Dabigatran With or Without Concomitant Aspirin Compared With Warfarin Alone in Patients With Nonvalvular Atrial Fibrillation (PETRO Study)

Dabigatran With or Without Concomitant Aspirin Compared With Warfarin Alone in Patients With Nonvalvular Atrial Fibrillation (PETRO Study)

Dabigatran With or Without Concomitant Aspirin Compared With Warfarin Alone in Patients With Nonvalvular Atrial Fibrillation (PETRO Study) Michael D. ...

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Dabigatran With or Without Concomitant Aspirin Compared With Warfarin Alone in Patients With Nonvalvular Atrial Fibrillation (PETRO Study) Michael D. Ezekowitz, MD, PhDa,*, Paul A. Reilly, PhDb, Gerhard Nehmiz, PhDc, Timothy A. Simmers, MDe, Rangadham Nagarakanti, MDa, Kambiz Parcham-Azad, MDa, K. Erik Pedersen, MDf, Dominick A. Lionetti, MAb, Joachim Stangier, PhDd, and Lars Wallentin, MD, PhDg This is the first evaluation of dabigatran, an oral direct thrombin inhibitor, in patients with atrial fibrillation (AF). Patients (n ⴝ 502) were randomized to receive blinded doses of 50-, 150-, or 300-mg dabigatran twice daily alone or combined with 81- or 325-mg aspirin or open-label warfarin administered to achieve an international normalized ratio of 2 to 3 for 12 weeks. Dabigatran plasma concentrations, activated partial thromboplastin time, D-dimer, urinary 11-dehydrothromboxane B2 (DTB2), and liver function were measured at baseline and at 1, 2, 4, 8, and 12 weeks. Clinical end points were assessed according to the treatment received at the time of the event. Overall, 92% of patients completed the study. Major hemorrhages were limited to the group treated with 300-mg dabigatran plus aspirin (4 of 64), and the incidence was significant versus 300-mg dabigatran alone (0 of 105, p <0.02). Total bleeding events were more frequent in the 300-mg (39 of 169, 23%) and 150-mg (30 of 169, 18%) dabigatran groups compared with the 50-mg groups (7 of 107, 7%; p ⴝ 0.0002 and p ⴝ 0.01, respectively). Thromboembolic events were limited to the 50-mg dabigatran dose groups (2 of 107, 2%). The mean trough D-dimer measurements were suppressed for the 2 highest doses of dabigatran and warfarin (international normalized ratio of 2 to 3). Aminotransferase levels >3 times the upper limit of normal were observed in 0.9% of the dabigatran recipients and in none of the warfarin recipients. Two dabigatran recipients had aminotransferase levels >5 times the upper limit of normal as a result of gallstones, which resolved. Trough activated partial thromboplastin time values were 1.2, 1.5, and 1.8 times the baseline level for the 50-, 150-, and 300-mg dabigatran groups, respectively. DTB2 concentrations after 12 weeks of 50-, 150-, and 300-mg dabigatran treatment were increased by 31%, 17%, and 23%, respectively, versus baseline (p ⴝ 0.02, p ⴝ 0.03, and p ⴝ 0.0004). In conclusion, major bleeding events were limited to patients treated with dabigatran 300 mg plus aspirin and thromboembolic episodes were limited to the 50-mg dabigatran groups. The 2 highest doses of dabigatran suppress D-dimer concentrations. Serious liver toxicity was not seen. The significance of the increase of DTB2 concentrations in dabigatran-treated patients needs resolution. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:1419 –1426)

Vitamin K antagonists are the only orally active anticoagulants currently available. They decrease the risk of stroke and systemic thromboembolism in patients with atrial fibrillation (AF) by 68%.1 However, vitamin K a

Lankenau Institute for Medical Research and The Heart Center, Wynnewood, Pennsylvania; bDepartment of Clinical Research, Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut; Departments of cMedical Data Services and dDrug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Biberach, Germany; eThorax Centre, Amphia Hospital, Breda, The Netherlands; fOdense University Hospital, Odense, Denmark; and g Uppsala Clinical Research Centre, Uppsala, Sweden. Manuscript received March 14, 2007; revised manuscript received and accepted June 10, 2007. Boehringer Ingelheim Pharmaceuticals, Biberach, Germany, is the sponsor of this study and has provided a research grant. The members and structure of the PETRO study group are given in the Appendix at the end of this article. *Corresponding author: Tel: 610-645-8451; fax: 610-645-8460. E-mail address: [email protected] (M.D. Ezekowitz). 0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2007.06.034

antagonists have a highly variable inter- and intraindividual anticoagulant response, with multiple drug and food interactions, necessitating regular monitoring and adjustment of dose.2 These factors, plus fear of hemorrhage, have resulted in substantial underuse of warfarin, particularly in patients with AF.3 A fixed-dose, orally effective anticoagulant without the need for monitoring would constitute a significant improvement. Dabigatran etexilate is an orally available prodrug that is converted to dabigatran, the active moiety. It is a potent, competitive, and reversible direct inhibitor of thrombin. Peak dabigatran plasma concentrations occur 0.5 to 2 hours after oral administration, resulting in a rapid onset of action. There is a bi-exponential distribution phase with a terminal half-life of 12 to 17 hours. As much as 80% of the drug is excreted unchanged by the kidneys. The average absolute bioavailability of dabigatran is 6.5%.4,5 www.AJConline.org

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Figure 1. Treatment distribution, down-titration, and discontinuations. If glomerular filtration rate was ⬍50 and aPTT was ⬎2.5 times the normal value, down-titration was performed. Broken lines, down-titration; solid lines, discontinuation.

This is the first evaluation of dabigatran in patients with AF. The main goal of the study was to identify a safe dose of dabigatran in patients with AF as determined by the occurrence of bleeding and clinical events, and to identify anticoagulant activity through activated partial thromboplastin time (aPTT) changes and the inhibition of D-dimer generation.6 Methods This study was conducted in 53 centers in Denmark, the Netherlands, Sweden, and the United States. The protocol was developed by the Steering Committee of the Prevention of Embolic and Thrombotic Events in Patients with Persistent AF (PETRO) study group. An independent adjudication committee blinded to treatment evaluated all bleeding events. An independent data and safety monitoring board monitored the study for safety. Boehringer Ingelheim (Biberach, Germany) sponsored the study and was responsible for the statistical analysis conducted according to a prospectively designed plan approved by the steering committee. All authors had access to the data. The protocol, protocol amendments, informed consent, and subject information forms were reviewed and approved by a local institutional review board or independent ethics committee before initiation. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki, International Conference on Harmonisation, and the Tripartite Guideline of Good Clinical Practice. Written informed consent was obtained from each patient. The PETRO study was a randomized trial of patients with AF at high risk for thromboembolic events. Inclusion criteria were documented AF with coronary artery disease plus ⱖ1 of the following: hypertension requiring medical treatment, diabetes mellitus (type 1 or 2), symp-

tomatic heart failure or left ventricular dysfunction (ejection fraction ⬍40%), previous stroke or transient ischemic attack, or age ⬎75 years. After entry of approximately half of the patients, the requirement for coronary artery disease was removed to facilitate recruitment. Exclusion criteria were mitral stenosis, prosthetic heart valves, planned cardioversion, recent (ⱕ1 month) myocardial infarction, recent stroke or transient ischemic attack, coronary stent placement within 6 months, any contraindication to or another indication for anticoagulant therapy, major hemorrhage in the past 6 months, severe renal impairment (glomerular filtration rate ⱕ30 ml/min), abnormal liver function, risk of pregnancy, investigational drug use within 30 days, or any other condition that would not allow participation in the study. The trial had a total of 10 treatment groups. Three doses of dabigatran etexilate (50, 150, and 300 mg twice daily) were combined in a 3 ⫻ 3 factorial fashion with no aspirin or 81- or 325-mg aspirin once daily. Patients received warfarin alone (international normalized ratio [INR] of 2 to 3) in the comparator group. The trial was double-blind with respect to dabigatran dose but openlabel for concomitant aspirin treatment and for randomization between dabigatran and warfarin groups. Randomization was stratified in the ratio 6:9:9:4 (50-, 150-, and 300-mg dabigatran, and warfarin, respectively) (Figure 1). The screening visit was the baseline visit for all laboratory tests and measurements with the exception of D-dimer, the baseline visit for which for pre-/post-treatment comparisons was the randomization visit. Two identical matching capsules containing 50- or 150-mg dabigatran or placebo were taken twice daily for 12 weeks. All patients had been treated with a vitamin K antagonist for ⱖ8 weeks before inclusion and required an INR between 2 and 3 at study entry. This ensured that baseline D-dimer measurements were obtained under the

Arrhythmias and Conduction Disturbances/Dabigatran in Nonvalvular AF

condition of full anticoagulation. At the screening visit, warfarin pretreatment was terminated. Patients randomized to receive warfarin or dabigatran started study treatment when the INR was ⱕ1.5 to avoid excessive anticoagulation. Participants were monitored as outpatients at 1, 2, 4, 8, and 12 weeks after randomization. Renal function was measured with the Levey equation at the initial visit.7 After 4 to 7 days of treatment, all patients with glomerular filtration rates ⱕ50 ml/min underwent down-titration to once-daily dabigatran if the aPTT ratio at trough was ⱖ2.5 times the local laboratory reference value. These patients were analyzed according to the group to which they were initially assigned. Major hemorrhages were observed in the group that received dabigatran 300 mg twice daily plus aspirin: 3 at the 325-mg aspirin dose and 1 at the 81-mg dose. The data and safety monitoring board recommended, and the steering committee agreed, that patients receiving 300-mg dabigatran twice daily plus aspirin should be switched to 300-mg dabigatran twice daily without aspirin. This decision occurred after patient recruitment had been completed. Stroke was defined as an acute onset of a focal neurologic deficit of vascular origin lasting for ⱖ24 hours. Systemic thromboembolism was defined as an acute nonintracerebral or noncoronary vascular event. Bleeding events were classified as major or minor and were assigned to the treatment the patient was receiving at the time of onset. Major bleeding was defined as fatal or life-threatening retroperitoneal, intracranial, intraocular, or intraspinal bleeding; or bleeding requiring surgery or transfusion of ⱖ2 U or associated with a decrease in hemoglobin of ⱖ2.0 g/L. Minor bleeding was further subdivided into clinically relevant or nuisance bleeding episodes. Clinically relevant bleeding was defined as skin hematoma ⬎25 cm2, spontaneous nose bleed of ⬎5 minutes duration, macroscopic hematuria, spontaneous rectal bleeding, gingival bleeding for ⬎5 minutes, any bleeding leading to hospitalization, any bleeding leading to transfusion ⬍2 U, or any other bleeding considered relevant by the investigator. Safety laboratory assessments were performed at screening and 1, 4, 8, and 12 weeks after randomization and, if necessary, at a further follow-up after the 12-week visit. Treatment was withdrawn if aspartate aminotransferase, alanine aminotransferase, bilirubin, or alkaline phosphatase concentrations were ⬎5 times the upper limit of normal at any time or ⬎3 times the upper limit of normal for 4 weeks, or if the patient developed clinical signs or symptoms of hepatic insufficiency. For the pharmacokinetic and pharmacodynamic analyses, samples were obtained at screening and randomization and then at 1, 2, 4, 8, and 12 weeks after randomization. Dabigatran plasma concentrations were assayed using a liquid chromatograph–tandem mass spectrometry method at AAI Deutschland, Neu-Ulm, Germany. The aPTT was measured centrally by a coagulation analyzer (Roche Diagnostics, Nutley, New Jersey) at Boehringer Ingelheim. Analyses of D-dimer were performed by the PLUS Assay for the turbidimetric determination of cross-

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linked fibrin degradation products (Dade Behring, Marburg, Germany). Soluble fibrin was determined by an automated latex photometric assay (LPIA-Iatro SF; Mitsubishi Kagaku Iatron, Gauting, Germany). Urinary samples for 11-dehydrothromboxane B2 (DTB2) excretion were obtained at screening and randomization and at cessation of treatment after the12-week visit. The determinations of DTB2 in urine were performed with an DTB2 enzyme immunoassay kit (Correlate-EIA; Assay Designs, Ann Arbor, Michigan). No formal statistical hypothesis was tested. However, the goal of the study was to determine whether there was a dose-related incidence of bleeding and to collect pharmacodynamic data to assist in the selection of a dose(s) for the phase 3 study. The primary end point was incidence of bleeding. A secondary objective was to measure suppression of D-dimer to evaluate the activity of dabigatran; week 12 values were compared with baseline values, defined as the value at the randomization visit for each treatment group. The mean trough measurements for each group were calculated and a 1-sample Wilcoxon test was used to determine statistical significance of changes from baseline. Generally, data were reported as means ⫾ SD or as median ⫾ interquartile range. Differences between groups were analyzed using the chi-square test or the Fisher exact test, and for quantitative data with 1-way analysis of variance or the Kruskal-Wallis test as appropriate. All analyses were performed with SAS software (version 8.2; SAS Institute, Cary, North Carolina). Results Of 502 patients randomized, 411 (81.9%) were men, with 192 (38.2%) having permanent AF, 195 (38.8%) persistent AF, and 115 (22.9%) paroxysmal AF. The median duration of AF was 4 years (range 0.05 to 30). Mean ages were 70.9 ⫾ 7.9 years in patients with CAD (n ⫽ 306) and 68.0 ⫾ 8.8 years in those without CAD. The baseline characteristics were balanced among the 10 randomized treatment groups (Table 1). Patients had a median of 3 risk factors for stroke. The mean rate of compliance with dabigatran treatment (excluding patients who withdrew or were discontinued) was 99.5%. Twelve patients underwent a dose down-titration (Figure 1). Thirteen patients stopped aspirin treatment during the trial. In the warfarin group, the INR was within the target range (i.e., 2 to 3) during 57.2% of the treatment time. The percent time in target range increased from 48.2% in the first 4 weeks to 62.1% in weeks 5 through 8 and to 64.5% in weeks 9 through 12. Overall, 38 patients discontinued trial treatment, 29 because of adverse events (Table 2); 3 withdrew consent; and 1 patient was not compliant with study medication. Another patient returned for the final visit, but it was not possible to determine whether the patient was compliant with study medication. The patient was classified as “discontinued.” The 4 remaining patients withdrew, 1 each as a result of percutaneous coronary intervention for coronary artery disease requiring clopidogrel, angiography planned before trial entry, difficulty with blood draws,

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Table 1 Baseline characteristics Variable

Age (mean ⫾ SD, yrs) Duration of AF median (interquartile range, yrs) Women Age ⬎75 yrs TIA or stroke Hypertension Diabetes mellitus Heart failure Coronary artery disease Current or former smoker ␤ blockers ACE inhibitor/angiotensin receptor–2 blocker Verapamil/diltiazem Other calcium inhibitors Amiodarone Digoxin Diuretic Statin

All Patients (n ⫽ 502) 70 (8.3) 4 (6.5)

Dabigatran 50 mg Twice Daily (n ⫽ 105)

Dabigatran 150 mg Twice Daily (n ⫽ 166)

Dabigatran 300 mg Twice Daily (n ⫽ 161)

Warfarin INR 2–3 (n ⫽ 70)

p Value for Equality of Groups

70 (8.8) 3.6 (6.9)

70 (8.1) 3.9 (6.6)

69.5 (8.4) 6.4 (4.3)

69 (8.3) 3.4 (5.0)

0.7 0.4

91 (18%) 158 (31.5%) 87 (17.3%) 356 (71%) 126 (25%) 147 (29.3%) 306 (61%) 365 (72.7%) 349 (69.5%) 355 (70.7%)

21 (20%) 36 (34.3%) 19 (18%) 70 (66.7%) 27 (25.7%) 35 (33.3%) 64 (61%) 76 (72.4%) 69 (65.7%) 70 (66.7%)

31 (18.7%) 51 (30.7%) 29 (17.5%) 118 (71%) 45 (27%) 52 (31.3%) 104 (63%) 120 (72.3%) 121 (73%) 116 (69.8%)

28 (17.4%) 52 (32.3%) 26 (16%) 119 (74%) 39 (24%) 36 (22.4%) 96 (59.6%) 116 (72%) 110 (68.3%) 112 (69.5%)

11 (15.7%) 19 (27%) 13 (18.6%) 49 (70%) 15 (21.4%) 24 (34.3%) 42 (60%) 53 (75.7%) 49 (70%) 57 (81.4%)

0.9 0.8 1.0 0.6 0.8 0.1 1.0 1.0 0.6 0.2

95 (19%) 115 (22.9%) 37 (7.4%) 219 (43.6%) 289 (57.5%) 290 (57.7%)

16 (15%) 26 (24.7%) 9 (8.5%) 46 (43.8%) 59 (56%) 58 (55%)

31 (18.7%) 37 (22.3%) 9 (5.4%) 75 (45%) 89 (53.6%) 100 (60%)

34 (21%) 38 (23.6%) 13 (8%) 66 (41%) 97 (60%) 95 (59%)

14 (20%) 14 (20%) 6 (8.5%) 32 (45.7%) 44 (63%) 37 (53%)

0.7 0.9 0.7 0.9 0.5 0.7

ACE ⫽ angiotensin-converting enzyme; TIA ⫽ transient ischemic attack. Table 2 Adverse events leading to discontinuation Event

Patients discontinuing with adverse events* Cardiovascular and peripheral embolic events† Major/clinically relevant hemorrhage Gastrointestinal symptoms‡ ALT/AST increased Other symptoms§

Dabigatran Dose (twice daily) 50 mg (n ⫽ 107)

150 mg (n ⫽ 169)

300 mg (n ⫽ 169)

5 4 0 2 0 2

9 2 4 2 0 1

15 1 7 8 1 4

Warfarin to INR of 2–3 (n ⫽ 70) 0 0 0 0 0 0

* Some patients had ⱖ1 event. Cardiac failure, acute coronary syndrome, cerebrovascular accident, and peripheral emboli, including renal infarction. ‡ Abdominal pain, dyspepsia, and nausea. § Fatigue, dyspnea, visual disturbance, worsening dizziness, renal pain, and chest pain. ALT ⫽ alanine aminotransferase; AST ⫽ aspartate aminotransferase. †

and personal reasons. Patients were followed for 2 weeks after discontinuation of study medication. The primary outcome was the frequency of bleeding events (Table 3). Major bleeding events were limited to the group treated with 300-mg dabigatran twice daily plus aspirin (4 of 64). The rate was statistically different compared with the group treated with dabigatran 300 mg twice daily without aspirin (0 of 105, p ⬍0.02). There was a significant difference in major plus clinically relevant bleeding episodes (11 of 64 vs 6 of 105, p ⫽ 0.03) and total bleeding episodes (25 of 64 vs 14 of 105, p ⫽ 0.0003) between 300-mg dabigatran twice daily plus aspirin and 300-mg dabigatran twice daily without aspirin. The frequency of bleeding in the group treated with 50-mg dabigatran twice daily was significantly lower than that in the warfarin group: 7 of 107 vs 12 of 70 (p ⫽ 0.044).

When the doses of dabigatran were compared with each other, irrespective of aspirin assignment, there were differences in total bleeding episodes in the 300-mg twice daily and 150-mg twice daily groups versus the 50-mg twice daily group (37 of 169 and 30 of 169 vs 7 of 107, p ⫽ 0.0002 and p ⫽ 0.01, respectively). There were 2 patients with systemic thromboembolic events (Table 3), both of whom received 50-mg dabigatran twice daily (1.96%). One patient had a peripheral embolism to the toe and the other patient had a stroke and a renal infarction. Seven patients reported angina, of which 2 patients were classified as having acute coronary syndrome: 1 treated with 50-mg dabigatran twice daily plus 81-mg aspirin and the other treated with 300-mg dabigatran twice daily plus 81-mg aspirin. Both patients were discontinued from the trial (Table 2). Four patients devel-

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Table 3 Major or clinically relevant bleeding episodes and thromboembolic events Dabigatran Dose (mg twice daily) 50 50 50 150 150 150 300 300 300 Warfarin once daily

Aspirin Dose (mg)

0 81 325 0 81 325 0 81 325 0

No. of Patients*

59 21 27 100 36 33 105 34 30 70

Bleeding Events

Thromboembolic Events

Major

Clinically Relevant Plus Major

Total

0 0 0 0 0 0 0 1 (2.9%) 3 (10%) 0

0 1 (4.8%) 1 (3.7%) 9 (9%) 2 (5.6%) 2 (6.1%) 6 (5.7%) 5 (14.7%) 6 (20%) 4 (5.7%)

2 (3.4%) 2 (9.5%) 3 (11.1%) 15 (15%) 8 (22.2) 7 (21.2%) 14 (13.3%) 11 (32.4%) 14 (46.7%) 12 (17.1%)

1 (1.7%) 1 (4.8%) 0 0 0 0 0 0 0 0

* Thirteen patients assigned to dabigatran plus aspirin stopped receiving aspirin during the trial (2 receiving 50-mg dabigatran, 3 receiving 150-mg dabigatran, and 8 receiving 300-mg dabigatran twice daily) and then were analyzed in dabigatran-alone groups.

Figure 2. Box and whisker plots of median trough plasma concentration of dabigatran (in nanograms per milliliter) on maintenance treatment for each dabigatran treatment group.

oped congestive heart failure, with 1 patient receiving 150-mg dabigatran twice daily discontinuing the trial. None of these events resulted in statistically significant differences between treatment groups. Dabigatran (plasma half-life of 12 to 17 hours) attained steady state by the time of the first follow-up at 4 to 7 days. The mean trough plasma concentration increased linearly with increasing dose (Figure 2). Reduced creatinine clearance resulted in higher dabigatran plasma concentrations (data not shown). The mean creatinine clearance was 81 ml/min; it was 69 ml/min in women and 83 ml/min in men. Trough plasma concentrations in women were 12% to 20% higher than those in men. Body mass index and weight did not influence dabigatran concentrations (data not shown). There was a general correlation between aPTT and dabigatran plasma concentrations with a flattening response at higher plasma concentrations (Figure 3). Trough aPTT values for each dose group had low interindividual variability, with coefficients of variation between 13% and 21%. Mean trough aPTT measurements obtained at steady state showed minimal variation between visits. The ratios of aPTT values at baseline and

Figure 3. Relation between dabigatran plasma concentration and aPTT.

trough levels with 50-, 150-, and 300-mg twice daily dabigatran doses were 1.2, 1.5, and 1.8, respectively (Figure 4). Plasma D-dimer measurements at an INR ⬍1.5 were higher than measurements at an INR ⬎2, with geometric means of 76.5 to 83.6 ng/ml (n ⫽ 432, p ⬍0.001), reflecting a washout of the warfarin effect. A comparison of the change in median D-dimer measurements of each group at baseline versus the last on-treatment measurement (Table 4), generally at 12 weeks, showed a 13% relative increase of D-dimer concentrations in the group treated with 50-mg dabigatran twice daily (p ⫽ 0.0008) and a 3% relative increase in the group treated with 150-mg dabigatran twice daily (p ⫽ 0.027), but no significant changes with 300-mg dabigatran twice daily (⫹0%, p ⫽ 0.413) or warfarin (⫺1%, p ⫽ 0.267). There was poor correlation between plasma measurements of soluble fibrin for dabigatran and warfarin (data not shown). Aspirin treatment had no effect on any of these analyses. DTB2 values after 12 weeks of treatment with dabigatran (Table 4) showed a non– dose-related increase between 17% and 31%. Values during warfarin treatment

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Figure 4. Box and whisker plots of median trough aPTT measurements during treatment with different dabigatran dosages.

were unchanged from baseline (⫹4%, p ⫽ 0.32). In the presence of aspirin, DTB2 concentrations decreased by 40% to 57% compared with baseline measurements. There was a 0.9% incidence of increased aminotransferase levels ⬎3 times the upper limit of normal in dabigatrantreated patients (4 of 432; Table 5). Adverse events were more frequent in the dabigatran groups than in the warfarin-treated patients. The most commonly reported adverse events were gastrointestinal disorders such as diarrhea, nausea, or vomiting (26%); followed by general system disorders such as fatigue or edema (12%), dizziness and headache (12%), and infections. Most of these were mild and required no change in treatment. All adverse events leading to treatment discontinuation are listed in Table 2. Discussion This phase 2 trial of several fixed doses of a direct thrombin inhibitor with and without aspirin compared with warfarin alone in AF established a dose response for bleeding and an upper limit of tolerability (300 mg twice daily plus aspirin) based on the frequency of major and clinically significant bleeding events. As anticipated, the frequency of thromboembolic events was too low to reach conclusions, but the only 2 strokes in this 12-week trial occurred in patients receiving the lowest dose of dabigatran (50 mg twice daily). Because many patients with AF have concomitant coronary disease and may require aspirin, the statistically significant effect of aspirin on bleeding rates is important in designing further trials. Efficacy and safety of dabigatran in prevention of venous thrombosis has already been demonstrated.8 The pharmacokinetic and pharmacodynamic measurements added further insights for dose selection. Dabigatran plasma concentrations increased consistently with dose, as did aPTT and D-dimer suppression. The aPTT is a readily accessible test that allows a real-time measurement of the effect of dabigatran on the coagulation cascade. D-dimer suppression may be a valuable marker of long-term effects on the level of anticoagulation.9 The changes in these parameters were consistent with the

clinical observations of bleeding at higher doses and thromboembolic events in the lowest dose group (50 mg twice daily). The median aPTT measurements in patients receiving dabigatran 150 mg twice daily are comparable to measurements reported with a therapeutic dose of ximelagatran (36 mg twice daily).10 Mean D-dimer concentrations were almost completely suppressed except at the lowest dose of dabigatran. The highest dose of dabigatran achieved D-dimer suppression similar to that achieved with warfarin. Based on bleeding rates and aPTT and D-dimer measurements, dabigatran 150 mg twice daily is well tolerated and shows anticoagulant activity. As expected, there was a pronounced depression of DTB2 excretion for all doses of aspirin treatment. Unexpectedly, urinary excretion of DTB2 was approximately 20% higher after 12 weeks of treatment with all dabigatran doses compared with warfarin in patients who did not receive aspirin. There was no dose effect for dabigatran. There have been no previous reports of effects of direct thrombin inhibitors on thromboxane excretion. An increase of thromboxane excretion may suggest a platelet-activating effect of treatment in the absence of concomitant aspirin treatment. This might theoretically cause a paradoxic increase in thrombotic risk, but this would need to be confirmed in a clinical outcomes trial. In contrast, ximelagatran, an oral thrombin inhibitor, decreased cardiac events in patients with recent myocardial infarction when administered in addition to aspirin.11 Despite initial regulatory concerns by the United States Food and Drug Administration, trials of ximelagatran in patients with AF showed no excess myocardial infarctions in patients receiving ximelagatran with or without aspirin compared with warfarin.12 A previous meta-analysis in acute coronary syndromes has reported a possible increased risk of cardiac events with univalent oral thrombin inhibitors compared with heparin, but this analysis included mostly dose-finding studies.13 Because of liver function abnormalities associated with ximelagatran, the present study had an extensive surveillance of liver function. Only 0.9% of patients had increased levels of alanine aminotransferase or aspartate aminotransferase ⬎3 times the upper limit of normal. No patient had a drug-related increase in bilirubin ⬎2 times the upper limit of normal within 30 days after an aminotransferase level increase ⬎3 times the upper limit of normal.14 However, the duration of the study was only 12 weeks. The long-term effects of dabigatran on liver function are currently being evaluated in the extension of the PETRO study and the phase 3 Randomized Evaluation of Long term anticoagulation therapy (RE-LY) study. Appendix Steering Committee: L. Wallentin (chairman), M. Ezekowitz (co-chairman United States national coordinator), T. Simmers (Netherlands national coordinator), and K. Erik Pedersen (Denmark national coordinator). The following representatives of Boehringer Ingelheim also participated in the Steering Committee as nonvoting members: L.E. Lins, G. Nehmiz, P. Reilly, J. Stangier, H. Paalum

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Table 4 Median plasma concentrations of D-dimer and median urinary 11-dehydrothromboxane B2 excretion: baseline versus final on-treatment value Measurement

Dabigatran (mg twice daily)

D-dimer

Baseline (ng/ml) (IQR) Change at 12 wks (IQR) p Value* DTB2† Baseline (pg/mg/creatinine) (IQR) Change at 12 wks (pg/mg/creatinine) (IQR) p Value*

Warfarin to INR of 2–3 (n ⫽ 59)

50

150

300

n ⫽ 95 75 (98.5) ⫹10 (43) 0.0008 n ⫽ 44 3,382 (2,176) ⫹1,040 (2,681) 0.019

n ⫽ 137 70 (92) ⫹2 (34) 0.027 n ⫽ 73 3,602 (2,585) ⫹610 (2,740) 0.028

n ⫽ 131 85 (112) 0 (34) 0.413 n ⫽ 73 3,178 (1,810) ⫹720 (2,470) 0.0004

84 (106) ⫺1 (32) 0.267 n ⫽ 51 3,409 (2,983) ⫹140 (1,970) 0.322

* p value determined by a 2-sided test of no difference from baseline: the differences among treatments were p ⫽ 0.003 and p ⫽ 0.01 for D-dimer and DTB2, respectively. † DTB2 for patients without aspirin. IQR ⫽ interquartile range. Table 5 Occurrence of increased alanine aminotransferase measurements ALT Measurement

⬎1 ⬎2 ⬎3 ⬎5

times times times times

ULN ULN ULN ULN

Dabigatran Total (n ⫽ 432) 24 (5.6%) 6 (1.4%) 4 (0.9%)* 2 (0.5%)†

Dabigatran (mg twice daily) 50 (n ⫽ 105)

150 (n ⫽ 166)

300 (n ⫽ 161)

6 (5.7%) 0 0 0

11 (6.6%) 3 (1.8%) 2 (1.2%)* 2 (1.2%)†

7 (4.3%) 3 (1.9%) 2 (1.2%)* 0

Warfarin (n ⫽ 70) 7 (10%) 0 0 0

* No simultaneous elevation of bilirubin ⬎2 times upper limits of normal (ULN). Concomitant increase of aspartate aminotransferase was observed in 1 case but did not exceed the ALT concentration. † One patient had obstructive jaundice and pancreatitis as a result of gallstones in the common bile duct and recovered completely after cholecystectomy. The other had gallstones and spontaneously recovered. Abbreviations as in Table 2.

(Trial Clinical Monitor until June 2004), A. Meijer (Trial Clinical Monitor from June 1, 2004, to December 1, 2004). The Data and Safety Monitoring Board of the PETRO Study group are: J. Godtfredsen (chairman), Kobenhavn, Denmark; J.G.P. Tijssen, Academic Medical Center, University of Amsterdam, The Netherlands; and H.R. Büller, Academic Medical Center, University of Amsterdam, The Netherlands. The Bleeding Adjudication Committee of the PETRO Study group are: M.H. Prins, University Hospital Maastricht, The Netherlands; U. Angerås, Kirurgkliniken, Göteborg, Sweden; A. Falk, Carlanderska Hospital, Göteborg, Sweden; and G. Andersen, Arhus Kommunehospital, Denmark. The investigators of the PETRO Study group are: S. Lind Rasmussen, E. Agner, K. Skagen, S. Husted, K. Egstrup, H. Kræmmer Nielsen, K. Skodebjerg Kristensen, L. Hvilsted Rasmussen, K. Korsgaard Thomsen, M. Ege Olsen, P. Fruergaard, and K. Klarlund (Denmark); M. Rosenqvist, S. Bandh, A. Englund, J.E. Karlsson, F. Rönn, P.L. Ågren, O. Nilsson, O. Hansen, B. Holmberg, F. Maru, and K. Eggers (Sweden); F.R. den Hartog, W.L. ten Holt, G.J. de Weerd, J.B. Winter, M.J. de Leeuw, J.G.M. Tans, L. Cozijnsen, C.M. Leenders, H.J.M. Thijssen, H.A. van de Klippe, T. Slagboom, and J.H. Fast (The Netherlands); and F. Cardona, L.W. Sprinkle Jr, D. Hotchkiss, F.A. McGrew, D. Philips, J. Cieszkowski, S. Jerome, T.D. Bahnson, J. Cooper, P. Zwerner, J. Leppo, D.J. Slotwiner, M.B. Cohen, and S.O. Gottlieb (United States).

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