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Revascularization First !!

Revascularization First !!. Jeffrey W. Moses, MD Professor of Medicine Columbia University Medical Center. Disclosure Statement of Financial Interest.

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Revascularization First !!

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  1. Revascularization First !! Jeffrey W. Moses, MD Professor of Medicine Columbia University Medical Center

  2. Disclosure Statement of Financial Interest I, Jeffrey Moses, have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation. Consultant: BSC (minor)

  3. New York, NY CASE 1 Patient Demographics Past Medical History Age: 60 Gender: Male Nephrolithiasis Clinical Presentation RiskFactors CCS Class II Stress test: Exercise ECG: 6:50 Minutes of Bruce Protocol, 2mm ST Depression, Stopped Because of Chest Pain Duke Treadmill Score: -11 Echo: EF: 55-60%, No Significant Valvular Disease Family History ↑ Lipids Hypertension Treatment: Med Rx, No Further Investigation

  4. CASE 2 • 81 y/o man with colon ca s/p chemo and resection 15 y/a, now presents with 3 months progressive L shoulder pain with exertion • ASA 81 mg daily, doxazosin 1 mg daily • Nuclear Stress test: small, mild, reversible inferolateral perfusion defect, LVEF 60%

  5. Symptoms and QOL

  6. COURAGE: Freedom from Angina OMT PCI + OMT P=0.010 P=0.30 P<0.001 P=0.005 P<0.001 P<0.001 Angina-free (%) P=0.35 Months 32 % Crossover at a Median of 10.8 months Weintraub et al, N Engl J Med 2008;359:677-681.

  7. COURAGE: Angina Frequency Top Tercile (weekly) Weintraub et al, N Engl J Med 2008;359:677-681.

  8. COURAGE: Angina Frequency Middle Tercile (monthly) Weintraub et al, N Engl J Med 2008;359:677-681.

  9. COURAGE: QOL PCI + OMT OMT 100 90 80 * * * Mean Score * 70 60 50 0 0 6 12 24 36 Months from Baseline Weintraub et al, N Engl J Med 2008;359:677-681.

  10. Safety Endpoint at 4.6 Years PCI PCI PCI OMT OMT OMT 40% P<0.001 At mean 10.8 mos 11% P=NS At mean 10 mos 13% P=NS % of Patients Death Spontaneous MI Revascularization NEJM 2007;356:1503-16; AHJ 2006;151:1173-9

  11. BARI 2D: Prompt Revascularization Reduces Ischemic Symptoms Over 3 Years Analysis of the BARI 2D trial Conclusion: In diabetic patients with stable ischemic heart disease, a strategy of early revascularization and optimal medical therapy achieves better angina outcomes than does optimal medical therapy alone. Dagenais GR, et al. Circulation. 2011;Epub ahead of print.

  12. BARI 2D: QOL by Revasc. Status DASI Self-rated Health 24 55 53 23 51 22 Rev 49 Rev 21 47 DASI 20 45 Self-rated Health Med 43 19 Med 41 18 39 17 37 16 35 Baseline Year 1 Year 2 Year 3 Year 4 Baseline Year 1 Year 2 Year 3 Year 4 Rev vs Med: Delta = 1.34, p = 0.002 Delta = 1.70, p = 0.017 Courtesy of Frederick Feit, MD TCT: September 23, 2010

  13. Costs of OMT OAT BARI 2D: Lifetime costs PCI vs OMT $200 less Dagenais GR, et al. Circulation. 2011; Epub ahead of print. Mark et al NEJM 2009;360:774

  14. COURAGE: Meds Can Make You Feels Worse! Angina Frequency Bottom Tercile (none) Weintraub et al, N Engl J Med 2008;359:677-681

  15. Meta-analysis of PCI for Chronic CAD Freedom From Angina PCI OMT Risk Ratio Risk Ratio Study or Subgroup Events Total Total Weight M-H, Random, 95% CI M-H, Random, 95% CI Events ACME-1 (3 years) 1992 50 85 43 90 9.6% 1.23 (0.93, 1.63) ACME-2 (5 years) 1997 27 51 18 50 5.6% 1.47 (0.94, 2.31) ALKK (5 years) 2003 115 149 92 151 13.8% 1.27 (1.09, 1.48) AVERT (1.5 years) 1999 95 177 67 164 11.2% 1.31 (1.04, 1.65) BARI 2D (5 years) 2009 486 798 476 807 16.1% 1.03 (0.95, 1.12) COURAGE (5 years) 2007 316 1149 296 1138 14.4% 1.06 (0.92, 1.21) 51 DEFER (5 years) 2001 90 61 91 11.1% 0.85 (0.67, 1.07) MASS-1 (5 years) 1995 44 69 17 72 5.6% 2.70 (1.72, 4.24) MASS-2 (5 years) 2004 119 205 92 203 12.5% 1.28 (1.06, 1.55) TOTAL (95% CI) 2773 2766 100.0% 1.20 (1.06, 1.37) <1 Year ACME-1 (3 years) 1992 61 96 47 102 14.2% 1.38 (1.06, 1.79) ACME-2 (5 years) 1997 27 51 18 50 8.0% 1.47 (0.94, 2.31) ALKK (5 years) 2003 134 149 124 151 21.3% 1.10 (1.00, 1.20) 319 798 194 807 19.0% 1.66 (1.43, 1.93) BARI 2D (5 years) 2009 680 1149 595 1138 21.8% 1.13 (1.05, 1.22) COURAGE (5 years) 2007 MASS-1 (5 years) 1995 107 205 74 203 15.7% 1.43 (1.14, 1.79) Subtotal (95% CI) 2448 2451 100.0% 1.32 (1.13, 1.54) 1328 1052 Total events 1-5 Years ACME-1 (3 years) 1992 50 85 43 90 33.7% 1.23 (0.93, 1.63) AVERT (1.5 years) 1999 95 177 67 164 35.8% 1.31 (1.04, 1.65) MASS-1 (5 years) 1995 58 72 23 72 30.5% 2.52 (1.77, 3.60) Subtotal (95% CI) 334 326 100.0% 1.57 (1.06, 2.32) Total events 203 133 >5 Years ALKK (5 years) 2003 115 149 92 151 18.6% 1.27 (1.09, 1.48) BARI 2D (5 years) 2009 486 798 476 807 21.3% 1.03 (0.95, 1.12) COURAGE (5 years) 2007 316 1149 296 1138 19.4% 1.06 (0.92, 1.21) 51 90 61 91 15.4% 0.85 (0.67, 1.07) DEFER (5 years) 2001 44 69 17 72 8.1% 2.70 (1.72, 4.24) MASS-1 (5 years) 1995 MASS-2 (5 years) 2004 119 205 92 203 17.1% 1.28 (1.06, 1.55) Subtotal (95% CI) 2460 2462 100.0% 1.17 (1.00, 1.38) Total events 1034 1131 0.1 0.2 0.5 1 2 5 10 Pursnani et al, Circ Cardiovasc Interv. 2012;5:476-490 Favors PCI Favors OMT

  16. Does PCI reduce Death and MI? Probably YES! (in the right pt)

  17. MASS II 10-year Follow-up 58% 3VD Hueb et al, Circ 2010 August

  18. FAME 2: Primary Outcomes PCI+MT vs. MT: HR 0.32 (0.19-0.53); p<0.001 30 PCI+MT vs. Registry: HR 1.29 (0.49-3.39); p=0.61 25 MT vs. Registry: HR 4.32 (1.75-10.7); p<0.001 20 Cumulative incidence (%) 15 10 5 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Months after randomization No. at risk MT 441 414 370 322 283 253 220 192 162 127 100 70 37 PCI+MT 447 414 388 351 308 277 243 212 175 155 117 92 53 Registry 166 156 145 133 117 106 93 74 64 52 41 25 13 De Bruyne B et al. NEJM 2012:on-line

  19. FAME 2: Kaplan-Meier Plots of Landmark Analysis of Death or MI 30 ≤7 days: HR 7.99 (0.99-64.6); p=0.038 >8 days: HR 0.42 (0.17-1.04); p=0.053 p-interaction = <. 003 25 2.5 20 2.0 PCI plus MT 1.5 Cumulative incidence (%) ≤7 days 1.0 15 Cumulative incidence (%) 0.5 MT alone 0 >8 days 0 1 2 3 4 5 6 7 10 Days after randomization MT alone 5 PCI plus MT 0 7days 0 1 2 3 4 5 6 7 8 9 10 11 12 Months after randomization

  20. JSAP:PCI In Stable Angina365 Patients Randomized PCI vs OMT 1.0 0.9 0.8 0.7 0.6 Death+ACS+CVA Death+ACS+CVA+hospitalization 1.0 PCI plus medical therapy PCI plus medical therapy 0.9 Initial medical therapy only 0.8 Initial medical therapy only 0.7 Hazard ratio, 0.541; 95% CI (0.287-0.983)P=0.045 Hazard ratio, 0.664; 95% CI (0.446-0.981)P=0.040 0 0 0 1 2 3 4 5 0 1 2 3 4 5 Years Years Initial-Medical* 182 177 166 115 18 PCI+Medical* 183 179 170 123 15 Initial-Medical* 176 166 146 97 14 PCI+Medical* 176 169 154 106 9 Kazuhiko N et al, J. AM. Coll. Cardiol. Intv. 2008;1;469-479

  21. Rates of Spontaneous MI: 12 RCTs 37,000 Patient-years MT PCI Trial Event N Event N IRR (95% CI) IRR (95% CI) % Weight No Stents ACME-1 ACME-2 ALKK-1 AVERT DEFER MASS-1 RITA-2 SWISS-2 3 5 9 4 2 3 25 9 105 51 149 177 90 72 504 96 6 5 12 4 0 3 23 40 107 50 151 164 91 72 514 105 0.51 (0.13, 2.04) 0.98 (0.28, 3.39) 0.76 (0.32, 1.80) 0.92 (0.23, 3.70) 5.06 (0.24, 105.30) 1.00 (0.20, 4.95) 1.11 (0.63, 1.95) 0.25 (0.12, 0.51) 0.72 (0.43, 1.22) 0.71 (0.50, 1.00) 3.00 3.66 6.74 3.00 0.67 2.30 12.30 8.84 40.52 D+L Subtotal (I-squared = 46.3%, P=0.071) I-V Subtotal Stents BARI 2D COURAGE JSAP MASS-2 57 108 3 21 798 1149 192 205 62 119 7 31 807 1138 192 203 0.93 (0.65, 1.33) 0.90 (0.69, 1.17) 0.43 (0.11, 1.66) 0.67 (0.39, 1.17) 0.86 (0.71, 1.05) 0.86 (0.71, 1.05) 19.56 24.14 3.13 12.64 59.48 D+L Subtotal (I-squared = 0.0%, P=0.556) I-V Subtotal D+L Overall (I-squared = 31.6%, P=0.138) 100.00 0.77 (0.60, 0.99) 0.82 (0.69, 0.97) I-V Overall Random Effects Poisson Regression 0.76 (0.58, 0.99) Test for interaction P=0.53 .1 1 10 Favors PCI Favors Medical Therapy Bangalore et al. Circ 2013;on-line

  22. Cardiac Mortality MT PCI Trial Event N Event N IRR (95% CI) IRR (95% CI) % Weight No Stents ALKK-1 AVERT DEFER MASS-1 RITA-2 SWISS-2 4 1 2 4 13 3 149 177 90 72 504 96 14 1 3 2 22 22 151 164 91 72 514 105 0.29 (0.10, 0.88) 0.92 (0.06, 14.79) 0.67 (0.11, 4.03) 2.00 (0.37, 10.92) 0.60 (0.30, 1.20) 0.15 (0.04, 0.50) 0.47 (0.24, 0.93) 0.48 (0.30, 0.77) 8.87 2.04 4.39 4.79 14.69 7.96 42.74 D+L Subtotal (I-squared = 36.6%, P=0.162) I-V Subtotal Stents BARI 2D COURAGE JSAP MASS-2 44 23 2 24 798 1149 192 205 33 25 3 25 807 1138 192 203 1.35 (0.86, 2.12) 0.91 (0.52, 1.61) 0.67 (0.11, 3.99) 0.95 (0.54, 1.66) 1.08 (0.80, 1.45) 1.08 (0.80, 1.45) 19.05 16.85 4.39 16.97 57.26 D+L Subtotal (I-squared = 0.0%, P=0.625) I-V Subtotal D+L Overall(I-squared = 49.7%,P=0.036) 100.00 0.74 (0.49, 1.11) 0.86 (0.67, 1.11) I-V Overall Random Effects Poisson Regression 0.70 (0.44, 1.09) Test for interactionP=0.03 .1 1 10 Favors PCI Favors Medical Therapy Bangalore et al. Circ 2013;on-line

  23. Rate of MI / Rate of Crossover MT Better 0 PCI Better -0.5 Log Incident Rate Ratio (Death) -1.0 -1.5 10 20 30 40 50 60 Crossovers (%) Bangalore et al. Circ 2013;on-line

  24. 17 RCTs: PCI vs. Medical TreatmentPrimary End Point: All-Cause Death 0.80 (0.64 to 0.99) 0.80 (0.68 to 0.95) Deaths/Total Year of Publication Trial PCI Medical Sievers et al. 1993 0/44 1/44 ACME-1 1997 16/115 15/112 ACME-2 1997 9/51 10/50 ACIP 1997 2/192 20/366 Dakik et al. 1998 1/21 1/23 AVERT 1999 1/177 1/164 MASS 1999 6/72 6/72 Bech et al. 2001 2/90 4/91 ALKK 2003 6/149 17/151 RITA-2 2003 43/504 43/514 TIME 2004 45/153 40/148 Hambrecht et al. 2004 0/50 0/51 DANAMI 2006 19/503 24/505 INSPIRE 2006 2/104 1/101 MASS II 2006 28/205 35/203 SWISSI II 2007 6/96 22/105 COURAGE 2007 85/1149 95/1138 Overall 271/3675 335/3838 Random effects model Fixed effects model Pheterogeneity=0.263; I2=17% .1 1 10 Kastrati et al; 2007 Odds Ratio (95% Confidence Interval)

  25. PCI vs. Med Rx-21Trials: Mortality Lower Limit Upper Limit Study OR Odds Ratio and 95% ACME-1 1.11 0.52 2.37 TOPS 0.14 0.00 7.31 Sievers et al 0.14 0.00 6.82 MASS I (PCI) 1.00 0.31 3.25 ACIP 0.31 0.13 0.76 RITA-2 1.02 0.66 1.59 ACME-2 0.86 0.32 2.32 DANAMI 0.82 0.43 1.53 Dakik et al 1.16 0.07 19.41 Horie et al 0.21 0.04 1.11 AVERT 0.93 0.06 14.90 TOAT 2.12 0.21 21.13 Bech et al 0.51 0.10 2.58 TIME 1.12 0.68 1.86 ALKK 0.36 0.15 0.84 MASS Il (PCI) 0.95 0.56 1.62 DECOPI 0.83 0.31 2.23 OAT 1.04 0.76 1.42 INSPIRE 1.90 0.20 18.51 SWISS II 0.30 0.13 0.66 COURAGE 0.90 0.64 1.27 0.67 1.00 0.01 0.1 1 10 100 0.82 Combined Favors Revasc. Favors Med. Jeremias et al, Am Jour Med 2009;122:152-161.

  26. Safety Endpoint at 4.6 Years PCI PCI PCI OMT OMT OMT 40% P<0.001 At mean 10.8 mos 11% P=NS At mean 10 mos 13% P=NS % of Patients Death Spontaneous MI Revascularization NEJM 2007;356:1503-16; AHJ 2006;151:1173-9

  27. Cardiac Mortality in Medically Treated Patients According to Ischemic Risk – CSMC database N=9,956 pts 5.4% cardiac mortality in 1.9 years - Is this “stable” angina? Cardiac Death Rate (%) (1.9 yr FU) N=7110 N=1331 N=718 N=545 N=252 0% 1- 5% 5-10% 11-20% >20% % Total Myocardial Ischemia Hachamovitch et al Circulation. 2003;107:2900-07

  28. MPS % Ischemic Myocardium(95% CI) Pre-Rx & 6-18 Months PCI + OMT (n=159) OMT (n=155) 40 40 35 35 Mean=-2.7% (95% CI=-3.8% to -1.7%) Mean=-0.5% (95% CI=-1.6% to 0.6%) 30 30 25 p<0.0001 25 20 20 15 15 8.6% 8.1% 8.2% 10 10 5.5% (6.9%-9.4%) 5 5 (4.7%-6.3%) 0 0 Pre-Rx 6-18m Pre-Rx 6-18m

  29. RCTs with Ischemia OMT vs PCI Identified 4 randomized controlled trials (RCT) ACME COURAGE AHJ (baseline ischemia substudy) FAME-2 SWISSI-II Comprised a total of 1769 patients 871 randomized to PCI 898 randomized to MT alone Length of follow-up ranged from ~7 mo – 10 yrs Weighted average of 4.5 years

  30. All-Cause Mortality: HR Analysis All-cause Mortality in Randomized Trials of PCI vs. MT (Patients with Ischemia or Equivalent) ES (95% CI) % Weight (I-V) Study ID ACME 0.73 (0.24, 2.22) 20.42 COURAGE AHJ 0.62 (0.30, 1.28) 48.00 FAME-2 4.65 0.33 (0.03, 3.17) SWISSI-II 26.93 0.42 (0.16, 1.11) Fixed Effects (I2=0.0%, p=0.84) 100.00 0.56 (0.34, 0.93) Random Effects 0.56 (0.34, 0.93) .1 1 10 PCI Better MT Better

  31. Summary of Results: Mortality Significant 44% reduction in all-cause mortality was observed with PCI vs. MT HR 0.56; 95% CI [0.34-0.93], p=0.02 Point estimate of the HR for mortality favoring PCI vs. MT varied from 0.33-0.73; I2=0% Baseline ischemia cohort of the COURAGE trial comprised 48% weight of the studies Analysis Using Count Data: 28/871 (3.2%) deaths with PCI 54/898 (6.0%) deaths with MT RR 0.56; 95% CI[0.36-0.87], p=0.01

  32. All-Cause Mortality: HR Analysis All-cause Mortality in Randomized Trials of PCI vs. MT* (Patients with Ischemia or Equivalent) ES (95% CI) % Weight (I-V) Study ID ACIP* 0.24 (0.05, 1.11) 5.73 ACME 0.73 (0.24, 2.22) 11.13 COURAGE AHJ 0.62 (0.30, 1.28) 26.16 DANAMI Symptomatic* 0.68 (0.30, 1.55) 20.42 DANAMI Silent* 0.93 (0.40, 2.16) 19.36 FAME-2 2.54 0.33 (0.03, 3.17) SWISSI-II 14.68 0.42 (0.16, 1.11) Fixed Effects (I2=0.0%, p=0.76) 100.00 0.61 (0.42, 0.89) Random Effects 0.61 (0.42, 0.89) .1 1 10 PCI Better MT Better *Secondary analysis includes studies with small no. of CABG pts

  33. Underuse and Adverse Outcomes 1625 pts with Chronic CAD and Cath: 3 year risk : Death /ACS HR: 0.61 (p=0.009) CABG HR: 0.57 (p=0.12) PCI HR: 0.99 Medical Proportion of Cardiac Catherization (%) n=311 n=326 n=991 ACC Appropriateness Categories Ko et al, JACC 2012; in press

  34. Hazards of Underutilization 9300 Patients with recent onset chest pains 57% appropriate patients did not get angio median follow-up: three years Angio + Angio – Death or ACS 11% 22% HR : 2.5 Hemingway et al, Annals of Int Med 2008;248:221

  35. Appropriateness Ratings by Low-Risk Findings on Noninvasive Imaging Study and Asymptomatic Low-Risk Findings on Non-invasive Study Asymptomatic Patel et al JACC 2009 53 (February): 530-553

  36. If the goal was really best outcomes why aren’t physicians monitored for potential underuse? Overuse may cost money Underuse costs lives

  37. We have hoodwinked the patients into denying themselves treatment If you have a treatment that may help and doesn’t harm you take it We have convinced the patient to do the opposite

  38. Conclusions In cases of moderate symptoms PCI provides immediate and superior symptomatic relief vs “OMT” (i.e., crossovers are Rx failure) with no cost of MI, death or CABG In cases of demonstrated ischemia or critical anatomy the overwhelming evidence favors revascularization to reduce death and MI “OMT” alone is safe for mild symptoms, little or no ischemia and noncritical anatomy …..Period

  39. ISCHEMIA Trial Design 8000 Ischemia-Eligible Stable Patient (Stable CAD, Moderate-Severe Ischemia) Blinded Coronary CTA CT Exclusion Ancillary Study Eligible Anatomy? NO YES RANDOMIZE Invasive Strategy (Cath with Optimal Revasc + OMT) OMT Strategy (OMT Alone) This is an Untested Hypothesis J. Hochman, TCT 2010

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