Rosuvastatin use improves measures of coagulation in patients with venous thrombosis

Rosuvastatin use improves measures of coagulation in patients with venous thrombosis Abstract Aims Observational studies indicate that statins reduce the risk of recurrent venous thrombosis (VT). However, trials have not been performed and the mechanism is unknown. We aimed to determine whether statin therapy improves the coagulation profile in patients with prior VT. Methods and results Randomized clinical trial (NCT01613794). Patients were randomized to rosuvastatin 20 mg/day for 4 weeks or no intervention. Blood was drawn at baseline and at end of study. The primary outcome was factor (F) VIII:C. In total, five coagulation factors were measured: FVIII:C, von Willebrand factor:Ag, FVII:C, FXI:C, and D-dimer. Among 247 randomized participants, mean age was 58 years, 62% were women and 49% had unprovoked VT. For all tested coagulation factors, mean levels were clearly decreased at end of study in rosuvastatin users, whereas they hardly differed in non-statin users. Results were most consistent for FVIII:C where mean FVIII:C levels were 7.2 IU/dL [95% CI (confidence interval) 2.9–11.5] lower in rosuvastatin users, while among non-users, no change in FVIII:C was observed (mean difference −0.1; 95% CI −3.0 to 2.9). The mean age and sex adjusted difference in FVIII:C change was −6.7 IU/dL (95% CI −12.0 to −1.4) in rosuvastatin users vs. non-users. Subgroup analyses revealed that the decrease in coagulation factors by rosuvastatin was more pronounced in participants with unprovoked VT and in those with cardiovascular risk factors. Conclusion Rosuvastatin 20 mg/day substantially improved the coagulation profile among patients with prior VT. These results suggest that statin therapy might be beneficial in patients at risk of recurrent VT. View largeDownload slide View largeDownload slide Hydroxymethylglutaryl-CoA reductase inhibitors, Thrombophilia, Venous thrombosis, Randomized clinical trial Introduction Venous thrombosis (VT), the collective term for deep vein thrombosis of the leg, pulmonary embolism, or both, is the third most common vascular disease after myocardial infarction and ischaemic stroke.1 Venous thrombosis affects 1–2 per thousand people per year, has a 2.6% immediate death rate and recurrence rates of 25% within 5 years.2 Currently, the only effective strategy to prevent recurrent events is to continue anticoagulation indefinitely.3 In view of bleeding complications, safer options to reduce the risk of recurrent VT are necessary.4 For this statins may form a suitable candidate as statins do not induce bleeding but may reduce the risk of VT.4,5 In this aspect, results from observational studies that showed that statins are associated with a 30–50% lower risk of first VT seem promising, but often included prevalent statin users.6–8 Such prevalent users can introduce two types of bias: (i) under-ascertainment of events that occur early after starting treatment (survivor bias) and (ii) the inability to control for differences between those who do or do not adhere to statin treatment (adherence bias).9,10 For this matter, it is interesting to note that in a meta-analysis of statin use and risk of first VT,8 only one of the seven mentioned studies included statin initiators in their study (new-user design) and reported an odds ratio (OR) of 1.02 [95% confidence interval (CI) 0.88–1.18],7 which was in contrast to the overall OR of 0.62 (95% CI 0.45–0.86).8 This suggests that the observed association between statin use and a decreased risk of first VT may have been biased due to the inclusion of prevalent users. However, after this publication, other studies in which prevalent user bias was excluded by design have been published. In a cohort study of nearly 2 million individuals from the UK, in which a new-user design was used, the authors showed that rosuvastatin use was associated with a strongly (∼40%) reduced risk of VT.11 This result closely resembles the results from a randomized clinical trial in which apparently healthy individuals were randomized to rosuvastatin or placebo (JUPITER trial) in which a 40% risk reduction for rosuvastatin compared with placebo was found.12 In the absence of other randomized trials with VT as the primary endpoint, Rahimi et al.13 presented a pooled analysis of 29 randomized statin studies in which venous thrombotic events were reported as serious adverse events. Although they failed to confirm a risk reduction of VT by overall statin treatment, the authors found that individuals who were randomized to rosuvastatin still had an approximately 40% reduced risk of VT (hazard ratio 0.65; 95% CI 0.33–1.28).13 Based on a report that showed that statins can reduce factor VIII,14 one would suspect that statin use protects to some extent against VT by downsizing a procoagulant state. This finding should be interpreted with caution as it comes from a non-randomized study. Recently published findings from randomized clinical trials of statin therapy suggest some effect of lowering levels of von Willebrand factor (vWF) and D-dimer.15,16 However, funnel plot analyses revealed that these positive results might be due to publication bias.15,16 Furthermore, no randomized clinical trials have investigated the impact of statin therapy on the risk of recurrent VT. Not knowing a clear pathophysiological mechanism behind the supposed causal association between statin use and a reduced risk of recurrent VT, may explain the lack of conducting such a costly and endeavouring trial. Therefore, the aim of the STAtins Reduce Thrombophilia (START) trial was to investigate whether statin therapy improves the coagulation profile in patients with a history of VT. For this purpose, the effect of rosuvastatin use on several coagulation markers was assessed. Rosuvastatin 20 mg/day was chosen as the study drug as literature has consistently shown the strongest association between rosuvastatin and a reduced risk of VT.11–13 Methods Trial design STAtins Reduce Thrombophilia is a multicentre, randomized, controlled, open label, and clinical trial that investigates whether the coagulation profile in persons with a history of VT will improve when using rosuvastatin. We undertook the study in accordance with the Declaration of Helsinki and International Conference on Harmonization guidelines for Good Clinical Practice. All participants gave written informed consent prior to participation. STAtins Reduce Thrombophilia was approved by the Medical Ethics Committee of the Leiden University Medical Center, Leiden, the Netherlands, and is registered at www.clinicaltrials.gov as NCT01613794. Participants Participants were recruited at three anticoagulation clinics in the Netherlands (Leiden, Hoofddorp, and Rotterdam), which monitor anticoagulant treatment with vitamin K antagonists of patients with VT in well-defined geographic areas. Individuals aged 18 years or older with (initial or recurrent) confirmed symptomatic proximal deep vein thrombosis or pulmonary embolism who were allowed to stop oral anticoagulant treatment by their treating physician, were eligible for the study. Reasons for exclusion were: individuals already using statins or lipid lowering drugs, or any other contraindications for rosuvastatin 20 mg/day use as provided by the instruction leaflet of the manufacturer.17 Intervention Informed consent was obtained at the study baseline visit. The study baseline visit was defined at the time of the last regular visit of the patient to the anticoagulation clinic. After informed consent, participants were screened on acquired risk factors for thrombosis through a questionnaire and tested on liver and kidney function. At randomization, participants were allocated to receive either rosuvastatin 20 mg/day or no study medication. The duration of the study was 28 days, based on the consideration that some small, non-randomized studies showed beneficial effects of statins on the coagulation system as early as after a 3-day statin administration.18 Measurements Patients stopped using their vitamin K antagonist for 1 month (to allow a wear off of anticoagulant drugs) after which a blood sample was drawn at randomization visit and at the end of the study period (i.e. 28 days later). All blood drawings were performed between 08:00 am and 15:00 pm. Blood was collected in tubes containing sodium citrate (3.2%) and centrifuged within 3 h of venepuncture at 2500 g for 15 min at 18°C, after which plasma was immediately stored at −80°C. Laboratory technicians, who were unaware of which participants were rosuvastatin-users, performed the assays after all participants had completed the study. From these blood samples, levels of coagulation markers that are related to liver function [factor (F) VII:C and FXI:C], and endothelial function [FVIII:C and vWF:Ag],19,20 and one-global assay (D-dimer) were assessed. We decided to use this set of coagulation assays as these could globally indicate if and by which pathway rosuvastatin reduces thrombophilia. All laboratory measurements (FVII:C, FVIII:C, FXI:C, D-dimer, and vWF:Ag), were analysed on the ACL-Top 700 analyser (Instrumentation Laboratory). FVIII:C and FXI C levels were measured using modified activated partial thromboplastins time assays using immunodepleted plasmas. Similarly, FVII:C was determined using a modified prothrombin time. von Willebrand factor:Ag and D-dimer levels were measured using an automated latex enhanced immunoassay using the HemosIL vWF:Ag and the HemosIL D-dimer HS 500 reagent kit, respectively. Study size Because high FVIII:C levels are strongly associated with recurrent VT,21,22 the sample size was powered on FVIII:C. In a prior study from our group, we observed that patients with VT have a mean FVIII:C of 141 IU/dL (standard deviation 48).21 With a number of 2 × 125 = 250 participants, we would be able to find a mean (between participants) difference of 17 IU/dL FVIII:C with a two-sided alpha of 0.05 and 80% power. Compliance Adherence to the study protocol was assessed in two ways. First, participants who were randomized for rosuvastatin took the first tablet within the presence of an investigator. Second, compliance of rosuvastatin use was monitored by measuring total cholesterol levels at baseline and at end of study in all participants. Statistical analysis The general characteristics of the participants are reported as means and ranges. The mean levels with 95% CI of the coagulation factors were calculated at time of randomization and at the end of the study period. Coagulation factors were log-transformed if not normally distributed (this happened to be the case for D-dimer). All analyses were set to be done by intention to treat, which was set to a modified intention to treat in the final analyses since there were post randomization exclusions. Changes of coagulation factors were first expressed as the mean difference (with 95% CI) of coagulation factors at the end of study period in rosuvastatin users vs. non-rosuvastatin users. Since, we observed that more men were randomized to non-rosuvastatin use and that non-rosuvastatin users were slightly older than those who were randomized to rosuvastatin, we a priori decided to perform both unadjusted and age and sex adjusted analysis by means of linear regression methods to determine the between participant difference of various coagulation factors. Furthermore, we evaluated the change in coagulation factor levels at an individual level. Prespecified exploratory subgroup analyses included the following potential or established prognostic determinants of recurrent VT: male/female sex,23 unprovoked/provoked first event,24 deep vein thrombosis or pulmonary embolism,25 and presence or absence of self-reported arterial cardiovascular risk factors. One post hoc analysis was performed in which we excluded all participants who reported signs or symptoms of an infection during the study, as infections can influence coagulation factors.26 All analyses were performed with SPSS version 24.0 (IBM, Armonk, NY, USA). Results Study population The START trial was completed as planned; Figure 1 shows the trial profile. A total of 255 participants were randomized between December 2012 and December 2016, with 131 assigned to the rosuvastatin-therapy group, and 124 to the non-rosuvastatin group. As eight participants did not complete the study (five rosuvastatin users and three non-rosuvastatin users), follow-up was thus 97% complete. The reported reasons for not completing the study are noted in Figure 1. Table 1 presents baseline characteristics. Mean age was 57 years (range 19–82) in rosuvastatin users and 59 years (range 21–81) in non-rosuvastatin users; 68 (54%) of participants allocated to rosuvastatin were men, while this number was 84 (69%) in participants allocated to no treatment. Other reported exposures were balanced at baseline. Table 1 Baseline characteristics Rosuvastatin Users (n = 126) Non-users (n = 121) General  Age (years) 57 (19–82) 59 (21–81)  Male 68 (54) 84 (69)  Body mass index (kg/m2) 27.4 (19.2–43.5) 27.7 (17.2–43.2)  Baseline cholesterol (mmol/L) 5.61 (2.95–8.99) 5.59 (3.33–7.89)  Use of antiplatelet drugs 5 (4) 5 (4) Venous thrombosis characteristics  Type of venous thrombosis   Deep vein thrombosis 72 (57) 65 (54)   Pulmonary embolism 54 (43) 56 (46)  Unprovoked 57 (45) 64 (53)  Provoked by 69 (55) 57 (47)   Surgery/trauma/ immobilization 32 (25) 31 (26)   Travel >4 h 22 (18) 14 (12)   Oestrogen use (% in women) 24 (41) 14 (38)   Pregnancy/puerperium (% in women) 0 (0) 2 (5)   Malignancy 2 (2) 8 (7)  Recurrent venous thrombosis 10 (8) 8 (7) Cardiovascular risk factors  Absent 37 (29) 26 (21)  Present 89 (71) 95 (79)   Current smoking 18 (14) 17 (14)   Hypertension 24 (19) 21 (17)   Diabetes 3 (2) 0 (0)   Overweight 54 (43) 51 (42)   Obesity 29 (23) 35 (29) Rosuvastatin Users (n = 126) Non-users (n = 121) General  Age (years) 57 (19–82) 59 (21–81)  Male 68 (54) 84 (69)  Body mass index (kg/m2) 27.4 (19.2–43.5) 27.7 (17.2–43.2)  Baseline cholesterol (mmol/L) 5.61 (2.95–8.99) 5.59 (3.33–7.89)  Use of antiplatelet drugs 5 (4) 5 (4) Venous thrombosis characteristics  Type of venous thrombosis   Deep vein thrombosis 72 (57) 65 (54)   Pulmonary embolism 54 (43) 56 (46)  Unprovoked 57 (45) 64 (53)  Provoked by 69 (55) 57 (47)   Surgery/trauma/ immobilization 32 (25) 31 (26)   Travel >4 h 22 (18) 14 (12)   Oestrogen use (% in women) 24 (41) 14 (38)   Pregnancy/puerperium (% in women) 0 (0) 2 (5)   Malignancy 2 (2) 8 (7)  Recurrent venous thrombosis 10 (8) 8 (7) Cardiovascular risk factors  Absent 37 (29) 26 (21)  Present 89 (71) 95 (79)   Current smoking 18 (14) 17 (14)   Hypertension 24 (19) 21 (17)   Diabetes 3 (2) 0 (0)   Overweight 54 (43) 51 (42)   Obesity 29 (23) 35 (29) Continuous variables denoted as mean (range) and categorical variables as n (%). Table 1 Baseline characteristics Rosuvastatin Users (n = 126) Non-users (n = 121) General  Age (years) 57 (19–82) 59 (21–81)  Male 68 (54) 84 (69)  Body mass index (kg/m2) 27.4 (19.2–43.5) 27.7 (17.2–43.2)  Baseline cholesterol (mmol/L) 5.61 (2.95–8.99) 5.59 (3.33–7.89)  Use of antiplatelet drugs 5 (4) 5 (4) Venous thrombosis characteristics  Type of venous thrombosis   Deep vein thrombosis 72 (57) 65 (54)   Pulmonary embolism 54 (43) 56 (46)  Unprovoked 57 (45) 64 (53)  Provoked by 69 (55) 57 (47)   Surgery/trauma/ immobilization 32 (25) 31 (26)   Travel >4 h 22 (18) 14 (12)   Oestrogen use (% in women) 24 (41) 14 (38)   Pregnancy/puerperium (% in women) 0 (0) 2 (5)   Malignancy 2 (2) 8 (7)  Recurrent venous thrombosis 10 (8) 8 (7) Cardiovascular risk factors  Absent 37 (29) 26 (21)  Present 89 (71) 95 (79)   Current smoking 18 (14) 17 (14)   Hypertension 24 (19) 21 (17)   Diabetes 3 (2) 0 (0)   Overweight 54 (43) 51 (42)   Obesity 29 (23) 35 (29) Rosuvastatin Users (n = 126) Non-users (n = 121) General  Age (years) 57 (19–82) 59 (21–81)  Male 68 (54) 84 (69)  Body mass index (kg/m2) 27.4 (19.2–43.5) 27.7 (17.2–43.2)  Baseline cholesterol (mmol/L) 5.61 (2.95–8.99) 5.59 (3.33–7.89)  Use of antiplatelet drugs 5 (4) 5 (4) Venous thrombosis characteristics  Type of venous thrombosis   Deep vein thrombosis 72 (57) 65 (54)   Pulmonary embolism 54 (43) 56 (46)  Unprovoked 57 (45) 64 (53)  Provoked by 69 (55) 57 (47)   Surgery/trauma/ immobilization 32 (25) 31 (26)   Travel >4 h 22 (18) 14 (12)   Oestrogen use (% in women) 24 (41) 14 (38)   Pregnancy/puerperium (% in women) 0 (0) 2 (5)   Malignancy 2 (2) 8 (7)  Recurrent venous thrombosis 10 (8) 8 (7) Cardiovascular risk factors  Absent 37 (29) 26 (21)  Present 89 (71) 95 (79)   Current smoking 18 (14) 17 (14)   Hypertension 24 (19) 21 (17)   Diabetes 3 (2) 0 (0)   Overweight 54 (43) 51 (42)   Obesity 29 (23) 35 (29) Continuous variables denoted as mean (range) and categorical variables as n (%). Figure 1 View largeDownload slide Trial profile. Astersik indicates one participant admitted to hospital with a diagnosis of acute asthma exacerbation. Figure 1 View largeDownload slide Trial profile. Astersik indicates one participant admitted to hospital with a diagnosis of acute asthma exacerbation. Rosuvastatin treatment reduced mean cholesterol levels with 1.96 mmol/L (95% CI 1.83–2.09), while this was 0.19 (95% CI 0.10–0.27) in the participants who received no treatment. Outcomes For all tested coagulation factors, mean levels at end of study as compared with baseline hardly differed in non-statin users, whereas they had clearly decreased at end of study in rosuvastatin users (Figure 2 and see Supplementary material online, Table S1). In non-users, no change in FVIII:C was observed (mean difference −0.1; 95% CI −3.0 to 2.9) or in any of the other coagulation factors. In contrast, in rosuvastatin users, mean FVIII:C levels were 7.2 IU/dL (95% CI 2.9–11.5) lower at end of study as compared with baseline. In addition, mean FVII:C levels were 3.6 IU/dL (95% CI 0.2–7.1) lower, and mean factor XI:C levels were 5.9 IU/dL (95% CI 2.7–9.0) lower at end of study as compared with baseline. von Willebrand factor:Ag levels did not differ significantly in rosuvastatin users (mean difference −3.1 IU/dL; 95% CI −9.5 to 3.2) in the main analysis. However, after excluding 8 participants who reported an infection during follow-up, a reduction of vWF:Ag levels by rosuvastatin use was revealed. In these rosuvastatin users without infection, the mean difference of vWF:Ag level was −7.0 IU/dL (95% CI −10.8 to −3.2), while among non-users, no change in vWF:Ag was observed (see Supplementary material online, Figure S1). Figure 2 View largeDownload slide Effects of rosuvastatin on measures of coagulation. Figure 2 View largeDownload slide Effects of rosuvastatin on measures of coagulation. For the comparison between the two groups, the mean age- and sex-adjusted differences in rosuvastatin users vs. non-users revealed very similar results as the within person calculations, i.e. that the mean changes in coagulation factor levels were lower or tended to be lower at end of study in rosuvastatin users than in non-users. For Ln D-dimer we observed that these levels were 0.15 ng/mL (95% CI −0.32 to 0.01) higher at end of study in non-statin users, while the mean levels remained the same in rosuvastatin users (mean change 0.01 ng/mL; 95% CI −0.08 to 0.10). The adjusted mean difference for Ln D-dimer was therefore 0.13 ng/mL (95% CI −0.03 to 0.30) lower in rosuvastatin users than in non-users. Subgroup analyses revealed similar results as in the main analysis (Figure 3 for FVIII:C outcomes and see Supplementary material online, Table S2 for all measures of coagulation), with the exception of participants with unprovoked VT or with cardiovascular risk factors. In these participants the decrease in coagulation factors by rosuvastatin was more pronounced than in those with provoked VT or without cardiovascular risk factors, respectively. Figure 3 View largeDownload slide Effects of rosuvastatin on measures of factor VIII:C in prespecified subgroups. Figure 3 View largeDownload slide Effects of rosuvastatin on measures of factor VIII:C in prespecified subgroups. Take home figure View largeDownload slide Rosuvastatin improves the coagulation profile in patients with venous thrombosis. Take home figure View largeDownload slide Rosuvastatin improves the coagulation profile in patients with venous thrombosis. Discussion This randomized study showed that 1 month treatment with rosuvastatin 20 mg/day led to an improved coagulation profile as compared with non-statin users in patients with prior VT. Of all tested measures of coagulation, FVIII:C, on which the study was powered, showed the most robust results since rosuvastatin decreased FVIII:C not only within persons, but also between persons and in various subgroups. Other measures of coagulation also showed a shift to a less procoagulant state in participants treated with rosuvastatin, although not always on the level of statistical significance. The START trial is confirmatory in terms of the finding that statins can reduce coagulation factor levels,14–16,18 and the first randomized evidence that rosuvastatin reduces coagulation factor levels in patients with prior VT. Findings from START also support studies that previously showed that statin use is associated with a reduced risk of first and recurrent VT.12,27 Interestingly, the decrease in coagulation factors appeared strongest in participants with unprovoked VT and in those with cardiovascular risk factors. This could make sense from a pathophysiological perspective as previous studies showed that patients with unprovoked VT more often have endothelial dysfunction or atherosclerosis than patients with provoked VT or control individuals.28,29 Statins can modify endothelial function as early as after 28 days of treatment, while endothelial dysfunction/atherosclerosis is associated with a procoagulant state.30–33 This result from our subgroup analysis therefore suggests that statins may have the strongest potential to decrease VT risk by halting/decreasing atherosclerosis, leading to a less procoagulant state in individuals with atherosclerosis. This also follows results from the JUPITER trial where a notable benefit was observed in the high-risk subgroups of participants with elevated waist circumference and metabolic syndrome.12 Nevertheless, these subgroup analyses must be handled with caution as the study was not designed or powered to analyse differences in subgroups.34 Since vWF is the carrier protein for FVIII in the blood circulation,35 it was a surprise that these two proteins appeared not to correlate when we performed the main analysis. However, we observed two outliers for vWF:Ag, in which one participant (on rosuvastatin) had an increase of 300 IU/dL at end of study as compared with baseline, and another (also on rosuvastatin) had an increase of 103 IU/dL. Both reported an infection at end of study, which may have caused this strong increase in vWF:Ag,26 and which made us decide to exclude all participants who reported an infection during follow-up. Doing so revealed that changes in vWF:Ag levels now followed those for FVIII:C. In our study, FXI:C and FVII:C also decreased after treatment with rosuvastatin, which suggests that the anticoagulant activity of rosuvastatin is not only related to measures of coagulation that are affected by endothelial function, but also with liver function.19,20,36 For Ln D-dimer, we observed that these levels were 0.13 ng/mL (95% CI −0.03 to 0.30) lower in rosuvastatin users as compared with non-users. Interestingly, this difference was not driven by a lowering of D-dimer levels, but by the absence of an increase in D-dimer by rosuvastatin. This interesting finding could be explained due to a rebound phenomenon in which several markers of coagulation, including D-dimer levels, increase after anticoagulant treatment is withheld.37–39 Halting an increase in D-dimer by rosuvastatin may therefore be beneficial in patients with previous VT in which anticoagulation is withdrawn. Larger studies with longer follow-up (e.g. the Saver trial, registered at www.clinicaltrials.gov as NCT02679664) are however needed to confirm this hypothesis as CIs around the differences in D-dimer levels were wide and included unity. We showed an overall mean decrease in FVIII:C levels of 7–8 IU/dL in rosuvastatin users, and a 10–12 IU/dL decrease of FVIII:C in participants with unprovoked VT. This could be clinically relevant, as every 10 IU/dL decrease in FVIII:C levels is associated with a 15% (95% CI 7–22%) decrease in the risk of VT.22 In addition, the anticoagulant effect of rosuvastatin was not limited to FVIII:C, but was shown for several measures of coagulation that are associated with VT. This suggests that the reduction of VT in the JUPITER trial when using rosuvastatin,12 and the 25–50% lower risk of recurrent VT in observational studies,27,40–42 may be mediated by an improved coagulation profile due to statin use. One might suspect that anticoagulant properties of statins may be associated with increased bleeding risk. Indeed, in a post hoc analysis of a randomized trial in patients with cerebrovascular disease, the risk for intracranial haemorrhage was 1.66 fold (95% CI 1.08–2.55) increased for those receiving atorvastatin relative to no statin.43 However, no increase in the rate of haemorrhage in individuals receiving rosuvastatin was observed in the JUPITER trial,12 while a meta-analysis of clinical trials demonstrated no difference in the incidence of intracranial haemorrhage between individuals treated with statin and controls.44 These findings suggest that statins do not increase the risk of bleeding. Several aspects of this trial warrant comment. First, the open label design was chosen as it was considered unlikely that knowledge as to whether a participant received rosuvastatin or non-statin could affect the outcome (change in coagulation) 1 month later. Second, we noticed a difference in distribution of sex and age after randomization, for which we a priori decided to correct our analysis for these potential confounding factors. These adjustments did not influence our results. Third, in vitro studies have convincingly shown that statins are able to alter tissue factor levels.5,45 However, there are differences in anticoagulant effects of various statins, e.g. pravastatin does not enhance thrombomodulin expression.5 It is also known that the mechanism of statins varies between the types of statins that are currently on the market today, showing different reducing effects on low-density lipoprotein, atherosclerosis, and inflammation.32,46,47 Interestingly, a previous meta-analysis of trials showed that the reduced risk for VT is the least strong in pravastatin users, followed by simvastatin users and atorvastatin users and is strongest in rosuvastatin users.13 This was the reason why rosuvastatin 20 mg/day was the statin of choice in START. Fourth, coagulation factors VIII:C and vWF can be raised because of acute phase reactions, and are also elevated in chronic inflammatory states. However, since we compared participants with themselves, and only included participants in an outpatient setting, where they were free from disease at time of randomization and excluded, in a post hoc analysis, participants who developed an infection during the 1 month of follow-up, we expect that acute phase reactions did not disturb our final results. The reason why rosuvastatin is able to improve coagulation is beyond the scope of this study. It nevertheless may have to do with the fact that of all statins that are currently available on the market, rosuvastatin is most related with halting/regression of atherosclerosis, dyslipidaemia, and inflammation.32,46,47 Some studies suggest that dyslipidaemia, inflammation, or atherosclerosis, i.e. determinants for arterial cardiovascular disease, also increase the risk of VT.28,48,49 The prime mover may therefore be found in one or more of these exposure categories, for which additional studies are warranted. Large randomized trials are not started in a vacuum, but they require a high-prior probability of success, some insight in pathophysiological mechanisms, and need to be performed in specific groups who may benefit the most.4,32 Since the question as to whether a therapy is effective is answered by the number needed to treat (NNT), the secondary prevention of VT after an unprovoked event with statins, where reasonable NNTs may be plausible because of high recurrent VT event rates,2 could be feasible. It is in this aspect interesting to note that guidelines suggest to discontinue anticoagulant treatment in patients with VT who are considered to be at high risk of anticoagulation-related bleeding.3 Although statins are unlikely to be as effective as anticoagulant drugs, they do have the major advantage over anticoagulants that they are less likely to induce bleeding.44,32 Therefore, a drug to prevent recurrent VT in patients at risk of bleeding, in which the NNT for the prevention of recurrence is sufficiently high and the risk of drug induced bleeding is expected to be low, is a remedy that we should continue to look for.4,50 The results of the START trial support the conduction of such a rosuvastatin trial from a pathophysiological perspective. Supplementary material Supplementary material is available at European Heart Journal online. Funding This study was supported by a grant from the Netherlands Heart Foundation (NHS 2011T012). Conflict of interest: none declared. 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Haematologica 2007 ; 92 : 199 – 205 . Google Scholar CrossRef Search ADS PubMed 26 Reitsma PH , Branger J , Van Den Blink B , Weijer S , Van Der Poll T , Meijers JC. Procoagulant protein levels are differentially increased during human endotoxemia . J Thromb Haemost 2003 ; 1 : 1019 – 1023 . Google Scholar CrossRef Search ADS PubMed 27 Kunutsor SK , Seidu S , Khunti K. Statins and secondary prevention of venous thromboembolism: pooled analysis of published observational cohort studies . Eur Heart J 2017 ; 38 : 1608 – 1612 . Google Scholar CrossRef Search ADS PubMed 28 Prandoni P , Bilora F , Marchiori A , Bernardi E , Petrobelli F , Lensing AW , Prins MH , Girolami A. An association between atherosclerosis and venous thrombosis . N Engl J Med 2003 ; 348 : 1435 – 1441 . Google Scholar CrossRef Search ADS PubMed 29 Migliacci R , Becattini C , Pesavento R , Davi G , Vedovati MC , Guglielmini G , Falcinelli E , Ciabattoni G , Dalla Valle F , Prandoni P , Agnelli G , Gresele P. Endothelial dysfunction in patients with spontaneous venous thromboembolism . Haematologica 2007 ; 92 : 812 – 818 . Google Scholar CrossRef Search ADS PubMed 30 Tawakol A , Fayad ZA , Mogg R , Alon A , Klimas MT , Dansky H , Subramanian SS , Abdelbaky A , Rudd JH , Farkouh ME , Nunes IO , Beals CR , Shankar SS. Intensification of statin therapy results in a rapid reduction in atherosclerotic inflammation: results of a multicenter fluorodeoxyglucose-positron emission tomography/computed tomography feasibility study . J Am Coll Cardiol 2013 ; 62 : 909 – 917 . Google Scholar CrossRef Search ADS PubMed 31 Deanfield JE , Halcox JP , Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance . Circulation 2007 ; 115 : 1285 – 1295 . 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Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis . BMJ 2003 ; 326 : 1423 . Google Scholar CrossRef Search ADS PubMed 47 Ridker PM , Danielson E , Fonseca FA , Genest J , Gotto AM Jr , Kastelein JJ , Koenig W , Libby P , Lorenzatti AJ , Macfadyen JG , Nordestgaard BG , Shepherd J , Willerson JT , Glynn RJ ; JUPITER Trial Study Group . Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial . Lancet 2009 ; 373 : 1175 – 1182 . Google Scholar CrossRef Search ADS PubMed 48 Horvei LD , Grimnes G , Hindberg K , Mathiesen EB , Njølstad I , Wilsgaard T , Brox J , Braekkan SK , Hansen JB. C-reactive protein, obesity, and the risk of arterial and venous thrombosis . J Thromb Haemost 2016 ; 14 : 1561 – 1571 . Google Scholar CrossRef Search ADS PubMed 49 Doggen CJ , Smith NL , Lemaitre RN , Heckbert SR , Rosendaal FR , Psaty BM. Serum lipid levels and the risk of venous thrombosis . Arterioscler Thromb Vasc Biol 2004 ; 24 : 1970 – 1975 . Google Scholar CrossRef Search ADS PubMed 50 Kunutsor SK , Whitehouse MR , Blom AW , Laukkanen JA. Statins and venous thromboembolism: do they represent a viable therapeutic agent? Expert Rev Cardiovasc Ther 2017 ; 15 : 629 – 637 . Google Scholar CrossRef Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal Oxford University Press

Rosuvastatin use improves measures of coagulation in patients with venous thrombosis

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Oxford University Press
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.
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0195-668X
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1522-9645
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10.1093/eurheartj/ehy014
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Abstract

Abstract Aims Observational studies indicate that statins reduce the risk of recurrent venous thrombosis (VT). However, trials have not been performed and the mechanism is unknown. We aimed to determine whether statin therapy improves the coagulation profile in patients with prior VT. Methods and results Randomized clinical trial (NCT01613794). Patients were randomized to rosuvastatin 20 mg/day for 4 weeks or no intervention. Blood was drawn at baseline and at end of study. The primary outcome was factor (F) VIII:C. In total, five coagulation factors were measured: FVIII:C, von Willebrand factor:Ag, FVII:C, FXI:C, and D-dimer. Among 247 randomized participants, mean age was 58 years, 62% were women and 49% had unprovoked VT. For all tested coagulation factors, mean levels were clearly decreased at end of study in rosuvastatin users, whereas they hardly differed in non-statin users. Results were most consistent for FVIII:C where mean FVIII:C levels were 7.2 IU/dL [95% CI (confidence interval) 2.9–11.5] lower in rosuvastatin users, while among non-users, no change in FVIII:C was observed (mean difference −0.1; 95% CI −3.0 to 2.9). The mean age and sex adjusted difference in FVIII:C change was −6.7 IU/dL (95% CI −12.0 to −1.4) in rosuvastatin users vs. non-users. Subgroup analyses revealed that the decrease in coagulation factors by rosuvastatin was more pronounced in participants with unprovoked VT and in those with cardiovascular risk factors. Conclusion Rosuvastatin 20 mg/day substantially improved the coagulation profile among patients with prior VT. These results suggest that statin therapy might be beneficial in patients at risk of recurrent VT. View largeDownload slide View largeDownload slide Hydroxymethylglutaryl-CoA reductase inhibitors, Thrombophilia, Venous thrombosis, Randomized clinical trial Introduction Venous thrombosis (VT), the collective term for deep vein thrombosis of the leg, pulmonary embolism, or both, is the third most common vascular disease after myocardial infarction and ischaemic stroke.1 Venous thrombosis affects 1–2 per thousand people per year, has a 2.6% immediate death rate and recurrence rates of 25% within 5 years.2 Currently, the only effective strategy to prevent recurrent events is to continue anticoagulation indefinitely.3 In view of bleeding complications, safer options to reduce the risk of recurrent VT are necessary.4 For this statins may form a suitable candidate as statins do not induce bleeding but may reduce the risk of VT.4,5 In this aspect, results from observational studies that showed that statins are associated with a 30–50% lower risk of first VT seem promising, but often included prevalent statin users.6–8 Such prevalent users can introduce two types of bias: (i) under-ascertainment of events that occur early after starting treatment (survivor bias) and (ii) the inability to control for differences between those who do or do not adhere to statin treatment (adherence bias).9,10 For this matter, it is interesting to note that in a meta-analysis of statin use and risk of first VT,8 only one of the seven mentioned studies included statin initiators in their study (new-user design) and reported an odds ratio (OR) of 1.02 [95% confidence interval (CI) 0.88–1.18],7 which was in contrast to the overall OR of 0.62 (95% CI 0.45–0.86).8 This suggests that the observed association between statin use and a decreased risk of first VT may have been biased due to the inclusion of prevalent users. However, after this publication, other studies in which prevalent user bias was excluded by design have been published. In a cohort study of nearly 2 million individuals from the UK, in which a new-user design was used, the authors showed that rosuvastatin use was associated with a strongly (∼40%) reduced risk of VT.11 This result closely resembles the results from a randomized clinical trial in which apparently healthy individuals were randomized to rosuvastatin or placebo (JUPITER trial) in which a 40% risk reduction for rosuvastatin compared with placebo was found.12 In the absence of other randomized trials with VT as the primary endpoint, Rahimi et al.13 presented a pooled analysis of 29 randomized statin studies in which venous thrombotic events were reported as serious adverse events. Although they failed to confirm a risk reduction of VT by overall statin treatment, the authors found that individuals who were randomized to rosuvastatin still had an approximately 40% reduced risk of VT (hazard ratio 0.65; 95% CI 0.33–1.28).13 Based on a report that showed that statins can reduce factor VIII,14 one would suspect that statin use protects to some extent against VT by downsizing a procoagulant state. This finding should be interpreted with caution as it comes from a non-randomized study. Recently published findings from randomized clinical trials of statin therapy suggest some effect of lowering levels of von Willebrand factor (vWF) and D-dimer.15,16 However, funnel plot analyses revealed that these positive results might be due to publication bias.15,16 Furthermore, no randomized clinical trials have investigated the impact of statin therapy on the risk of recurrent VT. Not knowing a clear pathophysiological mechanism behind the supposed causal association between statin use and a reduced risk of recurrent VT, may explain the lack of conducting such a costly and endeavouring trial. Therefore, the aim of the STAtins Reduce Thrombophilia (START) trial was to investigate whether statin therapy improves the coagulation profile in patients with a history of VT. For this purpose, the effect of rosuvastatin use on several coagulation markers was assessed. Rosuvastatin 20 mg/day was chosen as the study drug as literature has consistently shown the strongest association between rosuvastatin and a reduced risk of VT.11–13 Methods Trial design STAtins Reduce Thrombophilia is a multicentre, randomized, controlled, open label, and clinical trial that investigates whether the coagulation profile in persons with a history of VT will improve when using rosuvastatin. We undertook the study in accordance with the Declaration of Helsinki and International Conference on Harmonization guidelines for Good Clinical Practice. All participants gave written informed consent prior to participation. STAtins Reduce Thrombophilia was approved by the Medical Ethics Committee of the Leiden University Medical Center, Leiden, the Netherlands, and is registered at www.clinicaltrials.gov as NCT01613794. Participants Participants were recruited at three anticoagulation clinics in the Netherlands (Leiden, Hoofddorp, and Rotterdam), which monitor anticoagulant treatment with vitamin K antagonists of patients with VT in well-defined geographic areas. Individuals aged 18 years or older with (initial or recurrent) confirmed symptomatic proximal deep vein thrombosis or pulmonary embolism who were allowed to stop oral anticoagulant treatment by their treating physician, were eligible for the study. Reasons for exclusion were: individuals already using statins or lipid lowering drugs, or any other contraindications for rosuvastatin 20 mg/day use as provided by the instruction leaflet of the manufacturer.17 Intervention Informed consent was obtained at the study baseline visit. The study baseline visit was defined at the time of the last regular visit of the patient to the anticoagulation clinic. After informed consent, participants were screened on acquired risk factors for thrombosis through a questionnaire and tested on liver and kidney function. At randomization, participants were allocated to receive either rosuvastatin 20 mg/day or no study medication. The duration of the study was 28 days, based on the consideration that some small, non-randomized studies showed beneficial effects of statins on the coagulation system as early as after a 3-day statin administration.18 Measurements Patients stopped using their vitamin K antagonist for 1 month (to allow a wear off of anticoagulant drugs) after which a blood sample was drawn at randomization visit and at the end of the study period (i.e. 28 days later). All blood drawings were performed between 08:00 am and 15:00 pm. Blood was collected in tubes containing sodium citrate (3.2%) and centrifuged within 3 h of venepuncture at 2500 g for 15 min at 18°C, after which plasma was immediately stored at −80°C. Laboratory technicians, who were unaware of which participants were rosuvastatin-users, performed the assays after all participants had completed the study. From these blood samples, levels of coagulation markers that are related to liver function [factor (F) VII:C and FXI:C], and endothelial function [FVIII:C and vWF:Ag],19,20 and one-global assay (D-dimer) were assessed. We decided to use this set of coagulation assays as these could globally indicate if and by which pathway rosuvastatin reduces thrombophilia. All laboratory measurements (FVII:C, FVIII:C, FXI:C, D-dimer, and vWF:Ag), were analysed on the ACL-Top 700 analyser (Instrumentation Laboratory). FVIII:C and FXI C levels were measured using modified activated partial thromboplastins time assays using immunodepleted plasmas. Similarly, FVII:C was determined using a modified prothrombin time. von Willebrand factor:Ag and D-dimer levels were measured using an automated latex enhanced immunoassay using the HemosIL vWF:Ag and the HemosIL D-dimer HS 500 reagent kit, respectively. Study size Because high FVIII:C levels are strongly associated with recurrent VT,21,22 the sample size was powered on FVIII:C. In a prior study from our group, we observed that patients with VT have a mean FVIII:C of 141 IU/dL (standard deviation 48).21 With a number of 2 × 125 = 250 participants, we would be able to find a mean (between participants) difference of 17 IU/dL FVIII:C with a two-sided alpha of 0.05 and 80% power. Compliance Adherence to the study protocol was assessed in two ways. First, participants who were randomized for rosuvastatin took the first tablet within the presence of an investigator. Second, compliance of rosuvastatin use was monitored by measuring total cholesterol levels at baseline and at end of study in all participants. Statistical analysis The general characteristics of the participants are reported as means and ranges. The mean levels with 95% CI of the coagulation factors were calculated at time of randomization and at the end of the study period. Coagulation factors were log-transformed if not normally distributed (this happened to be the case for D-dimer). All analyses were set to be done by intention to treat, which was set to a modified intention to treat in the final analyses since there were post randomization exclusions. Changes of coagulation factors were first expressed as the mean difference (with 95% CI) of coagulation factors at the end of study period in rosuvastatin users vs. non-rosuvastatin users. Since, we observed that more men were randomized to non-rosuvastatin use and that non-rosuvastatin users were slightly older than those who were randomized to rosuvastatin, we a priori decided to perform both unadjusted and age and sex adjusted analysis by means of linear regression methods to determine the between participant difference of various coagulation factors. Furthermore, we evaluated the change in coagulation factor levels at an individual level. Prespecified exploratory subgroup analyses included the following potential or established prognostic determinants of recurrent VT: male/female sex,23 unprovoked/provoked first event,24 deep vein thrombosis or pulmonary embolism,25 and presence or absence of self-reported arterial cardiovascular risk factors. One post hoc analysis was performed in which we excluded all participants who reported signs or symptoms of an infection during the study, as infections can influence coagulation factors.26 All analyses were performed with SPSS version 24.0 (IBM, Armonk, NY, USA). Results Study population The START trial was completed as planned; Figure 1 shows the trial profile. A total of 255 participants were randomized between December 2012 and December 2016, with 131 assigned to the rosuvastatin-therapy group, and 124 to the non-rosuvastatin group. As eight participants did not complete the study (five rosuvastatin users and three non-rosuvastatin users), follow-up was thus 97% complete. The reported reasons for not completing the study are noted in Figure 1. Table 1 presents baseline characteristics. Mean age was 57 years (range 19–82) in rosuvastatin users and 59 years (range 21–81) in non-rosuvastatin users; 68 (54%) of participants allocated to rosuvastatin were men, while this number was 84 (69%) in participants allocated to no treatment. Other reported exposures were balanced at baseline. Table 1 Baseline characteristics Rosuvastatin Users (n = 126) Non-users (n = 121) General  Age (years) 57 (19–82) 59 (21–81)  Male 68 (54) 84 (69)  Body mass index (kg/m2) 27.4 (19.2–43.5) 27.7 (17.2–43.2)  Baseline cholesterol (mmol/L) 5.61 (2.95–8.99) 5.59 (3.33–7.89)  Use of antiplatelet drugs 5 (4) 5 (4) Venous thrombosis characteristics  Type of venous thrombosis   Deep vein thrombosis 72 (57) 65 (54)   Pulmonary embolism 54 (43) 56 (46)  Unprovoked 57 (45) 64 (53)  Provoked by 69 (55) 57 (47)   Surgery/trauma/ immobilization 32 (25) 31 (26)   Travel >4 h 22 (18) 14 (12)   Oestrogen use (% in women) 24 (41) 14 (38)   Pregnancy/puerperium (% in women) 0 (0) 2 (5)   Malignancy 2 (2) 8 (7)  Recurrent venous thrombosis 10 (8) 8 (7) Cardiovascular risk factors  Absent 37 (29) 26 (21)  Present 89 (71) 95 (79)   Current smoking 18 (14) 17 (14)   Hypertension 24 (19) 21 (17)   Diabetes 3 (2) 0 (0)   Overweight 54 (43) 51 (42)   Obesity 29 (23) 35 (29) Rosuvastatin Users (n = 126) Non-users (n = 121) General  Age (years) 57 (19–82) 59 (21–81)  Male 68 (54) 84 (69)  Body mass index (kg/m2) 27.4 (19.2–43.5) 27.7 (17.2–43.2)  Baseline cholesterol (mmol/L) 5.61 (2.95–8.99) 5.59 (3.33–7.89)  Use of antiplatelet drugs 5 (4) 5 (4) Venous thrombosis characteristics  Type of venous thrombosis   Deep vein thrombosis 72 (57) 65 (54)   Pulmonary embolism 54 (43) 56 (46)  Unprovoked 57 (45) 64 (53)  Provoked by 69 (55) 57 (47)   Surgery/trauma/ immobilization 32 (25) 31 (26)   Travel >4 h 22 (18) 14 (12)   Oestrogen use (% in women) 24 (41) 14 (38)   Pregnancy/puerperium (% in women) 0 (0) 2 (5)   Malignancy 2 (2) 8 (7)  Recurrent venous thrombosis 10 (8) 8 (7) Cardiovascular risk factors  Absent 37 (29) 26 (21)  Present 89 (71) 95 (79)   Current smoking 18 (14) 17 (14)   Hypertension 24 (19) 21 (17)   Diabetes 3 (2) 0 (0)   Overweight 54 (43) 51 (42)   Obesity 29 (23) 35 (29) Continuous variables denoted as mean (range) and categorical variables as n (%). Table 1 Baseline characteristics Rosuvastatin Users (n = 126) Non-users (n = 121) General  Age (years) 57 (19–82) 59 (21–81)  Male 68 (54) 84 (69)  Body mass index (kg/m2) 27.4 (19.2–43.5) 27.7 (17.2–43.2)  Baseline cholesterol (mmol/L) 5.61 (2.95–8.99) 5.59 (3.33–7.89)  Use of antiplatelet drugs 5 (4) 5 (4) Venous thrombosis characteristics  Type of venous thrombosis   Deep vein thrombosis 72 (57) 65 (54)   Pulmonary embolism 54 (43) 56 (46)  Unprovoked 57 (45) 64 (53)  Provoked by 69 (55) 57 (47)   Surgery/trauma/ immobilization 32 (25) 31 (26)   Travel >4 h 22 (18) 14 (12)   Oestrogen use (% in women) 24 (41) 14 (38)   Pregnancy/puerperium (% in women) 0 (0) 2 (5)   Malignancy 2 (2) 8 (7)  Recurrent venous thrombosis 10 (8) 8 (7) Cardiovascular risk factors  Absent 37 (29) 26 (21)  Present 89 (71) 95 (79)   Current smoking 18 (14) 17 (14)   Hypertension 24 (19) 21 (17)   Diabetes 3 (2) 0 (0)   Overweight 54 (43) 51 (42)   Obesity 29 (23) 35 (29) Rosuvastatin Users (n = 126) Non-users (n = 121) General  Age (years) 57 (19–82) 59 (21–81)  Male 68 (54) 84 (69)  Body mass index (kg/m2) 27.4 (19.2–43.5) 27.7 (17.2–43.2)  Baseline cholesterol (mmol/L) 5.61 (2.95–8.99) 5.59 (3.33–7.89)  Use of antiplatelet drugs 5 (4) 5 (4) Venous thrombosis characteristics  Type of venous thrombosis   Deep vein thrombosis 72 (57) 65 (54)   Pulmonary embolism 54 (43) 56 (46)  Unprovoked 57 (45) 64 (53)  Provoked by 69 (55) 57 (47)   Surgery/trauma/ immobilization 32 (25) 31 (26)   Travel >4 h 22 (18) 14 (12)   Oestrogen use (% in women) 24 (41) 14 (38)   Pregnancy/puerperium (% in women) 0 (0) 2 (5)   Malignancy 2 (2) 8 (7)  Recurrent venous thrombosis 10 (8) 8 (7) Cardiovascular risk factors  Absent 37 (29) 26 (21)  Present 89 (71) 95 (79)   Current smoking 18 (14) 17 (14)   Hypertension 24 (19) 21 (17)   Diabetes 3 (2) 0 (0)   Overweight 54 (43) 51 (42)   Obesity 29 (23) 35 (29) Continuous variables denoted as mean (range) and categorical variables as n (%). Figure 1 View largeDownload slide Trial profile. Astersik indicates one participant admitted to hospital with a diagnosis of acute asthma exacerbation. Figure 1 View largeDownload slide Trial profile. Astersik indicates one participant admitted to hospital with a diagnosis of acute asthma exacerbation. Rosuvastatin treatment reduced mean cholesterol levels with 1.96 mmol/L (95% CI 1.83–2.09), while this was 0.19 (95% CI 0.10–0.27) in the participants who received no treatment. Outcomes For all tested coagulation factors, mean levels at end of study as compared with baseline hardly differed in non-statin users, whereas they had clearly decreased at end of study in rosuvastatin users (Figure 2 and see Supplementary material online, Table S1). In non-users, no change in FVIII:C was observed (mean difference −0.1; 95% CI −3.0 to 2.9) or in any of the other coagulation factors. In contrast, in rosuvastatin users, mean FVIII:C levels were 7.2 IU/dL (95% CI 2.9–11.5) lower at end of study as compared with baseline. In addition, mean FVII:C levels were 3.6 IU/dL (95% CI 0.2–7.1) lower, and mean factor XI:C levels were 5.9 IU/dL (95% CI 2.7–9.0) lower at end of study as compared with baseline. von Willebrand factor:Ag levels did not differ significantly in rosuvastatin users (mean difference −3.1 IU/dL; 95% CI −9.5 to 3.2) in the main analysis. However, after excluding 8 participants who reported an infection during follow-up, a reduction of vWF:Ag levels by rosuvastatin use was revealed. In these rosuvastatin users without infection, the mean difference of vWF:Ag level was −7.0 IU/dL (95% CI −10.8 to −3.2), while among non-users, no change in vWF:Ag was observed (see Supplementary material online, Figure S1). Figure 2 View largeDownload slide Effects of rosuvastatin on measures of coagulation. Figure 2 View largeDownload slide Effects of rosuvastatin on measures of coagulation. For the comparison between the two groups, the mean age- and sex-adjusted differences in rosuvastatin users vs. non-users revealed very similar results as the within person calculations, i.e. that the mean changes in coagulation factor levels were lower or tended to be lower at end of study in rosuvastatin users than in non-users. For Ln D-dimer we observed that these levels were 0.15 ng/mL (95% CI −0.32 to 0.01) higher at end of study in non-statin users, while the mean levels remained the same in rosuvastatin users (mean change 0.01 ng/mL; 95% CI −0.08 to 0.10). The adjusted mean difference for Ln D-dimer was therefore 0.13 ng/mL (95% CI −0.03 to 0.30) lower in rosuvastatin users than in non-users. Subgroup analyses revealed similar results as in the main analysis (Figure 3 for FVIII:C outcomes and see Supplementary material online, Table S2 for all measures of coagulation), with the exception of participants with unprovoked VT or with cardiovascular risk factors. In these participants the decrease in coagulation factors by rosuvastatin was more pronounced than in those with provoked VT or without cardiovascular risk factors, respectively. Figure 3 View largeDownload slide Effects of rosuvastatin on measures of factor VIII:C in prespecified subgroups. Figure 3 View largeDownload slide Effects of rosuvastatin on measures of factor VIII:C in prespecified subgroups. Take home figure View largeDownload slide Rosuvastatin improves the coagulation profile in patients with venous thrombosis. Take home figure View largeDownload slide Rosuvastatin improves the coagulation profile in patients with venous thrombosis. Discussion This randomized study showed that 1 month treatment with rosuvastatin 20 mg/day led to an improved coagulation profile as compared with non-statin users in patients with prior VT. Of all tested measures of coagulation, FVIII:C, on which the study was powered, showed the most robust results since rosuvastatin decreased FVIII:C not only within persons, but also between persons and in various subgroups. Other measures of coagulation also showed a shift to a less procoagulant state in participants treated with rosuvastatin, although not always on the level of statistical significance. The START trial is confirmatory in terms of the finding that statins can reduce coagulation factor levels,14–16,18 and the first randomized evidence that rosuvastatin reduces coagulation factor levels in patients with prior VT. Findings from START also support studies that previously showed that statin use is associated with a reduced risk of first and recurrent VT.12,27 Interestingly, the decrease in coagulation factors appeared strongest in participants with unprovoked VT and in those with cardiovascular risk factors. This could make sense from a pathophysiological perspective as previous studies showed that patients with unprovoked VT more often have endothelial dysfunction or atherosclerosis than patients with provoked VT or control individuals.28,29 Statins can modify endothelial function as early as after 28 days of treatment, while endothelial dysfunction/atherosclerosis is associated with a procoagulant state.30–33 This result from our subgroup analysis therefore suggests that statins may have the strongest potential to decrease VT risk by halting/decreasing atherosclerosis, leading to a less procoagulant state in individuals with atherosclerosis. This also follows results from the JUPITER trial where a notable benefit was observed in the high-risk subgroups of participants with elevated waist circumference and metabolic syndrome.12 Nevertheless, these subgroup analyses must be handled with caution as the study was not designed or powered to analyse differences in subgroups.34 Since vWF is the carrier protein for FVIII in the blood circulation,35 it was a surprise that these two proteins appeared not to correlate when we performed the main analysis. However, we observed two outliers for vWF:Ag, in which one participant (on rosuvastatin) had an increase of 300 IU/dL at end of study as compared with baseline, and another (also on rosuvastatin) had an increase of 103 IU/dL. Both reported an infection at end of study, which may have caused this strong increase in vWF:Ag,26 and which made us decide to exclude all participants who reported an infection during follow-up. Doing so revealed that changes in vWF:Ag levels now followed those for FVIII:C. In our study, FXI:C and FVII:C also decreased after treatment with rosuvastatin, which suggests that the anticoagulant activity of rosuvastatin is not only related to measures of coagulation that are affected by endothelial function, but also with liver function.19,20,36 For Ln D-dimer, we observed that these levels were 0.13 ng/mL (95% CI −0.03 to 0.30) lower in rosuvastatin users as compared with non-users. Interestingly, this difference was not driven by a lowering of D-dimer levels, but by the absence of an increase in D-dimer by rosuvastatin. This interesting finding could be explained due to a rebound phenomenon in which several markers of coagulation, including D-dimer levels, increase after anticoagulant treatment is withheld.37–39 Halting an increase in D-dimer by rosuvastatin may therefore be beneficial in patients with previous VT in which anticoagulation is withdrawn. Larger studies with longer follow-up (e.g. the Saver trial, registered at www.clinicaltrials.gov as NCT02679664) are however needed to confirm this hypothesis as CIs around the differences in D-dimer levels were wide and included unity. We showed an overall mean decrease in FVIII:C levels of 7–8 IU/dL in rosuvastatin users, and a 10–12 IU/dL decrease of FVIII:C in participants with unprovoked VT. This could be clinically relevant, as every 10 IU/dL decrease in FVIII:C levels is associated with a 15% (95% CI 7–22%) decrease in the risk of VT.22 In addition, the anticoagulant effect of rosuvastatin was not limited to FVIII:C, but was shown for several measures of coagulation that are associated with VT. This suggests that the reduction of VT in the JUPITER trial when using rosuvastatin,12 and the 25–50% lower risk of recurrent VT in observational studies,27,40–42 may be mediated by an improved coagulation profile due to statin use. One might suspect that anticoagulant properties of statins may be associated with increased bleeding risk. Indeed, in a post hoc analysis of a randomized trial in patients with cerebrovascular disease, the risk for intracranial haemorrhage was 1.66 fold (95% CI 1.08–2.55) increased for those receiving atorvastatin relative to no statin.43 However, no increase in the rate of haemorrhage in individuals receiving rosuvastatin was observed in the JUPITER trial,12 while a meta-analysis of clinical trials demonstrated no difference in the incidence of intracranial haemorrhage between individuals treated with statin and controls.44 These findings suggest that statins do not increase the risk of bleeding. Several aspects of this trial warrant comment. First, the open label design was chosen as it was considered unlikely that knowledge as to whether a participant received rosuvastatin or non-statin could affect the outcome (change in coagulation) 1 month later. Second, we noticed a difference in distribution of sex and age after randomization, for which we a priori decided to correct our analysis for these potential confounding factors. These adjustments did not influence our results. Third, in vitro studies have convincingly shown that statins are able to alter tissue factor levels.5,45 However, there are differences in anticoagulant effects of various statins, e.g. pravastatin does not enhance thrombomodulin expression.5 It is also known that the mechanism of statins varies between the types of statins that are currently on the market today, showing different reducing effects on low-density lipoprotein, atherosclerosis, and inflammation.32,46,47 Interestingly, a previous meta-analysis of trials showed that the reduced risk for VT is the least strong in pravastatin users, followed by simvastatin users and atorvastatin users and is strongest in rosuvastatin users.13 This was the reason why rosuvastatin 20 mg/day was the statin of choice in START. Fourth, coagulation factors VIII:C and vWF can be raised because of acute phase reactions, and are also elevated in chronic inflammatory states. However, since we compared participants with themselves, and only included participants in an outpatient setting, where they were free from disease at time of randomization and excluded, in a post hoc analysis, participants who developed an infection during the 1 month of follow-up, we expect that acute phase reactions did not disturb our final results. The reason why rosuvastatin is able to improve coagulation is beyond the scope of this study. It nevertheless may have to do with the fact that of all statins that are currently available on the market, rosuvastatin is most related with halting/regression of atherosclerosis, dyslipidaemia, and inflammation.32,46,47 Some studies suggest that dyslipidaemia, inflammation, or atherosclerosis, i.e. determinants for arterial cardiovascular disease, also increase the risk of VT.28,48,49 The prime mover may therefore be found in one or more of these exposure categories, for which additional studies are warranted. Large randomized trials are not started in a vacuum, but they require a high-prior probability of success, some insight in pathophysiological mechanisms, and need to be performed in specific groups who may benefit the most.4,32 Since the question as to whether a therapy is effective is answered by the number needed to treat (NNT), the secondary prevention of VT after an unprovoked event with statins, where reasonable NNTs may be plausible because of high recurrent VT event rates,2 could be feasible. It is in this aspect interesting to note that guidelines suggest to discontinue anticoagulant treatment in patients with VT who are considered to be at high risk of anticoagulation-related bleeding.3 Although statins are unlikely to be as effective as anticoagulant drugs, they do have the major advantage over anticoagulants that they are less likely to induce bleeding.44,32 Therefore, a drug to prevent recurrent VT in patients at risk of bleeding, in which the NNT for the prevention of recurrence is sufficiently high and the risk of drug induced bleeding is expected to be low, is a remedy that we should continue to look for.4,50 The results of the START trial support the conduction of such a rosuvastatin trial from a pathophysiological perspective. Supplementary material Supplementary material is available at European Heart Journal online. Funding This study was supported by a grant from the Netherlands Heart Foundation (NHS 2011T012). Conflict of interest: none declared. 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Journal

European Heart JournalOxford University Press

Published: Jan 30, 2018

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