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)
Major Bleeding Primary Safety Endpoint	3.47 (350)	3.58 (374)	0.92 (0.84, 1.12)
Intracranial Hemorrhage	0.22 (23)	0.77 (82)	0.29 (0.18, 0.46)
Gastrointestinal (GI) Bleeding	1.59 (162)	1.05 (111)	1.51 (1.19, 1.92)
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

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 patients-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 STUDIES^6-10,13 

Results from real-world studies are not intended for comparisons with clinical trials. Real-world studies were observational trials. Differences in study designs, patients 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.

2019 FDA Medicare Study

Comparative Stroke, Bleeding, And Mortality Risks In Older Medicare Patients Treated With Oral Anticoagulants for Nonvalvular Atrial Fibrillation⁶

Objectives

To assess the outcomes of hospitalized thromboembolic stroke, intracranial hemorrhage, major extracranial bleeding (including major gastrointestinal bleeding), and all cause mortality associated with PRADAXA, rivaroxaban, apixaban, or warfarin treatment for stroke risk reduction in patients with NVAF.

Method

• Large, observational, retrospective, propensity-matched, new-user cohort study of NVAF patients enrolled in fee-for-service US Medicare between October 2010 and September 2015 who initiated warfarin (n=183,318), or a standard dose of dabigatran (150 mg twice daily; n=86,198), rivaroxaban (20 mg once daily; n=106,389), or apixaban (5 mg twice daily; n=73,039)

• Propensity score-adjusted Cox proportional hazards regression was used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the outcomes of thromboembolic stroke, intracranial hemorrhage, major extracranial bleeding, and all-cause mortality, comparing each NOAC with warfarin, and with each other NOAC

The value of real-world studies when evaluating NOACs

Dr. Richard Wright, a leading cardiology expert and Chairman of the Board of the Pacific Heart Institute, discusses a 2019 FDA Medicare study evaluating PRADAXA versus other NOACs used to reduce stroke in patients with nonvalvular atrial fibrillation.

2016 FDA Medicare Study

Stroke, bleeding, and mortality risks in elderly Medicare beneficiaries treated with dabigatran or rivaroxaban for nonvalvular atrial fibrillation.⁷

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)	1.8	0.80 (0.64, 1.00)	0.81 (0.65, 1.01)
Intracranial hemorrhage	3.7 (58)	5.8 (118)	2.3	1.58 (1.15, 2.16)	1.65 (1.20, 2.26)
Major extracranial bleeding event	26.6 (413)	39.4 (796)	13.0	1.47 (1.31, 1.66)	1.48 (1.32, 1.67)
Gastrointestinal	23.3 (362)	32.5 (656)	9.4	1.39 (1.22, 1.58)	1.40 (1.23, 1.59)
Mortality	22.2 (346)	24.7 (500)	3.1	1.12 (0.98, 1.29)	1.15 (1.00, 1.32)

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.

2014 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

2012 FDA Mini-Sentinel Assessment⁹

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 Findings⁹

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

Meta-analysis of 20 Studies^††10

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

Key Study Findings¹⁰

Meta-analysis included data from: Department of Defense study¹¹ and Brigham and Women's study.¹²

US Administrative Claims Study^‡‡13

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 Study¹³

Key Study Findings¹³

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.