ABSTRACT
Background: The ISCHEMIA trial compared an initial invasive versus an initial conservative management strategy for patients with chronic coronary disease and moderate or severe ischemia, with no major difference in most outcomes over a median of 3.2 years. Extended follow-up for mortality is ongoing. Methods: ISCHEMIA participants were randomized to an initial invasive strategy (INV) added to guideline-directed medical therapy or a conservative strategy (CON). Patients with moderate or severe ischemia, ejection fraction ≥35%, and no recent acute coronary syndromes were included. Those with an unacceptable level of angina were excluded. Extended follow-up for vital status is being conducted by sites or through central death index search. Data obtained through December 2021 are included in this interim report. We analyzed all-cause, cardiovascular, and non-cardiovascular mortality by randomized strategy, using nonparametric cumulative incidence estimators, Cox regression models and Bayesian methods. Undetermined deaths were classified as cardiovascular as pre-specified in the trial protocol. Results: Baseline characteristics for 5179 original ISCHEMIA trial participants included median age 65 years, 23 % women, 16% Hispanic, 4% Black, 42% diabetes, and median EF 0.60. A total of 557 deaths accrued over a median follow-up of 5.7 years, with 268 of these added in the extended follow-up phase. This included a total of 343 cardiovascular deaths, 192 non-cardiovascular deaths and 22 unclassified deaths. All-cause mortality was not different between randomized treatment groups (7-year rate 12.7% in INV, 13.4% in CON; adjusted hazard ratio (HR)=1.00, 95% CI: 0.85-1.18). There was a lower 7-year rate cardiovascular mortality (6.4% vs. 8.6%, adjusted HR=0.78, 95% CI: 0.63-0.96) with an initial invasive strategy but a higher 7-year rate of non-cardiovascular mortality (5.6% vs. 4.4%, adjusted HR=1.44, 95% CI: 1.08-1.91) compared with the conservative strategy. No heterogeneity of treatment effect was evident in prespecified subgroups, including multivessel coronary disease. Conclusions: There was no difference in all-cause mortality with an initial invasive strategy compared with an initial conservative strategy, but there was lower risk of cardiovascular mortality and higher risk of non-cardiovascular mortality with an initial invasive strategy over a median follow-up of 5.7 years. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT04894877; https://clinicaltrials.gov/ct2/show/NCT04894877.
ABSTRACT
Given the high case fatality rate of SARS-CoV-2, for which there is no cure and no vaccine, clinicians are forced to make decisions about how best to manage patients with limited high-quality evidence to guide treatment. Traditional randomized controlled trials provide strong experimental evidence, however, tend to be slow, inflexible, and have limited generalizability. Adaptive and pragmatic designs are an attractive alternative, which meet our ethical obligation during the SARS-CoV-2 pandemic to balance speed, agility, and generalizability with both prospective study and scientific rigor.