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
Randomized controlled trials (RCTs) remain the gold standard to evaluate clinical interventions, producing the highest level of evidence while minimizing potential bias. Inadequate recruitment is a commonly encountered problem that undermines the completion and generalizability of RCTs-and is even more challenging when enrolling amidst a pandemic. Here, we reflect on our experiences with virtual recruitment of non-hospitalized patients in the United States for ColCorona, an international, multicenter, randomized, placebo-controlled coronavirus disease 2019 (COVID-19) drug trial. Recruitment challenges during a pandemic include constraints created by shelter-in-place policies and targeting enrollment according to national and local fluctuations in infection rate. Presenting a study to potential participants who are sick with COVID-19 and may be frightened, overwhelmed, or mistrusting of clinical research remains a challenge. Strategies previously reported to improve recruitment include transparency, patient and site education, financial incentives, and person-to-person outreach. Active measures taken during ColCorona to optimize United States recruitment involved rapid expansion of sites, adjustment of recruitment scripts, assessing telephone calls versus text messages for initial contact with participants, institutional review board-approved financial compensation, creating an infrastructure to systematically identify potentially eligible patients, partnering with testing sites, appealing to both self-interest and altruism, and large-scale media efforts with varying degrees of success.