G. GRÖNEFELD, D. PAJITNEV, F. WEGENER, J.R. EHRLICH, S.H. HOHNLOSER
Introduction
Three cornerstones constitute the current treatment of atrial fibrillation:
rhythm control, rate control, and antithrombotic therapy for the prevention of systemic thromboembolic events. The loss of mechanical atrial contrac- tion leads to altered blood flow characteristics that can result in clot forma- tion; particularly, the left atrial appendage is the most important area of clot formation within the fibrillating atria. Left atrial thrombi can subsequently embolise to the brain, coronary arteries, peripheral limb arteries, or other end organs, resulting in irreversible and in many patients functionally devas- tating sequelae. The risk of systemic thromboembolism in patients with atri- al fibrillation (AF) is well-established [1, 2]. Five randomised controlled tri- als have convincingly demonstrated that the risk of AF-associated thrombe- mbolic events (predominantly strokes) can be reduced by 65% by therapy with vitamin K antagonists [2]. Accordingly, current guidelines strongly rec- ommend preventive oral anticoagulation in the presence of valvular heart disease, for patients with non-valvular AF who are age 65 years or older, or in the presence of additional risk factors (Table 1) [3–6]. The results from the AFFIRM [7] and other prospective trials comparing rhythm versus rate con- trol have additionally shown that, even when the strategy of rhythm control is effectively pursued, effective oral anticoagulation should be maintained in high-risk patients [8]. Despite this overwhelming body of evidence, however, there is a considerable underutilisation of vitamin K antagonists (Table 2) due to patients’ or doctors’ concerns as well as to an unwillingness to comply with the necessary modes of monitoring and dosage adjustments during
Division of Cardiology, Department of Medicine, J.W.Goethe-University, Frankfurt am Main, Germany
Table 1.Recommendations for antithrombotic therapy in patients with AF Annual stroke Risk stratificationRecommendationsNNT (95% CI) risk (%) Low (1%)Age<65years without additional risk factors (such as:previous stroke,TIA,or systemic embolismASA 227 (135–2500) hypertension,heart failure,or LVEF<50%) Low-moderate (1.5%)Age 65–74years without additional risk factorsASA152 (88–1667) Moderate (2.5%)Age 65–74years without additional risk factorsWarfarin32 (28–42) but comorbidity ofdiabetes or coronary artery disease High (6%)Age<75years with additional risk factors (such as:hypertension,heart failure,or LVEFWarfarin14 (12–17) or:age>75years without any risk factor<50%) Very high (10%)Age>75years with additional risk factors (such as:hypertension,heart failure,or LVEFWarfarin8 (7–10) or:any age with previous history ofstroke, TIA or systemic embolism<50%) NNTNumber needed to treat,ASAAcetyl salicylic acid,TIAtransient ischaemic attack,LVEFleft ventricular ejection fraction
Table 2.The real world:prescription oforal anticoagulants as reported in studies after 1992 StudyNumber ofpatientsPatientOAC populationprescription (%) Albers et al.1997171AF and stroke,19.8 mean age of75years Antani et al.199698AF,mean age of76years36.7 Bath et al.199395AF,age 32–100years29.3 Beyth et al.1996189NVAF24.0 Brass et al.1997488AF,age 65years;54% 38.4 were age 65–74years with additional risk factor Gottlieb et al.1994238AF,mean age of69years78.8 Gurwitz et al.1997413AF,66% age 85years31.5 Hendry et al.1994131 NVAF,age 53–95years15,2 Lip et al.1997111AF,age 50–105years22.3 Lip et al.1994170 AF,aged 38–95years36.0 Munschauer et al.1997651 Chronic AF38.1 O´Connell and Gray,199691 AF,mean age of77years24.1 Sudlow et al.1998207AF,age 65years 23.0 CQIN Investigators,19983575AF,aged 19–104 years23.8 Whittle et al.1997172AF,mean age of80years44.1 NVAF non valvular atrial fibrillation,OAC oral anticoagulation
long-term treatment [9]. Hence, more convenient and equally effective treat- ment alternatives to warfarin are currently under evaluation for the purpose of thromboembolic prophylaxis in patients with AF. The present short review provides an overview of the current state of development of an alternative to vitamin K antagonists for the prevention of AF-associated stroke.
Underuse of Vitamin K Antagonists
The use of oral vitamin K antagonist in patients with AF has stagnated dur- ing more than 15 years that have passed since the publication of the large anticoagulation trials [10]. At present, only 30–50% of high-risk AF patients without contraindications for oral anticoagulation receive this treatment [11]. The major reasons for this underutilisation include the reluctance of physicians and patients to follow the somewhat complicated and time-con- suming procedures of monitoring and patient counseling (Table 3). A fre- quent concern is the narrow therapeutic window of warfarin which may result in an increased bleeding risk, particularly in patients above the age of 80 years [11]. In addition, in many regions of the world, the health care sys- tem may be unable to provide the necessary resources.
Table 3.Main reasons for the underutilisation of warfarin Patient-related reasons
- Advanced age
- Suspected or given lack of compliance - Inconvenience of monitoring - Impaired quality of life
Physician-related reasons
- Failure to detect atrial fibrillation (i.e. in pacemaker patients) - Estimation of individual risk for embolism too low
- Estimation of individual risk for bleeding too high
- Results of randomised controlled trials (RCTs) not known or not accepted - INR-target range not achievable or not maintainable
- Guidelines not applicable for own patients
Health-care-system-related reasons - Limited coverage of frequent INR checks - Lack of specialised anticoagulation-clinics
Moreover, even when warfarin is appropriately prescribed, international normalized ratio (INR) values vary considerably due to individual metabo- lism and food or drug interactions, resulting in over- or undercoagulation.
Even in patients enrolled in prospective trials, the quality of anticoagulation therapy offers room for improvement. For instance, in the Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF III) trial [12], patients kept on open-label warfarin showed an INR within the target range of 2.0–3.0 only during 66% of the monitored intervals. After including a range of borderline effectiveness (INR 1.8–3.2), still 19% of the checked intervals were outside that target range. Accordingly, despite frequent clinical visits and well-supervised treatment, consistent levels of anticoagulation during vitamin K antagonist treatment are difficult to achieve.
Alternative Pharmacological Treatment Options
For many years, acetyl salicylic acid (ASA) has been used as an alternative for treating AF patients with contraindications to warfarin treatment.
However, ASA has limited effectiveness for stroke prevention compared to warfarin [13]. There is ample evidence from experimental and clinical stud- ies that a combination of different antiplatelet agents may increase antithrombotic efficacy compared to monotherapy. A currently ongoing prospective trial investigates the hypothesis that the addition of clopidogrel improves the effectiveness of ASA for the prevention of stroke. The Atrial Fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE) represents the largest prospective study ever performed in patients with AF and additional risk factors for stroke [14]. In this trial pro- gram, the combination of Clopidogrel and ASA compared to warfarin in patients without contraindications and compared to ASA alone in patients with contraindications for oral anticoagulation will be assessed in more than 14 000 patients [14].
Heparin and the low-molecular-weight heparins have gained wide spread acceptance during short-term therapy, i.e. for bridging warfarin treatment pauses due to concomitant interventions. In a prospective multicentre trial, the use of enoxiparin was compared against unfractionated heparin followed by phenprocoumon in patients scheduled for cardioversion of persistent AF (duration > 48 h, < 1 year). Enoxaparin was noninferior to the standard regimen with regard to the incidence of embolic events, all-cause death, and major bleeding complications on per-protocol analysis (7 of 216 patients vs 12 of 212 patients, respectively; P for noninferiority = 0.016) and in an intention-to-treat analysis (7 of 248 patients vs 12 of 248 patients, P = 0.013), respectively [15]. There are, however, only limited data from prospec-
tive studies addressing the benefits of long-term heparin therapy in patients with AF. Ultimately, cost and compliance issues may be seen as a limitation for further research along this avenue.
Thrombin plays a major role in thrombus formation through activation of platelets and conversion of fibrinogen to fibrin. Accordingly, a novel class of effective anticoagulants has been derived from hirudin, the first known direct thrombin inhibitor. More recently, the oral formulation of a direct thrombin inhibitor, ximelagatran, was developed. Hepatic transformation after oral administration leads to the active drug melagatran, which has been shown to be a potent, rapidly binding, competitive inhibitor of human alpha- thrombin that inhibits both, thrombin activity and generation. Melagatran also effectively inhibits both, free and clot-bound thrombin. This drug has a wide therapeutic interval that enables it to be administered safely across a wide range of doses with no increased risk of bleeding [16]. Recently, two prospective studies (SPORTIF III and V) demonstrated the effectiveness of this new compound in AF patients.
Ximelagatran for Stroke Prevention in Atrial Fibrillation
In clinical trials for the prevention and treatment of venous thrombosis, administration of ximelagatran in a fixed dose was comparable with conven- tional therapy (warfarin and/or low-molecular-weight heparin) [17, 18].
Similarly, a prospective study program with this drug for prevention of sys- temic thrombembolism in patients with non-valvular AF was performed.
The SPORTIF trials comprised the SPORTIF II study, a dose-finding trial that was continued during open-label long-term follow up as the SPORTIF IV study. SPORTIF III [12] was an open-label trial and SPORTIF V [19] was a double-blind trial comparing ximelagatran (fixed dose of 36 mg bid) to war- farin with an meticulously monitored treatment to keep the INR between 2.0 and 3.0.
In SPORTIF III, 3410 patients were prospectively randomised to warfarin or ximelagatran [12]. The primary endpoint was the occurrence of stroke (ischaemic and haemorrhagic) or peripheral arterial embolism. After a mean follow-up period of 17.4 months, this endpoint was observed in 56 patients on warfarin (2.3% per year) compared to 40 patients on ximelagatran (1.6%
per year). The sample size of this study was based on a non-inferiority hypothesis which was confirmed by the results. Total mortality did not differ between treatment groups (79 patients on warfarin vs 78 patients on ximela- gatran). Major bleedings were observed in 41 patients on warfarin (1.8%) compared to 29 patients on ximelagatran (1.3%). Combined analysis of major and minor bleeding resulted in a significantly lower event rate for
patients on ximelagatran (478 patients = 25.8%) than for those on warfarin (547 patients = 29.8%; P = 0.007). The overall incidence of side effects was similar between treatment groups. Abnormal liver function, (elevation of alanine transferase), however, occurred significantly more often in patients on ximelagatran (6% vs 1%, P < 0,0001). Forty-nine of the affected patients discontinued treatment and liver enzymes returned to normal in 42 of them;
while in 55 out of 59 patients, laboratory values returned to normal during continued therapy.
The second pivotal study (SPORTIF V) enrolled 3922 patients with non- valvular AF who were assigned in a double-blind fashion to treatment with either ximelagatran (36 mg bid) or warfarin. During a mean follow-up peri- od of 20 months, a primary endpoint event was observed in 37 patients ran- domised to warfarin compared to 51 patients randomised to receive ximela- gatran (P = 0.13) (Table 4). There was a reduced incidence of major and minor bleedings in ximelagatran-treated patients. However, similar to SPORTIF III, a significant elevation of the L-alanine aminotransferase (ALAT) of more than three times the upper normal limit was observed in 6%
of patients receiving ximelagatran. In a pooled analysis of both studies, ximelagatran was found to significantly reduce the combined endpoint of major bleeding or death (Table 4).
Conclusions
The benefits of oral anticoagulation have been consistently proven in many prospective studies. Hence, all patients at risk for thromboembolism due to AF and without contraindications for oral anticoagulants should receive appropriate treatment. According to more recent findings, thrombembolic Table 4.Results from the SPORTIF V trial and combined endpoint analysis from SPORTIF III and V trials
Endpoint Ximelagatran Warfarin P value
n (% per year) n (% per year)
Stroke or embolism 51 (1.6) 37 (1.2) 0.13
Intracranial haemorrhage (0.06) (0.06) 1
Major bleeding (2.4) (3.2) 0.16
Major and minor bleeding 37 47 < 0.001
ALAT > 3 upper limit (6.0) (0.8) < 0.001
Combined SPORTIF III+V
Major bleeding and death (5.2) (6.2) 0.038
ALATL-Alanine aminotransferase
prophylaxis should be continued even with the strategy of rhythm control since many paroxysmal episodes of AF may be asymptomatic and will go unrecognised by patients and doctors. The availability of oral direct throm- bin inhibitors may become a preferable alternative to warfarin. Ximelagatran has shown equal effectiveness compared to warfarin and has a lower risk of bleeding complications. Currently, the occurrence of liver toxicity has jeop- ardised approval of this drug for wider applications in Europe and the USA.
Other substances from the same class are currently under investigation in clinical phase I and phase II trials, but it may take more than 5 years until a protocol comparable to that of the SPORTIF trials and using any of these new compounds has been evaluated.
References
1. Albers GW, Dalen JE, Laupacis A et al (2001) Antithrombotic therapy in atrial fibrillation. Chest 119:S194-S206
2. Anonymous (1994) Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 154:1449–1457
3. Anonymous (1998) ASHP therapeutic position statement on antithrombotic the- rapy in chronic atrial fibrillation. American Society of Health-System Pharmacists.
Am J Health Syst Pharm 55:376–381
4. Fuster V, Ryden LE, Asinger RW et al (2001) ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to develop guidelines for the management of patients with atrial fibrillation) developed in collaboration with the North American Society of Pacing and Electrophysiology. Eur Heart J 22:1852–1923
5. Singer DE, Albers GW, Dalen JE et al (2004) Antithrombotic therapy in atrial fibril- lation: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126:S429–S456
6. Fuster V, Ryden LE, Asinger RW et al (2001) ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the North American Society of Pacing and Electrophysiology. Circulation 104:2118–2150
7. Wyse DG, Waldo AL, DiMarco JP et al (2002) A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 347:1825–1833 8. Gronefeld G, Hohnloser SH (2003) Rhythm or rate control in atrial fibrillation:
insights from the randomized controlled trials. J Cardiovasc Pharmacol Ther 8(suppl 1):S39–S44
9. Buckingham TA, Hatala R (2002) Anticoagulants for atrial fibrillation: why is the treatment rate so low? Clin Cardiol 25:447–454
10. Portnoi VA (1999) The underuse of warfarin treatment in the elderly. Arch Intern Med 159:1374–1375
11. Flaker GC, Schutz J (2004) Why is warfarin underutilized in patients with atrial fibrillation? J Interv Card Electrophysiol 10(suppl 1):21–25
12. Olsson SB (2003) Stroke prevention with the oral direct thrombin inhibitor ximela- gatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 362:1691–1698
13. Taylor FC, Cohen H, Ebrahim S (2001) Systematic review of long term anticoagula- tion or antiplatelet treatment in patients with non-rheumatic atrial fibrillation.
BMJ 322:321–326
14. Hohnloser SH, Connolly SJ (2003) Combined antiplatelet therapy in atrial fibrilla- tion: review of the literature and future avenues. J Cardiovasc Electrophysiol 14:S60-S63
15. Stellbrink C, Nixdorff U, Hofmann T et al (2004) Safety and efficacy of enoxaparin compared with unfractionated heparin and oral anticoagulants for prevention of thromboembolic complications in cardioversion of nonvalvular atrial fibrillation:
the Anticoagulation in Cardioversion using Enoxaparin (ACE) trial. Circulation 109:997–1003
16. Gustafsson D, Elg M (2003) The pharmacodynamics and pharmacokinetics of the oral direct thrombin inhibitor ximelagatran and its active metabolite melagatran: a mini-review. Thromb Res 109:S9–S15
17. Fiessinger JN, Huisman MV, Davidson BL et al (2005) Ximelagatran vs low-molecu- lar-weight heparin and warfarin for the treatment of deep vein thrombosis: a ran- domized trial. JAMA 293:681–689
18. Francis CW, Berkowitz SD, Comp PC et al (2003) Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replace- ment. N Engl J Med 349:1703–1712
19. Albers GW, Diener HC, Frison L et al (2005) Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial.
JAMA. 293:690–698
