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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 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 0.0002 and p 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           0.02,
                   p    0.03, and p     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 concen-
                   trations. 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 antico-                        antagonists have a highly variable inter- and intraindi-
agulants currently available. They decrease the risk of                         vidual anticoagulant response, with multiple drug and
stroke and systemic thromboembolism in patients with                            food interactions, necessitating regular monitoring and
atrial fibrillation (AF) by 68%.1 However, vitamin K                             adjustment of dose.2 These factors, plus fear of hemor-
                                                                                rhage, have resulted in substantial underuse of warfarin,
   a                                                                            particularly in patients with AF.3 A fixed-dose, orally
     Lankenau Institute for Medical Research and The Heart Center, Wynne-
wood, Pennsylvania; bDepartment of Clinical Research, Boehringer Ingelheim
                                                                                effective anticoagulant without the need for monitoring
Pharmaceuticals, Ridgefield, Connecticut; Departments of cMedical Data           would constitute a significant improvement. Dabigatran
Services and dDrug Metabolism and Pharmacokinetics, Boehringer Ingelheim        etexilate is an orally available prodrug that is converted
Pharmaceuticals, Biberach, Germany; eThorax Centre, Amphia Hospital,            to dabigatran, the active moiety. It is a potent, competi-
Breda, The Netherlands; fOdense University Hospital, Odense, Denmark; and       tive, and reversible direct inhibitor of thrombin. Peak
g
  Uppsala Clinical Research Centre, Uppsala, Sweden. Manuscript received        dabigatran plasma concentrations occur 0.5 to 2 hours
March 14, 2007; revised manuscript received and accepted June 10, 2007.
                                                                                after oral administration, resulting in a rapid onset of
    Boehringer Ingelheim Pharmaceuticals, Biberach, Germany, is the sponsor
of this study and has provided a research grant. The members and structure of
                                                                                action. There is a bi-exponential distribution phase with
the PETRO study group are given in the Appendix at the end of this article.     a terminal half-life of 12 to 17 hours. As much as 80% of
    *Corresponding author: Tel: 610-645-8451; fax: 610-645-8460.                the drug is excreted unchanged by the kidneys. The
    E-mail address: ezekowitzm@mlhs.org (M.D. Ezekowitz).                       average absolute bioavailability of dabigatran is 6.5%.4,5

0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved.                                              www.AJConline.org
doi:10.1016/j.amjcard.2007.06.034
1420                                           The American Journal of Cardiology (www.AJConline.org)




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                         tomatic heart failure or left ventricular dysfunction (ejec-
with AF. The main goal of the study was to identify a safe                       tion fraction 40%), previous stroke or transient isch-
dose of dabigatran in patients with AF as determined by                          emic attack, or age           75 years. After entry of
the occurrence of bleeding and clinical events, and to                           approximately half of the patients, the requirement for
identify anticoagulant activity through activated partial                        coronary artery disease was removed to facilitate recruit-
thromboplastin time (aPTT) changes and the inhibition of                         ment. Exclusion criteria were mitral stenosis, prosthetic
D-dimer generation.6                                                             heart valves, planned cardioversion, recent ( 1 month)
                                                                                 myocardial infarction, recent stroke or transient ischemic
Methods                                                                          attack, coronary stent placement within 6 months, any
                                                                                 contraindication to or another indication for anticoagu-
This study was conducted in 53 centers in Denmark, the                           lant therapy, major hemorrhage in the past 6 months,
Netherlands, Sweden, and the United States. The protocol                         severe renal impairment (glomerular filtration rate 30
was developed by the Steering Committee of the Preven-                           ml/min), abnormal liver function, risk of pregnancy, in-
tion of Embolic and Thrombotic Events in Patients with                           vestigational drug use within 30 days, or any other con-
Persistent AF (PETRO) study group. An independent                                dition that would not allow participation in the study.
adjudication committee blinded to treatment evaluated all
                                                                                    The trial had a total of 10 treatment groups. Three
bleeding events. An independent data and safety moni-
                                                                                 doses of dabigatran etexilate (50, 150, and 300 mg twice
toring board monitored the study for safety. Boehringer
                                                                                 daily) were combined in a 3 3 factorial fashion with no
Ingelheim (Biberach, Germany) sponsored the study and
                                                                                 aspirin or 81- or 325-mg aspirin once daily. Patients
was responsible for the statistical analysis conducted
according to a prospectively designed plan approved by                           received warfarin alone (international normalized ratio
the steering committee. All authors had access to the                            [INR] of 2 to 3) in the comparator group. The trial was
data.                                                                            double-blind with respect to dabigatran dose but open-
   The protocol, protocol amendments, informed con-                              label for concomitant aspirin treatment and for random-
sent, and subject information forms were reviewed and                            ization between dabigatran and warfarin groups. Ran-
approved by a local institutional review board or inde-                          domization was stratified in the ratio 6:9:9:4 (50-, 150-,
pendent ethics committee before initiation. The study                            and 300-mg dabigatran, and warfarin, respectively) (Fig-
was conducted in accordance with the ethical principles                          ure 1). The screening visit was the baseline visit for all
of the Declaration of Helsinki, International Conference                         laboratory tests and measurements with the exception of
on Harmonisation, and the Tripartite Guideline of Good                           D-dimer, the baseline visit for which for pre-/post-treat-
Clinical Practice. Written informed consent was obtained                         ment comparisons was the randomization visit.
from each patient.                                                                  Two identical matching capsules containing 50- or
   The PETRO study was a randomized trial of patients                            150-mg dabigatran or placebo were taken twice daily for
with AF at high risk for thromboembolic events. Inclu-                           12 weeks. All patients had been treated with a vitamin K
sion criteria were documented AF with coronary artery                            antagonist for 8 weeks before inclusion and required an
disease plus 1 of the following: hypertension requiring                          INR between 2 and 3 at study entry. This ensured that
medical treatment, diabetes mellitus (type 1 or 2), symp-                        baseline D-dimer measurements were obtained under the
                                Arrhythmias and Conduction Disturbances/Dabigatran in Nonvalvular AF                         1421


condition of full anticoagulation. At the screening visit,           linked fibrin degradation products (Dade Behring, Mar-
warfarin pretreatment was terminated. Patients random-               burg, Germany). Soluble fibrin was determined by an
ized to receive warfarin or dabigatran started study treat-          automated latex photometric assay (LPIA-Iatro SF; Mit-
ment when the INR was 1.5 to avoid excessive antico-                 subishi Kagaku Iatron, Gauting, Germany). Urinary sam-
agulation.                                                           ples for 11-dehydrothromboxane B2 (DTB2) excretion
   Participants were monitored as outpatients at 1, 2, 4, 8,         were obtained at screening and randomization and at
and 12 weeks after randomization. Renal function was                 cessation of treatment after the12-week visit. The deter-
measured with the Levey equation at the initial visit.7              minations of DTB2 in urine were performed with an
After 4 to 7 days of treatment, all patients with glomer-            DTB2 enzyme immunoassay kit (Correlate-EIA; Assay
ular filtration rates 50 ml/min underwent down-titration              Designs, Ann Arbor, Michigan).
to once-daily dabigatran if the aPTT ratio at trough was                 No formal statistical hypothesis was tested. However,
  2.5 times the local laboratory reference value. These              the goal of the study was to determine whether there was
patients were analyzed according to the group to which               a dose-related incidence of bleeding and to collect phar-
they were initially assigned.                                        macodynamic data to assist in the selection of a dose(s)
   Major hemorrhages were observed in the group that                 for the phase 3 study. The primary end point was inci-
received dabigatran 300 mg twice daily plus aspirin: 3 at            dence of bleeding. A secondary objective was to measure
the 325-mg aspirin dose and 1 at the 81-mg dose. The                 suppression of D-dimer to evaluate the activity of dabig-
data and safety monitoring board recommended, and the                atran; week 12 values were compared with baseline val-
steering committee agreed, that patients receiving                   ues, defined as the value at the randomization visit for
300-mg dabigatran twice daily plus aspirin should be                 each treatment group. The mean trough measurements for
switched to 300-mg dabigatran twice daily without aspi-              each group were calculated and a 1-sample Wilcoxon test
rin. This decision occurred after patient recruitment had            was used to determine statistical significance of changes from
been completed.                                                      baseline. Generally, data were reported as means SD or as
   Stroke was defined as an acute onset of a focal neu-               median      interquartile range. Differences between groups
rologic deficit of vascular origin lasting for 24 hours.              were analyzed using the chi-square test or the Fisher exact
Systemic thromboembolism was defined as an acute non-                 test, and for quantitative data with 1-way analysis of vari-
intracerebral or noncoronary vascular event.                         ance or the Kruskal-Wallis test as appropriate. All analyses
   Bleeding events were classified as major or minor and              were performed with SAS software (version 8.2; SAS In-
were assigned to the treatment the patient was receiving
                                                                     stitute, Cary, North Carolina).
at the time of onset. Major bleeding was defined as fatal
or life-threatening retroperitoneal, intracranial, intraocu-
lar, or intraspinal bleeding; or bleeding requiring surgery          Results
or transfusion of 2 U or associated with a decrease in
hemoglobin of 2.0 g/L. Minor bleeding was further                    Of 502 patients randomized, 411 (81.9%) were men, with
subdivided into clinically relevant or nuisance bleeding             192 (38.2%) having permanent AF, 195 (38.8%) persis-
episodes. Clinically relevant bleeding was defined as skin            tent AF, and 115 (22.9%) paroxysmal AF. The median
hematoma 25 cm2, spontaneous nose bleed of 5 min-                    duration of AF was 4 years (range 0.05 to 30). Mean ages
utes duration, macroscopic hematuria, spontaneous rectal             were 70.9      7.9 years in patients with CAD (n       306)
bleeding, gingival bleeding for 5 minutes, any bleeding              and 68.0 8.8 years in those without CAD. The baseline
leading to hospitalization, any bleeding leading to trans-           characteristics were balanced among the 10 randomized
fusion 2 U, or any other bleeding considered relevant                treatment groups (Table 1). Patients had a median of 3
by the investigator.                                                 risk factors for stroke.
   Safety laboratory assessments were performed at                      The mean rate of compliance with dabigatran treat-
screening and 1, 4, 8, and 12 weeks after randomization              ment (excluding patients who withdrew or were discon-
and, if necessary, at a further follow-up after the 12-week          tinued) was 99.5%. Twelve patients underwent a dose
visit. Treatment was withdrawn if aspartate aminotrans-              down-titration (Figure 1). Thirteen patients stopped as-
ferase, alanine aminotransferase, bilirubin, or alkaline             pirin treatment during the trial. In the warfarin group, the
phosphatase concentrations were 5 times the upper                    INR was within the target range (i.e., 2 to 3) during
limit of normal at any time or 3 times the upper limit of            57.2% of the treatment time. The percent time in target
normal for 4 weeks, or if the patient developed clinical             range increased from 48.2% in the first 4 weeks to 62.1%
signs or symptoms of hepatic insufficiency.                           in weeks 5 through 8 and to 64.5% in weeks 9 through 12.
   For the pharmacokinetic and pharmacodynamic anal-                    Overall, 38 patients discontinued trial treatment, 29
yses, samples were obtained at screening and randomiza-              because of adverse events (Table 2); 3 withdrew consent;
tion and then at 1, 2, 4, 8, and 12 weeks after random-              and 1 patient was not compliant with study medication.
ization. Dabigatran plasma concentrations were assayed               Another patient returned for the final visit, but it was not
using a liquid chromatograph–tandem mass spectrometry                possible to determine whether the patient was compliant
method at AAI Deutschland, Neu-Ulm, Germany. The                     with study medication. The patient was classified as “dis-
aPTT was measured centrally by a coagulation analyzer                continued.” The 4 remaining patients withdrew, 1 each as
(Roche Diagnostics, Nutley, New Jersey) at Boehringer                a result of percutaneous coronary intervention for coro-
Ingelheim. Analyses of D-dimer were performed by the                 nary artery disease requiring clopidogrel, angiography
PLUS Assay for the turbidimetric determination of cross-             planned before trial entry, difficulty with blood draws,
1422                                           The American Journal of Cardiology (www.AJConline.org)


Table 1
Baseline characteristics
Variable                        All Patients     Dabigatran 50 mg      Dabigatran 150 mg        Dabigatran 300 mg       Warfarin INR 2–3        p Value for
                                (n 502)            Twice Daily            Twice Daily              Twice Daily              (n 70)              Equality of
                                                    (n 105)                (n 166)                  (n 161)                                       Groups

Age (mean SD, yrs)               70 (8.3)           70 (8.8)                  70 (8.1)               69.5 (8.4)               69 (8.3)              0.7
Duration of AF median             4 (6.5)          3.6 (6.9)                 3.9 (6.6)                6.4 (4.3)              3.4 (5.0)              0.4
   (interquartile range, yrs)
Women                            91 (18%)           21 (20%)                 31 (18.7%)               28 (17.4%)               11 (15.7%)           0.9
Age 75 yrs                      158 (31.5%)         36 (34.3%)               51 (30.7%)               52 (32.3%)               19 (27%)             0.8
TIA or stroke                    87 (17.3%)         19 (18%)                 29 (17.5%)               26 (16%)                 13 (18.6%)           1.0
Hypertension                    356 (71%)           70 (66.7%)              118 (71%)                119 (74%)                 49 (70%)             0.6
Diabetes mellitus               126 (25%)           27 (25.7%)               45 (27%)                 39 (24%)                 15 (21.4%)           0.8
Heart failure                   147 (29.3%)         35 (33.3%)               52 (31.3%)               36 (22.4%)               24 (34.3%)           0.1
Coronary artery disease         306 (61%)           64 (61%)                104 (63%)                 96 (59.6%)               42 (60%)             1.0
Current or former smoker        365 (72.7%)         76 (72.4%)              120 (72.3%)              116 (72%)                 53 (75.7%)           1.0
  blockers                      349 (69.5%)         69 (65.7%)              121 (73%)                110 (68.3%)               49 (70%)             0.6
ACE inhibitor/angiotensin       355 (70.7%)         70 (66.7%)              116 (69.8%)              112 (69.5%)               57 (81.4%)           0.2
   receptor–2 blocker
Verapamil/diltiazem              95 (19%)           16 (15%)                 31 (18.7%)               34 (21%)                 14 (20%)             0.7
Other calcium inhibitors        115 (22.9%)         26 (24.7%)               37 (22.3%)               38 (23.6%)               14 (20%)             0.9
Amiodarone                       37 (7.4%)           9 (8.5%)                 9 (5.4%)                13 (8%)                   6 (8.5%)            0.7
Digoxin                         219 (43.6%)         46 (43.8%)               75 (45%)                 66 (41%)                 32 (45.7%)           0.9
Diuretic                        289 (57.5%)         59 (56%)                 89 (53.6%)               97 (60%)                 44 (63%)             0.5
Statin                          290 (57.7%)         58 (55%)                100 (60%)                 95 (59%)                 37 (53%)             0.7

  ACE       angiotensin-converting enzyme; TIA     transient ischemic attack.

Table 2
Adverse events leading to discontinuation
Event                                                                       Dabigatran Dose (twice daily)                            Warfarin to INR of 2–3
                                                                                                                                            (n 70)
                                                       50 mg (n      107)        150 mg (n    169)          300 mg (n   169)

Patients discontinuing with adverse events*                      5                        9                        15                          0
 Cardiovascular and peripheral embolic events†                   4                        2                         1                          0
 Major/clinically relevant hemorrhage                            0                        4                         7                          0
 Gastrointestinal symptoms‡                                      2                        2                         8                          0
 ALT/AST increased                                               0                        0                         1                          0
 Other symptoms§                                                 2                        1                         4                          0

  * Some patients had 1 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                             When the doses of dabigatran were compared with
after discontinuation of study medication.                                        each other, irrespective of aspirin assignment, there were
   The primary outcome was the frequency of bleeding                              differences in total bleeding episodes in the 300-mg twice
events (Table 3). Major bleeding events were limited to                           daily and 150-mg twice daily groups versus the 50-mg
the group treated with 300-mg dabigatran twice daily                              twice daily group (37 of 169 and 30 of 169 vs 7 of 107,
plus aspirin (4 of 64). The rate was statistically different                      p    0.0002 and p       0.01, respectively).
compared with the group treated with dabigatran 300 mg                               There were 2 patients with systemic thromboembolic
twice daily without aspirin (0 of 105, p 0.02).                                   events (Table 3), both of whom received 50-mg dabigatran
   There was a significant difference in major plus clin-                          twice daily (1.96%). One patient had a peripheral embolism
ically relevant bleeding episodes (11 of 64 vs 6 of 105, p                        to the toe and the other patient had a stroke and a renal
   0.03) and total bleeding episodes (25 of 64 vs 14 of                           infarction.
105, p 0.0003) between 300-mg dabigatran twice daily                                 Seven patients reported angina, of which 2 patients
plus aspirin and 300-mg dabigatran twice daily without                            were classified as having acute coronary syndrome: 1
aspirin. The frequency of bleeding in the group treated                           treated with 50-mg dabigatran twice daily plus 81-mg
with 50-mg dabigatran twice daily was significantly                                aspirin and the other treated with 300-mg dabigatran
lower than that in the warfarin group: 7 of 107 vs 12 of                          twice daily plus 81-mg aspirin. Both patients were dis-
70 (p     0.044).                                                                 continued from the trial (Table 2). Four patients devel-
                                        Arrhythmias and Conduction Disturbances/Dabigatran in Nonvalvular AF                                     1423


Table 3
Major or clinically relevant bleeding episodes and thromboembolic events
Dabigatran Dose         Aspirin Dose (mg)      No. of Patients*                       Bleeding Events                         Thromboembolic Events
(mg twice daily)
                                                                    Major     Clinically Relevant Plus Major      Total

 50                              0                    59               0                     0                  2 (3.4%)             1 (1.7%)
 50                             81                    21               0                1 (4.8%)                2 (9.5%)             1 (4.8%)
 50                            325                    27               0                1 (3.7%)                3 (11.1%)                0
150                              0                   100               0                9 (9%)                 15 (15%)                  0
150                             81                    36               0                2 (5.6%)                8 (22.2)                 0
150                            325                    33               0                2 (6.1%)                7 (21.2%)                0
300                              0                   105               0                6 (5.7%)               14 (13.3%)                0
300                             81                    34           1 (2.9%)             5 (14.7%)              11 (32.4%)                0
300                            325                    30           3 (10%)              6 (20%)                14 (46.7%)                0
Warfarin once daily              0                    70               0                4 (5.7%)               12 (17.1%)                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
                                                                                Figure 3. Relation between dabigatran plasma concentration and aPTT.
dabigatran treatment group.

oped congestive heart failure, with 1 patient receiving                        trough levels with 50-, 150-, and 300-mg twice daily
150-mg dabigatran twice daily discontinuing the trial.                         dabigatran doses were 1.2, 1.5, and 1.8, respectively
None of these events resulted in statistically significant                      (Figure 4).
differences between treatment groups.                                             Plasma D-dimer measurements at an INR 1.5 were
   Dabigatran (plasma half-life of 12 to 17 hours) at-                         higher than measurements at an INR 2, with geometric
tained steady state by the time of the first follow-up at 4                     means of 76.5 to 83.6 ng/ml (n          432, p 0.001),
to 7 days. The mean trough plasma concentration in-                            reflecting a washout of the warfarin effect. A comparison
creased linearly with increasing dose (Figure 2). Reduced                      of the change in median D-dimer measurements of each
creatinine clearance resulted in higher dabigatran plasma                      group at baseline versus the last on-treatment measure-
concentrations (data not shown). The mean creatinine                           ment (Table 4), generally at 12 weeks, showed a 13%
clearance was 81 ml/min; it was 69 ml/min in women and                         relative increase of D-dimer concentrations in the group
83 ml/min in men. Trough plasma concentrations in                              treated with 50-mg dabigatran twice daily (p     0.0008)
women were 12% to 20% higher than those in men. Body                           and a 3% relative increase in the group treated with
mass index and weight did not influence dabigatran con-                         150-mg dabigatran twice daily (p      0.027), but no sig-
centrations (data not shown).                                                  nificant changes with 300-mg dabigatran twice daily
   There was a general correlation between aPTT and                            ( 0%, p 0.413) or warfarin ( 1%, p 0.267). There
dabigatran plasma concentrations with a flattening re-                          was poor correlation between plasma measurements of
sponse at higher plasma concentrations (Figure 3).                             soluble fibrin for dabigatran and warfarin (data not
Trough aPTT values for each dose group had low inter-                          shown). Aspirin treatment had no effect on any of these
individual variability, with coefficients of variation be-                      analyses.
tween 13% and 21%. Mean trough aPTT measurements                                  DTB2 values after 12 weeks of treatment with dabig-
obtained at steady state showed minimal variation be-                          atran (Table 4) showed a non– dose-related increase be-
tween visits. The ratios of aPTT values at baseline and                        tween 17% and 31%. Values during warfarin treatment
1424                                      The American Journal of Cardiology (www.AJConline.org)


                                                                        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 con-
                                                                        centrations were almost completely suppressed except at
                                                                        the lowest dose of dabigatran. The highest dose of dabig-
                                                                        atran 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. Unex-
                                                                        pectedly, urinary excretion of DTB2 was approximately
                                                                        20% higher after 12 weeks of treatment with all dabig-
Figure 4. Box and whisker plots of median trough aPTT measurements      atran doses compared with warfarin in patients who did
during treatment with different dabigatran dosages.                     not receive aspirin. There was no dose effect for dabig-
                                                                        atran. There have been no previous reports of effects of
were unchanged from baseline ( 4%, p          0.32). In the             direct thrombin inhibitors on thromboxane excretion. An
presence of aspirin, DTB2 concentrations decreased by                   increase of thromboxane excretion may suggest a plate-
40% to 57% compared with baseline measurements.                         let-activating effect of treatment in the absence of con-
   There was a 0.9% incidence of increased aminotransfer-               comitant aspirin treatment. This might theoretically cause
ase levels 3 times the upper limit of normal in dabigatran-             a paradoxic increase in thrombotic risk, but this would
treated patients (4 of 432; Table 5).                                   need to be confirmed in a clinical outcomes trial. In
   Adverse events were more frequent in the dabigatran                  contrast, ximelagatran, an oral thrombin inhibitor, de-
groups than in the warfarin-treated patients. The most                  creased cardiac events in patients with recent myocardial
commonly reported adverse events were gastrointestinal                  infarction when administered in addition to aspirin.11
disorders such as diarrhea, nausea, or vomiting (26%);                  Despite initial regulatory concerns by the United States
followed by general system disorders such as fatigue or                 Food and Drug Administration, trials of ximelagatran in
edema (12%), dizziness and headache (12%), and infec-                   patients with AF showed no excess myocardial infarc-
tions. Most of these were mild and required no change in                tions in patients receiving ximelagatran with or without
treatment. All adverse events leading to treatment dis-                 aspirin compared with warfarin.12 A previous meta-anal-
continuation are listed in Table 2.                                     ysis in acute coronary syndromes has reported a possible
                                                                        increased risk of cardiac events with univalent oral
Discussion                                                              thrombin inhibitors compared with heparin, but this anal-
                                                                        ysis included mostly dose-finding studies.13
This phase 2 trial of several fixed doses of a direct                       Because of liver function abnormalities associated
thrombin inhibitor with and without aspirin compared                    with ximelagatran, the present study had an extensive
with warfarin alone in AF established a dose response for               surveillance of liver function. Only 0.9% of patients had
bleeding and an upper limit of tolerability (300 mg twice               increased levels of alanine aminotransferase or aspartate
daily plus aspirin) based on the frequency of major and clini-          aminotransferase 3 times the upper limit of normal. No
cally significant bleeding events. As anticipated, the frequency         patient had a drug-related increase in bilirubin 2 times
of thromboembolic events was too low to reach conclusions,              the upper limit of normal within 30 days after an amino-
but the only 2 strokes in this 12-week trial occurred in patients       transferase level increase 3 times the upper limit of
receiving the lowest dose of dabigatran (50 mg twice daily).            normal.14 However, the duration of the study was only 12
Because many patients with AF have concomitant coronary                 weeks. The long-term effects of dabigatran on liver func-
disease and may require aspirin, the statistically significant           tion are currently being evaluated in the extension of the
effect of aspirin on bleeding rates is important in designing           PETRO study and the phase 3 Randomized Evaluation of
further trials. Efficacy and safety of dabigatran in prevention of       Long term anticoagulation therapy (RE-LY) study.
venous thrombosis has already been demonstrated.8
   The pharmacokinetic and pharmacodynamic measure-                     Appendix
ments added further insights for dose selection. Dabigat-
ran plasma concentrations increased consistently with                   Steering Committee: L. Wallentin (chairman), M.
dose, as did aPTT and D-dimer suppression. The aPTT is                  Ezekowitz (co-chairman United States national coordina-
a readily accessible test that allows a real-time measure-              tor), T. Simmers (Netherlands national coordinator), and K.
ment of the effect of dabigatran on the coagulation cas-                Erik Pedersen (Denmark national coordinator). The follow-
cade. D-dimer suppression may be a valuable marker of                   ing representatives of Boehringer Ingelheim also partici-
long-term effects on the level of anticoagulation.9 The                 pated in the Steering Committee as nonvoting members:
changes in these parameters were consistent with the                    L.E. Lins, G. Nehmiz, P. Reilly, J. Stangier, H. Paalum
                                        Arrhythmias and Conduction Disturbances/Dabigatran in Nonvalvular AF                                                 1425


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)                                Warfarin to INR of 2–3
                                                                                                                                             (n 59)
                                                              50                       150                       300

D-dimer                                                     n 95                     n 137                     n 131
 Baseline (ng/ml) (IQR)                                      75 (98.5)                70 (92)                   85 (112)                        84 (106)
 Change at 12 wks (IQR)                                      10 (43)                   2 (34)                    0 (34)                          1 (32)
 p Value*                                                   0.0008                     0.027                    0.413                            0.267
DTB2†                                                       n 44                     n 73                      n 73                             n 51
 Baseline (pg/mg/creatinine) (IQR)                        3,382 (2,176)            3,602 (2,585)             3,178 (1,810)                   3,409 (2,983)
 Change at 12 wks (pg/mg/creatinine) (IQR)                1,040 (2,681)              610 (2,740)               720 (2,470)                     140 (1,970)
 p Value*                                                   0.019                      0.028                    0.0004                           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                Dabigatran Total                                    Dabigatran (mg twice daily)                                        Warfarin
                                  (n 432)                                                                                                             (n 70)
                                                               50 (n      105)               150 (n   166)              300 (n      161)

  1   times   ULN                 24 (5.6%)                        6 (5.7%)                   11 (6.6%)                      7 (4.3%)                 7 (10%)
  2   times   ULN                  6 (1.4%)                            0                       3 (1.8%)                      3 (1.9%)                     0
  3   times   ULN                  4 (0.9%)*                           0                       2 (1.2%)*                     2 (1.2%)*                    0
  5   times   ULN                  2 (0.5%)†                           0                       2 (1.2%)†                          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.


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