Novel Trial Design: CHIEF-HF.

BACKGROUND: The expense of clinical trials mandates new strategies to efficiently generate evidence and test novel therapies. In this context, we designed a decentralized, patient-centered randomized clinical trial leveraging mobile technologies, rather than in-person site visits, to test the efficacy of 12 weeks of canagliflozin for the treatment of heart failure, regardless of ejection fraction or diabetes status, on the reduction of heart failure symptoms. METHODS: One thousand nine hundred patients will be enrolled with a medical record-confirmed diagnosis of heart failure, stratified by reduced (≤40%) or preserved (>40%) ejection fraction and randomized 1:1 to 100 mg daily of canagliflozin or matching placebo. The primary outcome will be the 12-week change in the total symptom score of the Kansas City Cardiomyopathy Questionnaire. Secondary outcomes will be daily step count and other scales of the Kansas City Cardiomyopathy Questionnaire. RESULTS: The trial is currently enrolling, even in the era of the coronavirus disease 2019 (COVID-19) pandemic. CONCLUSIONS: CHIEF-HF (Canagliflozin: Impact on Health Status, Quality of Life and Functional Status in Heart Failure) is deploying a novel model of conducting a decentralized, patient-centered, randomized clinical trial for a new indication for canagliflozin to improve the symptoms of patients with heart failure. It can model a new method for more cost-effectively testing the efficacy of treatments using mobile technologies with patient-reported outcomes as the primary clinical end point of the trial. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04252287.

Does early detection of atrial fibrillation reduce the risk of thromboembolic events? Rationale and design of the Heartline study.

BACKGROUND: The impact of using direct-to-consumer wearable devices as a means to timely detect atrial fibrillation (AF) and to improve clinical outcomes is unknown. METHODS: Heartline is a pragmatic, randomized, and decentralized application-based trial of US participants aged ≥65 years. Two randomized cohorts include adults with possession of an iPhone and without a history of AF and those with a diagnosis of AF taking a direct oral anticoagulant (DOAC) for ≥30 days. Participants within each cohort are randomized (3:1) to either a core digital engagement program (CDEP) via iPhone application (Heartline application) and an Apple Watch (Apple Watch Group) or CDEP alone (iPhone-only Group). The Apple Watch Group has the watch irregular rhythm notification (IRN) feature enabled and access to the ECG application on the Apple Watch. If an IRN notification is issued for suspected AF then the study application instructs participants in the Apple Watch Group to seek medical care. All participants were "watch-naïve" at time of enrollment and have an option to either buy or loan an Apple Watch as part of this study. The primary end point is time from randomization to clinical diagnosis of AF, with confirmation by health care claims. Key secondary endpoint are claims-based incidence of a 6-component composite cardiovascular/systemic embolism/mortality event, DOAC medication use and adherence, costs/health resource utilization, and frequency of hospitalizations for bleeding. All study assessments, including patient-reported outcomes, are conducted through the study application. The target study enrollment is approximately 28,000 participants in total; at time of manuscript submission, a total of 26,485 participants have been enrolled into the study. CONCLUSION: The Heartline Study will assess if an Apple Watch with the IRN and ECG application, along with application-facilitated digital health engagement modules, improves time to AF diagnosis and cardiovascular outcomes in a real-world environment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04276441.

An Analysis of Telehealth in the Outpatient Management of Atrial Fibrillation During the COVID-19 Pandemic.

The COVID-19 pandemic accelerated adaption of a telehealth care model. We studied the impact of telehealth on the management of atrial fibrillation (AF) by electrophysiology providers in a large, multisite clinic. Clinical outcomes, quality metrics, and indicators of clinical activity for patients with AF during the 10-week period of March 22, 2020 to May 30, 2020 were compared with those from the 10-week period of March 24, 2019 to June 1, 2019. There were 1946 unique patient visits for AF (1,040 in 2020 and 906 in 2019). During 120 days after each encounter, there was no difference in hospital admissions (11.7% vs 13.5%, p = 0.25) or emergency department visits (10.4% vs 12.5%, p = 0.15) in 2020 compared with 2019. There was a total of 31 deaths within 120 days, with similar rates in 2020 and 2019 (1.8% vs 1.3%, p = 0.38). There was no significant difference in quality metrics. The following clinical activities occurred less frequently in 2020 than in 2019: offering escalation of rhythm control (16.3% vs 23.3%, p <0.001), ambulatory monitoring (29.7% vs 51.7%, p <0.001), and electrocardiogram review for patients on antiarrhythmic drug therapy (22.1% vs 90.2%, p <0.001). Discussions about risk factor modification were more frequent in 2020 compared with 2019 (87.9% vs 74.8%, p <0.001). In conclusion, the use of telehealth in the outpatient management of AF was associated with similar clinical outcomes and quality metrics but differences in clinical activity compared with traditional ambulatory encounters. Longer-term outcomes warrant further investigation.

Survival After Invasive or Conservative Management of Stable Coronary Disease.

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.

Site-level variability in the processes of care and outcomes over time among patients with COVID-19 and myocardial injury: Insights from the American Heart Association's COVID-19 Cardiovascular Disease Registry.

Background: Elevated cardiac troponin (cTn) levels in patients with COVID-19 has been associated with worse outcomes. Guidelines on best practices of those patients remain uncertain. Methods: We included patients with COVID-19 and cTn above the assay-specific upper limit of normal (ULN) enrolled in the American Heart Association's COVID-19 registry between March 2020-January 2021. Site-level variability in invasive coronary angiography, LVEF assessment, ICU utilization, and inpatient mortality were determined by calculating adjusted median odds ratio (MOR) using hierarchical logistic regression models. Temporal trends were assessed with Cochran-Armitage trend test. Results: Among 32,636 patients, we included 6234 (19.4 %) with cTn above ULN (age 68.7 ± 16.0 years, 56.5 % male, 51.5 % Caucasian), of whom 1365 (21.6 %) had ≥5-fold elevations. Across 55 sites, the median rate of invasive coronary angiography was 0.1 % with adjusted MOR 1.5(1.0,2.3), median LVEF assessment was 25.5 %, MOR 3.0(2.2,3.9), ICU utilization was 41.7 %, MOR 2.2(1.8,2.6), and mortality was 20.9 %, MOR 1.7(1.5,2.0). Over time, we noted a significant increase in invasive coronary angiography (p-trend = 0.001), and LVEF assessment (p-trend<0.001), and reduction in mortality (p-trend<0.001), without significant change in ICU admissions (p-trend = 0.08). Similar variability and temporal trends were seen among patients with ≥5-fold cTn elevation. Conclusions: The use of invasive coronary angiography among patients with COVID-19 and myocardial injury was very low during the early pandemic. We found moderate institutional variability in processes of care with an uptrend in invasive catheterization and LVEF assessment, and downtrend in mortality. Comparative effectiveness studies are needed to examine whether variability in care is associated with differences in outcomes.

The SGLT2 inhibitor canagliflozin in heart failure: the CHIEF-HF remote, patient-centered randomized trial.

Large traditional clinical trials suggest that sodium-glucose co-transporter 2 inhibitors improve symptoms in patients with heart failure and reduced ejection fraction (HFrEF) and in patients with heart failure and preserved ejection fraction (HFpEF). In the midst of the Coronavirus Disease 2019 pandemic, we sought to confirm these benefits in a new type of trial that was patient centered and conducted in a completely remote fashion. In the CHIEF-HF trial ( NCT04252287 ), 476 participants with HF, regardless of EF or diabetes status, were randomized to 100 mg of canagliflozin or placebo. Enrollment was stopped early due to shifting sponsor priorities, without unblinding. The primary outcome was change in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ TSS) at 12 weeks. The 12-week change in KCCQ TSS was 4.3 points (95% confidence interval, 0.8-7.8; P = 0.016) higher with canagliflozin than with placebo, meeting the primary endpoint. Similar effects were observed in participants with HFpEF and in those with HFrEF and in participants with and without diabetes, demonstrating that canagliflozin significantly improves symptom burden in HF, regardless of EF or diabetes status. This randomized, double-blind trial, conducted without in-person interactions between doctor and patient, can serve as a model for future all-virtual clinical trials.

In-Hospital Cardiac Arrest Survival in the United States During and After the Initial Novel Coronavirus Disease 2019 Pandemic Surge.

BACKGROUND: Recent reports on challenges in resuscitation care at hospitals severely affected by the novel coronavirus disease 2019 (COVID-19) pandemic raise questions about how the pandemic affected outcomes for in-hospital cardiac arrest throughout the United States. METHODS: Within Get With The Guidelines-Resuscitation, we conducted a retrospective cohort study to compare in-hospital cardiac arrest survival during the presurge (January 1-February 29), surge (March 1-May 15) and immediate postsurge (May 16-June 30) periods in 2020 compared to 2015 to 2019. Monthly COVID-19 mortality rates for each hospital's county were categorized, per 1 000 000 residents, as low (0-10), moderate (11-50), high (51-100), or very high (>100). Using hierarchical regression models, we compared rates of survival to discharge in 2020 versus 2015 to 2019 for each period. RESULTS: Of 61 586 in-hospital cardiac arrests, 21 208 (4309 in 2020), 26 459 (5949 in 2020), and 13 919 (2686 in 2020) occurred in the presurge, surge, and postsurge periods, respectively. During the presurge period, 24.2% survived to discharge in 2020 versus 24.7% in 2015 to 2019 (adjusted odds ratio, 1.12 [95% CI, 1.02-1.22]). In contrast, during the surge period, 19.6% survived to discharge in 2020 versus 26.0% in 2015 to 2019 (adjusted odds ratio, 0.81 [0.75-0.88]). Lower survival was most pronounced in communities with high (28% lower survival) and very high (42% lower survival) monthly COVID-19 mortality rates (interaction P<0.001). Resuscitation times were shorter (median: 22 versus 25 minutes; P<0.001), and delayed epinephrine treatment was more prevalent (11.3% versus 9.9%; P=0.004) during the surge period. Survival was lower even when patients with confirmed/suspected COVID-19 infection were excluded from analyses. During the postsurge period, survival rates were similar in 2020 versus 2015 to 2019 (22.3% versus 25.8%; adjusted odds ratio, 0.93 [0.83-1.04]), including communities with high COVID-19 mortality (interaction P=0.16). CONCLUSIONS: Early during the pandemic, rates of survival to discharge for IHCA decreased, even among patients without COVID-19 infection, highlighting the early impact of the COVID-19 pandemic on in-hospital resuscitation.

Outpatient Management of Heart Failure During the COVID-19 Pandemic After Adoption of a Telehealth Model.

OBJECTIVES: This study sought to determine whether the increased use of telehealth was associated with a difference in outcomes for outpatients with heart failure. BACKGROUND: The COVID-19 pandemic led to dramatic changes in the delivery of outpatient care. It is unclear whether increased use of telehealth affected outcomes for outpatients with heart failure. METHODS: In March 2020, a large Midwestern health care system, encompassing 16 cardiology clinics, 16 emergency departments, and 12 hospitals, initiated a telehealth-based model for outpatient care in the setting of the COVID-19 pandemic. A propensity-matched analysis was performed to compare outcomes between outpatients seen in-person in 2018 and 2019 and via telemedicine in 2020. RESULTS: Among 8,263 unique patients with heart failure with 15,421 clinic visits seen from March 15 to June 15, telehealth was employed in 88.5% of 2020 visits but in none in 2018 or 2019. Despite the pandemic, more outpatients were seen in 2020 (n = 5,224) versus 2018 and 2019 (n = 5,099 per year). Using propensity matching, 4,541 telehealth visits in 2020 were compared with 4,541 in-person visits in 2018 and 2019, and groups were well matched. Mortality was similar for telehealth and in-person visits at both 30 days (0.8% vs 0.7%) and 90 days (2.9% vs 2.4%). Likewise, there was no excess in hospital encounters or need for intensive care with telehealth visits. CONCLUSIONS: A telehealth model for outpatients with heart failure allowed for distanced encounters without increases in subsequent acute care or mortality. As the pressures of the COVID-19 pandemic abate, these data suggest that telehealth outpatient visits in patients with heart failure can be safely incorporated into clinical practice.