REVASCULARIZATION Vs MEDICAL THERAPY IN STABLE CAD Dr Binjo J Vazhappilly SR Cardiology MCH , Calicut

Introduction Coronary artery disease remains the leading cause of mortality in industrialized countries. Majority of percutaneous coronary interventions are performed in pts with chronic stable coronary artery disease. Benefit of revascularization among patients with chronic stable CAD is debatable

Introduction There are 30 randomized trials comparing medical treatment with revascularization (PCI or CABG ) in pts with chronic stable CAD. CABG was applied as revascularization therapy in 13 trials, of which 6 were performed more than 2 decades ago. Balloon angioplasty alone was used in 8 studies Subsequent trials used stents , but DES implantation was negligible except for BARI-2D.

COURAGE: Clinical Outcomes Utilizing Revascularization and Aggressive Guideline-Driven Drug Evaluation Hypothesis : PCI + Optimal Medical Therapy will be Superior to Optimal Medical Therapy Alone . Study period : 1999 to 2004 Follow-up : 2.5 to 7.0 yrs (median, 4.6). Primary Outcome : Death or non fatal MI

COURAGE Inclusion Criteria : 1, 2 or 3 vessel disease ( >70% visual stenosis of proximal coronary segment) , Anatomy suitable for PCI , CCS Class I-III angina , Objective evidence of ischemia at baseline. Exclusion criteria : Persistent CCS class IV angina Markedly positive stress test ( Stage 1 Bruce protocol +ve ) LMCA disease > 50% Refractory heart failure or cardiogenic shock EF less than 30% Revascularization within previous 6 months Coronary anatomy not suitable for PCI.

Enrollment

Enrollment and Outcomes

Baseline Clinical & Angiographic Characteristics PCI + OMT (N=1149) OMT (N=1138) P Value CLINICAL Stress test 0.84 Total patients - % 85 % 86 % Treadmill test 57 % Pharmacologic stress 43 % Nuclear imaging - % 70 % 72 % 0.59 Single reversible defect 22 % 23 % 0.09 Multiple reversible defects 65 % 68 % ANGIOGRAPHIC Vessels with disease – % 0.72 1, 2, 3 31, 39, 30 % 30, 39, 31 % Disease in graft 62 % 69 % 0.36 Proximal LAD disease 31 % 37 % 0.01 Ejection fraction 60.8 ± 11.2 60.9 ± 10.3 0.86

Baseline Clinical and Angiographic Characteristics PCI + OMT (N=1149) OMT (N=1138) P Value CLINICAL History – % Diabetes 32 % 35 % 0.12 Hypertension 66 % 67 % 0.53 CHF 5 % 4 % 0.59 Cerebrovascular disease 9 % 0.83 Myocardial infarction 38 % 39 % 0.80 Previous PCI 15 % 16 % 0.49 CABG 11 % 0.94

OUTCOMES

Need for Subsequent Revascularization At a median 4.6 yr follow-up, 21.1% of the PCI patients required an additional revascularization, compared to 32.6% of OMT group who required a 1st revascularization. 77 pts in the PCI group and 81 pts in OMT group required subsequent CABG surgery Median time to subsequent revascularization was 10.0 mo in the PCI group and 10.8 mo in the OMT group

Freedom from Angina During Long-Term Follow-up Characteristic PCI + OMT OMT CLINICAL Angina free – no. Baseline 12% 13% 1 Yr 66% 58% 3 Yr 72% 67% 5 Yr 74% The comparison between the PCI group and the medical-therapy group was significant at 1 year ( P<0.001) and 3 years (P=0.02) but not at baseline or 5 years.

Conclusions As an initial management strategy in pts with stable CAD , PCI did not reduce the risk of death, MI or other major CV events when added to OMT PCI resulted in better angina relief during most of the follow-up period, but medical therapy was also remarkably effective, with no difference in angina-free status at 5 yrs.

Limitations of COURAGE trial Only 6.3 % of screened pts were randomized. Among 70% of pts assigned to PCI who had 2-vessel disease, only 36% received > 1 stent. Only 2.7% were treated with a DES. 32% of OMT patients crossed over to PCI. Excluded high risk patients. Post angiography selection bias.

BARI 2D Trial: Study Design 2368 pts with mild to moderate CAD and Type 2 diabetes prior to randomization. CABG Stratum (N= 763) PCI Stratum (N= 1605) R R OMT alone (N= 385) CABG +OMT (N= 378) OMT alone (N= 807) PCI +OMT (N= 798) Study period : January 2001, to March 2005 Mean follow up : 5.3 yrs Primary Endpoint: Death (from any cause) Secondary Endpoint: Composite of Death, MI, or Stroke BARI 2D Study Group, NEJM 2009 24 17

BARI 2D Inclusion criteria: Diagnosis of both type 2 diabetes & CAD. CAD diagnosis by documented on angiography ( ≥50% stenosis of a major epicardial coronary artery associated with a positive stress test or ≥70% stenosis of a major epicardial coronary artery and classic angina). Exclusion criteria : Pts requiring immediate revascularization or had left main coronary disease Creatinine level > 2.0 mg per deciliter Glycated Hb > 13.0% Class III or IV heart failure or hepatic dysfunction Undergone PCI or CABG within the previous 12 months.

BARI 2D Trial: Primary Endpoint The 5-year death rate for the group receiving revascularization plus optimal medical therapy was 13.2% vs. 13.5% in the group receiving optimal medical therapy alone. The difference between the two treatment groups did not reach statistical significance. Death (%) n =155 n =161 Copyleft Clinical Trial Results. You Must Redistribute Slides BARI 2D Study Group, NEJM 2009

BARI 2D Trial: Secondary Endpoint The rates of MI, stroke and the combined secondary endpoint of death, MI and stroke were similar in 2 groups. The difference between the two treatment groups for the combined secondary endpoint of death, MI and stroke did not reach statistical significance (p=0.70) Cardiovascular Event (%) n=138 n=283 n=118 n=33 n=266 n=30 BARI 2D Study Group, NEJM 2009

BARI 2D Trial Summary : Prompt coronary revascularization in pts who had been treated with intensive medical therapy for diabetes and stable ischemic disease did not significantly reduce rate of death from any cause or major cardiovascular events. Limitations Patients who are at high risk for MI revascularization were excluded from the trial. BARI 2D Study Group, NEJM 2009

MASS II Trial Randomized Controlled Clinical Trial of therapeutic strategies for multivessel CAD, stable angina and preserved ventricular function. Study period : May 1995 and May 2000 Inclusion criteria: Pts with angiographically documented proximal multivessel coronary stenosis of more than 70% by visual assessment and documented ischemia. Exclusion criteria: Unstable angina or acute MI , ventricular aneurysm requiring surgical repair, LVEF < 40% , history of PCI or CABG and single-vessel disease. Primary end point : cardiac mortality, Q-wave myocardial infarction (MI) or refractory angina requiring revascularization.

Database: 20.769 coronary angiographies (suitable to PCI-CABG) MASS 2 TRIAL Database: 20.769 coronary angiographies coronary <70% lesion - 5192 single coronary disease - 3531 previous CABG/PCI - 2908 valvar disease 2701 other - 4361 excluded 18.692 patients: Eligible: 2.076 patients (suitable to PCI-CABG) refused to participate in this trial or refused the surgical procedure 1465 patients non-randomized: MASS II Randomized: 611 patients Angioplasty (n=205) Surgery (n=203) Medical Treatment (n=203) Hueb W, et al. J Am Coll CardioI 2004; 43:1743-51

Baseline Characteristics of MASS II MT (n = 203) PCI (n=205) CABG (n = 203) P Characteristic Demographic Profile Male, (%) Age (years) mean ± SD Medical History Previous MI (%) Smoker (%) Hypertension (%) Diabetes mellitus (%) CCS class 2 or 3 (%) 67 60±4 52 27 60 26 76 72 61±8 41 32 63 29 85 0.412 0.959 0.024 0.013 0.215 0.062 0.006 69 60±9 39 33 55 36 78

Overall Mortality-Free Survival

Ten-Year Follow-up Event-free Survival

CONCLUSION All three groups had similar rates of overall mortality. Compared with CABG, angioplasty was associated with elevated rate of myocardial infarction and need for revascularization. Medical therapy showed significant incidence of myocardial infarction and high rate of additional revascularization.

Limitations of MASS-II Trial Single center study Small number of subjects No DES usage Post-angiography selection bias

STICH TRIAL Randomized controlled trial, non-blinded Study period : July 2002 and May 2007 A total of 1212 pts were randomly assigned to medical therapy alone (602 patients) or medical therapy plus CABG (610 pts). Primary Endpoint All-cause mortality Major Secondary Endpoints Cardiovascular mortality Death (all-cause) + cardiovascular hospitalization

STICH TRIAL Inclusion criteria Pts with coronary artery disease that was amenable to CABG and EF of 35% or less Medical therapy eligible Absence of left main CAD as defined by an intraluminal stenosis of ≥ 50% Absence of CCS III angina or greater (angina markedly limiting ordinary activity) Exclusion criteria Recent acute MI (within 30 dys) ,Cardiogenic shock (within 72 hrs of randomization) , Plan for percutaneous intervention , Aortic valve disease requiring repair or replacement , Life expectancy of < 3 yrs . OUR RPIMARY ENDPOINT WAS ALLL CAUSE MORTALITY IMPORTANT SECONDARY ENDPOINTS INCLUDED CARDIOVASCULAR MORTALITY AND ALL CAUSE DEATH OR CARDIOVASCULAR HOSITALIZATION

STICH Revascularization Hypothesis Treatment Per Protocol 1212 Received MED only CABG 555 537 Randomized MED only 610 602 Randomized CABG 17% 9% 55 65 WE ALSO PERFORMED A PER PROTOCOL ANALYSIS COMPARING ONLY THE 537 PATIENTS RANDOMIZED TO MEDICAL THERAPY WHO REMAINED ON MEDICAL THERAPY AND THE 555 PATIENTS RANDOMIZED TO CABG WHO RECEIVED CABG BY PROTOCOL ONLY Per protocol: MED (537) vs. CABG (555)

All-Cause Mortality — As Randomized HR 0.86 (0.72, 1.04) P = 0.123 Adjusted HR 0.82 (0.68, 0.99) Adjusted P = 0.039 0.46 0.41 AFTER ADJUSTING FOR PRE-SPECIFIED BASELINE VARIABLES THE HAZARD RATIO FOR CABG WAS 0.82 WHICH CORRESPONDED TO A P VALUE OF 0.039 Model 3 Covariate adjusted – all variables prospectively specified in STICH protocol or with significant prognostic effect. Stratum, age, gender, race, HF class at baseline, MI history, previous revascularization, best available EF, number of diseased vessels, chronic renal insufficiency, MR, stroke hx, AF hx

Cardiovascular Mortality — As Randomized HR 0.81 (0.66, 1.00) P = 0.050 Adjusted HR 0.77 (0.62, 0.94) Adjusted P = 0.012 0.39 0.32 AMONG THE 602 PATIENTS RANDOMIZED TO MEDICAL THERAPY ALONE THE OVERALL CARDIOVASCULAR MORTALITY RATE WAS 39% AMONG THE 610 PATIENTS RANDOMIZED TO MEDICAL THERAPY WITH CABG THE OVERALL MORTALITY RATE WAS 32% THIS ABSOLUTE RISK REDUCTION OF 7% CORRESPONDED TO A HAZARD RATIO WITH CABG OF 0.8 1 AND A P VALUE OF 0.050

Death or Cardiovascular Hospitalization — As Randomized 0.68 0.58 HR 0.74 (0.64, 0.85) P < 0.001 Adjusted HR 0.70 (0.61, 0.81) P < 0.001 FOR THE ENDPOINT OF ALL CAUSE DEATH OR CARDIOVASCULAR HOSPITALIZATION THE OVERALL EVENT RATE WAS 68% WITH MEDICAL THERAPY ALONE AND 58% WITH CABG THIS ABSOLUTE EVENT REDUCTION OF 10% IN FAVOR OF CABG WAS STATISTICALLY SIGNIFICANT WITH AND WITHOUT ADJUSTMENT

Stich trial : summary No significant difference between the two study groups with respect to the primary end point of the rate of death from any cause. The rates of death from cardiovascular causes and of death from any cause or hospitalization for cardiac causes were lower among patients assigned to CABG than among those assigned to medical therapy.

Urgent revascularization FAME 2 Trial design: Patients with stable angina who were appropriate candidates for PCI and had a fractional flow reserve (FFR) value ≤0.80 were randomized to either PCI + optimal medical therapy (OMT) or OMT alone. Patients were followed for a mean of 7 months. Results (p < 0.001) (p < 0.001) Trial was terminated early. Primary endpoint (death/ MI/ urgent revascularization) for PCI + OMT vs. OMT: 4.3% vs. 12.7%, HR 0.32, 95% CI 0.19-0.53, p < 0.001 Mortality: 0.2% vs. 0.7%, p = 0.31; MI: 3.4% vs. 3.2%, p = 0.89; urgent revascularization: 1.6% vs. 11.1%, p < 0.001 Highest benefit if lesion FFR <0.65 100 100 % 50 % 50 12.7 11.1 Conclusions 4.3 1.6 FFR-guided PCI + OMT was superior to OMT in patients with stable angina, mainly due to a reduction in need for urgent revascularization These results suggest that a positive FFR may be a good method to risk stratify these patients Primary endpoint Urgent revascularization PCI + OMT (n = 447) OMT (n = 441) De Bruyne B, et al. N Engl J Med 2012;367:991-1001

Meta-Analysis of Randomized clinical trials

Risk of all-cause mortality Circ Cardiovasc Interv. 2012;5:476-490

Risk of cardiac death Circ Cardiovasc Interv. 2012;5:476-490

Risk of revascularization Circ Cardiovasc Interv. 2012;5:476-490

Freedom from angina Circ Cardiovasc Interv. 2012;5:476-490

Conclusions Pts with stable CAD there is no definitive evidence of an added benefit of PCI to reduce risk of mortality , cardiac death , nonfatal MI and need for revascularization when compared with medical therapy alone. PCI provides a benefit over medical therapy in symptom relief of angina in patients with stable CAD.

Meta-Analyses Assessing Impact of PCI Versus OMT J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S , V O L . 6 , N O . 1 0 , 2 0 1 3

ISCHEMIA :International Study of Comparative Health Effectiveness with Medical and Invasive Approaches Study Group : Stable CAD with atleast moderate ischemia. Primary Aim: to determine whether an initial PCI or CABG + OMT is superior to a conservative strategy of OMT alone, with cath reserved for OMT failure Primary Endpoint: CV death or MI Secondary Endpoint: angina-related QOL Sample size : 8000 Follow up : Average 4 years.

2013 ESC Guidelines Revascularization of stable CAD pts on OMT

ACCF/AHA/SCAI PCI Guidelines: Revascularization to Improve Survival

Revascularization to Improve Symptoms

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