Platelet aggregation inhibitors, vitamin K antagonists and risk of subarachnoid hemorrhage

Abstract

To cite this article: Risselada R, Straatman H, van Kooten F, Dippel DWJ, Van Der Lugt A, Niessen WJ, Firouzian A, Herings RMC, Sturkenboom MCJM. Platelet aggregation inhibitors, vitamin K antagonists and risk of subarachnoid hemorrhage. J Thromb Haemost 2011; 9: 517-23.Summary. Background: Use of platelet aggregation inhibitors and vitamin K antagonists has been associated with an increased risk of intracranial hemorrhage (ICH). Whether the use of these antithrombotic drugs is associated with an increased risk of subarachnoid hemorrhage (SAH) remains unclear, especially as confounding by indication might play a role. Objective: The aim of the present study was to investigate whether use of platelet aggregation inhibitors or vitamin K antagonists increase the risk of SAH. Methods: We applied population-based case-control, case-crossover and case-timecontrol designs to estimate the risk of SAH while addressing issues both of confounding by indication and time varying exposure within the PHARMO Record Linkage System database. This system includes drug dispensing records from community pharmacies and hospital discharge records of more than 3 million community-dwelling inhabitants in the Netherlands. Patients were considered a case if they were hospitalized for a first SAH (ICD-9-CM code 430) in the period between 1st January 1998 and 31st December 2006. Controls were selected from the source population, matched on age, gender and date of hospitalization. Conditional logistic regression was used to estimate multivariable adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of SAH during use of platelet aggregation inhibitors or vitamin K antagonists. In the case-crossover and case-time-control designs we selected 11 control periods preceding the index date in successive steps of 1 month in the past. Results: In all, 1004 cases of SAH were identified. In the case-control analysis the adjusted OR for the risk of SAH in current use of platelet aggregation inhibitors was 1.32 (95% CI: 1.02-1.70) and in current use of vitamin K antagonists 1.29 (95% CI: 0.89-1.87) compared with no use. In the case-crossover analysis the ORs for the risk of SAH in current use of platelet aggregation inhibitors and vitamin K antagonists were 1.04 (95% CI: 0.56-1.94) and 2.46 (95% CI: 1.04-5.82), respectively. In the case-time-control analysis the OR for platelet aggregation inhibitors was 0.50 (95% CI: 0.26-0.98) and for vitamin K antagonists 1.98 (95% CI: 0.82-4.76). Conclusion: The use of platelet aggregation inhibitors was not associated with an increased SAH risk; the modest increase observed in the case-control analysis could be as a result of confounding. The use of vitamin K antagonists seemed to be associated with an increased risk of SAH. The increase was most pronounced in the case-crossover analysis and therefore cannot be explained by unmeasured confounding.

Risk of Subarachnoid Hemorrhage and Early Case Fatality Associated With Outpatient Antithrombotic Drug Use

“…Our findings on phenprocoumon are in line with the results of a case-control study by Risselada et al, 21 which investigated the risk of SAH for phenprocoumon, acenocoumarol, and platelet aggregation inhibitors with the Institute for Drug Outcomes Research database in the Netherlands. Only 1 study has investigated the risk of SAH in patients receiving warfarin.…”

Risk of Subarachnoid Hemorrhage and Early Case Fatality Associated With Outpatient Antithrombotic Drug Use

“…Our findings on phenprocoumon are in line with the results of a case-control study by Risselada et al, 21 which investigated the risk of SAH for phenprocoumon, acenocoumarol, and platelet aggregation inhibitors with the Institute for Drug Outcomes Research database in the Netherlands. Only 1 study has investigated the risk of SAH in patients receiving warfarin.…”

Resumption of antiplatelet therapy in patients with primary intracranial haemorrhage: Balancing benefits and risks

“…These findings are similar to the study by Risselada et al which provided evidence that the use of antiplatelets was not associated with an increased risk of ICH [5]. Furthermore, a systematic review performed by Hawryluk et al looking at resumption of anticoagulation following central nervous system (CNS) haemorrhage found that early re-initiation of anticoagulants may be prudent [6].…”

Individual trigger factors for hemorrhagic stroke: Evidence from case-crossover and self-controlled case series studies

“…A total of 441 potentially relevant articles were screened. Finally, 39 candidate articles 4,13-50 met the eligibility criteria (Figure 1), including 28 CCOSs, 10 SCCSs, and 1 using both designs. Associations with the onset of HS were assessed among 32 categories of trigger factors (Table 1, Figure 2), which were classified into four main categories: medications ( n = 14), diseases/vaccination ( n = 13), pregnancy ( n = 5), and behavioral factors ( n = 7).…”

“…A significant association was found between the risk of HS and aspirin use within 7 days in a study of 19,600 patients with ICH in New England, 17 while similar results were not found for aspirin use within 56 days in a study of 3781 Chinese patients 18 or for antiplatelet use within 30 days. 19 The pooled results showed significant associations of HS with both NSAIDs (OR, 1.55; 95% CI, 1.29–1.87) and antiplatelets (OR, 1.10; 95% CI, 1.00–1.21; I 2 , 0.0%; p Q , 0.451), but a large heterogeneity existed for studies on NSAIDs ( I 2 , 85.8%; p Q < 0.001). The use of anticoagulants was also associated with the onset of HS, but with large heterogeneity (OR, 5.43; 95% CI, 2.04–14.46; I 2 , 82.2%; p Q , 0.018).…”

“…Within 1–2 weeks of anticoagulant use, a significantly increased risk of HS and SAH was identified in both Chinese and New English patients. 17,19…”

Risk of Subarachnoid Hemorrhage and Early Case Fatality Associated With Outpatient Antithrombotic Drug Use

“…Our findings on phenprocoumon are in line with the results of a case-control study by Risselada et al, 21 which investigated the risk of SAH for phenprocoumon, acenocoumarol, and platelet aggregation inhibitors with the Institute for Drug Outcomes Research database in the Netherlands. Only 1 study has investigated the risk of SAH in patients receiving warfarin.…”

Resumption of antiplatelet therapy in patients with primary intracranial haemorrhage: Balancing benefits and risks

“…These findings are similar to the study by Risselada et al which provided evidence that the use of antiplatelets was not associated with an increased risk of ICH [5]. Furthermore, a systematic review performed by Hawryluk et al looking at resumption of anticoagulation following central nervous system (CNS) haemorrhage found that early re-initiation of anticoagulants may be prudent [6].…”

Individual trigger factors for hemorrhagic stroke: Evidence from case-crossover and self-controlled case series studies

“…A total of 441 potentially relevant articles were screened. Finally, 39 candidate articles 4,13-50 met the eligibility criteria (Figure 1), including 28 CCOSs, 10 SCCSs, and 1 using both designs. Associations with the onset of HS were assessed among 32 categories of trigger factors (Table 1, Figure 2), which were classified into four main categories: medications ( n = 14), diseases/vaccination ( n = 13), pregnancy ( n = 5), and behavioral factors ( n = 7).…”

“…A significant association was found between the risk of HS and aspirin use within 7 days in a study of 19,600 patients with ICH in New England, 17 while similar results were not found for aspirin use within 56 days in a study of 3781 Chinese patients 18 or for antiplatelet use within 30 days. 19 The pooled results showed significant associations of HS with both NSAIDs (OR, 1.55; 95% CI, 1.29–1.87) and antiplatelets (OR, 1.10; 95% CI, 1.00–1.21; I 2 , 0.0%; p Q , 0.451), but a large heterogeneity existed for studies on NSAIDs ( I 2 , 85.8%; p Q < 0.001). The use of anticoagulants was also associated with the onset of HS, but with large heterogeneity (OR, 5.43; 95% CI, 2.04–14.46; I 2 , 82.2%; p Q , 0.018).…”

“…Within 1–2 weeks of anticoagulant use, a significantly increased risk of HS and SAH was identified in both Chinese and New English patients. 17,19…”

Risk of Subarachnoid Hemorrhage and Early Case Fatality Associated With Outpatient Antithrombotic Drug Use

“…Our findings on phenprocoumon are in line with the results of a case-control study by Risselada et al, 21 which investigated the risk of SAH for phenprocoumon, acenocoumarol, and platelet aggregation inhibitors with the Institute for Drug Outcomes Research database in the Netherlands. Only 1 study has investigated the risk of SAH in patients receiving warfarin.…”

Resumption of antiplatelet therapy in patients with primary intracranial haemorrhage: Balancing benefits and risks

“…These findings are similar to the study by Risselada et al which provided evidence that the use of antiplatelets was not associated with an increased risk of ICH [5]. Furthermore, a systematic review performed by Hawryluk et al looking at resumption of anticoagulation following central nervous system (CNS) haemorrhage found that early re-initiation of anticoagulants may be prudent [6].…”

Individual trigger factors for hemorrhagic stroke: Evidence from case-crossover and self-controlled case series studies

“…A total of 441 potentially relevant articles were screened. Finally, 39 candidate articles 4,13-50 met the eligibility criteria (Figure 1), including 28 CCOSs, 10 SCCSs, and 1 using both designs. Associations with the onset of HS were assessed among 32 categories of trigger factors (Table 1, Figure 2), which were classified into four main categories: medications ( n = 14), diseases/vaccination ( n = 13), pregnancy ( n = 5), and behavioral factors ( n = 7).…”

“…A significant association was found between the risk of HS and aspirin use within 7 days in a study of 19,600 patients with ICH in New England, 17 while similar results were not found for aspirin use within 56 days in a study of 3781 Chinese patients 18 or for antiplatelet use within 30 days. 19 The pooled results showed significant associations of HS with both NSAIDs (OR, 1.55; 95% CI, 1.29–1.87) and antiplatelets (OR, 1.10; 95% CI, 1.00–1.21; I 2 , 0.0%; p Q , 0.451), but a large heterogeneity existed for studies on NSAIDs ( I 2 , 85.8%; p Q < 0.001). The use of anticoagulants was also associated with the onset of HS, but with large heterogeneity (OR, 5.43; 95% CI, 2.04–14.46; I 2 , 82.2%; p Q , 0.018).…”

“…Within 1–2 weeks of anticoagulant use, a significantly increased risk of HS and SAH was identified in both Chinese and New English patients. 17,19…”