There are hints that the 10-year benefit seen in STICHES, the earlier trial, might be the result of inferior medical therapy.
In a tale of two eras, patients with ischemic heart failure (HF) treated with medical therapy alone in the STICHES trial had significantly worse outcomes than those treated with medical therapy in the REVIVED-BCIS2 study, a new study shows.
The analysis, which includes two studies looking into the benefits of revascularization in patients with ischemic LV dysfunction, highlights the efficacy of modern medical therapy when compared against medications used in an earlier era, senior investigator Divaka Perera, MD (King’s College London, England), told TCTMD.
“Perhaps international guideline committees may want to rethink the strength of recommendation for bypass surgery in patients with heart failure,” said Perera. “I wonder whether the magnitude of benefit we saw in STICHES would be replicated in contemporary practice. It is possible that some of the difference we saw between CABG and medical therapy reflected medical therapy not really hitting the mark back then. Remember, the STICH trial began recruiting patients almost 25 years ago.”
Treatment with CABG surgery plus medical therapy in STICHES was shown to reduce the risk of all-cause mortality at 10 years compared with medical therapy alone in patients with ischemic HF. While there was no difference between the treatment strategies at 5 years, CABG is recommended in the European Society of Cardiology guidelines as a strategy in patients with ischemic cardiomyopathy and multivessel disease as long as the risk of surgery is acceptable (class I, level of evidence B). Surgery is also recommended for these patients in the US guidelines.
The researchers, including lead author Matthew Ryan, MD (King’s College London), note that 20 years separate the launch of STICHES to the completion of REVIVED-BCIS2, a period of time that’s seen the approval of the mineralocorticoid receptor antagonist eplerenone, the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan (Entresto; Novartis), and SGLT2 inhibitors empagliflozin (Jardiance; Boehringer Ingelheim/Eli Lilly) and dapagliflozin (Farxiga; AstraZeneca).
Amazingly, said Perera, medical therapy has evolved further since the publication of the REVIVED-BCIS2 trial results 30 months ago.
“I think the clinical importance of the study is in how we consider patients with ischemic left ventricular dysfunction for revascularization,” Ryan told TCTMD in an email. “I don’t think the study is enough to downgrade guidelines on its own but should make us mindful of the fragility of the surgical data in an era of improved medical therapy and have confidence to lean into ongoing trials in the field like the STICH 3.0 Consortium.”
Better on Medical Therapy vs CABG
The contemporary REVIVED-BCIS2 trial, which recruited patients from 2013 to 2020, tested whether revascularization—this time with PCI—would have a similar benefit in patients with ischemic ventricular dysfunction. Here, coronary revascularization with PCI plus medical therapy was no better than medical therapy alone for reducing the risk of all-cause mortality or HF hospitalization after a median 3.4 years of follow-up.
“Ever since REVIVED came out, people have been saying, ‘Well, we have a positive trial for CABG and a neutral trial for PCI in pretty much the same population—therefore, we must conclude that CABG is better than PCI,’” said Perera. “But you really can’t compare the two trials because it’s like apples and oranges.”
REVIVED includes a more “real-world population,” with older, sicker patients, he said. Importantly, medical and device therapy used in STICHES and REVIVED substantially differed.
The main purpose of the current analysis, published in the European Heart Journal, was to compare clinical outcomes of patients treated with medical therapy alone in STICHES versus those in REVIVED-BCIS2. The secondary aim was to estimate if CABG would still provide incremental benefit over medical therapy used in the more contemporary trial.
In all, 1,912 participants were included in the pooled analysis (median age 63.6 years; 87.8% male). The mean LVEF was 26.7%.
All-cause mortality or hospitalization for HF was 54% lower among patients treated with medical therapy in REVIVED-BCIS2 than among those treated with medical therapy in STICHES (HR 0.46; 95% CI 0.34-0.62). The predicted event-free survival in REVIVED and STICHES was 145 and 57 months, respectively.
The difference in outcomes in the medical-therapy arms of the two trials is the “headline result of the study,” said Perera. “It tells you right off the top that medical therapy is superior in the modern era to the sort used in the STICHES era. What’s remarkable is that despite enrolling a population who, on average, is 10 years older, these patients still did better.”
There were also more primary-outcome events in participants treated with CABG in STICHES than in those treated with medical therapy alone in REVIVED-BCIS2. In fact, the risk of the primary outcome was significantly lower in patients treated with medical therapy in REVIVED than in those treated with CABG surgery in STICHES (HR 0.62; 95% CI 0.45-0.84). For those who underwent revascularization, treatment with PCI in REVIVED was associated with a lower risk of all-cause mortality or HF hospitalization than with CABG surgery in STICHES (HR 0.61; 95% CI 0.43-0.87).
That the medical-therapy arm of the neutral REVIVED study resulted in better outcomes than the revascularization arm of the positive STICHES study is a “real eye-opener,” said Perera.
“That’s something people are going to have to try to get their heads around,” he said, adding that the finding raises an important research question about HF therapy advances and the relevance of the control arm in all types of intervention studies, such as those testing revascularization or even ICDs.
From a clinical perspective, data from REVIVED-BCIS2 and STICHES should not be used to decide between PCI or CABG surgery given the fundamentally different medical therapy regimes, said Perera. “That needs to be addressed in a head-to-head trial.”
STICH3C will include roughly 750 patients with multivessel/left main coronary artery disease and ischemic LV dysfunction (LVEF ≤ 40%) amenable to revascularization randomized to either PCI or CABG surgery. All patients will be treated with guideline-directed medical therapy and followed for a median of 5 years. The primary endpoint of STICH3C is a composite of all-cause mortality, stroke, spontaneous MI, urgent repeat revascularization, or HF readmission.