Dabigatran

{{drugbox | | IUPAC_name = Ethyl 3-{[(2-{[(4-{N'-[(hexyloxy)carbonyl] carbamimidoyl}phenyl)amino]methyl}-1-methyl-1H- benzimidazol-5-yl)carbonyl] (2-pyridinyl)amino}propanoate | image = Dabigatran etexilate.png | width = 135px | CAS_number = 211915-06-9 | CAS_supplemental = 211914-51-1 | ATC_prefix = | ATC_suffix = | ATC_supplemental= | PubChem = 6445226 | DrugBank = | chemical_formula = | C=34 | H=41 | N=7 | I= | Br= | Cl= | F= | O=5 | P= | S= | Se= | Na= | charge= | molecular_weight = 627.734 (471.511 without etexilate) | specific_rotation = | sec_combustion = | bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion = | pregnancy_AU = | pregnancy_US = | pregnancy_category = | legal_AU = | legal_UK = | legal_US = | legal_status = | dependency_liability = unknown | routes_of_administration = oral }} Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]. Dr. Gibson has received research grant support from all major manufacturers of antithrombins and antiplatelets. For full disclosure information click here.

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Synonyms and keywords: Pradaxa, rendix

To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY or FDA at 1-800-FDA-1088 or the FDA Medwatch site.

Overview

Dabigatran is an anticoagulant from the class of the direct thrombin inhibitors. It is being studied for various clinical indications, for some of which it may replace warfarin as the preferred anticoagulant. It is orally administered as the prodrug dabigatran etexilate (planned trade names Rendix and Pradaxa). It was developed by pharmaceutical company Boehringer-Ingelheim.

Development

Dabigatran (then compound BIBR 953) was discovered from a panel of chemicals with similar structure to benzamidine-based thrombin inhibitor α-NAPAP (N-alpha-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide), which had been known since the 1980s as a powerful inhibitor of various serine proteases, specifically thrombin but also trypsin. Addition of a hydrophobic side chain led to the orally absorbed prodrug BIBR 1048 (dabigatran etexilate).
Phase 3 clinical trials are ongoing in treatment and prevention of secondary venous thromboembolism (VTE) in post-operative orthopedic patients (expected results by Oct 2007); long-term prophylaxis in acute coronary syndrome and stroke patients and symptomatic VTE because of various causes (expected results by 2009-2010).

Dosing

The dose approved for use in atrial fibrillation is 150 mg orally twice a day (PO bid) in patients with a CrCl > 30 ml/min. In patients with renal insufficiency (CrCl 15-30 ml/min), the dose is 75 mg orally twice a day (PO bid). Patients should be instructed not to chew, break, or open capsules. If a dose of PRADAXA is not taken at the scheduled time, the dose should be taken as soon as possible on the same day; the missed dose should be skipped if it cannot be taken at least 6 hours before the next scheduled dose. The dose of PRADAXA should not be doubled to make up for a missed dose.

Converting from or to Warfarin

When converting patients from warfarin therapy to PRADAXA, discontinue warfarin and start PRADAXA when the international normalized ratio (INR) is below 2.0. When converting from PRADAXA to warfarin, adjust the starting time of warfarin based on creatinine clearance as follows: • For CrCl >50 mL/min, start warfarin 3 days before discontinuing PRADAXA. • For CrCl 31-50 mL/min, start warfarin 2 days before discontinuing PRADAXA. • For CrCl 15-30 mL/min, start warfarin 1 day before discontinuing PRADAXA. • For CrCl <15 mL/min, no recommendations can be made. Because PRADAXA can contribute to an elevated INR, the INR will better reflect warfarin’s effect after PRADAXA has been stopped for at least 2 days.

Converting from or to Parenteral Anticoagulants

For patients currently receiving a parenteral anticoagulant, start PRADAXA 0 to 2 hours before the time that the next dose of the parenteral drug was to have been administered or at the time of discontinuation of a continuously administered parenteral drug (e.g., intravenous unfractionated heparin). For patients currently taking PRADAXA, wait 12 hours (CrCl ≥30 mL/min) or 24 hours (CrCl <30 mL/min) after the last dose of PRADAXA before initiating treatment with a parenteral anticoagulant.

Monitoring

Unlike coumadin, no INR monitoring is required.

Surgery and Interventions

If possible, discontinue PRADAXA 1 to 2 days (CrCl ≥50 mL/min) or 3 to 5 days (CrCl <50 mL/min) before invasive or surgical procedures because of the increased risk of bleeding. Consider longer times for patients undergoing major surgery, spinal puncture, or placement of a spinal or epidural catheter or port, in whom complete hemostasis may be required. If surgery cannot be delayed, there is an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention. Bleeding risk can be assessed by the ecarin clotting time (ECT). This test is a better marker of the anticoagulant activity of dabigatran than activated partial thromboplastin time (aPTT), prothrombin time (PT)/INR, or thrombin time (TT). If ECT is not available, the aPTT test provides an approximation of PRADAXA’s anticoagulant activity

WARNINGS AND PRECAUTIONS

• Risk of bleeding: PRADAXA can cause serious and, sometimes, fatal bleeding. Promptly evaluate signs and symptoms of blood loss.
• Temporary discontinuation: Avoid lapses in therapy to minimize risk of stroke
• P-gp inducers and inhibitors: Avoid coadministration of rifampin with PRADAXA because of effects on dabigatran exposure

Risk of Bleeding

PRADAXA increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. Risk factors for bleeding include the use of drugs that increase the risk of bleeding in general (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs) and labor and delivery. 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.

In the RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) study, a life-threatening bleed (bleeding that met one or more of the following criteria: fatal, symptomatic intracranial, reduction in hemoglobin of at least 5 grams per deciliter, transfusion of at least 4 units of blood, associated with hypotension requiring the use of intravenous inotropic agents, or necessitating surgical intervention) occurred at an annualized rate of 1.5% and 1.8% for PRADAXA 150 mg and warfarin, respectively.

Temporary Discontinuation of PRADAXA

Discontinuing anticoagulants, including PRADAXA, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of stroke. Lapses in therapy should be avoided, and if anticoagulation with PRADAXA must be temporarily discontinued for any reason, therapy should be restarted as soon as possible.

Effect of P-gp Inducers and Inhibitors on Dabigatran Exposure

The concomitant use of PRADAXA with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided. P-gp inhibitors ketoconazole, verapamil, amiodarone, quinidine, and clarithromycin do not require dose adjustments. These results should not be extrapolated to other Pgp inhibitors.

Adverse Reactions

Gastrointestinal Adverse Reactions

Patients on PRADAXA 150 mg had an increased incidence of gastrointestinal adverse reactions (35% vs. 24% on warfarin). These were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and gastrointestinal ulcer).

Hypersensitivity Reactions

In the RE-LY study, drug hypersensitivity (including urticaria, rash, and pruritus), allergic edema, anaphylactic reaction, and anaphylactic shock were reported in <0.1% of patients receiving PRADAXA.

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. 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, caution should be exercised when PRADAXA is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of PRADAXA in pediatric patients has 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.

Renal Impairment

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.

Overdosage

Accidental overdose may lead to hemorrhagic complications. There is no antidote to dabigatran etexilate or dabigatran. In the event of hemorrhagic complications, initiate appropriate clinical support, discontinue treatment with PRADAXA, and investigate the source of bleeding. Dabigatran is primarily excreted in the urine; therefore, maintain adequate diuresis. Dabigatran can be dialyzed (protein binding is low), with the removal of about 60% of drug over 2 to 3 hours; however, data supporting this approach are limited. Consider surgical hemostasis or the transfusion of fresh frozen plasma or red blood cells. There is some experimental evidence to support the role of activated prothrombin complex concentrates (e.g., FEIBA), or recombinant Factor VIIa, or concentrates of coagulation factors II, IX or X; however, their usefulness in clinical settings has not been established. Consider administration of platelet concentrates in cases where thrombocytopenia is present or long-acting antiplatelet drugs have been used. Measurement of aPTT or ECT may help guide therapy.

Clinical Pharmacology

Mechanism of Action

Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties.

Pharmacodynamics

At recommended therapeutic doses, dabigatran etexilate prolongs the aPTT, ECT, and TT. With an oral dose of 150 mg twice daily the median peak aPTT is approximately 2x control. Twelve hours after the last dose the median aPTT is 1.5x control, with less than 10% of patients exceeding 2x control. In the RE-LY trial, the median (10th to 90th percentile) trough aPTT in patients receiving the 150 mg dose was 52 (40 to 76) seconds. The median (10th to 90th percentile) trough ECT in patients receiving the 150 mg dose was 63 (44 to 103) seconds. The INR test is relatively insensitive to the activity of dabigatran and may or may not be elevated in patients on PRADAXA. When converting a patient from PRADAXA to warfarin therapy, the INR is unlikely to be useful until at least 2 days after discontinuation of PRADAXA.

Cardiac Electrophysiology

No prolongation of the QTc interval was observed with dabigatran etexilate at doses up to 600 mg.

Pharmacokinetics

Dabigatran etexilate mesylate is absorbed as the dabigatran etexilate ester. The ester is then hydrolyzed, forming dabigatran, the active moiety. Dabigatran is metabolized to four different acyl glucuronides and both the glucuronides and dabigatran have similar pharmacological activity. Pharmacokinetics described here refer to the sum of dabigatran and its glucuronides. Dabigatran displays dose-proportional pharmacokinetics in healthy subjects and patients in the range of doses from 10 to 400 mg.

Absorption

The absolute bioavailability of dabigatran following oral administration of dabigatran etexilate is approximately 3 to 7%. Dabigatran etexilate is a substrate of the efflux transporter P-gp. After oral administration of dabigatran etexilate in healthy volunteers, Cmax occurs at 1 hour post-administration in the fasted state. Coadministration of PRADAXA with a high-fat meal delays the time to Cmax by approximately 2 hours but has no effect on the bioavailability of dabigatran; PRADAXA may be administered with or without food. The oral bioavailability of dabigatran etexilate increases by 75% when the pellets are taken without the capsule shell compared to the intact capsule formulation. PRADAXA capsules should therefore not be broken, chewed, or opened before administration.

Distribution

Dabigatran is approximately 35% bound to human plasma proteins. The red blood cell to plasma partitioning of dabigatran measured as total radioactivity is less than 0.3. The volume of distribution of dabigatran is 50 to 70 L. Dabigatran pharmacokinetics are dose proportional after single doses of 10 to 400 mg. Given twice daily, dabigatran’s accumulation factor is approximately two.

Elimination

Dabigatran is eliminated primarily in the urine. Renal clearance of dabigatran is 80% of total clearance after intravenous administration. After oral administration of radiolabeled dabigatran, 7% of radioactivity is recovered in urine and 86% in feces. The half-life of dabigatran in healthy subjects is 12 to 17 hours.

Metabolism

After oral administration, dabigatran etexilate is converted to dabigatran. The cleavage of the dabigatran etexilate by esterase-catalyzed hydrolysis to the active principal dabigatran is the predominant metabolic reaction. Dabigatran is not a substrate, inhibitor, or inducer of CYP450 enzymes. Dabigatran is subject to conjugation forming pharmacologically active acyl glucuronides. Four positional isomers, 1-O, 2-O, 3-O, and 4-O-acylglucuronide exist, and each accounts for less than 10% of total dabigatran in plasma.

Renal Impairment

An open, parallel-group single-center study compared dabigatran pharmacokinetics in healthy subjects and patients with mild to moderate renal impairment receiving a single dose of PRADAXA 150 mg. Based on pharmacokinetic modeling, estimated exposure to dabigatran increases with the severity of renal function impairment. Similar findings were observed in the RE-LY trial.

Estimated Pharmacokinetic Parameters of Dabigatran by Renal Function

Renal Function	CrCl	Increase in AUC	Increase in Cmax	Half life
Normal	80	1X	1X	13
Mild	50	1.5X	1.1X	15
Moderate	30	3.2X	1.7X	18

Hepatic Impairment

Administration of PRADAXA in patients with moderate hepatic impairment (Child-Pugh B) showed a large inter-subject variability, but no evidence of a consistent change in exposure or pharmacodynamics.

Drug Interactions

Impact of Other Drugs on Dabigatran

P-gp Inducers

Rifampin: Rifampin 600 mg once daily for 7 days followed by a single dose of dabigatran decreased its AUC and Cmax by 66% and 67%, respectively. By Day 7 after cessation of rifampin treatment, dabigatran exposure was close to normal. P-gp Inhibitors In studies with the P-gp inhibitors ketoconazole, amiodarone, verapamil, and quinidine, the time to peak, terminal half-life, and mean residence time of dabigatran were not affected. Any observed changes in Cmax and AUC are described below.

Ketoconazole: Ketoconazole increased dabigatran AUC0-∞ and Cmax values by 138% and 135%, respectively, after a single dose of 400 mg, and 153%, and 149%, respectively, after multiple daily doses of 400 mg.

Verapamil: When dabigatran etexilate was coadministered with oral verapamil, the Cmax and AUC of dabigatran were increased. The extent of increase depends on the formulation of verapamil and timing of administration. If verapamil is present in the gut when dabigatran is taken, it will increase exposure to dabigatran with the greatest increase observed when a single dose of immediate-release verapamil is given one hour prior to dabigatran (AUC increased by a factor of 2.4). If verapamil is given 2 hours after dabigatran, the increase in AUC is negligible. In the population pharmacokinetics study from RE-LY, no important changes in dabigatran trough levels were observed in patients who received verapamil.

Amiodarone: When dabigatran etexilate was coadministered with a single 600 mg oral dose of amiodarone, the dabigatran AUC and Cmax increased by 58% and 50%, respectively. The increase in exposure was mitigated by a 65% increase in the renal clearance of dabigatran in the presence of amiodarone. The increase in renal clearance may persist after amiodarone is discontinued because of amiodarone’s long half-life. In the population pharmacokinetics study from RE-LY, no important changes in dabigatran trough levels were observed in patients who received amiodarone.

Quinidine: Quinidine was given as 200 mg dose every 2 hours up to a total dose of 1000 mg. Dabigatran etexilate was given over 3 consecutive days, the last evening dose on Day 3 with or without quinidine pre-dosing. Concomitant quinidine administration increased dabigatran’s AUC and Cmax by 53% and 56%, respectively.

Clarithromycin: Coadministered clarithromycin had no impact on the exposure to dabigatran.

Other Drugs

Clopidogrel: When dabigatran etexilate was given concomitantly with a loading dose of 300 mg or 600 mg clopidogrel, the dabigatran AUC and Cmax increased by approximately 30% and 40%, respectively. The concomitant administration of dabigatran etexilate and clopidogrel resulted in no further prolongation of capillary bleeding times compared to clopidogrel monotherapy. When comparing combined treatment and the respective mono-treatments, the coagulation measures for dabigatran’s effect (aPTT, ECT, and TT) remained unchanged, and inhibition of platelet aggregation (IPA), a measurement of clopidogrel’s effect, remained unchanged.

Enoxaparin: Enoxaparin 40 mg given subcutaneously for 3 days with the last dose given 24 hours before a single dose of PRADAXA had no impact on the exposure to dabigatran or the coagulation measures aPTT, ECT, or TT.

'''Diclofenac, Ranitidine, and Digoxin''': None of these drugs alters exposure to dabigatran.

In RE-LY, dabigatran plasma samples were also collected. The concomitant use of proton pump inhibitors, H2 antagonists, and digoxin did not appreciably change the trough concentration of dabigatran.

Impact of Dabigatran on Other Drugs

In clinical studies exploring CYP3A4, CYP2C9, P-gp and other pathways, dabigatran did not meaningfully alter the pharmacokinetics of amiodarone, atorvastatin, clarithromycin, diclofenac, clopidogrel, digoxin, pantoprazole, or ranitidine.

FDA Review of Data From the RE-LY Trial on September 20th, 2010

Design of RE-LY

RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy) was a 18,113 patient randomized, non-inferiority trial comparing unblinded warfarin to blinded dosing of dabigatran (either a dose of 110 mg or 150 mg twice a day) . RE-LY patients included those patients with non-valvular atrial fibrillation. Both patients who were warfarin naive and non-naive were enrolled. The primary endpoint was a composite of stroke and systemic embolism. The median duration of follow-up was 2 years.

FDA Commentary on the Design of RE-LY

An expert external panel was convened by the FDA to review data supporting the clinical use of Pradaxa in the management of patients with non-valvular atrial fibrillation. What follows are areas or questions of active interest on the part of the FDA.

Blinding

The trial was unblinded. The FDA has indicated that it could be difficult if not impossible to garner a superiority claim in the face of an unblinded trial design. Events that are submitted to an independent clinical event committee should be blinded to safeguard the adjudication process. The FDA, however, found that in 20% of patients, there was data in the source documents that could have unblinded the CEC.

Follow-up

Patients who dropped out of the study could be followed up by either telephone contact or in person in clinic. The FDA expressed concern that if a patient is evaluated for a follow-up visit in clinic this may yield a more complete ascertainment of endpoints than if the patient follow-up is conducted by phone. Similar rates of phone follow-up were observed for the three strategies (8%).

Drop outs and Drug Discontinuation

The FDA expressed concern if there are differential rates of drop out in the comparator arms. 96% of subjects completed the trial. 19% of dabigatran patients and 15% of warfarin patients discontinued therapy.

Event Rates for Warfarin

One question the FDA had was whether Warfarin was administered in the optimal fashion (a sufficient time in therapeutic range (TTR) is maintained) and whether the event rates were similar to those of patients enrolled in prior RCTs. The event rates for the warfarin control arm were similar to those of other RCTs.

Time in Therapeutic Range

Time in therapeutic range (TTR) of 64% is not too dissimilar to other RCTs. TTR in RELY is similar to that in SPORTIF III and V. The TTR rate may depend upon frequency of TTR monitoring. A high TTR may reflect a low frequency of INR monitoring, and the TTR must placed in the context of the frequency of INR monitoring.

Quality of Data and Adjudication

The rate of concordance between investigator and CEC reported events was 50% to 85%. In 20% of cases, the CEC could have been unblinded by the source documents.

Efficacy Results

Efficacy Results Published in the New England Journal of Medicine

Among patients treated with warfarin, the primary endpoint event rate was 1.69% per year. Among patients treated with 110 mg of dabigatran, the rate was 1.53% per year(relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority), and among patients treated with 150 mg of dabigatran the rate was 1.11% per year (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority).

FDA Interpretation of Efficacy Results

The FDA viewed the data as showing that both doses of dabigatran were non-inferior to warfarin and were within the pre-specified hazard ratio margin of 1.38. The 150 mg dose of dabigatran was actually superior to warfarin in the prevention of the primary endpoint. One FDA reviewer was not certain that dabigatran achieved superiority given the 1) open label nature of the study; 2) given the adequate but moderate time in a therapeutic range for warfarin use; and 3) given that this is a single study without replication. A p-value of 0.00125 is often required to establish superiority in a single trial.

There was an increased risk of clinically manifest MI associated with Dabigatran dosing. Although this was of concern, it was inconsistent with the observation that there was no increased risk of revascularization associated with dabigatran. There was no data available regarding study drug discontinuation in the day or days prior to the occurrence of an MI that might link rebound thrombin generation associated with drug discontinuation to an increased risk of MI. There was numerically a higher risk of major bleeds the week before an MI in the dabigatran group, although this number did not reach statistical significance. The excess number of MIs in the dabigatran group was observed months after drug discontinuation, raising questions as to the biologic plausability of the relationship of MI to study drug.

Bleeding Results

Bleeding Results from RE-LY Reported in the New England Journal of Medicine

Among patients treated with Warfarin, the rate of major bleeding was 3.36% per year versus 2.71% per year in the group receiving dabigatran at a dose of 110 mg (P = 0.003) versus 3.11% per year among patients treated with 150 mg of dabigatran (P = 0.31). Warfarin was associated with a 0.38% per year risk of hemorrhagic stroke versus 0.12% per year among patients treated with 110 mg of dabigatran (P<0.001) versus 0.10% per year among patients treated with 150 mg of dabigatran (P<0.001).

FDA Interpretation of Bleeding Results from RE-LY

There was a dose response curve for bleeding associated with dabigatran such that the 150 mg dose was associated with a higher rate of bleeding compared with 110 mg. 150 mg of dabigatran was associated with similar to increased risks of bleeding compared to warfarin while the 110 mg dose was associated with less bleeding than warfarin. In general, the more severe the type of bleeding examined, the lower the risk with dabigatran. While dyspepsia was increased with dabigatran, this was not associated with an increased risk of bleeding. A greater time in TTR was associated with no excess risk of bleeding for warfarin. One FDA reviewer stated that "if a patient is well-controlled on warfarin, then there is no reason to switch to dabigatran."

Net Clinical Benefit (NCB)

The 150 mg dose of dabigatran was associated with a greater reduction in stroke events than an increase in major bleeding events. While the clinical impact of efficacy and safety events must be carefully weighed, there was a net benefit observed for the 150 mg dose of dabigatran. This was true in those patients over the age of 75 as well. The patients over the age of 75 had a higher risk of bleeding, but an even higher risk of efficacy events as well. There was not a benefit of the 110 mg dose in those over the age of 75 and the net benefit of the 110 mg dose was less clear.

Drug Induced Liver Injury (DILI)

Dabigatran was not associated with an excess risks of DILI including Hy's law.

Questions posed by the FDA

Question 1: Was RELY adequately designed?

Unblindinded design was adequate but not optimal. Some argued that an unblinded trial actually parallels the real world practice better. Mortality was still favorable.

Question 2: Were the drug doses appropriate?

Yes.

Question 3: Were events after drug discontinuation handled appropriately?

An ITT analysis for efficacy is the appropriate method with mITT analyses providing supportive information. For safety analyses, mITT may be more informative.

Question 4: Was the trial adequately conducted?

The time in therapeutic range of 65% parallels clinical practice and is adequate for comparison. This rate is similar to other trials. Would not want to compare to unrealistic medical care.

Question 5: Was the follow-up of endpoints adequate?

Yes. Implausible that patients who were missing would have changed the results. Hepatotoxicity data good.

Was dabigatran effective in reducing the primary endpoint?

For stroke yes, non CNS embolism was not sufficiently powered.

Was dabigatran effective at both doses?

Yes was the majority view of the panel, but not by some of the FDA reviewers.

Is the 150 mg dose of dabigatran superior to warfarin?

Yes was the majority view of the panel (with a dissenting view by Dr. Steven Nissen). FDA reviewers were not convinced.

Is 150 mg superior to 110 mg?

Less compelling than the data showing superiority to warfarin. Majority view was yes.

Is there any evidence of hepatic injury

No, although idiosyncratic reactions may take years to appear.

Is there any evidence of less bleeding for the 110 mg dose vs warfarin?

Yes. Mixed reviews as to whether the data split by TTR is of relevance (criticized as a post-randomization event).

Is the risk of bleeding with 150 mg of dabigatran similar to warfarin?

150 mg dabigatran bleeding risk was slightly better but did not reach statistical significance.

Voting Question: Should dabigatran be approved for the reduction of stroke and non CNS embolization for non-valvular atrial fibrillation?

The panel voted 9 to 0 yes.

Should both 110 mg and 150 mg doses be approved?

Mixed views were expressed. 150 mg appears to be the preferred dose. 110 mg may also be appropriate in patients at high risk of bleeding, where the risk of bleeding may outweigh the potential benefit, but it should be realized that this 110 dose is not superior to warfarin with respect to efficacy.

What dose of dabigatran should be approved

There was mixed views on this. 4 Voted in favor of a single dose, 6 voted in favor of approving both doses. Steve Nissen and others recommended approval of both doses. While the primary benefit over warfarin is in the 150 mg dose, people at risk of bleeding may be getting nothing at all and could benefit from the 110 mg dose. Sanjay Kaul, Michael Lincoff and others would approve only the 150 mg dose.

Has the dabigatran dose relationship been adequately defined? Are further studies needed?

Although the lack of monitoring is convenient, some people advocated for PK/PD guided dosing to optimize the risk benefit ratio say in the elderly patients.

Comparison of RE-LY and Rocket AF Trials

Trial Design

• Both had non-inferiority to warfarin as primary endpoint
• Rocket AF required 2 risk factors for entry, RE-LY 1 risk factor
• Both randomized trials
• Rocket AF administered warfarin in a blinded fashion, RE-LY did not
• There was a dose adjustment for impaired CrCl in Rocket AF
• INR target range 2-3 in both

Statistical Methods

RELY: Primary Efficacy Evaluation: Stroke or non-CNS Embolism

Non-Inferiority: Intention-to-treat

Superiority: Intention-to-treat

Rocket AF: Primary Efficacy Evaluation: Stroke or non-CNS Embolism

Non-Inferiority: Protocol Compliant on treatment

Superiority: On Treatment and then by Intention-to-Treat

Trial Execution

Trial Design

	Re-LY	Rocket AF
Countries	44	45
Patients	18,113	14,264
Median Duration of Follow-Up	2 years (about 730 days)	589 days of exposure, 707 days with follow-up
Time in Therapeutic Range (TTR)	64%	57.8%

Statistical Methods

RELY: Primary Safety Evaluation: Major Bleeding

Rocket AF: Primary Safety Evaluation: Major or non-Major Clinically Relevant Bleeding

Rates of Drug Discontinuation

Rates of Drug Discontinuation

RE-LY
1 Year:
Dabigatran 110 mg:	14.5%
Dabigatran 150 mg:	15.5%
Warfarin:	10.2%
2 Years:
Dabigatran 110 mg:	20.7%
Dabigatran 150 mg:	21.2%
Warfarin:	16.6%
Rocket AF
Rivaroxaban:	23.9%
Warfarin:	22.4%

RE-LY: Baseline Characteristics

RE-LY: Baseline Characteristics

Characteristics	Dabigatran 110 mg	Dabigatran 150 mg	Warfarin
Randomized	6015	6076	6022
Mean age (years)	71.4	71.5	71.6
Male (%)	64.3	63.2	63.3
CHADS2 score	2.1	2.2	2.1
(mean)
0-1 (%)	32.6	32.2	30.9
2 (%)	34.7	35.2	37.0
3+ (%)	32.7	32.6	32.1
Prior stroke/TIA (%)	19.9	20.3	19.8
Prior MI (%)	16.8	16.9	16.1
CHF (%)	32.2	31.8	31.9
Baseline ASA (%)	40.0	38.7	40.6
Warfarin Naïve (%)	49.9	49.8	51.4

Rocket AF: Baseline Demographics

Rocket AF: Baseline Demographics

	Rivaroxaban (N=7081)	Warfarin (N=7090)
CHADS2 Score (mean)	3.48	3.46
2 (%)	13	13
3 (%)	43	44
4 (%)	29	28
5 (%)	13	12
6 (%)	2	2
Prior VKA Use (%)	62	63
Congestive Heart Failure (%)	63	62
Hypertension (%)	90	91
Diabetes Mellitus (%)	40	39
Prior Stroke/TIA/Embollism (%)	55	55
Prior Myocardial Infarction (%)	17	18

Rocket AF was a Higher Risk Patient Population

• Whereas 32.4% of patients in RE-LY were low risk CHADS 0-1, there were none of these patients in Rocket AF

• Whereas just over 32% of patients in RE-LY were high risk CHADS score of 3 or more, over 85% of Rocket AF patients had a CHADS score of 3 or more

• RE-LY patients were about 71.5 years old, and Rocket AF patients were 73 years old

• Prior stroke TIA embolism was about 20% in RE-LY and was 55% in Rocket AF

• About half of RE-LY patients were warfarin naïve, whereas 37.5% of Rocket AF patients were warfarin naïve

Estimates of Cost Per Year of Life Saved for Dabigatran

The annual cost of therapy with Dabigatran will therefore be $2,884 per patient.

The cost of Warfarin is approximately $0.30 per day, $109.5 per year.

(http://www.pharmacychecker.com/Pricing.asp?DrugName=Warfarin&DrugId=19462&DrugStrengthId=31721 )

There is a cost associated with INR monitoring of Warfarin of $2,134 per year in the first year (http://www.biomedcentral.com/1471-2296/8/6/ ) which drops to $1,170 in the second year once the patient is at a more stable level of anticoagulation. Let’s assume an average cost of $1,652 per year. The cost of Warfarin and its monitoring is therefore $1,761 per year.

Thus, the incremental drug acquisition and monitoring costs of DabigatranDabigatran over Warfarin would be $2,884 - $1,761 per year or $1,123 per year.

Given the 0.5% mortality reduction (which was of borderline statistical significance for the 150 mg dose), you would need to treat 200 patients for one year to save one life. That one year of therapy in 200 patients would cost an additional 200 X $1,123 or $224,600. The average age of patients in RE-LYwas 71.4 years. The average years of life a female can expect to live beyond 71 years is 14 years and a male is 13 years:

(http://www.census.gov/compendia/statab/cats/births_deaths_marriages_divorces/life_expectancy.html ).

Patients who have atrial fibrillation may live less than the usual 13.5 years for a 71 year old. The survival of an atrial fibrillation patient may depend upon co-morbidities. Although post CABG atrial fibrillation may have a limited impact on survival, some conditions such as systolic heart failure that are associated with atrial fibrillation are associated with a 1.9 fold higher risk of dying.

Given that the risk of dying is doubled in these patients, let’s assume that the survival of a 71-year old atrial fibrillation patient is cut in half to 6.75 years. Using this number will yield a conservative estimate of cost effectiveness.

Therefore, $224,600 in societal costs divided by those 6.75 years the person whose life was saved goes on to live equates to $33,274 per year of life saved. This is well within the acceptable limits for cost per year of life saved in the United States and similar to the cost per year of life saved for a defibrillator.

If complications of pharmacotherapy are included in the cost effectiveness analysis, the cost effectiveness of dabigatran may be even more favorable.

The lifetime cost of all cause stroke is estimated by the CDC to be $100,000. The rate of stroke per year was 1.57% for Warfarin and 1.01% for 150 mg of dabigatran. Therefore, there is a 0.56% lower rate of stroke per year. In our population of 200 patients, there would be expected to be 1.12 fewer strokes. If each stroke costs $100,000 over the lifetime of the patient then preventing 1.12 fewer cases with dabigatran would save $112,000.

In addition to the small but statistically significant reduction in mortality associated with Dabigatran therapy, there were also numerically (but not statistically significantly) fewer major bleeds (3.4% vs 3.1% per year). The cost of a major bleed is estimated to be $8000 (personal communication, Dr. David Cohen). The cost of treating 200 patients with dabigatran would be reduced slightly by 0.6 bleeds or $4,800 dollars.

There was an increased risk of MI of 0.21% (p=0.048) for dabigatran vs Warfarin (0.74% - 0.53%/year). The cost of a significant q wave MI is $7000 (Source: Dr. David Cohen). Treatment of the 200 patients with dabigatran would yield 0.4 of an MI at an increased cost of $2800.

Treating 200 patients with dabigatran for a year costs an additional $224,600 over Warfarin. Among 200 treated patients, there is a cost reduction of $112,000 due to 1.12 fewer stroke cases with dabigatran. Among these 200 treated patients, there is a cost reduction of $4,800 due to 0.6 fewer major bleeds. There is also a cost increase of $2,800 among these 200 treated patients due to 0.4 MI cases. The total additional cost of dabigatran treatment inclusive of complications in 200 patients is $110,600. The cost per year of life saved assuming 6.75 years of survival could therefore be as low as $16,385.

If society views $50,000 / year of life saved as cost effective, and' if it costs society $110,600 to save that life when the costs of complications are factored in, then' the survival of atrial fibrillation patients must only exceed 2.2 years for the therapy to be cost effective. (Spending $110,600 to save a life of someone who lives 2.2. years equates to $50,000 per year of life saved.) Most 71 year old atrial fibrillation patients survive more than 2.2 years.

There was a reduction in all cause stroke from 1.57% / year for Warfarin to 1.01% / year for dabigatran, a 0.56% / year reduction. You would need to treat 179 patients with dabigatran to prevent one stroke. This would incur an incremental cost of 179 x $1,123, or $200,535. On the other hand, the lifetime cost of all cause stroke is estimated by the CDC to be $100,000. The net total cost would therefore be $100,535. Patients with stroke have a 2.3 fold higher mortality, so survival was estimated to be 13.5 / 2.3 = 5.8 years. That’s $17,333 per year of stroke-free life saved.

These estimates are driven by “point estimates” A 0.5% improvement in mortality is small, and this point estimate may be unstable (p=0.051). Patients with atrial fibrillation may live longer than the 6.75 years assumed here. A longer survival time would reduce the cost per year of life saved.

No quality adjusted life expectancy data is presented. These data mix present cost with future costs. Some cost estimates are old. There may be heterogeneity in costs of stroke, bleeding and MI throughout the world.

Last year, in TIME magazine, Sir Michael Rawlins, chairman of the National Institute for Health and Clinical Excellence stated the following (http://www.time.com/time/health/article/0,8599,1888006,00.html#ixzz13Z0tUMuG ):

“Our Department of Transport, for instance, has a cost-per-life-saved threshold for new road schemes of about 1.5 million GBP per life, or around 30,000 GBP per life year gained. The judgment of our health economists is that somewhere in the region of 20,000-30,000 GBP per quality-adjusted life year is the [threshold], but it's not a strict limit. “

This would convert to 1.58 X 20,000 GBP = $31,600 USD to $47,400 USD. Thus, $16,000 to $33,000per year of life saved would fall within or even below this range.

While estimates of what governments are willing to pay for are generally about $50,000 per year of life saved, hemodialysis costs approximately $129,000 per year of life saved. (http://www.time.com/time/health/article/0,8599,1808049,00.html )

The annual difference in costs between dabigatran and Warfarin once the cost of monitoring is accounted for is approximately $1,123 US dollars. The estimated cost per year of life saved ($16,000 to $33,000 per year of life saved) is likely to fall within the range of acceptable cost effectiveness ($50,000 per year of life saved). The cost to prevent all cause stroke appears to be acceptable as well. While significant reductions in stroke and borderline significant reductions in mortality were observed, the point estimates were infrequent (around 0.5%) which may adversely impact the certainty of cost effectiveness estimates.