Clot Chronicles: PCSK9 Inhibitors – New Agents for VTE Prevention?

Hi, my name is Nick Marston. I’m a cardiologist at the Brigham and Women’s Hospital and an investigator at the TIMI Study Group. I’m joining the Clot Chronicles today to share with you the results of our recent study evaluating the efficacy of PCSK9 inhibition on the risk of venous thromboembolism (VTE). As this audience already knows, VTE carries significant cardiovascular morbidity and mortality, and there’s a lack of preventive therapies beyond anticoagulation. 

However, we do have data from the JUPITER trial, which found that high-intensity statin therapy significantly reduces VTE compared to placebo. Now, whether this was related to LDL reduction or statins pleiotropic effects—such as antithrombotic or anti-inflammatory properties—is not entirely clear. PCSK9 inhibitors, on the other hand, do not have any known pleiotropic effects, providing an ideal model for evaluating and testing whether lipid lowering is, in fact, associated with a reduction in VTE. 

So in this study, we tested this relationship between lipid lowering and VTE using data from the FOURIER trial, a randomized controlled trial of the PCSK9 inhibitor, evolocumab, in hopes of identifying mechanistic insights into the development and prevention of VTE. In this study, we evaluated over 27,000 patients from the FOURIER trial, all of whom had established atherosclerotic cardiovascular disease. Patients were randomized to either evolocumab or placebo, in addition to their background statin therapy. And VTE, defined as deep vein thrombosis or pulmonary embolism, was collected through safety event reporting. These patients were then followed for a median duration of 2.2 years. 

When evaluating the two arms of the trial, we found that evolocumab did, in fact, significantly reduce VTE with a 29% relative risk reduction compared to patients receiving placebo. This effect appeared to be delayed by 6-12 months, with the greatest reduction in VTE occurring at one year after therapy, at which point treated patients experienced a 46% relative risk reduction. Next, we combined the evolocumab results from FOURIER, with data from ODYSSEY Outcomes, which studied the other FDA-approved PCSK9 inhibitor, alirocumab. 

By combining data from the two major PCSK9 outcomes trials in a meta-analysis of nearly 50,000 patients, we found a consistent benefit across both evolocumab and alirocumab with a 31% reduction in VTE. This not only replicated the findings in FOURIER, but it also suggests that VTE risk reduction is a class effect of PCSK9 inhibitors. Therefore, as PCSK9 inhibitor use becomes increasingly widespread among patients with cardiovascular disease, we can expect an additional benefit of significantly reducing their overall burden of VTE. 

So the next question is whether this VTE reduction is mediated by LDL lowering or Lp(a) lowering, which PCSK9 inhibitors also reduce. Interestingly, we found that this reduction of VTE was not associated with LDL cholesterol lowering but rather baseline levels of Lp(a) and a degree of Lp(a) lowering. In fact, the reduction of VTE was seen primarily in patients with high baseline Lp(a) levels, who experienced the greatest reduction with evolocumab. 

The same signal was also seen with alirocumab, suggesting that Lp(a) may be an important mediator of the development of VTE and the potential target for preventive therapies. Fortunately, novel RNA therapeutics against Lp(a), including RNA interference and antisense oligonucleotides, have been developed and are entering phase 3 trials. If Lp(a) is indeed the mechanism by which PCSK9 inhibitors lower VTE risk, these more potent Lp(a) lowering drugs may not only confirm this hypothesis but will also have the potential to lower VTE risk to an even greater extent. 

So, I’ll close with three take-home messages. First, there is strong evidence that both FDA-approved PCSK9 inhibitors can significantly reduce the risk of VTE. Second, this reduction in VTE appears to be associated with the degree of Lp(a) lowering rather than LDL cholesterol lowering, suggesting that Lp(a) may be an important mediator of VTE risk. And third, RNA therapeutics targeting Lp(a) are being studied in phase 2 and phase 3 trials currently and may provide confirmatory data and an even more potent therapy for VTE prevention. 

Thank you for your attention and for tuning in to this edition of Clot Chronicles.

Related Articles