Surgical Treatment for Ischemic Heart Failure - STICH
Contribution To Literature:
The STICH trial showed that in patients with ischemic cardiomyopathy, coronary artery bypass grafting (CABG) + medical therapy resulted in higher mortality at 30 days, but with a significant improvement in long-term mortality (out to 10 years) compared with medical therapy alone.
The goal of the trial was to evaluate medical therapy versus surgical therapy for patients with obstructive coronary artery disease (CAD) and congestive heart failure (CHF).
Patients Enrolled: 2,112
New York Heart Association (NYHA) Class: III/IV: 37% (hypothesis 1), 49% (hypothesis 2)
Follow-Up: Median: 5.1 years (hypothesis 1), 4 years (hypothesis 2)
Mean Patient Age: 60 (hypothesis 1), 62 (hypothesis 2)
Female: 12% (hypothesis 1), 14.7% (hypothesis 2)
Mean Ejection Fraction: 28%
- LV ejection fraction ≤0.35 within 3 months of trial entry
- CAD suitable for CABG
- Eligible for medical therapy: (only for hypothesis 1)
- Absence of left main CAD, as defined by an intraluminal stenosis of ≥50%
- Absence of Canadian Cardiovascular Society (CCS) class III angina or greater (angina markedly limiting ordinary activity)
- Recent acute myocardial infarction (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 one prior CABG
- Noncardiac illness with a life expectancy of <3 years or imposing substantial operative mortality
- Hypothesis 1: All-cause mortality
- Hypothesis 2: Long-term survival free of cardiac hospitalization
- Cardiovascular (CV) mortality
- All-cause mortality and cardiovascular hospitalization
- Cost-effectiveness and quality of life for each treatment
- Exercise capacity
- 30-day mortality
- Cardiac hospitalization
- Noncardiac hospitalization
- Myocardial infarction
Hypothesis 1: Patients were randomized to either medical therapy + CABG or medical therapy. CABG was performed by surgeons who had an operative mortality of ≤5% when operating on at least 25 patients with ischemic cardiomyopathy.
Hypothesis 2: Patients with CAD and anterior-apical regional LV dysfunction were randomized to CABG (n = 499) or CABG + SVR (n = 501).
Hypothesis 1: Aspirin (84%), angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (89%), beta-blockers (90%), and statins (89%)
Hypothesis 2: For the CABG and CABG + SVR groups: beta-blockers (85%, 87%), angiotensin-converting enzyme inhibitors (80%, 82%), digoxin (17%, 14%), diuretics (69%, 66%), aspirin (77%, 77%), and statins (79%, 75%)
Of the total of 2,112 patients enrolled in the overall STICH trial, 1,212 were enrolled in hypothesis 1, comparing medical therapy alone (n = 602) to medical therapy + CABG (n = 610), and 1,000 patients in hypothesis 2, comparing CABG + SVR (n = 501) to CABG alone (n = 499).
Hypothesis 1: Baseline characteristics were fairly similar between the two arms. The majority of patients were Caucasian (67%) and about 12% were women. Diabetes was present in about 40% of the patients, prior stroke in 8%, and prior CABG in 3%. About 58% had CCS class I or II angina (37% had none), and about 85% of the patients had NYHA class I or II symptoms.
In the CABG arm, urgent surgery was performed in 5% of the patients, and there was a cross-over of about 17% from the medical therapy arm to CABG; 91% received at least one arterial conduit. Thirty-day mortality was higher in the CABG arm (4% vs. 1%, p = 0.006). Over 6 years of follow-up, the primary outcome of all-cause mortality was similar between the medical therapy + CABG and medical therapy arms (36% vs. 41%, hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.72-1.04, p = 0.12). However, cardiovascular mortality was lower in the medical therapy + CABG arm (28% vs. 33%, HR 0.81, 95% CI 0.66-1.00, p = 0.05), as was all-cause mortality or cardiovascular hospitalization (58% vs. 68%, HR 0.74, 95% CI 0.64-0.85, p < 0.001), and all-cause mortality or repeat revascularization (39% vs. 55%, HR 0.60, 95% CI 0.51-0.71, p < 0.001). No difference for the primary endpoint was noted for any of the subgroups tested, including diabetic patients. On per-protocol analysis, medical therapy + CABG resulted in a significant reduction in all-cause mortality over the duration of follow-up (HR 0.70, 95% CI 0.58-0.84, p < 0.001).
In the subgroup of patients in hypothesis 1 that underwent myocardial viability testing (n = 601), 298 were medically managed, and 303 received medical therapy + CABG. Myocardial viability testing was done with either single-photon emission computed tomography (SPECT) myocardial perfusion imaging or dobutamine echocardiography. Patients with viable myocardium were more likely to survive, irrespective of treatment strategy (33% vs. 50%, p = 0.003) in the unadjusted analysis, but not in the adjusted analysis (p = 0.21). Patients with myocardial viability had a reduction in the composite endpoint of death or or cardiovascular hospitalizations (p = 0.003 in the adjusted analysis). There was no significant interaction between treatment strategy and viability (p = 0.53).
Mitral regurgitation (MR) and outcomes: MR was assessed using a 4-point scale on-site into none or trace (n = 401), mild (n = 493), and moderate/severe (n = 195). In the medical therapy arm, increasing severity of MR was associated with increased long-term mortality at 5 years (30% vs. 47% vs. 55%, p < 0.05 for both). In the subgroup of patients with moderate to severe MR that underwent CABG, 49 patients also underwent mitral valve (MV) surgery (98% repair), and 42 did not. On propensity-matched analysis, patients that underwent concomitant MV surgery had a significant reduction in long-term mortality, as compared with those who did not (41% vs. 55%, HR 0.45, p < 0.05).
10-year results (STICH-Extended study [STICHES]): All-cause mortality for CABG + medical therapy vs. medical therapy alone: 58.9% vs. 66.1%, HR = 0.84, 95% CI 0.73-0.97, p = 0.02; NNT = 14). CV mortality: 40.5% vs. 49.3%, HR = 0.79, 95% CI 0.66-0.93; p = 0.006); all-cause mortality or MI: 61.6% vs. 67.9%, p = 0.03. Effect modification for primary endpoint observed based on angiographic severity of disease: patients with three-vessel disease had an even greater benefit (p for interaction = 0.04). On analyzing data based on age quartiles (<54, >54-≤60, >60-≤67, ≥67 years), older patients had more comorbidities such as type 2 diabetes mellitus and chronic kidney disease. All-cause mortality tended to be higher in older compared with younger patients in both arms, while CV mortality was not statistically significantly different across the spectrum of age. The benefit of CABG + medical therapy vs. medical therapy on all-cause mortality decreased with increasing age (47.5% vs. 60%; 53.1% vs. 59.2%; 66.7% vs. 68.1%; 68.1% vs. 78.6%, p interaction = 0.062), whereas the benefit of CABG on CV mortality had a U-shaped distribution (35.0% vs. 49.4%; 42.7% vs. 47.4%; 46.5% vs. 47.4%; 38.7% vs. 53.1%; p interaction = 0.307).
Hypothesis 2: No significant differences in baseline clinical characteristics were present between groups. However, more arterial conduits were utilized in patients undergoing CABG alone. SVR added a median of 27 minutes of cardiopulmonary bypass time to the procedure. A greater reduction in LV end-systolic volume index was observed in the SVR group (-19% vs. -6%, p < 0.001). However, there was no significant difference in the primary endpoint of death and cardiac hospitalization (58% vs. 59%, p = 0.90). There was no greater improvement in NYHA heart failure classification or CCS angina classification with SVR in addition to CABG.
Quality of life, as assessed by the Kansas City Cardiomyopathy Questionnaire, Seattle Angina Questionnaire, and Center for Epidemiological Studies Depression Scale, was not significantly different between groups. In the US cohort, medical costs were greater with CABG + SVR than with CABG alone ($70,717 vs. $56,122, p = 0.004).
On subgroup analysis, patients with better functional status prior to randomization, as evidenced by an ability to walk >300 m (HR 0.77, 95% CI 0.59-0.99, p = 0.038) or a physical activity score >55 (HR 0.79, 95% CI 0.62-1.01, p = 0.06), appeared to derive a benefit from CABG over medical therapy, although tests for heterogeneity were nonsignificant (p = 0.21 and p = 0.41, respectively).
Patients with evidence of angina did not have higher mortality with CABG or medical therapy. Patients undergoing CABG reported greater improvement in anginal symptoms compared with medical therapy alone (OR 0.70, 95% CI 0.55-0.90, p < 0.01).
Sudden cardiac death (SCD) in this patient population: Among patients without an implantable cardioverter-defibrillator (ICD; n = 1,411), 8% died from SCD and 22% from other causes. The 1-, 3-, and 5-year cumulative incidence of SCD after CABG was 2.8%, 6.1%, and 8.5%, respectively. The conditional risk of SCD per month was different: 0.35% in the first 30 days after CABG, and 0.43% between 31 and 90 days. After 6 months, the risk per month decreased to 0.14% and remained stable after that. Variables that were predictive of SCD on multivariable modeling were end-systolic volume index, B-type natriuretic peptide, Duke CAD score, history of atrial fibrillation/flutter (all with increased risk), statin use, serum sodium, and received CABG + SVR (all with lower risk).
Hypothesis 1: In patients with ischemic LV systolic dysfunction (ischemic cardiomyopathy), CABG + medical therapy resulted in higher mortality at 30 days, but with a significant improvement in long-term mortality (out to 10 years) compared with medical therapy alone. Only 14 patients needed to be treated with CABG to save one life over 10 years. CV mortality and morbidity were both lower with CABG. There was a high rate of cross-over from the medical therapy arm to CABG (mirroring clinical practice), and on per-protocol analysis, medical therapy + CABG was associated with a survival benefit over medical therapy alone even earlier. These are important findings, since randomized data comparing medical therapy to CABG in patients with ischemic cardiomyopathy in the modern era are scant. Age-based findings with CABG + medical therapy vs. medical therapy are interesting, and suggest that the benefit of CABG may diminish with older age due to competing risks.
Further, in the subgroup that underwent myocardial viability testing, there seemed to be no difference in outcomes in the adjusted analysis between patients who demonstrated viability versus those who did not, irrespective of treatment strategy. Although this is a subanalysis, this is an important observation, since many centers routinely perform viability testing prior to considering revascularization in patients with ischemic cardiomyopathy, and patients that do not demonstrate viability are automatically referred for medical management.
Given the overall benefit noted with CABG in these patients over medical management alone, this argues against routine viability testing in all patients with ischemic cardiomyopathy prior to consideration for revascularization. It is unclear though if the lack of benefit with myocardial viability testing noted in this analysis represents a lack of power (type II error), a lack of sensitivity of the testing tools utilized (SPECT/dobutamine echo vs. MRI/PET-FDG), or a true clinical finding. This needs to be further tested in trials specifically powered and designed to test this question. The role of ischemia and scar burden on outcomes also needs to be ascertained.
The results in patients stratified by severity of MR are interesting. In particular, the increasing mortality rates with increased severity of MR in the medical management arm are novel. These could, however, represent increased severity of illness too (for example, patients with larger LV end-systolic volumes have greater MR, and also higher mortality). The CABG + MV surgery results are interesting, and need further testing. Current guidelines recommend concomitant MV surgery in patients undergoing CABG if they have severe MR, and if EF >30%.
Hypothesis 2: The STICH trial represents the first multicenter randomized trial of CABG + SVR in patients with CAD. Although SVR was demonstrated to reduce LV end-systolic volume to a greater extent than CABG alone, this result did not translate into an improvement in cardiovascular morbidity or mortality in this study. Based on these results, routine SVR at the time of CABG should not be recommended at this time.
Rao MP, Al-Khatib SM, Pokorney S, et al., on behalf of the STICH Trial Investigators. Sudden Cardiac Death in Patients with Ischemic Heart Failure Undergoing Coronary Artery Bypass Grafting: Results from the Surgical Treatment for Ischemic Heart Failure (STICH) Randomized Clinical Trial. Circulation 2017;Feb 2:[Epub ahead of print].
Petrie MC, Jhund PS, She L, et al., on behalf of the STICH Trial Investigators. Ten-Year Outcomes After Coronary Artery Bypass Grafting According to Age in Patients With Heart Failure and Left Ventricular Systolic Dysfunction: An Analysis of the Extended Follow-Up of the STICH Trial (Surgical Treatment for Ischemic Heart Failure). Circulation 2016;134:1314-24.
Presented by Dr. Eric Velazquez at the European Society of Cardiology Congress, Rome, Italy, August 29, 2016.
Velazquez EJ, Lee KL, Jones RH, et al., on behalf of the STICH Investigators. Coronary-Artery Bypass Surgery in Patients with Ischemic Cardiomyopathy. N Engl J Med 2016;Apr 3:[Epub ahead of print].
Editorial: Guyton RA, Smith AL, et al. Coronary Bypass — Survival Benefit in Heart Failure. N Engl J Med 2016;Apr 3:[Epub ahead of print].
Presented by Dr. Eric J. Velazquez at the American College of Cardiology Annual Scientific Session, Chicago, IL, April 3, 2016.
Jolicœur EM, Dunning A, Castelvecchio S, et al. Importance of Angina in Patients With Coronary Disease, Heart Failure, and Left Ventricular Systolic Dysfunction: Insights From STICH. J Am Coll Cardiol 2015;66:2092-100.
Stewart RA, Szalewska D, She L, et al. Exercise Capacity and Mortality in Patients With Ischemic Left Ventricular Dysfunction Randomized to Coronary Artery Bypass Surgery or Medical Therapy: An Analysis From the STICH Trial (Surgical Treatment for Ischemic Heart Failure). JACC Cardiovasc Heart Fail 2014;2:335-43.
Presented by Dr. Marek Deja at the European Society of Cardiology Congress, Paris, France, August 2011.
Velazquez EJ, Lee KL, Deja MA, et al. Coronary-artery bypass surgery in patients with left ventricular dysfunction. N Engl J Med 2011;Apr 4:[Epub ahead of print].
Bonow RO, Maurer G, Lee KL, et al. Myocardial viability and survival in ischemic left ventricular dysfunction. N Engl J Med 2011;Apr 4:[Epub ahead of print].
Presented by Dr. Eric Velazquez at the ACC.11/i2 Summit, New Orleans, LA, April 4, 2011.
Presented by Dr. Robert Bonow at the ACC.11/i2 Summit, New Orleans, LA, April 4, 2011.
Surgical Treatment for Ischemic Heart Failure (STICH) Trial: CABG Versus CABG + SVR. Presented by Drs. Robert H. Jones and Daniel Mark at ACC.09/i2, Orlando, FL, March 2009.
Jones RH, Velazquez EJ, Michler RE, et al., on behalf of the STICH Hypothesis 2 Investigators. Coronary bypass surgery with or without surgical ventricular reconstruction. N Engl J Med 2009;360:1705-17.
Keywords: Myocardial Perfusion Imaging, Coronary Artery Disease, Myocardial Ischemia, Stroke, Tomography, Emission-Computed, Single-Photon, Mitral Valve Insufficiency, Constriction, Pathologic, Myocardium, Cost of Illness, Dobutamine, Cicatrix, Quality of Life, Cardiomyopathies, Heart Failure, Motor Activity, Cardiopulmonary Bypass, Coronary Artery Bypass, Ventricular Dysfunction, Left, Diabetes Mellitus, Echocardiography, Angina Pectoris, ESC Congress, Death, Sudden, Cardiac
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