Narrative review
Increased risk of myocardial infarction with dabigatran: fact or fiction? Ada F. Giglioa, Eloisa Basilea, Pasquale Santangelib,c,d, Luigi Di Biasec,d, Francesco Trottaa and Andrea Nataleb,c Dabigatran is a direct, competitive inhibitor of thrombin recently approved for the prophylaxis of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. In some of the clinical trials evaluating the efficacy and safety of dabigatran in different clinical settings [i.e., prevention of venous thromboembolism (VTE) after orthopedic surgery, secondary prevention of VTE, and acute coronary syndromes (ACS)], a trend toward an increase in acute coronary events among patients receiving dabigatran has been reported, thus raising concerns of a possible relationship between dabigatran and myocardial infarction, especially in high-risk patients. However, as shown in our article, current evidence is inconclusive on this topic; more data are needed to detail this hypothetical association, and other considerations, such as the well-known protective
Introduction Over the last few years, several new compounds have been introduced into the critical field of anticoagulant therapy. Of these, dabigatran is certainly one of the most interesting and studied molecules. Dabigatran is a direct, competitive inhibitor of thrombin; it is administered as an oral prodrug, dabigatran etexilate, which is rapidly converted by a serum esterase to the active drug dabigatran.1 The onset of action is rapid, and the pharmacodynamic effects are predictable and reproducible.2,3 In contrast to warfarin, dabigatran administration has low drug–drug and drug–food interactions and does not require International Normalized Ratio (INR) monitoring and dose adjustments, thus simplifying the management of therapy and potentially increasing patient compliance; in fact, it has been demonstrated that, although there is a well-established benefit for the use of anticoagulation therapy in atrial fibrillation patients at high risk for stroke, vitamin K antagonist prescription is inexplicably low, even in the absence of contraindications or patients’ comorbidities, and patient compliance to treatment is poor, thus affecting the efficacy of anticoagulation therapy for thromboembolic event prevention.4 Stroke prevention strategies in atrial fibrillation, either with novel anticoagulants, such as dabigatran, apixaban or rivaroxaban, or with nonpharmacological therapies, such as left atrial appendage ligation or excision, and left atrial occlusion devices, are therefore a most interesting and developing field.5,6 1558-2027 ß 2014 Italian Federation of Cardiology
effect of warfarin against ACS, should be taken into account as a possible explanation. J Cardiovasc Med 2014, 15:19–26 Keywords: atrial fibrillation, dabigatran, myocardial infarction a
Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy, Stanford University School of Medicine, Stanford, California, USA, cTexas Cardiac Arrhythmia Institute, St. David’s Medical Center, Austin, Texas, USA and d University of Foggia, Foggia, Italy b
Correspondence to Pasquale Santangeli, MD, Cardiac Arrhythmia Service, Stanford University School of Medicine, 300 Pasteur Dr MC 5319, Stanford, CA 94305, USA Tel: +1 650 621 0702; fax: +1 650 723 8392; e-mail: [email protected] Received 2 February 2013 Revised 29 May 2013 Accepted 30 June 2013
The most relevant data on dabigatran efficacy and safety in different clinical settings come from several randomized noninferiority trials (Tables 1 and 2). On the basis of the results of these trials, dabigatran was approved in 2008 by the European Medicines Agency for the prevention of venous thromboembolism (VTE) after orthopedic surgery (hip or knee replacement) and in 2010 by the Food and Drug Administration (FDA) for the prophylaxis of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.7 However, a trend toward a greater incidence of cardiac ischemic events in patients taking dabigatran compared with controls has been reported in randomized trials, thus raising concerns about the safety of dabigatran. The purpose of this article is to summarize the current evidence regarding any possible association between dabigatran and myocardial infarction (MI), highlighting the critical points and the unanswered questions in this controversial topic.
Evidence from randomized controlled trials on dabigatran in atrial fibrillation A pilot trial on the use of dabigatran in atrial fibrillation was conducted in 2007,8 which evaluated, across a 12-week period, the efficacy and safety of dabigatran at different doses (50, 150 and 300 mg twice daily), with or without concomitant aspirin therapy, versus adjusted-dose warfarin to achieve an INR value between 2.0 and 3.0 in patients DOI:10.2459/JCM.0b013e328364beb8
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20 Journal of Cardiovascular Medicine 2014, Vol 15 No 1
with atrial fibrillation. The two highest doses of dabigatran were as effective as warfarin for thromboembolic prevention, but the 300 mg dose was associated with higher risk of major hemorrhage. Two acute coronary events were reported in the dabigatran group during follow-up, whereas no events occurred in the warfarin group, although the small sample size of the trial did not allow the full evaluation of whether dabigatran was associated with increased risk of MI. The most important trial on dabigatran in the setting of atrial fibrillation, and the largest study on dabigatran to date, is the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study.9,10 In this noninferiority trial, 18 113 atrial fibrillation patients with increased risk of stroke were randomized to receive fixed-dose dabigatran (110 or 150 mg twice daily administered in a blinded fashion) or adjusted-dose warfarin in an openlabel manner to achieve a target INR of 2.0–3.0. The median follow-up period was 2 years. The primary outcome of the study was the occurrence of stroke or systemic embolism, whereas the primary safety outcome was major hemorrhage. Stroke, systemic embolism and death were the secondary outcomes; other reported outcomes were MI, transient ischemic attack, pulmonary embolism and hospitalization. The RE-LY study found that the lower dose of dabigatran (i.e., 110 mg twice daily) had similar thromboembolic protection compared with warfarin and was associated with a decreased risk of major hemorrhagic events. However, the higher dabigatran dose (i.e., 150 mg twice daily) was similar to warfarin in terms of major hemorrhagic events but was superior in terms of thromboembolic protection. The results of the RE-LY study prompted FDA approval of the highest dose of dabigatran for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Interestingly, in addition to the expected possible complications, such as major hemorrhage, patients treated with dabigatran had an increased risk of MI. Specifically, a rate of clinical MI of 0.74% per year was observed in the group receiving dabigatran 150 mg b.i.d., compared with a rate of 0.53% in the warfarin group; these figures accounted for a statistically significant increase in the relative risk [relative risk (RR) ¼ 1.38, P ¼ 0.048]. An increased rate of MI was also observed in the 110 mg b.i.d. dabigatran group (0.72% per year), but the difference to warfarin was not statistically significant (P ¼ 0.07). It is worth noting that the baseline clinical characteristics of the enrolled population, including the distribution of cardiovascular risk factors, were homogeneous between the three groups. On the basis of these findings, a subsequent and more thorough analysis of data collected in the RE-LY study was requested by the FDA to avoid underreporting of events. This analysis revealed 81 additional events in the study population, including stroke, bleeding, pulmonary and systemic embolism, 4 clinical MIs and 28 silent MIs (defined as
the appearance of new Q waves identified by routine electrocardiography), both in the dabigatran and warfarin groups.11 Although the new data confirmed a trend toward an increased incidence of MI in patients receiving dabigatran, with annual rates of 0.82 and 0.81% with dabigatran 110 mg b.i.d. and 150 mg b.i.d., respectively, compared with 0.64% of warfarin, the difference was longer statistical significant. Recently, a detailed analysis of the cardiac ischemic events that occurred in the RE-LY study was performed,12 taking into account not only clinical and silent MIs, but also the composite of MI and other myocardial ischemic events such as unstable angina, cardiac arrest and cardiac death, the composite of MI, unstable angina, percutaneous coronary intervention, coronary artery bypass grafting, cardiac arrest and cardiac death (including arrhythmic, pump failure and post-MI deaths), and the net clinical benefit, considering stroke, systemic and pulmonary embolism, major hemorrhage, MI or death. In this analysis, the risk of each study outcome, composite outcomes and the net clinical benefit were separately calculated for the subgroup of patients with a previous history of coronary artery disease (CAD) and MI, and therefore at higher risk of developing new coronary events, and these were compared with those patients with no history of CAD. No significant difference in the rate of the composite outcomes was found across the three treatment groups and between patients at high or low risk of new MI, whereas the net benefit analysis showed a significant reduction in the annual rates of thromboembolic and bleeding events in the group receiving dabigatran 150 mg [hazard ratio (HR) versus warfarin 0.90, 95% confidence interval (CI) 0.82–0.99, P ¼ 0.02]. Moreover, this analysis pointed out that onethird of MI events in the three groups occurred when patients were no longer taking the assigned study drug. The authors concluded that, despite a nonsignificant, dose-independent trend toward an increased risk of MI in patients receiving dabigatran, the rate of other myocardial ischemic events was similar between the groups and, importantly, there was an overall net benefit with dabigatran therapy across all subgroups of patients, including those with a previous MI. The results of the RE-LY study prompted the insertion of a warning in the 2010 Canadian Cardiovascular Society guidelines discouraging dabigatran administration in atrial fibrillation patients at high risk of coronary events.13 However, such statement was not included in the 2011 American College of Cardiology/American Heart Association/Heart Rhythm Society atrial fibrillation guidelines update.14 An update of the European Society of Cardiology (ESC) guidelines for the management of atrial fibrillation was published in 2012, stating that novel anticoagulants, such as dabigatran, apixaban, and rivaroxaban, have a better efficacy, safety and convenience profile compared with vitamin K antagonists, and therefore should be
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Dabigatran and myocardial infarction Giglio et al. 21
considered for most nonvalvular atrial fibrillation patients for whom anticoagulant therapy is indicated.15 However, some concerns exist relating to the absence of reliable and readily available laboratory tests examining the efficacy of anticoagulation to compliance issues and to specific clinical settings. It is crucial, therefore, to clarify the safety profile of each of these novel agents in different populations (e.g., CAD, chronic kidney disease and very elderly patients), in order to tailor anticoagulation therapy according to single-patient comorbidities, preferences and thrombotic/hemorrhagic risk factors.
Evidence from randomized controlled trials on dabigatran in acute coronary syndromes Up to date, only one multicenter, prospective, randomized, double-blind, placebo-controlled trial on dabigatran in acute coronary syndromes (ACS) has been completed. The Dabigatran versus Placebo in Patients With Acute Coronary Syndromes on Dual Antiplatelet Therapy (RE-DEEM) trial enrolled 1861 patients, 60% with ST elevation MI and 40% with non-ST elevation MI within the last 14 days, in 161 centers across 24 countries.16 Patients were considered for inclusion in the trial if they were at risk for cardiovascular complications following the acute events, that is, patients aged 65 years or more, with diabetes mellitus, previous MI, congestive heart failure, left ventricular ejection fraction less than 40% or moderate chronic renal insufficiency. The main exclusion criteria were conditions associated with increased risk of bleeding (major surgery within the last month, treatment with vitamin K antagonists or fibrinolytic drugs and a history of gastrointestinal bleeding), severe anemia or reduced platelet count, uncontrolled hypertension, severe congestive heart failure (New York Heart Association class IV) and renal insufficiency at stage 4 or 5. Almost all patients (99.2%) were receiving dual antiplatelet therapy with aspirin and clopidogrel or thienopyridine. Patients included in the study were randomized to receive dabigatran 50, 75, 110 or 150 mg twice daily or placebo for 6 months. The primary outcome of the trial was a composite of major or clinically relevant minor bleeding events. Secondary outcomes were reduction of cardiovascular ischemic events, including nonfatal MI, nonhemorrhagic stroke and cardiovascular death, and of D-dimer blood levels, which were considered as a surrogate indicator of the efficacy of the drug. At 6 months follow-up, a significant dose-dependent increase of major and minor bleeding events was recorded for patients receiving dabigatran. D-dimer levels were reduced with all doses of dabigatran compared with placebo, reflecting drug-induced reduction in thrombin generation. The number of patients reaching the secondary composite outcome of nonhemorrhagic stroke, nonfatal MI or cardiovascular death showed a trend toward a reduction in the two groups receiving the two highest doses of
dabigatran. However, separate analysis of the different components of the secondary composite outcome showed a reduction of nonhemorrhagic stroke events, whereas the number of patients experiencing nonfatal MI was higher in all dabigatran groups compared with placebo.
Evidence from randomized controlled trials of dabigatran for the prevention and treatment of venous thromboembolism Several studies have evaluated the efficacy and safety of dabigatran in the clinical setting of both short-term and long-term thromboprophylaxis after orthopedic surgery, and in the acute treatment of VTE. In the Dabigatran Etexilate versus Enoxaparin in Prevention of Venous Thromboembolism Following Total Hip Arthroplasty (RENOVATE) trial, a randomized, double-blind, noninferiority study, 3494 patients in 115 centers undergoing total hip replacement were randomly assigned to receive oral dabigatran 220 or 150 mg once daily, or subcutaneous enoxaparin 40 mg once daily.17 The median treatment duration was 33 days. The primary efficacy outcome was a composite of VTE occurrence and death from all causes, whereas the secondary efficacy outcomes were major VTE and VTE-related mortality, proximal deep-vein thrombosis and the single elements of the primary outcome. Bleeding events occurring during the treatment period constituted the primary safety outcome. Both doses of dabigatran were found noninferior to enoxaparin in the prevention of VTE, with a similar bleeding rate between the two drugs. Few acute coronary events were reported in this study during follow-up, with no difference between the groups. Analogous findings were reported by the RENOVATE II study,18 a randomized, double-blind, noninferiority trial comparing oral dabigatran at a 220 mg dose with subcutaneous enoxaparin 40 mg daily, administered for 28–35 days, for the prevention of VTE in patients undergoing total hip replacement. The Oral Dabigatran Etexilate versus Subcutaneous Enoxaparin for the Prevention of Venous Thromboembolism after Total Knee Replacement (RE-MODEL) study19 was a randomized, double-blind, noninferiority study comparing short-term therapy (6–10 days) with 220 or 150 mg daily oral dabigatran with subcutaneous to enoxaparin (40 mg once daily). In the RE-MODEL, a total of 2076 patients undergoing total knee replacement were randomized. The primary efficacy outcome was a composite of VTE events and death from all causes during study treatment, whereas the primary safety outcome was bleeding events. After a follow-up of 3 months, both doses of dabigatran were found to be noninferior to enoxaparin for the prevention of VTE, with similar bleeding rates. The incidence of acute coronary events (unstable angina, MI and cardiac death) was low and not statistically different between the groups, occurring in three and eight patients in the dabigatran group (220 and 150 mg, respectively) and in six patients in the enoxaparin group.
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22 Journal of Cardiovascular Medicine 2014, Vol 15 No 1
The Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism (RE-COVER) study20 evaluated the efficacy and safety of dabigatran versus warfarin in the treatment of acute VTE. RE-COVER was a randomized, double-blind, double-dummy trial with a noninferiority design, and included 2564 patients with acute VTE treated initially with parenteral anticoagulation therapy (median of 9 days), and then randomized to 6 months of therapy with either dabigatran 150 mg twice daily or adjusted-dose warfarin to achieve and maintain an INR value of between 2.0 and 3.0. The primary efficacy outcomes assessed in the RE-COVER study were symptomatic recurrence of VTE and VTE-related deaths. Bleeding events, ACS, liver enzyme elevation or other adverse events were investigated as safety endpoints. Dabigatran was found to be noninferior to warfarin for the primary efficacy outcomes, with a similar risk of recurrent VTE and VTE-related death between the two drugs. Major and minor bleeding, as well as other adverse events, did not differ between the two treatment groups. The occurrence of ACS and, specifically, of MI was also assessed during the 6 months of follow-up. Five patients (0.4%) in the dabigatran group and three patients (0.2%) in the warfarin group experienced an ACS, with four (0.3%) and two (0.2%) classified as MI, respectively. In line with the results of previous trials, the absolute number of events was very low, and the difference did not reach statistical significance. Given the low rate of the primary outcome found in this trial, a subsequent study with the same design and objectives but with a larger sample size was performed to confirm the results of the RE-COVER. The RE-COVER II study21 enrolled 2568 patients and yielded similar results, confirming the noninferiority of dabigatran compared with warfarin in the setting of acute VTE. As previously, in the RE-COVER II study, the absolute number of ACS events was higher in the dabigatrantreated group than in those receiving warfarin (five versus three ACS, respectively), but again the difference was not statistically significant. Another trial, the RE-MEDY,22 tested the efficacy and safety of dabigatran for the extended treatment of VTE (i.e., secondary prophylaxis), randomizing 2866 patients who had already received at least 3 months of full anticoagulation therapy for an acute episode of VTE, and who were considered to be at increased risk for recurrent VTE, to a further 6–36 months of therapy with dabigatran 150 mg twice daily or warfarin. The results of this trial confirmed the noninferiority of dabigatran compared with warfarin for the prevention of thromboembolic events, with a lower bleeding rate. However, the analysis of other safety endpoints showed a significant difference in ACS (MI or unstable angina) events rate between the 2 treatment groups, with 13 patients (0.9%) in the dabigatran group versus 3 patients (0.2%) in the warfarin group experiencing an ACS during follow-up (RR with
dabigatran 4.32; 95% CI 1.23–15.13). In this regard, it is important to point out that there were baseline differences in the distribution of cardiovascular risk factors between the two treatment arms, with a greater number of patients in the dabigatran group having diabetes, hypertension, or a previous history of CAD. Finally, another randomized, double-blind trial evaluating dabigatran efficacy and safety in post-VTE long-term treatment was the Twice-daily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the Long Term Prevention of Recurrent Symptomatic VTE (RE-SONATE) trial.23 Dabigatran 150 mg twice daily or placebo were administered in a blinded fashion to 1353 patients who had experienced a VTE or pulmonary embolism and completed 6–18 months of anticoagulant therapy. A significant reduction of recurrent thromboembolic events was obtained with dabigatran (HR 0.61; 95% CI 0.42– 0.88), and only two major bleeding events were reported. In contrast to the active-control study, in this case no difference was observed in ACS incidence between the two groups of treatment, with a single ACS event reported in each group.
Evidence from meta-analysis A recent meta-analysis on the possible association between dabigatran and a higher risk of cardiac ischemic events was performed by Uchino and Hernandez.24 Seven noninferiority randomized controlled trials (RCTs), including a total of 30 514 patients reporting on MI and ACS rates as secondary outcomes (PETRO,8 RE-LY,9,10 RE-COVER,20 RE-DEEM,16 RE-NOVATE,17 RENOVATE II,18 and RE-MODEL19), were included in the analysis. The primary outcomes of the meta-analysis were MI or ACS, whereas the overall mortality constituted the secondary outcome. The authors found that dabigatran was associated with a significantly higher risk of acute coronary events compared with controls; this association persisted when including either the original RE-LY results [odds ratio (OR) 1.33; 95% CI 1.03–1.71; P ¼ 0.03] or the revised ones (OR 1.27; 95% CI 1.00–1.61; P ¼ 0.05). The absolute increase in acute coronary events during followup was 0.27%. No interaction was found between the increased risk of ACS with dabigatran and baseline cardiovascular risk factors. However, the authors also reported a beneficial effect of dabigatran on all-cause mortality (dabigatran 4.83% versus control treatments 5.02%; OR 0.89; 95% CI 0.80–0.99; P ¼ 0.04), even if this was not the primary outcome of the meta-analysis. Overall, the results of this meta-analysis should be carefully interpreted, given the heterogeneity of the trials included and the dominant weight of the RE-LY in the pooled analysis, because of the larger sample size and the longer duration of follow-up. Furthermore, the absolute increase in risk of ACS with dabigatran, although statistically significant, was very small (0.27%), and the clinical relevance of this finding is unclear.24
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Randomized; OL for treatment; DB for dabigatran dose
Randomized; OL for treatment; DB for dabigatran dose, NI Randomized DB; parallel groups
PETRO5 (2007)
RE-LY6,7 (2009)
Randomized; DB, NI, parallel groups Randomized; DB, NI
Randomized; DB, DD, NI
RE-NOVATE II14 (2011)
RE-COVER16 (2009)
Randomized; DB, DD
Randomized; DB, NI; parallel groups Randomized DB parallel groups
RE-MEDY18,20 (2011) Extended secondary VTE prevention Extended secondary VTE prevention
Acute VTE
Acute VTE
Total knee replacement
Total hip replacement
Total hip replacement
ACS
AF
AF
Population
1343
2856
2568
2539
2076
2013
3463
1861
18 113
502
Population sizea
VTE and related deaths VTE and related deaths VTE and related deaths VTE and related deaths
VTE and death from all causes VTE and death from all causes
VTE and death from all causes
Major and minor bleedings
Stroke or systemic embolism
Bleedings
Primary outcome 50 mg (n ¼ 105); 150 mg (n ¼ 166); 300 mg (n ¼ 161); PO b.i.d., with or without ASA 110 mg (n ¼ 6015) 150 mg (n ¼ 6076); PO b.i.d. 50 mg (n ¼ 369); 75 mg (n ¼ 368); 110 mg (n ¼ 406); 150 mg (n ¼ 347); PO b.i.d. 220 mg (n ¼ 1146); 150 mg (n ¼ 1163); PO q.d. 220 mg (n ¼ 1010); PO q.d. 220 mg (n ¼ 679); 150 mg (n ¼ 703); PO q.d. 150 mg (n ¼ 1273); PO b.i.d. 150 mg (n ¼ 1279); PO b.i.d. 150 mg (n ¼ 1430); PO b.i.d. 150 mg (n ¼ 681); PO b.i.d.
Dabigatran treatment
Adj. dose warfarin (n ¼ 1266) Adj. dose warfarin (n ¼ 1289) Adj. dose warfarin (n ¼ 1426) Placebo (n ¼ 662)
Enoxaparin 40 mg (n ¼ 1003); s.c. q.d. Enoxaparin 40 mg (n ¼ 694); s.c. q.d.
Enoxaparin 40 mg (n ¼ 1154); s.c. q.d.
Placebo (n ¼ 371)
Adj. dose warfarin (n ¼ 6022)
Adj. dose warfarin (n ¼ 70)
Control treatment
6 months
6–36 months
6 months
6 months
28–35 (mean 32) days 6–10 days
28–35 (mean 33) days
6 months
2 years
3 months
Treatment duration
6 months
6–36 months
6 months
6 months
3 months
3 months
3 months
6 months
2 years
3 months
Follow-up duration
ACS, acute coronary syndromes; adj. dose, adjusted dose; AF, atrial fibrillation; ASA, acetylsalicylic acid; b.i.d., twice a day; DB, double-blind; DD, double-dummy; NI, noninferiority; OL, open label; PO, per os; q.d., once a day; s.c., subcutaneously; VTE, venous thrombo-embolism. a Number of patients randomized and who took at least one dose of the randomized drug.
RE-SONATE19,20 (2012)
RE-COVER II
(2011)
17
RE-MODEL15 (2007)
Randomized; DB, NI
RE-NOVATE13 (2007)
RE-DEEM12 (2011)
Design
Clinical trials on dabigatran
Trial
Table 1
Dabigatran and myocardial infarction Giglio et al. 23
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24 Journal of Cardiovascular Medicine 2014, Vol 15 No 1
Dabigatran and myocardial infarction: is there something missing? The higher rate of MI events in the dabigatran-treated patients compared with patients receiving other anticoagulant therapies or placebo found in noninferiority randomized trials was certainly unexpected. However, before accepting or denying the presence of such an association, several considerations have to be taken into account. In all the trials, the absolute number of myocardial ischemic events was low; therefore, possible differences between the groups are difficult to evaluate, and the results could be both exaggerated and underestimated through chance alone. Moreover, none of these trials was specifically designed to detect ischemic events. These considerations may raise concerns regarding the reliability of data indicating an increased risk of cardiac ischemic events with dabigatran. Nevertheless, the trend toward an increased rate of MI in patients receiving dabigatran remains quite consistent across different studies,10,22 in different clinical settings, and with different therapeutic regimens and follow-up periods; therefore, there seems to be a real indication that dabigatran might increase the risk of ACS, although the clinical relevance of this risk is still to be established. Although currently available data seem to indicate a possible relation between dabigatran and cardiac ischemic events, the possible biological mechanism underlying such an association is still unclear. Apparently, there is no logical reason why a compound with anticoagulant properties, such as dabigatran, should be associated with an increased rate of coronary plaque complication and instability. However, ximelagatran, one of the first developed direct thrombin inhibitors, has been associated with increased levels of several proinflammatory biomarkers in post-MI patients, thus suggesting that direct thrombin inhibition could have other side-effects possibly affecting atherosclerotic disease.25 However, there is no evidence at present that this hypothetical mechanism could be associated with dabigatran. Warfarin has a well-documented protective effect against the recurrence of ischemic events.26,27 Therefore, it has been proposed that the numerical excess of MIs observed Table 2
in patients receiving dabigatran, particularly in the RE-LY study, could be because of the loss of a warfarin-related beneficial effect rather than due to a direct harmful effect of dabigatran.12,28 This hypothesis is biologically plausible, as the inhibition of the synthesis of factor X, responsible for thrombin generation, could be more efficacious in mitigating the prothrombotic burst triggered by plaque rupture28 compared with the downstream selective inhibition of thrombin. Accordingly, no increase of ACS rate has been reported with factor Xa inhibitors when compared with warfarin.29 It has been recently demonstrated in vitro that warfarin is more effective than dabigatran in attenuating thrombin generation; this can be explained by the different mechanism of action of the two drugs. While warfarin blocks the production of functional coagulation factors VII, IX and X, and the generation of factor II prothrombin, the precursor of thrombin, thus affecting the initiation and amplification of thrombin generation, dabigatran is a stoichiometric inhibitor of thrombin. It is possible, therefore, that in the setting of the complicated coronary atherosclerotic plaque, in which high concentrations of thrombin are generated as a consequence of plasma contact with plaque components and tissue factor exposition, dabigatran concentration could be overcome by thrombin level.30 However, this hypothesis should be properly explored by directly comparing dabigatran with a real placebo (not warfarin). Thus far, there are only two randomized trials comparing dabigatran with placebo. In the RE-DEEM trial, a trend toward an increased risk of MI in the dabigatran arm has been reported. It should be noted, however, that as a phase II, dose-finding study, the RE-DEEM had low power for the evaluation of efficacy outcomes. In contrast, in the RE-SONATE trial no difference was reported between the groups receiving dabigatran or placebo with regard to the incidence of ACS, in the same clinical setting, but in comparing dabigatran with warfarin treatment, an increased number of acute cardiac events was again observed in the dabigatran group. These results seem to support the hypothesis that the greater number of events observed when comparing dabigatran with warfarin may be because of the greater and well established efficacy of warfarin in
Acute coronary events in dabigatran groups and controls
Trial PETRO5 (2007) RE-LY6,7 (2009) RE-DEEM12 (2011) RE-NOVATE13 (2007) RE-NOVATE II14 (2011) RE-MODEL15 (2007) RE-COVER16 (2009) RE-COVER II17 (2011) RE-MEDY18 (2011) RE-SONATE19 (2012)
ACE dabigatran group (no./patients treated)
ACE control group (no./patients treated)
2/432 195/12 091 32/1490 13/2309 1/1010 10/1382 4/1273 5/1279 13/1430 3/681
0/70 75/6022 4/371 9/1154 1/1003 4/694 2/1266 3/1289 3/1426 2/662
OR (95% CI) 0.79 1.30 2.01 0.72 0.99 1.26 1.99 1.68 4.35 1.46
(0.04–16.73) (0.99–1.71) (0.67–6.75) (0.29–1.83) (0.03–36.29) (0.39–4.02) (0.36–10.90) (0.35–8.87) (1.16–19.26) (0.20–12.49)
P value 0.56 0.05 0.18 0.28 0.49 0.69 0.68 0.47 0.01 0.68
ACEs, acute coronary events; CI, confidence interval; OR, odds ratio.
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Dabigatran and myocardial infarction Giglio et al. 25
preventing ACS recurrence, rather than to detrimental effects of dabigatran. At present, there is no conclusive evidence supporting an association between dabigatran etexilate and increased risk of MI. The meta-analysis performed by Uchino and Hernandez was intended to resolve the uncertainties on this topic, but, as mentioned, it was affected by several methodological limitations. The trials included in the analysis were very different with regard to the sample size, treatment doses and duration of follow-up. Furthermore, very different therapies (warfarin, enoxaparin, and placebo) were mixed together as ‘control’ treatment. Moreover, the results of the meta-analysis were heavily influenced by the inclusion of the RE-LY study, which alone accounted for 18 113 (59%) patients out of the total of 30 514, and for the majority (74%) of the events reported. Overall, more data are necessary to investigate the possible harm of dabigatran in increasing the risk of MI. Given the potentially wide field of application of this novel anticoagulant agent, this topic should be specifically investigated by properly designed clinical trials, re-evaluating the overall efficacy and safety profile of this drug especially in patients at high risk of cardiac ischemic events (Tables 1 and 2).
3
4
5
6
7
8
9
10
11
12
Conclusion Dabigatran etexilate is a potent oral direct thrombin inhibitor not requiring dose adjustment and INR monitoring, has low drug–drug and drug–food interactions, and is currently approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, and for VTE prophylaxis after orthopedic surgery. Some concerns about the safety profile of this drug, however, have arisen. In particular, an association with a higher risk of MI cannot be excluded on the basis of the current available evidence, although the evidence base is inconclusive for claiming an increased risk of MI in patients receiving dabigatran. Further properly designed studies are warranted to definitely assess the presence and the clinical relevance of such an association, and the risk–benefit profile of dabigatran in different populations of patients.
13
14
15
Acknowledgements None. Conflicts of interest
16
There are no conflicts of interest.
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2
Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008; 47:285–295. Stangier J, Eriksson BI, Dahl OE, et al. Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. J Clin Pharmacol 2005; 45:555–563.
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Liesenfeld KH, Schafer HG, Troconiz IF, Tillmann C, Eriksson BI, Stangier J. Effects of the direct thrombin inhibitor dabigatran on ex vivo coagulation time in orthopaedic surgery patients: a population model analysis. Br J Clin Pharmacol 2006; 62:527–537. Pereira de Sousa L, Burba I, Ruperto C, Lattuada L, Barbone F, Di Chiara A. Vitamin K antagonists in patients with nonvalvular atrial fibrillation: appropriateness and quality of treatment in an Italian cohort. J Cardiovasc Med (Hagerstown) 2013; 14:534–540. Solomon MD, Ullal AJ, Hoang DD, Freeman JV, Heidenreich P, Turakhia MP. Cost-effectiveness of pharmacologic and invasive therapies for stroke prophylaxis in atrial fibrillation. J Cardiovasc Med (Hagerstown) 2012; 13:86–96; doi: 10.2459/JCM.0b013e32834f23cf. [review]. Mohammed I, Mohmand-Borkowski A, Burke JF, Kowey PR. Stroke prevention in atrial fibrillation. J Cardiovasc Med (Hagerstown) 2012; 13:73–75; doi: 10.2459/JCM.0b013e32834f2336. [review]. European Medicines Agency. Pradaxa: authorization details. http//:www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/ medicines/000829/ human_med_000981.jsp&mid=WC0b01ac058001d124. Ezekowitz MD, Reilly PA, Nehmiz G, et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am J Cardiol 2007; 100:1419–1426. Ezekowitz MD, Connolly S, Parekh A, et al. Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. Am Heart J 2009; 157:805–810; 810.e1– 810.e2. Connolly SJ, Ezekowitz MD, Yusuf S, et al., RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139–1151. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L, Randomized Evaluation of Long-Term Anticoagulation Therapy Investigators. Newly identified events in the RE-LY trial. N Engl J Med 2010; 363:1875– 1876. Hohnloser SH, Oldgren J, Yang S, Wallentin L, Ezekowitz M, Reilly P, et al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) Trial. Circulation 2012; 125:669–676. Cairns JA, Connolly S, McMurtry S, et al. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: prevention of stroke and systemic thromboembolism in atrial fibrillation and flutter. Can J Cardiol 2011; 27:74–90. Wann LS, Curtis AB, January CT, et al. 2006 WRITING COMMITTEE MEMBERS, Fuster V, Ryde´n LE, Cannom DS, Le Heuzey JY, Crijns HJ, Lowe JE, Curtis AB, Olsson SB, Ellenbogen KA, Prystowsky EN, Halperin JL, Tamargo JL, Kay GN, Wann LS; ACCF/AHA TASK FORCE MEMBERS, Jacobs AK, Anderson JL, Albert N, Hochman JS, Buller CE, Kushner FG, Creager MA, Ohman EM, Ettinger SM, Stevenson WG, Guyton RA, Tarkington LG, Halperin JL, Yancy CW. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (Updating the 2006 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Heart Rhythm 2011; 8:157–176. Camm AJ, Lip GY, De Caterina R, et al. ESC Committee for Practice Guidelines (CPG), Bax JJ, Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Kirchhof P, Knuuti J, Kolh P, McDonagh T, Moulin C, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Torbicki A, Vahanian A, Windecker S; Document Reviewers, Vardas P, Al-Attar N, Alfieri O, Angelini A, Blo¨mstrom-Lundqvist C, Colonna P, De Sutter J, Ernst S, Goette A, Gorenek B, Hatala R, Heidbu¨chel H, Heldal M, Kristensen SD, Kolh P, Le Heuzey JY, Mavrakis H, Mont L, Filardi PP, Ponikowski P, Prendergast B, Rutten FH, Schotten U, Van Gelder IC, Verheugt FW. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Eur Heart J 2012; 33:2719–2747. Oldgren J, Budaj A, Granger CB, et al., RE-DEEM Investigators. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur Heart J 2011; 32:2781–2789. Eriksson BI, Dahl OE, Rosencher N, et al., RE-NOVATE Study Group. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, noninferiority trial. Lancet 2007; 370:949–956. Eriksson BI, Dahl OE, Huo MH, et al., RE-NOVATE II Study Group. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II): a randomised, double-blind, noninferiority trial. Thromb Haemost 2011; 105:721–729.
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Eriksson BI, Dahl OE, Rosencher N, et al., RE-MODEL Study Group. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007; 5:2178–2185. Schulman S, Kearon C, Kakkar AK, et al., RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361:2342–2352. Schulman S, Kakkar AK, Schellong SM, et al. A randomized trial of dabigatran versus warfarin in the treatment of acute venous thromboembolism (RE-COVER II). Am Soc Hematol 2011; Abstract 205. Schulman S, Baanstra D, Eriksson H, et al. Dabigatran or warfarin for extended maintenance therapy of venous thromboembolism (Abstract O-TH-033). J Thromb Hemost 2011; 9:22. Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013; 368:709–718. Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch Intern Med 2012; 172:397–402.
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Christersson C, Oldgren J, Wallentin L, Siegbahn A. Treatment with an oral direct thrombin inhibitor decreases platelet activity but increases markers of inflammation in patients with myocardial infarction. J Intern Med 2011; 270:215–223. 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. 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. Eikelboom JW, Weitz JI. Anticoagulation therapy: dabigatran and risk of myocardial infarction. Nat Rev Cardiol 2012; 9:260–262; doi: 10.1038/ nrcardio.2012.34. Granger CB, Alexander JH, McMurray JJ, et al., ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365:981–992. Dale B, Eikelboom JW, Weitz JI, et al. Dabigatran attenuates thrombin generation to a lesser extent than warfarin: could this explain their differential effects on intracranial hemorrhage and myocardial infarction? J Thromb Thrombolysis 2013; 35:295–301.
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Increased risk of myocardial infarction with dabigatran: fact or fiction? Ada F. Giglioa, Eloisa Basilea, Pasquale Santangelib,c,d, Luigi Di Biasec,d, Francesco Trottaa and Andrea Nataleb,c Dabigatran is a direct, competitive inhibitor of thrombin recently approved for the prophylaxis of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. In some of the clinical trials evaluating the efficacy and safety of dabigatran in different clinical settings [i.e., prevention of venous thromboembolism (VTE) after orthopedic surgery, secondary prevention of VTE, and acute coronary syndromes (ACS)], a trend toward an increase in acute coronary events among patients receiving dabigatran has been reported, thus raising concerns of a possible relationship between dabigatran and myocardial infarction, especially in high-risk patients. However, as shown in our article, current evidence is inconclusive on this topic; more data are needed to detail this hypothetical association, and other considerations, such as the well-known protective
Introduction Over the last few years, several new compounds have been introduced into the critical field of anticoagulant therapy. Of these, dabigatran is certainly one of the most interesting and studied molecules. Dabigatran is a direct, competitive inhibitor of thrombin; it is administered as an oral prodrug, dabigatran etexilate, which is rapidly converted by a serum esterase to the active drug dabigatran.1 The onset of action is rapid, and the pharmacodynamic effects are predictable and reproducible.2,3 In contrast to warfarin, dabigatran administration has low drug–drug and drug–food interactions and does not require International Normalized Ratio (INR) monitoring and dose adjustments, thus simplifying the management of therapy and potentially increasing patient compliance; in fact, it has been demonstrated that, although there is a well-established benefit for the use of anticoagulation therapy in atrial fibrillation patients at high risk for stroke, vitamin K antagonist prescription is inexplicably low, even in the absence of contraindications or patients’ comorbidities, and patient compliance to treatment is poor, thus affecting the efficacy of anticoagulation therapy for thromboembolic event prevention.4 Stroke prevention strategies in atrial fibrillation, either with novel anticoagulants, such as dabigatran, apixaban or rivaroxaban, or with nonpharmacological therapies, such as left atrial appendage ligation or excision, and left atrial occlusion devices, are therefore a most interesting and developing field.5,6 1558-2027 ß 2014 Italian Federation of Cardiology
effect of warfarin against ACS, should be taken into account as a possible explanation. J Cardiovasc Med 2014, 15:19–26 Keywords: atrial fibrillation, dabigatran, myocardial infarction a
Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy, Stanford University School of Medicine, Stanford, California, USA, cTexas Cardiac Arrhythmia Institute, St. David’s Medical Center, Austin, Texas, USA and d University of Foggia, Foggia, Italy b
Correspondence to Pasquale Santangeli, MD, Cardiac Arrhythmia Service, Stanford University School of Medicine, 300 Pasteur Dr MC 5319, Stanford, CA 94305, USA Tel: +1 650 621 0702; fax: +1 650 723 8392; e-mail: [email protected] Received 2 February 2013 Revised 29 May 2013 Accepted 30 June 2013
The most relevant data on dabigatran efficacy and safety in different clinical settings come from several randomized noninferiority trials (Tables 1 and 2). On the basis of the results of these trials, dabigatran was approved in 2008 by the European Medicines Agency for the prevention of venous thromboembolism (VTE) after orthopedic surgery (hip or knee replacement) and in 2010 by the Food and Drug Administration (FDA) for the prophylaxis of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.7 However, a trend toward a greater incidence of cardiac ischemic events in patients taking dabigatran compared with controls has been reported in randomized trials, thus raising concerns about the safety of dabigatran. The purpose of this article is to summarize the current evidence regarding any possible association between dabigatran and myocardial infarction (MI), highlighting the critical points and the unanswered questions in this controversial topic.
Evidence from randomized controlled trials on dabigatran in atrial fibrillation A pilot trial on the use of dabigatran in atrial fibrillation was conducted in 2007,8 which evaluated, across a 12-week period, the efficacy and safety of dabigatran at different doses (50, 150 and 300 mg twice daily), with or without concomitant aspirin therapy, versus adjusted-dose warfarin to achieve an INR value between 2.0 and 3.0 in patients DOI:10.2459/JCM.0b013e328364beb8
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20 Journal of Cardiovascular Medicine 2014, Vol 15 No 1
with atrial fibrillation. The two highest doses of dabigatran were as effective as warfarin for thromboembolic prevention, but the 300 mg dose was associated with higher risk of major hemorrhage. Two acute coronary events were reported in the dabigatran group during follow-up, whereas no events occurred in the warfarin group, although the small sample size of the trial did not allow the full evaluation of whether dabigatran was associated with increased risk of MI. The most important trial on dabigatran in the setting of atrial fibrillation, and the largest study on dabigatran to date, is the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study.9,10 In this noninferiority trial, 18 113 atrial fibrillation patients with increased risk of stroke were randomized to receive fixed-dose dabigatran (110 or 150 mg twice daily administered in a blinded fashion) or adjusted-dose warfarin in an openlabel manner to achieve a target INR of 2.0–3.0. The median follow-up period was 2 years. The primary outcome of the study was the occurrence of stroke or systemic embolism, whereas the primary safety outcome was major hemorrhage. Stroke, systemic embolism and death were the secondary outcomes; other reported outcomes were MI, transient ischemic attack, pulmonary embolism and hospitalization. The RE-LY study found that the lower dose of dabigatran (i.e., 110 mg twice daily) had similar thromboembolic protection compared with warfarin and was associated with a decreased risk of major hemorrhagic events. However, the higher dabigatran dose (i.e., 150 mg twice daily) was similar to warfarin in terms of major hemorrhagic events but was superior in terms of thromboembolic protection. The results of the RE-LY study prompted FDA approval of the highest dose of dabigatran for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Interestingly, in addition to the expected possible complications, such as major hemorrhage, patients treated with dabigatran had an increased risk of MI. Specifically, a rate of clinical MI of 0.74% per year was observed in the group receiving dabigatran 150 mg b.i.d., compared with a rate of 0.53% in the warfarin group; these figures accounted for a statistically significant increase in the relative risk [relative risk (RR) ¼ 1.38, P ¼ 0.048]. An increased rate of MI was also observed in the 110 mg b.i.d. dabigatran group (0.72% per year), but the difference to warfarin was not statistically significant (P ¼ 0.07). It is worth noting that the baseline clinical characteristics of the enrolled population, including the distribution of cardiovascular risk factors, were homogeneous between the three groups. On the basis of these findings, a subsequent and more thorough analysis of data collected in the RE-LY study was requested by the FDA to avoid underreporting of events. This analysis revealed 81 additional events in the study population, including stroke, bleeding, pulmonary and systemic embolism, 4 clinical MIs and 28 silent MIs (defined as
the appearance of new Q waves identified by routine electrocardiography), both in the dabigatran and warfarin groups.11 Although the new data confirmed a trend toward an increased incidence of MI in patients receiving dabigatran, with annual rates of 0.82 and 0.81% with dabigatran 110 mg b.i.d. and 150 mg b.i.d., respectively, compared with 0.64% of warfarin, the difference was longer statistical significant. Recently, a detailed analysis of the cardiac ischemic events that occurred in the RE-LY study was performed,12 taking into account not only clinical and silent MIs, but also the composite of MI and other myocardial ischemic events such as unstable angina, cardiac arrest and cardiac death, the composite of MI, unstable angina, percutaneous coronary intervention, coronary artery bypass grafting, cardiac arrest and cardiac death (including arrhythmic, pump failure and post-MI deaths), and the net clinical benefit, considering stroke, systemic and pulmonary embolism, major hemorrhage, MI or death. In this analysis, the risk of each study outcome, composite outcomes and the net clinical benefit were separately calculated for the subgroup of patients with a previous history of coronary artery disease (CAD) and MI, and therefore at higher risk of developing new coronary events, and these were compared with those patients with no history of CAD. No significant difference in the rate of the composite outcomes was found across the three treatment groups and between patients at high or low risk of new MI, whereas the net benefit analysis showed a significant reduction in the annual rates of thromboembolic and bleeding events in the group receiving dabigatran 150 mg [hazard ratio (HR) versus warfarin 0.90, 95% confidence interval (CI) 0.82–0.99, P ¼ 0.02]. Moreover, this analysis pointed out that onethird of MI events in the three groups occurred when patients were no longer taking the assigned study drug. The authors concluded that, despite a nonsignificant, dose-independent trend toward an increased risk of MI in patients receiving dabigatran, the rate of other myocardial ischemic events was similar between the groups and, importantly, there was an overall net benefit with dabigatran therapy across all subgroups of patients, including those with a previous MI. The results of the RE-LY study prompted the insertion of a warning in the 2010 Canadian Cardiovascular Society guidelines discouraging dabigatran administration in atrial fibrillation patients at high risk of coronary events.13 However, such statement was not included in the 2011 American College of Cardiology/American Heart Association/Heart Rhythm Society atrial fibrillation guidelines update.14 An update of the European Society of Cardiology (ESC) guidelines for the management of atrial fibrillation was published in 2012, stating that novel anticoagulants, such as dabigatran, apixaban, and rivaroxaban, have a better efficacy, safety and convenience profile compared with vitamin K antagonists, and therefore should be
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Dabigatran and myocardial infarction Giglio et al. 21
considered for most nonvalvular atrial fibrillation patients for whom anticoagulant therapy is indicated.15 However, some concerns exist relating to the absence of reliable and readily available laboratory tests examining the efficacy of anticoagulation to compliance issues and to specific clinical settings. It is crucial, therefore, to clarify the safety profile of each of these novel agents in different populations (e.g., CAD, chronic kidney disease and very elderly patients), in order to tailor anticoagulation therapy according to single-patient comorbidities, preferences and thrombotic/hemorrhagic risk factors.
Evidence from randomized controlled trials on dabigatran in acute coronary syndromes Up to date, only one multicenter, prospective, randomized, double-blind, placebo-controlled trial on dabigatran in acute coronary syndromes (ACS) has been completed. The Dabigatran versus Placebo in Patients With Acute Coronary Syndromes on Dual Antiplatelet Therapy (RE-DEEM) trial enrolled 1861 patients, 60% with ST elevation MI and 40% with non-ST elevation MI within the last 14 days, in 161 centers across 24 countries.16 Patients were considered for inclusion in the trial if they were at risk for cardiovascular complications following the acute events, that is, patients aged 65 years or more, with diabetes mellitus, previous MI, congestive heart failure, left ventricular ejection fraction less than 40% or moderate chronic renal insufficiency. The main exclusion criteria were conditions associated with increased risk of bleeding (major surgery within the last month, treatment with vitamin K antagonists or fibrinolytic drugs and a history of gastrointestinal bleeding), severe anemia or reduced platelet count, uncontrolled hypertension, severe congestive heart failure (New York Heart Association class IV) and renal insufficiency at stage 4 or 5. Almost all patients (99.2%) were receiving dual antiplatelet therapy with aspirin and clopidogrel or thienopyridine. Patients included in the study were randomized to receive dabigatran 50, 75, 110 or 150 mg twice daily or placebo for 6 months. The primary outcome of the trial was a composite of major or clinically relevant minor bleeding events. Secondary outcomes were reduction of cardiovascular ischemic events, including nonfatal MI, nonhemorrhagic stroke and cardiovascular death, and of D-dimer blood levels, which were considered as a surrogate indicator of the efficacy of the drug. At 6 months follow-up, a significant dose-dependent increase of major and minor bleeding events was recorded for patients receiving dabigatran. D-dimer levels were reduced with all doses of dabigatran compared with placebo, reflecting drug-induced reduction in thrombin generation. The number of patients reaching the secondary composite outcome of nonhemorrhagic stroke, nonfatal MI or cardiovascular death showed a trend toward a reduction in the two groups receiving the two highest doses of
dabigatran. However, separate analysis of the different components of the secondary composite outcome showed a reduction of nonhemorrhagic stroke events, whereas the number of patients experiencing nonfatal MI was higher in all dabigatran groups compared with placebo.
Evidence from randomized controlled trials of dabigatran for the prevention and treatment of venous thromboembolism Several studies have evaluated the efficacy and safety of dabigatran in the clinical setting of both short-term and long-term thromboprophylaxis after orthopedic surgery, and in the acute treatment of VTE. In the Dabigatran Etexilate versus Enoxaparin in Prevention of Venous Thromboembolism Following Total Hip Arthroplasty (RENOVATE) trial, a randomized, double-blind, noninferiority study, 3494 patients in 115 centers undergoing total hip replacement were randomly assigned to receive oral dabigatran 220 or 150 mg once daily, or subcutaneous enoxaparin 40 mg once daily.17 The median treatment duration was 33 days. The primary efficacy outcome was a composite of VTE occurrence and death from all causes, whereas the secondary efficacy outcomes were major VTE and VTE-related mortality, proximal deep-vein thrombosis and the single elements of the primary outcome. Bleeding events occurring during the treatment period constituted the primary safety outcome. Both doses of dabigatran were found noninferior to enoxaparin in the prevention of VTE, with a similar bleeding rate between the two drugs. Few acute coronary events were reported in this study during follow-up, with no difference between the groups. Analogous findings were reported by the RENOVATE II study,18 a randomized, double-blind, noninferiority trial comparing oral dabigatran at a 220 mg dose with subcutaneous enoxaparin 40 mg daily, administered for 28–35 days, for the prevention of VTE in patients undergoing total hip replacement. The Oral Dabigatran Etexilate versus Subcutaneous Enoxaparin for the Prevention of Venous Thromboembolism after Total Knee Replacement (RE-MODEL) study19 was a randomized, double-blind, noninferiority study comparing short-term therapy (6–10 days) with 220 or 150 mg daily oral dabigatran with subcutaneous to enoxaparin (40 mg once daily). In the RE-MODEL, a total of 2076 patients undergoing total knee replacement were randomized. The primary efficacy outcome was a composite of VTE events and death from all causes during study treatment, whereas the primary safety outcome was bleeding events. After a follow-up of 3 months, both doses of dabigatran were found to be noninferior to enoxaparin for the prevention of VTE, with similar bleeding rates. The incidence of acute coronary events (unstable angina, MI and cardiac death) was low and not statistically different between the groups, occurring in three and eight patients in the dabigatran group (220 and 150 mg, respectively) and in six patients in the enoxaparin group.
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22 Journal of Cardiovascular Medicine 2014, Vol 15 No 1
The Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism (RE-COVER) study20 evaluated the efficacy and safety of dabigatran versus warfarin in the treatment of acute VTE. RE-COVER was a randomized, double-blind, double-dummy trial with a noninferiority design, and included 2564 patients with acute VTE treated initially with parenteral anticoagulation therapy (median of 9 days), and then randomized to 6 months of therapy with either dabigatran 150 mg twice daily or adjusted-dose warfarin to achieve and maintain an INR value of between 2.0 and 3.0. The primary efficacy outcomes assessed in the RE-COVER study were symptomatic recurrence of VTE and VTE-related deaths. Bleeding events, ACS, liver enzyme elevation or other adverse events were investigated as safety endpoints. Dabigatran was found to be noninferior to warfarin for the primary efficacy outcomes, with a similar risk of recurrent VTE and VTE-related death between the two drugs. Major and minor bleeding, as well as other adverse events, did not differ between the two treatment groups. The occurrence of ACS and, specifically, of MI was also assessed during the 6 months of follow-up. Five patients (0.4%) in the dabigatran group and three patients (0.2%) in the warfarin group experienced an ACS, with four (0.3%) and two (0.2%) classified as MI, respectively. In line with the results of previous trials, the absolute number of events was very low, and the difference did not reach statistical significance. Given the low rate of the primary outcome found in this trial, a subsequent study with the same design and objectives but with a larger sample size was performed to confirm the results of the RE-COVER. The RE-COVER II study21 enrolled 2568 patients and yielded similar results, confirming the noninferiority of dabigatran compared with warfarin in the setting of acute VTE. As previously, in the RE-COVER II study, the absolute number of ACS events was higher in the dabigatrantreated group than in those receiving warfarin (five versus three ACS, respectively), but again the difference was not statistically significant. Another trial, the RE-MEDY,22 tested the efficacy and safety of dabigatran for the extended treatment of VTE (i.e., secondary prophylaxis), randomizing 2866 patients who had already received at least 3 months of full anticoagulation therapy for an acute episode of VTE, and who were considered to be at increased risk for recurrent VTE, to a further 6–36 months of therapy with dabigatran 150 mg twice daily or warfarin. The results of this trial confirmed the noninferiority of dabigatran compared with warfarin for the prevention of thromboembolic events, with a lower bleeding rate. However, the analysis of other safety endpoints showed a significant difference in ACS (MI or unstable angina) events rate between the 2 treatment groups, with 13 patients (0.9%) in the dabigatran group versus 3 patients (0.2%) in the warfarin group experiencing an ACS during follow-up (RR with
dabigatran 4.32; 95% CI 1.23–15.13). In this regard, it is important to point out that there were baseline differences in the distribution of cardiovascular risk factors between the two treatment arms, with a greater number of patients in the dabigatran group having diabetes, hypertension, or a previous history of CAD. Finally, another randomized, double-blind trial evaluating dabigatran efficacy and safety in post-VTE long-term treatment was the Twice-daily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the Long Term Prevention of Recurrent Symptomatic VTE (RE-SONATE) trial.23 Dabigatran 150 mg twice daily or placebo were administered in a blinded fashion to 1353 patients who had experienced a VTE or pulmonary embolism and completed 6–18 months of anticoagulant therapy. A significant reduction of recurrent thromboembolic events was obtained with dabigatran (HR 0.61; 95% CI 0.42– 0.88), and only two major bleeding events were reported. In contrast to the active-control study, in this case no difference was observed in ACS incidence between the two groups of treatment, with a single ACS event reported in each group.
Evidence from meta-analysis A recent meta-analysis on the possible association between dabigatran and a higher risk of cardiac ischemic events was performed by Uchino and Hernandez.24 Seven noninferiority randomized controlled trials (RCTs), including a total of 30 514 patients reporting on MI and ACS rates as secondary outcomes (PETRO,8 RE-LY,9,10 RE-COVER,20 RE-DEEM,16 RE-NOVATE,17 RENOVATE II,18 and RE-MODEL19), were included in the analysis. The primary outcomes of the meta-analysis were MI or ACS, whereas the overall mortality constituted the secondary outcome. The authors found that dabigatran was associated with a significantly higher risk of acute coronary events compared with controls; this association persisted when including either the original RE-LY results [odds ratio (OR) 1.33; 95% CI 1.03–1.71; P ¼ 0.03] or the revised ones (OR 1.27; 95% CI 1.00–1.61; P ¼ 0.05). The absolute increase in acute coronary events during followup was 0.27%. No interaction was found between the increased risk of ACS with dabigatran and baseline cardiovascular risk factors. However, the authors also reported a beneficial effect of dabigatran on all-cause mortality (dabigatran 4.83% versus control treatments 5.02%; OR 0.89; 95% CI 0.80–0.99; P ¼ 0.04), even if this was not the primary outcome of the meta-analysis. Overall, the results of this meta-analysis should be carefully interpreted, given the heterogeneity of the trials included and the dominant weight of the RE-LY in the pooled analysis, because of the larger sample size and the longer duration of follow-up. Furthermore, the absolute increase in risk of ACS with dabigatran, although statistically significant, was very small (0.27%), and the clinical relevance of this finding is unclear.24
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Randomized; OL for treatment; DB for dabigatran dose
Randomized; OL for treatment; DB for dabigatran dose, NI Randomized DB; parallel groups
PETRO5 (2007)
RE-LY6,7 (2009)
Randomized; DB, NI, parallel groups Randomized; DB, NI
Randomized; DB, DD, NI
RE-NOVATE II14 (2011)
RE-COVER16 (2009)
Randomized; DB, DD
Randomized; DB, NI; parallel groups Randomized DB parallel groups
RE-MEDY18,20 (2011) Extended secondary VTE prevention Extended secondary VTE prevention
Acute VTE
Acute VTE
Total knee replacement
Total hip replacement
Total hip replacement
ACS
AF
AF
Population
1343
2856
2568
2539
2076
2013
3463
1861
18 113
502
Population sizea
VTE and related deaths VTE and related deaths VTE and related deaths VTE and related deaths
VTE and death from all causes VTE and death from all causes
VTE and death from all causes
Major and minor bleedings
Stroke or systemic embolism
Bleedings
Primary outcome 50 mg (n ¼ 105); 150 mg (n ¼ 166); 300 mg (n ¼ 161); PO b.i.d., with or without ASA 110 mg (n ¼ 6015) 150 mg (n ¼ 6076); PO b.i.d. 50 mg (n ¼ 369); 75 mg (n ¼ 368); 110 mg (n ¼ 406); 150 mg (n ¼ 347); PO b.i.d. 220 mg (n ¼ 1146); 150 mg (n ¼ 1163); PO q.d. 220 mg (n ¼ 1010); PO q.d. 220 mg (n ¼ 679); 150 mg (n ¼ 703); PO q.d. 150 mg (n ¼ 1273); PO b.i.d. 150 mg (n ¼ 1279); PO b.i.d. 150 mg (n ¼ 1430); PO b.i.d. 150 mg (n ¼ 681); PO b.i.d.
Dabigatran treatment
Adj. dose warfarin (n ¼ 1266) Adj. dose warfarin (n ¼ 1289) Adj. dose warfarin (n ¼ 1426) Placebo (n ¼ 662)
Enoxaparin 40 mg (n ¼ 1003); s.c. q.d. Enoxaparin 40 mg (n ¼ 694); s.c. q.d.
Enoxaparin 40 mg (n ¼ 1154); s.c. q.d.
Placebo (n ¼ 371)
Adj. dose warfarin (n ¼ 6022)
Adj. dose warfarin (n ¼ 70)
Control treatment
6 months
6–36 months
6 months
6 months
28–35 (mean 32) days 6–10 days
28–35 (mean 33) days
6 months
2 years
3 months
Treatment duration
6 months
6–36 months
6 months
6 months
3 months
3 months
3 months
6 months
2 years
3 months
Follow-up duration
ACS, acute coronary syndromes; adj. dose, adjusted dose; AF, atrial fibrillation; ASA, acetylsalicylic acid; b.i.d., twice a day; DB, double-blind; DD, double-dummy; NI, noninferiority; OL, open label; PO, per os; q.d., once a day; s.c., subcutaneously; VTE, venous thrombo-embolism. a Number of patients randomized and who took at least one dose of the randomized drug.
RE-SONATE19,20 (2012)
RE-COVER II
(2011)
17
RE-MODEL15 (2007)
Randomized; DB, NI
RE-NOVATE13 (2007)
RE-DEEM12 (2011)
Design
Clinical trials on dabigatran
Trial
Table 1
Dabigatran and myocardial infarction Giglio et al. 23
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24 Journal of Cardiovascular Medicine 2014, Vol 15 No 1
Dabigatran and myocardial infarction: is there something missing? The higher rate of MI events in the dabigatran-treated patients compared with patients receiving other anticoagulant therapies or placebo found in noninferiority randomized trials was certainly unexpected. However, before accepting or denying the presence of such an association, several considerations have to be taken into account. In all the trials, the absolute number of myocardial ischemic events was low; therefore, possible differences between the groups are difficult to evaluate, and the results could be both exaggerated and underestimated through chance alone. Moreover, none of these trials was specifically designed to detect ischemic events. These considerations may raise concerns regarding the reliability of data indicating an increased risk of cardiac ischemic events with dabigatran. Nevertheless, the trend toward an increased rate of MI in patients receiving dabigatran remains quite consistent across different studies,10,22 in different clinical settings, and with different therapeutic regimens and follow-up periods; therefore, there seems to be a real indication that dabigatran might increase the risk of ACS, although the clinical relevance of this risk is still to be established. Although currently available data seem to indicate a possible relation between dabigatran and cardiac ischemic events, the possible biological mechanism underlying such an association is still unclear. Apparently, there is no logical reason why a compound with anticoagulant properties, such as dabigatran, should be associated with an increased rate of coronary plaque complication and instability. However, ximelagatran, one of the first developed direct thrombin inhibitors, has been associated with increased levels of several proinflammatory biomarkers in post-MI patients, thus suggesting that direct thrombin inhibition could have other side-effects possibly affecting atherosclerotic disease.25 However, there is no evidence at present that this hypothetical mechanism could be associated with dabigatran. Warfarin has a well-documented protective effect against the recurrence of ischemic events.26,27 Therefore, it has been proposed that the numerical excess of MIs observed Table 2
in patients receiving dabigatran, particularly in the RE-LY study, could be because of the loss of a warfarin-related beneficial effect rather than due to a direct harmful effect of dabigatran.12,28 This hypothesis is biologically plausible, as the inhibition of the synthesis of factor X, responsible for thrombin generation, could be more efficacious in mitigating the prothrombotic burst triggered by plaque rupture28 compared with the downstream selective inhibition of thrombin. Accordingly, no increase of ACS rate has been reported with factor Xa inhibitors when compared with warfarin.29 It has been recently demonstrated in vitro that warfarin is more effective than dabigatran in attenuating thrombin generation; this can be explained by the different mechanism of action of the two drugs. While warfarin blocks the production of functional coagulation factors VII, IX and X, and the generation of factor II prothrombin, the precursor of thrombin, thus affecting the initiation and amplification of thrombin generation, dabigatran is a stoichiometric inhibitor of thrombin. It is possible, therefore, that in the setting of the complicated coronary atherosclerotic plaque, in which high concentrations of thrombin are generated as a consequence of plasma contact with plaque components and tissue factor exposition, dabigatran concentration could be overcome by thrombin level.30 However, this hypothesis should be properly explored by directly comparing dabigatran with a real placebo (not warfarin). Thus far, there are only two randomized trials comparing dabigatran with placebo. In the RE-DEEM trial, a trend toward an increased risk of MI in the dabigatran arm has been reported. It should be noted, however, that as a phase II, dose-finding study, the RE-DEEM had low power for the evaluation of efficacy outcomes. In contrast, in the RE-SONATE trial no difference was reported between the groups receiving dabigatran or placebo with regard to the incidence of ACS, in the same clinical setting, but in comparing dabigatran with warfarin treatment, an increased number of acute cardiac events was again observed in the dabigatran group. These results seem to support the hypothesis that the greater number of events observed when comparing dabigatran with warfarin may be because of the greater and well established efficacy of warfarin in
Acute coronary events in dabigatran groups and controls
Trial PETRO5 (2007) RE-LY6,7 (2009) RE-DEEM12 (2011) RE-NOVATE13 (2007) RE-NOVATE II14 (2011) RE-MODEL15 (2007) RE-COVER16 (2009) RE-COVER II17 (2011) RE-MEDY18 (2011) RE-SONATE19 (2012)
ACE dabigatran group (no./patients treated)
ACE control group (no./patients treated)
2/432 195/12 091 32/1490 13/2309 1/1010 10/1382 4/1273 5/1279 13/1430 3/681
0/70 75/6022 4/371 9/1154 1/1003 4/694 2/1266 3/1289 3/1426 2/662
OR (95% CI) 0.79 1.30 2.01 0.72 0.99 1.26 1.99 1.68 4.35 1.46
(0.04–16.73) (0.99–1.71) (0.67–6.75) (0.29–1.83) (0.03–36.29) (0.39–4.02) (0.36–10.90) (0.35–8.87) (1.16–19.26) (0.20–12.49)
P value 0.56 0.05 0.18 0.28 0.49 0.69 0.68 0.47 0.01 0.68
ACEs, acute coronary events; CI, confidence interval; OR, odds ratio.
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Dabigatran and myocardial infarction Giglio et al. 25
preventing ACS recurrence, rather than to detrimental effects of dabigatran. At present, there is no conclusive evidence supporting an association between dabigatran etexilate and increased risk of MI. The meta-analysis performed by Uchino and Hernandez was intended to resolve the uncertainties on this topic, but, as mentioned, it was affected by several methodological limitations. The trials included in the analysis were very different with regard to the sample size, treatment doses and duration of follow-up. Furthermore, very different therapies (warfarin, enoxaparin, and placebo) were mixed together as ‘control’ treatment. Moreover, the results of the meta-analysis were heavily influenced by the inclusion of the RE-LY study, which alone accounted for 18 113 (59%) patients out of the total of 30 514, and for the majority (74%) of the events reported. Overall, more data are necessary to investigate the possible harm of dabigatran in increasing the risk of MI. Given the potentially wide field of application of this novel anticoagulant agent, this topic should be specifically investigated by properly designed clinical trials, re-evaluating the overall efficacy and safety profile of this drug especially in patients at high risk of cardiac ischemic events (Tables 1 and 2).
3
4
5
6
7
8
9
10
11
12
Conclusion Dabigatran etexilate is a potent oral direct thrombin inhibitor not requiring dose adjustment and INR monitoring, has low drug–drug and drug–food interactions, and is currently approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, and for VTE prophylaxis after orthopedic surgery. Some concerns about the safety profile of this drug, however, have arisen. In particular, an association with a higher risk of MI cannot be excluded on the basis of the current available evidence, although the evidence base is inconclusive for claiming an increased risk of MI in patients receiving dabigatran. Further properly designed studies are warranted to definitely assess the presence and the clinical relevance of such an association, and the risk–benefit profile of dabigatran in different populations of patients.
13
14
15
Acknowledgements None. Conflicts of interest
16
There are no conflicts of interest.
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