journal club presentation: courage trial
DESCRIPTION
COURAGE trialTRANSCRIPT
Yogita RochlaniPGY2
EVALUATION AND MANAGEMENT OF STABLE ISCHEMIC HEART DISEASE
Spectrum of IHD
Acute Coronary Syndrome • ST elevation MI• Non ST elevation MI• Unstable angina • SCD
Stable IHD• Chronic stable
angina• New onset angina in
patients with suspected IHD
Differences in plaque morphology
Vulnerable Plaque (ACS)
Thin fibrous caps
Large lipid core
Less SM cells and macrophages and less collagen
Expansive remodeling of wall
Cause supply ischemia
Stable Plaque (CSA)
Thick fibrous caps
Small lipid core
more SM cells and macrophages, and more collagen
Constrictive remodeling of wall
Cause demand ischemia
Case Scenario• 72 year old female reports experiencing chest pain 3 weeks ago while she was out walking. Her chest and left shoulder felt tight. She stopped walking and rested and the pain eased. She did not seek medical help at the time because she thought it was a side stitch. Soon she began to experience some chest heaviness during her daily walks and she had to stop a few times for it to ease up before she could continue walking again. Today she comes to clinic for her primary care appointment.
• What would you do?
Approach
History
• Age, Gender• Pain
characteristics• Associated
symptoms• History of
cardiovascular disease
• Cardiovascular risk factors
Physical Exam
• e/o atherosclerotic disease in other organs (PVD, AAA, carotid disease)
• r/o non coronary causes
• Other cardiopulmonary findings
Lab exam
• CBC• Renal chem 10• UA for DM and
microalbuminuria
• Lipid panel• HbA1c• Thyroid
function (if indicated)
• CRP• CXR may show
cardiomegaly, pul edema
ECG
• LVH• Rhythm
disturbances• Signs of old MI• Conduction
delays• Normal
Clinical Classification of Chest Pain
Anginal Equivalents : Dyspnea, Nausea, Fatigue, usually in elderly and diabetic patients
Angina
Stable
Unstable
Low risk
Moderate risk
High riskVasospastic
Features of unstable angina
Rest angina Angina occurring at rest and usually prolonged >20 min, occurring within 1 week of presentation
New-onset angina Angina of at least CCS Class III severity with onset within 2 months of initial presentation
Increasing angina Previously diagnosed angina that is distinctly more frequent, longer in duration, or lower in threshold (i.e., increased by ≥1 CCS class within 2 mo of initial presentation to at least CCS Class III severity)
Canadian Cardiovascular Society classification of severity of angina
What would you do next?
1) Admit for ACS rule out
2) Schedule for cardiac catheterization
3) Outpatient TMST
4) Outpatient Dobutamine stress echo
5) Discharge with medical management
APPROACH TO DIAGNOSIS AND RISK ASSESSMENT IN PATIENTS WITH NEW ONSET ANGINA OR STABLE ANGINA
2012 ACC/AHA/ACP Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease
1) Initial diagnostic approach to a patient with suspected IHD or new onset anginal symptoms ( once ACS has been ruled out)
2) Risk assessment approach to determine the risk of death, AMI in patients with stable ischemic heart disease.
3) Outline management strategies
Pretest Likelihood of CAD in Symptomatic Patients According to Age and Sex* (Combined Diamond/Forrester and CASS Data)
*Each value represents the percent with significant CAD on catheterization.
*Each value represents the percent with significant CAD on catheterization.
Pre- test Probability of IHDEstimated based on age, gender, and character of chest pain
Low Probability (<10%) Asymptomatic men and women of all ages Women < 50 years with atypical chest pain
Intermediate Probability (10%-90%)
Men of all ages with atypical angina Women ≥ 50 years with atypical anginaWomen 30-50 years with typical angina
High Probability (90%) Men ≥ 40 years with typical angina Women ≥60 years with typical angina
Ref: MKSAP
Coronary Calcium Scoring
2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease
Non Invasive Testing for diagnosis of stable IHD
Exercise testing• ECG • Echocardiography• MPI
Pharmacologic testing• Stressor – dobutamine stress echocardiogrpahy• Vasodilator - adenosine, dipyridamole or regadenoson used for
nuclear perfusion imaging
Anatomic testing• CCTA• CMRA• CAC scoring
Exercise Electrocardiography
• Diagnostic endpoint is 1 mm horizontal or down-sloping ST-segment depression at peak exercise or ST-segment elevation consistent with an ACS.
• Sensitivity 61% and specificity ranges from 70% to 77%.
Advantages:• Improved diagnostic accuracy with additional non-ECG factors, such
as exercise duration, chronotropic incompetence, angina, ventricular arrhythmias, heart rate recovery, and hemodynamic response to exercise (i.e., drop in systolic BP).
Limitations and Risks:• Resting ECG abnormalities • Maximal exercise testing is associated with a low but finite incidence
of cardiac arrest, AMI, and even death.
Pharmacologic stress echocardiography
• Diagnostic endpoint is new or worsening wall motion abnormalities and changes in global LV function during or immediately after stress.
• Advantages- Information about LV function and valvular abnormalities, if any.
• Limitations & Risks:
- Reduced image quality in obese individuals and those with chronic lung diseases.
- Drug-specific adverse events (dobutamine: ventricular arrhythmias)
Exercise Pharmacologic
Sensitivity 70-85% 85-90%
Specificity 77-89% 79-90%
Nuclear Myocardial Perfusion SPECTVasodilator agents administered as a continuous infusion (adenosine,dipyridamole) or bolus (regadenoson) injection to expose hetrogenity in perfusion.
• Diagnostic endpoint of nuclear MPI is reduction in myocardial perfusion.
• Limitations and Risks:- Diagnostic image quality is affected in obese patients, women with
large breasts.- Global reductions in myocardial perfusion, such as in the setting of left
main or 3-vessel CAD, can result in balanced reduction and an underestimation of ischemic burden.
- Radiation exposure.
Exercise Pharmacologic
Sensitivity 82-88% 88-91%
Specificity 70-88% 75-90%
Risk Stratification
*Although the published data are limited; patients with these findings will probably not be at low risk in the presence of either a high-risk treadmill score or severe resting LV dysfunction (LVEF <35%).
Treatment Strategies1. Patient education 2. Risk factor modification pharmacological
and non-pharmacological methods.3. Anti-anginal therapy with nitrates, beta
blockers, CCBs. 4. Use revascularization by percutaneous
catheter-based techniques or CABG when there is clear evidence of the potential to improve patients’ symptoms and/or survival.
*** Cornerstone of management is MEDICAL THERAPY and benefits of PCI as an initial management approach are questionable.
Algorithm for Guideline-Directed Medical Therapy for Patients With SIHD
NEJM April 2007
CLINICAL OUTCOMES UTILIZINGREVASCULARIZATION AND AGGRESSIVEDRUG EVALUATION (COURAGE) TRIAL
Background• Until 2004, 85% PCI procedures we done electively on patients with stable coronary artery disease.
• PCI is known to have mortality benefit in acute coronary syndromes.
• Mortality benefit in stable ischemic heart disease is unclear, although there is evidence for symptomatic benefit (relief from pain and increase in exercise tolerance).
Question•PCI coupled with optimal medical therapy reduces the risk of death and non fatal myocardial infarction in patients with stable coronary artery disease when compared with optimal medical therapy alone.
Study Description• Multicenter, open-label, parallel-group, randomized, controlled trial
• Permuted block randomization • N=2,287
• PCI plus OMT (n=1,149) • OMT alone (n=1,138)
• Setting: 50 centers in US and Canada • Enrollment: June 1999 to January 2004 • Median follow-up: 4.6 years • Analysis: Intention-to-treat
Study PopulationInclusion Criteria• Stable CAD with Canadian Cardiovascular Society (CCS) class I, II, III or stabilized class IV angina AND
• ≥70% stenosis in at least one coronary artery and objective myocardial ischemia, with any of: 1. Substantial changes in ST segment depression or T wave
inversion on the resting EKG
2. Inducible ischemia with either exercise or pharmacologic stress test
OR • 80% stenosis with classic angina without provocative testing
Exclusion Criteria• Persistent CCS class IV angina • Markedly positive treadmill test (significant ST segment depressions and/or hypotensive response during stage I of Bruce protocol)
• LVEF <30% • Refractory CHF • Cardiogenic shock • ≥50% left main disease • Revascularization within the previous 6 months • Coronary lesions deemed unsuitable for PCI
Study design
Intervention
Group 1N=1149
PCI + OMT
Group 2N=1138
OMT
Optimal Medical Therapy (OMT)
1. Antiplatelet agents – Aspirin 81 to 325 mg per day or 75 mg of Clopidogrel per day, if aspirin intolerance for all patients. Combination in patients with PCI.
2. Beta blockers – Long acting Metoprolol
3. Calcium channel blockers - Amlodipine
4. Nitrates - ISMN
5. ACE/ ARBs – Lisinopril/ Losartan
6. Lipid level reduction – Simvastatin alone or with Ezetimibe for target level of LDL level of60 to 85 mg per deciliter.
7. Guideline based recommendations for smoking cessation, diet and exercise.
• After the LDL cholesterol target was achieved, HDL cholesterol increase to a level above 40 mg per and triglyceride level decrease to less than 150 mg per deciliter (1.69 mmol per liter) with exercise, extended-release niacin, or fibrates, alone or in combination were attempted.
Percutaneous Intervention and OMT
Target-lesion revascularization always attempted and complete revascularization was performed as clinically appropriate.
• Angiographic success ;
Normal coronary-artery flow with
1. < 50% stenosis after balloon angioplasty, or
2. < 20% after coronary stent implantation
• Clinical success was defined as angiographic success plus absence of in hospital myocardial infarction, emergency CABG, or death.
• Drug-eluting stents were not approved for clinical use until the final 6 months of the study, so only used in 31 patients.
Outcomes
Primary
Composite of death from any
cause and nonfatal
myocardial infarction.
Secondary
Composite of death, MI, stroke
and hospitalization for unstable angina with negative biomarkers.
Statistical Analysis• Crude survival analysis using Kaplan-Mier method for primary and secondary outcomes.
• Adjusted analysis for co-variates using Cox proportional harzards regression model.
• Analyses were performed according to the intention to treat principle.
• T test for continuous variables.• Chi square test for categorical variables.
Results – Baseline Characteristics
Primary Outcome: Composite of death and non fatal MI • 211 patients in the PCI group and 202 patients
in the medical-therapy group.
• Estimated 4.6-year cumulative primary event rates were 19.0% in the PCI group and 18.5% in the medical-therapy group (unadjusted hazard ratio for the PCI group, 1.05; 95% CI, 0.87 to 1.27;P = 0.62)
• In subgroup analysis, even among patients with multivessel coronary artery disease, previous myocardial infarction, and diabetes, the rate of the primary end point was similar for both groups.
Secondary Outcomes
• For the pre specified composite outcome of death, nonfatal myocardial infarction, and stroke, the event rate was 20.0% in the PCI group and 19.5% in the OMT group.
PCI +OMT OMT Hazard Ratio
Death 7.6% 8.3% 0.87; 95% CI, 0.65 to 1.16
Rate of MI 13.2% 12.3% 1.13; 95% CI, 0.89 to 1.43; P = 0.33
Stroke 2.1% 1.5% 1.56; 95% CI, 0.80 to 3.04; P = 0.19
Rates of hospitalization for ACS
12.4% 11.8% 1.07;95% CI, 0.89 to 1.43; P=0.33
Additional outcomes• Reduction in prevalence of angina was noted in both groups.
-- Initial statistically significant difference noted in favor of the PCI group.
-- At 5 years, 74% of patients in the PCI group and 72% in the medical therapy group were free of angina (P = 0.35).
• Additional revascularization performed for angina that was unresponsive to maximal medical therapy or when there was objective evidence of worsening ischemia on noninvasive testing.
-- 21.1% of patients in the PCI group
-- 32.6% of those in the medical-therapy group
(hazard ratio, 0.60; 95% CI, 0.51 to 0.71; P<0.001).
Survival Analysis
Subgroup Analysis
What does this mean?• Addition of PCI to optimal medical therapy did not reduce long term rates of death, nonfatal myocardial infarction, strokes, and hospitalizations for ACS.
• Greater symptom relief from angina noted with PCI in the initial period but it by the end of the follow up period, medical therapy group also achieved similar results.
• Hence, as an initial management approach, optimal medical therapy without routine PCI can be implemented safely in the majority of patients with stable coronary artery disease, even in those with extensive, multi-vessel involvement and inducible ischemia.
Limitations• Preponderance of male patients (85%)and lack of ethnic diversity ( only 14% non white patients).
• Bare metal stents used for most PCIs as DES were only approved for use towards the end of the study.
• Likely incomplete revascularization given discordance between the incidence of multivessel disease and procedures with multiple stents placed
• Unclear how long patients took clopidogrel or if extended duration of therapy would improve outcomes in the PCI group
Strengths• Randomized• Large population• Compliance• Adequate follow up• VA population
Impact
Howard D, Shen Y. Trends in PCI Volume after Negative Results from the COURAGE Trial. Health Services Research; 49(1pt1): 153-170.
17- 25% reduction in PCI for stable heart disease.
(United States: 1979-2006). Source: NCHS and NHLBI.
350
400
450
500
550
79 80 85 90 95 00 06
Years
De
ath
s in
Th
ou
sa
nd
s
Males Females
CVD disease mortality trends for males and females
Other Studies• Bypass Angioplasty Revascularization Investigation 2
Diabetes (BARI 2D 2009) - 2,368 patients with T2DM and stable CAD randomized to CABG, OMT or OMT and PCI. PCI and only OMT groups did not show any difference.
Frye RL, et al. "A Randomized Trial of Therapies for Type 2 Diabetes and Coronary Artery Disease". The New England Journal of Medicine. 2009. 360(24):2503-2515.
• FAME (FFR guided PCI vs. angiography guided PCI) and FAME 2 ( FFR guided PCI vs. OMT) -patients with multivessel CAD, an FFR-guided approach reduces the composite of death, nonfatal MI, and need for repeat/urgent revascularization.
De Bruyne B, et al. "Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease". The New England Journal of Medicine. 2012. 367(11):991-1001.
• ISCHEMIA trial (2012-1019, 8000 patients) - Initial invasive strategy of cardiac catheterization followed by optimal revascularization with OMT compared with only OMT. Ongoing.