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AHRQ’s Effective Health Care Program: Applying Existing Evidence to Guide Prescription Medication Use

Slide Presentation in Text Format

Monday, November 22, 2010

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  • On the top of the slide are the logos for the Department of Health and Human Services and the Agency for Healthcare Research and Quality (AHRQ).

 

Slide 2

Questions

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CALL-IN NUMBER: (888)-632-5065  ACCESS CODE:89036596#

Slide 3

Agenda

  • Brief Overview of AHRQ’s Effective Health Care Program - Amanda Brodt, facilitator
  • Comparative Effectiveness of ACE Inhibitors and/or ARBs Added to Standard Medical Therapy for Treating Patients With Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic Function - C. Michael White, Pharm.D., FCP, FCCP
  • Q&A from Audience

 

Slide 4

Questions

To submit a question:

  • Press the “Ask Question” button located at the bottom of the screen. 
  • When you click on the button, a box will appear at the bottom of your screen requesting that you enter your question. 
  • Once completed, press the “Submit” button.


Slide 5

Patient-Centered Outcomes Research and AHRQ’s Effective Health Care Program

Amanda Brodt, M.P.P.
AHRQ’s Office of Communications and Knowledge Transfer


Slide 6

Patient-Center Outcomes Research

  • Also known as comparative effectiveness research

 

  • Unbiased and practical, evidence-based information
  • Compares drugs, devices, tests and surgeries, and approaches to health care
    • benefits and harms
    • what is known and what isn’t

 

  • Descriptive, not prescriptive


Slide 7

A Framework for Patient-Centered Outcomes Research

This framework outlines the step-by-step process for how the development and implementation of patient-centered outcomes research leads to improvement in health care. Once a topic is nominated, a horizon scan and synthesis of the evidence is completed, followed by evidence generation. Then the research is translated, disseminated and implemented.

 

Slide 8

Research Focus: 14 Priority Conditions

  • Arthritis and nontraumatic joint disorders
  • Cancer
  • Cardiovascular disease, including stroke and hypertension
  • Dementia, including Alzheimer’s disease
  • Depression and other mental health disorders
  • Developmental delays, ADHD and autism
  • Diabetes mellitus
  • Functional limitations and disability
  • Infectious disease including HIV/AIDS
  • Obesity
  • Peptic ulcer disease and dyspepsia
  • Pregnancy including preterm birth
  • Pulmonary disease/asthma
  • Substance abuse

 

Slide 9

Effective Health Care Program Translation Products

The slide has multiple images of the different products that the Effective Health Care Program creates from the systematic review report.  These products include: CE modules, interactive case studies, faculty slides, patient decision aid, policymaker summary, consumer guide, clinician guide, Web site, and executive summary.


Slide 10

Medication Resources

The slide has two images of two consumer guides titled, “ACE Inhibitors” and “ARBs” To Protect Your Heart?: A Guide for Patients Being Treated for Stable Coronary Heart Disease, and Treating High Cholesterol: A Guide for Adults.


Slide 11

Public Involvement

This slide shows multiple images of what must be done during the research process in order to disseminate the findings in multiple ways.  The research process includes: topic generation, topic development, topic refinement, research review, and research needs and development.  The multiple ways that information is disseminated includes: Web links, newsletter blurbs, articles or comment, Web conferences, and continuing education.


Slide 12

Comparative Effectiveness of ACE Inhibitors and/or ARBs Added to Standard Medical Therapy for Treating Patients With Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic Function

C. Michael White, Pharm.D., FCP, FCCP
Professor of Pharmacy, University of Connecticut
Director, UCONN/HH Evidence-based Practice Center, Hartford, CT

 

 

Slide 13

Outline of Material

  • Background
  • Questions addressed
  • Results for each question

 

Slide 14

Hear Impact of Cardiovascular Disease in the United States

  • An estimated 80 million American adults (1 in 3) have one or more forms of cardiovascular disease.
    • 38.1 million are estimated to be age 60 or older.
    • 16.8 million adults have ischemic heart disease, also known as coronary heart disease.

 

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


Slide 15

Standard Therapy for Stable Ischemic Heart Disease

  • Standard therapy that can reduce cardiovascular events:
    • Antiplatelet therapy
    • Statins
    • β-blockers
    • Aggressive modification of risk factors
  • ACEIs and ARBs have established benefit in patients with heart failure and myocardial infarctions with left ventricular (LV) dysfunction.

 

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


Slide 16

Rationale for Additional Therapies for Patients With Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic Function

  • Despite standard medical therapy, these patients continue to experience considerable morbidity and mortality.
  • ACEIs and ARBs have established benefit in patients with heart failure and left ventricular dysfunction.
  • The evidence for prophylactic use of ACEIs and ARBs in patients without heart failure and with preserved left ventricular systolic function is less clear.

 

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


Slide 17

RAAS System

This slide shows a diagram, where ACE inhibitors and angiotensin receptor blockers work and how they both work on the renin angiotensin aldosterone system, even though they don’t work in exactly the same place.  The diagram also shows where the ACE inhibitors are blocking angiotensin-converting enzyme, trying to prevent angiotensin I from turning into the biologically active angiotensin II, where angiotensin receptor blockers block the angiotensin II type I receptor, which are the receptors that cause a pharmacologic effect. 


Slide 18

The Development Process

  • The topic was nominated in a public process.
  • A specialized Technical Expert Panel guided selection of the clinical questions that the research would address.
  • The research was based on a well-defined systematic literature review process.
  • The methods used followed the Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews.
  • The draft underwent public comment and peer review.
  • The final report is available online at http://effectivehealthcare.ahrq.gov/ehc/products/57/335/bodyfinal.pdf.

 

Slide 19

Rating the Strength of Evidence: Modified GRADE

  • The GRADE system of the Cochrane Collaboration was used to rate the strength of evidence resulting from the research but with a slight modification.
  • The modified system uses four domains—risk of bias, consistency, directness, and precision—for assessment.
  • For the purposes of the review, the strength of evidence pertaining to each key question was classified into three broad categories or grades:

 

High: There are consistent results from good quality clinical trials.  Further research is very unlikely to change the conclusions.
Moderate:  Findings are supported, but further research could change the conclusions.
Low:  There are very few clinical trials, or existing trials are flawed.

 

Slide 20

Clinical Questions Addressed

  • The comparative effectiveness of different combination treatments:
    • ACEI or ARB + Standard Therapy Versus Standard Therapy Alone
    • ACEI + ARB + Standard Therapy Versus ACEI + Standard Therapy
    • ACEI or ARB + Standard Therapy Versus Standard Therapy Alone Close to a Revascularization Procedure
  • The benefits and harms associated with each treatment modality.
  • The differences in the benefits or harms between various subpopulations of patients.

 

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


Slide 21

  • End Points: Benefits
    • Total mortality
    • Cardiovascular (CV) death
    • Nonfatal myocardial infarction (MI)
    • Stroke
    • Composite endpoint (CV death, nonfatal MI, stroke)
    • Revascularization
    • Quality-of-life measures

 

  • End Points: Harms
    • Hyperkalemia
    • Cough
    • Angioedema
    • Hypotension
    • Rash
    • Blood dyscrasias
    • Syncope
    • Withdrawal from trial

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

 

 

Slide 22

Trials Evaluating the Addition of an ACEI or ARB to Standard Medical Therapy for Stable IHD and Preserved LV Function

Clinical Trial

Group

Drug

N

Followup (Yrs)

PEACE

ACEI

Trandolapril

8,290

4.8

PART-2

ACEI

Ramipril

617

4.7

TRANSCEND

ARB

Telmisartan

5,926

4.7

HOPE

ACEI

Ramipril

9,297

4.5

EUROPA

ACEI

Perindopril

12,218

4.2

SCAT

ACEI

Enalapril

460

4.0

CAMELOT

ACEI

Enalapril

1,991

2.0

Kondo J, et al.

ARB

Candesartan

397

2.0

SMILE-ISCHEMIA

ACEI

Zofenopril

349

0.5

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

This table is a brief overview summary of the randomized, placebo-controlled trials that met the inclusion criteria for the comparative effectiveness review (CER).


Slide 23

Drugs and Target Doses

Clinical Trial

Group

Drug

Trial Target Dose (mg/day)

HOPE

ACEI

Ramipril

10

PART-2

ACEI

Ramipril

5-10

SCAT

ACEI

Enalapril

20

CAMELOT

ACEI

Enalapril

20

EUROPA

ACEI

Perindopril

4-8

PEACE

ACEI

Trandolapril

4

SMILE ISCHEMIA

ACEI

Zofenopril

60

TRANSCEND

ARB

Telmisartan

80

Kondo J, et al.

ARB

Candesartan

4

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

This table summarizes the daily target dose of the angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II-receptor blocker (ARB) used in the randomized placebo-controlled clinical trials that met the inclusion criteria for the comparative effectiveness review (CER).

 

 

Slide 24

Benefits with HIGH Levels of Evidence From Adding an ACEI to Standard Medical Therapy for Stable IHD With Preserved LV Function

Event Rate/100 Patients Over the Next 4 Years


Outcomes
Without ACEI With ACEI Absolute Difference In Event Rate Relative Risk Reduction* Number Needed to Treat With ACEI to Prevent one Additional Adverse Outcome†

Total mortality

8.5

7.4

1.3

13%

91

Nonfatal myocardial infraction

6.1

5.0

1.1

17%

91

Heart failure-related hospitalizations

2.6

2.0

0.6

22%

167

Need for revascularization

13.6‡

12.3‡

1.3‡

10%

77

*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.


Slide 25

Benefits with HIGH Levels of Evidence From Adding an ACEI to Standard Medical Therapy for Stable IHD With Preserved LV Function*

Event Rate/100 Patients Over the Next 5 Years


Outcomes
Without ARB With ARB Absolute Difference in Event Rate Relative Risk Reduction Number Needed to Treat With an ARB to Prevent One Additional Adverse Outcome

Combined risk of death from heart related cause, suffering a nonfatal myocardial infraction, or having a stroke

14.8

13.0

1.8

12%

56

Slide 26

Evidence-Based Harms of Adding an ACEI or an ARB to Standard Medical Therapy for Stable IHD With preserved LV function

 

Outcomes

ACEI

ARB

Risk

Level of Evidence

Risk

Level of Evidence

Synscope

Increased

Low

No evidence

--

Cough

Increased

Low

No evidence

--

Angioedema

No effect

Low

No evidence

--

Hyperkalemia

Increased

Low

Increased

Low

The balance of benefits to harms is favorable.

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


Slide 27

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

  • Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) was the only trial that investigated the addition of an ACEI/ARB combination to standard medical therapy versus standard medical therapy plus an ACEI alone.
  • There was no evidence of any greater clinical benefit with the addition of the ACEI/ARB combination as opposed to an ACEI alone.
    • In third arm, ARB therapy provided similar benefits to ACE inhibitor.

 

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

 

Slide 28

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

 

 

Outcomes

 

ACEI Alone (N=8,576)

 

ACEI/ARB Combination (N=8,502)

 

ACEI/ARB Combination Versus ACEI Alone

 

n

n

(I’ value)

Total number of discontinuations

 

2,099

 

2,495

 

<0.001

Hypotension

149

406

<0.001

Syncope

15

29

0.03

Renal impairment

60

94

<0.001

Diarrhea

12

39

<0.001

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

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


Slide 29

The Addition of ACEI or ARB to Standard Medical Therapy (SMT) Versus SMT Alone Close to a Revascularization Procedure in IHD with Preserved LV Function

Trial

Treatment Group

Drug

MARCATOR

ACEI given the same day post-PTCA

cilazapril

APRES

ACEI given 5 to 7 days after CABG or 1 to 2 days after PTCA

ramipril

Kondo J, et al.

ACEI given after coronary stenting

quinapril

PARIS

ACEI given 48 hours after coronary stenting

quinapril

QUIET

ACEI given 12 to 72 hours after angioplasty

quinapril

IMAGINE

ACEI given 7 days after CABG

quinapril

AACHEN

ARB given 7 to 14 days before coronary stenting

candesartan

CABG = coronary artery bypass grafting surgery; PTCA = percutaneous transluminal coronary angioplasty.

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


Slide 30

ACEI or an ARB to Standard Medical Therapy (SMT) Versus SMT Alone Close to a Revascularization Procedure in Stable IHD and Preserved LV Function

  • The balance of benefits to harms was not favorable
    • There were no clinical benefits from adding ACEIs or ARBs close to a revascularization procedure.
    • There was an increased risk for these harms:

 

Increased Risk of Harms

Drug

Level of Evidence

Hypotension

ACEI

Moderate

Need for subsequent revascularization

ACEI or ARB

High

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

 

Slide 31

Final Summary of Results

Clinical Comparison

Adding an ACEI to standard therapy versus standard therapy alone
Benefits:  Reduced total mortality, nonfatal myocardial infraction, heart failure-related hospitalizations, and the need for revascularization procedures
Harms:  Possible increase in syncope, cough, and hyperkalemia

Adding an ARB to standard therapy versus standard therapy alone
Benefits:  Reduced incidence of one or more of the following: cardiovascular mortality, nonfatal myocardial infraction, and stroke
Harms:  Possible increase in hyperkalemia

Adding an ACEI/ARB combination to standard therapy
Benefits:  No clinical benefit compared to adding just ACEI to standard therapy
Harms:  Increased risk of hypotension, syncope, and renal impairment

Adding an ACEI or an ARB close to a revascularization procedure versus standard therapy alone
Benefits:  No clinical benefit
Harms:  Increased risk for repeat revascularizations; Increased risk of hypotension.

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

 

Slide 32

Informed Decisionmaking Process Using These Project Results

  1. Review the critical evidence to help your patients understand:
  • Relevance of risk reductions after adding an ACEI to their regimen
  • Risks for cough, syncope, and hyperkalemia after adding an ACEI and what they could mean
  • The option of using an ARB if intolerant to ACEIs
  • The harms of adding an ACEI or an ARB too close to a revascularization procedure
  1. Explore each patient’s values by asking
  • What worries you most about taking these types of medications?
  • Do you have concerns about the cost of your medicines?
  • Do you have any problems remembering to take your medicines?

 

  1. Encourage your patients to be involved in their care:
    • Discuss the benefits and risks of each choice.
    • Talk about the impact their comorbidities will have on the decision to add an ACEI or ARB.
    • Discuss other things they can do to help reduce their risk of heart attack and stroke.


Slide 33

Gaps in Knowledge

  • Additional data needed to address the benefits and harms in the following patient subpopulations:
    • Patients who are receiving antiplatelet therapy
    • Patients of different ethnicities (especially African Americans and Latinos)
    • Patients who have genetic polymorphisms of the angiotensin-converting enzyme gene or the angiotensin II type I receptor gene

 

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


Slide 34

Questions

To submit a question:

  • Press the “Ask Question” button located at the bottom of the screen. 
  • When you click on the button, a box will appear at the bottom of your screen requesting that you enter your question. 
  • Once you have completed your question, press the “Submit” button.


Slide 35

For more information about…

 

 

Slide 36

Thank you!

  • Thank you for joining us today!
  • Please take a moment to provide us feedback at the end of this event.
  • A recording and transcript for today’s event will be available on AHRQ’s Web site.