Operational challenges and mitigation measures during the COVID-19 pandemic-Lessons from DELIVER.

BACKGROUND: Catastrophic disruptions in care delivery threaten the operational efficiency and potentially the validity of clinical research efforts, in particular randomized clinical trials. Most recently, the COVID-19 pandemic affected essentially all aspects of care delivery and clinical research conduct. While consensus statements and clinical guidance documents have detailed potential mitigation measures, few real-world experiences detailing clinical trial adaptations to the COVID-19 pandemic exist, particularly among, large, global registrational cardiovascular trials. METHODS: We outline the operational impact of COVID-19 and resultant mitigation measures in the Dapagliflozin Evaluation to Improve the LIVEs of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial, one of the largest and most globally diverse experiences with COVID-19 of any cardiovascular clinical trial to date. Specifically, we address the needed coordination between academic investigators, trial leadership, clinical sites, and the supporting sponsor to ensure the safety of participants and trial staff, to maintain the fidelity of trial operations, and to prospectively adapt statistical analyses plans to evaluate the impact of COVID-19 and the pandemic at large on trial participants. These discussions included key operational issues such as ensuring delivery of study medications, adaptations to study visits, enhanced COVID-19 related endpoint adjudication, and protocol and analytical plan revisions. CONCLUSION: Our findings may have important implications for establishing consensus on prospective contingency planning in future clinical trials. CLINICALTRIAL: gov: NCT03619213. CLINICALTRIAL: GOV: NCT03619213.

Nationwide Utilization of Danish Government Electronic letter system for increasing inFLUenza vaccine uptake (NUDGE-FLU): Study protocol for a nationwide randomized implementation trial.

BACKGROUND: Annual influenza vaccination is widely recommended in older adults and other high-risk groups including patients with cardiovascular disease. The real-world effectiveness of influenza vaccination is limited by suboptimal uptake and effective strategies for increasing vaccination rates are therefore needed. The purpose of this trial is to investigate whether behavioral nudges digitally delivered via the Danish nationwide mandatory governmental electronic letter system can increase influenza vaccination uptake among older adults. METHODS: The NUDGE-FLU trial is a randomized implementation trial randomizing all Danish citizens aged 65 years and above without an exemption from the Danish mandatory governmental electronic letter system to receive no digitally delivered behavioral nudge (usual care arm) or to receive one of 9 electronic letters (intervention arms) each leveraging different behavioral science strategies. The trial has randomized 964,870 participants with randomization clustered at the household level (n = 691,820 households). Intervention letters were delivered on September 16, 2022, and follow-up is currently ongoing. All trial data are captured using the nationwide Danish administrative health registries. The primary end point is the receipt of an influenza vaccine on or before January 1, 2023. The secondary end point is time to vaccination. Exploratory end points include clinical events such as hospitalization for influenza or pneumonia, cardiovascular events, all-cause hospitalization, and all-cause mortality. DISCUSSION: The nationwide randomized NUDGE-FLU trial is one of the largest implementation trials ever conducted and will provide important insights into effective communication strategies to maximize vaccination uptake among high-risk groups. TRIAL REGISTRATION: Clinicaltrials.gov: NCT05542004, registered September 15, 2022, https://clinicaltrials.gov/ct2/show/NCT05542004.

Effect of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Initiation on Organ Support-Free Days in Patients Hospitalized With COVID-19: A Randomized Clinical Trial.

IMPORTANCE: Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective: To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS: In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non-critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS: Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES: The primary outcome was organ support-free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS: On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support-free days among critically ill patients was 10 (-1 to 16) in the ACE inhibitor group (n = 231), 8 (-1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support-free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE: In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02735707.

Investigating the Association Between Telemedicine Use and Timely Follow-Up Care After Acute Cardiovascular Hospital Encounters

Background Telemedicine use increased dramatically during the COVID-19 pandemic;however, questions remain as to how telemedicine use impacts care. Objectives The purpose of this study was to examine the association of increased telemedicine use on rates of timely follow-up and unplanned readmission after acute cardiovascular hospital encounters. Methods We examined hospital encounters for acute coronary syndrome, arrhythmia disorders, heart failure (HF), and valvular heart disease from a large U.S., multisite, integrated academic health system among patients with established cardiovascular care within the system. We evaluated 14-day postdischarge follow-up and 30-day all-cause unplanned readmission rates for encounters from the pandemic "steady state” period from May 24, 2020 through December 31, 2020, when telemedicine use was high and compared them to those of encounters from the week-matched period in 2019 (May 26, 2019, through December 31, 2019), adjusting for patient and encounter characteristics. Results The study population included 6,026 hospital encounters. In the pandemic steady-state period, 40% of follow-ups after these encounters were conducted via telemedicine vs 0% during the week-matched period in 2019. Overall, 14-day follow-up rates increased from 41.7% to 44.9% (adjusted difference: +2.0 percentage points [pp], 95% CI: −1.1 to +5.1 pp, P = 0.20). HF encounters experienced the largest improvement from 50.1% to 55.5% (adjusted difference: +6.5 pp, 95% CI: +0.5 to +12.4 pp, P = 0.03). Overall 30-day all-cause unplanned readmission rates fell slightly, from 18.3% to 16.9% (adjusted difference −1.6 pp;95% CI: −4.0 to +0.8 pp, P = 0.20). Conclusions Increased telemedicine use during the COVID-19 pandemic was associated with earlier follow-ups, particularly after HF encounters. Readmission rates did not increase, suggesting that the shift to telemedicine did not compromise care quality. Central Illustration

Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction remains less certain. METHODS: We randomly assigned 6263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of worsening heart failure (which was defined as either an unplanned hospitalization for heart failure or an urgent visit for heart failure) or cardiovascular death, as assessed in a time-to-event analysis. RESULTS: Over a median of 2.3 years, the primary outcome occurred in 512 of 3131 patients (16.4%) in the dapagliflozin group and in 610 of 3132 patients (19.5%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P<0.001). Worsening heart failure occurred in 368 patients (11.8%) in the dapagliflozin group and in 455 patients (14.5%) in the placebo group (hazard ratio, 0.79; 95% CI, 0.69 to 0.91); cardiovascular death occurred in 231 patients (7.4%) and 261 patients (8.3%), respectively (hazard ratio, 0.88; 95% CI, 0.74 to 1.05). Total events and symptom burden were lower in the dapagliflozin group than in the placebo group. Results were similar among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%, and results were similar in prespecified subgroups, including patients with or without diabetes. The incidence of adverse events was similar in the two groups. CONCLUSIONS: Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure and a mildly reduced or preserved ejection fraction. (Funded by AstraZeneca; DELIVER ClinicalTrials.gov number, NCT03619213.).

Impact of the COVID-19 Pandemic on Cardiovascular Health in 2020: JACC State-of-the-Art Review.

The impact of COVID-19 on the burden of cardiovascular diseases (CVD) during the early pandemic remains unclear. COVID-19 has become one of the leading causes of global mortality, with a disproportionate impact on persons with CVD. Studies of health facility admissions for CVD found significant decreases during the pandemic. Studies of hospital mortality for CVD were more variable. Studies of population-level CVD mortality differed across countries, with most showing decreases, although some revealed increases in deaths. In some countries where large increases in CVD deaths were reported in vital registration systems, misclassification of COVID-19 as CVD may have occurred. Taken together, studies suggest heterogeneous effects of the COVID-19 pandemic on CVD without large increases in CVD mortality in 2020 for a number of countries. Clinical and population science research is needed to examine the ways in which the pandemic has affected CVD burden.

Investigating Lipid-Modulating Agents for Prevention or Treatment of COVID-19: JACC State-of-the-Art Review.

Coronavirus disease-2019 (COVID-19) is associated with systemic inflammation, endothelial activation, and multiorgan manifestations. Lipid-modulating agents may be useful in treating patients with COVID-19. These agents may inhibit viral entry by lipid raft disruption or ameliorate the inflammatory response and endothelial activation. In addition, dyslipidemia with lower high-density lipoprotein cholesterol and higher triglyceride levels portend worse outcomes in patients with COVID-19. Upon a systematic search, 40 randomized controlled trials (RCTs) with lipid-modulating agents were identified, including 17 statin trials, 14 omega-3 fatty acids RCTs, 3 fibrate RCTs, 5 niacin RCTs, and 1 dalcetrapib RCT for the management or prevention of COVID-19. From these 40 RCTs, only 2 have reported preliminary results, and most others are ongoing. This paper summarizes the ongoing or completed RCTs of lipid-modulating agents in COVID-19 and the implications of these trials for patient management.

Prescription Filling Patterns of Evidence-Based Medical Therapies for Heart Failure During the COVID-19 Pandemic in the United States.

BACKGROUND: Maintaining a steady medication supply during a public health crisis is a major health priority. We leveraged a large U.S. pharmacy-claims database to understand the use of evidence-based therapies in heart failure (HF) care during the coronavirus disease-2019 (COVID-19) pandemic. METHODS: We analyzed 27,027,650 individual claims from an all-payer pharmacy-claims database across 56,155 chain, independent and mail-order pharmacies in 14,164 zip codes in 50 states. Prescriptions dispensed (in 2-week intervals) of evidence-based HF therapies in 2020 were indexed to comparable timeframes in 2019. We normalized these year-to-year changes in HF medical therapies relative to those observed with a stable basket of drugs. RESULTS: Fills of losartan, lisinopril, carvedilol, and metoprolol all peaked in the weeks of March 2020 and demonstrated trajectories thereafter that were relatively consistent with the reference set of drugs. Fills of spironolactone (+4%) and eplerenone (+18%) showed modest trends toward increased relative use during 2020. Fills of empagliflozin (+75%), dapagliflozin (+65%) and sacubitril/valsartan (+61%) showed striking longitudinal increases throughout 2020 that deviated substantially from year-to-year trends of the overall basket of drugs. For all 3 therapies, fills of all quantity sizes increased relatively throughout 2020. For both generic and brand-name therapies, prescription fill patterns from mail-order pharmacies increased substantially over expected trends beginning in March 2020 CONCLUSION: Prescription fills of most established generic therapies used in HF care were maintained, whereas those of sacubitril/valsartan and the sodium-glucose cotransporter-2 inhibitors steeply increased during the COVID-19 pandemic. These nationwide pharmacy claims data provide reassurance about therapeutic access, during a public health crisis, to evidence-based medications used in HF care.

Effect of government-issued state of emergency and reopening orders on cardiovascular hospitalizations during the COVID-19 pandemic.

OBJECTIVE: Little is known about the effect of government-issued State of Emergency (SOE) and Reopening orders on health care behaviors. We aimed to determine the effect of SOE and Phase 1 of Reopening orders on hospitalizations for acute myocardial infarction (AMI) or acute decompensated heart failure (ADHF). METHODS: Hospitalizations for AMI and ADHF in the UNC Health system, which includes 10 hospitals in both urban and rural counties, were identified. An interrupted time series design was used to compare weekly hospitalization rates for eight weeks before the March 10th SOE declaration, eight weeks between the SOE order and Phase 1 of Reopening order, and the subsequent eight weeks. RESULTS: Overall, 3,792 hospitalizations for AMI and 7,223 for ADHF were identified. Rates before March 10th were stable. AMI/ADHF hospitalizations declined about 6% per week in both urban and rural hospitals from March 11th to May 5th. Larger declines in hospitalizations were seen in adults ≥65 years old (-8% per week), women (-7% per week), and White individuals (-6% per week). After the Reopening order, AMI/ADHF hospitalizations increased by 8% per week in urban centers and 9% per week in rural centers, including a significant increase in each demographic group. The decline and rebound in acute CV hospitalizations were most pronounced in the two weeks following the government orders. CONCLUSIONS: AMI and ADHF hospitalization rates closely correlated to SOE and Reopening orders. These data highlight the impact of public health measures on individuals seeking care for essential services; future policies may benefit from clarity regarding when individuals should present for care.