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