Advertisement

Protective role of statins during anticoagulation for venous thromboembolism: beyond their lipid lowering effect?

      Venous thromboembolism (VTE) is a leading cause of morbidity and mortality [
      • Smith SB
      • Geske JB
      • Maguire JM
      • Zane NA
      • Carter RE
      • Morgenthaler TI
      Early anticoagulation is associated with reduced mortality for acute pulmonary embolism.
      ]. VTE represents a major health problem for high prevalence, incidence, and costs [
      • Beckman MG
      • Hooper WC
      • Critchley SE
      • Ortel TL
      Venous thromboembolism: a public health concern.
      ]. The number of people affected by VTE is unknown, although as many as 900,000 people could be affected (1 to 2 per 1,000) each year in the United States [
      • Beckman MG
      • Hooper WC
      • Critchley SE
      • Ortel TL
      Venous thromboembolism: a public health concern.
      ]. Estimates suggest that 10 to 30% of people will die within one month of diagnosis and that sudden death is the first symptom in about one-quarter (25%) of those who have a PE. Vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) are highly effective for the acute and long-term treatment of VTE and VTE recurrences,[
      • Agnelli G
      • Buller HR
      • Cohen A
      • Curto M
      • Gallus AS
      • Johnson M
      • Porcari A
      • Raskob GE
      • Weitz JI
      AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism.
      ,
      • Schulman S
      • Kearon C
      • Kakkar AK
      • Schellong S
      • Eriksson H
      • Baanstra D
      • Kvamme AM
      • Friedman J
      • Mismetti P
      • Goldhaber SZ
      RE-MEDY Trial Investigators; RE-SONATE Trial Investigators
      Extended use of dabigatran, warfarin, or placebo in venous thromboembolism.
      but are burdened by a two- to threefold increased risk of causing a clinically significant bleeding episode compared with placebo [
      • Agnelli G
      • Buller HR
      • Cohen A
      • Curto M
      • Gallus AS
      • Johnson M
      • Porcari A
      • Raskob GE
      • Weitz JI
      AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism.
      ,
      • Schulman S
      • Kearon C
      • Kakkar AK
      • Schellong S
      • Eriksson H
      • Baanstra D
      • Kvamme AM
      • Friedman J
      • Mismetti P
      • Goldhaber SZ
      RE-MEDY Trial Investigators; RE-SONATE Trial Investigators
      Extended use of dabigatran, warfarin, or placebo in venous thromboembolism.
      ]. On the other hand, if anticoagulation therapy is discontinued, the risk of VTE recurrence is up to 10% per year in patients with unprovoked VTE,[
      • Becattini C
      • Agnelli G
      • Schenone A
      • Eichinger S
      • Bucherini E
      • Silingardi M
      • Bianchi M
      • Moia M
      • Ageno W
      • Vandelli MR
      • Grandone E
      • Prandoni P
      WARFASA Investigators
      Aspirin for preventing the recurrence of venous thromboembolism.
      ] while the recurrence rate of VTE during anticoagulation is 3% in the first 3 to 6 months [
      • Bauersachs R
      • Berkowitz SD
      • Brenner B
      • Buller HR
      • Decousus H
      • Gallus AS
      • Lensing AW
      • Misselwitz F
      • Prins MH
      • Raskob GE
      • Segers A
      • Verhamme P
      • Wells P
      • Agnelli G
      • Bounameaux H
      • Cohen A Davidson BL
      • Piovella F
      • Schellong S
      EINSTEIN Investigators
      Oral rivaroxaban for symptomatic venous thromboembolism.
      ,
      • Schulman S
      • Kearon C
      • Kakkar AK
      • Mismetti P
      • Schellong S
      • Eriksson H
      • Baanstra D
      • Schnee J
      • Goldhaber SZ
      RE-COVER Study Group
      Dabigatran versus warfarin in the treatment of acute venous thromboembolism.
      ]. Therefore, it is important to warrant medications capable of decreasing the risk of VTE recurrences without increasing the risk of major bleeding and mortality. Currently, the role of statins during anticoagulation for VTE is a matter of debate. Preliminary data are available on primary and secondary prevention as well as on bleeding and mortality rates in statins users during anticoagulation for VTE [
      • Undas A
      • Brummel-Ziedins KE
      • Mann KG
      Anticoagulant effects of statins and their clinical implications.
      ].
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Internal Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Smith SB
        • Geske JB
        • Maguire JM
        • Zane NA
        • Carter RE
        • Morgenthaler TI
        Early anticoagulation is associated with reduced mortality for acute pulmonary embolism.
        Chest. 2010; 137: 1382-1390
        • Beckman MG
        • Hooper WC
        • Critchley SE
        • Ortel TL
        Venous thromboembolism: a public health concern.
        Am J Prev Med. 2010; 38: S495-S501https://doi.org/10.1016/j
        • Agnelli G
        • Buller HR
        • Cohen A
        • Curto M
        • Gallus AS
        • Johnson M
        • Porcari A
        • Raskob GE
        • Weitz JI
        AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism.
        N Engl J Med. 2013; 368: 699-708
        • Schulman S
        • Kearon C
        • Kakkar AK
        • Schellong S
        • Eriksson H
        • Baanstra D
        • Kvamme AM
        • Friedman J
        • Mismetti P
        • Goldhaber SZ
        • RE-MEDY Trial Investigators; RE-SONATE Trial Investigators
        Extended use of dabigatran, warfarin, or placebo in venous thromboembolism.
        N Engl J Med. 2013; 368: 709-718
        • Becattini C
        • Agnelli G
        • Schenone A
        • Eichinger S
        • Bucherini E
        • Silingardi M
        • Bianchi M
        • Moia M
        • Ageno W
        • Vandelli MR
        • Grandone E
        • Prandoni P
        • WARFASA Investigators
        Aspirin for preventing the recurrence of venous thromboembolism.
        N Engl J Med. 2012; 366: 1959-1967
        • Bauersachs R
        • Berkowitz SD
        • Brenner B
        • Buller HR
        • Decousus H
        • Gallus AS
        • Lensing AW
        • Misselwitz F
        • Prins MH
        • Raskob GE
        • Segers A
        • Verhamme P
        • Wells P
        • Agnelli G
        • Bounameaux H
        • Cohen A Davidson BL
        • Piovella F
        • Schellong S
        • EINSTEIN Investigators
        Oral rivaroxaban for symptomatic venous thromboembolism.
        N Engl J Med. 2010; 363: 2499-2510
        • Schulman S
        • Kearon C
        • Kakkar AK
        • Mismetti P
        • Schellong S
        • Eriksson H
        • Baanstra D
        • Schnee J
        • Goldhaber SZ
        • RE-COVER Study Group
        Dabigatran versus warfarin in the treatment of acute venous thromboembolism.
        N Engl J Med. 2009; 361: 2342-2352
        • Undas A
        • Brummel-Ziedins KE
        • Mann KG
        Anticoagulant effects of statins and their clinical implications.
        Thromb Haemost. 2014; 111: 392-400
        • Glynn RJ
        • Danielson E
        • Fonseca FAH
        • Genest J
        • Gotto AM
        • Kastelein JJP
        • Koenig W
        • Libby P
        • Lorenzatti AJ
        • MacFadyen JG
        • Nordestgaard BG
        • Shepherd J
        • Willerson JT
        • Ridker PM
        A randomized trial of rosuvastatin in the prevention of venous thromboembolism.
        N Engl J Med. 2009; 360: 1851-1861
        • Squizzato A
        • Galli M
        • Romualdi E
        • Dentali F
        • Kamphuisen PW
        • Guasti L
        • Venco A
        • Ageno W
        Statins, fibrates, and venous thromboembolism: a meta-analysis.
        Eur Heart J. 2010; 31: 1248-1256
        • Pai M
        • Evans NS
        • Shah SJ
        • Green D
        • Cook D
        • Crowther MA
        Statins in the prevention of venous thromboembolism: a meta-analysis of observational studies.
        Thromb Res. 2011; 128: 422-430
        • Nguyen CD
        • Andersson C
        • Jensen TB
        • Gjesing A
        • Schjerning Olsen AM
        • Malta Hansen C
        • Büller H
        • Torp-Pedersen C
        • Gislason GH
        Statin treatment and risk of recurrent venous thromboembolism: a nationwide cohort study.
        BMJ Open. 2013; 7e003135
        • Biere-Rafi S
        • Hutten BA
        • Squizzato A
        • Ageno W
        • Souverein PC
        • de Boer A
        • Gerdes VE
        • Büller HR
        • Kamphuisen PW
        Statin treatment and the risk of recurrent pulmonary embolism.
        Eur Heart J. 2013; 34: 1800-1806
        • Wells PS
        • Gebel M
        • Prins MH
        • Davidson BL
        • Lensing AW
        Influence of statin use on the incidence of recurrent venous thromboembolism and major bleeding in patients receiving rivaroxaban or standard anticoagulant therapy.
        Thromb J. 2014; 26: 12-26
        • Schmidt M
        • Cannegieter SC
        • Johannesdottir SA
        • Dekkers OM
        • Horváth-Puhó E
        • Sørensen HT
        Statin use and venous thromboembolism recurrence: a combined nationwide cohort and nested case-control study.
        J Thromb Haemost. 2014; 12: 1207-1215
        • Tagalakis V
        • Eberg M
        • Kahn S
        • Azoulay L
        Use of statins and reduced risk of recurrence of VTE in an older population. A population-based cohort study.
        Thromb Haemost. 2016; 115: 1220-1228
        • Delluc A
        • Tromeur C
        • Le Moigne E
        • Nowak E
        • Mottier D
        • Le Gal G
        • Lacut K
        Lipid lowering drugs and the risk of recurrent venous thromboembolism.
        Thromb Res. 2012; 130: 859-863
        • Siniscalchi C
        • Quintavalla R
        • Rocci A
        • Riera-Mestre A
        • Trujillo-Santos J
        • Suriñach JM
        • Jara-Palomares L
        • Bikdeli B
        • Moustafa F
        • Monreal M
        • RIETE Investigators
        Statin and all-cause mortality in patients receiving anticoagulant therapy for venous thromboembolism. Data from the RIETE registry.
        Eur J Intern Med. 2019; 68: 30-35
        • Antoniou T
        • Macdonald EM
        • Yao Z
        • Hollands S
        • Gomes T
        • Tadrous M
        • Mamdani MM
        • Juurlink DN
        • Canadian Drug
        • Safety and Effectiveness Research Network
        Association between statin use and ischemic stroke or major hemorrhage in patients taking dabigatran for atrial fibrillation.
        CMAJ. 2017; 189 (9): E4-E10
        • Goldstein LB
        • SPARCL Investigators
        Haemorrhagic stroke in the stroke prevention by aggressive reduction in cholesterol levels study.
        Neurology. 2008; 70: 2364-2370
        • Collins R
        • Armitage J
        • Parish S
        • Sleight P
        • Peto R
        • Heart Protection Study Collaborative Group
        Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions.
        Lancet. 2004; 363: 757-767
        • Ridker PM
        • Danielson E
        • Fonseca FA
        • Genest J
        • Gotto Jr, AM
        • Kastelein JJ
        • Koenig W
        • Libby P
        • Lorenzatti AJ
        • MacFadyen JG
        • Nordestgaard BG
        • Shepherd J
        • Willerson JT
        • Glynn RJ
        • JUPITER Study Group
        Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.
        N Engl J Med. 2008; 359: 2195-2207
        • Glynn RJ
        • Danielson E
        • Fonseca FA
        • Genest J
        • Jr Gotto AM
        • Kastelein JJ
        • Koenig W
        • Libby P
        • Lorenzatti AJ
        • MacFadyen JG
        • Nordestgaard BG
        • Shepherd J
        • Willerson JT
        • Ridker PM
        A randomized trial of rosuvastatin in the prevention of venous thromboembolism.
        N Engl J Med. 2009; 360: 1851-1886
        • Hackam DG
        • Woodward M
        • Newby LK
        • Bhatt DL
        • Shao M
        • Smith EE
        • Donner A
        • Mamdani M
        • Douketis JD
        • Arima H
        • Chalmers J
        • MacMahon S
        • Tirschwell DL
        • Psaty BM
        • Bushnell CD
        • Aguilar MI
        • Capampangan DJ
        • Werring DJ
        • De Rango P
        • Viswanathan A
        • Danchin N
        • Cheng CL
        • Yang YH
        • Verdel BM
        • Lai MS
        • Kennedy J
        • Uchiyama S
        • Yamaguchi T
        • Ikeda Y
        • Mrkobrada M
        Statins and intracerebral hemorrhage: collaborative systematic review and metaanalysis.
        Circulation. 2011; 124: 2233-2242
        • Morgenstern LB
        • Hemphill III, JC
        • Anderson C
        • Becker K
        • Broderick JP
        • Connolly Jr, ES
        • Greenberg SM
        • Huang JN
        • MacDonald RL
        • Messé SR
        • Mitchell PH
        • Selim M
        • Tamargo RJ
        American heart association stroke council and council on cardiovascular nursing. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American heart association/American stroke association.
        Stroke. 2010; 41: 2108-2129
        • Hong KS
        • Lee JS
        Statins in acute ischemic stroke: a systematic review.
        J Stroke. 2015; 17: 282-301
        • Ní Chróinín D
        • Asplund K
        • Åsberg S
        • Callaly E
        • Cuadrado-Godia E
        • Díez-Tejedor E
        • Di Napoli M
        • Engelter ST
        • Furie KL
        • Giannopoulos S
        • Jr Gotto AM
        • Hannon N
        • Jonsson F
        • Kapral MK
        • Martí-Fàbregas J
        • Martínez-Sánchez P
        • Milionis HJ
        • Montaner J
        • Muscari A
        • Pikija S
        • Probstfield J
        • Rost NS
        • Thrift AG
        • Vemmos K
        • Kelly PJ
        Statin therapy and outcome after ischemic stroke: systematic review and meta-analysis of observational studies and randomized trials.
        Stroke. 2013; 44: 448-456
        • Szummer K
        • Lundman P
        • Jacobson SH
        • Schon S
        • Lindback J
        • Stenestrand U
        • Wallentin L
        • Jernberg T
        Association between statin treatment and outcome in relation to renal function in survivors of myocardial infarction.
        Kidney Int. 2011; 79: 997-1004
        • Tonelli M
        • Moye L
        • Sacks FM
        • Kiberd B
        • Curhan G
        Cholesterol and recurrent events (CARE) trial investigators: pravastatin for secondary prevention of cardiovascular events in persons with mild chronic renal insufficiency.
        Ann Intern Med. 2003; 138: 98-104
        • Zhang X
        • Jing J
        • Zhao X
        • Liu L
        • Wang C
        • Pan Y
        • Meng X
        • Wang Y
        • Wang Y
        Statin use during hospitalization and short-term mortality in acute ischaemic stroke with chronic kidney disease.
        Eur Neurol. 2018; 79 (296–202)
        • Oesterle A
        • Laufs U
        • Liao JK
        Pleiotropic effects of statins on the cardiovascular system.
        Circ Res. 2017; 120: 229-243
        • Schäfer A
        • Fraccarollo D
        • EigenthalerM Tas P
        • Firnschild A
        • Frantz S
        • Ertl G
        • Bauersachs J
        Rosuvastatin reduces platelet activation in heart failure: role of no bioavailability.
        Arterioscler Thromb Vasc Biol. 2005; 25: 1071-1077
        • Gertz K
        • Laufs U
        • Lindauer U
        • Nickenig G
        • Böhm M
        • Dirnagl U
        • Endres M
        Withdrawal of statin treatment abrogates stroke protection in mice.
        Stroke. 2003; 34: 551-557
        • Laufs U
        • Gertz K
        • Huang P
        • Nickenig G
        • Böhm M
        • Dirnagl U
        • Endres M
        Atorvastatin upregulates type III nitricoxidesynthase in thrombocytes, decreasesplatelet activation, and protects fromcerebral ischemia innormocholesterolemicmice.
        Stroke. 2000; 31: 2442-2449
        • Ni R
        • Peleg T
        • Gross PL
        Atorvastatin delays murine platelet activation in vivo even in the absence of endothelial NO synthase.
        Arterioscler Thromb Vasc Biol. 2012; 32: 2609-2615
        • Aoki I
        • Aoki N
        • Kawano K
        • Shimoyama K
        • Maki A
        • Homori M
        • Yanagisawa A
        • Yamamoto M
        • Kawai Y
        • Ishikawa K
        Platelet-dependent thrombin generation in patients with hyperlipidemia.
        J Am Coll Cardiol. 1997; 30: 91-96
        • Puccetti L
        • Pasqui AL
        • Pastorelli M
        • Bova G
        • Cercignani M
        • Palazzuoli A
        • Angori P
        • Auteri A
        • Bruni F
        Time-dependent effect of statins on platelet function in hypercholesterolaemia.
        Eur J Clin Invest. 2002; 32: 901-908
        • Haramaki N
        • Ikeda H
        • Takenaka K
        • Katoh A
        • Sugano R
        • Yamagishi S
        • Matsuoka H
        • Imaizumi T
        Fluvastatin alters platelet aggregability in patients with hypercholesterolemia: possible improvement of intraplatelet redox imbalance viaHMG-CoAreductase.
        Arterioscler Thromb Vasc Biol. 2007; 27: 1471-1477
        • Colli S
        • Eligini S
        • LalliM CameraM
        • Paoletti R
        • Tremoli E
        Vastatins inhibit tissue factor in cultured human macrophages. A novel mechanism of protection against atherothrombosis.
        Arterioscler Thromb Vasc Biol. 1997; 17: 265-272
        • Eto M
        • Kozai T
        • Cosentino F
        • Joch H
        • Lüscher TF
        Statin prevents tissue factor expression in human endothelial cells: role of Rho/Rhokinase and Akt pathways.
        Circulation. 2002; 105: 1756-1759
        • Sahebkar A
        • Serban C
        • Ursoniu S
        • Mikhailidis DP
        • Undas A
        • Lip GY
        • Bittner V
        • Ray K
        • Watts GF
        • Hovingh GK
        • Rysz J
        • Kastelein JJ
        • Banach M
        • Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group
        The impact of statin therapy on plasma levels of von Willebrand factor antigen. Systematic review and meta-analysis of randomised placebo controlled trials.
        Thromb Haemost. 2016; 115: 520-532
        • Sahebkar A
        • Serban C
        • Mikhailidis DP
        • Undas A
        • Lip GY
        • Muntner P
        • Bittner V
        • Ray KK
        • Watts GF
        • Hovingh GK
        • Rysz J
        • Kastelein JJ
        • Banach M
        • Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group
        Association between statin use and plasma D-dimer levels. A systematic review and meta-analysis of randomised controlled trials.
        Thromb Haemost. 2015; 114: 546-557
        • Biedermann JS
        • Kruip MJHA
        • van der Meer FJ
        • Rosendaal FR
        • Leebeek FWG
        • Cannegieter SC
        • Lijfering WM
        Rosuvastatin use improves measures of coagulation in patients with venous thrombosis.
        Eur Heart J. 2018; 39: 1740-1747