Importance: Pharmacologic thromboprophylaxis is widely used for medical inpatients, but its contemporary benefits remain uncertain for clinically relevant venous thromboembolism (VTE).

Objective: To evaluate and compare the benefits and risks associated with currently approved in-hospital pharmacologic thromboprophylaxis regimens to prevent symptomatic and clinically relevant VTE and bleeding in acutely ill medical inpatients.

Data sources: MEDLINE, Embase, Web of Science, and the Cochrane CENTRAL databases were searched until January 31, 2026. Reference lists from retrieved articles and reference literature were also examined.

Study selection: Randomized clinical trials that involved adult patients hospitalized for an acute medical illness and compared pharmacologic thromboprophylaxis regimens (low-molecular-weight heparin [LMWH], unfractionated heparin [UHF], and direct oral anticoagulants [DOACs]) with no treatment or placebo were selected.

Data extraction and synthesis: Dual independent screening, data extraction, and risk-of-bias assessment were performed. Relative risks (RRs) were pooled using network meta-analyses with random effects. The PRISMA reporting guideline was used.

Main outcomes and measures: The effectiveness outcomes were the risk of confirmed symptomatic VTE, clinically relevant VTE, and any VTE. Safety outcomes were mortality, major bleeding, and clinically relevant nonmajor bleeding. Pairwise and network meta-analyses were computed.

Results: Among the 22 studies (involving 43 840 patients) included, the 90-day pooled risk of symptomatic VTE was 1.7% (95% CI, 0.6%-4.4%) in the no-treatment group. Compared with no treatment, LMWH was associated with reduced symptomatic VTE risk (RR, 0.68; 95% CI, 0.49-0.94). Point estimates for DOACs (RR, 0.69; 95% CI, 0.36-1.31) and UFH (RR, 0.75; 95% CI, 0.40-1.40) were less than 1, although the results were not statistically significant. LMWH (RR, 0.57; 95% CI, 0.43-0.74), DOACs (RR, 0.58; 95% CI, 0.41-0.82), and UFH (RR, 0.66; 95% CI, 0.45-0.97) were associated with reduced risk of clinically relevant VTE. Using a theoretical conversion rate of asymptomatic into symptomatic VTE, both LMWH and DOACs were associated with decreased risk of symptomatic VTE (RR, 0.63 [95% CI, 0.48-0.83] and 0.66 [95% CI, 0.44-0.99]). DOACs (RR, 2.62; 95% CI, 1.25-5.49) and UFH (RR, 2.33; 95% CI, 1.13-4.79) were associated with an increased risk of major bleeding, compared with no treatment, while LMWH (RR, 1.23; 95% CI, 0.81-1.85) had no association. Mortality was unaffected by the treatment regimens.

Conclusions and relevance: In this systematic review and network meta-analysis, DOACs, LMWH, and UFH were associated with reduced clinically relevant VTE in medical inpatients; DOACs and UFH had higher risks of major bleeding than LMWH. Proper selection of patients is critical given the overall low absolute risk of VTE.