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Three Part Question

In [patients with a history of venous thromboembolism], what is the [incidence of recurrent thromboembolism] in patients on [extended anticoagulation therapy compared to placebo]?

Clinical Scenario

A 48-year-old man with a history of pulmonary embolism (PE) and antiphospholipid antibody syndrome taking rivaroxaban presents to the ED with shortness of breath, hemoptysis, and pleuritic chest pain. Chest CT demonstrated multiple PEs. You wonder what is the incidence of recurrent venous thromboembolism (VTE) despite anticoagulation.

Search Strategy

Medline 1966-07/18 using PubMed, CINAHL, Cochrane Library (2018), and Embase
[(exp anticoagulants AND exp recurrent venous thromboembolism AND exp secondary prevention)]. Limit to English language.

Search Outcome

112 studies were identified; one systematic review from the Cochrane library addressed the clinical question. This review, published in 2017, analyzed six studies with a combined total of 3436 participants.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Robertson L, et al December 2017 United Kingdom	6 RCTs including patients initially treated with anticoagulants randomized to extended prophylaxis versus no prophylaxis or placebo	Systematic Review	Extended prophylaxis of any kind versus placebo in the prevention of VTE-related mortality and recurrent VTE using odds ratios (ORs)	Extended prophylaxis was no more effective than placebo in preventing VTE-related mortality (OR 0.98, P = 0.98); or recurrent VTE (OR 0.63, P = 0.07).	Included studies were low quality and involved several different agents; patient-level data were insufficient to perform subgroup analysis; and the time frame for measuring outcomes ranged from 9 - 37 months among studies. One study compared a DOAC (rivaroxaban) versus aspirin but mortality and safety data were not available.
			Incidence of major bleeding, all-cause mortality, and clinically relevant non-major bleeding	No differences in the rates of major bleeding (OR 1.84, P = 0.86), all-cause mortality (OR 1.00, P = 0.99), or clinically relevant non-major bleeding (OR 1.78, P = 0.30).
			Extended prophylaxis versus any other type of prophylaxis in the prevention of VTE-related mortality and recurrent VTE.	Rivaroxaban was associated with fewer recurrent VTEs than aspirin (OR 0.28, P = 0.0001).

Comment(s)

Most patients with VTE are anticoagulated for a finite period (3 to 12 months) following a first episode of thrombosis. Select patients at increased risk of recurrent thrombosis beyond the conventional period may benefit from extended anticoagulation. Anticoagulation is administered in this setting to reduce the lifetime risk of recurrent thrombosis and VTE-associated death. Oral therapeutic options for extended thromboprophylaxis include vitamin K antagonists, antiplatelet agents and direct oral anticoagulants (DOACs). This review found that trials are too few to demonstrate whether extended anticoagulation is safe and effective. Recurrent VTE despite therapeutic anticoagulation is rare (about 2%) and can occur regardless of the type of anticoagulant used. Further good-quality and large-scale studies are needed, especially involving DOACs such as rivaroxaban.

Clinical Bottom Line

Evidence is insufficient to permit definitive conclusions concerning the effectiveness and safety of extended thromboprophylaxis in prevention of recurrent VTE after initial oral anticoagulation therapy. At present, physicians must rely on their assessment of risk of recurrence (e.g., malignancy, antiphospholipid syndrome), the risk of bleeding and consider the patient’s preference.

References

1. Robertson L, Yeoh SE, Ramli A Secondary prevention of recurrent venous thromboembolism after initial oral anticoagulation therapy in patients with unprovoked venous thromboembolism Cochrane Database Syst Rev 2017 Dec 15;12:CD011088