Safety of PRADAXA Established

In the RE‑LY® Trial,
Proven safety with PRADAXA vs. warfarin in NVAF1

Bleeding Events in Pivotal RE‑LY® Trial
Adjudicated Major
Bleeding Events in
Treated Patients*
PRADAXA
150 mg BID
(N=6059)
warfarin
(N=5998)
HR
(95% CI)
Events=%/year (n)
About equal Major Bleeding
Primary Safety Endpoint
3.47
(350)
3.58
(374)
0.97
(0.84, 1.12)
Decrease Intracranial
Hemorrhage
0.22
(23)
0.77
(82)
0.29
(0.18, 0.46)
Increase Gastrointestinal
(GI) Bleeding
1.59
(162)
1.05
(111)
1.51
(1.19, 1.92)
About equal Fatal Bleeding
0.07
(7)
0.15
(16)
0.45
(0.19, 1.10)
  • Higher rate of total GI bleeds (6.6% [637 events] vs. 4.2% [427 events], HR: 1.6, 95% CI [1.4, 1.8])1,2
  • Trend towards a higher incidence of major bleeding on PRADAXA 150 mg for patients ≥75 years of age (HR: 1.2, 95% CI [1.0, 1.5])1
  • Risk-benefit profile is favorable in all age groups1
*
Patients during treatment or within 2 days of stopping study treatment. Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events in multiple subcategories.
Annual event rate per 100 pt-years = 100 * number of subjects with event/subject-years. Subject-years is defined as cumulative number of days from first drug intake to event date, date of last drug intake + 2, death date (whatever occurred first) across all treated subjects divided by 365.25. In case of recurrent events of the same category, the first event was considered.

In a long-term safety extension trial,
Safety profile of PRADAXA supported in RELY-ABLE®2-5

Bleeding Events in RELY-ABLE®
Event PRADAXA 150 mg BID
(N=2937)
Events=%/year (n)
Major Bleeding 3.74
(238)
Fatal Bleeding 0.24
(15)
Intracranial Hemorrhage 0.33
(21)
Gastrointestinal Bleeding 1.54
(98)

Rates of major bleeding were similar to those seen during the RE‑LY® Trial§

Patients during treatment or within 6 days of stopping study treatment.
§
There was no adjudication of outcome events occurring in RELY-ABLE®. (Adjudication in RE‑LY® confirmed ~93% of reported major bleeds on both doses.) Only half of the patients continued from RE‑LY® to RELY-ABLE®. Patients enrolled in RELY-ABLE® were different from those in RE‑LY®, and they may have been at lower risk of events. Warfarin patients were not followed as a comparator group. Data analysis was not intention to treat and different from RE‑LY® analysis.5

Adverse Reactions in clinical trials

The most serious adverse reactions reported with PRADAXA were related to bleeding1

Drug discontinuation
  • The rates of adverse reactions leading to treatment discontinuation were 21% for PRADAXA 150 mg and 16% for warfarin in the RE‑LY® Trial1
  • The most frequent adverse reactions leading to discontinuation of PRADAXA in the RE‑LY® Trial were bleeding and GI events (i.e., dyspepsia, nausea, upper abdominal pain, GI hemorrhage, and diarrhea)1
Clinical MI events1
  • In the active-controlled DVT/PE studies, a higher rate of clinical MI was reported in patients who received PRADAXA [20 events (0.66 per 100 patient-years)] than in those who received warfarin [5 events (0.17 per 100 patient-years)]
  • In the placebo-controlled DVT/PE study, a similar rate of non-fatal and fatal clinical MI was reported in patients who received PRADAXA [1 event (0.32 per 100 patient-years)] and in those who received placebo [1 event (0.34 per 100 patient-years)]
  • In the DVT/PE after hip replacement studies, clinical MI was reported in 2 (0.1%) patients who received PRADAXA 220  mg and 6 (0.3%) patients who received enoxaparin
Gastrointestinal adverse reactions1
  • In the RE‑LY® Trial, increased incidence of GI adverse reactions (35% on PRADAXA vs. 24% on warfarin) were:
    • Dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort)
    • Gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and GI ulcer)
  • In the 4 pivotal DVT/PE studies, similar incidence of GI adverse reactions (24.7% on PRADAXA vs. 22.7% on warfarin) were:
    • Dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort), which occurred in 7.5% on PRADAXA vs. 5.5% on warfarin
    • Gastritis-like symptoms (including gastritis, GERD, esophagitis, erosive gastritis, and gastric hemorrhage), which occurred in 3.0% on PRADAXA vs. 1.7% on warfarin
  • In the DVT/PE after hip replacement studies, the rate of major GI bleeds in patients receiving PRADAXA 220 mg and enoxaparin was the same; rate of any GI bleeds was higher in patients receiving PRADAXA 220 mg vs. enoxaparin. GI adverse reactions were the same in patients receiving PRADAXA 220 mg vs. enoxaparin. These were:
    • Dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort)
    • Gastritis-like symptoms (including gastritis, GERD, esophagitis, erosive gastritis and gastric hemorrhage)
Hypersensitivity reactions1
  • In the RE‑LY® Trial, drug hypersensitivity (including urticaria, rash, and pruritus), allergic edema, anaphylactic reaction, and anaphylactic shock were reported in <0.1% of patients receiving PRADAXA
  • In the 4 pivotal DVT/PE studies, drug hypersensitivity (including urticaria, rash, and pruritus), allergic edema, anaphylactic reaction, and anaphylactic shock were reported in 0.1% of patients receiving PRADAXA
  • In the DVT/PE after hip replacement studies, drug hypersensitivity (such as urticaria, rash, and pruritus) was reported in 0.3% of patients receiving PRADAXA 220 mg

Safety supported in multiple real-world studies6-9,12

Results from real-world studies are not intended for comparisons with clinical trials. Real-world studies were observational trials. Differences in study designs, patient populations, outcome definitions, and methods of collecting data make it difficult to make comparisons with clinical trials or with each other. Real-world data should be viewed as complementary information.

Stroke, bleeding, and mortality risks in elderly Medicare beneficiaries treated with dabigatran or rivaroxaban for nonvalvular atrial fibrillation.6

Note
There are no randomized head-to-head comparisons of PRADAXA and rivaroxaban for safety and efficacy.

Objective
Assess primary outcomes of:
  • Thromboembolic stroke
  • Intracranial hemorrhage
  • Major extracranial bleeding, including gastrointestinal bleeding
  • Mortality
Method
  • Retrospective, observational FDA- & CMS-funded analysis under SafeRx program
  • 118,891 patients ≥65 years old with NVAF enrolled in Medicare
  • PRADAXA 150 mg BID or rivaroxaban 20 mg QD
  • From November 2011- June 2014
  • Differences in baseline characteristics were adjusted using stabilized inverse probability of treatment weights based on propensity scores
Effects of
PRADAXA 150 mg vs rivaroxaban 20 mg
in elderly Medicare beneficiaries study
Primary Outcomes Crude (unadjusted) incidence rate per 1000 person-years
(No. of events)
Adjusted incidence rate difference per 1000 person-years Hazard ratio
(95% CI)
PRADAXA
(n=52,240)
Rivaroxaban
(n=66,651)
Crude Adjusted
Thromboembolic
stroke
9.7
(150)
7.7
(156)
Decrease 1.8
0.80
(0.64, 1.00)
0.81
(0.65, 1.01)
Intracranial
hemorrhage
3.7
(58)
5.8
(118)
Increase 2.3
1.58
(1.15, 2.16)
1.65
(1.20, 2.26)
Major
extracranial
bleeding event
26.6
(413)
39.4
(796)
Increase 13.0
1.47
(1.31, 1.66)
1.48
(1.32, 1.67)
Gastrointestinal 23.3
(362)
32.5
(656)
Increase 9.4
1.39
(1.22, 1.58)
1.40
(1.23, 1.59)
Mortality 22.2
(346)
24.7
(500)
Increase 3.1
1.12
(0.98, 1.29)
1.15
(1.00, 1.32)
Adjusted incidence rate difference = (rivaroxaban adjusted rate) – (PRADAXA adjusted rate).
Results

Compared to PRADAXA, treatment with rivaroxaban was associated with increased rates of intracranial hemorrhage, major extracranial bleeding, including major gastrointestinal bleeding, and mortality. Rivaroxaban use was associated with a non-significant reduction in thromboembolic stroke.

Limitations
  • Mean follow-up time of <4 months led to a smaller sample size at longer durations of use
  • Participants restricted to patients aged ≥65 years—while this age group accounts for 80% of patients with NVAF, the comparative effects of treatment with PRADAXA and rivaroxaban could be different in younger populations
  • Study was observational, and so may also be subject to residual confounding by unmeasured factors
  • Study examined first-time users of PRADAXA and rivaroxaban; results could differ in patients switching from warfarin to a NOAC
Funding/Support: This study was performed as part of the SafeRx project, a joint initiative of the Centers for Medicare & Medicaid Services (CMS) and the US Food and Drug Administration (FDA), and was funded through an interagency agreement. Role of the Funder/Sponsor: The authors are employees or contractors of the CMS or the FDA; however, other officials at the CMS and the FDA had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Disclaimer: The views expressed are the authors’ and not necessarily those of the FDA, the CMS, or the Department of Health and Human Services.

FDA Mini-Sentinel Assessment7

50,000+ NVAF Patients
The U.S. FDA retrospective observational assessment of a NOAC investigated actual rates of GI and intracranial hemorrhage for new users of PRADAXA and warfarin.

Sponsored by the FDA
Pilot project to create an active surveillance system using pre‑existing electronic healthcare data from multiple sources to assess the safety of approved drugs and other medical products.

Key Study Findings7

  • Bleeding rates associated with PRADAXA did not appear to be higher than those associated with warfarin

FDA Medicare Study8

134,000+ NVAF Patients
The U.S. FDA retrospective observational study evaluated the safety and effectiveness of PRADAXA vs. warfarin in patients 65 years or older.

Pooled analysis of PRADAXA 150 mg BID/75 mg BID vs. warfarin in FDA Medicare Study¶8

Key Study Findings8

Ischemic Stroke Intracranial Hemorrhage Death Major GI Bleeding Major Bleeding
Lower
Risk
Lower
Risk
Lower
Risk
Increased
Risk
Similar
Risk**
Because of covariate imbalances between dabigatran and warfarin cohorts after stratification by dose, patients were rematched within strata defined by daily dabigatran dose, resulting in a total of 67,098 patients in each cohort rather than 67,2017 from the primary analysis.8
**
The rate of major bleeding was analyzed by pooling 75-mg and 150-mg dose results.

Meta-analysis of 20 Studies††9

A systematic review and meta-analysis of retrospective observational studies of 711,000+ NVAF patients.

Key Study Findings9

Ischemic Stroke Intracranial Hemorrhage Death Any GI Bleeding Major Bleeding
Lower
Risk
Lower
Risk
Lower
Risk
Increased
Risk
Lower
Risk
††
Studies analyzed 75-mg, 110-mg, and 150-mg dose results. While studied in the RE‑LY® pivotal trial, the 110-mg dose is not approved for use in patients with NVAF.9

Meta-analysis included data from: Department of Defense study10 and Brigham and Women's study.11

US Administrative Claims Study‡‡12

A retrospective analysis of the safety and effectiveness of PRADAXA vs. warfarin.

Pooled analysis of PRADAXA 150 mg/75 mg BID vs warfarin in US Administrative Claims Study12

Key Study Findings12

Stroke/SE Ischemic Stroke Intracranial Hemorrhage Major GI
Bleeding
Major Bleeding
Similar
Risk
Similar
Risk
Lower
Risk
Similar
Risk
Lower
Risk

Findings were generally similar to those of the RE‑LY® Trial, with the exception of GI bleeding, which was significantly higher in patients treated with PRADAXA vs. warfarin in RE‑LY.

‡‡
Other NOACs were included in this study: rivaroxaban and apixaban.12
PRADAXA Real-World Data Portal
Are you a formulary decision maker?
Visit the PRADAXA Real-World Data Portal where you can:
  • Access the latest assessments of PRADAXA in real-world studies
  • Review analyses to help inform your formulary decisions
  • Download studies to review at your convenience
  • Receive e-mail notifications when new studies are added
HR=hazard ratio; CI=confidence interval.
References: 1. Pradaxa [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 2. Data on file. Boehringer Ingelheim Pharmaceuticals, Inc. 3. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L; for the Randomized Evaluation of Long-Term Anticoagulation Therapy Investigators. Newly identified events in the RE‑LY Trial [Letter to the Editor]. N Engl J Med. 2010;363(19):1875-1876. 4. Connolly SJ, Wallentin L, Yusuf S. Additional events in the RE‑LY Trial [Letter to the Editor]. N Engl J Med. 2014;371(15):1464-1465. 5. Connolly SJ, Wallentin L, Ezekowitz MD, et al. The long-term multicenter observational study of dabigatran treatment in patients with atrial fibrillation (RELY-ABLE) study. Circulation. 2013;128(3):237-243. 6. Graham DJ, Reichman ME, Wernecke M, et al. Stroke, bleeding, and mortality risks in elderly Medicare beneficiaries treated with dabigatran or rivaroxaban for nonvalvular atrial fibrillation. JAMA Intern Med. 2016;176(11):1662-1671. 7. Southworth MR, Reichman ME, Unger EF. Dabigatran and Postmarketing Reports of Bleeding. N Engl J Med. 2013;368:1272-1274. 8. Graham DJ, Reichman ME, Wernecke M, et al. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for non-valvular atrial fibrillation. Circulation. 2015;131(2):157-164. 9. Carmo J, Moscoso Costa F, Ferreira J, Mendes M. Dabigatran in real-world atrial fibrillation. Meta-analysis of observational comparison studies with vitamin K antagonists. Thromb Haemost. 2016;116(4):754-763. 10. Villines TC, Schnee J, Fraeman K, et al. A comparison of the safety and effectiveness of dabigatran and warfarin in non‑valvular atrial fibrillation patients in a large healthcare system. Thromb Haemost. 2015;114(6):1290-1298. 11. Seeger JD, Bykov K, Bartels DB, et al. Safety and effectiveness of dabigatran and warfarin in routine care of patients with atrial fibrillation. Thromb Haemost. 2015;114(6):1277-1289. 12. Yao X, Abraham NS, Sangaralingham LR, et al. Effectiveness and safety of dabigatran, rivaroxaban, and apixaban versus warfarin in nonvalvular atrial fibrillation. J Am Heart Assoc. 2016;5(6):1-19.

IMPORTANT SAFETY INFORMATION

WARNING: (A) PREMATURE DISCONTINUATION OF PRADAXA INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA

(A) PREMATURE DISCONTINUATION OF PRADAXA INCREASES THE RISK OF THROMBOTIC EVENTS
Premature discontinuation of any oral anticoagulant, including PRADAXA, increases the risk of thrombotic events. If anticoagulation with PRADAXA is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant

INDICATIONS AND USAGE

Pradaxa® (dabigatran etexilate mesylate) capsules is indicated:
  • to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation;
  • for the treatment of deep venous thrombosis and pulmonary embolism in patients who have been treated with a parenteral anticoagulant for 5-10 days;
  • to reduce the risk of recurrence of deep venous thrombosis and pulmonary embolism in patients who have been previously treated

IMPORTANT SAFETY INFORMATION

WARNING: (A) PREMATURE DISCONTINUATION OF PRADAXA INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA

(A) PREMATURE DISCONTINUATION OF PRADAXA INCREASES THE RISK OF THROMBOTIC EVENTS
Premature discontinuation of any oral anticoagulant, including PRADAXA, increases the risk of thrombotic events. If anticoagulation with PRADAXA is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant

(B) SPINAL/EPIDURAL HEMATOMA

Epidural or spinal hematomas may occur in patients treated with PRADAXA who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:

  • use of indwelling epidural catheters
  • concomitant use of other drugs that affect hemostasis, such as non-steroidal anti‑inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
  • a history of traumatic or repeated epidural or spinal punctures
  • a history of spinal deformity or spinal surgery
  • optimal timing between the administration of PRADAXA and neuraxial procedures is not known

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients who are or will be anticoagulated.

INDICATIONS AND USAGE

Pradaxa® (dabigatran etexilate mesylate) capsules is indicated:
  • to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation;

CONTRAINDICATIONS

PRADAXA is contraindicated in patients with:

  • active pathological bleeding;
  • known serious hypersensitivity reaction to PRADAXA (e.g., anaphylactic reaction or anaphylactic shock);
  • mechanical prosthetic heart valve

WARNINGS & PRECAUTIONS

Increased Risk of Thrombotic Events after Premature Discontinuation

Premature discontinuation of any oral anticoagulant, including PRADAXA, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. If PRADAXA is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant and restart PRADAXA as soon as medically appropriate.

Risk of Bleeding

  • PRADAXA increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. Promptly evaluate any signs or symptoms of blood loss (e.g., a drop in hemoglobin and/or hematocrit or hypotension). Discontinue PRADAXA in patients with active pathological bleeding.
  • Risk factors for bleeding include concomitant use of medications that increase the risk of bleeding (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs). PRADAXA’s anticoagulant activity and half-life are increased in patients with renal impairment.
  • Reversal of Anticoagulant Effect: A specific reversal agent (idarucizumab) for dabigatran is available when reversal of the anticoagulant effect of dabigatran is needed:
    • For emergency surgery/urgent procedures
    • In life-threatening or uncontrolled bleeding
  • Hemodialysis can remove dabigatran; however clinical experience for hemodialysis as a treatment for bleeding is limited. Prothrombin complex concentrates or recombinant Factor VIIa may be considered but their use has not been evaluated. Protamine sulfate and vitamin K are not expected to affect dabigatran anticoagulant activity. Consider administration of platelet concentrates where thrombocytopenia is present or long-acting antiplatelet drugs have been used.

Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves

The use of PRADAXA is contraindicated in patients with mechanical prosthetic valves due to a higher risk for thromboembolic events, especially in the post-operative period, and an excess of major bleeding for PRADAXA vs. warfarin. Use of PRADAXA for the prophylaxis of thromboembolic events in patients with AFib in the setting of other forms of valvular heart disease, including bioprosthetic heart valve, has not been studied and is not recommended.

Effect of P-gp Inducers & Inhibitors on Dabigatran Exposure

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 major independent factors in increased exposure to dabigatran. Concomitant use of P‑gp inhibitors in patients with renal impairment is expected to increase exposure of dabigatran compared to either factor alone.
Reduction of Risk of Stroke/Systemic Embolism in NVAF

  • For patients with moderate renal impairment (CrCl 30‑50 mL/min), reduce the dose of PRADAXA to 75 mg twice daily when dronedarone or systemic ketoconazole is coadministered with PRADAXA.
  • For patients with severe renal impairment (CrCl 15‑30 mL/min), avoid concomitant use of PRADAXA and P‑gp inhibitors.
Treatment and Reduction in the Risk of Recurrence of DVT/PE & Prophylaxis of DVT/PE Following Hip Replacement Surgery
  • For patients with CrCl <50 mL/min, avoid use of PRADAXA and concomitant P‑gp inhibitors

ADVERSE REACTIONS

The most serious adverse reactions reported with PRADAXA were related to bleeding.

Other Measures Evaluated

In NVAF patients, a higher rate of clinical MI was reported in patients who received PRADAXA (0.7/100 patient-years for 150 mg dose) than in those who received warfarin (0.6).

USE IN SPECIFIC POPULATIONS

  • Pregnancy: The limited available data on PRADAXA use in pregnant women are insufficient to determine drug-associated risks for adverse developmental outcomes.
  • Lactation: Breastfeeding is not recommended.
  • Geriatric: Risk of bleeding increases with age.
CL-PX-100008 March 2018