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Drugs

, Volume 66, Issue 5, pp 671–692 | Cite as

Triflusal

A Review of its Use in Cerebral Infarction and Myocardial Infarction, and as Thromboprophylaxis in Atrial Fibrillation
  • David Murdoch
  • Greg L. Plosker
Adis Drug Evaluation

Summary

Abstract

Triflusal (Aflen®, Disgren®, Tecnosal®, Triflux®) is a novel platelet antiaggregant with structural similarities to salicylates, but which is not derived from aspirin. It has similar efficacy to aspirin in patients with cerebral or myocardial infarction, but has a reduced risk of haemorrhagic complications. In addition, triflusal plus moderate-intensity anticoagulation has demonstrated efficacy when used as thromboprophylaxis in atrial fibrillation. As such, triflusal has a role in the primary prevention of cerebrovascular events in atrial fibrillation, and for the secondary prevention of cerebral and myocardial infarction, primarily as an alternative to aspirin in patients for whom aspirin is unsuitable.

Pharmacological Properties

Triflusal and its principal metabolite, 2-hydroxy-4-(trifluoromethyl)benzoic acid (HTB), inhibit cyclo-oxygenase (COX) isoform 1 and therefore inhibit thromboxane biosynthesis. In addition, both triflusal and HTB inhibit cyclic adenosine monophosphate (cAMP) phosphodiesterase, thereby restricting cAMP breakdown in platelets and also restricting calcium mobilisation and calcium-dependent platelet aggregation. Triflusal appears to have a selective activity against platelet COX-1 relative to vascular endothelial COX-2.

After oral administration, triflusal is rapidly hydrolysed to HTB. After a single dose of 900mg in healthy volunteers, values for absorption half-life of 0.40 and 2.44 hours were documented for triflusal and HTB, respectively. Corresponding values for mean maximum plasma concentration were 11.6 and 92.7 mg/L, and for terminal elimination half-life were 0.53 and 34.3 hours. Triflusal elimination is primarily renal: >60% of the parent compound is excreted in the urine, as unchanged triflusal, HTB and an HTB-glycine conjugate, within 48 hours of administration. There are no major differences in the pharmacokinetic profiles of triflusal and HTB in elderly and younger individuals, such that triflusal dosage adjustments are unnecessary in elderly patients.

Therapeutic Efficacy

In large-scale, randomised, double-blind, multicentre studies in patients with nondisabling ischaemic stroke or a transient ischaemic attack (TLA) in the previous 6 months, triflusal 600 mg/day was equally as effective as aspirin 300–330 mg/day, as evident from the incidence of the primary composite endpoint of serious vascular events (12.7–19.8% vs 12.4–28.8%).

The TIM (Triflusal in Myocardial Infarction) study also revealed no significant triflusal-aspirin difference in occurrence of the composite primary endpoint of death, nonfatal myocardial reinfarction and nonfatal cerebrovascular events within 35 days of acute myocardial infarction (9.1% vs 10.2%). Subgroup analyses of TIM study data suggested that triflusal may be a superior therapeutic option to aspirin in elderly patients receiving concurrent therapy with either alteplase (recombinant tissue plasminogen activator) or an ACE inhibitor; however, this possibility requires further investigation.

In patients with nonvalvular or valvular atrial fibrillation, triflusal plus reduced-intensity acenocoumarol therapy (target international normalised ratio [INR] 1.25–2.4) was significantly more effective than monotherapy with either triflusal or standard-intensity acenocoumarol (target INR 2.0–3.0) regarding a lower incidence of the composite primary endpoint of vascular death, TIA, and nonfatal stroke or systemic embolism; this applied even in patients at high risk of developing thromboembolism.

A randomised, multicentre pilot study of triflusal versus standard-intensity acenocoumarol therapy in patients who had undergone bioprosthetic valve replacement found no significant primary endpoint difference between the two treatments, and triflusal was associated with a significantly lower incidence of haemorrhagic adverse events than acenocoumarol.

Tolerability

Large-scale clinical trials reported that, with the exception of a significantly lower rate of haemorrhagic events in triflusal recipients (e.g. 13.7% vs 21.8%; p < 0.001 in the TACIP [Triflusal versus Aspirin in Cerebral Infarction Prevention] study), the tolerability profile of triflusal was generally similar to that of aspirin. These trials documented a treatment withdrawal rate due to adverse events of 2.3–5.1% in triflusal recipients and of 3.0–6.0% in aspirin recipients. The overall incidence of treatment-related adverse events was 34–54% in both groups. In the largest trial, the TIM study, the main triflusal-induced adverse events involved the gastrointestinal tract (26.8% of patients; primarily dyspepsia, constipation and flatulence) and central and peripheral nervous systems (8.9%; e.g. headache), with no significant difference in incidence rates relative to aspirin recipients. In the second-largest trial (TACIP), the most frequently reported nonhaemorrhagic adverse events in triflusal-treated patients were dyspepsia (27.4%), abdominal pain (21.8%), nausea (8.5%) and vomiting (5.1%).

A large meta-analysis of five studies found no significant difference between triflusal and aspirin in the overall incidence of adverse events (55.3% vs 55.6%), whereas serious treatment-related adverse events were significantly less frequent (4.0% vs 5.2%; p = 0.03), and nonhaemorrhagic gastrointestinal adverse events significantly more frequent (44.0% vs 40.1%; p = 0.004), in triflusal than in aspirin recipients.

Bleeding complications were consistently less common, in large-scale clinical trials and a large meta-analysis, in patients treated with triflusal rather than aspirin. For instance, significantly (p < 0.05) lower rates of the following haemorrhagic complications were evident: CNS-related bleeding in the TIM study (0.3% vs 1.0%); haematoma (3.8% vs 6.7%), gastrointestinal (4.6% vs 7.6%) or any bleeding (13.7% vs 21.8%) in the TACIP study; and bleeding-related adverse events (8.5% vs 13.3%), fatal or nonfatal haemorrhagic stroke (0.5% vs 1.1%), nonfatal haemorrhagic stroke (0.2% vs 0.6%), intracranial or other major extracranial bleeding (1.2% vs 3.0%), any major extracranial bleeding (0.7% vs 1.8%), and any minor (7.6% vs 11.2%) or gastrointestinal bleeding (2.4% vs 4.3%) in a large meta-analysis.

Keywords

Aspirin Atrial Fibrillation Acute Myocardial Infarction Dipyridamole Alteplase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, AucklandNew Zealand

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