Myocardial Ischemic Events in Patients with Atrial Fibrillation

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Myocardial Ischemic Events in Patients with Atrial Fibrillation Treated with

Dabigatran or Warfarin in the RE-LY Trial

Running title: Hohnloser et al.; Dabigatran and myocardial ischemic events

Stefan H. Hohnloser, MD1; Jonas Oldgren, MD2; Sean Yang, PhD3; Lars Wallentin, MD2;

Michael Ezekowitz, MD4; Paul Reilly, MD5; John Eikelboom, MD2; Martina Brueckmann, MD6;

Salim Yusuf, MD3; Stuart J. Connolly, MD3

1 Dept of Cardiology, J.W. Goethe University, Frankfurt, Germany; 2Uppsala Clinical Research Center & Dept of Medical Sciences, Uppsala University, Uppsala, Sweden; 3McMaster

University, Population Health Research Institute, Hamilton, Canada; 4Lankenau Medical Center, Thomas Jefferson Medical College, Wynnewood, PA; 5Boehringer Ingelheim Pharmaceuticals,

Ridgefield, CT; 6Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany

Correspondence:

Stefan H. Hohnloser, MD, FACC, FESC, FHRS

Division of Clinical Electrophysiology

J. W. Goethe University Hospital

Theodor-Stern-Kai 7

D 60590 Frankfurt, Germany

Phone: +49-69-6301-7404

Fax: +49-69-6301-7017

Email: [email protected]

Journal Subject Codes: [4] Acute myocardial infarction; [5] Arrhythmias, clinical electrophysiology, drugs; [118] Cardiovascular Pharmacology; [70] Anticoagulants

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Abstract:

Background - There is a modest risk of myocardial infarction (MI) and myocardial ischemic

events in patients with atrial fibrillation.

Methods and Results - Using data from the RE-LY study, rates of MI, unstable angina, cardiac

arrest and cardiac death, pre-specified net clinical benefit and treatment effects of dabigatran

versus warfarin are reported. MI occurred at annual rates of 0.82% and 0.81% on dabigatran 110

mg or 150 mg BID, compared to 0.64% on warfarin (hazard ratio (HR) 1.29, 95% confidence

interval (CI) 0.96-1.75; p=0.09 for dabigatran 110 mg; and HR 1.27, 95% CI 0.94-1.71; p=0.12

for dabigatran 150 mg). Annual rates of a composite of MI, unstable angina, cardiac arrest, and

cardiac death were 3.16%/yr on dabigatran 110 mg, 3.33%/yr on dabigatran 150 mg, and

3.41%/yr on warfarin (HR versus warfarin 0.93 (95% CI 0.80-1.06; p=0.28) for dabigatran 110

mg and 0.98 (95% CI 0.85-1.12; p=0.77) for dabigatran 150 mg. Events pre-specified as net

clinical benefit (all strokes, systemic embolism, MI, PE, major bleeding, all-cause death)

occurred 7.34%/yr on dabigatran 110 mg, 7.11%/yr on dabigatran 150 mg, and 7.91%/yr on

warfarin (HR 0.92 (95% CI 0.81-1.01; p=0.09) for dabigatran 110 mg and 0.90 (95% CI 0.82-

0.99; p=0.02 for dabigatran 150 mg). The relative effects of dabigatran versus warfarin on

myocardial ischemic events were consistent in patients with or without a baseline history of

MI/CAD.

Conclusions - There was a non-significant increase in MI with dabigatran compared to warfarin,

but other myocardial ischemic events were not increased. Treatment effects of dabigatran are

consistent in patients at higher and lower risk of myocardial ischemic events.

Clinical Trial Registration Information - ClinicalTrials.gov; NCT 00262600

Key words: atrial fibrillation, stroke, myocardial infarction, coronary artery disease, dabigatran



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Vitamin K antagonists have long been the mainstay of stroke prevention therapy in atrial

fibrillation (AF). However, VKA therapy is difficult to use because of its narrow therapeutic

window, the need for coagulation monitoring, and its interactions with diets and medications 1.

Dabigatran etexilate is a novel, potent competitive and reversible direct thrombin inhibitor that

has been recently compared to warfarin for prevention of thromboembolic events in 18,113

patients with non-valvular AF (Randomized Evaluation of long-term anticoagulation therapy,

RE-LY trial)2-4. At a dose of 110 mg twice daily, dabigatran had similar efficacy as warfarin in

preventing stroke and systemic embolism but lower rates of major hemorrhage3. At a dose of

150 mg twice daily, dabigatran was associated with lower rates of stroke and systemic embolism

than warfarin but similar rates of major hemorrhage3. However; there were numerically more

non fatal clinical myocardial infarctions (MI) in dabigatran patients than in warfarin patients

3,4.The number of MI (both clinical and silent) were relatively few (compared to stroke) and so

the trial had low power to detect differences in this outcome and the results may be exaggerated

or diluted by chance. However, a recent meta-analysis of randomized non-inferioity trials

concluded that dabigatran was associated with an increased risk of MI or acute coronary

syndrome5.

In order to better understand the effects of dabigatran on myocardial ischemic events,

relative to warfarin, this paper presents a detailed analyses of MI and other clinical events

typically related to myocardial ischemia and the relative effects of dabigatran and warfarin both

overall as well as in patients at higher risk of myocardial ischemia, such as those with prior

coronary disease.



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Methods

Patients and study conduct

Details of the RE-LY study protocol and its main results have been reported2-4. In brief,

RE-LY was a randomized trial designed to compare two fixed doses of dabigatran (110 mg or

150 mg BID), each administered in a blinded manner, with open-label use of warfarin in patients

with AF who were at increased risk for stroke. Patients with documented atrial fibrillation were

eligible if they had at least one of the following characteristics: previous stroke or TIA, LVEF <

0.40, NYHA class II or higher heart failure symptoms within 6 months of screening, and an age

of at least 75 years or an age of 65 to 74 years plus diabetes mellitus, hypertension, or coronary

artery disease. A total of 18,113 patients were randomly assigned to one of the treatment arms

and followed for a median of 2 years. The primary study outcome of the RE-LY trial was stroke

or systemic embolism and the primary safety endpoint was major hemorrhage.

Definition of myocardial infarction

Clinical myocardial infarction was defined as the presence of at least 2 of the following 3

criteria: i) typical prolonged severe chest pain or related symptoms or signs (e.g. ST-changes of

T wave inversion in the ECG) suggestive of myocardial infarction; ii) elevation of troponin or

CKMB to more than upper level of normal (ULN) or, if CKMB was elevated at baseline, re-

evaluation to more than 50% increase above the previous level; iii) development of significant

Q-waves in at least 2 adjacent ECG leads. In patients after percutaneous coronary intervention

(within 24 h) or following coronary bypass surgery (within 72 h), elevation of troponin or

CKMB to more than 3 x ULN or 5 x ULN, respectively, or, if CKMB was elevated at baseline,

re-evaluation to more than 3xULN or 5y ULN, respectively, and a more than 50% increase



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above the previous level, and/or development of significant Q-waves in at least 2 adjacent ECG

leads was requested.

Silent MI was defined as new asymptomatic ECG changes with significant new Q waves

(40 msec or greater in two related leads)2. The first report of RELY included only clinical MI as

data on silent MI had not been centrally reported or adjudicated. After database lock and during

the review process of the FDA an analysis of silent MI was performed by assessing all reports of

routine ECGs where a new significant Q wave was observed. All original ECGs from such

patients were reviewed by 2 blinded adjudicators and 28 cases of silent MI diagnosed4.

Definition of other myocardial ischemic events

The outcomes of unstable angina and cardiac arrest were collected as adverse or serious

adverse events. All deaths were classified as either cardiac, non-cardiac vascular, or non-

vascular. Cardiac deaths included sudden/arrhythmic, pump failure and post-MI deaths.

Other Events

Coronary artery bypass graft surgery was collected as a cause of hospitalization.

Percutaneous coronary intervention was collected either as a cause of hospitalization or

associated with a report of myocardial infarction. Net clinical benefit was a protocol pre-

specified outcome that included stroke, systemic embolism, pulmonary embolism, MI, death or

major hemorrhage.

Statistics

We examined the effects of dabigatran 110 mg bid, dabigatran 150 mg bid and warfarin

on occurrence of clinical and silent MI; the composite of MI and other clinical events typically

related to myocardial ischemia, including unstable angina cardiac arrest and cardiac death; a

composite of MI, unstable angina, CABG, PCI, cardiac arrest or cardiac death; the latter



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composite with the addition of stroke or systemic embolism; and the pre-specified net clinical

benefit. Cox regression was used to calculate hazard ratios, confidence intervals and p values.

Kaplan Meier curves were constructed for each of the three treatment groups for the outcome of

MI. We also determined the risk of other study outcomes, and composite outcomes, for the

subgroup of patients with known coronary artery disease or previous MI at baseline who are

considered to be a particularly high risk for developing new MI. The net clinical benefit

(prospectively defined in the RE-LY trial as the composite of stroke, systemic embolism,

pulmonary embolism, all-cause death, MI, and major hemorrhage) was calculated in this

subgroup and compared to that of patients without a history of MI or coronary artery disease:

All analyses are based on the intent-to-treat principle and were performed using SAS software,

version 9.1 (SAS institute Inc, Cary, NC). In addition, an on-treatment analysis was performed as

a sensitivity analysis. A 2-sided p-value of less than 0.05 was considered statistically significant.

Results

Impact of treatments on myocardial ischemic events

In the dabigatran 110 and 150 mg arms, there were 98 and 97 MIs at annual rates of

0.82%/yr and 0.81%/yr, respectively; compared to the warfarin arm where there were 75 MIs

(0.64%/yr) (Table 1). The hazard ratio (HR) was 1.29 (95% confidence interval (CI) 0.96-1.75;

p=0.09) for dabigatran 110 versus warfarin; and 1.27 (95% CI 0.94-1.71; p=0.12) for dabigatran

150 versus warfarin. Figure 1 shows the cumulative Kaplan Meier incidence curves for new

MIs in the three treatment arms. When both dabigatran doses together were compared to

warfarin, results were similar to that obtained by the 2 separate comparisons (Table 1).



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To capture a broader spectrum of myocardial ischemic events (many of which may be

caused by plaque rupture with superimposed coronary thrombosis) a composite outcome was

analyzed which included MI, unstable angina, cardiac arrest, and cardiac death. The annual rates

of this composite were 3.16%/yr on dabigatran 110 mg, 3.33%/yr on dabigatran 150 mg, and

3.41%/yr on warfarin group. The HR versus warfarin were 0.93 (95% CI 0.80-1.06; p=0.28) for

dabigatran 110 mg and 0.98 (95% CI 0.85-1.12; p=0.77) for dabigatran 150 mg. When

revascularization events were also included, again no significant differences between the three

treatment groups emerged (Table 1).

A broader composite which included these event as well as both stroke and systemic

embolic events occurred at annual rates of 4.76%/yr on dabigatran 110 mg, 4.47%/yr on

dabigatran 150 mg, and 5.10%/yr on warfarin. The HRs versus warfarin were 0.93 (95% CI 0.83-

1.04; p=0.24) for dabigatran 110 mg and 0.88 (95% CI 0.78-0.98; p=0.0252) for dabigatran 150

mg (Table 1, Figure 1).

Events pre-specified in net clinical benefit analysis occurred at annual rates of 7.34%/yr

on dabigatran 110 mg, 7.11%/yr on dabigatran 150 mg, and 7.91%/yr on warfarin. The HRs

versus warfarin were 0.92 (95% CI 0.81-1.01; p=0.09) for dabigatran 110 mg and 0.90 (95% CI

0.82-0.99; p=0.02) for dabigatran 150 mg (Table 1, Figure 1).

As a sensitivity analysis, an on-treatment analysis of cardiac events during RE-LY was

performed with consistent results to the intent-to-treat analysis (Table 2).

Baseline characteristics of patients with new MI and myocardial ischemic events

Table 3 shows characteristics of patients with or without coronary events during the RE-

LY trial. Patients who suffered at least one myocardial ischemic event were older and had more

coronary risk factors, particularly more prior MIs, compared to the remainder population. Across



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all treatment groups these patients received more antiplatelet medications, beta-blocker, and

statins at baseline. They also more often had a CHADS2 score > 2.

Timing of clinical myocardial infarct in relation to study drug intake

Fifty-six of 87 clinical MI in the dabigatran 110 group, 59/89 in the dabigatran 150

group, and 46/66 in the warfarin group occurred on study drug treatment (Table 4). MI occurring

> 6 days after study drug discontinuation was observed in 17, 20, and 12 patients in the three

groups. Accordingly, 33%, 34%, and 30% of all clinical MI were diagnosed when patients were

off study drug in the respective treatment arms.

Effects of dabigatran versus warfarin in patients with and without prior coronary artery

disease

Patients with a baseline history of coronary artery disease and/or previous MI (CAD/MI)

are at risk for recurrent ischemic events. There were 1886 (31%) CAD/MI patients in the

dabigatran 110 group, 1915 (31%) in the dabigatran 150 group, and 1849 (31%) in the warfarin

group. Figure 2 shows the effects of dabigatran and warfarin on important outcomes and

composite outcomes for the subgroups of patients with previous CAD/MI compared to those

without. The effects of dabigatran compared to warfarin were highly consistent between patients

with prior CAD/MI compared to those without (all p-values for interaction were non-significant).

Discussion

Main findings

The present detailed analysis of the RE-LY trial demonstrates a trend to an increase in Mi

but a lack of significant excess in other myocardial ischemic events in AF patients receiving

dabigatran compared to warfarin. Dabigatran exerts consistent effects in patients with and



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without previous manifestation of CAD. In this large cohort of AF patients treated for stroke

prevention, coronary events were less common than cerebrovascular events, even in patients with

previous CAD. The predefined net clinical benefit which includes major ischemic and

thrombotic events as well as major bleeding was statistically less common with dabigatran 150

mg BID as compared to warfarin. Thus there is an overall net benefit with dabigatran compared

to warfarin, even in patients with previous MI or CAD.

Myocardial ischemic events in patients on dabigatran

The publication of the RE-LY trial raised the issue that dabigatran may be associated with

an elevated rate of new MI in patients with AF3. The original finding was corrected after a repeat

data analysis, requested by the FDA, which showed 4 previously unreported clinical MI and 28

silent MI events4. There were no longer any statistically significant differences in the rate of new

MI between the three groups and all hazard ratios were associated with wide confidence

intervals. Of note, a third of all MI occurred in patients off study drug as shown in the present

analysis.

RE-LY was not designed to detect a difference in MI between treatments and due to the

low MI rates observed, the study does not have the power to conclude either that there is a

difference in MI between treatments or that there is not.

The present analysis provides more information on MI events and also on other

myocardial ischemic events including unstable angina, need for coronary revascularization,

cardiac arrest or cardiac death. There was no evidence that dabigatran treatment is associated

with an excess in any of these other events. Furthermore, there was no sign of a dose-dependent

effect of the dabigatran on coronary events. The pre-specified net clinical benefit analysis



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including a combination of thrombo-embolic and major bleeding events demonstrated a

significant benefit for the dabigatran 150 mg dose.

Effects of dabigatran in high risk coronary patients

Patients with a known history of CAD are at high risk for recurrent coronary events and

for bleeding. Accordingly, we examined the effects of dabigatran versus warfarin for this

important subgroup of patients in the RE-LY trial. There was no significant interaction between

the treatment effects and the presence or absence of a history of previous CAD/MI indicating

that the beneficial effects of dabigatran over warfarin were similarly present in this high risk

group of patients. Analysis of the net clinical benefit confirmed the superiority of dabigatran 150

mg concerning stroke and net clinical benefit and the dabigatran 110 mg dose concerning major

bleeding as compared to warfarin even in these subgroups.

Previous studies

Several large randomized trials of new anticoagulant drugs versus warfarin have been

completed in recent years6-9. In all of these trials, rates of new MI were low across all treatment

groups. For instance, in the ACTIVE W trial only 23 of 3371 patients in the warfarin group and

36 of 3335 patients treated with aspirin plus clopidogrel suffered from a new MI during a median

follow up of 1.28 years6. Similarly low MI rates were observed in the SPORTIF III and V

studies7,8. These low MI rates are in agreement with those observed in RE-LY and imply that any

differences in new MI events between treatment groups may be subject to a play of chance. All

of these studies were underpowered to detect an effect of treatment on risk of MI.

A few studies have specifically examined the effects of direct thrombin inhibitors on

recurrent MI in patients who had survived a recent acute coronary syndrome10,11. Wallentin et al

reported that ximelagatran plus acetylsalicylic acid was more effective than acetylsalicylic acid



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alone in preventing major cardiovascular events including new MIs during a six month treatment

period10. In a similar trial evaluating dabigatran, Oldgren et al reported a small and non

significant higher number of MIs in dabigatran-treated patients compared to a placebo group; but

cardiovascular deaths occurred less frequently on dabigatran 110 mg or 150 mg than in the

placebo group (all differences not statistically significant)11. A recent meta-analysis of

randomized dabigatran studies similarly reported a higher incidence of MI or acute coronary

syndromes on the thrombin inhibitor5. However, the control arms of these studies included

placebo, warfarin, or enoxaparin treatments; thus, a more detailed analysis of dabigatrans effects

on coronary events against the different comparators seems to be necessary.

The above data suggest that the available information is too sparse to assess the effects of

direct thrombin inhibitors on MI. Further, given that in the AF trials the comparison of direct

thrombin inhibitors is versus warfarin, even if there is a higher rate of Mi with direct thrombin

inhibitors, this may be because warfarin is very effective and direct thrombin inhibitors may be

less so (but more effective than no treatment). Previous controlled trials have shown that

warfarin is very effective at reducing recurrent MI in coronary patients12,13. In AF trials with

new antithrombotic agents concomitant use of clopidogrel or other platelet inhibitors than low

dose aspirin and recent coronary events have usually been exclusion criteria which lowers the MI

risk in the exposed population. The current dilemma can therefore only be resolved by large

trials of direct thrombin inhibitors versus placebo or aspirin in individuals at high risk of

coronary events. Given the higher rates of stroke and systemic embolic events in AF patients and

the relatively low rates of MI, the current evidence from RE-LY indicates that in AF patients the

benefits on stroke reduction and bleeding with dabigatran compared to warfarin is likely to

outweigh any potential impact on MI.



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Limitations of the study

The analyses presented in this paper were not pre-specified and are post-hoc. Thus, some

of the outcome events were not prespecified and adjudicated. Whereas all deaths and MI were

adjudicated, other events such as unstable angina or need for revascularization were derived from

hospitalization forms or AE/SAE reports. It would be preferable if all the events presented in this

paper had been pre-specified, collected on purpose-designed case report forms and adjudicated.

Nonetheless, the collection of adverse events was assiduously done and provides reliable

information.

Conclusions

A non-significant higher number of MI was observed with dabigatran compared to

warfarin in RELY, but there was no excess of other myocardial ischemic events. The composite

of MI, stroke, other thrombotic events and major bleeding, occurred less frequently on each dose

of dabigatran than on warfarin and for the higher dose of dabigatran was nominally statistically

significant.

Funding Sources: The study was funded by a grant from Boehringer Ingelheim.

Conflict of Interest Disclosures: Stefan H. Hohnloser reports to receive consulting and lecture

fees from Boehringer Ingelheim, BMS, Bayer, Pfizer, and Sanofi Aventis; Jonas Oldgren,

institutional grant support from Boehringer Ingelheim, consulting fees, and lecture fees from

Bayer, Boehringer Ingelheim, and BMS; Sean Yang, nothing to declare; Lars Walentin,

consulting fees, lecture fees,and grant support from Boehringer Ingelheim, consulting fees from

Regado and Athera, lecture fees from Boehringer Ingelheim, AstraZeneca, and Eli Lilly, and

grant support from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, and Schering Plough;



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Michael Ezekovitz, consulting fees, lecture fees, and grant support from Boehringer Ingelheim

and Aryx Therapeutics, consulting fees from Sanofi- Aventis, and lecture fees and grant support

from Portola Pharmaceuticals; Paul Reilly reports being an employer of Boehringer Ingelheim;

John Eikelboom, consulting fees, lecture fees, and grant support from Boehringer Ingelheim,

AstraZeneca, Sanofi-Aventis, and GlaxoSmithKline, consulting fees and lecture fees from Eisai

Pharmaceuticals, Eli Lilly, and McNeil, and consulting fees from Bristol-Myers Squibb,

Corgenix Medical Corporation, and Daiichi-Sankyo; Martina Brueckmann reports being an

employer of Boehringer Ingelheim; Salim Yusuf, consulting fees, lecture fees and grant support

from Boehringer Ingelheim and consulting fees from AstraZeneca, Bristol-Myers Squibb, and

Sanofi-Aventis ;Stuart J. Connolly reports receiving consulting fees, lecture fees, and grant

support from Boehringer Ingelheim.

References:

1. Eikelboom JW, Weitz JI. Update on antithrombotic therapy. New Anticoagulants. Circulation. 2010;121:1523-32. 2. Ezekowitz MD, Connolly SJ,Parekh A, Reilly PA, Varrone J, Wang S, Oldgren J, Themeless E, Wallentin L, Yusuf S. Rationale and design of RE-LY: Randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. Am Heart J. 2009;157:805-810. 3. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; the RE-LY Steering Committee and Investigators. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2009;361:1139-51. 4. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L. Newly identified events in the RE-LY trial. N Engl J Med.2010;363:1875-76. 5. The ACTIVE Writing Group on behalf of the ACTIVE Investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet. 2006;367:1903-19. 6. Uchino K, Hernandez AV. Dabigatran is associated with higher risk of acute coronary events: a meta-analysis of non-inferiority randomized controlled trials. Arch Intern Med. 2011(in press).



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7. Olsson SB. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet. 2003; 362:1691-1698. 8. Albers GW, Diener HC, Frison L, Grind M, Nevinson M, Partridge S, Halperin JL, Horrow J, Olsson SB, Petersen P, Vahanian A. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. JAMA. 2005; 293:690-698. 9. AMADEUS Investigators. Comparison of idraparinux with vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation: a randomised, open-label, non-inferiority trial. Lancet. 2008;371:315-321. 10. Wallentin L, Wilcox RG, Weaver WD, Emanuelsson H, Goodvin A, Nystrm P, Bylock A, for the ESTEEM Investigators. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial. Lancet. 2003;362:789-97. 11. Oldgren J, Budaj A, Granger CB, Khder Y, Roberts J, Siegbahn A, Tijssen JGP, Van de Werf F, Wallentin L. Dabigatran versus placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomised, double-blind, phase II trial. Europ Heart J. 2011, epub May 7th, 2011. 12. Smith P, Arnesen H, Holme I. The effect of warfarin on mortality and reinfarction after myocardial infarction. N Engl J Med. 1990;323:147-152. 13. Hurlen M, Adelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002;347:969-974. by guest on M


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Table 1. Cardiac events during RELY

Dabig = dabigatran; Warf = warfarin; RR = relative risk; CI = confidence interval; PCI = percutaneous coronary intervention; CABG = coronary artery bypass surgery; MI = myocardial infarct; UA = unstable angina; Net clinical benefit defined as a composite of stroke, MI, cardiovascular death, pulmonary embolism systemic embolism or major bleeding; BID = twice daily Of note, the comparisons of the two dabigatran doses together versus warfarinwere not pre-specified and are for information and hypothesis generation only.

Dabig 110mg BID N=6015

Dabig 150mg BID N=6076

Warf N=6022 Dabig 110mg BID vs. Warf Dabig 150mg BID vs. Warf

Dabigatran vs. Warfarin

N Rate / 100 Person Yrs N

Rate / 100 Person Yrs N

Rate / 100 Person Yrs HR 95% CI p HR 95% CI p HR 95% CI p

Total MI 98 0.82 97 0.81 75 0.64 1.29 0.96-1.75 0.09 1.27 0.94-1.71 0.12 1.28 0.98-1.67 0.07 Clinical MI 87 0.73 89 0.74 66 0.56 1.30 0.95-1.80 0.10 1.32 0.96-1.81 0.09 1.31 0.99-1.74 0.06 Silent MI 11 0.09 8 0.07 9 0.08 1.22 0.50-2.93 0.66 0.87 0.34-2.27 0.72 1.04 0.47-2.31 0.92 Fatal MI (death within 30 days)

16 0.13 13 0.11 12 0.10 1.32 0.63-2.80 0.46 1.06 0.49-2.33 0.88 1.19 0.61-2.34 0.61

Other myocardial events

Unstable angina 133 1.12 163 1.35 166 1.41 0.79 0.63-1.00 0.047 0.96 0.78-1.20 0.74 0.88 0.73-1.06 0.19 Cardiac death 177 1.49 161 1.34 174 1.48 1.01 0.82-1.24 0.94 0.91 0.73-1.12 0.37 0.96 0.80-1.15 0.64 Cardiac arrest 23 0.19 25 0.21 25 0.21 0.91 0.52-1.60 0.74 0.98 0.56-1.70 0.94 0.94 0.58-1.53 0.81 MI, UA, Cardiac arrest or Cardiac death

376 3.16 401 3.33 402 3.41 0.93 0.80-1.06 0.28 0.98 0.85-1.12 0.77 0.95 0.84-1.07 0.42

PCI or CABG surgery 48 0.40 44 0.37 46 0.39 1.04 0.69-1.55 0.87 0.94 0.62-1.42 0.76 0.99 0.69-1.40 0.93 MI, UA, CABG, PCI, Cardiac arrest or Cardiac death

402 3.38 425 3.53 424 3.60 0.94 0.82-1.07 0.36 0.98 0.86-1.13 0.82 0.96 0.85-1.08 0.50

Stroke, SEE, MI, UA, CABG,PCI, Cardiac arrest, Cardiac death

567 4.76 538 4.47 601 5.10 0.93 0.83-1.05 0.24 0.88 0.78-0.98 0.03 0.90 0.82-1.00 0.05

Net clinical benefit 873 7.34 855 7.11 933 7.91 0.92 0.84-1.01 0.09 0.90 0.82-0.99 0.02 0.91 0.84-0.99 0.02



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Table 2. Cardiac events during RELY, on-treatment analysis

Dabig = dabigatran; Warf = warfarin; RR = relative risk; CI = confidence interval; PCI = percutaneous coronary intervention; CABG = coronary artery bypass surgery; MI = myocardial infarct; UA = unstable angina; Net clinical benefit defined as a composite of stroke, MI, cardiovascular death, pulmonary embolism systemic embolism or major bleeding; BID = twice daily

Dabig 110mg BID

N=5983

Dabig 150mg BID

N=6059 Warf

N=5998 Dabig 110mg BID vs. Warf Dabig 150mg BID vs. Warf

N

Rate / 100

Person Yrs N

Rate / 100

Person Yrs N

Rate / 100

Person Yrs HR 95% CI p HR 95% CI p

Total MI 80 0.78 79 0.77 63 0.59 1.32 0.95-1.84 0.10 1.30 0.93-1.81 0.12 Clinical MI 71 0.69 71 0.69 54 0.51 1.37 0.96-1.95 0.08 1.36 0.96-1.94 0.09 Silent MI 9 0.09 8 0.07 9 0.08 1.05 0.42-2.63 0.92 0.93 0.36-2.41 0.88 Fatal MI (death within 30 days) 12 0.12 8 0.08 11 0.10 1.14 0.50-2.59 0.75 0.76 0.31-1.89 0.55 Other myocardial events Unstable angina 122 1.19 142 1.38 154 1.44 0.82 0.65-1.04 0.10 0.95 0.76-1.20 0.69 Cardiac death 123 1.20 101 0.98 126 1.18 1.01 0.79-1.30 0.91 0.83 0.64-1.08 0.17 Cardiac arrest 19 0.18 19 0.18 21 0.20 0.94 0.50-1.74 0.84 0.94 0.50-1.75 0.84 MI, UA, Cardiac arrest or Cardiac death

322 3.13 329 3.19 343 3.21 0.97 0.83-1.13 0.70 0.99 0.85-1.15 0.92

PCI or CABG surgery 41 0.40 37 0.36 37 0.35 1.15 0.74-1.79 0.54 1.03 0.66-1.63 0.88 MI, UA, CABG, PCI, Cardiac arrest or Cardiac death

348 3.38 350 3.40 361 3.38 1.00 0.86-1.15 0.96 1.00 0.87-1.16 0.97

Stroke, SEE, MI, UA, CABG,PCI, Cardiac arrest, Cardiac death

517 5.03 467 4.53 545 5.10 0.98 0.87-1.10 0.71363 0.88 0.78-1.00 0.048

Net clinical benefit 868 8.44 853 8.28 931 8.71 0.96 0.87-1.05 0.37106 0.94 0.86-1.03 0.20



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17

Table 3. Baseline Characteristics of Patients with MI during RELY

Characteristics Patients with MI in RELY N (%)

Patients without MI in RELY N (%)

p-value Patients with MI/UA/CABG/

PCI/Cardiac death/Cardiac arrest N(%)

Patients without MI/UA/CABG/P

CI/Cardiac death/Cardiac arrest N(%)

P value

Randomized patients 270 17843 1251 16862 Mean age (years) 73.0(7.8) 71.5(8.7) 0.002 71.6(9.1) 71.5(8.6) 0.600 Female gender 93 (34) 6505 (37) 0.495 383(31) 6215(37) 0.000 History of CAD/MI Prior myocardial infarct 100 (37) 2905 (16) 0.000 432(35) 2573(15) 0.000 Other CAD 140(52) 4894(27) 0.000 598(48) 4436(26) 0.000 Diabetes 95 (35) 4126 (23) 0.000 412(33) 3809(23) 0.000 Hypertension 229 (85) 14054 (79) 0.016 998(80) 13285(79) 0.408 Prior heart failure 105 (39) 5688 (32) 0.014 594(48) 5199(31) 0.000 Prior stroke/TIA 58 (22) 3565 (20) 0.540 230(18) 3393(20) 0.138 Type of atrial fibrillation Paroxysmal Persistent Permanent

96 (36) 87 (32) 87 (32)

5847(33) 5702 (32) 6288 (35)

0.333 0.926 0.303

430(34) 377(30) 444(36)

5513(33) 5412(32) 5931(35)

0.222 0.151 0.820

CHADS2 score 0-1 2 3-6

58 (22) 95 (35) 117 (43)

5725 (32) 6358 (36) 5759 (32.3)

0.000 0.879 0.000

278(22) 458(37) 515(41)

5505(33) 5995(36) 5361(32)

0.000 0.451 0.000

Creatinine clearance Mean (ml/min) 30-49 ml/min 50-79 ml/min 80 ml/min

67.7 (26) 77 (29) 115 (43) 76 (28)

73.7 (65.7) 3484 (20) 8432 (47) 5778 (32)

0.000 0.000 0.128 0.140

69.6(28) 330(26) 543(43) 363(29)

73.9(67) 3231(19) 8004(48) 5491(33)

0.000 0.000 0.005

0.010 Baseline medications ASA Clopidogrel ASA & clopidogrel Betablocker ACE/ARB Statins

130 (48) 29 (11) 20 (8) 188 (70) 188 (70) 160 (59)

7023 (39) 991 (6) 641 (4) 11210 (63) 11795 (66) 7897 (44)

0.003 0.000 0.000 0.021 0.224 0.000

604(48) 134(11) 96(8)

837(67) 900(72) 653(52)

6549(39)

886(5) 565(3)

10561(63) 11083(66) 7404(44)

0.000 0.000 0.000 0.003 0.000 0.000



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18

Table 4. Timing of myocardial ischemic events

Patients with MI Patients with MI,UA,CABG,PCI,Cardiac arrest or Cardiac death

Dabigatran 110 mg N (%)


Warfarin N (%)



Warfarin N (%)

Total randomized 6015 6076 6022 6015 6076 6022 First Event on study drug only 56 (0.9) 59 (1.0) 46 (0.8) 304 (5.1) 308 (5.1) 325 (5.4)

First Event 1 to 6 days off study drug

13 (0.2) 10 (0.2) 8 (0.1) 18 (0.3) 19 (0.3) 15 (0.2)

First Event > 6 days off study drug 17 (0.3) 20 (0.3) 12 (0.2) 65 (1.1) 90 (1.5) 75 (1.2) First Event > 90 days off study drug 13 (0.2) 14 (0.2) 6 (0.1) 42 (0.7) 61 (1.0) 39 (0.6)



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19

Figure Legends:

Figure 1. Time to MI, time to stroke/SEE/MI/UA/PCI/CABG/cardiac arrest/ cardiac death, and

time to net clinical benefit (pre-specified as the composite of stroke, systemic embolism,

pulmonary embolism, MI, cardiovascular death or major bleed). Only for net clinical benefit a

significant difference in favor of dabigatran 150 mg emerged.

Figure 2. Cardiovascular events and bleeding in patients with prior CAD or MI.



ownloaded from


Years of Follow-up

Cum

ulat

ive

Haz

ard

Rat

es0.

00.

050.

100.

150.

200.

25

0 0.5 1.0 1.5 2.0 2.5

MI

Stroke/SEE/MI/UA/PCI/CABG/Cardiac arrest/Cardiac death

Net clinical benefit

Dabigatran 110Dabigatran 150Warfarin



ownloaded from


1.55 1.46 1.93Prior CAD/MI

1.53 0.95 1.61No Prior CAD/MI 0.45

MI1.5 1.54 1.17Prior CAD/MI0.51 0.46 0.39No Prior CAD/MI 0.95

MI,UA,PCI,CABG,Cardiov arrest,Cardiac death

5.89 5.88 6.32Prior CAD/MI2.23 2.43 2.36No Prior CAD/MI 0.91

Major bleeding3.94 4.24 4.52Prior CAD/MI2.39 2.88 3.14No Prior CAD/MI 0.35

Net clinical benefit9.86 9.44 10.38Prior CAD/MI6.18 6.01 6.8No Prior CAD/MI

Stroke/SEE

0.61

0.50 1.00 1.50

Rate(% per year)D110D150WAR

P(INTER)Dabigatran110 vs. WARFARIN

Dabigatran better Warfarin better

0.28

0.72

0.49

0.85

0.66

0.50 1.00 1.50





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John Eikelboom, Martina Brueckmann, Salim Yusuf and Stuart J. ConnollyStefan H. Hohnloser, Jonas Oldgren, Sean Yang, Lars Wallentin, Michael Ezekowitz, Paul Reilly,

Warfarin in the RE-LY TrialMyocardial Ischemic Events in Patients with Atrial Fibrillation Treated with Dabigatran or

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright 2012 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation published online January 3, 2012;Circulation.

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http://circ.ahajournals.org/content/early/2012/01/03/CIRCULATIONAHA.111.055970http://circ.ahajournals.org/content/suppl/2013/10/14/CIRCULATIONAHA.111.055970.DC1http://www.ahajournals.org/site/rights/http://www.lww.com/reprintshttp://circ.ahajournals.org//subscriptions/http://circ.ahajournals.org/

40

summary

.

, ,

warfarin dabigatran

RE-LY(Randomized

Evaluation of Long-Term Anticoagulation Therapy)

.

dabigatran 110mg 150mg 0.82%,

0.81%, warfarin 0.64%(dabigatran

110mg: HR, 1.29; 95% CI, 0.961.75; P=0.09;

dabigatran 150mg: HR, 1.27; 95% CI, 0.941.71;

P=0.12). , , ,

dabigatran 110mg 150mg

3.16%, 3.33%, warfarin

3.41%(dabigatran 110mg: HR, 0.93; 95% CI,

0.801.06; P=0.28. dabigatran 150mg: HR, 0.98;

95% CI, 0.851.12; P=0.77).

( , , ,

, , ) dabigatran

110mg 150mg 7.34%, 7.11%,

warfarin 7.91%(dabigatran 110mg: HR,

0.92; 95% CI, 0.841.01; P=0.09. dabigatran 150mg:

HR, 0.90; 95% CI, 0.820.99; P=0.02). Warafrin

dabigatran

.

Dabigatran warfarin

, . Dabigatran

.

Dabigatran

41Arrhythmia

commentary

RE-LY

,

. thrombin ximelagatran

.1

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.2

thrombin

.

RE-LY (

3 2 : (1)

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2 40ms

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,

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,

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. dabigatran

,

warfarin

.

References Fiessinger JN, Huisman MV, Davidson BL, Bounameaux H, Francis CW, Eriksson 1. H, Lundstrm T, Berkowitz SD, Nystrm P, Thorsn M, Ginsberg JS; THRIVE Treatment Study Investigators. Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial. JAMA. 2005;293:681-689.2. Wallentin L, Wilcox RG, Weaver WD, Emanuelsson H, Goodvin A, Nystrm P, 2. Bylock A; ESTEEM Investigators. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial. Lancet. 2003;362:789-797.3. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, 3. Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.

42

Myocardial Ischemic Events in Patients With AtrialFibrillation Treated With Dabigatran or Warfarin in the

RE-LY (Randomized Evaluation of Long-TermAnticoagulation Therapy) Trial

Stefan H. Hohnloser, MD; Jonas Oldgren, MD; Sean Yang, PhD; Lars Wallentin, MD;Michael Ezekowitz, MD; Paul Reilly, MD; John Eikelboom, MD; Martina Brueckmann, MD;

Salim Yusuf, MD; Stuart J. Connolly, MD

BackgroundThere is a modest risk of myocardial infarction (MI) and myocardial ischemic events in patients with atrialfibrillation.

Methods and ResultsData from the RE-LY study (Randomized Evaluation of Long-Term Anticoagulation Therapy)were used to report rates of MI, unstable angina, cardiac arrest, and cardiac death and the prespecified net clinical benefitand treatment effects of dabigatran versus warfarin. MI occurred at annual rates of 0.82% and 0.81% with dabigatran110 or 150 mg BID compared with 0.64% with warfarin (hazard ratio [HR] 1.29, 95% confidence interval [CI]0.961.75, P0.09 for dabigatran 110 mg; HR 1.27, 95% CI 0.941.71, P0.12 for dabigatran 150 mg). Annual ratesof a composite of MI, unstable angina, cardiac arrest, and cardiac death were 3.16% per year with dabigatran 110 mg,3.33% per year with dabigatran 150 mg, and 3.41% per year with warfarin (HR versus warfarin 0.93, 95% CI 0.801.06,P0.28 for dabigatran 110 mg and HR 0.98, 95% CI 0.851.12, P0.77 for dabigatran 150 mg). Events prespecifiedas net clinical benefit (all strokes, systemic embolism, MI, pulmonary embolism, major bleeding, and all-cause death)occurred at a rate of 7.34% per year with dabigatran 110 mg, 7.11% per year with dabigatran 150 mg, and 7.91% peryear with warfarin (HR 0.92, 95% CI 0.841.01, P0.09 for dabigatran 110 mg and HR 0.90, 95% CI 0.820.99,P0.02 for dabigatran 150 mg). The relative effects of dabigatran versus warfarin on myocardial ischemic events wereconsistent in patients with or without a baseline history of MI or coronary artery disease.

ConclusionsThere was a nonsignificant increase in MI with dabigatran compared with warfarin, but other myocardialischemic events were not increased. Treatment effects of dabigatran were consistent in patients at higher and lower riskof myocardial ischemic events.

Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT 00262600.(Circulation. 2012;125:669-676.)

Key Words: atrial fibrillation stroke myocardial infarction coronary artery disease dabigatran

Vitamin K antagonists have long been the mainstay ofstroke prevention therapy in atrial fibrillation (AF);however, vitamin K antagonist therapy is difficult to usebecause of its narrow therapeutic window, the need forcoagulation monitoring, and its interactions with diets andmedications.1 Dabigatran etexilate is a novel, potent, compet-itive, and reversible direct thrombin inhibitor that recently hasbeen compared with warfarin for prevention of thromboem-bolic events in 18 113 patients with nonvalvular AF (Ran-domized Evaluation of Long-Term Anticoagulation Therapy[RE-LY trial]).24 At a dose of 110 mg twice daily, dabigatran

had similar efficacy as warfarin in preventing stroke andsystemic embolism but lower rates of major hemorrhage.3 Ata dose of 150 mg twice daily, dabigatran was associated withlower rates of stroke and systemic embolism than warfarinbut similar rates of major hemorrhage.3 However, there werenumerically more nonfatal clinical myocardial infarctions(MIs) in dabigatran patients than in warfarin patients.3,4 Thenumber of MIs (both clinical and silent) was relatively few(compared with stroke), and thus, the trial had low power todetect differences in this outcome, and the results may beexaggerated or diluted by chance. However, a recent meta-

Received July 13, 2011; accepted November 17, 2011.From the Department of Cardiology, J.W. Goethe University, Frankfurt, Germany (S.H.H.); Uppsala Clinical Research Center and Department of

Medical Sciences, Uppsala University, Uppsala, Sweden (J.O., L.W.); McMaster University, Population Health Research Institute, Hamilton, Ontario,Canada (S. Yang, J.E., S. Yusuf, S.J.C.); Lankenau Medical Center, Thomas Jefferson Medical College, Wynnewood, PA (M.E.); Boehringer IngelheimPharmaceuticals, Ridgefield, CT (P.R.); and Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany (M.B.).

Correspondence to Stefan H. Hohnloser, MD, FACC, FESC, FHRS, Division of Clinical Electrophysiology, J.W. Goethe University Hospital,Theodor-Stern-Kai 7, D 60590 Frankfurt, Germany. E-mail [email protected]

2012 American Heart Association, Inc.

Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.111.055970

669 by IMED Korea on April 23, 2012http://circ.ahajournals.org/Downloaded from

43

analysis of randomized noninferiority trials concluded thatdabigatran was associated with an increased risk of MI oracute coronary syndrome.5

Clinical Perspective on pTo better understand the effects of dabigatran on myocar-

dial ischemic events relative to warfarin, the present reportpresents detailed analyses of MIs and other clinical eventstypically related to myocardial ischemia and the relativeeffects of dabigatran and warfarin, both overall and inpatients at higher risk of myocardial ischemia, such as thosewith prior coronary disease.

MethodsPatients and Study ConductDetails of the RE-LY study protocol and its main results have beenreported previously.24 In brief, RE-LY was a randomized trialdesigned to compare 2 fixed doses of dabigatran (110 or 150 mgBID), each administered in a blinded manner, with open-label use ofwarfarin in patients with AF who were at increased risk for stroke.Patients with documented AF were eligible if they had at least 1 ofthe following characteristics: Previous stroke or transient ischemicattack, left ventricular ejection fraction 0.40, New York HeartAssociation class 2 or higher heart failure symptoms within 6 monthsof screening, and an age of at least 75 years or an age of 65 to 74years plus diabetes mellitus, hypertension, or coronary artery disease(CAD). A total of 18 113 patients were randomly assigned to 1 of thetreatment arms and followed up for a median of 2 years. The primarystudy outcome of the RE-LY trial was stroke or systemic embolism,and the primary safety end point was major hemorrhage.

Definition of MIClinical MI was defined as the presence of at least 2 of the following3 criteria: (1) Typical prolonged severe chest pain or relatedsymptoms or signs (eg, ST changes or T-wave inversion in the ECG)suggestive of MI; (2) elevation of troponin or creatine kinase-MB tomore than the upper level of normal, or if creatine kinase-MB waselevated at baseline, reevaluation to more than 50% increase abovethe previous level; and (3) development of significant Q waves in atleast 2 adjacent ECG leads. In patients after percutaneous coronaryintervention (within 24 hours) or after coronary bypass surgery(within 72 hours), elevation of troponin or creatine kinase-MB tomore than 3 or 5 times the upper limit of normal, respectively, or ifcreatine kinase-MB was elevated at baseline, reevaluation to morethan 3 or 5 times the upper limit of normal, respectively, and a morethan 50% increase above the previous level, and/or development ofsignificant Q waves in at least 2 adjacent ECG leads was required.

Silent MI was defined as new asymptomatic ECG changes withsignificant new Q waves (40 ms in 2 related leads).2 The firstreport of RE-LY included only clinical MI, because data on silent MIhad not been centrally reported or adjudicated. After database lockand during the review process of the Food and Drug Administration,an analysis of silent MI was performed by assessment of all reportsof routine ECGs in which a new significant Q wave was observed.All original ECGs from such patients were reviewed by 2 blindedadjudicators, and 28 cases of silent MI were diagnosed.4

Definition of Other Myocardial Ischemic EventsThe outcomes of unstable angina and cardiac arrest were collected asadverse or serious adverse events. All deaths were classified as eithercardiac, noncardiac vascular, or nonvascular. Cardiac deaths in-cluded sudden/arrhythmic, pump failure, and post-MI deaths.

Other EventsCoronary artery bypass graft surgery was collected as a cause ofhospitalization. Percutaneous coronary intervention was collectedeither as a cause of hospitalization or associated with a report of MI.

Net clinical benefit was a protocol-prespecified outcome that in-cluded stroke, systemic embolism, pulmonary embolism, MI, death,or major hemorrhage.

Statistical AnalysisWe examined the effects of dabigatran 110 mg BID, dabigatran 150mg BID, and warfarin on the occurrence of clinical and silent MI; thecomposite of MI and other clinical events typically related tomyocardial ischemia, including unstable angina, cardiac arrest, andcardiac death; a composite of MI, unstable angina, coronary arterybypass grafting, percutaneous coronary intervention, cardiac arrest,or cardiac death; the latter composite with the addition of stroke orsystemic embolism; and the prespecified net clinical benefit. Coxregression was used to calculate hazard ratios (HRs), confidenceintervals (CIs), and probability values. Kaplan-Meier curves wereconstructed for each of the 3 treatment groups for the outcome of MI.We also determined the risk of other study outcomes and compositeoutcomes for the subgroup of patients with CAD or previous MI atbaseline, who were considered to be at particularly high risk fordeveloping new MI. The net clinical benefit (prospectively definedin the RE-LY trial as the composite of stroke, systemic embolism,pulmonary embolism, all-cause death, MI, and major hemorrhage)was calculated in this subgroup and compared with that of patientswithout a history of MI or CAD.

All analyses were based on the intention-to-treat principle andwere performed with SAS software version 9.1 (SAS Institute Inc,Cary, NC). In addition, an on-treatment analysis was performed as asensitivity analysis. A 2-sided probability value of less than 0.05 wasconsidered statistically significant.

ResultsImpact of Treatments on MyocardialIschemic EventsIn the dabigatran 110- and 150-mg arms, there were 98 and97 MIs at annual rates of 0.82% per year and 0.81% per year,respectively, compared with the warfarin arm, in which therewere 75 MIs (0.64% per year; Table 1). The HR was 1.29(95% CI 0.961.75, P0.09) for dabigatran 110 mg versuswarfarin and 1.27 (95% CI 0.941.71, P0.12) for dabiga-tran 150 mg versus warfarin. Figure 1 shows the cumulativeKaplan-Meier incidence curves for new MIs in the 3 treat-ment arms. When both dabigatran doses together werecompared with warfarin, results were similar to those ob-tained by the 2 separate comparisons (Table 1).

To capture a broader spectrum of myocardial ischemicevents (many of which may be caused by plaque rupture withsuperimposed coronary thrombosis), a composite outcomewas analyzed that included MI, unstable angina, cardiacarrest, and cardiac death. The annual rates of this compositewere 3.16% per year with dabigatran 110 mg, 3.33% per yearwith dabigatran 150 mg, and 3.41% per year in the warfaringroup. The HRs versus warfarin were 0.93 (95% CI 0.801.06, P0.28) for dabigatran 110 mg and 0.98 (95% CI0.851.12, P0.77) for dabigatran 150 mg. When revascu-larization events were also included, again no significantdifferences emerged among the 3 treatment groups (Table 1).

A broader composite that included these events and bothstroke and systemic embolic events occurred at annual ratesof 4.76% per year with dabigatran 110 mg, 4.47% per yearwith dabigatran 150 mg, and 5.10% per year with warfarin.The HRs versus warfarin were 0.93 (95% CI 0.831.05,P0.24) for dabigatran 110 mg and 0.88 (95% CI 0.780.98,P0.03) for dabigatran 150 mg (Table 1; Figure 1).

670 Circulation February 7, 2012

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44

Events prespecified in the net clinical benefit analysisoccurred at annual rates of 7.34% per year with dabigatran110 mg, 7.11% per year with dabigatran 150 mg, and7.91% per year with warfarin. The HRs versus warfarin

were 0.92 (95% CI 0.84 1.01, P0.09) for dabigatran 110mg and 0.90 (95% CI 0.82 0.99, P0.02) for dabigatran150 mg (Table 1; Figure 1). As a sensitivity analysis, anon-treatment analysis of cardiac events during RE-LY was

Table 1. Cardiac Events During RE-LY

Dabigatran 110 mgBID (n6015)

Dabigatran 150 mgBID (n6076) Warfarin (n6022) Dabigatran 110 mg BID

vs WarfarinDabigatran 150 mg BID

vs Warfarin Dabigatran vs Warfarin

nRate per 100Person-Years n

Rate per 100Person-Years n

Rate per 100Person-Years HR 95% CI P HR 95% CI P HR 95% CI P

Total MI 98 0.82 97 0.81 75 0.64 1.29 0.961.75 0.09 1.27 0.941.71 0.12 1.28 0.981.67 0.07

Clinical MI 87 0.73 89 0.74 66 0.56 1.30 0.951.80 0.10 1.32 0.961.81 0.09 1.31 0.991.74 0.06

Silent MI 11 0.09 8 0.07 9 0.08 1.22 0.502.93 0.66 0.87 0.342.27 0.72 1.04 0.472.31 0.92

Fatal MI (deathwithin 30 d)

16 0.13 13 0.11 12 0.10 1.32 0.632.80 0.46 1.06 0.492.33 0.88 1.19 0.612.34 0.61

Othermyocardialevents

UA 133 1.12 163 1.35 166 1.41 0.79 0.631.00 0.047 0.96 0.781.20 0.74 0.88 0.731.06 0.19

Cardiacdeath

177 1.49 161 1.34 174 1.48 1.01 0.821.24 0.94 0.91 0.731.12 0.37 0.96 0.801.15 0.64

Cardiacarrest

23 0.19 25 0.21 25 0.21 0.91 0.521.60 0.74 0.98 0.561.70 0.94 0.94 0.581.53 0.81

MI, UA, cardiacarrest, orcardiac death

376 3.16 401 3.33 402 3.41 0.93 0.801.06 0.28 0.98 0.851.12 0.77 0.95 0.841.07 0.42

PCI or CABGsurgery

48 0.40 44 0.37 46 0.39 1.04 0.691.55 0.87 0.94 0.621.42 0.76 0.99 0.691.40 0.93

MI, UA, CABG,PCI, cardiacarrest, orcardiac death

402 3.38 425 3.53 424 3.60 0.94 0.821.07 0.36 0.98 0.861.13 0.82 0.96 0.851.08 0.50

Stroke, SEE,MI, UA, CABG,PCI, cardiacarrest, cardiacdeath

567 4.76 538 4.47 601 5.10 0.93 0.831.05 0.24 0.88 0.780.98 0.03 0.90 0.821.00 0.05

Net clinicalbenefit

873 7.34 855 7.11 933 7.91 0.92 0.841.01 0.09 0.90 0.820.99 0.02 0.91 0.840.99 0.02

RE-LY indicates Randomized Evaluation of Long-Term Anticoagulation Therapy; BID, twice daily; HR, hazard ratio; CI, confidence interval; MI, myocardial infarction;UA, unstable angina; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft; and SEE, systemic embolic event.

Net clinical benefit was defined as a composite of stroke, MI, cardiovascular death, pulmonary embolism, SEE, or major bleeding. The comparisons of the 2dabigatran doses together versus warfarin were not prespecified and are presented for information and hypothesis generation only.

0.25

Dabigatran 110

Time to MI, Stroke/SEE/MI/UA/PCI/CABG/Cardiac arrest/Cardiac death and Net clinical benefit

s

0.20

Dabigatran 110Dabigatran 150Warfarin

azar

d R

ates

0.15 Net clinical benefit

umul

ativ

e H

0.10

Cu

0.05 Stroke/SEE/MI/UA/PCI/CABG/

Cardiac arrest/Cardiac death

0.0

MI

Years of Follow-up

0 0.5 1.0 1.5 2.0 2.5

Figure 1. Time to myocardial infarction (MI), timeto stroke/systemic embolic event (SEE)/MI/unsta-ble angina (UA)/percutaneous coronary interven-tion (PCI)/coronary artery bypass grafting (CABG)/cardiac arrest/cardiac death, and time to netclinical benefit (prespecified as the composite ofstroke, SEE, pulmonary embolism, MI, cardiovas-cular death, or major bleeding). A significant differ-ence in favor of dabigatran 150 mg emerged onlyfor net clinical benefit.

Hohnloser et al Dabigatran and Myocardial Ischemic Events 671


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performed with results consistent with the intention-to-treat analysis (Table 2).

Baseline Characteristics of Patients With New MIsand Myocardial Ischemic EventsTable 3 shows characteristics of patients with or withoutcoronary events during the RE-LY trial. Patients who had atleast 1 myocardial ischemic event were older and had morecoronary risk factors, particularly more prior MIs, than theremainder of the study population. Across all treatmentgroups, these patients received more antiplatelet medications,-blockers, and statins at baseline. They also more often hada CHADS2 score 2.

Timing of Clinical MI in Relation to StudyDrug IntakeFifty-six of 87 clinical MIs in the dabigatran 110-mg group,59 of 89 in the dabigatran 150-mg group, and 46 of 66 in thewarfarin group occurred on study drug treatment (Table 4).MIs that occurred 6 days after study drug discontinuationwere observed in 17, 20, and 12 patients in the 3 groups.Accordingly, 33%, 34%, and 30% of all clinical MIs werediagnosed when patients were not taking the study drug in therespective treatment arms.

Effects of Dabigatran Versus Warfarin in PatientsWith and Without Prior CADPatients with a baseline history of CAD or previous MI are atrisk for recurrent ischemic events. There were 1886 (31%)CAD/MI patients in the dabigatran 110-mg group, 1915(31%) in the dabigatran 150-mg group, and 1849 (31%) in the

warfarin group. Figure 2 shows the effects of dabigatran andwarfarin on important outcomes and composite outcomes forthe subgroups of patients with previous CAD/MI comparedwith those without. The effects of dabigatran compared withwarfarin were highly consistent between patients with priorCAD/MI compared with those without (all probability valuesfor interaction were nonsignificant).

DiscussionMain FindingsThe present detailed analysis of the RE-LY trial demonstratesa trend to an increase in MIs but a lack of significant excessin other myocardial ischemic events in AF patients receivingdabigatran compared with warfarin. Dabigatran exerts con-sistent effects in patients with and without previous manifes-tations of CAD. In this large cohort of AF patients treated forstroke prevention, coronary events were less common thancerebrovascular events, even in patients with previous CAD.The predefined net clinical benefit, which included majorischemic and thrombotic events as well as major bleeding,was statistically less common with dabigatran 150 mg BIDthan with warfarin. Thus, there was an overall net benefit withdabigatran compared with warfarin, even in patients withprevious MI or CAD.

Myocardial Ischemic Events in PatientsTaking DabigatranThe publication of the RE-LY trial raised the issue thatdabigatran may be associated with an elevated rate of new MIin patients with AF.3 The original finding was corrected after

Table 2. Cardiac Events During RE-LY: On-Treatment Analysis

Dabigatran 110 mgBID (n5983)

Dabigatran 150 mgBID (n6059) Warfarin (n5998) Dabigatran 110 mg BID

vs WarfarinDabigatran 150 mg BID

vs Warfarin

nRate per 100Person-Years n

Rate per 100Person-Years n

Rate per 100Person-Years HR 95% CI P HR 95% CI P

Total MI 80 0.78 79 0.77 63 0.59 1.32 0.951.84 0.10 1.30 0.931.81 0.12

Clinical MI 71 0.69 71 0.69 54 0.51 1.37 0.961.95 0.08 1.36 0.961.94 0.09

Silent MI 9 0.09 8 0.07 9 0.08 1.05 0.422.63 0.92 0.93 0.362.41 0.88

Fatal MI (death within 30 d) 12 0.12 8 0.08 11 0.10 1.14 0.502.59 0.75 0.76 0.311.89 0.55

Other myocardial events

UA 122 1.19 142 1.38 154 1.44 0.82 0.651.04 0.10 0.95 0.761.20 0.69

Cardiac death 123 1.20 101 0.98 126 1.18 1.01 0.791.30 0.91 0.83 0.641.08 0.17

Cardiac arrest 19 0.18 19 0.18 21 0.20 0.94 0.501.74 0.84 0.94 0.501.75 0.84

MI, UA, cardiac arrest, orcardiac death

322 3.13 329 3.19 343 3.21 0.97 0.831.13 0.70 0.99 0.851.15 0.92

PCI or CABG surgery 41 0.40 37 0.36 37 0.35 1.15 0.741.79 0.54 1.03 0.661.63 0.88

MI, UA, CABG, PCI, cardiacarrest, or cardiac death

348 3.38 350 3.40 361 3.38 1.00 0.861.15 0.96 1.00 0.871.16 0.97

Stroke, SEE, MI, UA, CABG,PCI, cardiac arrest, cardiacdeath

517 5.03 467 4.53 545 5.10 0.98 0.871.10 0.71 0.88 0.781.00 0.048

Net clinical benefit 868 8.44 853 8.28 931 8.71 0.96 0.871.05 0.37 0.94 0.861.03 0.20

RE-LY indicates Randomized Evaluation of Long-Term Anticoagulation Therapy; BID, twice daily; HR, hazard ratio; CI, confidence interval; MI, myocardial infarction;UA, unstable angina; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft; and SEE, systemic embolic event.

Net clinical benefit was defined as a composite of stroke, MI, cardiovascular death, pulmonary embolism, SEE, or major bleeding.



46

a repeated data analysis, requested by the Food and DrugAdministration, which showed 4 previously unreported clin-ical MIs and 28 silent MI events.4 There were no longer anystatistically significant differences in the rate of new MIsamong the 3 groups, and all HRs were associated with wideCIs. Of note, one third of all MIs occurred in patients nottaking the study drug, as shown in the present analysis.

RE-LY was not designed to detect a difference in MIbetween treatments, and because of the low MI rates ob-served, the study does not have the power to conclude eitherthat there is a difference in MI between treatments or thatthere is not. The present analysis provides more informationon MI events and on other myocardial ischemic events,including unstable angina, need for coronary revasculariza-tion, cardiac arrest, or cardiac death. There was no evidencethat dabigatran treatment was associated with an excess in

any of these other events. Furthermore, there was no sign ofa dose-dependent effect of the dabigatran on coronary events.The prespecified net clinical benefit analysis, which includeda combination of thromboembolic and major bleeding events,demonstrated a significant benefit for the dabigatran 150-mgdose.

Effects of Dabigatran in High-RiskCoronary PatientsPatients with a known history of CAD are at high risk forrecurrent coronary events and for bleeding. Accordingly, weexamined the effects of dabigatran versus warfarin for thisimportant subgroup of patients in the RE-LY trial. There wasno significant interaction between the treatment effects andthe presence or absence of a history of previous CAD/MI,which indicates that the beneficial effects of dabigatran over

Table 3. Baseline Characteristics of Patients With MI During RE-LY

CharacteristicsPatients WithMI in RE-LY

Patients WithoutMI in RE-LY P

Patients WithMI/UA/CABG/PCI/Cardiac

Death/Cardiac Arrest

Patients WithoutMI/UA/CABG/PCI/Cardiac

Death/Cardiac Arrest P

Randomized patients, n 270 17 843 1251 16 862

Mean age (SD), y 73.0 (7.8) 71.5 (8.7) 0.002 71.6 (9.1) 71.5 (8.6) 0.600

Female gender, n (%) 93 (34) 6505 (37) 0.495 383 (31) 6215 (37) 0.000

History of CAD/MI, n (%)

Prior MI 100 (37) 2905 (16) 0.000 432 (35) 2573 (15) 0.000

Other CAD 140 (52) 4894 (27) 0.000 598 (48) 4436 (26) 0.000

Diabetes, n (%) 95 (35) 4126 (23) 0.000 412 (33) 3809 (23) 0.000

Hypertension, n (%) 229 (85) 14 054 (79) 0.016 998 (80) 13 285 (79) 0.408

Prior heart failure, n (%) 105 (39) 5688 (32) 0.014 594 (48) 5199 (31) 0.000

Prior stroke/TIA, n (%) 58 (22) 3565 (20) 0.540 230 (18) 3393 (20) 0.138

Type of AF, n (%)

Paroxysmal 96 (36) 5847 (33) 0.333 430 (34) 5513 (33) 0.222

Persistent 87 (32) 5702 (32) 0.926 377 (30) 5412 (32) 0.151

Permanent 87 (32) 6288 (35) 0.303 444 (36) 5931 (35) 0.820

CHADS2 score, n (%)

01 58 (22) 5725 (32) 0.000 278 (22) 5505 (33) 0.000

2 95 (35) 6358 (36) 0.879 458 (37) 5995 (36) 0.451

36 117 (43) 5759 (32.3) 0.000 515 (41) 5361 (32) 0.000

Creatinine clearance

Mean (SD), mL/min 67.7 (26) 73.7 (65.7) 0.000 69.6 (28) 73.9 (67) 0.000

3049 mL/min, n (%) 77 (29) 3484 (20) 0.000 330 (26) 3231 (19) 0.000

5079 mL/min, n (%) 115 (43) 8432 (47) 0.128 543 (43) 8004 (48) 0.005

80 mL/min, n (%) 76 (28) 5778 (32) 0.140 363 (29) 5491 (33) 0.010

Baseline medications, n (%)

ASA 130 (48) 7023 (39) 0.003 604 (48) 6549 (39) 0.000

Clopidogrel 29 (11) 991 (6) 0.000 134 (11) 886 (5) 0.000

ASA and clopidogrel 20 (8) 641 (4) 0.000 96 (8) 565 (3) 0.000

-blocker 188 (70) 11 210 (63) 0.021 837 (67) 10 561 (63) 0.003

ACE/ARB 188 (70) 11 795 (66) 0.224 900 (72) 11 083 (66) 0.000

Statins 160 (59) 7897 (44) 0.000 653 (52) 7404 (44) 0.000

MI indicates myocardial infarction; RE-LY, Randomized Evaluation of Long-Term Anticoagulation Therapy; UA, unstable angina; CABG, coronaryartery bypass graft; PCI, percutaneous coronary intervention; CAD, coronary artery disease; TIA, transient ischemic attack; AF, atrial fibrillation;CHADS2, score based on congestive heart failure, hypertension, age 75 years, diabetes mellitus, and prior stroke or TIA; ASA, acetylsalicylic acid;ACE, angiotensin-converting enzyme; and ARB, angiotensin receptor blocker.



47

warfarin were similarly present in this high-risk group ofpatients. Analysis of the net clinical benefit confirmed thesuperiority of dabigatran 150 mg concerning stroke and thenet clinical benefit and the benefit of the dabigatran 110-mgdose concerning major bleeding compared with warfarin evenin these subgroups.

Previous StudiesSeveral large randomized trials of new anticoagulant drugsversus warfarin have been completed in recent years.69 In allof these trials, rates of new MIs were low across all treatmentgroups. For instance, in the ACTIVE W trial (Atrial fibrilla-

tion Clopidogrel Trial with Irbesartan for prevention ofVascular Events), only 23 of 3371 patients in the warfaringroup and 36 of 3335 patients treated with aspirin plusclopidogrel had a new MI during a median follow-up of 1.28years.6 Similarly low MI rates were observed in the SPORTIF(Stroke Prevention using an Oral Thrombin Inhibitor in AtrialFibrillation) III and V studies.7,8 These low MI rates are inagreement with those observed in RE-LY and imply that anydifferences in new MI events between treatment groups maybe subject to a play of chance. All of these studies wereunderpowered to detect an effect of treatment on risk of MI.

A few studies have specifically examined the effects ofdirect thrombin inhibitors on recurrent MI in patients who

Table 4. Timing of Myocardial Ischemic Events

Patients With MIPatients With MI, UA, CABG, PCI,Cardiac Arrest, or Cardiac Death

Dabigatran110 mg

Dabigatran150 mg Warfarin

Dabigatran110 mg

Dabigatran150 mg Warfarin

Total randomized, n 6015 6076 6022 6015 6076 6022

First event on study drug only, n (%) 56 (0.9) 59 (1.0) 46 (0.8) 304 (5.1) 308 (5.1) 325 (5.4)

First event 1 to 6 d off study drug, n (%) 13 (0.2) 10 (0.2) 8 (0.1) 18 (0.3) 19 (0.3) 15 (0.2)

First event 6 d off study drug, n (%) 17 (0.3) 20 (0.3) 12 (0.2) 65 (1.1) 90 (1.5) 75 (1.2)

First event 90 d off study drug, n (%) 13 (0.2) 14 (0.2) 6 (0.1) 42 (0.7) 61 (1.0) 39 (0.6)

MI indicates myocardial infarction; UA, unstable angina; CABG, coronary artery bypass graft; and PCI, percutaneous coronary intervention.

Rate(% per year)

D110 D150 WAR



1.55 1.46 1.93Prior CAD/MI

1.53 0.95 1.61 54.0IM/DAC roirP oN

Stroke/SEE

0.28

MI

1.5 1.54 1.17Prior CAD/MI

0.51 0.46 0.39 59.0IM/DAC roirP oN 0.72

MI,UA,PCI,CABG,Cardiov arrest,Cardiac death

5.89 5.88 6.32Prior CAD/MI

2.23 2.43 2.36 19.0IM/DAC roirP oN 0.49

Major bleeding

3.94 4.24 4.52Prior CAD/MI

2.39 2.88 3.14 53.0IM/DAC roirP oN 0.85

Net clinical benefit

9.86 9.44 10.38Prior CAD/MI

6.18 6.01 6.8 16.0IM/DAC roirP oN 0.66

0.50 1.00 1.50


0.50 1.00 1.50


Figure 2. Cardiovascular events and bleeding in patients with prior coronary artery disease (CAD) or myocardial infarction (MI). D110indicates dabigatran 110 mg BID; D150, dabigatran 150 mg BID; WAR, warfarin; SEE, systemic embolic event; UA, unstable angina;PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; and P(INTER), P for interaction.



48

had survived a recent acute coronary syndrome.10,11 Wallen-tin et al10 reported that ximelagatran plus acetylsalicylic acidwas more effective than acetylsalicylic acid alone in prevent-ing major cardiovascular events, including new MIs, during a6-month treatment period. In a similar trial evaluating dab-igatran, Oldgren et al11 reported a small and nonsignificantlyhigher number of MIs in dabigatran-treated patients than in aplacebo group, but cardiovascular deaths occurred less fre-quently with dabigatran 110 or 150 mg than in the placebogroup (all differences not statistically significant). A recentmeta-analysis of randomized dabigatran studies similarlyreported a higher incidence of MI or acute coronary syn-dromes in patients taking the thrombin inhibitor.5 However,the control arms of these studies included placebo, warfarin,or enoxaparin treatments, and thus, a more detailed analysisof the effects of dabigatran on coronary events against thedifferent comparators appears to be necessary.

The above data suggest that the available information is toosparse to assess the effects of direct thrombin inhibitors on MI.Furthermore, given that in the AF trials, the comparison of directthrombin inhibitors is versus warfarin, even if there is a higherrate of MI with direct thrombin inhibitors, this may be becausewarfarin is very effective and direct thrombin inhibitors may beless so (but more effective than no treatment). Previous con-trolled trials have shown that warfarin is very effective atreducing recurrent MI in coronary patients.12,13 In AF trials withnew antithrombotic agents, concomitant use of clopidogrel orplatelet inhibitors other than low-dose aspirin and recent coro-nary events have usually been exclusion criteria, which lowersthe MI risk in the exposed population. The current dilemma cantherefore only be resolved by large trials of direct thrombininhibitors versus placebo or aspirin in individuals at high risk ofcoronary events. Given the higher rates of stroke and systemicembolic events in AF patients and the relatively low rates of MI,the current evidence from RE-LY indicates that in AF patients,the benefits on stroke reduction and bleeding with dabigatrancompared with warfarin are likely to outweigh any potentialimpact on MI.

Study LimitationsThe analyses presented in the present report were not pre-specified and are post hoc. Thus, some of the outcome eventswere not prespecified and adjudicated. Although all deathsand MIs were adjudicated, other events, such as unstableangina or need for revascularization, were derived fromhospitalization forms or adverse events/serious adverseevents reports. It would be preferable if all the eventspresented in the present report had been prespecified, col-lected on purpose-designed case report forms, and adjudi-cated. Nonetheless, the collection of adverse events wasperformed assiduously and provides reliable information.

ConclusionsA nonsignificantly higher number of MIs were observed withdabigatran than with warfarin in RE-LY, but there was noexcess of other myocardial ischemic events. The composite ofMI, stroke, other thrombotic events, and major bleedingoccurred less frequently with each dose of dabigatran than

with warfarin and for the higher dose of dabigatran wasnominally statistically significant.

Sources of FundingThis study was funded by a grant from Boehringer Ingelheim.

DisclosuresDr Hohnloser reports having received consulting and lecture feesfrom Boehringer Ingelheim, BMS, Bayer, Pfizer, and Sanofi-aventis.Dr Oldgren has received institutional grant support from BoehringerIngelheim and consulting fees and lecture fees from Bayer, Boeh-ringer Ingelheim, and BMS. Dr Wallentin has received consultingfees, lecture fees, and grant support from Boehringer Ingelheim;consulting fees from Regado and Athera; lecture fees from Boeh-ringer Ingelheim, AstraZeneca, and Eli Lilly; and grant support fromAstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, and ScheringPlough. Dr Ezekowitz has received consulting fees, lecture fees, andgrant support from Boehringer Ingelheim and Aryx Therapeutics;consulting fees from sanofi-aventis; and lecture fees and grantsupport from Portola Pharmaceuticals. Drs Reilly and Brueckmannare employees of Boehringer Ingelheim. Dr Eikelboom has receivedconsulting fees, lecture fees, and grant support from BoehringerIngelheim, AstraZeneca, Sanofi-aventis, and GlaxoSmithKline; con-sulting fees and lecture fees from Eisai Pharmaceuticals, Eli Lilly,and McNeil; and consulting fees from Bristol-Myers Squibb, Cor-genix Medical Corporation, and Daiichi-Sankyo. Dr Yusuf hasreceived consulting fees, lecture fees, and grant support fromBoehringer Ingelheim and consulting fees from AstraZeneca,Bristol-Myers Squibb, and sanofi-aventis. Dr Connolly reports re-ceiving consulting fees, lecture fees, and grant support from Boeh-ringer Ingelheim. Dr Yang reports no conflicts.

References1. Eikelboom JW, Weitz JI. Update on antithrombotic therapy: new antico-

agulants. Circulation. 2010;121:15231532.2. Ezekowitz MD, Connolly SJ, Parekh A, Reilly PA, Varrone J, Wang S,

Oldgren J, Themeless E, Wallentin L, Yusuf S. Rationale and design ofRE-LY: randomized evaluation of long-term anticoagulant therapy,warfarin, compared with dabigatran. Am Heart J. 2009;157:805810.

3. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A,Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, XavierD, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, WallentinL; RE-LY Steering Committee and Investigators. Dabigatran versuswarfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:11391151.

4. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L. Newlyidentified events in the RE-LY trial. N Engl J Med. 2010;363:18751876.

5. Uchino K, Hernandez AV. Dabigatran is associated with higher risk ofacute coronary events: a meta-analysis of non-inferiority randomizedcontrolled trials. January 9, 2012. doi:10.1001/archinternmed.2011.1666.Arch Intern Med. Accessed January 10, 2012.

6. The ACTIVE Writing Group on behalf of the ACTIVE Investigators.Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillationin the Atrial fibrillation Clopidogrel Trial with Irbesartan for preventionof Vascular Events (ACTIVE W): a randomised controlled trial. Lancet.2006;367:19031919.

7. Olsson SB. Stroke prevention with the oral direct thrombin inhibitorximelagatran compared with warfarin in patients with non-valvular atrialfibrillation (SPORTIF III): randomised controlled trial. Lancet. 2003;362:16911698.

8. Albers GW, Diener HC, Frison L, Grind M, Nevinson M, Partridge S,Halperin JL, Horrow J, Olsson SB, Petersen P, Vahanian A. Ximelagatranvs warfarin for stroke prevention in patients with nonvalvular atrialfibrillation: a randomized trial. JAMA. 2005;293:690698.

9. AMADEUS Investigators. Comparison of idraparinux with vitamin Kantagonists for prevention of thromboembolism in patients with atrialfibrillation: a randomised, open-label, non-inferiority trial. Lancet. 2008;371:315321.

10. Wallentin L, Wilcox RG, Weaver WD, Emanuelsson H, Goodvin A,Nystrom P, Bylock A; for the ESTEEM Investigators. Oral ximelagatran



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for secondary prophylaxis after myocardial infarction: the ESTEEM ran-domised controlled trial. Lancet. 2003;362:789797.

11. Oldgren J, Budaj A, Granger CB, Khder Y, Roberts J, Siegbahn A, TijssenJGP, Van de Werf F, Wallentin L. Dabigatran versus placebo in patients withacute coronary syndromes on dual antiplatelet therapy: a randomised, double-blind, phase II trial. Eur Heart J. 2011;32:27812789.

12. Smith P, Arnesen H, Holme I. The effect of warfarin on mortality andreinfarction after myocardial infarction. N Engl J Med. 1990;323:147152.

13. Hurlen M, Adelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin,aspirin, or both after myocardial infarction. N Engl J Med. 2002;347:969974.

CLINICAL PERSPECTIVEDabigatran etexilate is a novel, potent, competitive, and reversible direct thrombin inhibitor that recently has beencompared with warfarin for prevention of thromboembolic events in 18 113 patients with nonvalvular atrial fibrillation(Randomized Evaluation of Long-Term Anticoagulation Therapy [RE-LY trial]). At a dose of 110 mg twice daily,dabigatran had similar efficacy as warfarin in preventing stroke and systemic embolism but lower rates of majorhemorrhage. At a dose of 150 mg twice daily, dabigatran was associated with lower rates of stroke and systemic embolismthan warfarin but similar rates of major hemorrhage. This post hoc study evaluated the incidence of myocardial ischemicevents, including myocardial infarction (MI), in the 3 treatment arms. MI occurred at annual rates of 0.82% and 0.81% withdabigatran 110 mg or 150 mg BID compared with 0.64% in patients taking warfarin (hazard ratio 1.29, 95% confidenceinterval 0.961.75, P0.09 for dabigatran 110 mg; hazard ratio 1.27, 95% confidence interval 0.941.71, P0.12 fordabigatran 150 mg). Events prespecified as net clinical benefit (all strokes, systemic embolism, MI, pulmonaryembolism, major bleeding, and all-cause death) occurred at a rate of 7.34% per year with dabigatran 110 mg, 7.11% peryear with dabigatran 150 mg, and 7.91% per year with warfarin (hazard ratio 0.92, 95% confidence interval 0.841.01,P0.09 for dabigatran 110 mg; 0.90, 95% confidence interval 0.820.99, P0.02 for dabigatran 150 mg). In conclusion,in patients with atrial fibrillation, there was a nonsignificant increase in MIs with dabigatran compared with warfarin, butother myocardial ischemic events were not increased. The net clinical benefit favors dabigatran over warfarin in patientswith or without a baseline history of MI or coronary artery disease.



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Myocardial Ischemic Events in Patients with Atrial Fibrillation