Getting Smart About Secondary Prevention of VTE: Practical Strategies for the Use of New Therapies CMEAlexander T. Cohen, MBBS, MD, MSc, FRACS

CME Released: 01/02/2013; Valid for credit through 01/02/2014Venous thromboembolism (VTE), comprising deep-vein thrombosis (DVT) and its complication pulmonary embolism (PE), is a common preventable disorder that affects both hospitalized as well as non-hospitalized patients. VTE is often clinically silent, and as a result its exact incidence is unknown, but an estimated 1 million individuals in the United States and over 1.5 million individuals in the European Union are believed to be affected by it annually.[1,2]Approximately two-thirds of VTE cases arise in institutionalized (during or in the 3 months following institutionalization) patients.[3] VTE is associated with significant mortality. Within a month of their diagnoses, approximately 12% of PE cases and 6% of DVT cases are fatal.[4] Most of the mortality associated with VTE is attributed to PE, which accounts for approximately 300,000 deaths in the United States annually.[5] PE is also a relatively common cause of preventable hospital deaths.[6,7] VTE is associated with long-term complications, including recurrent VTE, post-thrombotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension (CTEPH). About 40% of patients develop VTE recurrence within 10 years of their index event,[8] which contributes to the chronicity of this condition. PTS, characterized by pain, heaviness, swelling, cramps, itching, tingling in the affected limb, and venous ulceration in severe cases, develops in 20% to 60% of patients within 1 to 2 years of a symptomatic DVT.[9,10] CTEPH is less common than PTS, affecting up to 4% of patients within 2 years of a first episode of symptomatic PE, but is associated with significant morbidity and mortality.[11] In addition to affecting patient survival and quality of life, VTE also carries a substantial economic burden, costing the US health care system more than $1.5 billion/year.[12] Much of the cost of VTE is associated with managing the acute event; estimates indicate that an initial episode of DVT costs between $7712 to $10,804 to manage, whereas an initial PE event costs between $9566 to $16,644. However, the long-term complications of VTE are also associated with significant costs. A recurrent VTE event requiring hospitalization is estimated to cost $12,326.[13] Despite its substantial morbidity, mortality, and economic burden, VTE remains under-recognized and undertreated, and its prevention is suboptimal.[7,14,15] Increased effort is needed to raise awareness among healthcare providers on the appropriate treatment and prevention of VTE.

What percentage of your VTE patients has recurrent VTE?

0-10%

11-20%

21-30%

31-40%Save and Proceed

The management of VTE entails 2 phases: An acute treatment phase, which aims to stabilize the thrombus, and an extended-treatment phase, which aims to prevent thrombus recurrence. Unfractionated heparin (UFH), low-molecular weight heparin (LMWH), or fondaparinux are the mainstay treatments for the acute phase, although UFH is used less often due to its potential for toxicity.[16] Vitamin K antagonists (VKAs) and LMWHs are the current options for long-term treatment and prevention of VTE recurrence; both classes of drugs, however, have limitations which make the long-term use of these drugs challenging. Until recently, VKAs were the only oral anticoagulants approved for use in the long-term treatment of VTE in the United States. These drugs exert their antithrombotic effects by inhibiting multiple steps in the coagulation cascade. Warfarin is the most widely administered VKA, with over half a century of clinical experience. Despite its widespread use, warfarin is far from the ideal anticoagulant. It has a slow onset of action, a narrow therapeutic window, and multiple food and drug interactions that require frequent coagulation monitoring and dose adjustment.[17] Warfarin is not equally effective in all patients; in some patient groups, warfarin is associated with higher risks of recurrent VTE and major bleeding, for example, patients with active cancer. [18,19] In pregnant women, warfarin is contraindicated because of the risk for teratogenicity.[20] LMWHs are the preferred anticoagulant for long-term treatment and prevention of VTE recurrence in these patient groups. [21-24] LMWHs (eg, enoxaparin, dalteparin, and tinzaparin) have several advantages over VKAs. They are more specific, and they bind to antithrombin, thus inhibiting activated factor Xa primarily and thrombin to a lesser extent.[25] They also have a rapid onset and offset of action, predictable dose-response and drug-drug interactions, and in most circumstances, require no routine monitoring of anticoagulant effect.[26] However, the long-term use of LMWH for secondary prophylaxis is mainly limited by its parenteral route of administration. Several lines of evidence suggest a possible role for antiplatelet therapies, particularly aspirin, in secondary prevention of VTE. Platelet activation and recruitment plays a critical role in the formation and propagation of venous thrombi;[27-29] patients with VTE have increased levels of markers of platelet activation;[30,31] and in clotting blood, aspirin has been shown to inhibit thrombin formation.[32] The concept was tested in primary VTE prophylaxis in a placebo-controlled, randomized trial (Pulmonary Embolism Prevention [PEP] trial) among patients with hip fracture (N=13,356) and lower limb arthroplasty (N=4088).[33]Aspirin therapy at a dose of 160 mg daily was started preoperatively and continued for 35 days. Among hip fracture patients, aspirin prophylaxis resulted in a significant 43% proportional reduction of PE (P=.002), a 29% proportional reduction of symptomatic DVT (P=.03), and an overall 36% proportional reduction of VTE (P=.0003). The proportional effects of aspirin, however, did not differ significantly from placebo among arthroplasty patients. Furthermore, unlike similar studies with anticoagulants, there was no reduction in total mortality with aspirin. Despite these shortcomings, the study did demonstrate that aspirin reduces the risk of PE or DVT by about a third when all randomized patients were considered (34%; P=.0003). Based on the encouraging results from the PEP trial, 2 placebo-controlled trials, WARFASA and ASPIRE, evaluated the possibility of using low-dose aspirin (100 mg daily) for the long-term prevention of recurrent symptomatic VTE after initial oral anticoagulation therapy in patients with first-ever unprovoked VTE. In WARFASA (N=402), low-dose aspirin therapy administered over a median period of 24 months resulted in a significant 42% annual reduction of VTE recurrence compared with placebo (6.6% vs 11.2% per year; hazard ratio [HR] with aspirin, 0.58; 95% confidence interval [CI], 0.36 to 0.93; P=.02).[34] There was no difference in the incidence of major or clinically relevant nonmajor bleeding between the groups. The rate of major bleeding was about 0.3% per patient-year in both groups.

In ASPIRE (N=822), aspirin treatment over a median period of 37.2 months reduced VTE recurrence annually by 26% compared with placebo, but the reduction did not reach statistical significance (6.5% vs 4.8% per year; HR with aspirin, 0.74; 95% CI, 0.52 to 1.05; P=.09).[35] However, aspirin therapy significantly reduced the rates of major vascular events; the rates of VTE, myocardial infarction (MI), stroke, or cardiovascular death was reduced by 34% (5.2% vs 8.0% per year; HR with aspirin, 0.66; 95% CI, 0.48 to 0.92; P=.01) and the rate of VTE, MI, stroke, major bleeding, or death from any cause was reduced by 33% (HR, 0.67; 95% CI, 0.49 to 0.91; P=.01). Rates of major or clinically relevant nonmajor bleeding episodes were similar between the groups (1.1% vs 0.6% per year, P=.22). Although the failure of ASPIRE to show a significant reduction of VTE recurrence with aspirin may call into question the role of aspirin in VTE secondary prevention, it should be noted that this trial was underpowered to show a significant difference in the primary outcome because of lower than planned enrollment of patients. [35] As WARFASA and ASPIRE had a similar study design, a prospectively planned combined analysis was amenable. The combined analysis demonstrated that aspirin reduces the rate of VTE recurrence and major vascular events by a third (VTE recurrence, 32%, reduction, P=.007; major vascular events, 34% reduction, P=.002). Furthermore, these reductions were achieved without compromising bleeding. Although the combined results of WARFASA and ASPIRE are impressive, VTE risk reduction with aspirin is about 2-to 3-fold less than that observed with anticoagulants (warfarin as well as the newer anticoagulants). [36,37] Warfarin and the newer anticoagulants, however, are associated with an increased risk of bleeding.[3639] Warfarin is associated with an approximately 2.4% annual risk of major bleeding,[38] whereas the annual risk of major bleeding with low-dose aspirin is 0.3%.[34] Although further trials are needed to confirm the efficacy and safety of aspirin, it could potentially represent a low-cost, population-level strategy for secondary prevention of VTE. Current guidelines do not advocate the use of aspirin or antiplatelet agents for the secondary prevention of VTE. [23] Given the limitations of currently available anticoagulants and equipped with an improved understanding of the molecular mechanisms of coagulation and thrombosis, newer antithrombotic agents have been developed or are in development for the primary and secondary prevention as well as treatment of VTE.[40] Treatment and secondary prevention trials of some of these agents are briefly reviewed here.

RivaroxabanRivaroxaban is a direct factor Xa inhibitor that selectively and reversibly inactivates free and clot-associated factor Xa and prothrombinase activity. After oral administration, rivaroxaban is rapidly absorbed, achieving maximal plasma concentrations within 2 to 4 hours with a bioavailability of 80% and a half-life of up to 9 hours in healthy young subjects and 12 to 13 hours in healthy elderly subjects.[41] Rivaroxaban has a dual mode of elimination; one-third is eliminated unchanged in the urine mainly via active renal secretion and the other twothirds are metabolized in the liver via CYP3A4, CYP2J2, and CYP-independent mechanisms. Approximately half of the metabolites are eliminated by the hepatobiliary route in the feces and the other half eliminated in the urine.[42] Rivaroxaban has been approved in the United States for the prevention of VTE after elective total hip or knee replacement,[43] based on the RECORD studies,[44-47] and for reducing the risk for stroke and systemic embolism in patients with nonvalvular atrial fibrillation,[48] based on the ROCKET AF study.[49] In early November, rivaroxaban received approval for the treatment and secondary prevention of VTE based on the results of 3 Phase 3 trialsEINSTEIN-DVT, EINSTEIN-PE, and EINSTEIN-Extension.[37,50,51] EINSTEIN-DVT is a noninferiority study that compared rivaroxaban 15 mg twice-daily for 3 weeks followed by 20 mg once-daily with standard therapy (enoxaparin followed by dose-adjusted VKA [INR 2-3]) for 3, 6, or 12 months in patients with acute symptomatic DVT.[37] Treatment with rivaroxaban was noninferior to enoxaparin/VKA in preventing recurrent VTE, the primary outcome measure (Table 1). Bleeding event rates were similar between the groups. All-cause mortality was lower and net clinical benefit (defined as venous thromboembolism plus major bleeding) was significantly lower, favoring rivaroxaban.

EINSTEIN-PE had a similar study design to EINSTEIN-DVT, except that it enrolled patients with acute symptomatic PE with or without DVT.[50] The results again showed the noninferiority of rivaroxaban to standard therapy in preventing VTE recurrence (Table 1). Although there was no difference in major or clinically relevant nonmajor bleeding between the groups, major bleeding was significantly lower with rivaroxaban with clinically significant reductions in critical site bleeding (0.3% vs 1.1%). All-cause mortality and net-clinical benefit were similar between the treatment groups. EINSTEIN-Extension is a placebo-controlled superiority trial that assessed extended treatment with rivaroxaban 20 mg once-daily in patients with symptomatic DVT or PE who had already received 6 to 12 months of treatment with rivaroxaban or VKA therapy.[51] Extended treatment with rivaroxaban proved to be superior to placebo with an 82% relative risk reduction in the recurrence of VTE (Table 1). The rate of major bleeding for the rivaroxaban group was low and nonstatistically significant, but the rate of major or clinically relevant nonmajor bleeding was significantly elevated with rivaroxaban. Table 1. Main Efficacy and Safety Outcomes With Rivaroxaban for the Treatment and Secondary Prevention of VTE

Outcome EINSTEIN-DVT37 Primary, efficacy HR 95% CI P valu e Bleeding 0.68 0.44-1.04 Noninferiority,