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J Am Coll Cardiol, 2003; 41:1445-1451, doi:10.1016/S0735-1097(03)00255-9 © 2003 by the American College of Cardiology Foundation |
* Department of Neurology, University State Hospital, Rigshospitalet, Copenhagen, Denmark
Department of Clinical Science and Medicine, AstraZeneca R&D Charnwood, Loughborough, United Kingdom
Department of Biostatistics, AstraZeneca R&D, Mölndal, Sweden
Manuscript received September 17, 2002; revised manuscript received December 20, 2002, accepted December 27, 2002.
* Reprint requests and correspondence: Dr. Palle Petersen, Department of Neurology, University State Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
pape{at}rh.dk
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Abstract |
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 Top Abstract MethodsResultsDiscussionAPPENDIXReferences |
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BACKGROUND: Anticoagulants such as warfarin lower the risk of stroke in patients with NVAF. Ximelagatran is a novel, oral direct thrombin inhibitor with predictable pharmacokinetics and no known food or pharmacokinetic drug interactions.
METHODS: This was a 12-week, randomized, parallel-group, dose-guiding study of NVAF patients with at least one additional risk factor for stroke. The primary end point was the number of thromboembolic events and bleedings. Three groups received ximelagatran (n = 187) at 20, 40, or 60 mg twice daily, given in a double-blind fashion, without routine coagulation monitoring. In a fourth group, warfarin (n = 67) was managed and monitored according to normal routines, aiming for an International Normalized Ratio of 2.0 to 3.0.
RESULTS: A total of 254 patients received study drug. One ischemic stroke (nonfatal) and one transient ischemic attack (TIA) occurred in the ximelagatran group. Two TIAs occurred in the warfarin group. No major bleeds were observed in the ximelagatran group. One major bleed occurred in a warfarin-treated patient. The number of minor and multiple minor bleeds was low, but there was a slight increase by ximelagatran dose. The 60-mg dose resulted in the same number of bleeding events as that with warfarin. S-alanine aminotransferase was increased in eight patients (4.3%) taking ximelagatran, but normalized with continuous treatment or cessation of the drug.
CONCLUSIONS: Fixed oral doses of ximelagatran up to 60 mg twice daily were well tolerated, without the need for dose adjustment or coagulation monitoring.
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The benefits of treatment with oral warfarin in reducing the risk of stroke in patients with NVAF have been well established by multiple randomized trials. In a meta-analysis of five studies, anticoagulation with warfarin produced a 62% relative risk reduction for stroke, compared with placebo (4–9), and this benefit accrued for either primary or secondary prevention (10,11). Indeed, long-term oral anticoagulation therapies in patients with NVAF who have one or more additional risk factors for stroke are supported by several published guidelines (3,12).
Aspirin at doses between 75 and 325 mg/day has also been reported to reduce the risk of stroke in patients with NVAF, although the risk reduction is less than that with warfarin. In one meta-analysis, the relative risk reduction for stroke was 22% after aspirin treatment compared with placebo (4). Current treatment guidelines therefore suggest aspirin rather than warfarin for NVAF patients with a low risk of stroke (i.e., those <60 years of age or those without additional risk factors) (3,12). Higher risk patients who are treated with aspirin instead of warfarin remain at a significant disadvantage in terms of ongoing stroke risk (4).
Ximelagatran (Exanta; AstraZeneca, Mölndal, Sweden) is a novel, oral direct thrombin inhibitor that inhibits the final step in the coagulation process—namely, the conversion of fibrinogen to insoluble fibrin by thrombin. Ximelagatran is converted to its active form, melagatran, after oral administration. Consistent pharmacokinetic properties make the need for dose titration or routine coagulation monitoring unnecessary, creating advantages that are likely to increase compliance with ximelagatran treatment compared with currently available anticoagulants (13). This 12-week study of ximelagatran in patients with chronic NVAF with a medium to high risk of stroke is the first to investigate the tolerability (with special regard for thromboembolic events and bleedings) and safety of three fixed, oral doses of ximelagatran (20, 40, and 60 mg twice daily) compared with dose-adjusted warfarin (aiming for an International Normalized Ratio [INR] of 2.0 to 3.0).
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Methods |
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TopAbstractMethodsResultsDiscussionAPPENDIXReferences |
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End points and outcome events. All strokes and TIAs that occurred during the study were assessed centrally by computed tomography or magnetic resonance imaging scans and classified by an independent neuroradiologist blinded to study treatment as ischemic, ischemic with hemorrhagic transformation, or primary hemorrhagic stroke. The severity of the stroke was assessed according to the modified Rankin scale (14) and the Barthel index of activities of daily living (15) three months after the event.
Safety was assessed by monitoring for bleeding events and adverse events (AEs), clinical chemistry, hematology, urinary erythrocytes (U-Hb), and fecal hemoglobin (Fe-Hb). Blood samples for safety parameters (i.e., hematology and clinical chemistry) were taken at baseline and at 2, 4, 8, and 12 weeks. A central laboratory (BARC Laboratory, Ghent, Belgium) analyzed all samples. Bleeding events were identified by three methods—specific questioning at each visit; AE reporting; and review of the clinical laboratory reports—and were categorized as major or minor according to the following criteria: 1) clinically overt; 2) critical site (e.g., intracranial, retroperitoneal, intraocular, spinal, or pericardial); 3) bleeding index (number of units transfused and a drop of 
2.0 Hb [g/dl] before and after the bleed); and 4) need for medical or surgical intervention.
A "major bleed" was defined as satisfying criterion 1 in combination with any of criteria 2, 3, or 4, and a "minor bleed" as satisfying criterion 1 and none of criteria 2, 3, or 4. Bleeding detected by U-Hb and Fe-Hb dipstick testing was reported separately.
An independent Data Safety Monitoring Board (DSMB) was established to monitor patient safety in the study (i.e., all AEs, withdrawals, major bleeds, and strokes/TIAs). The DSMB reviewed the progress of the study for safety concerns after 100, 200, and 400 patient-months of drug treatment. The DSMB could recommend to the principal investigator and the sponsor whether or not study treatment should be terminated for any safety concerns.
Pharmacokinetics and pharmacodynamics. The pharmacokinetic data from this study will be reported separately (16). The pharmacodynamic profiles of both ximelagatran and warfarin were investigated using activated partial thromboplastin time (aPTT) and INR assays, respectively. For patients receiving ximelagatran, aPTT was analyzed centrally (BARC Laboratory). For those receiving warfarin, the INR was analyzed locally.
Statistical analysis. The tolerability and safety of the three ximelagatran dose levels were assessed exploratively, with the warfarin group as a reference. Data from a sample size of a total of 220 patients randomized in equal numbers to one of three different dose levels of ximelagatran or warfarin to achieve 50 evaluable patients in each of the four treatment groups was considered sufficient to allow for the detection of important tolerability and safety events (e.g., those with minor and major bleeding during any of the four treatment regimens), although no formal statistical power calculation was performed for this dose-guiding study. All statistical analyses were prespecified before the study treatment code was broken. In this primary analysis, the number of thromboembolic events, bleeding, and safety were compared. Descriptive statistics were used in the study, according to the intention-to-treat principle. The final statistical analyses and reporting of the data were performed by the sponsor in collaboration with the authors.
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Results |
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In addition to NVAF, all but one of the patients (99.6%) had at least one additional risk factor for stroke or TIA, 75% of patients had at least two additional risk factors, 42% had three or more risk factors, and one patient had six risk factors (Table 2), thus indicating a moderate- to high-risk patient population. The most common combinations of risk factors in addition to NVAF were age 65 years (14.6%), age 65 years and hypertension (11.8%), age 65 years, hypertension and coronary heart disease (7.1%), and hypertension (4.7%).
Patient disposition. Of 257 patients randomized, 207 completed the study. Forty-seven patients discontinued assigned treatment prematurely, 18 owing to AEs. There was no notable difference in the rates of withdrawal from the ximelagatran and warfarin groups. Four patients discontinued for more than one reason. One patient in the 20-mg ximelagatran group and two patients in the warfarin group discontinued due to AEs and a lack of eligibility criteria. One patient in the 60-mg ximelagatran group did not meet the eligibility criteria and was withdrawn from drug treatment.
Compliance. Mean compliance was 100%, 96%, and 98% for the 20-, 40-, and 60-mg ximelagatran groups, respectively, as assessed by returned tablet counts.
Warfarin control. Attainment of optimal INR values (2.0 to 3.0) increased from 34% of patients at the start of the study to 57% after 12 weeks (Fig. 2). The INR was also assessed, off-protocol, in two patients receiving ximelagatran who had an INR of approximately 2.0.
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65 years of age, hypertension, left ventricular dysfunction, and diabetes mellitus), and two had one risk factor (65 years of age). None were taking aspirin before or during the study.
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Minor and multiple minor bleeds consisted mainly of hematuria, purpura, epistaxis, hematomas after venipuncture, gingival bleeding, or rectal bleeding. These occurred in four, five, and seven patients receiving ximelagatran 20-, 40-, and 60-mg, respectively, compared with six patients in the warfarin group. Figure 3 represents the time of onset and cumulative number of patients experiencing any bleeding since randomization. Numerically, there were fewer bleeds in the 20- and 40-mg ximelagatran treatment groups, compared with the 60-mg ximelagatran and warfarin groups, and they accumulated more slowly during the 12-week treatment period in this study. Most bleeds in the latter two groups occurred within two weeks after the start of the study. There was no statistically significant correlation between bleeding and either creatinine clearance or age in any of the four groups.
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Urine erythrocytes (U-Hb) were positive in 22 patients (i.e., 5, 5, 4, and 8 patients in the 20-, 40-, and 60-mg ximelagatran, and warfarin treatment groups, respectively). Fecal hemoglobin was seen in a total of 22 patients (i.e., 6, 4, 7, and 5 patients in the 20-, 40-, and 60-mg ximelagatran, and warfarin treatment groups, respectively). Thus, there was no real difference between the different doses of ximelagatran compared with warfarin. No other significant clinical or laboratory abnormalities were seen.
Pharmacodynamics. The aPTT increased with increasing ximelagatran doses; there was a nonlinear relation to the plasma concentration of melagatran (r2 = 0.43).
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Discussion |
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TopAbstractMethodsResultsDiscussionAPPENDIXReferences |
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Owing to treatment with warfarin prior to inclusion into the study, 34% of warfarin-treated patients had INRs within the target range at the initiation of the study. However, the INR improved with time, and approximately two-thirds of the warfarin group was maintained in the therapeutic window of an INR of 2.0 to 3.0 at the end of the study. Based on earlier observations, INR levels seem to improve in patients under controlled conditions, such as in clinical trials. This study documents that control of warfarin levels was consistent with what might be expected in a well-run anticoagulation clinic. The INR assays are designed to evaluate the effect of warfarin on the activity of vitamin K–dependent coagulation factors and cannot be used to monitor therapy with thrombin inhibitors such as ximelagatran (19). Our experience and data from this study, undertaken without dose adjustment or coagulation monitoring and with no increase in bleeding events in ximelagatran-treated patients during 12 weeks of treatment, support the evaluation of ximelagatran without routine coagulation monitoring in larger trials of patients with NVAF.
Two clinical events (one TIA and one nonfatal ischemic stroke) occurred in patients receiving ximelagatran (both in the 60-mg group), and two events (TIA) occurred in the warfarin group. There were no thromboembolic events in the 20- or 40-mg ximelagatran groups and no systemic embolic events in any patient group. Interpretation of these findings from this short-term study is limited, and long-term studies involving considerably larger patient populations are ongoing.
Bleeding is an expected AE in trials of anticoagulant drugs, and in this respect, there was no significant difference between ximelagatran and warfarin during this 12-week study. There was a slightly higher rate of minor bleeding with increasing ximelagatran dose, although no statistically significant differences were detected between the groups, and the same number of bleeding events occurred in the 60-mg ximelagatran group as in the warfarin group. No obvious clinical factors (e.g., age, body weight, creatinine clearance) identified patients susceptible to bleeding during treatment.
Asymptomatic elevation in S-ALAT levels developed in 4.3% of patients treated with ximelagatran after four to eight weeks. All values normalized whether treatment was interrupted or continued. The mechanism of action responsible for this finding is not understood, but a similar experience has been reported with unfractionated and low-molecular-weight heparins (20). This phenomenon is being further investigated in ongoing and planned long-term studies of ximelagatran.
Conclusions. Fixed, oral doses of ximelagatran up to 60 mg twice daily were well tolerated, without the need for dose adjustments or coagulation monitoring, during a three-month treatment period in NVAF patients at risk for stroke and systemic embolism. This small, dose-guiding study has several limitations, including a small sample size, a short assessment period, and noncentrally adjudicated bleeding events (although this would be expected to reduce the number of bleeding events reported). In addition, as warfarin was given in an open-label fashion, there may have been a potential for bias. However, larger clinical trials are ongoing to compare ximelagatran with warfarin for long-term prophylaxis against stroke and systemic embolic events in patients with AF.
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APPENDIX |
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TopAbstractMethodsResultsDiscussionAPPENDIXReferences |
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Acknowledgments |
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Footnotes |
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References |
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TopAbstractMethodsResultsDiscussionAPPENDIXReferences |
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the S, Wollbratt M, Eriksson UG. Pharmacokinetics of the oral direct thrombin inhibitor ximelagatran in patients with nonvalvular atrial fibrillation receiving long-term treatment: a population analysis by nonlinear mixed effect modeling. Clin Pharmacol Ther 2002:71:31
hlander K, Lindahl TL. Effect of melagatran on prothrombin time assays depends on the sensitivity of the thromboplastin and the final dilution of the plasma sample. Thromb Haemost. 2001;86:611–615[Medline]
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