April 19
10th Annual Cardiovascular Update & 54th Annual Carl J . Wiggers Memorial Lecture
The Ritz-Carlton Cleveland , OH
|
April 28 – 29
Puerto Rico Chapter of the American College of Cardiology
Cond . Medical Center Plaza Calle 3 SE # 1051 , Ofic . LC-10 Urb . La Riviera San Juan , P . R .
|
September 29 – October 1
SC / NC Chapters ACC 23rd Annual Joint Meeting
Kiawah Island Golf Resort Kiawah Island , SC
|
October 14 – 21
Ohio Chapter Annual Meeting 2017
Columbus Hilton at Easton Columbus , OH
|
Table 3 ( Cont ' d ) PRADAXA 150 mg twice daily N (%)
Warfarin N (%)
Bleeding sites for
MBE b
Intracranial
|
2 ( 0.1 ) |
5 ( 0.2 ) |
Retroperitoneal |
2 ( 0.1 ) |
1 ( 0.04 ) |
Intraarticular |
2 ( 0.1 ) |
4 ( 0.2 ) |
Intramuscular |
2 ( 0.1 ) |
6 ( 0.2 ) |
Gastrointestinal |
15 ( 0.6 ) |
14 ( 0.5 ) |
Urogenital |
7 ( 0.3 ) |
14 ( 0.5 ) |
Other |
8 ( 0.3 ) |
8 ( 0.3 ) |
Clinically relevant non-major bleeding
Hazard Ratio ( 95 % CI ) c
101 ( 4.0 ) |
170 ( 6.7 ) |
0.58 |
|
|
( 0.46 , 0.75 ) |
Any bleeding |
411 ( 16.1 ) |
567 ( 22.7 ) |
0.70 |
|
|
|
( 0.61 , 0.79 ) |
Note : MBE can belong to more than one criterion . a
Patients with at least one MBE . b
Bleeding site based on investigator assessment . Patients can have more than one site of bleeding .
c
Confidence interval The rate of any gastrointestinal bleeds in patients receiving PRADAXA 150 mg in the full treatment period was 3.1 % ( 2.4 % on warfarin ). The RE-MEDY and RE-SONATE studies provided safety information on the use of PRADAXA for the reduction in the risk of recurrence of deep vein thrombosis and pulmonary embolism . RE-MEDY was an activecontrolled study ( warfarin ) in which 1430 patients received PRADAXA 150 mg twice daily following 3 to 12 months of oral anticoagulant regimen . Patients in the treatment studies who rolled over into the RE-MEDY study had a combined treatment duration of up to more than 3 years , with mean exposure of 473 days . Table 4 shows the number of patients experiencing bleeding events in the study .
Table 4 Bleeding Events in RE-MEDY Treated Patients |
PRADAXA
150 mg twice daily N (%)
|
Warfarin
N (%)
|
Hazard Ratio
( 95 % CI ) c
|
Patients |
N = 1430 |
N = 1426 |
|
Major bleeding event a |
13 ( 0.9 ) |
25 ( 1.8 ) |
0.54 ( 0.25 , 1.16 ) |
Fatal bleeding |
0 |
1 ( 0.1 ) |
|
Bleeding in a critical area |
7 ( 0.5 ) |
11 ( 0.8 ) |
|
or organ |
|
|
|
Fall in hemoglobin |
7 ( 0.5 ) |
16 ( 1.1 ) |
|
≥2g / dL or transfusion ≥2 units of whole blood or packed red blood cells |
|
|
|
Bleeding sites for MBE b Intracranial |
2 ( 0.1 ) |
4 ( 0.3 ) |
|
Intraocular |
4 ( 0.3 ) |
2 ( 0.1 ) |
|
Retroperitoneal |
0 |
1 ( 0.1 ) |
|
Intraarticular |
0 |
2 ( 0.1 ) |
|
Intramuscular |
0 |
4 ( 0.3 ) |
|
Gastrointestinal |
4 ( 0.3 ) |
8 ( 0.6 ) |
|
Urogenital |
1 ( 0.1 ) |
1 ( 0.1 ) |
|
Other |
2 ( 0.1 ) |
4 ( 0.3 ) |
|
Clinically relevant nonmajor bleeding |
71 ( 5.0 ) |
125 ( 8.8 ) |
0.56 ( 0.42 , 0.75 ) |
Any bleeding |
278 ( 19.4 ) |
373 ( 26.2 ) |
0.71 ( 0.61 , 0.83 ) |
Figure 1
Subgroup
Major bleeding events , on treatment + 2 days , safety set
Patients |
PRADAXA 150 |
Warfarin |
N (% |
|
Total no . |
n |
N |
|
|
|
(% per yr ) |
n |
per yr ) |
Note : MBE can belong to more than one criterion . a
Patients with at least one MBE . b
Bleeding site based on investigator assessment . Patients can have more than one site of bleeding .
c
Confidence interval
In the RE-MEDY study , the rate of any gastrointestinal bleeds in patients receiving PRADAXA 150 mg was 3.1 % ( 2.2 % on warfarin ). RE-SONATE was a placebo-controlled study in which 684 patients received PRADAXA 150 mg twice daily following 6 to 18 months of oral anticoagulant regimen . Patients in the treatment studies who rolled over into the RE-SONATE study had combined treatment duration up to 9 months , with mean exposure of 165 days . Table 5 shows the number of patients experiencing bleeding events in the study .
Table 5 Bleeding Events in RE-SONATE Treated Patients |
PRADAXA
150 mg twice daily N (%)
|
Placebo
N (%)
|
Hazard Ratio
( 95 % CI ) c
|
Patients |
N = 684 |
N = 659 |
Major bleeding event a |
2 ( 0.3 ) |
0 |
|
Bleeding in a critical area |
0 |
0 |
|
or organ |
|
|
|
Gastrointestinal b |
2 ( 0.3 ) |
0 |
|
Clinically relevant non-major bleeding |
34 ( 5.0 ) |
13 ( 2.0 ) |
2.54 ( 1.34 , 4.82 ) |
Any bleeding |
72 ( 10.5 ) |
40 ( 6.1 ) |
1.77 ( 1.20 , 2.61 ) |
Note : MBE can belong to more than one criterion . |
a
Patients with at least one MBE .
|
b
Bleeding site based on investigator assessment . Patients can have more
|
than one site of bleeding . |
c
Confidence interval
In the RE-SONATE study , the rate of any gastrointestinal bleeds in patients receiving PRADAXA 150 mg was 0.7 % ( 0.3 % on placebo ). Clinical Myocardial Infarction Events : In the active-controlled VTE studies , a higher rate of clinical myocardial infarction was reported in patients who received PRADAXA [ 20 ( 0.66 per 100 patient-years )] than in those who received warfarin [ 5 ( 0.17 per 100 patient-years )]. In the placebocontrolled study , a similar rate of non-fatal and fatal clinical myocardial infarction was reported in patients who received PRADAXA [ 1 ( 0.32 per 100 patient-years )] and in those who received placebo [ 1 ( 0.34 per 100 patient-years )]. Gastrointestinal Adverse Reactions : In the four pivotal studies , patients on PRADAXA 150 mg had a similar incidence of gastrointestinal adverse reactions ( 24.7 % vs . 22.7 % on warfarin ). Dyspepsia ( including abdominal pain upper , abdominal pain , abdominal discomfort , and epigastric discomfort ) occurred in patients on PRADAXA in 7.5 % vs . 5.5 % on warfarin , and gastritis-like symptoms ( including gastritis , GERD , esophagitis , erosive gastritis and gastric hemorrhage ) occurred at 3.0 % vs . 1.7 %, respectively . Hypersensitivity Reactions : In the 4 pivotal studies , drug hypersensitivity ( including urticaria , rash , and pruritus ), allergic edema , anaphylactic reaction , and anaphylactic shock were reported in 0.1 % of patients receiving PRADAXA .
Postmarketing Experience : The following adverse reactions have been identified during post approval use of PRADAXA . Because these reactions are reported voluntarily from a population of uncertain size , it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure . The following adverse reactions have been identified during post approval use of PRADAXA : angioedema , thrombocytopenia , esophageal ulcer .
In RE-LY , a higher rate of clinical myocardial infarction was reported in patients who received PRADAXA ( 0.7 per 100 patient-years for 150 mg dose ) than in those who received warfarin ( 0.6 ).
Adjudicated Major Bleeding by Baseline Characteristics Including Hemorrhagic Stroke Treated Patients
PRADAXA 150 vs Warfarin Hazard ratio & 95 % CI
HR ( 95 % CI )
All patients |
18040 |
350 6059 ( 3.47 ) |
374 5998 ( 3.58 ) |
0.97 ( 0.84 , 1.12 ) |
VKA use at entry Naive ( 50.4 %) |
9091 |
167 3019 ( 3.51 ) |
175 3082 ( 3.51 ) |
1.00 ( 0.81 , 1.24 ) |
|
|
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|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Experienced ( 49.6 % ) |
8946 |
183 3039 ( 3.43 ) |
199 2916 ( 3.64 ) |
0.94 ( 0.77 , 1.15 ) |
|
|
|
|
|
|
|
|
|
|
Age ( years ) < 65 ( 16.5 %) |
2971 |
14 1028 ( 0.77 ) |
40 950 ( 2.39 ) |
0.32 ( 0.18 , 0.59 ) |
|
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|
≥ 65 and < 75 ( 43.6 % ) |
7864 |
117 2574 ( 2.62 ) |
146 2635 ( 3.11 ) |
0.84 ( 0.66 , 1.08 ) |
|
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|
≥ 75 ( 39.9 %) |
7205 |
219 2457 ( 5.75 ) |
188 2413 ( 4.62 ) |
1.24 ( 1.02 , 1.50 ) |
|
|
|
|
|
|
|
|
|
|
Gender Male ( 63.6 %) |
11480 |
221 3831 ( 3.37 ) |
246 3796 ( 3.64 ) |
0.93 ( 0.77 , 1.11 ) |
|
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|
Female ( 36.4 %) |
6560 |
129 2228 ( 3.65 ) |
128 2202 ( 3.47 ) |
1.05 ( 0.82 , 1.34 ) |
|
|
|
|
|
|
|
|
|
|
Weight ( kg ) ≤ 60 ( 10.9 %) |
1959 |
43 646 ( 4.59 ) |
50 683 ( 4.78 ) |
0.96 ( 0.64 , 1.44 ) |
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|
> 60 ( 89.1 %) |
16074 |
307 5412 ( 3.35 ) |
324 5312 ( 3.45 ) |
0.97 ( 0.83 , 1.13 ) |
|
|
|
|
|
|
|
|
|
|
History of stroke / TIA No ( 80.0 %) |
14428 |
264 4827 ( 3.28 ) |
285 4808 ( 3.41 ) |
0.96 ( 0.81 , 1.14 ) |
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|
Yes ( 20.0 %) |
3612 |
86 1232 ( 4.20 ) |
89 1190 ( 4.28 ) |
0.98 ( 0.73 , 1.32 ) |
|
|
|
|
|
|
|
|
|
|
Diabetes at baseline No ( 76.7 %) |
13836 |
239 4661 ( 3.06 ) |
271 4593 ( 3.36 ) |
0.91 ( 0.76 , 1.08 ) |
|
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|
|
|
Yes ( 23.3 %) |
4204 |
111 1398 ( 4.87 ) |
103 1405 ( 4.33 ) |
1.13 ( 0.86 , 1.47 ) |
|
|
|
|
|
|
|
|
|
|
CHADS2 score ≤ 1 ( 31.9 %) |
5763 |
72 1955 ( 2.10 ) |
91 1860 ( 2.72 ) |
0.77 ( 0.57 , 1.05 ) |
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|
= 2 ( 35.6 %) |
6422 |
119 2129 ( 3.37 ) |
127 2212 ( 3.29 ) |
1.02 ( 0.79 , 1.31 ) |
|
|
|
|
|
|
|
|
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|
|
|
|
|
|
≥ 3 ( 32.5 %) |
5855 |
159 1975 ( 5.08 ) |
156 1926 ( 4.81 ) |
1.05 ( 0.85 , 1.32 ) |
|
|
|
|
|
|
|
|
|
|
CrCL ( mL / min ) < 30 ( 0.4 %) |
74 |
3 31 ( 10.28 ) |
1 29 ( 2.57 ) |
3.84 ( 0.40,36.90 ) |
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≥ 30 and ≤ 50 ( 18.4 % |
) 3327 |
105 1152 ( 6.18 ) |
101 1048 ( 6.05 ) |
1.02 ( 0.77 , 1.34 ) |
|
|
|
|
|
> 50 and ≤ 80 ( 45.8 % |
) 8269 |
161 2770 ( 3.51 ) |
184 2794 ( 3.80 ) |
0.92 ( 0.75 , 1.14 ) |
|
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|
|
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|
> 80 ( 31.3 %) |
5641 |
70 1880 ( 2.07 ) |
79 1872 ( 2.29 ) |
0.90 ( 0.65 , 1.25 ) |
|
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|
Region USA ( 29.7 %) |
5352 |
162 1811 ( 5.23 ) |
161 1774 ( 5.00 ) |
1.04 ( 0.84 , 1.30 ) |
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OUS ( 70.3 %) |
12688 |
188 4248 ( 2.69 ) |
213 4224 ( 2.95 ) |
0.91 ( 0.75 , 1.11 ) |
|
|
|
|
|
ASA use at baseline No ( 60.3 %) |
10887 |
195 3721 ( 3.08 ) |
202 3567 ( 3.15 ) |
0.98 ( 0.80 , 1.19 ) |
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Yes ( 39.7 %) |
7153 |
155 2338 ( 4.12 ) |
172 2431 ( 4.27 ) |
0.96 ( 0.78 , 1.20 ) |
|
|
|
|
|
DRUG INTERACTIONS : Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation : The concomitant use of PRADAXA with P-gp inducers ( e . g ., rifampin ) reduces exposure to dabigatran and should generally be avoided . P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran . Concomitant use of P-gp inhibitors in patients with renal impairment is expected to produce increased exposure of dabigatran compared to that seen with either factor alone . In patients with moderate renal impairment ( CrCl 30-50 mL / min ), reduce the dose of PRADAXA to 75 mg twice daily when administered concomitantly with the P-gp inhibitors dronedarone or systemic ketoconazole . The use of the P-gp inhibitors verapamil , amiodarone , quinidine , clarithromycin , and ticagrelor does not require a dose adjustment of PRADAXA . These results should not be extrapolated to other P-gp inhibitors [ see Warnings and Precautions and Use in Specific Populations ]. The concomitant use of PRADAXA and P-gp inhibitors in patients with severe renal impairment ( CrCl 15-30 mL / min ) should be avoided [ see Warnings and Precautions and Use in Specific Populations ]. Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism : Avoid use of PRADAXA and P-gp inhibitors in patients with CrCl < 50 mL / min [ see Warnings and Precautions and Use in Specific Populations ].
USE IN SPECIFIC POPULATIONS : Pregnancy : Pregnancy Category C : There are no adequate and well-controlled studies in pregnant women . Dabigatran has been shown to decrease the number of implantations when male and female rats were treated at a dosage of 70 mg / kg ( about 2.6 to 3.0 times the human exposure at maximum recommended human dose [ MRHD ] of 300 mg / day based on area under the curve [ AUC ] comparisons ) prior to mating and up to implantation ( gestation Day 6 ). Treatment of pregnant rats after implantation with dabigatran at the same dose increased the number of dead offspring and caused excess vaginal / uterine bleeding close to parturition . Although dabigatran increased the incidence of delayed or irregular ossification of fetal skull bones and vertebrae in the rat , it did not induce major malformations in rats or rabbits . Labor and Delivery : Safety and effectiveness of PRADAXA during labor and delivery have not been studied in clinical trials . Consider the risks of bleeding and of stroke in using PRADAXA in this setting [ see Warnings and Precautions ]. Death of offspring and mother rats during labor in association with uterine bleeding occurred during treatment of pregnant rats from implantation ( gestation Day 7 ) to weaning ( lactation Day 21 ) with dabigatran at a dose of 70 mg / kg ( about 2.6 times the human exposure at MRHD of 300 mg / day based on AUC comparisons ). Nursing Mothers : It is not known whether dabigatran is excreted in human milk . Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from PRADAXA , a decision should be made whether to discontinue nursing or to discontinue the drug , taking into account the importance of the drug to the mother . Pediatric Use : Safety and effectiveness of PRADAXA in pediatric patients have not been established . Geriatric Use : Of the total number of patients in the RE-LY study , 82 % were 65 and over , while 40 % were 75 and over . The risk of stroke and bleeding increases with age , but the risk-benefit profile is favorable in all age groups [ see Warnings and Precautions and Adverse Reactions ]. Renal Impairment : Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation : No dose adjustment of PRADAXA is recommended in patients with mild or moderate renal impairment . Reduce the dose of PRADAXA in patients with severe renal impairment ( CrCl 15-30 mL / min ). Dosing recommendations for patients with CrCl < 15 mL / min or on dialysis cannot be provided . Adjust dose appropriately in patients with renal impairment receiving concomitant P-gp inhibitors [ see Warnings and Precautions and Drug Interactions ]. Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism : Patients with severe renal impairment ( CrCl ≤30 mL / min ) were excluded from RE-COVER . Dosing recommendations for patients with CrCl ≤30 mL / min or on dialysis cannot be provided . Avoid use of PRADAXA with concomitant P-gp inhibitors in patients with CrCl < 50 mL / min [ see Warnings and Precautions and Drug Interactions ].
OVERDOSAGE : Accidental overdose may lead to hemorrhagic complications . In the event of hemorrhagic complications , initiate appropriate clinical support , discontinue treatment with PRADAXA , and investigate the source of bleeding . A specific reversal agent ( idarucizumab ) is available . Dabigatran is primarily eliminated by the kidneys with a low plasma protein binding of approximately 35 %. Hemodialysis can remove dabigatran ; however , data supporting this approach are limited . Using a high-flux dialyzer , blood flow rate of 200 mL / min , and dialysate flow rate of 700 mL / min , approximately 49 % of total dabigatran can be cleared from plasma over 4 hours . At the same dialysate flow rate , approximately 57 % can be cleared using a dialyzer blood flow rate of 300 mL / min , with no appreciable increase in clearance observed at higher blood flow rates . Upon cessation of hemodialysis , a redistribution effect of approximately 7 % to 15 % is seen . The effect of dialysis on dabigatran ’ s plasma concentration would be expected to vary based on patient specific characteristics . Measurement of aPTT or ECT may help guide therapy [ see Warnings and Precautions ].
Revised : November 2015 PXD-BS ( 12-15 )
Copyright 2015 Boehringer Ingelheim Pharmaceuticals , Inc . ALL RIGHTS RESERVED
PC-PXD-0337-PROF
0.1 0.5 1 1.5 2
PRADAXA Better
Warfarin Better
Note : The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified . The 95 % confidence limits that are shown do not take into account how many comparisons were made , nor do they reflect the effect of a particular factor after adjustment for all other factors . Apparent homogeneity or heterogeneity among groups should not be over-interpreted .