Subscribe to RSS
DOI: 10.1160/TH12-12-0928
Antithrombotic therapy in obesity
Publication History
Received:
17 December 2012
Accepted after minor revision:
11 March 2013
Publication Date:
01 December 2017 (online)
summary
Clinical management of obese subjects to reduce their risk of suffering cardiovascular events is complex. Obese patients typically require preventive strategies, life-style modifications, and multi-drug therapy to address obesity-induced co-morbidities. Data regarding the effects of excess weight on the pharmacokinetics of most drugs is scarce as these individuals are often excluded from clinical trials. However, the physiological alterations observed in obese patients and their lower response to some antiplatelet agents and anticoagulants have suggested that dosage regimes need to be adjusted for these subjects. In this review we will briefly discuss platelet alterations that can contributeto increased thrombotic risk, analyse existing data regarding the effects of obesity on drug pharmacokinetics focusing on antiplatelet agents and anticoagulants, and we will describe the beneficial effects of weight loss on thrombosis.
-
References
- 1 Alberti KG, Eckel RH, Grundy SM. et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009; 120: 1640-1645.
- 2 Mottillo S, Filion KB, Genest J. et al. The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol 2010; 56: 1113-1132.
- 3 Onat A. Metabolic syndrome: nature, therapeutic solutions and options. Expert Opin Pharmacother 2011; 12: 1887-1900.
- 4 Eckel RH, Barouch WW, Ershow AG. Report of the National Heart, Lung, and Blood Institute-National Institute of Diabetes and Digestive and Kidney Diseases Working Group on the pathophysiology of obesity-associated cardiovascular disease. Circulation 2002; 105: 2923-2928.
- 5 Despres JP. Cardiovascular disease under the influence of excess visceral fat. Crit Pathw Cardiol 2007; 6: 51-59.
- 6 Anfossi G, Russo I, Trovati M. Platelet dysfunction in central obesity. Nutr Metab Cardiovasc Dis 2009; 19: 440-449.
- 7 Targher G, Zoppini G, Moghetti P. et al. Disorders of coagulation and hemostasis in abdominal obesity: emerging role of fatty liver. Semin Thromb Hemost 2010; 36: 41-48.
- 8 Anfossi G, Russo I, Trovati M. Platelet resistance to the anti-aggregating agents in the insulin resistant states. Curr Diabetes Rev 2006; 2: 409-430.
- 9 Anfossi G, Mularoni EM, Burzacca S. et al. Platelet resistance to nitrates in obesity and obese NIDDM, and normal platelet sensitivity to both insulin and nitrates in lean NIDDM. Diabetes Care 1998; 21: 121-126.
- 10 Anfossi G, Russo I, Massucco P. et al. Impaired synthesis and action of antiaggregating cyclic nucleotides in platelets from obese subjects: possible role in platelet hyperactivation in obesity. Eur J Clin Invest 2004; 34: 482-489.
- 11 Angelico F, Alessandri C, Ferro D. et al. Enhanced soluble CD40L in patients with the metabolic syndrome: Relationship with in vivo thrombin generation. Diabetologia 2006; 49: 1169-1174.
- 12 De Pergola G, Pannacciulli N, Coviello M. et al. sP-selectin plasma levels in obesity: association with insulin resistance and related metabolic and prothrombotic factors. Nutr Metab Cardiovasc Dis 2008; 18: 227-232.
- 13 Natal C, Restituto P, Inigo C. et al. The proinflammatory mediator CD40 ligand is increased in the metabolic syndrome and modulated by adiponectin. J Clin Endocrinol Metab 2008; 93: 2319-2327.
- 14 Coban E, Ozdogan M, Yazicioglu G. et al. The mean platelet volume in patients with obesity. Int J Clin Pract 2005; 59: 981-982.
- 15 Bavbek N, Kargili A, Kaftan O. et al. Elevated concentrations of soluble adhesion molecules and large platelets in diabetic patients: are they markers of vascular disease and diabetic nephropathy?. Clin Appl Thromb Hemost 2007; 13: 391-397.
- 16 Greisenegger S, Endler G, Hsieh K. et al. Is elevated mean platelet volume associated with a worse outcome in patients with acute ischemic cerebrovascular events?. Stroke 2004; 35: 1688-1691.
- 17 Gasparyan AY, Ayvazyan L, Mikhailidis DP. et al. Mean platelet volume: a link between thrombosis and inflammation?. Curr Pharm Des 2011; 17: 47-58.
- 18 Ishibashi T, Kimura H, Uchida T. et al. Human interleukin 6 is a direct promoter of maturation of megakaryocytes in vitro. Proc Natl Acad Sci USA 1989; 86: 5953-5957.
- 19 Kaushansky K. The molecular mechanisms that control thrombopoiesis. J Clin Invest 2005; 115: 3339-3347.
- 20 Alessi MC, Lijnen HR, Bastelica D. et al. Adipose tissue and atherothrombosis. Pathophysiol Haemost Thromb 2003; 33: 290-297.
- 21 Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease. Circ Res 2005; 96: 939-949.
- 22 Fain JN. Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. Vitam Horm 2006; 74: 443-477.
- 23 Goralski KB, Sinal CJ. Type 2 diabetes and cardiovascular disease: getting to the fat of the matter. Can J Physiol Pharmacol 2007; 85: 113-132.
- 24 van der Loo B, Martin JF. A role for changes in platelet production in the cause of acute coronary syndromes. Arterioscler Thromb Vasc Biol 1999; 19: 672-679.
- 25 Hernández Vera R, Vilahur G, Ferrer-Lorente R. et al. Platelets derived from the bone marrow of diabetic animals show dysregulated endoplasmic reticulum stress proteins that contribute to increased thrombosis. Arterioscler Thromb Vasc Biol 2012; 32: 2141-2148.
- 26 Hernández Vera R, Vilahur G, Badimon L. Obesity with insulin resistance increase thrombosis in wild-type and bone marrow-transplanted Zucker fatty rats. Thromb Haemost 2013; 109: 319-327.
- 27 Visser M, Bouter LM, McQuillan GM. et al. Elevated C-reactive protein levels in overweight and obese adults. J Am Med Assoc 1999; 282: 2131-2135.
- 28 Molins B, Pena E, Vilahur G. et al. C-reactive protein isoforms differ in their effects on thrombus growth. Arterioscler Thromb Vasc Biol 2008; 28: 2239-2246.
- 29 Molins B, Pena E, de la Torre R. et al. Monomeric C-reactive protein is prothrombotic and dissociates from circulating pentameric C-reactive protein on adhered activated platelets under flow. Cardiovasc Res 2011; 92: 328-337.
- 30 Murakami T, Horigome H, Tanaka K. et al. Impact of weight reduction on production of platelet-derived microparticles and fibrinolytic parameters in obesity. Thromb Res 2007; 119: 45-53.
- 31 Basili S, Pacini G, Guagnano MT. et al. Insulin resistance as a determinant of platelet activation in obese women. J Am Coll Cardiol 2006; 48: 2531-2538.
- 32 Davi G, Guagnano MT, Ciabattoni G. et al. Platelet activation in obese women: role of inflammation and oxidant stress. J Am Med Assoc 2002; 288: 2008-2014.
- 33 Brocks DR, Ben-Eltriki M, Gabr RQ. et al. The effects of gastric bypass surgery on drug absorption and pharmacokinetics. Expert Opin Drug Metab Toxicol 2012; 8: 1505-1519.
- 34 Jain R, Chung SM, Jain L. et al. Implications of obesity for drug therapy: limitations and challenges. Clin Pharmacol Ther 2011; 90: 77-89.
- 35 Enriori PJ, Evans AE, Sinnayah P. et al. Leptin resistance and obesity. Obesity 2006; 14 (Suppl. 05) 254S-258S.
- 36 Hajer GR, van Haeften TW, Visseren FL. Adipose tissue dysfunction in obesity, diabetes, and vascular diseases. Eur Heart J 2008; 29: 2959-2971.
- 37 Maury E, Brichard SM. Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome. Mol Cell Endocrinol 2010; 314: 1-16.
- 38 Clauson PG, Linde B. Absorption of rapid-acting insulin in obese and nonobese NIDDM patients. Diabetes Care 1995; 18: 986-991.
- 39 Sanderink GJ, Le Liboux A, Jariwala N. et al. The pharmacokinetics and pharmacodynamics of enoxaparin in obese volunteers. Clin Pharmacol Ther 2002; 72: 308-318.
- 40 Edelman AB, Cherala G, Stanczyk FZ. Metabolism and pharmacokinetics of contraceptive steroids in obese women: a review. Contraception 2010; 82: 314-323.
- 41 Hanley MJ, Abernethy DR, Greenblatt DJ. Effect of obesity on the pharmacokinetics of drugs in humans. Clin Pharmacokinet 2010; 49: 71-87.
- 42 Morrish GA, Pai MP, Green B. The effects of obesity on drug pharmacokinetics in humans. Expert Opin Drug Metab Toxicol 2011; 7: 697-706.
- 43 Blouin RA, Warren GW. Pharmacokinetic considerations in obesity. J Pharm Sci 1999; 88: 1-7.
- 44 Green B, Duffull SB. What is the best size descriptor to use for pharmacokinetic studies in the obese?. Br J Clin Pharmacol 2004; 58: 119-133.
- 45 La Colla L, Albertin A, La Colla G. et al. Predictive performance of the ‘Minto’ remifentanil pharmacokinetic parameter set in morbidly obese patients ensuing from a new method for calculating lean body mass. Clin Pharmacokinet 2010; 49: 131-139.
- 46 McLeay SC, Morrish GA, Kirkpatrick CM. et al. Encouraging the move towards predictive population models for the obese using propofol as a motivating example. Pharm Res 2009; 26: 1626-1634.
- 47 Pietilainen KH, Rissanen A, Kaprio J. et al. Acquired obesity is associated with increased liver fat, intra-abdominal fat, and insulin resistance in young adult monozygotic twins. Am J Physiol Endocrinol Metab 2005; 288: E768-E774.
- 48 Ijaz S, Yang W, Winslet MC. et al. Impairment of hepatic microcirculation in fatty liver. Microcirculation 2003; 10: 447-456.
- 49 Bordeaux BC, Qayyum R, Yanek LR. et al. Effect of obesity on platelet reactivity and response to low-dose aspirin. Prev Cardiol 2010; 13: 56-62.
- 50 Tamminen M, Lassila R, Westerbacka J. et al. Obesity is associated with impaired platelet-inhibitory effect of acetylsalicylic acid in nondiabetic subjects. Int J Obes Relat Metab Disord 2003; 27: 907-911.
- 51 Westerbacka J, Yki-Jarvinen H, Turpeinen A. et al. Inhibition of platelet-collagen interaction: an in vivo action of insulin abolished by insulin resistance in obesity. Arterioscler Thromb Vasc Biol 2002; 22: 167-172.
- 52 Trovati M, Anfossi G, Massucco P. et al. Insulin stimulates nitric oxide synthesis in human platelets and, through nitric oxide, increases platelet concentrations of both guanosine-3', 5'-cyclic monophosphate and adenosine-3', 5'-cyclic monophosphate. Diabetes 1997; 46: 742-749.
- 53 Trovati M, Mularoni EM, Burzacca S. et al. Impaired insulin-induced platelet antiaggregating effect in obesity and in obese NIDDM patients. Diabetes 1995; 44: 1318-1322.
- 54 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Platelet aggregation according to body mass index in patients undergoing coronary stenting: should clopidogrel loading-dose be weight adjusted?. J Invasive Cardiol 2004; 16: 169-174.
- 55 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Is a 300 mg clopidogrel loading dose sufficient to inhibit platelet function early after coronary stenting? A platelet function profile study. J Invasive Cardiol 2004; 16: 325-329.
- 56 Feher G, Koltai K, Alkonyi B. et al. Clopidogrel resistance: role of body mass and concomitant medications. Int J Cardiol 2007; 120: 188-192.
- 57 Kelly RV, Hsu A, Topol E. et al. The influence of body mass index on outcomes and the benefit of antiplatelet therapy following percutaneous coronary intervention. J Invasive Cardiol 2006; 18: 115-119.
- 58 Wiviott SD, Antman EM, Winters KJ. et al. Randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention: results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trial. Circulation 2005; 111: 3366-3373.
- 59 Wiviott SD, Braunwald E, McCabe CH. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
- 60 Cayla G, Cuisset T, Silvain J. et al. Prasugrel monitoring and bleeding in real world patients. Am J Cardiol 2013; 111: 38-44.
- 61 Wallentin L, Becker RC, Budaj A. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045-1057.
- 62 Storey RF, Becker RC, Harrington RA. et al. Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes. Eur Heart J 2011; 32: 2945-2953.
- 63 Martin JL, Jia G, Martin SS. et al. The relationship of obesity to ischemic outcomes following coronary stent placement in contemporary practice. Catheter Cardiovasc Interv 2006; 67: 563-570.
- 64 Stein PD, Beemath A, Olson RE. Obesity as a risk factor in venous thromboembolism. Am J Med 2005; 118: 978-980.
- 65 Ageno W, Becattini C, Brighton T. et al. Cardiovascular risk factors and venous thromboembolism: a meta-analysis. Circulation 2008; 117: 93-102.
- 66 Allman-Farinelli MA, Chey T, Bauman AE. et al. Age, period and birth cohort effects on prevalence of overweight and obesity in Australian adults from 1990 to 2000. Eur J Clin Nutr 2008; 62: 898-907.
- 67 Eichinger S, Hron G, Bialonczyk C. et al. Overweight, obesity, and the risk of recurrent venous thromboembolism. Arch Int Med 2008; 168: 1678-1683.
- 68 Geerts WH, Bergqvist D, Pineo GF. et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (Suppl. 06) 381S-453S.
- 69 Spinler SA. The skinny on treatment of venous thromboembolism in obesity. J Thromb Haemost 2005; 3: 854-855.
- 70 Raschke RA, Reilly BM, Guidry JR. et al. The weight-based heparin dosing nomogram compared with a "standard care" nomogram. A randomized controlled trial. Ann Intern Med 1993; 119: 874-881.
- 71 Spinler SA, Inverso SM, Cohen M. et al. Safety and efficacy of unfractionated heparin versus enoxaparin in patients who are obese and patients with severe renal impairment: analysis from the ESSENCE and TIMI 11B studies. Am Heart J 2003; 146: 33-41.
- 72 Barba R, Marco J, Martin-Alvarez H. et al. The influence of extreme body weight on clinical outcome of patients with venous thromboembolism: findings from a prospective registry (RIETE). J Thromb Haemost 2005; 3: 856-862.
- 73 Barba R, Zapatero A, Losa JE. et al. Body mass index and mortality in patients with acute venous thromboembolism: findings from the RIETE registry. J Thromb Haemost 2008; 6: 595-600.
- 74 Curtis JP, Selter JG, Wang Y. et al. The obesity paradox: body mass index and outcomes in patients with heart failure. Archives of internal medicine 2005; 165: 55-61.
- 75 Galal W, van Domburg RT, Feringa HH. et al. Relation of body mass index to outcome in patients with known or suspected coronary artery disease. Am J Cardiol 2007; 99: 1485-1490.
- 76 Turpie AG, Bauer KA, Eriksson BI. et al. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Int Med 2002; 162: 1833-1840.
- 77 Raftopoulos I, Cortese-Hassett A, Gourash W. et al. Pharmacokinetic properties of fondaparinux sodium in morbidly obese volunteers indicate that a single, weight-independent daily dose for thromboprophylaxis is feasible. Presented at: Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). Philadelphia,PA, USA: 2008
- 78 Lavie CJ, Milani RV, Ventura HO. Obesity and cardiovascular disease: risk factor, paradox, and impact of weight loss. J Am Coll Cardiol 2009; 53: 1925-1932.
- 79 Daskalopoulou SS, Mikhailidis DP, Elisaf M. Prevention and treatment of the metabolic syndrome. Angiology 2004; 55: 589-612.
- 80 Charakida M, Finer N. Drug treatment of obesity in cardiovascular disease. Am J Cardiovasc Drugs 2012; 12: 93-104.
- 81 Williamson DF, Thompson TJ, Thun M. et al. Intentional weight loss and mortality among overweight individuals with diabetes. Diabetes Care 2000; 23: 1499-1504.
- 82 Esposito K, Pontillo A, Di Palo C. et al. Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial. J Am Med Assoc 2003; 289: 1799-1804.
- 83 You T, Berman DM, Ryan AS. et al. Effects of hypocaloric diet and exercise training on inflammation and adipocyte lipolysis in obese postmenopausal women. J Clin Endocrinol Metab 2004; 89: 1739-1746.
- 84 Hamdy O, Ledbury S, Mullooly C. et al. Lifestyle modification improves endothelial function in obese subjects with the insulin resistance syndrome. Diabetes Care 2003; 26: 2119-2125.
- 85 Sciacqua A, Candigliota M, Ceravolo R. et al. Weight loss in combination with physical activity improves endothelial dysfunction in human obesity. Diabetes Care 2003; 26: 1673-1678.
- 86 Vazzana N, Santilli F, Sestili S. et al. Determinants of increased cardiovascular disease in obesity and metabolic syndrome. Curr Med Chem 2011; 18: 5267-5280.
- 87 Russo I, Traversa M, Bonomo K. et al. In central obesity, weight loss restores platelet sensitivity to nitric oxide and prostacyclin. Obesity 2010; 18: 788-797.
- 88 Estelles A, Dalmau J, Falco C. et al. Plasma PAI-1 levels in obese children--effect of weight loss and influence of PAI-1 promoter 4G/5G genotype. Thromb Haemost 2001; 86: 647-652.
- 89 Sudi KM, Gallistl S, Trobinger M. et al. The influence of weight loss on fibrinolytic and metabolic parameters in obese children and adolescents. J Pediatr Endocrinol Metab 2001; 14: 85-94.
- 90 National Institutes of Health - National Heart Lung and Blood Institute. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults:. The Evidence Report. Available at http://www.nhlbi.nih.gov/guidelines/obesity/ob_gdlns.pdf Accessed February 7. 2013 .
- 91 Wang Q, Perrard XD, Perrard JL. et al. Effect of the cannabinoid receptor-1 antagonist rimonabant on inflammation in mice with diet-induced obesity. Obesity 2011; 19: 505-513.
- 92 Eldar S, Heneghan HM, Brethauer SA. et al. Bariatric surgery for treatment of obesity. Int J Obes 2011; 35 (Suppl. 01) S16-S21.