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Dabigatran and Heart Valves

posted Dec 6, 2013, 11:42 AM by Ewa Rakowski
Brought to you by RAT resident Christopher Velez:

Has the Promise of a Post-Warfarin Era Been Broken? 

Earlier this year I took care of an elderly gentleman with atrial fibrillation who, on paper, looked like a perfect warfarin candidate. The only exception was his noncompliance with INR checks. When he was admitted with an INR value above 10, enough was enough: he was switched to rivaroxaban. He could not have been happier.

With the development of new oral anticoagulants (NOACs) over the past decade, there has been much excitement about the possibility of a “post-warfarin” era. We are all accustomed to the enthusiasm surrounding NOACs: warfarin is a burden for both patients and providers. Additionally, those patients who would derive the most benefit from warfarin are the same ones most likely to suffer from the side effects of anti-coagulation, especially elderly individuals with supra-therapeutic INRs. Given the relative ease of NOACs, there is an inertia driven both by the healthcare industry and patient preference to abandon worrisome warfarin completely.

For a while, this seemed possible. NOACs like dabigatran and rivaroxaban have obtained approval for a gradually growing list of conditions. It seemed inevitable that the indications for NOAC use would continue to multiply. This was until a study published in September looking at dabigatran in patients with mechanical valves dashed such hopes of a post-warfarin age.

What are NOACs?
I have noticed colleagues using terms like “direct thrombin inhibitors” interchangeably with NOACs and strictly speaking this is not correct. Currently approved NOACs have two mechanisms of action. Agents like dabigatran are true direct thrombin inhibitors. In contrast, rivaroxaban (and similar medications like apixaban) is a factor Xa inhibitor, not a direct thrombin inhibitor. They have the added benefit of a relatively rapid onset of action, unlike warfarin1.

When can we use NOACs?
Starting in 2008, regulatory agencies both in Europe and North America began to approve dabigatran and rivaroxaban for use in two sets of conditions: non-valvular atrial fibrillation and venous thromboembolic disease including pulmonary embolism. These indications were made as various articles (principally non-inferiority studies of NOACs in comparison to warfarin) were being published. These include: RE-LY (dabigatran in atrial fibrillation – 2009)2, RECOVER (dabigatran for venous thromboembolism – 2009)3, EINSTEIN (rivaroxaban in venous thromboembolism – 2010)4, and ROCKET-AF (rivaroxaban in atrial fibrillation – 2011)5.

When should NOACs be avoided?
First, those patients who should avoid the traditional anticoagulants due to a high risk of bleeding should also avoid NOACs. This was especially the case in the RE-LY trial, which demonstrated a higher risk of gastrointestinal bleeding. Undoubtedly, the inability to easily reverse NOAC therapy plays a role. Second, there have not been substantive trials examining the use of NOACs for other conditions where anticoagulation therapy is indicated, such as hypercoagulable states like anti-phospholipid syndrome. Finally, there was no significant trial supporting the use of NOACs in mechanical heart valves, which is why the RE-ALIGN trial was performed6.

How was the RE-ALIGN trial designed?
RE-ALIGN was an attempt to provide evidence similar to the RE-LY and RECOVER studies to allow for an expanded use of dabigatran including thromboembolic prophylaxis in patients with mechanical heart valves. In RE-ALIGN, two groups of patients were analyzed. One group consisted of patients with peri-operative mitral and aortic valve replacement, while the other group was defined by those patients who had undergone valve replacement more remotely. The primary endpoint was not non-inferiority; the study was designed to find the optimal dose of dabigatran using trough serum values. Given how effective NOACs are in atrial fibrillation and venous thromboembolic disease, it was reasonable to assume non-inferiority for dabigatran a priori (which was more of a secondary outcome in RE-ALIGN).

What did RE-ALIGN show?
The study was terminated prematurely, as there were three surprising “secondary” outcomes. First, dabigatran use in mechanical valves was associated with higher thromboembolic complications such as stroke when compared to warfarin. Second, even though the thromboembolic events occurred more often in the dabigatran arm, there was a higher risk of bleeding. Third, these events were not correlated to any specific trough level.

Will NOACs ever be approved for heart valves? Will warfarin live to fight another day?
RE-ALIGN represents the first time that the seemingly inevitable expansion of indications for NOACs has been halted. There were several problems with the study including small sample size and the over representation of peri-operative patients (who may have additional thrombotic risk factors). In addition, much work remains to determine whether NOACs can be used for other conditions like anti-phospholipid syndrome. It is also still possible with a different study design that NOACs will be found to be non-inferior to warfarin in patients with mechanical heart valves. However, in terms of the implications for clinical practice, it is unlikely in the near future that warfarin will go the way of treating patients with blood-letting to improve the balance of their humors.


References:

1) Garcia D, Libby E, Crowther MA. The new oral anticoagulants. Blood 2010; 115:15-20
2) Connolly SJ, Ezekowitz MD, Yusuf S et al. Dabigatran versus warfarin in patients with atrial fibrillation. New England Journal of Medicine 2009; 361:1139-51
3) Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. New England Journal of Medicine 2009; 361:2342-52
4) The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. New England Journal of Medicine 2010; 363:2499-510
5) Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. New England Journal of Medicine 2011; 365:883-91
6) Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. New England Journal of Medicine 2013; 369: 1206-14.
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Ewa Rakowski,
Dec 6, 2013, 11:42 AM
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Ewa Rakowski,
Dec 6, 2013, 11:42 AM
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Ewa Rakowski,
Dec 6, 2013, 11:42 AM
Ċ
Ewa Rakowski,
Dec 6, 2013, 11:42 AM
Ċ
Ewa Rakowski,
Dec 6, 2013, 11:42 AM
Ċ
Ewa Rakowski,
Dec 6, 2013, 11:42 AM
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