peptic ulcer disease and dyspepsiadyspepsia

Pregnancy including Pregnancy including preterm birthpreterm birth

Pulmonary disease/asthmaPulmonary disease/asthma

Substance abuseSubstance abuse

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Effective Health Care Program Effective Health Care Program Translation ProductsTranslation Products

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Executive Summary

Web Site

ClinicianGuide

ConsumerGuide Policymaker

Summary

Interactive Case Study

CE Modules

Faculty Slides

Patient Decision Aid(available soon)

Systematic Review Report

Medication ResourcesMedication Resources

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Public InvolvementPublic Involvement

Topic Topic GenerationGeneration

Topic Topic DevelopmentDevelopment

Topic Topic RefinementRefinement

Research Research ReviewReview

Research Research Needs Needs

DevelopmentDevelopment

Report Report Translation & Translation & DisseminationDissemination

During the Research ProcessDuring the Research Process

Web links

Newsletter blurbs

Articles or

commentaries

Web conferences

Continuing Education

Disseminating the FindingsDisseminating the Findings

• Nominate topics using the online Nominate topics using the online formform• Participate in key question Participate in key question refinementrefinement• Comment via the web on draft key Comment via the web on draft key questions and reportsquestions and reports

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Comparative Effectiveness of ACE Inhibitors Comparative Effectiveness of ACE Inhibitors and/or ARBs Added to Standard Medical and/or ARBs Added to Standard Medical Therapy for Treating Patients With Stable Therapy for Treating Patients With Stable

Ischemic Heart Disease and Preserved Left Ischemic Heart Disease and Preserved Left Ventricular Systolic FunctionVentricular Systolic Function

C. Michael White, Pharm.D., FCP, FCCPC. Michael White, Pharm.D., FCP, FCCPProfessor of Pharmacy, University of Professor of Pharmacy, University of

ConnecticutConnecticutDirector, UCONN/HH Evidence-based Practice Director, UCONN/HH Evidence-based Practice

Center, Hartford, CTCenter, Hartford, CT 1212

BackgroundBackground

Questions addressed Questions addressed

Results for each questionResults for each question

Outline of MaterialOutline of Material

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An estimated 80 million American adults (1 An estimated 80 million American adults (1 in 3) have one or more forms of in 3) have one or more forms of cardiovascular disease.cardiovascular disease.

38.1 million are estimated to be age 60 or 38.1 million are estimated to be age 60 or older. older.

16.8 million adults have ischemic heart 16.8 million adults have ischemic heart disease, also known as coronary heart disease, also known as coronary heart disease.disease.

Health Impact of Cardiovascular Health Impact of Cardiovascular Disease in the United StatesDisease in the United States

Miniño AM, et al. Natl Vital Stat Rep 2006;54(19):1-49; Lloyd-Jones D, et al. Circulation 2009;119:e21-181.

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Standard therapy that can reduce Standard therapy that can reduce cardiovascular events:cardiovascular events: Antiplatelet therapyAntiplatelet therapy

StatinsStatins

β-β-blockersblockers

Aggressive modification of risk factorsAggressive modification of risk factors

ACEIs and ARBs have established benefit in ACEIs and ARBs have established benefit in patients with heart failure and myocardial patients with heart failure and myocardial infarctions with left ventricular infarctions with left ventricular (LV) (LV) dysfunction.dysfunction.

Standard Therapy forStandard Therapy forStable Ischemic Heart Stable Ischemic Heart

DiseaseDisease

Gibbons RJ, et al. J Am Coll Cardiol 2002;41:159-68; Fraker TD, Fihn SD. J Am Coll Cardiol 2007;50:2264-74.

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Despite standard medical therapy, these patients Despite standard medical therapy, these patients continue to experience considerable morbidity and continue to experience considerable morbidity and mortality.mortality.

ACEIs and ARBs have established benefit in ACEIs and ARBs have established benefit in patients with heart failure and left ventricular patients with heart failure and left ventricular dysfunction.dysfunction.

The evidence for prophylactic use of ACEIs and The evidence for prophylactic use of ACEIs and ARBs in patients without heart failure and with ARBs in patients without heart failure and with preserved left ventricular systolic function is less preserved left ventricular systolic function is less clear.clear.

Rationale for Additional Therapies for Rationale for Additional Therapies for Patients With Stable Ischemic Heart Disease Patients With Stable Ischemic Heart Disease

and Preserved Left Ventricular Systolic and Preserved Left Ventricular Systolic FunctionFunction

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II-receptor blocker. 1616

RAAS SystemRAAS System

AngiotensinogenAngiotensinogen

Angiotensin IAngiotensin I

Angiotensin IIAngiotensin II

KininogenKininogen

BradykininBradykinin

InactiveInactive

Ceconi C, et al. Cardiovasc Res 2007;73:237-46; Faxon DP, et al. Circulation 2004;109:2617-2625; Schmidt-Ott KM, et al. Regul Pept 2000; 93:65-77; Song JC, White CM. Pharmacotherapy 2000;20:130-9; Song JC, White CM. Clin Pharmacokinet 2002;41:207-24; Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.

Angiotensin-converting enzyme

Renin Kallikrein

Kininase II

Angiotensin-converting enzyme inhibitor

Angiotensin-converting enzyme inhibitor

Angiotensin II-receptor blocker

Angiotensin II-receptor blocker

Aldosterone secretionAldosterone secretion

Increased Na+ and H2O reabsorptionIncreased Na+ and H2O reabsorption

VasoconstrictionVasoconstriction

Increased peripheral vascular resistance

Increased peripheral vascular resistance

Angiotensin II Type I Receptors

Angiotensin II Type I Receptors

VasodilationVasodilation

Decreased peripheralvascular resistance

Decreased peripheralvascular resistance

Stimulatory signal

Reaction

Inhibitory pharmacologic effect

LEGEND

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The topic was nominated in a public process.The topic was nominated in a public process. A specialized Technical Expert Panel guided A specialized Technical Expert Panel guided

selection of the clinical questions that the research selection of the clinical questions that the research would address.would address.

The research was based on a well-defined The research was based on a well-defined systematic literature review process.systematic literature review process.

The methods used followed the Methods Reference The methods used followed the Methods Reference Guide for Effectiveness and Comparative Guide for Effectiveness and Comparative Effectiveness Reviews.Effectiveness Reviews.

The draft underwent public comment and peer The draft underwent public comment and peer review.review.

The final report is available online at The final report is available online at http://effectivehealthcare.ahrq.gov/ehc/products/57/335/bodyfinal.pdf. .

The Development ProcessThe Development Process

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The GRADE system of the Cochrane Collaboration was The GRADE system of the Cochrane Collaboration was used to rate the strength of evidence resulting from the used to rate the strength of evidence resulting from the research but with a slight modification.research but with a slight modification.

The modified system uses four domains — risk of bias, The modified system uses four domains — risk of bias, consistency, directness, and precision — for assessment.consistency, directness, and precision — for assessment.

For the purposes of the review, the strength of evidence For the purposes of the review, the strength of evidence pertaining to each key question was classified into three pertaining to each key question was classified into three broad categories or grades:broad categories or grades:

Rating the Strength of Rating the Strength of Evidence: Modified GRADEEvidence: Modified GRADE

AHRQ. Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews, Version 1.0; Brozek J, et al. GRADEpro Version 3.2 for Windows. Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.

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The comparative effectiveness of different The comparative effectiveness of different combination treatments:combination treatments: ACEI or ARB + Standard Therapy Versus Standard Therapy AloneACEI or ARB + Standard Therapy Versus Standard Therapy Alone ACEI + ARB + Standard Therapy Versus ACEI + Standard TherapyACEI + ARB + Standard Therapy Versus ACEI + Standard Therapy ACEI or ARB + Standard Therapy Versus Standard Therapy Alone ACEI or ARB + Standard Therapy Versus Standard Therapy Alone

Close to a Revascularization ProcedureClose to a Revascularization Procedure

The benefits and harms associated with each The benefits and harms associated with each treatment modality.treatment modality.

The differences in the benefits or harms The differences in the benefits or harms between various subpopulations of patients.between various subpopulations of patients.

Clinical Questions Clinical Questions AddressedAddressed

Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009. 2020

Outcomes of InterestOutcomes of Interest

End Points: BenefitsEnd Points: Benefits Total mortalityTotal mortality

Cardiovascular (CV) deathCardiovascular (CV) death

Nonfatal myocardial Nonfatal myocardial infarction (MI)infarction (MI)

StrokeStroke

Composite endpoint (CV Composite endpoint (CV death, nonfatal MI, stroke)death, nonfatal MI, stroke)

RevascularizationRevascularization

Quality-of-life measuresQuality-of-life measures

End Points: HarmsEnd Points: Harms HyperkalemiaHyperkalemia

CoughCough

AngioedemaAngioedema

HypotensionHypotension

RashRash

Blood dyscrasiasBlood dyscrasias

SyncopeSyncope

Withdrawal from trialWithdrawal from trial

Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.

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Trials Evaluating the Addition of an ACEI or Trials Evaluating the Addition of an ACEI or ARB to Standard Medical Therapy for Stable ARB to Standard Medical Therapy for Stable

IHD and Preserved LV FunctionIHD and Preserved LV Function

Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.

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Drugs and Target DosesDrugs and Target Doses

Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009. 2323

Benefits With HIGH Levels of Evidence From Benefits With HIGH Levels of Evidence From Adding an ACEI to Standard Medical Therapy for Adding an ACEI to Standard Medical Therapy for

Stable IHD With Preserved LV FunctionStable IHD With Preserved LV Function

*The difference between the two event rates, divided by the event rate for patients not treated with an ACEI.†The difference between the event rate in patients treated without an ACEI and with an ACEI × 100.‡Event rate over 3.7 years.

Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009. 2424

Benefits With HIGH Levels of Evidence From Benefits With HIGH Levels of Evidence From Adding an ACEI to Standard Medical Therapy for Adding an ACEI to Standard Medical Therapy for

Stable IHD With PreservedStable IHD With Preserved LV Function*LV Function*

* Only the data from the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) trial were used in the analysis.

†The difference between the two event rates, divided by the event rate for patients not treated with an ARB.‡The difference between the event rate in patients treated without an ARB and with an ARB × 100.

Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.

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Evidence-Based Harms of AddingEvidence-Based Harms of Adding an ACEIan ACEI or an or an ARB to Standard Medical Therapy for Stable IHD ARB to Standard Medical Therapy for Stable IHD

With Preserved LV FunctionWith Preserved LV Function

Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.

The balance of benefits to harms is favorable.The balance of benefits to harms is favorable.

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Ongoing Telmisartan Alone and in Combination with Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) was Ramipril Global Endpoint Trial (ONTARGET) was the only trial that investigated the addition of an the only trial that investigated the addition of an ACEI/ARB combination to standard medical therapy ACEI/ARB combination to standard medical therapy versus standard medical therapy plus an ACEI versus standard medical therapy plus an ACEI alone. alone.

There was no evidence of any greater clinical There was no evidence of any greater clinical benefit with the addition of the ACEI/ARB benefit with the addition of the ACEI/ARB combination as opposed to an ACEI alone.combination as opposed to an ACEI alone.

In third arm, ARB therapy provided similar benefits to ACE In third arm, ARB therapy provided similar benefits to ACE inhibitor.inhibitor.

ACEI/ARB Combination vs. ACEI Alone for ACEI/ARB Combination vs. ACEI Alone for Stable IHD With Preserved LV FunctionStable IHD With Preserved LV Function

Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009. 2727

Balance of benefits to harms not favorable.Balance of benefits to harms not favorable. No benefits, risks elevated (Moderate Level of Evidence).No benefits, risks elevated (Moderate Level of Evidence).

Harms of ACEI/ARB Combination vs. Harms of ACEI/ARB Combination vs. ACEI Alone for Stable IHD With ACEI Alone for Stable IHD With Preserved LV Systolic FunctionPreserved LV Systolic Function

Modified from Yusuf S, et al. New Engl J Med 2008;358:1547-59. 2828

CABG = coronary artery bypass grafting surgery; PTCA = percutaneous transluminal coronary angioplasty.Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.

The Addition of ACEI or ARB to Standard Medical Therapy The Addition of ACEI or ARB to Standard Medical Therapy (SMT) Versus SMT Alone Close to a Revascularization (SMT) Versus SMT Alone Close to a Revascularization

Procedure in IHD with Preserved LV FunctionProcedure in IHD with Preserved LV Function

Seven trials conducted.Seven trials conducted.

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The balance of benefits to harms was not favorableThe balance of benefits to harms was not favorable There were no clinical benefits from adding ACEIs or There were no clinical benefits from adding ACEIs or

ARBs close to a revascularization procedure.ARBs close to a revascularization procedure.

There was an increased risk for these harms:There was an increased risk for these harms:

ACEI or an ARB to Standard Medical Therapy (SMT) ACEI or an ARB to Standard Medical Therapy (SMT) Versus SMT Alone Close to a Revascularization Versus SMT Alone Close to a Revascularization

Procedure in Stable IHD and Preserved LV FunctionProcedure in Stable IHD and Preserved LV Function

Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009. 3030

Final Summary of ResultsFinal Summary of Results

Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.3131

Informed Decisionmaking Process Using Informed Decisionmaking Process Using These Project ResultsThese Project Results

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Additional data needed to address the Additional data needed to address the benefits and harms in the following benefits and harms in the following patient subpopulations:patient subpopulations: Patients who are receiving antiplatelet therapy Patients who are receiving antiplatelet therapy

Patients of different ethnicities (especially Patients of different ethnicities (especially African Americans and Latinos)African Americans and Latinos)

Patients who have genetic polymorphisms of Patients who have genetic polymorphisms of the angiotensin-converting enzyme gene or the the angiotensin-converting enzyme gene or the angiotensin II type I receptor geneangiotensin II type I receptor gene

Gaps in KnowledgeGaps in Knowledge

Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009. 3333

Questions Questions

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at the bottom of the screen. at the bottom of the screen.

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– Once completed, press the “Submit” Once completed, press the “Submit” button. button.

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If you have a question about utilizing AHRQ If you have a question about utilizing AHRQ resources please e-mail us at: resources please e-mail us at: EHC_Clinicians@ahrq.hhs.gov.. 3535

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