Uso de estatina reduz tromboembolismo venoso? SBPT II CURSO NACIONAL DE CIRCULAÇÃO PULMONAR Uso de estatina reduz tromboembolismo venoso? TEV inclui TVP + TEP A pergunta (Uso de estatina reduz tromboembolismo venoso?) tem um sentido de profilaxia. Daniel Waetge UFRJ

Estatinas = Inibidores da HMG-CoA redutase Estatinas e síntese de colesterol Estatina = Inibidor da 3-hidroxi-3-metil-glutaril-Coenzima A (HMG-CoA) reductase

Acetil-CoA Estatina HMG-CoA HMG-CoA Redutase Mevalonato Colesterol A inibição da HMG-CoA é a principal reação reguladora da Síntese Colesterol Mevalonato, que é o produto da HMG-CoA, tb é precursor não apenas do colesterol mas tb de compostos isoprenoides que permitem a ligação de ptns sinalizadoras na membrana celular. Colesterol

Estatinas = Inibidores da HMG-CoA redutase Estatinas e síntese de colesterol Efeitos colesterol-indenpendentes Aumento da disponibilidade do óxido nítrico Estabilização da placa ateroesclerótica Redução da resposta inflamatória Propriedades antitrombóticas Regulação da angiogenese Disfunção endotelial Stains and Blood Coagulation. Arterioscler Thromb Vasc Biol. 2005;25:287 Pleiotropic effects of statins. Arterioscler Thromb Vasc Biol. 2001;21:1712 Antiatherothrombotic properties of statins. Implications for cardiovascular event reduction. JAMA. 1998;279:1643 New nonlipid effects of statins and their clinical relevance in cardiovascular disease. Thromb Haemost. 2004;91:1065

Effect of statins on a wide range of health outcomes: a cohort study validated by comparison with randomized trials People who initiated treatment with a statin (n = 129 288) were compared with a matched sample of 600 241 people who did not initiate treatment, with a median follow-up period of 4.4 years. Statin use was not associated with an effect on a wide range of outcomes, including infections, fractures, venous thromboembolism, gastrointestinal haemorrhage, or on specific eye, neurological or autoimmune diseases. A protective effect against dementia was observed (hazard ratio 0.80, 99% confidence interval 0.68, 0.95). Of note, users were more likely to be current or ex-smokers, have higher BMI and be diagnosed with hyperlipidaemia, diabetes or a range of cardiovascular diseases. Non-users were more likely to have other serious chronic disease such as dementia or cancer. Br J Clin Pharmacol 67:1 99–109 2008

Ação das estatinas em diversas doenças Infecções: Pandemic influenza: a potential role for statins in treatment and prophylaxis. Clin Infect Dis 2006; 43: 199–205 Sepse: US Pharm. 2008;33(2):HS-3-HS-15 Câncer: Statins and risk of cancer: a systematic review and metaanalysis. Int J Cancer 2007; 120:833. Should we lower cholesterol as much as possible? BMJ 2006; 332: 1330–2 Demência: Statins and the risk of dementia. Lancet 2000; 356: 1627–31 Fraturas: Statinas and the risk of hip fractures in elderly patients. JAMA 2000; 283:3211 Olhos: Cataract and the use of statins: a case–control study. QJM 2003; 96:337. A case-control study of age related macular degeneration and use of statins. Br J Ophth 2005; 89: 1171 Neurológico: Statins, neuromuscular degenerative disease and an ALS-like syndrome: an analysis of individual case safety reports from vigibase. Drug Saf 2007; 30:515 Doenças imunológicas: Statins as antiinflammatory and immunomodulatory agents: a future in rheumatologic therapy? Arthritis Rheum 2006; 54: 393–407

Coagulação sanguínea: reações modificadas pelas estatinas Além das propriedades prófibrinolíticas e efeitos antiplaquetários, evidências indicam que as estatinas tb modulam a cascata da coagulação em múltiplos níveis, levando à redução na trombogenicidade. Statins have been shown to exhibit several vascular protective effects, including antithrombotic properties, that are not related to changes in lipid profile. There is growing evidence that treatment with statins can lead to a significant downregulation of the blood coagulation cascade, most probably as a result of decreased tissue factor expression, which leads to reduced thrombin generation. Accordingly, statin use has been associated with impairment of several coagulant reactions catalyzed by this enzyme. Moreover, evidence indicates that statins, via increased thrombomodulin expression on endothelial cells, may enhance the activity of the protein C anticoagulant pathway. Most of the antithrombotic effects of statins are attributed to the inhibition of isoprenylation of signaling proteins. These novel properties of statins, suggesting that these drugs might act as mild anticoagulants, may explain, at least in part, the therapeutic benefits observed in a wide spectrum of patients with varying cholesterol levels, including subjects with acute coronary events. Tissue factor =thromboplastin = fator III Undas, A. Arterioscler Thromb Vasc Biol 2005;25:287-294

Coagulação sanguínea: reações modificadas pelas estatinas BIOCHEMISTRY 2002 (67) 1

Estudos iniciais que procuravam estabelecer a relação entre estatinas e prevenção de TEV The anti-thrombotic effects of statins. JACC 1999;33:1305-1307. Kearney D. Heart and Estrogen/Progestin Replacement Study. Postmenopausal hormone therapy increases risk for VTE disease. Ann Intern Med 2000;132:689-696. Grady D. Use of Statins and the Subsequent Development of Deep Vein Thrombosis Arch Intern Med. 2001;161:1405-1410 …

Ray, J. G. et al. Arch Intern Med 2001;161:1405-1410. Rate of deep vein thrombosis (DVT) among men and women according to agent Conclusion: Among selected individuals aged 65 years or older, statins were associated with a 22% relative risk reduction in the risk of DVT. A randomized clinical trial is needed to evaluate the efficacy of statins for the primary and secondary prevention of DVT. RR 22% de redução da TVP Ray, J. G. et al. Arch Intern Med 2001;161:1405-1410.

Justification of the Use of Statins in Primary Prevention: an Intervention Trial Using Rosuvastatin (JUPITER) 20 mg de rosuvastatina diária comparada com placebo: Reduziria a frequência de eventos cardiovasculares “major” Reduziria a ocorrência de TEV (“end-point” secundário) Uso de rosuvastatina 20 mg/dia x placebo NEJM 2008 e NEJM 2009

Volume 359(21), 20 Nov 2008, p 2195–2207

Volume 360(18), 30 April 2009, p 1851–1861 This trial included a selected population, in that participants were men and women without arterial vascular disease, without an indication for statin treatment, and with C reactive protein > 2 mg/L

0,38% 0,67% A Randomized Trial of Rosuvastatin in the Prevention of VTE. NEJM 2009 360(18)1851

26 pcts (0,29 %) 0,38% 0,67% NNT = 344 A Randomized Trial of Rosuvastatin in the Prevention of VTE. NEJM 2009 360(18)1851

Incidência cumulativa de TEV A Randomized Trial of Rosuvastatin in the Prevention of VTE. NEJM 2009 360(18)1851

A new indication for statins to prevent venous thromboembolism? Not yet. Cushman M. J Thromb Haemost 2009; 7: 511–3.

Uso profilático de estatinas Sub grupos onde a doença tem maior incidência seriam mais beneficiados? Profilaxia primária: câncer, cirurgia de alto risco, HAP, obesidade, idosos, síndrome antifosfolipídico... Profilaxia secundária? Mas é sabido que 1/3 dos pacientes que desenvolvem TEV não tem fator de risco esclarecido Para responder à pergunta (Uso de estatina reduz tromboembolismo venoso?) é necessário estudar subgrupos, pois as estatinas não estão indicadas para a população em geral, mesmo a que foi mais amplamente estudada com LDL < 130 e PCRt > 2,0

Uso de estatina reduz tromboembolismo venoso?