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Ideas and Opinions |

Dabigatran: Uncharted Waters and Potential Harms

Ryan P. Radecki, MD
[+] Article and Author Information

This article was published at www.annals.org on 29 May 2012.


From the University of Texas Health Science Center at Houston, Houston, Texas.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-2956.

Requests for Single Reprints: Ryan P. Radecki, MD, Department of Emergency Medicine, University of Texas Health Science Center at Houston, 6431 Fannin Street, JJL 450, Houston, TX 77030; e-mail, Ryan.P.Radecki@uth.tmc.edu.

Author Contributions: Conception and design: R.P. Radecki.

Analysis and interpretation of the data: R.P. Radecki.

Drafting of the article: R.P. Radecki.

Critical revision of the article for important intellectual content: R.P. Radecki.

Final approval of the article: R.P. Radecki.

Collection and assembly of data: R.P. Radecki.


Ann Intern Med. 2012;157(1):66-68. doi:10.7326/0003-4819-157-1-201207030-00467
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Dabigatran has received much attention after its approval for prevention of thromboembolic stroke in the setting of atrial fibrillation in the United States and for prevention and treatment of venous thromboembolism in Europe. This commentary discusses emerging reports of dabigatran-related adverse events, including bleeding and thromboembolic events, and unanticipated safety risks. The author urges physicians considering dabigatran for individual patients to be conservative in considering whether it is an appropriate replacement for warfarin.

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Letters

December 18, 2012
Patricio A. Pazmiño, MD, PhD
AIM. 2012;157(12):916  doi:10.7326/0003-4819-157-12-201212180-00016



December 18, 2012
Ryan P. Radecki, MD
AIM. 2012;157(12):916  doi:10.7326/0003-4819-157-12-201212180-00017



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Dabigatran Side Effects: Nephrological Perspective and Opinion
Posted on July 19, 2012
Patricio A. Pazmiño, MD, PhD, FACP, FASN
Nephrology, Internal Medicine and Hypertension (NIH) Center, E=1701 N. Mesa, El Paso Texas 79902-3503
Conflict of Interest: None Declared

 

 

 

I read with interest the article by Radecki 1 and agree with his concerns.  Some of the potential harms are due to dabigatran’s misuse for not approved indications, or use in populations that have not been well studied.  Dabigatran (Pradaxa®) approval in the USA   was based mostly on the results of the  RE-LY (Randomized Evaluation of Long Term Anticoagulation) trial on more than 18,000 patients.2      Unfortunately, this trial did not include patients with creatinine clearances of less than 30 ml/min/1.73 m2, a situation frequently present in the elderly and chronic kidney disease (CKD) patients stages 4 or 5. 

 

The FDA approved dabigatran’s use at usual doses of 150 mg po twice daily in patients with creatinine clearances of 15 to 30 ml/min/1.73m2.  This is in stark contrast to the guidelines in Canada, Europe, United Kingdom, Japan Australia, New Zealand where dabigatran use is contraindicated in CKD stage 4.3

 

Not surprisingly, flurries of reported side effects have emerged in the post marketing experience.3 In 2011, dabigatran accounted for 3,781 domestic serious adverse events (both manufactures and direct reports), including 542 patient deaths, hemorrhage (2,367 cases), acute renal failure (291) stroke (644), and suspected liver failure (15 cases)4

 

Thirteen months after dabigatran’s approval in the USA, Boehringer Ingelheim changed the dosages and product information guidelines3,5    It includes now a new dose of 75 mg twice daily5 for patients with creatinine clearance of 15-30 ml/min/1.73 m2

 

A creatinine clearance requires a 24 -hour urine collection and is a cumbersome test to obtain on a routine clinical situation3    Recently, Boehringer Ingelheim is promoting as an alternative, the use of a slide rule with the Cockcroft-Gault formula, described more than 35 years ago.      Nevertheless, a better option is to obtain a comprehensive metabolic panel (CMP) before and after the initiation of dabigatran.3    When a CMP is ordered, most laboratories in the USA now provide an estimated glomerular filtration rate (e-GFR) and   the stage of chronic kidney disease.     This facilitates the CKD staging and choosing the proper dose.

 

As far as the reversal of dabigatran anticoagulant activity, a useful choice to consider, in cases of dabigatran’s overdose is hemodialysis, which can  be done also without use of heparin.  Dabigatran is not protein bound and about 60%   is dialyzable with a 2-3 hour hemodialysis.3,5,  A nephrology consultant should be involved early on, as noted in recent case of successfully treated Dabigatran Associated Acute Renal Failure (DAARF).3

 

       Patricio A. Pazmiño PhD MD FACP FASN

       Nephrology, Internal Medicine & Hypertension (NIH) Center

       1701 N. Mesa, El Paso, TX 79902-3503

 

 

 

REFERENCES:

 

  1. Radecki RP. Dabigatran:  Uncharted Waters and Potential Harms. Ann  Intern  Med 2012;157:66-68.

.     2.  Connolly SI, 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;381(12):1139-1151.

     .3.  Pazmiño PA. Dabigatran Associated Acute Renal failure (DAARF).  El Paso Physician 2011; 34(6):7-9.  Abstract: Am J Kidney Dis 2012:59(4)A63:196.

      4.  Moore TJ, Furberg CD, Cohen MR. Anticoagulants The Leading Reported Drug Risk in 2011. May 31, 2012. New data from 2011, Quarters 3-4     Executive Summary. Annual Report Issue. QuarterWatch 2012. Alexandria, VA. Institute for Safe Medicine Practices; 2012.  URL: http://www.ismp.org/QuarterWatch/pdfs/May 31,2012.:

      5.  Pradaxa (Prescribing Information). Ridgefield, CT. Boehringer Ingelheim Pharmaceuticals Inc. November 2011.

 

 

Erratum Request
Posted on August 2, 2012
Seamus McMillan, PhD
Janssen Pharmaceuticals Inc.
Conflict of Interest: None Declared

Dear Sir

I write in regard to a recent article in Annals of Internal Medicine by Ryan P. Radecki, MD, "Dabigatran: uncharted waters and potential harms" published July 3rd, 2012, Volume 157, Number 1, page 66.
There is a sentence towards the bottom of the left column of the last page which reads:
"Rivaroxaban seems beneficial in the treatment of the acute coronary syndrome (18) but received a black-box warning in the approval process because of apparent prothrombotic effects after discontinuation of therapy."
This reads as if rivaroxaban has been approved for use in acute coronary syndrome with a black-box warning in the label. Unfortunately this is not correct.
May we therefore request publication of an Erratum at the earliest opportunity, noting the following specific points:

1. To date rivaroxaban (Xarelto(r)) has not been approved for use in acute coronary syndrome in any jurisdiction

2. The black-box warning is in regard to the approved indication of stroke prevention in patients with atrial fibrillation

3. The black-box warning was issued to address events occurring following withdrawal of anticoagulant therapy. There is no evidence for any intrinsic prothrombotic effect of rivaroxaban

If I can provide any further information please do not hesitate to let me know.

 Kind regards

Seamus McMillan, PhD
Scientific Director

Author's Response
Posted on August 22, 2012
Ryan P. Radecki, MD, Assistant Professor of Emergency Medicine
The University of Texas Health Science Center at Houston, 6431 Fannin St., JJL 450, Houston, TX 77030
Conflict of Interest: None Declared

I would like to thank Dr. Pazmiño for his insightful perspective regarding the contribution of renal insufficiency to the enhanced anticoagulant effect of dabigatran. Despite the favorable safety profile compared to warfarin demonstrated in the RE-LY (Randomized Evaluation of Long Term Anticoagulation) trial,[1] the exclusion of patients with impaired glomerular filtration rates reduces the external validity of their findings. This demonstrates a familiar principle in medical practice regarding observed discrepancies between efficacy in controlled trials and effectiveness in clinical practice.While I agree with theoretical utility of hemodialysis in the setting of dabigatran overdose, this reversal strategy is better suited towards reversal absent life-threatening bleeding.[3] Use of hemodialysis to control unanticipated, life-threatening, post-operative bleeding in a patient enrolled in RE-LY succeeded only with co-administration of 26 units of packed red cells, 22 units of fresh frozen plasma, 5 adult doses of platelets, 50 units of cryoprecipitate, protamine, and repeated administrations of high-dose recombinant Factor VIIa.[4] At my institution, one of the busiest trauma centers in the United States, the in-hospital mortality of trauma patients receiving oral direct thrombin inhibitors or Factor Xa inhibitors triples those receiving warfarin.(McCarthy JJ, personal communication, August 20, 2012) Prescribers should exercise extraordinary caution in their use of modern agents without viable emergency reversal strategies in the setting of life-threatening bleeding.

References

1. Connolly SI, 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;381(12):1139-1151.

2. Wanek MR, Horn ET, et al. Safe use of hemodialysis for dabigatran removal before cardiac surgery. Ann Pharmacother 2012;46[epub ahead of print] doi: 10.1345/aph.1R081

3. Warkentin TE, Margetts P, et al. Recombinant factor VIIa (rFVIIa) and hemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding. Blood 2012 Mar 1;119(9):2172-4.

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