Luận văn Thạc sĩ Statin Therapy Associated With Improved Thrombus Resolution In Patients With Deep Vein Thrombosis

Yale University EliScholar – A Digital Platform for Scholarly Publishing at Yale Yale Medicine Thesis Digital Library School of Medicine January 2020 Statin Therapy Associated With Improved Thrombus Resolution In Patients With Deep Vein Thrombosis Charles Hsu Follow this and additional works at: https://elischolar.library.yale.edu/ymtdl Recommended Citation Hsu, Charles, "Statin Therapy Associated With Improved Thrombus Resolution In Patients With Deep Vein Thrombosis" (2020) Yale Medicine Thesis Digital Library 3911 https://elischolar.library.yale.edu/ymtdl/3911 This Open Access Thesis is brought to you for free and open access by the School of Medicine at EliScholar – A Digital Platform for Scholarly Publishing at Yale It has been accepted for inclusion in Yale Medicine Thesis Digital Library by an authorized administrator of EliScholar – A Digital Platform for Scholarly Publishing at Yale For more information, please contact elischolar@yale.edu Statin Therapy Associated with Improved Thrombus Resolution in Patients with Deep Vein Thrombosis A Thesis Submitted to the Yale University School of Medicine in Partial Fulfillment of the Requirements for the Degree of Doctor in Medicine By Charles Hsu 2020 Abstract Objectives: Statin therapy has been associated with a decreased incidence of venous thromboembolism (VTE) in clinical trials and enhanced thrombus resolution in animal models The effect of statins on thrombus resolution has not been reported clinically This study investigates the association of statins with thrombus resolution or improvement in patients with deep vein thrombosis (DVT) Methods: A retrospective study of the electronic medical records of consecutive adult patients presenting with lower extremity DVT was performed Patients were divided into two groups based on statin therapy (statin group) or lack thereof (non-statin group) The two groups were compared with respect to demographics, comorbidities, and risk factors for VTE Initial as well as all subsequent ultrasound reports were reviewed for each patient to determine extent of DVT and subsequent change in thrombus characteristics Long-term outcomes examined were thrombus improvement or resolution on follow up ultrasound, VTE recurrence, mortality Multivariable analysis was used to determine independent predictors of thrombus resolution or improvement, VTE recurrence, and mortality Results: A total of 818 patients with DVT were identified [statin group: n = 279 (34%), non-statin group: n = 539 (66%)] The patients in the statin group were significantly older (P < 001) Patients on statin were more likely to have risk factors for and manifestations of atherosclerosis and to be on antiplatelet therapy (P < 001) while those in the non-statin group were more likely to have a hypercoagulable disorder (P = 009) or prior DVT (P = 033) There was no significant difference in provoked DVT, extent of DVT, or association with PE (pulmonary embolus), but patients on statin were more likely to have high-risk PE (P = 046) There was no difference in patients receiving anticoagulation, type and duration of anticoagulation, inferior vena cava filter placement, or treatment with lytic therapy There was no difference in thrombus resolution, mortality, or recurrence of DVT, PE, or VTE between the groups On multivariable analysis, age, proximal DVT, CAD, and cancer were associated with higher mortality while anticoagulation with warfarin and DOACs and antiplatelet therapy were associated with lower mortality Statin therapy, antiplatelet therapy and younger age were associated with thrombus resolution or improvement Conclusions: Statin therapy is associated with greater thrombus resolution or improvement in patients with DVT However, statin therapy in this study was not associated with different clinical outcomes of VTE recurrence or mortality Acknowledgements: This work was performed under the guidance of Cassius Iyad Ochoa Chaar, MD, MS, Associate Professor of Surgery, the Division of Vascular Surgery, Department of Surgery, Yale University School of Medicine Other contributors to this work include Anand Brahmandam, MD, Kirstyn E Brownson, MD, Nancy Huynh, MD, Jesse Reynolds, MS, Alfred I Lee, MD, PhD, and Wassim H Fares, MD, MSc Contributions are described in detail in the Methods section This work was made possible by the grant from the National Heart, Lung and Blood Institute of the National Institutes of Health The content is solely the responsibility of the author and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health under award Number T35HL007649 Table of Contents Introduction Page Aim 12 Methods 13 Results 18 Discussion 22 Conclusion 31 References 32 Tables 39 Introduction: Venous thromboembolism (VTE) is a common condition affecting hundreds of thousands of patients every year, including those with deep vein thrombosis (DVT) and pulmonary embolism (PE), a potentially life-threatening condition.1 Patients with VTE are often managed using anticoagulation agents, the medications of choice for the prevention and treatment of VTE, however there remains an unmet need for those who cannot tolerate their side effects or may be inadequately treated Studies suggest that statins, also known as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors and most commonly known for their cholesterol-lowering effects, may also play a role in reducing the risk of initial or recurrent DVT.2,3 In addition, population studies of VTE patients on statins have shown that longer duration of statin use is also associated with greater reduction of recurrent VTE.4 The precise mechanisms of this observed antithrombotic effect have been explored in a variety of preclinical experiments In animals, atorvastatin and rosuvastatin have been shown to reduce venous thrombus burden and DVT-induced vein wall scarring, while simvastatin has been found to promote thrombus resolution in a leporine posterior vena cava thrombus model.5,6 Clinically, residual vein thrombosis has been shown to be a risk factor for VTE recurrence.7 Thus, it is plausible that the effects of statins on VTE recurrence are potentially mediated by enhancing thrombus resolution However, the effect of statins on thrombus remodeling has not been studied clinically The following sections review both the nonclinical and clinical literature supporting the above concepts to establish the context and rationale for the work performed in this thesis Anti-thrombotic effects of statins on the coagulation cascade Statins are most commonly known for their efficacy in the management of hyperlipidemia and its associated sequelae (i.e coronary artery disease), and have also shown to significantly reduce the risk of major cardiovascular events.8 However, statins have also been shown to provide cardiovascular benefit via a number of “pleiotropic” effects independent from cholesterol lowering, notably including anti-thrombotic properties at multiple levels of the coagulation cascade The lipophilic statins simvastatin and fluvastatin (but not the hydrophilic pravastatin) decrease tissue factor (TF) expression in macrophages via nuclear factor κB (NF-κB) inhibition in vitro, an effect which was not reversed by the addition of cholesterol, suggesting that statin’s effect on TF occurs independently of intracellular cholesterol lowering Instead, a different downstream product, geranylgeranyl pyrophosphate (GGPP) is thought to play a crucial role in the regulation of TF expression 10 As TF expression has been shown to be upregulated in lipid-laden macrophages at the core of atherosclerotic plaques and is thought to promote intravascular thrombosis, the down-regulating effect of statins on TF would explain another cholesterol-independent aspect of statins’ cardioprotective properties.11 Indeed, a study in humans found that carotid artery plaques removed from patients treated with atorvastatin for 4-6 months had significantly lower TF antigen levels and activity as compared with those on placebo.12 Further downstream in the coagulation cascade is thrombin, the key to activating thrombus formation and the common target of several marketed anticoagulant therapies Statins, particularly atorvastatin, simvastatin, and pravastatin, have been shown in both experimental and clinical studies to decrease thrombin formation, however measurements of thrombin markers such as prothrombin fragments 1.2 (F1.2) and thrombinantithrombin complex (TAT) have yielded less consistent findings, ranging between mild to neutral effects This effect is particularly notable in patients with hypercholesterolemia, where even 3-days of simvastatin (40mg/d) treatment in fourteen men with LDL cholesterol levels >130 mg/dL on low-dose aspirin (75mg/d) resulted in a significantly reduced level of prothrombin activation at sites of microvascular injury, accompanied by delayed Factor Va generation and accelerated activated Protein Cmediated Factor Va inactivation, on top of the anticoagulant effects of aspirin alone 13-15 To a lesser degree of scientific concordance, statins have also been found to exert antithrombotic effects on the coagulation cascade via decreased fibrinogen cleavage, decreased Factor XIII activation, increased thrombomodulin expression, and increased Factor Va inactivation.16-18 Other pleiotropic effects of statins include improved endothelial function via increased nitric oxide bioavailability, inflammation suppression, atherosclerotic plaque stabilization, immune-modulation, inhibition of cardiac hypertrophy, and reduced smooth muscle cell proliferation 16 These mechanisms, in concert with each other, are likely to underpin the anti-thrombotic and vascular protective effects observed in animal and clinical studies Statins and the risk of venous thromboembolism The clinical relevance of the antithrombotic effects of statins has been investigated by many studies In 2000, the Heart and Estrogen/Progesterone Replacement Study (HERS) found in a secondary analysis of the impact of hormonal therapy on the risk of VTE that use of statins (but not any other lipid-lowering drug) in a postmenopausal population was associated with a decreased risk of VTE (relative hazard 0.5 [0.2 – 0.9]).19 In 2001, Ray et al showed through a large Canadian retrospective cohort study that any dose of statin use in individuals greater than 65 years old was associated with a 22% lowered incidence of venous thromboembolisms.20 This association has been supported by a number of case-control, cohort, or observational studies, including studies finding statin-associated VTE risk reduction in patients with underlying hypercoagulable states such as cancer and nephrotic syndrome.21-23 One study by Ramcharan et al found that different statin types and treatment durations were all associated with a decreased risk of VTE (OR 0.45 [0.36 – 0.56]).23 However, not all studies have found a positive association between statins and reduced VTE risk, including a population-based retrospective follow-up nested casecontrol analysis of the United Kingdom’s General Practice Research Database and a prospective open cohort study in England and Wales.24,25 Considering the divergent findings in these various retrospective studies, perhaps the single most important trial is then the randomized, double-blinded, placebo-controlled Justification for the Use of statins in Prevention: an Interventional Trial Evaluating Rosuvastatin (JUPITER) study published in 2009 In the JUPITER study, the trialists found that 20 mg/d of rosuvastatin reduced the risk of VTE in asymptomatic patients (men over 50 years old and women over 60 years old) with no evidence of cardiovascular disease, LDL-cholesterol 2 mg/L (at first visit) over the course of 1.9-years of follow-up The study found significant reductions in DVT or PE (34 events in the treatment arm vs 60 events in the placebo arm, HR 0.57 [0.37–0.86]), with the largest reduction in isolated 35 24 Yang CC, Jick SS, Jick H Statins and the risk of idiopathic venous thromboembolism Br J Clin Pharmacol 2002;53:101-5 25 Hippisley-Cox J, Coupland C Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database BMJ 2010;340:c2197 26 Tan M, Mos IC, Klok FA, Huisman MV Residual venous thrombosis as predictive factor for recurrent venous thromboembolim in patients with proximal deep vein thrombosis: a sytematic review Br J Haematol 2011;153:168-78 27 G LEG, Carrier M, Kovacs MJ, et al Residual vein obstruction as a predictor for recurrent thromboembolic events after a first unprovoked episode: data from the REVERSE cohort study J Thromb Haemost 2011;9:1126-32 28 Henke PK, Comerota AJ An update on etiology, prevention, and therapy of postthrombotic syndrome J Vasc Surg 2011;53:500-9 29 Kahn SR The post thrombotic syndrome Thromb Res 2011;127 Suppl 3:S89-92 30 Ochoa Chaar CI, Aurshina A Endovascular and Open Surgery for Deep Vein Thrombosis Clin Chest Med 2018;39:631-44 31 Haig Y, Enden T, Grotta O, et al Post-thrombotic syndrome after catheter- directed thrombolysis for deep vein thrombosis (CaVenT): 5-year follow-up results of an open-label, randomised controlled trial Lancet Haematol 2016;3:e64-71 32 D'Aloia A, Vizzardi E, Caretta G, et al An echo-guided case report of rapid regression of unstable mobile thrombus aortic atheroma after aggressive statin and antiplatelet combination therapy Am J Ther 2014;21:e61-5 36 33 Caprini JA Identification of patient venous thromboembolism risk across the continuum of care Clin Appl Thromb Hemost 2011;17:590-9 34 Brownson KE, Brahmandam A, Huynh N, et al Characteristics of provoked deep venous thrombosis in a tertiary care center J Vasc Surg Venous Lymphat Disord 2017;5:477-84 35 Jaff MR, McMurtry MS, Archer SL, et al Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association Circulation 2011;123:1788-830 36 Jain MK, Ridker PM Anti-inflammatory effects of statins: clinical evidence and basic mechanisms Nat Rev Drug Discov 2005;4:977-87 37 Brækkan SK, Caram-Deelder C, Siegerink B, et al Statin use and risk of recurrent venous thrombosis: results from the MEGA follow-up study Research and Practice in Thrombosis and Haemostasis 2017;1:112-9 38 Kunutsor SK, Seidu S, Khunti K Statins and secondary prevention of venous thromboembolism: pooled analysis of published observational cohort studies Eur Heart J 2017;38:1608-12 39 Smith NL, Harrington LB, Blondon M, et al The association of statin therapy with the risk of recurrent venous thrombosis J Thromb Haemost 2016;14:1384-92 40 El-Refai SM, Black EP, Adams VR, Talbert JC, Brown JD Statin use and venous thromboembolism in cancer: A large, active comparator, propensity score matched 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deep vein thrombosis in 11 086 patients J Thromb Haemost 2009;7:2028-34 52 Martin F, Leroyer C, Oger E, et al [Pulmonary embolism and the level of thrombosis A prospective study of 155 patients] Rev Mal Respir 1995;12:465-9 53 Baer HJ, Glynn RJ, Hu FB, et al Risk factors for mortality in the nurses' health study: a competing risks analysis Am J Epidemiol 2011;173:319-29 54 Gillespie CD, Wigington C, Hong Y, Centers for Disease C, Prevention Coronary heart disease and stroke deaths - United States, 2009 MMWR Suppl 2013;62:157-60 55 Ferlay J, Soerjomataram I, Dikshit R, et al Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012 Int J Cancer 2015;136:E359-86 56 Brownson K, Satoskar S, Reynolds J, et al Thrombus Resolution as Guide to Anticoagulation Therapy for Provoked Deep Vein Thrombosis: TRUDVT Pilot Study Journal of Vascular Surgery: Venous and Lymphatic Disorders 2016;4:149 57 Undas A, Stepien E, Potaczek DP, Tracz W Tissue factor +5466A>G polymorphism determines thrombin formation following vascular injury and thrombinlowering effects of simvastatin in patients with ischemic heart disease Atherosclerosis 2009;204:567-72 39 Table 1: Patient characteristics Age (years ± SD) Female Hypertension Diabetes Hyperlipidemia CHF CAD PAD CVD Hypercoagulable disorder History of prior DVT History of prior PE History of cancer History of smoking Antiplatelet therapy Caprini score ± SD Statin group (n = 279) % (n) 72 ± 13 51 (140) 82 (229) 38 (105) 73 (205) 17 (48) 35 (98) (25) 20 (57) (7) 14 (40) (21) 41 (113) 56 (156) 55 (154) 6.7 ± 2.9 Non-statin group (n = 539) % (n) 63 ± 17 52 (278) 50 (268) 17 (92) 14 (76) 10 (55) (51) (11) (38) (37) 20 (110) 11 (60) 44 (235) 56 (301) 20 (107) 6.3 ± 2.8 P value