Sleep Apnea and Incident Unprovoked Venous Thromboembolism: Data from the Pays de la Loire Sleep Cohort

Abstract

Background Previous studies have reported inconsistent findings regarding the association between obstructive sleep apnea (OSA) and incident venous thromboembolism (VTE). More specifically, the association between OSA and unprovoked VTE was barely evaluated. We aimed to evaluate whether apnea hypopnea index (AHI) and nocturnal hypoxemia markers were associated with unprovoked VTE incidence in patients investigated for OSA.

Material and Methods Data from the Pays de la Loire Sleep Cohort were linked to the French health administrative data to identify incident unprovoked VTE in patients suspected for OSA and no previous VTE disease. Cox proportional hazards models were used to evaluate the association of unprovoked VTE incidence with AHI and nocturnal hypoxemia markers including the time spent under 90% of saturation (T90), oxygen desaturation index, and hypoxic burden (HB), a more specific marker of respiratory events related to hypoxia. The impact of continuous positive airway pressure (CPAP) was evaluated in the subgroup of patients who were proposed the treatment.

Results After a median [interquartile range] follow-up of 6.3 [4.3–9.0] years, 104 of 7,355 patients developed unprovoked VTE, for an incidence rate of 10.8 per 1,000 patient-years. In a univariate analysis, T90 and HB predicted incident VTE. In the fully adjusted model, T90 was the only independent predictor (hazard ratio: 1.06; 95% confidence interval: [1.01–1.02]; p = 0.02). The CPAP treatment has no significant impact on VTE incidence.

Conclusion Patients with more severe nocturnal hypoxia are more likely to have incident unprovoked VTE.

Keywords

sleep apnea - venous thromboembolism - hypoxia

Publication History

Received: 22 July 2022

Accepted: 08 December 2022

Accepted Manuscript online:
19 December 2022

Article published online:
20 January 2023

• References

• 1 Bikov A, Meszaros M, Schwarz EI. Coagulation and fibrinolysis in obstructive sleep apnoea. Int J Mol Sci 2021; 22 (06) 2834
• 2 Geiser T, Buck F, Meyer BJ, Bassetti C, Haeberli A, Gugger M. In vivo platelet activation is increased during sleep in patients with obstructive sleep apnea syndrome. Respiration 2002; 69 (03) 229-234
• 3 Bokinsky G, Miller M, Ault K, Husband P, Mitchell J. Spontaneous platelet activation and aggregation during obstructive sleep apnea and its response to therapy with nasal continuous positive airway pressure. A preliminary investigation. Chest 1995; 108 (03) 625-630
• 4 Robinson GV, Pepperell JCT, Segal HC, Davies RJ, Stradling JR. Circulating cardiovascular risk factors in obstructive sleep apnoea: data from randomised controlled trials. Thorax 2004; 59 (09) 777-782
• 5 Zhang J, Gu J, Kuang Y, Zhu Y, Tang K, Guo Y. Prevalence of obstructive sleep apnea in venous thromboembolism: a systematic review and meta-analysis. Sleep Breath 2019; 23 (04) 1283-1289
• 6 Lin C-C, Keller JJ, Kang J-H, Hsu TC, Lin HC. Obstructive sleep apnea is associated with an increased risk of venous thromboembolism. J Vasc Surg Venous Lymphat Disord 2013; 1 (02) 139-145
• 7 Peng Y-H, Liao W-C, Chung W-S. et al. Association between obstructive sleep apnea and deep vein thrombosis / pulmonary embolism: a population-based retrospective cohort study. Thromb Res 2014; 134 (02) 340-345
• 8 Genuardi MV, Rathore A, Ogilvie RP. et al. Incidence of VTE in patients with OSA: a cohort study. Chest 2022; 161 (04) 1073-1082
• 9 Azarbarzin A, Sands SA, Stone KL. et al. The hypoxic burden of sleep apnoea predicts cardiovascular disease-related mortality: the Osteoporotic Fractures in Men Study and the Sleep Heart Health Study. Eur Heart J 2019; 40 (14) 1149-1157
• 10 Azarbarzin A, Sands SA, Taranto-Montemurro L. et al. The sleep apnea-specific hypoxic burden predicts incident heart failure. Chest 2020; 158 (02) 739-750
• 11 Trzepizur W, Blanchard M, Ganem T. et al. Sleep apnea-specific hypoxic burden, symptom subtypes, and risk of cardiovascular events and all-cause mortality. Am J Respir Crit Care Med 2022; 205 (01) 108-117
• 12 Blanchard M, Gervès-Pinquié C, Feuilloy M. et al. Association of nocturnal hypoxemia and pulse rate variability with incident atrial fibrillation in patients investigated for obstructive sleep apnea. Ann Am Thorac Soc 2021; 18 (06) 1043-1051
• 13 Berry RB, Budhiraja R, Gottlieb DJ. et al; American Academy of Sleep Medicine, Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. J Clin Sleep Med 2012; 8 (05) 597-619
• 14 Thereaux J, Lesuffleur T, Czernichow S. et al. To what extent does posthospital discharge chemoprophylaxis prevent venous thromboembolism after bariatric surgery?: results from a nationwide cohort of more than 110,000 patients. Ann Surg 2018; 267 (04) 727-733
• 15 Delluc A, Ianotto J-C, Tromeur C. et al. Real-world incidence of cancer following a first unprovoked venous thrombosis: Results from the EPIGETBO study. Thromb Res 2018; 164: 79-84
• 16 Konstantinides SV, Meyer G, Becattini C. et al; The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). Eur Respir J 2019; 54 (03) 1901647
• 17 Kendzerska T, Gershon AS, Atzema C. et al. Sleep apnea increases the risk of new hospitalized atrial fibrillation: a historical cohort study. Chest 2018; 154 (06) 1330-1339
• 18 Kendzerska T, Gershon AS, Hawker G, Leung RS, Tomlinson G. Obstructive sleep apnea and risk of cardiovascular events and all-cause mortality: a decade-long historical cohort study. PLoS Med 2014; 11 (02) e1001599
• 19 Justeau G, Gervès-Pinquié C, Le Vaillant M. et al; ERMES Study Group. Association between nocturnal hypoxemia and cancer incidence in patients investigated for OSA: data from a large multicenter French cohort. Chest 2020; 158 (06) 2610-2620
• 20 Yang H, Yang G, Xu M. et al. Impact of high altitude on the incidence of postoperative venous thromboembolism and its genetic susceptibility: a meta-analysis and systematic review. Sci Total Environ 2022; 838 (Pt 4): 156632
• 21 McKerrow Johnson I, Shatzel J, Olson S, Kohl T, Hamilton A, DeLoughery TG. Travel-associated venous thromboembolism. Wilderness Environ Med 2022; 33 (02) 169-178
• 22 Koizume S, Takahashi T, Yoshihara M. et al. Cholesterol starvation and hypoxia activate the FVII gene via the SREBP1-GILZ pathway in ovarian cancer cells to produce procoagulant microvesicles. Thromb Haemost 2019; 119 (07) 1058-1071
• 23 Bertoletti L, Couturaud F, Sanchez O, Jimenez D. Pulmonary embolism and chronic obstructive pulmonary disease. Semin Thromb Hemost 2022; DOI: 10.1055/s-0042-1756190.
• 24 García-Ortega A, Mañas E, López-Reyes R. et al. Obstructive sleep apnoea and venous thromboembolism: pathophysiological links and clinical implications. Eur Respir J 2019; 53 (02) 1800893
• 25 Toraldo DM, De Benedetto M, Scoditti E, De Nuccio F. Obstructive sleep apnea syndrome: coagulation anomalies and treatment with continuous positive airway pressure. Sleep Breath 2016; 20 (02) 457-465
• 26 Delaney C, Davizon-Castillo P, Allawzi A. et al. Platelet activation contributes to hypoxia-induced inflammation. Am J Physiol Lung Cell Mol Physiol 2021; 320 (03) L413-L421
• 27 Butala NM, Strom JB, Faridi KF. et al. Validation of administrative claims to ascertain outcomes in pivotal trials of transcatheter aortic valve replacement. JACC Cardiovasc Interv 2020; 13 (15) 1777-1785
• 28 White RH. The epidemiology of venous thromboembolism. Circulation 2003; 107 (23, Suppl 1): I4-I8