In a randomized trial, patients with severe Covid-19 were assigned to receive either therapeutic-dose anticoagulation or usual-care pharmacologic thromboprophylaxis. At 21 days, therapeutic-dose ...anticoagulation did not improve hospital survival or the number of days free of cardiovascular or respiratory organ support.
IMPORTANCE: Randomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) ...across individuals. Better understanding of HTE could facilitate individualized clinical decision-making. OBJECTIVE: To evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE. DESIGN, SETTING, AND PARTICIPANTS: Exploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial. EXPOSURES: Participants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis. MAIN OUTCOMES AND MEASURES: Organ support–free days, assigning a value of −1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge; and hospital survival. RESULTS: Baseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years; 38% female; 32% known non-White race; 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support–free days (median value for the posterior distribution of the OR, 1.05; 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose heparin on organ support–free days differed between patients requiring organ support at baseline or not (median OR, 0.85 vs 1.30; posterior probability of difference in OR, 99.8%), between females and males (median OR, 0.87 vs 1.16; posterior probability of difference in OR, 96.4%), and between patients with lower body mass index (BMI <30) vs higher BMI groups (BMI ≥30; posterior probability of difference in ORs >90% for all comparisons). In risk-based analysis, patients at lowest risk of poor outcome had the highest propensity for benefit from heparin (lowest risk decile: posterior probability of OR >1, 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR <1, 87%). In effect-based analysis, a subset of patients identified at high risk of harm (P = .05 for difference in treatment effect) tended to have high BMI and were more likely to require organ support at baseline. CONCLUSIONS AND RELEVANCE: Among patients hospitalized for COVID-19, the effect of therapeutic-dose heparin was heterogeneous. In all 3 approaches to assessing HTE, heparin was more likely to be beneficial in those who were less severely ill at presentation or had lower BMI and more likely to be harmful in sicker patients and those with higher BMI. The findings illustrate the importance of considering HTE in the design and analysis of RCTs. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT02735707, NCT04505774, NCT04359277, NCT04372589
Therapeutic-dose heparin decreased days requiring organ support in noncritically ill patients hospitalized for COVID-19, but its impact on persistent symptoms or quality of life (QOL) is unclear.
In ...the Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE (ACTIV-4a) trial, was randomization of patients hospitalized for COVID-19 illness to therapeutic-dose vs prophylactic heparin associated with fewer symptoms and better QOL at 90 days?
This was an open-label randomized controlled trial at 34 hospitals in the United States and Spain. A total of 727 noncritically ill patients hospitalized for COVID-19 from September 2020 to June 2021 were randomized to therapeutic-dose vs prophylactic heparin. Only patients with 90-day data on symptoms and QOL were analyzed. We ascertained symptoms and QOL by the EQ-5D-5L at 90-day follow-up in a preplanned analysis for the ACTIV-4a trial. Individual domains assessed by the EQ-5D-5L included mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Univariate and multivariate analyses were performed.
Among 571 patients, 288 (50.4%) reported at least one symptom. Among 410 patients, 148 (36.1%) reported moderate to severe impairment in one or more domains of the EQ-5D-5L. The presence of 90-day symptoms was associated with moderate-severe impairment in the EQ-5D-5L domains of mobility (adjusted OR aOR, 2.37; 95% CI, 1.22-4.59), usual activities (aOR, 3.66; 95% CI, 1.75-7.65), pain (aOR, 2.43; 95% CI, 1.43-4.12), and anxiety (aOR, 4.32; 95% CI, 2.06-9.02), compared with patients reporting no symptoms There were no differences in symptoms or in the overall EQ-5D-5L index score between treatment groups. Therapeutic-dose heparin was associated with less moderate-severe impairment in all physical functioning domains (mobility, self-care, usual activities) but was independently significant only in the self-care domain (aOR, 0.32; 95% CI, 0.11-0.96).
In a randomized controlled trial of hospitalized noncritically ill patients with COVID-19, therapeutic-dose heparin was associated with less severe impairment in the self-care domain of EQ-5D-5L. However, this type of impairment was uncommon, affecting 23 individuals.
ClinicalTrials.gov; No.: NCT04505774; URL: www.clinicaltrials.gov
Display omitted
Therapeutic-dose heparin decreased days requiring organ support in noncritically ill patients hospitalized for COVID-19, but its impact on persistent symptoms or quality of life (QOL) is unclear.
In ...the Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE (ACTIV-4a) trial, was randomization of patients hospitalized for COVID-19 illness to therapeutic-dose vs prophylactic heparin associated with fewer symptoms and better QOL at 90 days?
This was an open-label randomized controlled trial at 34 hospitals in the United States and Spain. A total of 727 noncritically ill patients hospitalized for COVID-19 from September 2020 to June 2021 were randomized to therapeutic-dose vs prophylactic heparin. Only patients with 90-day data on symptoms and QOL were analyzed. We ascertained symptoms and QOL by the EQ-5D-5L at 90-day follow-up in a preplanned analysis for the ACTIV-4a trial. Individual domains assessed by the EQ-5D-5L included mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Univariate and multivariate analyses were performed.
Among 571 patients, 288 (50.4%) reported at least one symptom. Among 410 patients, 148 (36.1%) reported moderate to severe impairment in one or more domains of the EQ-5D-5L. The presence of 90-day symptoms was associated with moderate-severe impairment in the EQ-5D-5L domains of mobility (adjusted OR aOR, 2.37; 95% CI, 1.22-4.59), usual activities (aOR, 3.66; 95% CI, 1.75-7.65), pain (aOR, 2.43; 95% CI, 1.43-4.12), and anxiety (aOR, 4.32; 95% CI, 2.06-9.02), compared with patients reporting no symptoms There were no differences in symptoms or in the overall EQ-5D-5L index score between treatment groups. Therapeutic-dose heparin was associated with less moderate-severe impairment in all physical functioning domains (mobility, self-care, usual activities) but was independently significant only in the self-care domain (aOR, 0.32; 95% CI, 0.11-0.96).
In a randomized controlled trial of hospitalized noncritically ill patients with COVID-19, therapeutic-dose heparin was associated with less severe impairment in the self-care domain of EQ-5D-5L. However, this type of impairment was uncommon, affecting 23 individuals.
ClinicalTrials.gov; No.: NCT04505774; URL: www.
gov.
Abstract only
Background:
SARS-CoV-2 infection potentiates thromboinflammation contributing to poor outcomes in COVID-19. In non-critically ill patients hospitalized for COVID-19, therapeutic-dose ...heparin improves clinical outcomes. We hypothesized therapeutic-dose heparin impacts thromboinflammatory biomarkers in patients hospitalized for COVID-19 infection.
Methods:
We conducted a pre-specified secondary analysis of a multi-platform open-label, randomized trial comparing therapeutic-dose versus usual-care thromboprophylaxis-dose heparin in non-critically ill patients hospitalized for COVID-19. Inflammatory markers were analyzed using Wilcoxon rank-sum test and compared based on treatment. Ordinal logistic regression models evaluated for relative D-Dimer change (measured at baseline, day 1, day 3). Odds ratio of a 3-level ordinal outcome (death, survival with organ support, or survival without organ support through 21 days) was determined for relative change.
Results:
Of 1510 patients, 528 had a D-Dimer on baseline and day 1, and 432 on baseline and day 3. Median age was 60 years (IQR: 50-69) with 41% female and 66% under-represented minorities. Compared to usual-care, therapeutic-dose heparin was associated with a greater drop in D-Dimer at days 1 and 3; other biomarkers were unaffected by treatment (Table 1). D-Dimer at baseline and day 1 had an OR 0.93 (95% CI: 0.88, 0.98) whereas baseline and day 3 had an OR 0.86 (95% CI: 0.78, 0.94) of the ordinal outcome translating in a higher odds of surviving without the need for organ support (adjusted for treatment, gender, and age).
Conclusion:
In this randomized controlled trial therapeutic-dose heparin was associated with an early reduction in D-Dimer and clinical improvement, suggesting thromboinflammatory mechanisms whereby treatment conferred a clinical benefit. Temporal changes in D-dimer could predict treatment response or may signal need for alternative therapies.
PDF
