Critical appraisal of Stitch Trial by Dr. Akshay Mehta

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  • Difference statistically significant after allowing for baseline differences 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 hxHR 0.83 (0.68, 0.99) p = 0.039.
  • Need to convert this into HR plot
  • Nejm editorial on stich
  • HR 95% Cl PO.65 0.48 0.86 0.003
  • Critical appraisal of Stitch Trial by Dr. Akshay Mehta

    1. 1. STICH Trial-A Critical Appraisal -Dr Akshay Mehta Dr B Nanavati Hospital Asian Heart Institute
    2. 2. Background 1 CAD is the commonest substrate for HF The role of CABG for Rx of CAD with HF not clearly established. Landmark trials in the 1970s comparing CABG with medical therapy alone, were predominantly in pts with chronic stable angina.
    3. 3. Background 2 These trials excluded patients with severe LV dysfunction (patients with an ejection fraction of <35%). A meta-analysis of the trials showed that 7.2% of the patients who underwent randomization had an EF of 40% or less Only 4.0% had primary symptoms of heart failure rather than angina Predate the major developments in medical therapy and cardiac surgery
    4. 4. Surgical Treatment for Ischemic Heart Failure –STICH Trial Two Hypotheses I II Surgical LV restoration Revascularization hypothesis Hypothesis
    5. 5. I] Surgical Revascularization Hypothesis Primary Hypothesis: In patients with HF, LVD and CAD amenable to surgical revascularization, CABG added to intensive medical therapy (MED) will decrease all-cause mortality compared to MED alone. Secondary hypothesis: Presence and extent of dysfunctional but viable myocardium, as defined by radionuclide imaging, dobutamine stress echocardiography, or both, will identify patients with greatest survival advantage of MED + CABG compared with MED alone.
    6. 6. II] LV restoration hypothesisIn patients with dominant anterior wall LV akinesia or dyskinesia, LV shape and size optimization by SVR combined with CABG and MED improves long-term survival free of cardiac hospitalization compared with CABG and MED without SVR.
    7. 7. Original Article Coronary-Artery Bypass Surgery in Patients with Left Ventricular DysfunctionEric J. Velazquez, M.D., Kerry L. Lee, Ph.D., Marek A. Deja, M.D., Ph.D., Anil Jain, M.D., George Sopko, M.D., M.P.H., Andrey Marchenko, M.D., Ph.D., Imtiaz S. Ali, M.D., Gerald Pohost, M.D., Sinisa Gradinac, M.D., Ph.D., William T. Abraham, M.D., Michael Yii, M.S., F.R.C.S., F.R.A.C.S., DorairajPrabhakaran, M.D., D.M., Hanna Szwed, M.D., Paolo Ferrazzi, M.D., Mark C. Petrie, M.D., Christopher M. OConnor, M.D., Pradit Panchavinnin, M.D., Lilin She, Ph.D., Robert O. Bonow, M.D., Gena Roush Rankin, M.P.H., R.D., Robert H. Jones, M.D., Jean-Lucien Rouleau, M.D., for the STICH Investigators N Engl J Med Volume 364(17):1607-1616 April 28, 2011
    8. 8. STICH Revascularization Hypothesis Randomized MED only 602 1212 Randomized CABG HF, LVD and CAD 610 amenable to CABG
    9. 9. All-Cause Mortality Adjusted HR 0.82 (0.68,0.99) Adjusted P = 0.039
    10. 10. Thus Primary End Point:As randomized, CABG led to a 14% RRR in all-cause mortality compared to MED (not significant)
    11. 11. Has CABG no role in Ischemic HF ?“We were unable to show a significant benefit forCABG in our primary analysis, but if you dive deeper,the data are much more supportive of bypasssurgery,” -Dr Eric J. Velazquez, M.D.
    12. 12. Cardiovascular Mortality HR 0.81 (0.66, 1.00) P = 0.050 Adjusted HR 0.77 (0.62, 0.94) Adjusted P = 0.012
    13. 13. • Death from any cause adjusted outcomes models. Model 1: surgical ventricular reconstruction eligibility (i.e., enrollment stratum); Model 2: Model 1 + age, sex, race, baseline New York Heart Association heart failure class, myocardial infarction history, previous revascularization, best available core lab ejection fraction; Model 3: Model 2+ number of diseased vessels, presence of chronic renal insufficiency, mitral regurgitation grade, stroke history, atrial fibrillation or flutter.
    14. 14. Death or CardiovascularDeath or Cardiovascular hospitalization Hospitalization-nt done HR 0.74 (0.64, 0.85) P < 0.001 Adjusted HR 0.70 (0.61, 0.81) P < 0.001
    15. 15. Time-varying Hazard Ratios0.25 0.5 1 2 4 CABG MED group group better better
    16. 16. STICH Revascularization HypothesisEffect of Actual Treatment Received 1212Randomized 602 610 Randomized MED only CABG 537 65 555 55Received Received Received MED CABG MED Per protocol: MED (537) vs. CABG (555) As treated: MED (592) vs. CABG (620)
    17. 17. All-Cause MortalityAll cause mortality-as treated — As Treated (nt done) HR 0.70 (0.58 – 0.84) P < 0.001
    18. 18. All-cause mortality:Mortality All-Cause as per protocol — As Per Protocol (nt done) HR 0.76 (0.62, 0.92) P = 0.005
    19. 19. Conclusions STICH trial supports bypass surgery on top of best medical therapy vs medical therapy alone to reduce cardiovascular morbidity and mortality “Although the totality of information supports CABG, there is an early hazard A fair approach is to evaluate each patient’s prognosis. If they have a low likelihood of living two years or don’t want to take the risk of having surgery medical therapy may be a good option.” - Dr Eric Velazquez
    20. 20.  Also, as a start, aggressive medical therapy should be initiated and optimized, according to evidence-based guidelines. For patients with persistent or progressive symptoms, revascularization can be offered. Patients who are being treated for HF should be evaluated for coronary disease Heart failure without angina shouldnt exclude patients from an angiographic evaluation.
    21. 21. Myocardial Viability and Survivalin Ischemic Left Ventricular Dysfunction Robert O. Bonow, MD On behalf of the STICH Trial Investigators
    22. 22. STICH Viability HypothesisIn this prospective substudy, we tested the hypothesis that assessment of myocardial viability identifies patients with CAD and LV dysfunction who have the greatest survival benefit with CABG compared to aggressive medical therapy
    23. 23. STICH ViabilityViability testing was optional at enrolling sites and was not a prerequisite for enrollment. Dobutamine echo SPECT protocols: protocols: • Thallium-201 stress- • Staged increase in redistribution- dobutamine starting reinjection at 5 μg/kg/min • Thallium-201 rest- redistribution • Nitrate-enhanced Tc- 99m perfusion imaging
    24. 24. Patients randomized Patients with no Patients with no usable myocardial myocardial viability test viability test 594 611 Unusable test1212 17 • Timing • Poor quality 618 601 Patients with Patients with usable myocardial myocardial viability test viability test
    25. 25. Patients randomized in STICH Revascularization Hypothesis 1212 SPECT Dobutamine echo n=471 n=280 321 150 130 Patients with no 611 usable myocardial viability test Patients withusable myocardial 601 viability test 114 Nonviable 487 Viable
    26. 26. STICH Viability Results …demonstrate that association between myocardial viability and survival, is non- significant when subjected to a multivariable analysis that includes other baseline variables. …fail to demonstrate a significant interaction between myocardial viability and medical versus surgical treatment with respect to mortality, whether assessed according to treatment assigned (intention to treat) or to the treatment actually received.
    27. 27. STICH ViabilityImplications: In patients with CAD and LV dysfunction, assessment of myocardial viability does not identify patients who will have the greatest survival benefit from adding CABG to aggressive medical therapy
    28. 28. However, Limitations of the TrialPatients were selected for viability testing individually at thephysicians discretionPatients represent a subpopulation of STICH (<50%)The number of patients without substantial viability was small(114)which limited statistical powerUse of two different imaging methods for assessing myocardialviability and their limitations of specificity/sensitivity.Analysis limited to SPECT and dobutamine echo, not PET or cardiacMRI while the analysis looked at "substantial viability" as an "all-or-none" variable, decisions whether to revascularize or not have generally depended on the extent of viability—that is, as a continuous variable.
    29. 29. Take home message:Despite all its imperfections the viability study suggests that assessment of myocardial viability alone may not be the deciding factor in selecting the best therapy for patients with ischemic heart disease and LV dysfunction.Besides viability one should also look at other factors like target vessels, LV volumes, EF etc.This is specially true if SPECT or Dobutamine echo only are used for viability testing. Whether they have viability or not, STICH like patients benefit fromcoronary bypass and we shouldnt be using viability studies such as these to exclude patients from cardiac surgery.We should await similar randomized studies with other methods of viability detection like MRI etc.
    30. 30. Myocardial Viabilityand Mortality Myocardial Viability and Mortality 1.0 Variables associated with mortality Chi-square p Risk score Chi- p33.26 <0.001 0.8 square LV ejection fraction 24.80 <0.001 HR 95% Cl scoreP Risk LV EDVI 33.26 <0.001 35.36 <0.001 O.65 0.48 0.86 0.003 LV ESVI 24.80 LV ejection fraction <0.001 Mortality Rate LV EDVI 35.36 33.90 <0.001 <0.001 0.6 LV ESVI Myocardial viability 33.90 8.54 <0.001 0.003 Myocardial viability 8.54 0.003 0.4 50% 0.2 33% 0.0 0 1 2 3 4 5 6 Years from RandomizationWithout viabilityWith viability
    31. 31. Myocardial Viability and Mortality Univariate MultivariableVariable No. Chi-square p value Chi-square p valueSPECT and/or DE 601 8.54 0.003 1.57 0.210SPECT alone 471 7.35 0.007 0.58 0.444DE alone 280 1.18 0.277 0.42 0.518
    32. 32. Myocardial Viability and Cardiovascular Mortality Univariate Multivariable Chi-square p value Chi-square p value HR 95% Cl P 0.61 0.44 0.84 0.003 8.81 0.003 0.91 0.339
    33. 33. Myocardial Viability and Mortality + CV Hospitaliztion Univariate Multivariable Chi-square p value Chi-square p value 20.27 <0.001 8.60 0.003
    34. 34. Patients with viability tests 601Patients with Patients myocardial without viability 487 114 myocardial viability 243 244 60 54 MED CABG MED CABG 49.9% 50.1% 52.6% 47.4%
    35. 35. Myocardial Viability and Mortality 56% 35% 42% 31%Subgroup N Deaths HR 95% CI Interaction P valueWithout viability 114 58 0.70 0.41, 1.18 0.528With viability 487 178 0.86 0.64, 1.16 0.25 0.5 1 2 CABG MED better better
    36. 36.  the patients without substantial viability, "who had perhaps less likelihood of functional recovery [than those with substantial viability], did as well from CABG as patients who did. . . . I think thats what we have to take away from this: we shouldnt be using [viability] studies to exclude patients from cardiac surgery -Dr Eric Velazquez
    37. 37. Surgical Treatment for Ischemic Heart Failure –STICH Trial In patients with HF, LVD < 35% and CAD amenable to CABG, CABG +MED will decrease all-cause mortality I compared to MED alone+ (Viability Substudy) Hypotheses In pts with dominant anterior wall LV II akinesia or dyskinesia, SVR + CABG + MED > hosp free survival compared with CABG + MED without SVR.
    38. 38. For management of patients withHF with surgically revascularizable CAD and decreased LV function (1) Is contemporary CABG surgery superior to contemporary medical/secondary prevention therapy in prolonging survival in these pts? (2) Among patients with significant anterior wall dysfunction, does the addition of surgical ventricular reconstruction (SVR) to CABG improve hospitalization-free survival?
    39. 39. Surgical Treatment for Ischemic Heart Failure trial stratum and treatment assignment. CAD EF <= 0.35 SVR YES NO NO Medical SVR eligible? Not in trial eligibility eligible? NO YES YES Stratum A Stratum B Stratum C CABG + SVRMED CABG CABG + SVR CABG MED CABG
    40. 40. Hypotheses : In patients with heart failure, left ventricular EF of 0.35 or less(1) coronary artery bypass grafting with intensive medical therapy improves long-term survival compared with survival with medical therapy alone, and(2) in patients with anterior left ventricular dysfunction, surgical ventricular reconstruction to a more normal left ventricular size plus coronary artery bypass grafting improves survival free of subsequent hospitalization for cardiac cause when compared with that with coronary artery bypass grafting alone.
    41. 41. Major STICH hypotheses Primary Major secondary Hypotheses hypotheses H1 Coronary revascularization hypothesis Presence and extent of dysfunctional but viable ● Improvement in myocardial myocardium, as defined by perfusion by CABG combined radionuclide imaging, with MED improves long-term dobutamine stress survival compared with MED echocardiography, or both, alone. will identify patients with greatest survival advantage H2: LV restoration hypothesis of MED and CABG compared ● In patients with dominant anterior with MED alone. wall LV akinesia or dyskinesia, LV shape and size optimization by SVR combined with CABG and MED improves long-term survival free of cardiac hospitalization compared with CABG and MED without SVR.
    42. 42. The conclusions that can be drawnfrom this substudy are limited by a number of factors Viability data were not available for all the patients who were enrolled in the STICH main trial.3 The substudy patients represent slightly less than 50% of the randomized group. Furthermore, viability testing was not performed on a randomly selected subgroup of patients but, rather, was obtained according to test availability and the judgment of the recruiting investigator. Third, the possibility cannot be excluded that the results of viability testing could have influenced subsequent clinical decision-making
    43. 43.  Despite the goal of uniform testing in this trial, the nonrandom and nonblinded selection for viability testing of only 601 of the 1212 eligible patients (49.6%) introduces considerable biases. Moreover, viability was defined in a binary fashion, and revascularization was not guided by the presence of viable myocardium within specific coronary- artery territories. In addition, the study is underpowered in the group with nonviable myocardium (i.e., 60 patients who received medical therapy and 54 patients who underwent CABG). Finally, viability assessment was restricted to single- photon-emission computed tomography (SPECT) and dobutamine echocardiography, which have well-known limitations in their ability to detect viability.1 We believe there is need for a randomized study of revascularization versus medical therapy after viability assessment with a standard technique such as contrast-enhanced magnetic resonance imaging (MRI) or positron-emission tomography (PET),1-3 which would allow targeted revascularization based on the presence of viable myocardium within specific coronary-artery territor
    44. 44.  "The analysis of intention-to-treat vs actual treatment is interesting, but the biological effect that our patients feel is what treatment they receive, and under that analysis, as a surgeon, you must conclude that patients with left ventricular dysfunction should receive coronary bypass." - Dr Steven Bolling (University of Michigan Cardiovascular Center, Ann Arbor)
    45. 45. Study Design Randomized controlled trial, non-blinded 99 clinical sites in 22 countries Investigator-initiated and led National Heart, Lung and Blood Institute funded Duke Clinical Research Institute managed Independent Data and Safety Monitoring Committee Clinical Events Adjudication Committee Blinded Core Laboratories
    46. 46. EndpointsPrimary Endpoint – All-cause mortalityMajor Secondary Endpoints – Cardiovascular mortality – Death (all-cause) + cardiovascular hospitalization
    47. 47. Important Inclusion Criteria LVEF ≤ 0.35 within 3 months of trial entry CAD suitable for CABG MED 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)
    48. 48. Major Exclusion Criteria Recent acute MI (within 30 days) Cardiogenic shock (within 72 hours of randomization) Plan for percutaneous intervention Aortic valve disease requiring valve repair or replacement History of more than 1 prior CABG Non-cardiac illness with a life expectancy of less than 3 years or imposing substantial operative mortality
    49. 49. Surgical Treatment for Ischemic Heart Failure trial stratum and treatment assignment. CAD EF <= + CABG amenable 0.35 SVR YES NO SVR NO Medical eligible? eligible? Not in trial eligibility NO YES YES Stratum A Stratum B Stratum C CABG + SVRMED CABG CABG + SVR CABG MED CABG
    50. 50. STICH Viability• All randomized patients were eligible for viability testing with SPECT myocardial perfusion imaging or dobutamine echo.• Viability testing was optional at enrolling sites and was not a prerequisite for enrollment.
    51. 51. STICH ViabilityCriteria for myocardial viability were prospective and pre- specifiedSPECT: • 17 segment model • ≥11 segments manifesting viability based on relative tracer activityDobutamine echo: • 16 segment model • ≥5 segments with dysfunction at rest manifesting contractile reserve with dobutamine
    52. 52. STICH Viability Primary endpoint: ▪ All-cause mortalitySecondary endpoints: ▪ Mortality plus cardiovascular hospitalization ▪ Cardiovascular mortalityIntention-to-treat analysis
    53. 53. Baseline CharacteristicsPatients With and Without Myocardial Viability Viable Non-ViableVariable (n=487) (n=114) P valueAge 61 ± 10 61 ± 9 NSMultivessel CAD 73% 73% NSProximal LAD stenosis 64% 70% NSRisk score* 12.4 ± 8.7 12.9 ± 9.3 NSPrevious MI 76.6% 94.7% <0.001LV ejection fraction (percent) 28 ± 8 23 ± 9 <0.001LV end-diastolic volume index (ml/m2* ) 117 ± 37 147 ± 53 <0.001LV end-systolic volume index (ml/m2) 86 ± 33 116 ± 50 <0.001 Significant covariates in risk model: Age, renal function, heart failure, ejection fraction, CAD index, mitral regurgitation, stroke
    54. 54. Background• LV dysfunction in patients with CAD is not always an irreversible process, as LV function may improve substantially after CABG• Assessment of myocardial viability is often used to predict improvement in LV function after CABG and improvement in survival
    55. 55. THANK YOU!!

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