Take-aways During the lifetime of a patient with AF on anticoagulation to reduce stroke risk, therapy will likely need to be interrupted for bleeding or medical procedures. The optimal approach to bridging therapy is unclear. As for the alternatives to warfarin, given the lack of antidote, there is concern that being on these agents might increase bleeding when surgery or invasive procedures are required. Interrupting anticoagulation is clearly not without danger and new data help to answer important questions relating to risk.

For AF patients on anticoagulant therapy, interrupting anticoagulation in the event of bleeding or a medical procedure is not uncommon. Unfortunately, there has been sparse evidence regarding just how to handle such interruptions. In the warfarin era, given that it is a long-acting agent, unfractionated heparin or a low-molecular-weight heparin might be used to bridge high-risk patients. In the modern era with short-acting orally active agents, what’s the best approach for bridging? And, for both warfarin and new alternatives, what’s the bleeding risk depending on time of anticoagulation discontinuation?

Michael D. Ezekowitz, MD, PhD, is a world-class leader in the evaluation of antithrombotic therapy. Dr. Ezekowitz led the first double-blind study of warfarin for stroke prevention in nonrheumatic AF and was a co-principal investigator of RE-LY, the pivotal study of dabigatran. Physicians, he said, are more influenced by events induced (bleeding) than events prevented (strokes). Consequently, he finds that the decision to use warfarin in nonvalvular AF is driven by perceived risks, such as intracerebral bleeds.

That’s not just an opinion. About half of all individuals with nonvalvular AF who are eligible for warfarin therapy do not receive it, leading Dr. Ezekowitz and colleagues to conduct a survey of physicians, who estimated off the top of their heads the annual rate of warfarin-associated intracerebral hemorrhage (ICH). The “guesstimates” were fairly consistent and tended to be more than 10-fold higher than literature-based estimates.

Not surprisingly physicians who estimated ICH risk much higher than data suggest were less likely to prescribe anticoagulation.¹ Specifically, there was no relationship between the perceived benefits of warfarin and its use, but the survey showed that perceived risk for warfarin-associated hemorrhage was strongly associated with reported warfarin use (p < 0.001).

Anticoagulation Interruptus

Although there has been little information to guide decisions regarding anticoagulation interruption, a 2004 study by Kovacs et al. illustrated the risk; the study showed higher than anticipated rates for both thrombotic and bleeding events when warfarin was stopped 5 days pre-procedure and replaced with dalteparin.²

In an effort to provide more contemporary data, subgroup analysis was conducted to assess outcomes in patients undergoing surgery or invasive procedures during the RE-LY trial. The new analysis was limited to first surgery or procedure per patient and the peri-procedural period evaluated was 7 days pre-procedure to 30 days post-procedure; 4,591 patients were included in this subanalysis.³ There was an even distribution of patients and surgery types across treatment arms, including dental, pacemaker-related, and cataract surgical procedures.

Warfarin was managed according to local practice. Dabigatran was withheld prior to the procedures: from December 2005 to August 2008, this was 24 hours pre-procedure for all patients; from August 2008 to March 2009, this was increased to 2–5 days (based on creatinine clearance) for high-risk procedures. After the procedure, dabigatran was restarted after achieving adequate homeostasis. Time from last anticoagulant dose to procedure was 49 hours for dabigatran (range = 35–85 hours) and 114 hours for warfarin (range = 87–144). Periprocedural bridging with heparin was used in 15.3% of the lower-dose dabigatran arm (110 mg twice daily), 17.0% of those in the higher-dose group (150 mg twice daily), and 28.5% of patients randomized to warfarin (p < 0.001).

In the overall trial, there was no significant difference in risk of bleeding regardless of dabigatran dose versus warfarin. There was a low incidence of thromboembolic events across all treatment groups (again no significant difference among the study groups). However, there was a significantly lower rate of bleeding with dabigatran (both doses) for patients undergoing surgery within 48 hours of anticoagulation disruption (TABLE).

Table 1
	% patients (n/N)			D110 vs. Warfarin		D150 vs. Warfarin
	D110	D150	Warfarin	RR (95% CI)	p Value	RR (95% CI)	p Value
<24 hrs	2.8 (5/180)	6.8 (13/192)	15.4 (12/78)	0.18 (0.007–0.50)	< 0.001	0.44 (0.21–0.92)	0.027
24–48 hrs	3.2 (16/505)	3.3 (17/520)	9.0 (8/89)	0.35 (0.16–0.80)	< 0.01	0.36 (0.16–0.82)	0.01
48–72 hrs	4.5 (14/310)	4.5 (14/309)	5.7 (71/122)	0.79 (0.33–1.90)	0.60	0.79 (0.33–1.91)	0.60
>72 hrs	4.7 (21/451)	6.2 (29/468)	3.6 (45/1,237)	1.28 (0.77–2.12)	0.34	1.70 (1.08–2.68)	0.02
p Trend				0.002		0.001

ROCKET AF

There have been concerns regarding increased bleeding risk in patients on alternatives to warfarin that do not have an antidote, plus there has been evidence suggesting a possible prothombotic state early after discontinuation of rivaroxaban. Recently, Patel et al. performed a post-hoc analysis of data from ROCKET AF regarding the risk of stroke or non–central nervous system (CNS) embolism within 30 days after temporary interruption of study drug, which was either warfarin or rivaroxaban.⁴

Stroke and non-CNS embolism occurred at similar rates after temporary interruptions, and after early permanent discontinuation. Patients transitioning to open-label therapy, usually warfarin at study’s end, had a higher rate of strokes if they were previously taking rivaroxaban, which likely reflects the longer time it took to achieve a therapeutic INR.

These results do not suggest a prothrombotic effect of discontinuation of rivaroxaban, but highlight the risk of interrupting therapeutic anticoagulation for this group of patients.

The paper, published in JACC, reported that roughly 60% of patients who had received warfarin during the trial had an INR ≥2.0 when next measured 3 days after trial end, and 81% had an INR ≥2.0 at least once in the 30-day post-trial period. In contrast, only about 25% of rivaroxaban patients had an INR ≥2.0 in the first 7–10 days after study end, and only 49% ever became therapeutic within 30 days.

Independent analysis of these data by the FDA corroborates that the quality of vitamin K antagonist anticoagulation in the rivaroxaban patients was poorer during this timeframe than in the warfarin patients—and also showed that the last recorded INR preceding end-of-study stroke events was subtherapeutic roughly two-thirds of the time.⁵

In an accompanying editorial, Matthew R. Reynolds, MD, MSc, said additional details will be needed to further understand these issues fully.⁶ “What is clearest from this important subanalysis of the ROCKET AF trial,” he wrote, “is that bad things will happen to high-risk AF patients if they are left untreated with effective anticoagulant therapy for sustained periods—and that in a population as large as this one, it does not take much time for those events to begin to accumulate.”

Bridging with unfractionated or low-molecular-weight heparin was raised as a consideration in the trial’s development, but was not mandated by the study protocol during either temporary interruptions or at the end of ROCKET AF. Subsequently, a black box warning was added to the labeling: Discontinuing rivaroxaban in patients with atrial fibrillation increases the risk of thrombotic events. According to Dr. Reynolds, “Although the black box warning may seem to single out rivaroxaban unfairly in delivering this message, it at least serves as a reminder that interruptions and transitions with short-acting anticoagulant drugs must be planned and managed carefully.”

Of course, defining what carefully means requires much more evidence than currently available. The bottom line, according to Dr. Ezekowitz: reduce time off of effective anticoagulation.

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References

1. Gross CP, Vogel EW, Dhond AJ, et al. Clin Ther. 2003;25:1750-64.
2. Kovacs MJ, Kearon C, Rodger M, et al. Circulation. 2004;110:1658-63.
3. Healey JS, Eikelboom J, Douketis J, et al. Circulation. 2012;126:343-8.
4. Patel MR, Hellkamp AS, Lokhnygina Y, et al. J Am Coll Cardiol. 2013;61:651-8. http://content.onlinejacc.org/article.aspx?articleid=1567632
5. United States Food and Drug Administration. FDA Draft Briefing Document for the Cardiovascular and Renal Drugs Advisory Committee (CRDAC). September 8, 2011. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM270796.pdf Accessed August 25, 2013.
6. Reynolds MR. J Am Coll Cardiol. 2013;61:659-60. http://content.onlinejacc.org/article.aspx?articleid=1567631

To listen to an interview with Michael D. Ezekowitz, MD, PhD, about bridging anticoagulation therapy, visit youtube.cswnews.org. The interview was conducted by Paul Sorajja, MD.

Keywords: Vitamin K, Stroke, Heparin, Low-Molecular-Weight, Dalteparin, Creatinine, International Normalized Ratio, Incidence, beta-Alanine, Benzimidazoles, Atrial Fibrillation, Homeostasis, Embolism, Cataract, United States, Cerebral Hemorrhage

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