Paracetamol, Ibuprofen, and Recurrent Major Cardiovascular and Major Bleeding Events in 19 120 Patients With Recent Ischemic Stroke

Abstract

T he association between nonsteroidal anti-inflammatory drugs (NSAIDs) and cardiovascular risk is well established, particularly in high-risk populations.1 Paracetamol (acetaminofen) is the most widely used analgesic and antipyretic worldwide.2 It is commonly accepted that it has a better safety profile than NSAIDs, and thus it is usually the treatment of choice in many medical conditions. In patients with a high cardiovascular risk, recommendations state that paracetamol should be chosen over NSAIDs.3 Recently, this assumed safety profile has been questioned. First, Hinz et al found that paracetamol produces a substantial selective cyclooxygenase 2 (COX-2) inhibition to a degree comparable to nonselective Background and Purpose-The presumed safety of paracetamol in high-cardiovascular risk patients has been questioned.We determined whether paracetamol or ibuprofen use is associated with major cardiovascular events (MACE) or major bleeding in 19 120 patients with recent ischemic stroke or transient ischemic attack of mainly atherothrombotic origin included in the Prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) trial. Methods-We performed 2 nested case-control analysis (2153 cases with MACE during trial follow-up and 4306 controls matched on Essen stroke risk score; 809 cases with major bleeding matched with 1616 controls) and a separate timevarying analysis. Results-12.3% were prescribed paracetamol and 2.5% ibuprofen. Median duration of treatment was 14 (interquartile range 5-145) days for paracetamol and 9 (5-30) days for ibuprofen. Paracetamol, but not ibuprofen, was associated with increased risk of MACE (odds ratio 1.21, 95% confidence interval [CI] 1.04-1.42) or a major bleeding (odds ratio 1.60, 95% CI 1.26-2.03), with no impact of daily dose and duration of paracetamol treatment. Time-varying analysis found an increased risk of MACE with both paracetamol (hazard ratio 1.22, 95% CI 1.05-1.43) and ibuprofen (hazard ratio 1.47, 95% CI 1.06-2.03) and of major bleeding with paracetamol (hazard ratio 1.95, 95% CI 1.45-2.62). Conclusions-There was a weak and inconsistent signal for association between paracetamol or ibuprofen and MACE or major bleeding, which may be related to either a genuine but modest effect of these drugs or to residual confounding. Clinical Trial Registration-http://www.isrctn.com. Unique identifier: ISRCTN66157730.

The Intracranial-B₂LEED₃S Score and the Risk of Intracranial Hemorrhage in Ischemic Stroke Patients Under Antiplatelet Treatment

“…Patients with large, severe ischemic stroke with residual handicap measured by a modified Rankin score >3, who are more prone to bleed than those with minor ischemic stroke, were also excluded in both trials. Interaction with other drugs prescribed during the course of the trial may also be an important bleeding factor, such as paracetamol or ibuprofen prescriptions [27]. We found that these drugs were associated with almost a doubling in major hemorrhages [27].…”

“…Interaction with other drugs prescribed during the course of the trial may also be an important bleeding factor, such as paracetamol or ibuprofen prescriptions [27]. We found that these drugs were associated with almost a doubling in major hemorrhages [27]. It is thus reasonable to think, but yet to be validated, that in the Intracranial-B 2 LEED 3 S score addition of paracetamol or ibuprofen can be substituted by the ‘dual antiplatelet therapy' variable.…”

Pain Management in Patients with Impaired Kidney Function

“…and they found increased relative rate of mortality from 0.95 to 1.63 and for cardiovascular adverse events risk ratio of all events increased from 1.19 to 1.68 and also that gastrointestinal adverse events or bleeds were found to increase from 1.11 to 1.49; moreover, kidney damage odds ratio increased more than 30% [23]. Another notable paper published on acetaminophen's cardiovascular side effect could only demonstrate small association with major cardiovascular events and short-term use of acetaminophen (odds ratio 1.21, 95% confidence interval 1.04-1.42) [24].…”

Elevated Serum Oleic Acid Epoxide Concentration in Acetaminophen (Paracetamol) Poisoning

“…Acetaminophen causes major bleeding events at therapeutically relevant doses in patients with recent ischemic stroke [13]. Possible mechanisms could involve the participation of acetaminophen metabolites such as NAPQI [10] or cis-EpOA, rather than thromboxane A2 inhibition in platelets by acetaminophen [7].…”