0
Commentary |

The Association of Direct Thrombin Inhibitor Anticoagulants With Cardiac ThrombosesDirect Thrombin Inhibitors and Cardiac Thromboses FREE TO VIEW

Bruce L. Davidson, MD, MPH, FCCP
Author and Funding Information

From the Division of Pulmonary and Critical Care Medicine, University of Washington School of Medicine, Seattle WA.

CORRESPONDENCE TO: Bruce L. Davidson, MD, MPH, FCCP, 12209 Shorewood Dr SW, Burien WA 98146; e-mail: brucedavidson@pobox.com


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(1):21-24. doi:10.1378/chest.14-2028
Text Size: A A A
Published online

Direct thrombin inhibitor (anti-factor IIa) anticoagulants such as dabigatran and bivalirudin, now established for treatment and prevention of cardiac thromboembolism and VTE, have been repeatedly associated with a significantly increased frequency of thrombosis on abnormal cardiac endothelium when compared head-to-head with indirectly acting therapeutic anticoagulants in studies of sufficient patient number and duration. Although there is uncertainty as to the mechanism, the weight of evidence as a class effect warrants prescribing effective anticoagulants other than direct thrombin inhibitors.

Although no mechanism has been proven, the apparent paradoxical association of administering direct thrombin inhibitor anticoagulants with developing cardiac thromboses is being reported repeatedly. Their guilt appears undeniable.

The direct thrombin inhibitor anticoagulants bivalirudin, dabigatran, argatroban, desirudin, and lepirudin are indicated for therapeutic or prophylactic antithrombotic use. However, when clinical trials of substantial duration and patient number have compared a direct thrombin inhibitor to another active anticoagulant, there has been an unmistakable signal for increased myocardial infarction and/or ischemia, or coronary stent or cardiac valve thrombosis.

For bivalirudin, there are three such trials. Compared with IV unfractionated heparin usually given with a glycoprotein IIb/IIIa inhibitor, bivalirudin, administered for cardiac ischemia during transport to primary percutaneous coronary intervention,1 was found to be associated with 6.1 times the risk of definite stent thrombosis in the first 24 h (95% CI, 1.4-27.2; P = .007; number needed to harm [NNH] = 111), despite continued administration of IV bivalirudin 4 h after the procedure ended and the coadministration of a potent oral platelet inhibitor to most of the patients. A previous trial2 of bivalirudin found 5.3 times the risk of stent thrombosis in the first 24 h (95% CI, 1.80-15.3; P = .001; NNH = 100) compared with unfractionated heparin. Just published online3 was the third randomized trial comparing bivalirudin with unfractionated heparin in primary percutaneous coronary intervention, in which the excess stent thrombosis rate with bivalirudin was 3.3 (95% CI, 1.3-8.1; P = .007; NNH = 50.)

A large database from many comparative clinical trials in several indications is available for assessing the cardiac thrombosis risk associated with dabigatran, compared with well-controlled warfarin treatment. It points in the same direction: Recipients of dabigatran had more cardiac ischemic and thrombotic events. In the > 18,000-patient trial comparing two dosage regimens of dabigatran with warfarin to prevent embolic complications in atrial fibrillation, dabigatran was associated with 1.38 and 1.35 times the risk of myocardial infarction compared with warfarin for the 150 mg bid and 110 mg bid dabigatran regimens (P = .05 and .07, NNH = 476 and 526, respectively).4 The lower dosage is not approved in the United States. A correction5 published later by the authors declaring they undercounted heart attacks (by 32) and also embolic events (by four) and major bleeds (by 68 or 69) edged the increased heart attack risk just into statistical insignificance. In acute VTE treatment, where acute coronary syndrome while taking active anticoagulant therapy was uncommon, the pooled odds for two clinical trials6,7 of acute coronary syndrome for patients receiving dabigatran vs warfarin was 1.8 (95% CI, 0.6-6.2; NNH = 313) but nonsignificant, with only 747 patients receiving dabigatran and 692 receiving warfarin in the first, and 976 and 952, respectively, in the second, completing 6 months of anticoagulant therapy.

In a comprehensive review of individual patient data from atrial fibrillation and VTE clinical trials, scientists from dabigatran’s sponsor, Boehringer-Ingelheim GmbH, concluded “the rate of myocardial infarction with well-controlled warfarin (for stroke prevention in patients with atrial fibrillation and acute VTE treatment or secondary VTE prevention) is lower than with dabigatran 150 mg twice daily”(OR, 1.4 [95% CI, 1.1-1.9] for 150 mg bid and OR, 1.3 [95% CI, 0.96-1.8] for 110 mg bid.8

Subsequent dabigatran clinical trials have provided more evidence of this direct thrombin inhibitor’s association with thrombosis on abnormal cardiac endothelium. On-treatment myocardial infarction occurred in 13 patients receiving dabigatran vs three patients receiving warfarin, all receiving extended anticoagulant treatment after VTE (OR 4.3; 95% CI, 1.2-15.2; P = .02; NNH = 143).9 This trial had > 1,400 patients per treatment group; these differences did not emerge in trials with fewer patients or when dabigatran was compared with placebo in a similar population.9 A clinical trial10 comparing dabigatran with warfarin for patients with mechanical heart valves was stopped prematurely because of a high rate of adverse events in those receiving dabigatran, including stroke presumably related to valve thrombosis (nine events vs zero events; P = .03; NNH = 20).

Argatroban, lepirudin, and desirudin are each direct thrombin inhibitors marketed in various venues for treatment of heparin-induced thrombocytopenia (HIT). Desirudin is also sold for thromboprophylaxis in hip replacement surgery. Because large numbers of patients with HIT cannot be accumulated for clinical trials, the treatment studies used historical control subjects. Of course, the patients with HIT were highly prothrombotic. Ruling in or out a small but significant increase in cardiac thrombosis associated with those drugs from those studies cannot be done.

Historically, from two clinical trials reported together11 of the oral direct thrombin inhibitor ximelagatran compared with injected anticoagulant followed by warfarin for acute DVT with or without pulmonary embolism, there was an increased odds of acute coronary syndrome with ximelagatran treatment (OR, 10.1; 95% CI, 1.3-79; P = .006; NNH = 124). A meta-analysis that included ximelagatran and dabigatran (as well as other antithrombotic drugs) for atrial fibrillation suggested warfarin provided superior protection against myocardial infarction compared with the two oral direct thrombin inhibitors.12

Why should direct thrombin inhibitors be associated with higher cardiac thrombotic risk than warfarin or heparin? Authors of the heart valve study10 speculated that the combination of tissue factor- and contact activation-generated thrombin might overwhelm a pharmacokinetically controlled dabigatran level. Ex vivo, plasma samples from warfarin-administered patients generated lower peak thrombin levels than those from dabigatran-administered patients.13 What is known is that both vitamin K antagonists like warfarin as well as heparin indirectly inhibit thrombin but also inhibit other clotting factors. To date, no increase in cardiac thromboses for direct (eg, rivaroxaban, apixaban) and indirect (eg, fondaparinux) specific inhibitors of activated factor X is evident in their many published active-comparator-controlled clinical trials.

Physicians now have at least one sound alternative (injected unfractionated and low-molecular-weight heparins, oral vitamin K antagonists, and factor Xa inhibitors) to using direct thrombin inhibitors for percutaneous coronary intervention, for the prevention of systemic embolism in patients with atrial fibrillation, for patients with mechanical heart valves, for patients with acute or chronic DVT or pulmonary embolism, for perioperative thromboprophylaxis, and even for patients without renal function compromise who have HIT—injected fondaparinux appears highly effective for HIT,14 although the direct thrombin inhibitor argatroban, but not fondaparinux, has regulatory approved for HIT treatment.

Proponents of direct thrombin inhibitors point out that overall mortality rates were not higher than those of the comparator in these trials, but this is explained readily. In the current era, myocardial infarction uncommonly results in death within a few-year time frame, especially in patients under surveillance in industry-sponsored clinical trials with ready access to study center resources like physician-investigators and study coordinators. For example, lower myocardial infarction mortality rates in participants in clinical trials compared with registry participants occur because the former are more likely to receive guideline-recommended medications proven to reduce mortality.15 Heart wall damage, like kidney damage, is a burden that becomes clinically manifest over longer periods in the presence of comorbidities. Excess myocardial infarctions are not innocuous, even if they do not lead promptly to death.

Diminishing or ceasing altogether bivalirudin and dabigatran prescriptions would have far-reaching implications for patients, doctors, and sponsors. For 2013, bivalirudin’s sponsor reported $608 million net from bivalirudin sales, $550 million of that from the United States. For 2013, dabigatran’s sponsor reported $1.6 billion net from dabigatran sales. Roughly one-half of that was from the United States, with > 40,000 dabigatran US prescriptions reportedly filled every week. Revenues from these drugs support advertisements in many peer-reviewed medical journals, medical society annual meetings, smaller-scale educational activities, key physician opinion leaders, and clinical trial investigators.

Other than for patients with HIT and renal insufficiency for whom IV argatroban could be a good therapeutic choice, are there other patients who should receive a direct thrombin inhibitor? How does a conscientious doctor balance benefit with risk in this instance? The myocardial infarction risk for a patient with an acute coronary syndrome likely exceeds that of a patient with DVT contemplating continued anticoagulant therapy but in each instance, the cardiac thrombosis risk is likely higher than with comparator therapy. Is there a precedent in medicine for continuing to prescribe a drug confirmed by its sponsor’s scientists to be associated with a significantly higher risk of myocardial infarction than comparator therapy, when comparator therapy is readily available at similar or reduced expense and convenience? Bleeding risk with a direct thrombin inhibitor was lower than the comparator in some clinical trials, but that can be patient, protocol, and adjudicator dependent and may also be lower with safe administration of an anti-factor Xa drug or home-managed warfarin.16 Young patients without risk for coronary disease may escape myocardial infarction during direct thrombin inhibitor treatment of acute VTE, but unless important financial considerations tip the judgment that way, why should they face a possibly increased risk? Other than in the exceptional circumstances noted above, physicians should avoid prescribing direct thrombin inhibitors.

Financial/nonfinancial disclosures: The author has reported to CHEST the following conflicts of interest: In the past 3 years, Dr Davidson has received consultant payments for serving on steering committees for VTE trials of rivaroxaban (Bayer/Janssen Pharmaceuticals, Inc) and edoxaban (Daiichi Sankyo, Inc) and on advisory boards for both drugs.

HIT

heparin-induced thrombocytopenia

NNH

number needed to harm

Steg PG, van ’t Hof A, Hamm CW, et al; EUROMAX Investigators. Bivalirudin started during emergency transport for primary PCI. N Engl J Med. 2013;369(23):2207-2217. [CrossRef] [PubMed]
 
Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med. 2008;358(21):2218-2230. [CrossRef] [PubMed]
 
Shahzad A, Kemp I, Mars C, et al. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial [published online ahead of print July 5, 2014]. Lancet. doi:10.1016/S0140-6736(14)60924-7.
 
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(12):1139-1151. [CrossRef] [PubMed]
 
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(19):1875-1876. [CrossRef] [PubMed]
 
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(24):2342-2352. [CrossRef] [PubMed]
 
Schulman S, Kakkar AK, Goldhaber SZ, et al; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7):764-772. [CrossRef] [PubMed]
 
Clemens A, Fraessdorf M, Friedman J. Cardiovascular outcomes during treatment with dabigatran: comprehensive analysis of individual subject data by treatment. Vasc Health Risk Manag. 2013;9:599-615. [CrossRef] [PubMed]
 
Schulman S, Kearon C, Kakkar AK, et al; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368(8):709-718. [CrossRef] [PubMed]
 
Eikelboom JW, Connolly SJ, Brueckmann M, et al; RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369(13):1206-1214. [CrossRef] [PubMed]
 
Fiessinger JN, Huisman MV, Davidson BL, et al; 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(6):681-689. [CrossRef] [PubMed]
 
Lip GY, Lane DA. Does warfarin for stroke thromboprophylaxis protect against MI in atrial fibrillation patients? Am J Med. 2010;123(9):785-789. [CrossRef] [PubMed]
 
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(2):295-301. [CrossRef] [PubMed]
 
Warkentin TE, Davidson BL, Buller HR, et al. Prevalence and risk of preexisting heparin-induced thrombocytopenia antibodies in patients with acute VTE. Chest. 2011;140(2):366-373. [CrossRef] [PubMed]
 
Bahit MC, Cannon CP, Antman EM, et al; TIMI 9 Trial and TIMI 9 Registry. Thrombolysis In Myocardial Infarction. Direct comparison of characteristics, treatment, and outcomes of patients enrolled versus patients not enrolled in a clinical trial at centers participating in the TIMI 9 Trial and TIMI 9 Registry. Am Heart J. 2003;145(1):109-117. [CrossRef] [PubMed]
 
Heneghan C, Ward A, Perera R, et al; Self-Monitoring Trialist Collaboration. Self-monitoring of oral anticoagulation: systematic review and meta-analysis of individual patient data. Lancet. 2012;379(9813):322-334. [CrossRef] [PubMed]
 

Figures

Tables

References

Steg PG, van ’t Hof A, Hamm CW, et al; EUROMAX Investigators. Bivalirudin started during emergency transport for primary PCI. N Engl J Med. 2013;369(23):2207-2217. [CrossRef] [PubMed]
 
Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med. 2008;358(21):2218-2230. [CrossRef] [PubMed]
 
Shahzad A, Kemp I, Mars C, et al. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial [published online ahead of print July 5, 2014]. Lancet. doi:10.1016/S0140-6736(14)60924-7.
 
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(12):1139-1151. [CrossRef] [PubMed]
 
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(19):1875-1876. [CrossRef] [PubMed]
 
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(24):2342-2352. [CrossRef] [PubMed]
 
Schulman S, Kakkar AK, Goldhaber SZ, et al; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7):764-772. [CrossRef] [PubMed]
 
Clemens A, Fraessdorf M, Friedman J. Cardiovascular outcomes during treatment with dabigatran: comprehensive analysis of individual subject data by treatment. Vasc Health Risk Manag. 2013;9:599-615. [CrossRef] [PubMed]
 
Schulman S, Kearon C, Kakkar AK, et al; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368(8):709-718. [CrossRef] [PubMed]
 
Eikelboom JW, Connolly SJ, Brueckmann M, et al; RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369(13):1206-1214. [CrossRef] [PubMed]
 
Fiessinger JN, Huisman MV, Davidson BL, et al; 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(6):681-689. [CrossRef] [PubMed]
 
Lip GY, Lane DA. Does warfarin for stroke thromboprophylaxis protect against MI in atrial fibrillation patients? Am J Med. 2010;123(9):785-789. [CrossRef] [PubMed]
 
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(2):295-301. [CrossRef] [PubMed]
 
Warkentin TE, Davidson BL, Buller HR, et al. Prevalence and risk of preexisting heparin-induced thrombocytopenia antibodies in patients with acute VTE. Chest. 2011;140(2):366-373. [CrossRef] [PubMed]
 
Bahit MC, Cannon CP, Antman EM, et al; TIMI 9 Trial and TIMI 9 Registry. Thrombolysis In Myocardial Infarction. Direct comparison of characteristics, treatment, and outcomes of patients enrolled versus patients not enrolled in a clinical trial at centers participating in the TIMI 9 Trial and TIMI 9 Registry. Am Heart J. 2003;145(1):109-117. [CrossRef] [PubMed]
 
Heneghan C, Ward A, Perera R, et al; Self-Monitoring Trialist Collaboration. Self-monitoring of oral anticoagulation: systematic review and meta-analysis of individual patient data. Lancet. 2012;379(9813):322-334. [CrossRef] [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
Guidelines
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543