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Direct Thrombin Inhibitors: Novel Antithrombotics on the Horizon in the Thromboprophylactic Management of Atrial Fibrillation R Katira, a Chauhan, R S More

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Direct Thrombin Inhibitors: Novel Antithrombotics on the Horizon in the Thromboprophylactic Management of Atrial Fibrillation R Katira, a Chauhan, R S More 370 REVIEW Postgrad Med J: first published as 10.1136/pgmj.2004.024521 on 3 June 2005. Downloaded from Direct thrombin inhibitors: novel antithrombotics on the horizon in the thromboprophylactic management of atrial fibrillation R Katira, A Chauhan, R S More ............................................................................................................................... Postgrad Med J 2005;81:370–375. doi: 10.1136/pgmj.2004.024521 Antithrombotic agents have verified efficacy in reducing prevention and 2.5%/year for secondary preven- tion (numbers needed to treat of 66 and 40 the thromboembolic risk associated with atrial fibrillation. respectively). This article focuses on the emergence of a new oral direct thrombin inhibitor, ximelagatran, into the arena of atrial ORAL ANTICOAGULANT THERAPY: fibrillation thromboprophylaxis. This review does not cover EVIDENCE FOR WARFARIN Warfarin, which was introduced 60 years ago, is atrial fibrillation in the context of valvular heart disease. the current mainstay of oral antithrombotic The efficacy of aspirin and warfarin will be discussed therapy for AF. However, despite its confirmed briefly. superior efficacy as compared with aspirin, warfarin therapy can be problematic with ........................................................................... some patients swinging between bleeding and clotting.410 trial fibrillation (AF) is the most common- Table 2 summarises five randomised con- lyly encountered arrhythmia in clinical trolled trials of warfarin compared with control Apractice1 because of an increasingly aging or placebo for the prevention of stroke in patients population coupled with improved survival of with NVAF. All of these trials were stopped early patients with cardiac disease. The median age of because of strongly positive results in favour of patients presenting with AF is 75 years; with 84% warfarin.11 12 19–21 Meta-analysis of the five pri- older than 65 years.2 Consequently in medical mary prevention trials showed that the relative circles, AF is increasingly being recognised as the risk of stroke was reduced by 67% (from 4.5%/ ‘‘modern global epidemic’’ resulting in a huge year to 1.6%/year; 95% CI 50% to 79% p,0.001) burden on health resources; about 1 in 100 of the but with an increased risk of major bleeding population have AF and the rate rises to greater from 1.0% to 1.3%.22 The European atrial 3 fibrillation trial, which compared warfarin, than 1 in 10 in the elderly. http://pmj.bmj.com/ AF is far from being a ‘‘benign arrhythmia’’ aspirin and placebo in NVAF patients with recent and is associated with increased morbidity and transient ischaemic attacks or minor ischaemic mortality. The Framingham study showed an stroke, mirrored these results with a relative risk 23 increased incidence of stroke in AF patients with reduction of 66% with warfarin (p,0.001). The annual incidence being similar to patients with absolute reduction in strokes was much greater rheumatic and non-rheumatic AF.45 It is asso- (80/year/1000 compared with 31/year/1000) ciated with doubling of overall morbidity and because the baseline stroke rate in the study 23 mortality from cardiovascular disease6 and has population was higher. on September 26, 2021 by guest. Protected copyright. now become the leading cause of embolic stroke.7 Patients with non-valvular atrial fibrilla- ASPIRIN COMPARED WITH WARFARIN tion (NVAF) have a 5.6-fold greater risk for Table 3 shows the results of five randomised embolism and those with AF of rheumatic trials comparing aspirin with warfarin for pri- valvular origin have a 17.6-fold greater risk as mary prevention of stroke in NVAF; meta- compared with healthy controls.8 This quantifies analysis found that warfarin reduces the risk of as increased risk of about 5% per year for primary stroke compared with aspirin by 36% (95% CI events and 12% per year for recurrent events.910 14% to 52%).11 13 18 23–25 Low intensity warfarin alone or in combination with aspirin is signifi- See end of article for cantly less effective than adjusted dose warfarin ANTIPLATELET THERAPY: EVIDENCE FOR 26 authors’ affiliations in this patient population. ....................... ASPIRIN Several professional bodies have issued guide- Aspirin does not have a similar thromboprophy- lines to assist physicians in managing AF. Most Correspondence to: lactic efficacy in AF to warfarin, with the degree have recommended adjusted dose warfarin Dr R Katira, Department of of reduction in risk of stroke being less pro- Cardiology, Victoria (international normalised ratio (INR), 2.0–3.0) Hospital, Whinney Heys nounced. Table 1 summarises the six randomised for patients at increased risk of future stroke.27–30 Road, Blackpool FY3 8NR, trials of aspirin compared with placebo; meta- UK; Ravish@katira. analysis of these trials shows an overall reduc- wanadoo.co.uk tion of risk of all strokes of 22% (95%CI 2% to Abbreviations: AF, atrial fibrillation; NVAF, non- 11–18 valvular atrial fibrillation; SPORTIF, stroke prevention Submitted 24 May 2004 38%). There was no significant increased using an oral thrombin inhibitor in atrial fibrillation; TIA, Accepted 28 October 2004 risk of bleeding. Aspirin leads to an absolute transient ischaemic attack; ALAT, alanine ....................... stroke risk reduction of 1.5%/year for primary aminotransferase www.postgradmedj.com Direct thrombin inhibitors 371 PROBLEMS ASSOCIATED WITH WARFARIN USE seem to imply that coagulation monitoring and dose Postgrad Med J: first published as 10.1136/pgmj.2004.024521 on 3 June 2005. Downloaded from Warfarin therapy is efficacious, but is beset with its own adjustments are unnecessary. However, this has to be problems. Warfarin reduces the synthesis of vitamin K tempered by the fact that recent data do suggest that a dependent procoagulant factors II, VII, IX, and X to exert reduction in dose or an increase in the administration its pharmacokinetic effects. Its dose response is influenced by interval in patients with severe renal impairment, or both, various drugs as it is metabolised by the P450 enzyme would be required.54 Furthermore, in the future drug complex. Other factors that can affect its dose response are interactions or a need for dose change may become evident. liver dysfunction, genetic factors, changes in gut flora, One important negative factor of ximelagatran is that at patient compliance, and alcohol intake.31 A very narrow present there is no agent available to counteract drug related therapeutic window along with pronounced variability in its haemorrhage. Because of its short half life, there may be no dose response necessitates frequent checks and hospital clinical need for an antidote. In animal experiments, Feiba visits.32 Home monitoring has been touted as one possible (factor eight inhibitor bypassing activity, a coagulation factor solution; but adds to the initial cost and many patients may concentrate) reversed the prolonged bleeding time and prefer first to choose this option. Clinical trial data have melagatran induced inhibition of thrombin without being shown that ischaemic stroke is far more likely with an prothrombotic.55 INR,2.0, whereas an INR.4.0 increases the risk of Additional potential advantages of ximelagatran include a 33–35 intracranial haemorrhage. targeted specificity for thrombin, the ability to inactivate clot These concerns with warfarin use have led to the bound thrombin, and an absence of plasma protein and development of cautious prescription and under-treatment platelet interactions thus avoiding potential problems such as 36–38 in an increasing litiginous society. Patients are considered thrombocytopenia associated with heparin use. to be at an increased risk of major bleeding secondary to risk The role of ximelagatran in the prevention of stroke in AF factors such as hypertension, history of falls, gastrointestinal patients has been studied in the stroke prevention using an haemorrhage, drug interaction worries, living alone with lack oral thrombin inhibitor in atrial fibrillation (SPORTIF) of assurance about compliance.39–43 Attempts to reduce the programme. The SPORTIF programme consists of a group potential risk of bleeding by using a low and fixed dose of of studies comparing the efficacy and safety of warfarin and warfarin have proved unsuccessful, being associated with a ximelagatran in more than 7700 patients. The programme fourfold increased risk of stroke.43–45 comprises two dose guiding and long term safety studies (SPORTIF II56 and SPORTIF IV57) and two randomised, phase XIMELAGATRAN III trials—SPORTIF III and V58 59), assessing ximelagatran Ximelagatran is a novel oral direct thrombin inhibitor (fig 1) against warfarin. Bleeding was categorised as major when that is rapidly hydrolysed to melagatran, its active form, after associated with functional deficit, haemoglobin decreased by absorption.46 Melagatran has been shown to be a potent 20 g/l, two units or more of transfusion was given, or critical competitive inhibitor of human a thrombin that inhibits both anatomical sites (intracranial, intraspinal, intraocular, retro- thrombin activity and generation.47 Melagatran has a wide peritoneal, pericardial, or intra-articular) were involved. All therapeutic window—that is, unlike warfarin it can be given other overt bleeding was classified as minor. safely across a wide range of doses without a progressive increase in risk of bleeding. Although melagatran has all the requisite pharmacodynamic properties of a new antithrom- SPORTIF II AND IV TRIALS:
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