1. LATE PERCUTANEOUS CORONARY INTERVENTION AFTER MYOCARDIAL INFARCTION: A META-ANALYSIS Presenter: Darryn L. Appleton, MBChB Coauthors: Antonio Abbate, MD, Giuseppe GL Biondi-Zoccai, MD, Venkat Ramachandran, MD, Michael J. Lipinski, MD, Pierfrancesco Agostoni, MD, George W Vetrovec, MD

2. Background Late presentation with acute STEMI a relatively common and challenging problem Late presentation with acute STEMI a relatively common and challenging problem Clear evidence supporting efficacy of primary PCI early in acute STEMI (within 12hrs) Clear evidence supporting efficacy of primary PCI early in acute STEMI (within 12hrs) Utility of PCI late in the course of STEMI in otherwise stable patients (>12hrs) has not been proven Utility of PCI late in the course of STEMI in otherwise stable patients (>12hrs) has not been proven

3. Late Open-Artery Hypothesis Late patency of the IRA correlates closely with improved survival after acute MI Late patency of the IRA correlates closely with improved survival after acute MI Observational studies (retrospective) have shown improved outcomes in patients with patent IRA vs permanent occlusion Observational studies (retrospective) have shown improved outcomes in patients with patent IRA vs permanent occlusion Experimental data in lab animals shows increased apoptosis and adverse remodeling with permanent coronary occlusion Experimental data in lab animals shows increased apoptosis and adverse remodeling with permanent coronary occlusion

4. Clinical Question & Objectives Clinical Question: Clinical Question: Does mechanical intervention (PCI) to achieve reperfusion of the IRA late in the course of acute MI (>12hrs from symptom onset) translate to clinical benefit? Does mechanical intervention (PCI) to achieve reperfusion of the IRA late in the course of acute MI (>12hrs from symptom onset) translate to clinical benefit? Hypothesis: That PCI late in acute MI improves survival by means of reduced adverse remodeling and improved cardiac function Hypothesis: That PCI late in acute MI improves survival by means of reduced adverse remodeling and improved cardiac function Objectives: to perform a meta-analysis of all relevant trials testing the above hypothesis Objectives: to perform a meta-analysis of all relevant trials testing the above hypothesis

5. Methods Databases: Pubmed, PubMed Central and mRCT Databases: Pubmed, PubMed Central and mRCT Search updated Sept 06 (and later March 07) Search updated Sept 06 (and later March 07) Search terms: Search terms: ‘randomized’, ‘percutaneous coronary intervention’, ‘PCI’, ‘stent’, ‘angioplasty’, ‘revasc*’, ‘recanaliz*’, ‘acute myocardial infarction’, ‘AMI’, ‘infarct*’, ‘occlusion’, ‘occlu*’(where * denotes a wildcard) ‘randomized’, ‘percutaneous coronary intervention’, ‘PCI’, ‘stent’, ‘angioplasty’, ‘revasc*’, ‘recanaliz*’, ‘acute myocardial infarction’, ‘AMI’, ‘infarct*’, ‘occlusion’, ‘occlu*’(where * denotes a wildcard) Inclusion criteria for trials: Inclusion criteria for trials: Random treatment allocation Random treatment allocation Comparison of PCI to optimal medical management Comparison of PCI to optimal medical management Randomized >12 hrs following onset of proven acute myocardial infarction Randomized >12 hrs following onset of proven acute myocardial infarction Hemodynamically stable patients that would not need and urgent cardiac cathetization for other indications such as post-infarction angina or inducible ischemia Hemodynamically stable patients that would not need and urgent cardiac cathetization for other indications such as post-infarction angina or inducible ischemia

6. Methods Data collection Data collection Pre-specified forms used to collect data on baseline characteristics and outcomes Pre-specified forms used to collect data on baseline characteristics and outcomes Statistical methods Statistical methods performed using Review Manager 4.2.4 performed using Review Manager 4.2.4 binary outcomes combined with Peto fixed effect model binary outcomes combined with Peto fixed effect model continuous variables compared using fixed effect inverse variance weighting method continuous variables compared using fixed effect inverse variance weighting method formal Cochran Q chi-square tests performed to investigate heterogeneity between trials formal Cochran Q chi-square tests performed to investigate heterogeneity between trials reported values were two-tailed and results were considered statistically significant at the 0.05 level. reported values were two-tailed and results were considered statistically significant at the 0.05 level.

7. Methods Methods Primary outcome: Death from all causes Primary outcome: Death from all causes Secondary outcomes: Secondary outcomes: Composite endpoint of death, recurrent MI or hospitalization for CHF Composite endpoint of death, recurrent MI or hospitalization for CHF Change in Left-ventricular EF Change in Left-ventricular EF Cardiac remodeling: changes in ESV and EDV Cardiac remodeling: changes in ESV and EDV

8. Results 4361 citations from initial search 17 articles retrieved 9 studies excluded8 studies selected Total of 1193 patients 601 patients with late PCI 592 patients with medical management only 4345 excluded as non-relevant at citation level

9. Results: Study characteristics YearPatientsClinical scenarioTime to PCI (days) Longest F/U (months) Primary outcome TOPS199287STEMI712LVEF TOMIIS199444STEMI114LVEF Horie et al.199883STEMI8.360LVEF TOAT200266Anterior STEMI2612LVEF (baseline not available, LV size, exercise tolerance Zeymer et al.2003300STEMI2356Death, AMI, revascularization, hospitalization DECOPI2004212Q-wave AMI (>48 hours after pain) 535Cardiac death, AMI, VT/VF BRAVE-22005365STEMI1.13Infarct size (3 months) Silva et al.200536Anterior STEMI8.36LVEDV

10. Results: Primary outcome Study PCI Medical Rx Peto OR Weight Peto OR or sub-category n/N 95% CI % Year TOPS 0/42 0/45 Not estimable 1992 TOMIIS 1/25 1/19 3.14 0.75 [0.04, 12.76] 1994 Horie 1/44 5/39 9.20 0.21 [0.04, 1.11] 1998 TOAT 2/32 1/34 4.76 2.12 [0.21, 21.13] 2002 Zeymer et al 6/149 17/151 34.92 0.36 [0.15, 0.84] 2003 DECOPI 8/109 9/103 25.73 0.83 [0.31, 2.23] 2004 BRAVE-2 4/182 8/183 19.07 0.51 [0.16, 1.60] 2005 Silva et al 0/18 2/18 3.18 0.13 [0.01, 2.12] 2005 Total (95% CI) 601 592100.00 0.49 [0.30, 0.81] Total events: 22 (PCI), 43 (Medical Rx) Test for heterogeneity: Chi² = 5.09, df = 6 (P = 0.53), I² = 0% Test for overall effect: Z = 2.80 (P = 0.005) 0.1 0.2 0.5 1 2 5 10 Favours PCI Favours medical Rx Outcome: Death from all causes

11. Results: Secondary outcomes Study PCI Medical Rx Peto OR Weight Peto OR or sub-category n/N 95% CI % Year TOPS 2/42 3/45 4.18 0.71 [0.12, 4.26] 1992 TOMIIS 1/25 1/19 1.68 0.75 [0.04, 12.76] 1994 Horie 4/44 12/39 11.42 0.25 [0.09, 0.75] 1998 TOAT 9/32 8/34 11.23 1.27 [0.42, 3.79] 2002 Zeymer et al 9/149 24/151 25.85 0.37 [0.18, 0.76] 2003 DECOPI 14/109 16/103 22.68 0.80 [0.37, 1.73] 2004 BRAVE-2 13/182 12/183 20.48 1.10 [0.49, 2.47] 2005 Silva et al 0/18 3/18 2.48 0.12 [0.01, 1.23] 2005 Total (95% CI) 100.00 0.61 [0.42, 0.88] Total events: 52 (PCI), 79 (Medical Rx) Test for heterogeneity: Chi² = 10.56, df = 7 (P = 0.16), I² = 33.7% Test for overall effect: Z = 2.63 (P = 0.008) 0.1 0.2 0.5 1 2 5 10 Favours PCI Favours medical Rx Outcome: Composite of death, non-fatal MI, hospitalization for CHF

12. Results: Secondary outcomes Study EF change % (random) Weight EF change % (random) or sub-category EF change % (SE) 95% CI % Year Total (95% CI) 100.00 3.17 [1.65, 4.68] Test for heterogeneity: Chi² = 7.51, df = 4 (P = 0.11), I² = 46.7% Test for overall effect: Z = 4.1 (P < 0.0001) Horie 2.8000 (1.2100) 17.50 2.80 [0.43, 5.17] 1998 TOPS 2.0000 (1.1800) 18.00 2.00 [-0.31, 4.31] 1992 TOMIIS 1.2000 (1.5100) 13.28 1.20 [-1.76, 4.16] 1994 DECOPI 5.0000 (0.8500) 24.61 5.00 [3.33, 6.67] 2004 Silva et al 4.2400 (1.9100) 9.45 4.24 [0.50, 7.98] 2005 10 5 0 -5 -10 Favours PCI Favours Medical Rx Outcome: Change in LVEF

13. Results: Impact of OAT & TOSCA-2 studies NIH funded OAT study published Dec 2006 in NEJM NIH funded OAT study published Dec 2006 in NEJM 2166 patients 3-28 days following acute STEMI, randomized to PCI or optimal medical management, followed for mean of 3 years 2166 patients 3-28 days following acute STEMI, randomized to PCI or optimal medical management, followed for mean of 3 years TOSCA-2 is a subgroup of the patients randomized in the OAT who had additional baseline and follow-up EF measurements TOSCA-2 is a subgroup of the patients randomized in the OAT who had additional baseline and follow-up EF measurements

14. Results: Impact of OAT study Study PCI Medical Rx Peto OR or sub-category n/N 95% CI Year Dzavik et al (1994) 1/25 1/19 0.75 [0.04, 12.76] 1994 OAT (2006) 87/1082 84/1084 1.04 [0.76, 1.42] 2006 Ellis et al 0/42 0/45 Not estimable 1992 Hochman et al 2/32 1/34 2.12 [0.21, 21.13] 2002 Horie et al 1/44 5/39 0.21 [0.04, 1.11] 1998 Schoemig et al 4/182 8/183 0.51 [0.16, 1.60] 2005 Silva et al 0/18 2/18 0.13 [0.01, 2.12] 2005 Steg et al 8/109 9/103 0.83 [0.31, 2.23] 2004 Zeymer et al 6/149 17/151 0.36 [0.15, 0.84] 2003 Total (95% CI) 1683 1676 0.84 [0.65, 1.10] Total events: 109 (PCI), 127 (Medical Rx) Test for heterogeneity: Chi² = 11.38, df = 7 (P = 0.12), I² = 38.5% Test for overall effect: Z = 1.26 (P = 0.21) 0.1 0.2 0.5 1 2 5 10 Favours PCI Favours medical Rx Outcome: Death from all causes

15. Results: Impact of OAT study Study PCI Medical Rx Peto OR or sub-category n/N 95% CI Year Dzavik et al (1994) 1/25 1/19 0.75 [0.04, 12.76] 1994 OAT (2006) 173/1082 153/1084 1.16 [0.91, 1.47] 2006 Ellis et al 2/42 3/45 0.71 [0.12, 4.26] 1992 Hochman et al 9/32 8/34 1.27 [0.42, 3.79] 2002 Horie et al 4/44 12/39 0.25 [0.09, 0.75] 1998 Schoemig et al 13/182 12/183 1.10 [0.49, 2.47] 2005 Silva et al 0/18 3/18 0.12 [0.01, 1.23] 2005 Steg et al 14/109 16/103 0.80 [0.37, 1.73] 2004 Zeymer et al 9/149 24/151 0.37 [0.18, 0.76] 2003 Total (95% CI) 1683 1676 0.96 [0.79, 1.17] Total events: 225 (PCI), 232 (Medical Rx) Test for heterogeneity: Chi² = 18.82, df = 8 (P = 0.02), I² = 57.5% Test for overall effect: Z = 0.39 (P = 0.69) 0.1 0.2 0.5 1 2 5 10 Favours PCI Favours medical Rx Outcome: Composite of death, non-fatal MI, hospitalization for CHF

16. Results: Impact of OAT Study EF change % (random) or sub-category EF change % (SE) 95% CI Year Dzavik et al (1994) 1.2000 (1.5100) 1.20 [-1.76, 4.16] 1994 TOSCA-2 (2006) 0.8000 (0.4500) 0.80 [-0.08, 1.68] 2006 Ellis et al -1.0000 (0.8600) -1.00 [-2.69, 0.69] 1992 Horie et al 3.8000 (0.7600) 3.80 [2.31, 5.29] 1998 Silva et al 4.2400 (1.9100) 4.24 [0.50, 7.98] 2005 Steg et al 5.0000 (0.8500) 5.00 [3.33, 6.67] 2004 Total (95% CI) 2.25 [0.30, 4.19] Test for heterogeneity: Chi² = 38.41, df = 5 (P < 0.00001), I² = 87.0% Test for overall effect: Z = 2.26 (P = 0.02) 10 5 0 -5 -10 Favours PCI Favours Medical Rx Outcome: Change in LVEF

17. Results: Impact of OAT Outcomes: Changes in EDV and ESV Study ESVI change (random) or sub-category ESVI change (SE) 95% CI Year Horie et al -7.3000 (1.7900) -7.30 [-10.81, -3.79] 1998 Silva et al -6.4000 (2.2900) -6.40 [-10.89, -1.91] 2005 TOSCA-2 (OAT) 2006 -2.7000 (1.6900) -2.70 [-6.01, 0.61] 2006 Total (95% CI) -5.33 [-8.32, -2.35] Test for heterogeneity: Chi² = 3.84, df = 2 (P = 0.15), I² = 47.9% Test for overall effect: Z = 3.50 (P = 0.0005) -10 -5 0 5 10 Favours PCI Favours medical Rx Study EDVI change (random) or sub-category EDVI change (SE) 95% CI Year Horie et al -8.7000 (2.0000) -8.70 [-12.62, -4.78] 1998 Silva et al -5.2000 (2.5700) -5.20 [-10.24, -0.16] 2005 TOSCA-2 (OAT) 2006 -2.1000 (1.1100) -2.10 [-4.28, 0.08] 2006 Total (95% CI) -5.10 [-9.44, -0.77] Test for heterogeneity: Chi² = 8.64, df = 2 (P = 0.01), I² = 76.9% Test for overall effect: Z = 2.31 (P = 0.02) -10 -5 0 5 10 Favours PCI Favours medical Rx

18. Limitations Conflicting results for clinical end-points before and after addition OAT trial data Conflicting results for clinical end-points before and after addition OAT trial data Inherent limitations of individual studies within meta-analysis impact on overall result Inherent limitations of individual studies within meta-analysis impact on overall result Possible small study selection bias Possible small study selection bias Wide range of publication dates Wide range of publication dates Significant improvements in the medical management of acute MI over time Significant improvements in the medical management of acute MI over time Change in PCI technology itself over time Change in PCI technology itself over time Some important differences in study design Some important differences in study design Lack of apparent statistical heterogeneity Lack of apparent statistical heterogeneity Important to note some key methodologic differences Important to note some key methodologic differences Pre-treatment with thrombolytics Pre-treatment with thrombolytics Inclusion of patients with total IRA occlusion vs “significant stenosis” Inclusion of patients with total IRA occlusion vs “significant stenosis” Variable length of follow-up Variable length of follow-up

19. Conclusions Regarding PCI in stable survivors of acute STEMI, current data including the recent OAT shows that late (> 12hrs) PCI is neither superior nor inferior to optimal medical therapy alone in terms of altering survival, or any other combined clinical endpoint Regarding PCI in stable survivors of acute STEMI, current data including the recent OAT shows that late (> 12hrs) PCI is neither superior nor inferior to optimal medical therapy alone in terms of altering survival, or any other combined clinical endpoint

20. Conclusions Change in EF and measurements of EDV and ESV show statistically significant improvement with PCI beyond medical therapy alone Change in EF and measurements of EDV and ESV show statistically significant improvement with PCI beyond medical therapy alone Discrepancy between lack of clinical benefit and apparent improvement in EF raises interesting questions: Discrepancy between lack of clinical benefit and apparent improvement in EF raises interesting questions: Is the difference in the change in EF a real phenomenon, and if so, is it large enough to be clinically relevant? Is the difference in the change in EF a real phenomenon, and if so, is it large enough to be clinically relevant? Are benefits of reduction in adverse cardiac remodeling and improved EF offset by late adverse events? Are benefits of reduction in adverse cardiac remodeling and improved EF offset by late adverse events?

21. Acknowledgements A special thanks to Dr George Vetrovec and the VCU Pauley Heart Center Department of Cardiology A special thanks to Dr George Vetrovec and the VCU Pauley Heart Center Department of Cardiology

23. Discussion Areas of ongoing uncertainty Areas of ongoing uncertainty Patients with contraindications to important medications considered standard of care post-MI, e.g. beta-blockers, statins, ACE inhibitors Patients with contraindications to important medications considered standard of care post-MI, e.g. beta-blockers, statins, ACE inhibitors Subgroups of patients may preferentially benefit from revascularization in the setting of late MI Subgroups of patients may preferentially benefit from revascularization in the setting of late MI Patients with more severe LV dysfunction e.g. < 30% Patients with more severe LV dysfunction e.g. < 30% Patients presenting between 12-72 hours Patients presenting between 12-72 hours Patients with demonstrable myocardial viability Patients with demonstrable myocardial viability

24. Excluded Studies Study Reason for exclusion Gershlick AH, et al. NEJM 2005 Dec 29;353(26):2758-68. Randomized within 12 hrs Sutton AG, et al. MERLIN trial. JACC 2004 Jul 21;44(2):287-96. Randomized within 12 hrs Miyamoto S, et al. Jpn Circ J. 2001 May;65(5):389-94. Randomized within 12 hrs Vermeer F, et al. Heart 1999 Oct;82(4):426-31. Randomized within 12 hrs Ellis SG, et al. Circulation 1994 Nov;90(5):2280-4. Randomized within 8 hrs Topol EJ, et al. Circulation. 1992 Jun;85(6):2090-9. Randomized within 12 hrs Gibson CM, et al. Am J Cardiol. 1997 Jul 1;80(1):21-6. Comparison of PCTA vs non-PCTA outcomes was retrospective and non- randomized. Barbash GI, et al. 1990 Sep 1;66(5):538-45. Randomized to angiography rather than intervention, only small percentage of invasive arm had intervention, significant cross-over observed for recurrent ischemia in the control arm – rate of angioplasty in invasive arm 49/97 (50.5%), rate of angioplasty in conservative arm 20/104 (19.2%) van Loon RB, et al. The VIAMI-trial Curr Control Trials Cardiovasc Med. 2004 Nov 11;5(1):11. Randomization limited to angiography and not specifically to the PCI as the intervention of interest. Only 77 out of 106 patients randomized to angiography were then non-randomly selected to undergo PCI.

25. Study Design of Included Studies Study Key Study Features TOPS Lytics within 6hrs of symptom onset Negative / Equivocal stress test IRA stenosis ≥ 50% (total occlusion not a requirement) TOMIIS First Q-wave MI 5 days to 6 weeks from onset Randomized if found to have total IRA occlusion Horie et al. STEMI 24hrs to 3 weeks from onset TOAT Acute anterior MI, stable patients EF < 50% or ≥ 3 pathologic Q-waves EF < 50% or ≥ 3 pathologic Q-waves Total IRA occlusion on angiogram Zeymer et al. STEMI within 8-42 days IRA occlusion OR significant stenosis (total occlusion not a requirement) DECOPI First Q-wave MI Total occlusion of IRA on angiogram performed at least 48hrs from onset BRAVE-2 STEMI 12-48 hrs from onset Excluded if unstable or if lytics given Silva et al. Anterior MI 12hrs to 14 days from onset Total occlusion of IRA and persistent ST elevation of ≥ 1mm in ≥2 leads OAT Evidence of acute MI within past 3-28 days Total occlusion of IRA Stable (no ischemia / angina, hemodynamically stable), ≥ 1 high risk feature

26. Studies excluded from EF data Study Reason for excluding from EF calculations Zeymer Baseline and follow-up EF data not available for comparison BRAVE-2 Follow-up EF data not available for comparison TOAT Earliest EF data at 6 weeks post- randomization, thus no true baseline EF data available for comparison

27. Results: Secondary outcomes (sensitivity analysis including TOAT) Study EF change % (random) Weight EF change % (random) or sub-category EF change % (SE) 95% CI % Year TOPS 2.0000 (1.1800) 18.00 2.00 [-0.31, 4.31] 1992 TOMIIS 1.2000 (1.5100) 13.28 1.20 [-1.76, 4.16] 1994 Horie 2.8000 (1.2100) 17.50 2.80 [0.43, 5.17] 1998 TOAT 2.0000 (1.2300) 17.17 2.00 [-0.41, 4.41] 2002 DECOPI 5.0000 (0.8500) 24.61 5.00 [3.33, 6.67] 2004 Silva et al 4.2400 (1.9100) 9.45 4.24 [0.50, 7.98] 2005 Total (95% CI) 100.00 2.98 [1.67, 4.30] Test for heterogeneity: Chi² = 8.63, df = 5 (P = 0.12), I² = 42.1% Test for overall effect: Z = 4.45 (P < 0.00001) 10 5 0 -5 -10 Favours PCI Favours Medical Rx Outcome: Change in LVEF

28. Test for small study bias

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