How to run the ultimate CTO trial and achieve Class IA in the Guidelines?
- 1. Cardiovascular Clinical Research Center How to Run the Ultimate CTO Trial and Achieve Class IA in the Guidelines Gregg W. Stone, MD The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, NY and the Cardiovascular Research Foundation
- 2. Cardiovascular Clinical Research Center Disclosures No specific CTO-related disclosures
- 3. Cardiovascular Clinical Research Center What is a Class 1A Indication? ACC/AHA Guidelines
- 4. Cardiovascular Clinical Research Center CTO PCI vs MT Randomized Trials Trial Number of pts / setting Years of enrollment Primary endpoint Results Other findings IMPACTOR- CTO 94 pts at 1 center / CCS 2010 - 2014 Change in % myocardial ischemia at 12 months (adenosine stress CMR) Reduced ischemia (P<0.01) Improved 12-mo QOL (SF-36) and 6MWT; no diff in MACE REVASC 205 pts at 1 center / CCS 2007 - 2015 Change in segmental wall thickening in the CTO territory at 6 months (CMR) No difference (median 4.1% vs 6.0% change, p=0.57); Pos if isolated CTO 1-year MACE lower driven by fewer revasc events EXPLORE 304 pts at 14 centers / recent STEMI 2007 - 2015 LVEF and LVEDV at 4 months (CMR) No change in either endpoint (p=0.60 and 0.70); LVEF improved in LAD-CTO subgroup No diff in 4-mo MACE EUROCTO 396 pts at 14 centers / CCS 2012 - 2015 Change in health status (SAQ 19 item, 5 subscales) at 12 months Improved SAQ AF and QOL (both p<0.01); NS for physical limitation, angina stability, treatment satisfaction No diff in 12-mo MACE DECISION CTO 834 pts at 19 centers / CCS or ACS 2010 - 2016 Long-term MACE (median 4.0-year FU) No difference (P=0.86) No difference in QOL (SAQ and AQ5D)
- 5. Cardiovascular Clinical Research Center Meta-analysis: CTO PCI vs MT Trials 5 RCTs, 1,792 randomized pts. CTO was the RCA in ~54% of cases. PCI procedural success rate ~86%. FU ranged from 4 to 60 months. Barbarawi M et al Am J Cardiol. 2019;123:2060-2 MACCE 17.8% MT vs. 14.2% PCI; 17% RRR; mod-sev heterogeneity No modifiers by meta-regression (SYNTAX score, %LAD, J-CTO score, LVEF) PCI better MT better
- 6. Cardiovascular Clinical Research Center Meta-analysis: CTO PCI vs MT Trials 5 RCTs, 1,792 randomized pts. CTO was the RCA in ~54% of cases. PCI procedural success rate ~86%. FU ranged from 4 to 60 months. Barbarawi M et al Am J Cardiol. 2019;123:2060-2 Mortality CV mortality PCI better MT better PCI better MT better
- 7. Cardiovascular Clinical Research Center Meta-analysis: CTO PCI vs MT Trials 5 RCTs, 1,792 randomized pts. CTO was the RCA in ~54% of cases. PCI procedural success rate ~86%. FU ranged from 4 to 60 months. Barbarawi M et al Am J Cardiol. 2019;123:2060-2 Spontaneous MI Stent thrombosis PCI better MT better PCI better MT better
- 8. Cardiovascular Clinical Research Center Meta-analysis: CTO PCI vs MT Trials 5 RCTs, 1,792 randomized pts. CTO was the RCA in ~54% of cases. PCI procedural success rate ~86%. FU ranged from 4 to 60 months. Barbarawi M et al Am J Cardiol. 2019;123:2060-2 Target vessel revascularization All revascularization PCI better MT better PCI better MT better
- 9. Cardiovascular Clinical Research Center Current Guidelines for CTO PCI 2018 ESC Guidelines on Myocardial Revascularization Neumann FJ et al EHJ. 2019;40:87–165 PCI vs. CABG: Predicted surgical mortality, the anatomical complexity of CAD, and the anticipated completeness of revascularization are important criteria for decision- making with respect to the type of revascularization No mention of CTO revascularization in any US guideline Likely to change after ISCHEMIA!
- 10. Cardiovascular Clinical Research Center Principles for the Class 1A Guideline CTO Trial Lessons from prior trials All trials were unblinded - makes QOL and soft endpoints (revasc) suspect All trials were under-powered for clinical events, and most for QOL △ • Too few patients • Low procedural success rates and high crossover rates in some trials were not accounted for • Suboptimal follow-up rates in some trials further impacted power • PCI of non-CTO lesions in both arms were allowed in some trials, further biasing the results toward the null (i.e. reducing study power) • Medical Rx wasn’t maxed out at baseline or carefully controlled (or even tracked!) after randomization in some trials → likely differential use
- 11. Cardiovascular Clinical Research Center Principles for the Class 1A Guideline CTO Trial Primary endpoint options to drive a class IA indication #1: Death (all-cause or cardiac), or composite death or MI ± Including repeat revasc or unplanned CV hosp (weaker) #2: Improved QOL (or exercise performance) - Validated instrument - e.g. SAQ, SF-36 - Disease specific domains > general health status #3: Death (all-cause or cardiac) or MI or change in QOL - Finkelstein-Schoenfeld/WIN ratio hierarchical testing
- 12. Cardiovascular Clinical Research Center Principles for the Class 1A Guideline CTO Trial Secondary endpoints • Annual rates of MACE, TVF, TLF, death (all, cardiac, non-cardiac), MI (all, procedural and non-procedural), TLR, TVR, any revasc - ≥3-year FU • Annual rates of angina (CCS scale), angina diaries, hospitalization (all, cardiovascular, non-cardiovascular) • Annual QOL (SAQ, SF-12, Rose dyspnea, EQ5D) and actigraphy • Improvement in echo (or cardiac MRI) regional wall motion/strain and global LV function from baseline to 6 or 12 months (in pts with baseline depressed LV function) • Improvement in exercise performance and reduction in ischemia • Costs and cost-effectiveness
- 13. Cardiovascular Clinical Research Center Principles for the Class 1A Guideline CTO Trial Key inclusion criteria • Single or multiple CTOs • Either documented ischemia or myocardial viability in the distribution of the CTO (SPECT, MRI, PET, stress echo) • Class II-III angina (SAQ ≤70) or Class 0-I angina if hibernating myocard. • CTO located in prox-mid LAD, prox LCX or prox-mid-distal RCA • Prior CABG and prior stenting OK, but: • No prior PCI within 12 months • No (non-CTO) PCI procedures planned for at least 12 months
- 14. Cardiovascular Clinical Research Center Principles for the Class 1A Guideline CTO Trial Key exclusion criteria • Acute or recent STEMI or class IV angina • LVEF <20% • Cardiogenic shock, pulmonary edema • Calculated creatinine clearance <30 ml/min or dialysis
- 15. Cardiovascular Clinical Research Center Principles for the Class 1A Guideline CTO Trial Essential design elements • Maximally-tolerated GDMT before randomization in both groups (at least 3 of 4 anti-anginal drugs, APT, lipid lowering, HF drugs, etc.) • Sham control trial (qualifying angiography only in control group) with cath lab and subsequent blinding procedures in place • Pts and all post-cath lab health care assessors are blinded, proven with a blinding/perception questionnaire at d/c and 1 yr • Utilize expert operators to maximize success and minimize complications • Crossovers from GDMT to CTO-PCI are tracked and strictly controlled
- 16. Cardiovascular Clinical Research Center Conclusions: The Class 1A Guideline CTO Trial • CTO procedural success rates have dramatically improved over the last decade, with stable complication rates despite increasingly complex cases being performed • Nonetheless, CTOs are frequently untreated: • Angina and reduced QOL • Likely increased mortality (especially LAD-CTOs) • Still the #1 reason pts are referred for CABG A huge opportunity!
- 17. Cardiovascular Clinical Research Center Conclusions: The Class 1A Guideline CTO Trial • A single properly designed and powered RCT, in concert with the 5 prior completed trials, would achieve a class IA guideline recommendation, markedly drive adoption, expand centers of excellence, and potentially increase reimbursement • To maximize its chance of success (and to minimize criticism), such a trial would require ~1000-1500 randomized pts, should be global (e.g. ~50 expert sites), and must be meticulously designed and performed “Nobody said it would be easy, and nobody was right” President George W. Bush