CHRONIC Stable angina best managed with optimal medical treatment

1. CHRONIC Stable angina best managed with optimal medical treatment UpendraKaul Chairman, Batra Heart Centre Dean Academics and Research Batra Hospital and Medical Research Centre New Delhi Bengaluru December 15th 2018

2. PCI most gratifying procedure for acs IMPROVES SURVIVAL REDUCES HOSPITALIZATIONS IMPROVES QOL WHAT ABOUT CHRONIC STABLE ANGINA ?

3. Optimal Medical Treatment FOR CSA Control of risk factors and anti ischemic treatment • Statins (> 50% reduction in LDLc) • ACEI/ARB’s • Aspirin/thienopyridine • Beta blockers/Non dihydropyridines • Nitrates • Ranolazine/Trimetazidine • Ivabradine Treatment of Diabetes HbA1c<7 % Treatment of HT. BP<130/ 80 mms Hg

4. WhatShould We Expect from OMT in Chronic StableAngina? • Improvement in Survival and Freedom from MI in short and Long Term. • Improvement in symptoms andquality of life and/or… • Reduced economic burden (cost of health care, disability or lostwork)

5. PCI vsomt in ConsistentlyDeliveringTheseBenefits IN STABLE ANGINA PATIENTS ?

6. 2287 patients with CAD and objective evidence of ischemia randomized to OMT with or withoutPCI The COURAGE Trial: A TurningPoint N EnglJ Med2008;359:677-87 * 70% had nuclearscintigraphy

7. COURAGE Primary: Freedom from Death orMI 1.0 Optimal MedicalTherapy 18.5% 0.9 Event-freeSurvival 0.8 19.0% PCI + Optimal MedicalTherapy 0.7 0.6 HR= 1.05(0.87-1.27) P =0.62 0.5 0 1 2 3 4 5 6 7 Years N Engl J Med2008;359:677-87.

8. Secondary Endpoints and Components ofPrimary N Engl J Med2008;359:677-87.

9. 100% 90% 80% 100%100% Benefits OF pci Dwindle WITH TIME: BaselineAngina PCI +OMT OMT 90% 79% 81% 76% 68% 73% 70% 65% 67% 70% 64% 62% 62% 60% 50% 40% 30% 20% 10% 0% 6 Months Baseline 1 3 12 24 36 N Engl J Med2008;359:677-87.

10. Courage: Did PCI Provide Superior AnginaRelief? *Small, but significant difference at 1 and 3 years, but not 5years

11. The Observations fromCOURAGE Regarding Lack of Incremental Angina Relief are NotNew

12. 70% BARI 2D Trial: Freedom from Angina overTime PCI+OMT OMT 61% 60% 60% 59% 60% 54% 56% 53% 48% 50% 40% 40% 30% 24% 20% P<0.001 P=NS P=NS P=NS P=NS 10% 0% 3 Years 1 2 4 5 Circulation.2011;123:1492-1500

13. Courage Trial: Quality of Life Score overTime

14. Courage: Angina Frequency Scores overTime

15. Courage Trial: Rates of TreatmentSatisfaction No significantdifferences after 1year

16. Meta-Analysis: Survival after PCI vs. MedicalRx Study(year) OR Pvalue Odds Ratio and 95%CI FavorsPCI Favors MedicalRx Mitchell JD, Brown DL. J Am Heart Assoc. 2017 Nov;6(11).

17. Myocardial Infarction: PCI vs. MedicalTherapy Study(year) OR Pvalue Odds Ratio and 95%CI Favors MedicalRx FavorsPCI Mitchell JD, Brown DL. J Am Heart Assoc. 2017 Nov;6(11).

18. Courage: Is PCI in Stable AnginaCost-effective? The Cost difference in Indian milleau will be even more significant “ The added cost of PCI was approximately $10 000, without significant gain in life-years or quality-adjusted life-years. The incremental cost- effectiveness ratio varied from just over $168 000 to just under $300 000 per life-year or quality-adjusted life-year gained withPCI.” Circ Cardiovasc Qual Outcomes.2008;1:12-20.

19. ORBITA Design: Simple andElegant • 230 patients with angina and severe coronary stenosis (mean FFR0.69) • Randomized to PCI or sham (placebo)procedure • Primary endpoint change in treadmill exercise time • Other assessment included angina questionnaire. CCS angina grade, and peak O2uptake

20. ORBITA Primary Endpoint: Change in Treadmill Exercise Time for PCI 60 Difference = 16.6seconds 50 (95% CI -8.9 to42.0) P=0.20 40 Change inexercise time(seconds) 28.4 30 20 11.8 10 0 PCI Placebo Lancet 2018; 391:31–40

21. Change in CCS Angina Grade: PCI vs.Placebo 60% PCI Placebo 55% 50% 49% 40% Change inCCS AnginaGrade 30% 26% 26% 24% 20% 21% 10% 0% Nochange 1 class improvement ≥2 class improvement Lancet 2018; 391:31–40

22. ORBITA: Peak Oxygen Uptake PCI vs.Placebo 2,000 Difference -12.9ml/min P =0.74 Pre-Procedure Post=Procedure 1,900 Peak Oxygen Uptake(ml/min) 1,800 1,700 1718.3 1715.0 1713.0 1707.4 1,600 1,500 1,400 1,300 1,200 PCI Placebo Lancet 2018; 391:31–40

23. Seattle Angina Questionnaire: PCI vs.Placebo 14 PCI Placebo 12 11.2 10 8 Change in score: Pre-randomization to followup 7.7 7.4 6 5.0 4 P =0.42 P =0.26 2 0 PhysicalLimitation AnginaFrequency Lancet 2018; 391:31–40

24. Conclusions of ORBITA TRIAL In patients with medically treated angina and severe coronary stenosis, PCI did not increase exercise time by more than the effect of a placebo procedure. The efficacy of invasive procedures can be assessed with a placebo control, as is standard for pharmacotherapy.

25. What about FAME2? thestudy showedbenefits of FFR guided intervention vs. medicaltherapy?

26. FAME-2Design • In 1220 patients with stable coronary artery disease, assessed using fractional flow reserve (FFR) • Patients with least one stenosis with an FFR <0.80 randomized to PCI plus medical therapy or medical therapyalone. • Patients with no stenosis with FFR >0.80 received medical therapy alone and included in aregistry.

27. ___ Pd FFR= Pa (AO pressure via Guide catheter) Pa Pd (PressureWire) FFR; The true definition Definition of FFR Maximum achievable blood flow in stenotic coronary artery divided by Maximum blood flow in the same artery without stenosis” At maximum hyperemia Normal > 0.8

28. FFR 0.89 FFR 0.88 FFR 0.87 FFR 0.50

29. FAME 2: Key Endpoints andComponents N Engl J Med2014;371:1208-17.

30. Is “Need” for Revascularization a Reliable or BiasedEndpoint? • Both physicians and patients unblinded to FFR measurements and PCIresults. • The keyconcern: • In the context of a non-blinded trial, are decisions regarding interventions during follow-up biased by the knowledge of the previous treatmentassignment. • Need for revascularization is a highly biasedendpoint

31. Proportion of Patients Experiencing Chest Pain after Being Told They Had No SignificantLesion DEFERTrial FAME 2Trial 100 90 80 70 60 50 40 30 20 10 0 80 88 67 70 Percent with Class II-IVAngina Percent with ChestPain 60 50 54 40 30 16 20 10 0 Before being toldno significantlesion After being toldno significantlesion Before being toldno significantlesion After being toldno significantlesion Adapted from Circ Cardiovasc Qual Outcomes.2018;11

32. Do we really need sham-controlled trials for interventionalprocedures?

33. A recurrent pattern is present in the history of various treatments for angina pectoris. When a drug or surgical procedure is introduced, proponents of the new therapy…report remarkable benefits, with therapeutic effectiveness seen in the vast majority of patients…..Only later do more adequately controlled studies appear…These skeptical investigators, who operate under circumstances that minimize the placebo effect,find that the therapy is no better than inert, control placebo…

34. Who Thinks We Need Sham ControlledTrials? “ The placebo effect in treating angina ispowerful.”

35. Laser Revascularization for Myocardial Revascularization : TMR & PTMR Concept of Reptilan Heart

36. Positive Results : Non Blinded Trials

37. SHAM CONTROLLED TRIAL Am J of Cardiology ,2002 No benefit beyond that of a similar sham procedure in patients blinded to their treatment status.

38. Simplicity-2: Renal Denervation vs. Control(RCT) 200 Baseline 6Months 180 160 140 120 100 80 60 40 20 179.0 178.0 178.0 146.0 OfficeSystolic BP(mmHg) Difference 33mmHg P<0.0001 0 Denervation Control Lancet 2010; 376:1903–09

39. Simplicity-3 Trial: Renal Denervation vs.Sham 200 Baseline 6Months 180 160 140 120 100 80 60 40 20 180.2 179.7 168.5 165.6 OfficeSystolic BP(mmHg) Difference 2.4mmHg P=0.26 0 Denervation Sham N Engl J Med2014;370:1393-401

40. Why Doesn’t PCI ReduceMorbidity/Mortality or Provide Better Relief ofAngina?

41. PCI Does Not Treat the Lesions Responsible for Most Major CardiovascularEvents • The pivotal issue: Stenoses do not cause myocardial infarction or suddendeath. • Rupture of non-stenotic plaques cause major morbidity-mortality.

42. The Epicardial Stenosis is Only One Factor in the Pathophysiology ofAngina • Microvascular disease is well recognized as a key component of chest pain syndromes (notaddressed byPCI). • Dynamic vasoconstriction superimposed on fixed coronary obstructions can alter exercise threshold (mixed anginapectoris). • Myocardial hypertrophy affects ischemicburden.

43. A paradigm that suggests why randomized trials have not demonstrated a survival benefit for revascularization in SIHD Severe Obstruction (angina, no rupture) vs Mild Obstruction (no angina, likely to rupture) • Vulnerable plaque • Minor obstruction • Eccentric plaque • Lipid pool • Thin cap • Severe fibrotic plaque • Severe obstruction • No lipid • Fibrosis, Ca2+ • Plaque rupture • Acute MI • Unstable angina • Sudden death • Exertional angina • (+) ETT Revascularization Anti-anginal Rx Pharmacologic stabilization Early identification of high-risk? Courtesy of PH Stone, MD.

44. OMT for CSA has Improved Over the Years • Improved survival with high dose statins • PCSK9 Inhibitors for patients not reaching targets • 30% Patients are Diabetics • New Therapies SGLT2 inhibitors and GLP1 Analogues improve All Cause Mortality and endpoints significantly

45. Remaining Gap • Is there any high risk group of SIHD patients, (other then LM) in whom a strategy of routine revascularization improves outcomes in the era of modern medical therapy?

46. Observational study: Revascularization was associated with lower risk of cardiac death only in those with >10% ischemia on perfusion imaging 5 N=10,627 no known CAD 146 CD Medical Rx* 4 3 log Hazard Ratio Revasc* 2 *p<0.001 1 0 0 12.5% 25% 32.5% 50% % Ischemic Myocardium Source: Hachamovitch Circulation 2003;107:2900-2907.

47. COURAGE Serial Nuclear Substudy: Outcomes in 105 Patients with Moderate-to-Severe Baseline Ischemia Who Returned for 2nd Study @ 6-18 months A: PCI reduces ischemia better than OMT alone 16% 34% B: For both groups combined, ischemia reduction is associated with fewer events Unadjusted p=0.001 Risk-Adjusted p=0.082 C: Does PCI Reduce Events? Shaw et al. Circulation. 2008;117:1283-1291.

48. Stable Patient At Least Moderate Ischemia* (determined by site; read by core lab) Blinded CCTA1 no Core lab anatomy eligible?2 Late screen failure yes Study Completed Recruitment . Results Awaited RANDOMIZE CONSERVATIVE Strategy OMT3 alone Cath reserved for OMT failures INVASIVE Strategy OMT3 + Cath + Optimal Revascularization Average 3 Years of Follow-up Primary Endpoint: Composite of CV Death and MI Secondary endpoint- Angina related QOL * Patients with eGFR <30 or on dialysis will be enrolled in the ISCHEMIA CKD ancillary trial 1CCTA may not be performed in participants with eGFR <60 mL/min 2Exclude participants with LM disease or no obstructive disease 3OMT=optimal medical therapy

49. All patients with CSA should be given OMT as the first line treatment • Improvement in angina occurs for mostpatientswith robust reduction in mortality and symptoms • PCI should be reserved for patients who continue to have symptoms on OMT or do not tolerate medicines. • We await the results of ISCHEMIA study for patients with moderate to severe Ischemia Conclusions