Table 1.

Outline of specification and emulation of a target trial of thromboprophylaxis in COVID-19 patients with no signs of increased thrombotic risk

Component	Target trial specification	Target trial emulation
Eligibility	•age ≥ 18 yr •admission for ≥ 24 hours to La Paz University Hospital between March 16 and April 15, 2020 •RT-PCR–confirmed COVID-19 diagnosis •no active bleeding, no severe thrombocytopenia (platelet count < 50,000/mL), no long-term use of anticoagulation, no thrombosis, no signs of increased thrombotic risk (C-reactive protein > 150 mg/dL, D-dimer >1,500 ng/mL, ferritin > 1,000 μg/L, or lymphocyte count ≤ 800/mL).	Same.
Treatment strategies	1.Standard dose: LMWH at standard prophylactic dose (i.e., 4,000–5,999 IU of enoxaparin or 2,500–3,999 IU of bemiparin for nonobese individuals and 4,000–7,999 IU of enoxaparin or 2,500–4,999 IU of bemiparin for obese individuals subcutaneously every 24 hours). 2.Variable dose: Same, except that dose is increased (i.e., 6,000–8,999 IU of enoxaparin or 4,000–7,499 IU of bemiparin for nonobese individuals and 8,000–8,999 IU of enoxaparin or 5,000–7,499 IU of bemiparin for obese individuals subcutaneously every 24 hours) within 48 hours if analytic abnormalities (C-reactive protein >150 mg/dL, D-dimer >1,500 ng/mL, ferritin >1,000 μg/L, or lymphocyte count <800/mL) are detected. Under both strategies, the choice of drug is left to the physician's discretion. Individuals are excused from following the assigned strategy after thrombosis (when anticoagulation treatment must be started) and after active bleeding or platelet count <50,000/mL (when anticoagulation must be discontinued).	Same.
Treatment assignment	Individuals are randomly assigned to one of the strategies. Individuals are aware of the strategy they are assigned to.	Individuals are assigned to the strategy their baseline data are compatible with.
Follow-up	For each individual, follow-up starts at the time of assignment to a strategy and ends at death, hospital discharge, or 28 days after hospitalization.	Same.
Primary end point	All-cause mortality at 28 days. We assume no deaths occurred after hospital discharge.	Same.
Causal contrast	Per-protocol effect. Intention-to-treat effect.	Observational analog of the per-protocol effect.
Statistical analysis	Intention-to-treat analysis: 28-day survival curves and hazard ratios are estimated using pooled logistic regression models. Individuals who are discharged are assumed to remain alive through day 28. Per-protocol analysis: Same as intention-to-treat analyses, with two exceptions. First, individuals are censored when their data stop being compatible with the strategy they are assigned to. Second, each individual receives a time-varying inverse probability weight to adjust for the potential selection bias introduced by censoring.	Same as per-protocol analysis except that, for individuals having treatment and laboratory data compatible with both strategies at baseline, we created two clones and assigned each clone to a different strategy.