Lipid lowering therapies for the prevention of venous thromboembolism: an additive component network meta-analysis of randomized controlled trials.

Ioannis T. Farmakis (Mainz)1, K. Christodoulou (Mainz)1, L. Hobohm (Mainz)2, S. Konstantinides (Mainz)1, L. Valerio (Mainz)1

1Universitätsmedizin der Johannes Gutenberg-Universität Mainz Centrum für Thrombose und Hämostase Mainz, Deutschland; 2Universitätsmedizin der Johannes Gutenberg-Universität Mainz Zentrum für Kardiologie Mainz, Deutschland


Background: Studies have suggested that statins may be associated with reduced risk of venous thromboembolism (VTE). We aimed to assess the evidence regarding the comparative effect of all lipid lowering therapies (LLT) in primary VTE prevention.
Methods: After a systematic search of PubMed, CENTRAL, and Web of Science, we selected randomized controlled trials (RCTs) of statins (high- or low-/moderate-intensity), ezetimibe, or proprotein convertase subtilisin/kexin type 9 inhibitors (PCKS9i) administered in monotherapy or in combination. We performed a frequentist random-effects additive component network meta-analysis to compare VTE incidence during long-term follow-up across different combinations of LLT.
Results: We identified 44 RCTs (n = 253,818 patients) reporting a total of 1,947 VTE events (Figure 1). The included studies followed a population with mean age 61.6 ± 9.1 years (33.5% women) for 41.3 ± 21.8 months. Compared to placebo, the combination of PCSK9i with high-intensity statin showed the largest reduction in VTE incidence (risk ratio [RR] 0.58; 95% confidence interval [CI] 0.42-0.79), while the effect was trending towards reduction for high-intensity (0.84; 0.70-1.02) and low-/moderate-intensity (0.89; 0.79-1.00) statin monotherapy (Figure 2). Ezetimibe monotherapy did not affect the VTE incidence (1.04; 0.83-1.30). When compared to low-/moderate-intensity statin monotherapy, the combination of PCSK9i and high-intensity statin was significantly more likely to reduce VTE incidence (0.65; 0.48-0.88). There was a gradual increase in the summary effect of VTE reduction with increasing intensity of the LLT, as depicted from the P-scores (PCSK9i + high-intensity statin 0.88, PCSK9i 0.84, high-intensity statin 0.53, ezetimibe + high-intensity statin 0.44, low/moderate-intensity statin 0.41, ezetimibe + low/moderate-intensity statin 0.30, placebo 0.09). There was no heterogeneity in the network (I2 = 0%) and the additivity assumption was fulfilled (p-value of Cochran’s Q = 0.50). There was no evidence of publication bias (Egger’s test p=0.85). Compared to low-/moderate-intensity statin monotherapy, the combination of PCSK9 inhibitor and high-intensity statin was significantly more likely to reduce VTE incidence (RR 0.65, 95% CI 0.48-0.88, p=0.0057). Regarding VTE locations, the combination of high-intensity statin with PCSK9i, compared to placebo, showed reduction in DVT (0.29; 0.14-0.60), while statistical significance for PE reduction was not reached (0.54; 0.26-1.11).
Conclusions: RCTs suggest that LLT treatment may have a potential for VTE prevention, particularly in high-intensity dosing and in combination. The combination of a PCSK9 inhibitor with high-statin may represent the most promising regimen for the reduction of VTE incidence. Future interventional studies should confirm these findings.

Figure 1. 

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