The STICH Trial Unravelled (2010)

The STICH trial was designed to compare coronary bypass (CABG) alone vs. CABG plus surgical ventricular reconstruction (SVR) in patients with left ventricular (LV) dysfunction and akinetic or dyskinetic LV segments from prior anterior wall myocardial infarction (MI). It reported1 that adding SVR to coronary bypass CABG was not associated with a greater improvement in symptoms, exercise tolerance, or reduced intermediate mortality. This trial was federally funded to provide evidence-based methodology for this comparison, but its implementation was faulty in many ways. Surgical ventricular reconstruction treats congestive heart failure (CHF) by reducing LV volume, perhaps the most powerful predictor of mortality in dilated cardiomyopathy and more predictive than ejection fraction (EF)2–4 (Figures 1 and 2). The 490 patients who underwent SVR in STICH was predicated on favourable reports of recovery in over 5000 patients worldwide and registry data from approximately 1200 patients that decreased LV end-systolic volume index (LVESVI) ∼40% (ranging 30–58%, Table 1),5–8 but had different results. Is SVR an improper concept or was the STICH trial improperly executed? Eligibility for STICH required that ‘all patients will be evaluated further for appropriateness of SVR indicated by evidence of absent viability in the anterior ventricle by nuclear scan determination, LVESVI ≥60 ml/m2, and akinesia ≥35% of the anterior wall’ (http://clinicaltrials.gov/archine/NTC00023595/2005_06_23). Echocardiography was specifically excluded for measuring LV volume because of its inaccuracy when regional asynergy is present.9 Selection of STICH centres was based on capability to measure volume by cardiac magnetic resonance (CMR) imaging (Excerpt 1). However, STICH enrolled a quite different group of patients, namely those with NYHA Class II–IV CHF (within 3 months of entry), coronary artery disease that was amenable to CABG, an EF ≤35% [defined by echocardiogram, left ventriculogram, CMR, or gated single photon (SPECT) studies], and ‘dominant anterior left ventricular dysfunction’. Accurate viability and LV volume were not done in all patients as planned. STICH required that all patients have dyskinesia or akinesia with evidence of non-viability in 35% of the anterior ventricular wall (Excerpt 2). Dyskinesia is caused by no reperfusion of the LV after infarction. Akinesia accompanies early thrombolysis or angioplasty and results in a dilated but thick LV. STICH, however, reports that only half of patients had akinesia or dyskinesia and 13% had no prior history of infarction. Surgical ventricular reconstruction has never been reported or recommended in patients with regional dysfunction alone and absent scar.5,7 The STICH surgical therapy committee specifically defined SVR as ‘any ventricular reconstruction method that consistently results in a low operative mortality, an average EF increase of ≥10%, and an average LVESVI decrease of ≥30% as assessed on the four-month post-operative CMR measurement’ (Excerpt 3). STICH, however, measured LVESVI in only 212 of 490 patients (43%) in the CABG-only group and in 161 of 490 patients (33%) in the CABG plus SVR group by echocardiography. The number of CMR measurements is not given. STICH reported that SVR lowered LVESVI an average of only 19%. Patients should be excluded from the analysis if the originally defined goals were not met. Patients in the SVR trial underwent SVR based on qualitative rather than quantitative assessment. Perhaps they had hibernation of ischaemic areas or post-infarction stunning, both of which are clearly not indications for SVR. Surgeons cannot know when SVR should be performed without accurate viability and volume information. The STICH patients cannot be compared with previously reported patients with SVR. Dor's5,7 1000 patients and the 1198 patients in the RESTORE group had prior history of MI, akinesia, or dyskinesia involving ≥35% of the LV, reduced EF, and LVESVI ≥60 mL/m2. Furthermore, only 49% of patients in STICH had NYHA class III or IV CHF vs. >66% in the RESTORE registry.5 STICH trial original protocol deviations can be viewed in ‘history of changes’ on: http://clinicaltrials.gov/show/NCT00023595. Why was accurate LVESVI by CMR or nuclear study retracted? The principal investigator may change the protocol, but only with approval from the NIH grant administration officer. Though it does not require approval from other trial participants, the grant administrator must assume the responsibility for investigational review board (IRB) notification of changes for all trial participants. The STICH publication does not report changes during the trial. The 50 original STICH centres expanded to 127 in 26 countries (Excerpt 4). A total of 489 patients underwent CABG plus SVR, an average of only four operations per site done by surgeons whose only certification was an operative mortality of 5% or less in 25 patients who underwent CABG with EF ≤40% with ‘consistent post-operative decrease in LV volume in five consecutive patients who survived the operation’. STICH surgeons did not meet the benchmark reduction in LVESVI of ≥30%, as the average decrease in volume was only 19%. Were the operations in the STICH trial true SVR operations, consistent with those described in multiple publications, or merely small LV plications or limited intracavitary reconstructions? Originally, eligible patients for SVR in STICH were those with discreet scar, an asynergic area of ≥35%, and LVESVI ≥60 mL/m2. This volume was also chosen because progressive ventricular remodelling is not prevented after aortic or mitral valve replacement if the LVESVI ≥60 mL/m2.2,10 An analysis of STICH SVR patients with preoperative LVESVI ≥60 mL/m2 and accurate post-operative LV reduction of >30% should be reported, as these are the patients who benefit from SVR according to all published series. We conclude that the STICH trial is misleading because SVR procedures were not uniformly or effectively performed in properly selected patients. STICH has failed to meet the goals expected from an evidence-based study. Internists and cardiologists must be aware of the extensive registry data that confirms the long-term efficacy of SVR in a select group of patients operated on by experienced surgeons who can reliably exclude scarred LV segments, thereby reducing volume and reshaping the chamber. Extensive worldwide application of SVR confirms its beneficial effect on remote muscle function, regional wall synchronicity, and global systolic function. Surgical ventricular reconstruction reduces neurohormonal activators and improves the functional status of CHF patients.11 Such findings cannot be ignored on the basis of a single flawed study. Surgical ventricular reconstruction is an effective operation when performed by properly trained surgeons in correctly selected patients. An accurately executed trial with evidence-based methodology is required to refine the indications of SVR in subgroups of CHF patients. Excerpt 1 Initial evaluation of patients for eligibility for randomization in specified stratum Therefore, a two-step process is proposed. The first step uses the best available LV assessment by either a contrast, gated SPECT, or CMR ventriculogram read at the clinical sites or a resting echocardiogram read by the Echo Laboratory. This first step will identify patients meeting LVEF entry criteria and characterize the extent of anterior LV wall dysfunction needed to evaluate SVR eligibility After completion of the first step, patients will be approached for informed consent for randomization The second step to confirm the accuracy of these criteria by CMR or RN LV assessment proceeds only in consenting patients ‘Unpublished information from funded STICH Grant document, that is “publicly available” through the Freedom of Information Act’. Bold type added by authors Excerpt 2 B.3. Rationale for noninvasive cardiac imaging studies The common clinical practice of not offering CABG to patients with LV dysfunction in regions found to be non-viable on noninvasive studies is not justified by published data The STICH trial proposes to use core laboratories for cardiac magnetic resonance (CMR), echocardiography (ECHO), and radionuclide (RN) studies to insure standardization of testing practices and of data analysis for operational use of these studies in the STICH trial ‘Unpublished information from funded STICH Grant document, that is “publicly available” through the Freedom of Information Act’. Bold type added by authors Excerpt 3 CABG + SVR definition. The two criteria used by the Surgical Therapy Committee to define the acceptable range of specific operative manoeuvres essential to be considered an acceptable technical SVR operation for the STICH trial will be any ventricular reconstruction method that consistently results in: (i) a low operative mortality; and (ii) an average EF increase of 10% and average LVESVI decrease of 30% as assessed on the 4-month postoperative CMR measurement ‘Unpublished information from funded STICH Grant document, that is “publicly available” through the Freedom of Information Act’. Bold type added by authors Excerpt 4 Over 3 years, 50 clinical sites will recruit 2800 patients with heart failure, left ventricular ejection fraction less than 0.35, and CAD amenable to CABG From http://clinicaltrials.gov/show/NCT00023595 Conflict of interest: C.L.A. and G.D.B. are co-holders of a left ventricular reconstruction device patent. This device is not commercially produced.