Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors and/or Angiotensin II Receptor...

Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors and/or Angiotensin II Receptor Blockers Added to Standard Medical Therapy for Treating Patients With Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic Function

Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors and/or Angiotensin II Receptor Blockers Added to Standard Medical Therapy for Treating Patients With Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic Function

Prepared for:Agency for Healthcare Research and Quality (AHRQ)

www.ahrq.gov

Outline of MaterialOutline of Material

Background Process for developing the

Comparative Effectiveness Review (CER)

Questions addressed in the CER Results for each question in the CER Informed decisionmaking for

physicians and patients

Health Impact of Cardiovascular Diseasein the United States

Health Impact of Cardiovascular Diseasein 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.

Every year, cardiovascular disease has accounted for more deaths than any other single cause or group of causes of death in the United States since 1900 (excluding 1918). Nearly 2,400 Americans die of cardiovascular disease

each day, an average of one death every 37 seconds. Miniño AM, et al. Natl Vital Stat Rep 2006;54(19):1-49; Lloyd-Jones D, et al. Circulation 2009;119:e21-181.

Characteristics of Stable Ischemic Heart DiseaseCharacteristics of Stable Ischemic Heart Disease

Atherosclerosis reduces the supply of blood and oxygen to the myocardium.

Symptoms range from asymptomatic ischemic episodes to severely debilitating symptoms.

Disease can manifest in large vessels or as diffuse microvascular disease.

There is an increased risk of acute coronary syndrome.

Gibbons RJ, et al. J Am Coll Cardiol 2003;41:159-68; Fraker TD, Fihn SD. J Am Coll Cardiol 2007;50:2264-74; Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.

Standard Therapy forStable Ischemic Heart DiseaseStandard Therapy forStable Ischemic Heart Disease

Standard therapy that can reduce cardiovascular events: Single or dual antiplatelet therapy Statins β-blockers Aggressive modification of risk factors

Standard therapy that can help with symptoms: Fast-acting nitrates Negative chronotropic agents (β-blockers;

nondihydropyridine calcium channel blockers) Vasodilators (calcium channel blockers; long-acting

nitrates)

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

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

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.

Guidelines for the Use of ACEIs, ARBs, orBoth to Treat Patients With Cardiac Disease

Guidelines for the Use of ACEIs, ARBs, orBoth to Treat Patients With Cardiac Disease

American College of Cardiology and American Heart Association guidelines say that ACEIs can be used in addition to standard therapy in patients who have: Chronic heart failure. Myocardial infarction and left ventricular dysfunction (defined as

a left ventricular ejection fraction (LVEF) ≤40%).

ARBs are reserved for patients who cannot tolerate ACEIs. In patients with heart failure, combining an ACEI with an ARB

may provide additional benefit over an ACEI alone. For these reasons, clinical trials have been conducted

to evaluate the use of ACEIs, ARBs, or both in patients with stable ischemic heart disease but without heart failure or left ventricular systolic dysfunction (e.g., patients with an LVEF >40%).

Baker WL, et al. Ann Intern Med 2009 Oct 19. [Epub ahead of print]; Hunt SA, et al. Circulation 2005;112:e154-235; Pfeffer MA, et al. N Engl J Med 2003;149:1893-906; Smith SC, et al. Circulation 2006;113:2363-72.

Pharmacologic Effects of Agonists on the Renin-Angiotensin-Aldosterone SystemPharmacologic Effects of Agonists on the Renin-Angiotensin-Aldosterone System

Angiotensinogen

Angiotensin I

Angiotensin II

Kininogen

Bradykinin

Inactive

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 II-receptor blocker

Aldosterone secretion

Increased Na+

and H2O reabsorption

Vasoconstriction

Increased peripheral vascular resistance

Angiotensin II Type I Receptors

Vasodilation

Decreased peripheral

vascular resistance

Stimulatory signal

Reaction

Inhibitory pharmacologic effect

LEGEND

The CER Development ProcessThe CER Development Process

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

the clinical questions that the CER would address. The research for the CER was based on a well-defined

systematic literature review. The methods used for data collection and meta-analysis

followed the Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews.

The draft CER was made available for public comment and underwent a rigorous peer-review process to improve the final product.

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

Rating the Strength of Evidence From the CER:A Modification of the GRADE Methodology

Rating the Strength of Evidence From the CER:A Modification of the GRADE Methodology

The GRADE system of the Cochrane Collaboration was used to rate the strength of evidence resulting from the CER 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 CER, the strength of evidence pertaining to each key question was classified into three broad categories or grades:

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.

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.

Comparative Effectiveness Review:Outcomes of InterestComparative Effectiveness Review:Outcomes of Interest

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.

Clinical Questions Addressed by the Comparative Effectiveness Review for Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic Function

Clinical Questions Addressed by the Comparative Effectiveness Review for Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic Function

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.


Results of Trials Evaluating the Addition of an ACEI or an ARB to Standard Therapy for Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic Function

Results of Trials Evaluating the Addition of an ACEI or an ARB to Standard Therapy for Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic Function

Adding an ACEI or an ARB can provide additional clinical benefits for some patients.

Adding an ACEI may increase the risk of cough, syncope, or hyperkalemia.

Adding an ARB may increase the risk of hyperkalemia.

Adding an ACEI does not impact cardiovascular mortality in patients with end-stage renal disease and left ventricular hypertrophy.

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

Summary of Evaluated Trials That Investigated the Addition of an ACEI or an ARB to Standard Medical Therapy for Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic Function

Summary of Evaluated Trials That Investigated the Addition of an ACEI or an ARB to Standard Medical Therapy for Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic Function

Clinical Trial Group Drug NFollowup

(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 0.5Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.

Target Doses for ACEIs and ARBs in Trials Investigating the Addition of an ACEI or an ARB to Standard Medical Therapy for Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic Function

Target Doses for ACEIs and ARBs in Trials Investigating the Addition of an ACEI or an ARB to Standard Medical Therapy for Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic Function

Clinical Trial Group Drug

TrialTarget 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


Overall Summary of the Evidence-Based Benefits of Adding an ACEI or an ARB to Standard Medical Therapy for Stable Ischemic Heart Disease With Preserved Left Ventricular Systolic Function

Overall Summary of the Evidence-Based Benefits of Adding an ACEI or an ARB to Standard Medical Therapy for Stable Ischemic Heart Disease With Preserved Left Ventricular Systolic Function

Outcome

ACEI ARB

RiskLevel ofEvidence Risk

Level ofEvidence

Total Mortality Decreased High No effect Moderate

CV Mortality Decreased Moderate No effect Moderate

Nonfatal MI Decreased HighNo evidence

--

Stroke Decreased Moderate No effect Moderate

Combined Risk of CV Mortality, Nonfatal MI, and Stroke

No effect Moderate Decreased Moderate

Atrial Fibrillation No effect High No effect High

Total Hospitalizations No effect Moderate No effect Moderate

Angina-Related Hospitalizations

No effect High No effect High

HF-Related Hospitalizations

Decreased High No effect Moderate

Revascularization Decreased High No effect ModerateColeman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.

CV = cardiovascular; HF = heart failure; MI = myocardial infarction.

Overall Summary of the Evidence-Based Harms of Adding an ACEI or an ARB to Standard Medical Therapy for Stable Ischemic Heart Disease With Preserved Left Ventricular Systolic Function

Overall Summary of the Evidence-Based Harms of Adding an ACEI or an ARB to Standard Medical Therapy for Stable Ischemic Heart Disease With Preserved Left Ventricular Systolic Function

Outcomes

ACEI ARB

RiskLevel of Evidence Risk

Level of Evidence

Syncope Increased Low No evidence –

Cough Increased Low No evidence –

Angioedema

No effect Low No evidence –

Hyperkalemia

Increased Low Increased Low


Benefits With HIGH Levels of Evidence That Result From Adding an ACEI to Standard Medical Therapy for Stable Ischemic Heart Disease With Preserved Left Ventricular Systolic Function

Benefits With HIGH Levels of Evidence That Result From Adding an ACEI to Standard Medical Therapy for Stable Ischemic Heart Disease With Preserved Left Ventricular Systolic Function

Outcomes

Event Rate/100 Patients Over the Next 4 Years

Relative Risk

Reduction*

Number Needed to Treat

With ACEI to Prevent One Additional

Adverse Outcome†

WithoutACEI

WithACEI

Absolute Difference

In Event Rate

Totalmortality

8.5 7.4 1.3 13% 91

Nonfatal myocardial infarction

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.


Benefits With HIGH Levels of Evidence That Result From Adding an ARB to Standard Medical Therapy for Stable Ischemic Heart Disease With Preserved Left Ventricular Systolic Function*

Benefits With HIGH Levels of Evidence That Result From Adding an ARB to Standard Medical Therapy for Stable Ischemic Heart Disease With Preserved Left Ventricular Systolic Function*

Outcomes

Event Rate/100 Patients

Over the Next 5 Years

Relative Risk

Reduction†

Number Needed to Treat With an ARB to

Prevent One

Additional Adverse

Outcome ‡

Without

ARBWithARB

Absolute Differen

ce In Event

Rate

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

14.8 13.0 1.8 12% 56* 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.


Results of Trials That Evaluated the Addition of an ACEI/ARB Combination Versus an ACEI Alone to Standard Medical Therapy for Stable Ischemic Heart Disease With Preserved Left Ventricular Systolic Function

Results of Trials That Evaluated the Addition of an ACEI/ARB Combination Versus an ACEI Alone to Standard Medical Therapy for Stable Ischemic Heart Disease With Preserved Left Ventricular Systolic Function

The 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.

There was evidence that patients who received the ACEI/ARB combination were at increased risk for adverse events.


Overall Summary of the Evidence-Based Benefits and Harms of Adding anACEI/ARB Combination Versus an ACEI Alone to Standard Medical Therapy forStable Ischemic Heart Disease With Preserved Left Ventricular Systolic Function

Overall Summary of the Evidence-Based Benefits and Harms of Adding anACEI/ARB Combination Versus an ACEI Alone to Standard Medical Therapy forStable Ischemic Heart Disease With Preserved Left Ventricular Systolic Function

There were no clinical benefits for the ACEI/ARB (ramipril + telmisartan) combination (Moderate Level of Evidence). The risk of harms was higher in the ACEI/ARB combination treatment group (Moderate Level of Evidence).

Outcomes

ACEI Alone (N =

8,576)

ACEI/ARB Combinatio

n (N = 8,502)

ACEI/ARB CombinationVersus ACEI

Alone

n n (P 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

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

Results of Trials Evaluating the Addition of an ACEI or an ARB to Standard Medical Therapy (SMT) Versus SMT Alone Close to a Revascularization Procedure

Results of Trials Evaluating the Addition of an ACEI or an ARB to Standard Medical Therapy (SMT) Versus SMT Alone Close to a Revascularization Procedure


Seven trials met the inclusion criteria for this analysis.

There was no clinical benefit from adding an ACEI or an ARB to standard medical therapy in close proximity to a revascularization procedure.

There was an increased risk of adverse events.

Trial Treatment Group Drug

MARCATOR ACEI given the same day post-PTCA cilazapril

APRESACEI 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 stentingcandesartan

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


Characteristics of Trials Evaluating the Addition of an ACEI or an ARB to Standard Medical Therapy (SMT) Versus SMT Alone Close to a Revascularization Procedure

Characteristics of Trials Evaluating the Addition of an ACEI or an ARB to Standard Medical Therapy (SMT) Versus SMT Alone Close to a Revascularization Procedure

Analysis of Trials That Tested the Addition of an ACEI or an ARB to Standard Medical Therapy (SMT) Versus SMT Alone Close to a Revascularization Procedure

Analysis of Trials That Tested the Addition of an ACEI or an ARB to Standard Medical Therapy (SMT) Versus SMT Alone Close to a Revascularization Procedure

Overall, there were no clinical benefits to adding ACEIs or ARBs to standard medical therapy close to a revascularization procedure.

There was an increased risk for these harms:

Increased Risk of Harms Drug Level of Evidence

Hypotension ACEI Moderate

Subsequent revascularization ACEI or ARB High


Identifying Trade-offs for Your Patients:Summary of Results on Comparative Effectiveness of Adding ACEIs and/or ARBs to Standard Medical Therapy

Identifying Trade-offs for Your Patients:Summary of Results on Comparative Effectiveness of Adding ACEIs and/or ARBs to Standard Medical Therapy

Clinical Comparison Benefits* Harms*

Adding an ACEI to standard therapy versus standard therapy alone

Reduced total mortality, nonfatal myocardial infarction, heart failure-related hospitalizations, and the need for revascularization procedures

Possible increase in syncope, cough, and hyperkalemia

Adding an ARB to standard therapy versus standard therapy alone

Reduced incidence of one or more of the following: cardiovascular mortality, nonfatal myocardial infarction, and stroke

Possible increase in hyperkalemia

Adding an ACEI/ARB combination to standard therapy

No clinical benefit compared to adding just an ACEI to standard therapy

Increased risk of hypotension, syncope, and renal impairment

Adding an ACEI or an ARB close to a revascularization procedure versus standard therapy alone

No clinical benefit Increased risk for repeat revascularizations; Increased risk of hypotension


Gaps in Knowledge About ACEIs and ARBs as Treatment for Stable Ischemic Heart Disease With Preserved Left Ventricular Systolic Function

Gaps in Knowledge About ACEIs and ARBs as Treatment for Stable Ischemic Heart Disease With Preserved Left Ventricular Systolic Function

Meta-analyses or future clinical trials that evaluate the use of ACEIs or ARBs to treat patients who have stable ischemic heart disease and preserved left ventricular systolic function are needed to address the benefits and harms in the following patient subpopulations: Patients who are receiving antiplatelet therapy or who have a history

of revascularization. Patients of different ethnicities (especially African Americans and

Latinos). Patients with stenosis in the left anterior descending artery, as

compared to other arteries. Patients with single-vessel versus multi-vessel disease. Patients who have genetic polymorphisms of the angiotensin-

converting enzyme gene or the angiotensin II type I receptor gene. Patients on different dosing intensities of ACE inhibitors or ARBs.Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009.

Steps in the Informed Decisionmaking Process for Adding an ACEI or an ARB to Standard Medical Therapy for Stable Ischemic Heart Disease With Preserved Left Ventricular Systolic Function

Steps in the Informed Decisionmaking Process for Adding an ACEI or an ARB to Standard Medical Therapy for Stable Ischemic Heart Disease With Preserved Left Ventricular Systolic Function

1. Review the critical evidence to help your patients understand:

2. Explore each patient’s values by asking:

3. Encourage your patients to be involved in their care:

• 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.

• 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?

• 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.

Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors and/or Angiotensin II Receptor...

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