In this pilot study of patients with acute proximal DVT and/or PE, the addition of atorvastatin (40 mg daily) to standard anticoagulation therapy did not significantly reduce either ETP or peak thrombin at 3 months. However, the study was underpowered due to early termination for futility. Therefore, we could not fully evaluate the potential effects of statins on thrombin generation in this study. The mean LDL was significantly reduced at 3 months in patients receiving atorvastatin. Other biomarkers such as D-dimer and hs-CRP were not significantly reduced with atorvastatin.
Our study was limited by the small sample size. Although a total of 80 patients were originally planned, over the course of 3.5 years, only 21 patients consented to enrollment, despite screening over 500 potentially eligible patients. We limited the type of anticoagulants allowed due to the effort to minimize the impact of different anticoagulants on thrombin generation assays. We initially included only patients on warfarin. However, direct oral anticoagulants quickly became the anticoagulant of choice for VTE afterwards, which limited enrollment. The protocol was amended in September 2015 to include patients on both warfarin and rivaroxaban. The research staff routinely screened Doppler ultrasound reports on a daily basis to identify potential study participants. We also worked with Emergency Department to encourage referrals of patients with newly diagnosed VTE. Despite these efforts, recruitment remained slow, and eventually continuation of the study was deemed futile and the study was terminated early. The most common reasons for ineligibility included active cancer, current statin treatment, and chronic DVT. The most common reasons for non-consent in eligible patients included refusal of additional medication and discomfort with randomization and clinical research protocols. This highlights the need for alternative eligibility criteria and/or study design.
In this pilot study, we chose to use surrogate endpoints such as thrombin generation based on previous report of a positive association between thrombin generation and recurrent VTE (25). We acknowledged that surrogate endpoints had limitations and may or may not correlate with clinical outcomes. Ultimately, clinical outcomes including recurrent VTE and bleeding events are the gold standard, which would require a much larger sample size. In addition, long-term compliance with medications was problematic in our cohort. There was a significant reduction of LDL at 3 months in patients on the atorvastatin plus anticoagulation arm compared to the anticoagulation only arm, indirectly indicated compliance to atorvastatin at least at 3 months. However, only three patients on atorvastatin self-reported continued adherence to statin therapy at 9 months, and more-than-expected number of patients were lost to follow up or declined study blood draw (N = 7) at 9 months. The low adherence could be partially due to participants’ relative young age on minimal medications prior to the VTE event. To ensure adequate compliance monitoring, future studies could consider incorporating the use of smartphone applications or pill bottle caps with a radio frequency identification (RFID) reader.
The START (The STAtins Reduce Thrombophilia) trial published in 2019 randomized 245 patients with a history of VTE (48.6% unprovoked) who have completed a course of anticoagulation to rosuvastatin 20 mg daily or no statin for 4 weeks (29). All patients stopped vitamin K antagonists for one month prior to enrollment. Patients on rosuvastatin had a significantly reduced ETP by 10% and peak thrombin by 5% at 4 weeks (29). Our results are different for a few reasons. First, we used atorvastatin instead of rosuvastatin, and the potency can vary among different statins (30). We chose atorvastatin because it was widely available as a generic compound (whereas rosuvastatin was a brand-name only compound during the time of study period). Moreover, atorvastatin had previously been shown to reduce thrombin generation in patients with cardiovascular disease or diabetes (28, 31). Second, we started atorvastatin within 3 weeks of the index acute VTE, along with anticoagulation, instead of waiting until after patients had stopped anticoagulation. We chose to add atorvastatin up front to investigate the effects of early addition of statins and their potential long-term benefits. In addition, prior study in patients on warfarin for atrial fibrillation had shown that 3 months of statins could cause a reduction in ETP (17). However, anticoagulation itself can reduce thrombin generation. Our original goal was to determine if early adjunct atorvastatin could also reduce post-anticoagulation thrombin generation at the 9-month visit, assuming that most patients would be prescribed a standard 3- or 6-month anticoagulant regimen for their VTE, as recommended in VTE guidelines (20). Unfortunately, due to the significant loss of follow up at 9 months, the data on thrombin generation could only be analyzed on 3-month samples, and all patients remained on anticoagulation at that time. Therefore, we suspect that the effects of statin on thrombin generation were obscured by the presence of anticoagulation. Nonetheless, atorvastatin did not appear to enhance the inhibition of thrombin generation in the presence of anticoagulation, suggesting that adjuvant atorvastatin would not increase the risk of bleeding associated with anticoagulation. This was supported by the lack of major bleeding in our cohort, although we acknowledge that the number of patients was small and the observation was preliminary. Larger trials will be needed to determine the safety and efficacy of adjunct statin therapy.
Our study included exploratory lipidomic profile analyses. Lipidomics is a mean of global mapping of lipid metabolites which may provide further detailed information of the effects of atorvastatin in patients with VTE, which has not been published previously. Previous studies have evaluated detailed lipidomic profiles as effects of simvastatin or rosuvastain in patients with hyperlipidemia (32, 33). We found in our study that VTE patients receiving atorvastatin in addition to anticoagulation had reduced CE (cholesterol ester), CER (ceramides), PC (phosphatidylcholine) and SM (sphingomyelin), as well as increased LCER (lactosyl ceramide) at 3 months. Other lipid classes did not show significant changes with or without 3 months of statins. The statistical analysis was not adjusted for multiple comparisons, so this analysis was exploratory in nature, but it could provide insights into mechanisms and be hypothesis generating. While anticoagulation is generally not considered to cause significant alterations on lipid profiles, whether there are interactions between anticoagulation and statin agents on lipid profile warrants further investigation.
Although our study was terminated early for low accrual and funding issues, we believe that it provides insights into strategies needed for future trials of statin therapy in patients with VTE. Our study showed that multiple adjustments in the current study design are needed to improve feasibility. These could include: expansion of eligibility criteria (such as inclusion of patients with different types of VTE, provoked, unprovoked, cancer-associated, etc), relaxation of time frame for enrollment after index VTE, inclusion of all care settings for enrollment including primary care and subspecialty clinics, and utilization of established network for multicenter collaboration. The ongoing SAVER (StAtins for Venous Event Reduction in patients with venous thromboembolism) pilot trial (NCT02679664) aims to investigate the feasibility of recruitment in this population and the effects of rosuvastatin for prevention of PTS. The upcoming SAVER full trial will further investigate the use of rosuvastatin for secondary prevention of VTE. These important trials will shed lights on the use of statins in patients with VTE.