Getting Smart About Secondary Prevention of VTE: Practical Strategies for the Use of New Therapies CME

Alexander T. Cohen, MBBS, MD, MSc, FRACS

CME Released: 01/02/2013; Valid for credit through 01/02/2014

Venous 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.

Rivaroxaban
Rivaroxaban 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, <.001

EINSTEIN-PE50 EINSTEIN-Extension51

1.12 0.75-1.68 Noninferiority, . 003

0.18 0.09-0.39 Superiority,.001

Major or clinically relevant nonmajor HR 95% CI P valu e Major HR 95% CI P valu e 0.65 0.33-1.30 .21 0.49 0.31-0.79 .003 .11 Not-estimable* 0.97 0.76-1.22 .77 0.90 0.76-1.07 .23 5.19 2.3-11.7 <.001

All-cause Mortality HR 95% 0.67 0.44-1.02 1.13 0.77-1.65 Not-estimable

CI Pvalue .06 .53

Net Clinical Benefit HR 95% CI P valu e 0.67 0.47-0.95 .03 0.85 0.63-1.14 .28 NR

*There were 4 major bleeds (0.7%) in the rivaroxaban group vs none in the placebo group. There was 1 death (0.2) in the rivaroxaban group vs 2 (0.3) in the placebo group. Venous thromboembolism plus major bleeding

Dabigatran Etexilate
Dabigatran etexilate is a specific, potent, direct, and reversible thrombin inhibitor. A prodrug, it is rapidly transformed into its active metabolite dabigatran following oral administration by a mechanism independent of the CYP450 enzymes and other oxidoreductases.[52] Peak plasma concentrations of dabigatran are reached within 2 hours of oral administration.[53] The bioavailability of dabigatran, however, is low (6-7%).[52] The halflife of dabigatran is 14 to 17 hours in healthy subjects.[53] Dabigatran undergoes predominantly renal elimination. More than 80% of systemically available dabigatran is excreted in the urine, 77% as unchanged dabigatran.[52] Dabigatran etexilate has received approval In Europe for the primary prevention of VTE events in adult patients who have undergone elective total hip or knee replacement surgery in Europe (2008) based on positive data from the RE-MODEL[54] and RE-NOVATE[55] trials, respectively. In the United States, dabigatran etexilate was approved in 2010 for use in patients with nonvalvular atrial fibrillation to reduce the risk for stroke and systemic embolism,[56] based on data from the RE-LY trial.[57] The efficacy and safety of dabigatran etexilate in the treatment and secondary prevention of VTE have been evaluated in 4 phase 3 trials (RE-COVER, RE-COVER II, RE-MEDY, and RE-SONATE).[36, 58-60] RE-COVER and RE-COVER II are identical trials that compared dabigatran etexilate 150 mg twice daily with dose-adjusted warfarin (to achieve an international normalization ratio [INR] of 2-3) for 6-month treatment of acute symptomatic VTE after initial treatment with parenteral anticoagulation for 5 to 10 days.[58,59] In both trials, dabigatran etexilate was found to be noninferior to warfarin for the primary outcome of 6-month incidence of recurrent symptomatic, objectively confirmed VTE and death associated with VTE (Table 2). Bleeding events were comparable or lower with dabigatran etexilate. The incidence of death and acute coronary events was similar between the groups. RE-MEDY is a secondary prevention trial that evaluated extended treatment with dabigatran etexilate. [60] Patients with acute symptomatic VTE were treated with dabigatran etexilate 150 mg twice daily or warfarin (INR 2-3) for 6 to 36 months, after being treated with standard doses of an approved anticoagulant for 3 to 12 months. Similar to the RE-COVER trials, dabigatran etexilate was shown to be noninferior to warfarin in preventing recurrent VTE and related deaths during the extended treatment period averaging 16 months (Table 2). Dabigatran etexilate was also associated with a reduced risk for bleeding. All-cause mortality and other adverse events were similar between the groups but the incidence of acute coronary events was significantly higher with dabigatran etexilate (0.9% vs 0.2%, P=.02). RE-SONATE, like RE-MEDY, is a secondary prevention trial that evaluated the use of dabigatran etexilate as 6month extended treatment of VTE in patients who completed 6 to 18 months of treatment with an approved

anticoagulant.[36] But unlike RE-MEDY, RE-SONATE compared dabigatran etexilate150 mg twice daily with placebo. Treatment with dabigatran etexilate produced a 92% relative risk reduction for recurrent VTE compared with placebo (Table 2). Clinically relevant bleeding was significantly higher with dabigatran etexilate, but the incidence of major bleeding events was not significantly different between the groups (although events only occurred in the dabigatran etexilate group [2 vs 0]). The incidence of cardiovascular events and all-cause mortality did not differ between the groups. Table 2. Main Efficacy and Safety Outcomes With Dabigatran Etexilate for the Treatment and Secondary Prevention of VTE

Outcome RE-COVER58 RE-COVER II59 RE-MEDY60 RE-SONATE36 Primary, efficacy HR 95% CI P valu e 1.10 0.65-1.84 Noninferiorit y <.001 Bleeding Major HR 95% CI P valu e 0.82 0.45-1.48 0.38 0.69 0.36-1.32 NS 0.52 0.27-1.02 0.06 Not estimable* 0.04-1.05 0.5 1.08 0.64-1.80 Noninferiority <.001 .014 1.44 0.78-2.64 Noninferior ity 0.08 0.02-0.25 Superiority <.001

Major or clinically relevant non-major HR 95% CI P valu e 0.63 0.47-0.84 .002 0.62 0.45-0.84 .001 0.54 0.41-0.71 <.001 2.92 1.52-5.60 .0013

*There were 2 major bleeds (0.3%) in the dabigatran group versus none in the placebo group.

Apixaban
Apixaban is a potent, direct factor Xa inhibitor that selectively and reversibly inhibits both free factor Xa and prothrombinase activity. Following oral administration, peak plasma concentrations of apixaban are reached within 1 to 3 hours. Apixaban has a half-life of 8 to 15 hours.[61] Apixaban has a multimodal mechanism of excretion; most of the drug is excreted in the feces (>46%), a portion is metabolized via CYP3A4-dependent mechanisms in the liver, and one-fourth of the drug is eliminated in the urine.[61,62] Apixaban is currently not

indicated for any VTE-related use in the United States but is approved in Canada for the primary prevention of VTE. Ongoing phase 3 trials (AMPLIFY and AMPLIFY-EXT) are evaluating its efficacy and safety for the treatment and secondary prevention of VTE.[63,64] AMPLIFY will compare apixaban 10 mg twice daily for 1 week followed by 5 mg twice daily for 6 months with enoxaparin followed by warfarin (INR 2-3) for 6 months for the treatment of symptomatic DVT or PE. The primary outcome is VTE recurrence or death during the treatment period, and the secondary outcome is bleeding events.[63] AMPLIFY-EXT is a secondary prevention trial that assessed apixaban for extended treatment of DVT or PE. Patients who have received 6 to 12 months of treatment for their DVT or PE were randomized to receive apixaban 2.5 mg twice daily, apixaban 5 mg twice daily, or placebo for up to 12 months.[64] Extended treatment with 2.5 mg twice daily of apixaban produced a 67% relative risk reduction while treatment with the 5 mg twice daily dose resulted in a 64% relative risk reduction of symptomatic recurrent VTE or death from any cause (composite primary outcome) compared with placebo (Table 3). This benefit of extended treatment with apixaban was observed without an increase in major bleeding (primary safety outcome); but, major or clinically relevant nonmajor bleeding was elevated. All-cause mortality and the composite outcome of VTE, VTE-related death, myocardial infarction, stroke, cardiovascular disease-related death, or major bleeding were lower in apixaban-treated patients. A reduction in this composite outcome was considered to represent the net clinical benefit. Table 3: Main efficacy and safety outcomes with apixaban for the secondary prevention of VTE64

Outcome Primary, efficacy Relative risk 95% CI Bleeding Major Relative risk 95% CI

Apixaban, 2.5 mg

Apixaban, 5 mg

Placebo

0.33 0.22-0.48

0.36 0.25-0.53

0.49 0.09-2.64

0.25 0.03-2.24

Major or clinically relevant nonmajor Relative risk 95% CI All-cause Mortality % 0.8 0.5 1.7 1.29 0.72-2.33 1.82 1.05-3.18

VTE, VTE-related death, myocardial infarction, stroke, cardiovascular diseaserelated death, or major bleedinga Relative risk 95% CI 0.23 0.14-0.37 0.24 0.15-0.38

aA reduction in this composite outcome was considered to represent the net clinical benefit.

Edoxaban
Edoxaban, like rivaroxaban and apixaban, is a direct factor Xa inhibitor. After oral administration, it is rapidly absorbed, reaching peak plasma concentrations within 1 to2 hours. The terminal half-life of edoxaban is 6 to11 hours after single dosing and 9 to10 hours after multiple dosing.[65,66] Approximately one-third of edoxaban is eliminated via renal secretion and the remainder is excreted in the feces.[67] Edoxaban has been approved in Japan for the prevention of VTE after major orthopedic surgery, based on the STARS studies.[68] A phase 3 study (HOKUSAI VTE) evaluating edoxaban's efficacy and safety for the treatment and secondary prevention of VTE is currently underway.[69] HOKUSAI VTE is the largest VTE treatment and secondary prevention trial to date, with completed enrollment of more than 8250 patients. Patients with acute DVT and/or PE will be randomly assigned to edoxaban or warfarin after an initial heparin treatment period (UFH or LMWH) of 5 to 12 days. The primary efficacy end point is the composite of DVT, nonfatal, and fatal PE over a 12-month treatment period from randomization. The secondary efficacy end point is the composite of symptomatic recurrent DVT, nonfatal symptomatic recurrent PE, and all-cause mortality; the safety end point is major or clinically relevant non-major bleeding during treatment.[69] In summary, the treatment and/or secondary prevention trials of rivaroxaban, dabigatran, and apixaban indicate that these agents are as effective in reducing the risk for recurrent VTE but may be associated with some bleeding risk.

When the new oral anticoagulants are approved for use in VTE treatment and secondary prevention, do you think there will still be a place for warfarin?
No, not at all

Yes, in cases where there are tolerability issues with the new agents

Yes, if cost is an issue with the new agents

Not sure

Advantages of New Oral Anticoagulants

The new oral anticoagulants have a number of advantages over warfarin.[70,71] They target specific procoagulant complexes within the coagulation cascade and thus have a more predictable anticoagulant effect compared with warfarin. Maximal plasma concentrations of these agents are attained within 1 to 4 hours of dosing; thus, they produce a more rapid onset of anticoagulant effect versus warfarin (72-96 hours). The new agents also have shorter half-lives and thus a faster offset of action. The faster onset and offset of action of the new agents may eliminate the need for parenteral anticoagulant bridge therapy for the treatment of VTE. The feasibility of this approach was demonstrated in the EINSTEIN-DVT and EINSTEIN-PE trials where rivaroxaban treatment was initiated without initial parenteral (bridge) therapy.[37,50] A similar approach is being tested out in the AMPLIFY study with apixaban. If used for long-term treatment, the faster onset and offset of action of the new agents may also eliminate the need for parenteral bridge therapy in patients who require invasive procedures. The new anticoagulants, thus, could potentially simplify VTE management.

One of the greatest disadvantages of warfarin is the need for regular monitoring of its anticoagulant effect and dose adjustment because of its numerous food and drug interactions and its narrow therapeutic window. The new oral anticoagulants, on the contrary, have few, if any, food interactions; fewer drug interactions; and a linear, predictable, therapeutic effect compared with warfarin. They can be administered in fixed doses without the need for routine anticoagulation monitoring. With the elimination of routine monitoring, the new anticoagulants could potentially reduce the burden of anticoagulant management by being more convenient for patients and providers and may contribute to reducing some of the barriers to anticoagulant therapy. Despite the advantages, the new oral anticoagulants are, however, not without limitations and concerns. These issues are reviewed below. Rivaroxaban has been approved for the treatment and secondary prevention of VTE in the United States and Europe and the other new agents are expected to be approved in the near future. As such, it is appropriate to review some of the unanswered questions and challenges with respect to the use of these agents that clinicians are likely to face.

How would you determine the duration of anticoagulant therapy for secondary prevention of VTE?
Based on the patients risk for recurrence

Based on the patients D-dimer levels

Based on the severity of the index event

Based on the patients risk for recurrence and risk for bleeding

Duration of Anticoagulant Therapy

Guidelines recommended that the treatment of acute DVT and PE requires the initial administration of a therapeutic course of a parenteral anticoagulant with VKA therapy, both initiated simultaneously.[23] Parenteral therapy is continued for a minimum of 5 days and until the INR is 2.0 for at least 24 hours, after which parenteral therapy is discontinued. Treatment with the VKA is recommended for at least 3 months in most patients. In patients with unprovoked VTE and a low or moderate risk for bleeding, extended treatment (beyond 3 months) is recommended. The duration of extended treatment, however, is not specified in the guidelines because of a paucity of evidenced-based data, but periodic assessment for the need for continued therapy is recommended (trimonthly to annually). In the absence of specific guidelines, physicians need to rely on their clinical judgment taking 2 risks into consideration to help guide therapy duration: the risk for recurrent VTE, with and without anticoagulation, and the risk for anticoagulant-induced bleeding. This task, however, is complicated by the large number of risk factors associated with recurrence, as well as the overlap in risk factors for bleeding and recurrent thrombosis. In addition, like all therapies, individual preferences need to be also factored into the decision.

Identifying Patients at Risk for VTE Recurrence

Patients who have experienced a primary VTE event are at risk for VTE recurrence.[72] The magnitude of the risk, however, varies greatly among patients and is influenced by a number of factors, including the presence or absence and nature of identifiable triggering risk factors at the time of the index event; the characteristics of the index event; and patient demographic and clinical features.[73-76]

VTE may be triggered by a number of identifiable risk factors that may be transient or reversible in nature, such as recent major surgery, major trauma or fracture, immobilization, confinement to bed, lengthy travel, estrogen therapy, and pregnancy. Other identifiable risk factors may be persistent or irreversible in nature, such as cancer, paralysis, and antiphospholipid syndrome.[74] VTE that occurs in association with these transient or persistent identifiable risk factors is referred to as provoked VTE. VTE may also arise in the absence of identifiable risk factors, in which case it is referred to as unprovoked or idiopathic VTE. In general, the risk for recurrence is higher in patients with persistent or unknown risk factors compared with transient risk factors. The cumulative annual incidence of recurrent VTE events is approximately 15% in the absence of identifiable risk factors;[8] up to 27% when VTE is associated with active cancer;[18] and 3% when VTE occurs in association with a transient risk factor within 1 year of discontinuing anticoagulant therapy.[77] Among VTE associated with transient risk factors, the greater the transient nature of the risk factor, the lower the risk for recurrence. A prospective cohort study reported a 0% 2-year cumulative incidence of recurrence after discontinuing anticoagulant therapy with surgery-related VTE and 8.8% with nonsurgical risk factor-related VTE (fracture, illness, immobilization, travel, or estrogen therapy).[75] Among patients with DVT as an index event, the location of the initial DVT influences the risk for recurrence, with proximal DVT having a 2-fold greater risk for recurrence than distal DVT.[78] In addition, the more proximal the DVT, the higher the risk for recurrence; the risk for recurrence is 2-fold higher with iliofemoral DVT versus femoral or popliteal DVT.[79] In general, the risk for recurrence is significantly higher in patients with PE than with proximal DVT soon after discontinuing anticoagulant therapy. However, the difference in risk diminishes over time and the cumulative risk over a 24-month period is similar between the types of VTE.[78] Patient demographic features such as age, body mass index, and male gender can impact the risk for VTE recurrence. Increasing age and body mass index at the time of the index VTE event are independent predictors of recurrence; every per decade increase in age increases the risk for recurrence by 17% and every 10-point increase in body mass index increases the risk by 24%.[72] In patients with unprovoked VTE, however, age does not appear to predict VTE recurrence.[80] Compared with women, men are 50% more likely to be at risk for VTE recurrence, regardless of the nature of the initial VTE (unprovoked or provoked), location of thrombosis, or number of events.[81]Thrombophilic abnormalities such as increased procoagulant factor VIII and factor IX activities; deficiency of antithrombin, protein C, or protein S; hyperhomocysteinemia; and antiphospholipid antibodies have all been associated with an increased risk for VTE recurrence.[76] After anticoagulant withdrawal, abnormal plasma levels of D-dimer, the major degradation product of cross-linked fibrin, is a strong predictor of VTE recurrence. A systematic review reported a 8.9% annual risk for recurrence with an abnormal D-dimer result whereas a normal D-dimer result was associated with a 3.5% annual risk for recurrence.[82] Time after the index event and after discontinuing anticoagulant therapy also plays a contributory role to the risk for recurrence. In general, the risk for recurrence is the greatest during the first 6 months after the initial event; it decreases thereafter, but never reaches zero.[72] After discontinuation of anticoagulant therapy, the risk for recurrence is greatest just after therapy termination.[73, 83] A shorter duration of anticoagulant therapy of 1 or 1.5 months is associated with a higher risk for recurrence compared with 3 or more months of therapy. Beyond 3 months, the duration of therapy does not influence the risk for recurrence.[78] A long-term prospective study reported a cumulative incidence of VTE recurrence of 11% within 1 year after discontinuing anticoagulant therapy, 29% within 5 years, and 40% within 10 years.[8] Given the large number of factors that can influence the risk for VTE recurrence, identifying patients at risk is a daunting task. To help guide risk stratification, several risk prediction scores have been developed,[84] including the recent Vienna Risk Prediction Model[85] and the D-dimer, age, sex, and hormonal therapy (DASH) score. [86] The Vienna Risk Prediction Model was developed using data from a prospective cohort study of patients with primary unprovoked VTE (without a strong thrombophilic defect such as a natural inhibitor deficiency, the lupus anticoagulant, and homozygous or combined defects), followed for a median of 43 months after discontinuation of anticoagulation. During the follow-up period, male gender, proximal DVT, PE, and elevated plasma levels of D-dimer were found to be associated with a higher risk for recurrence. Using these risk factors,

a scoring system was developed that estimates the cumulative probability of recurrence in an individual patient with unprovoked VTE. The DASH score was also developed in patients with a first unprovoked VTE event using data from 7 prospective studies.[86] These patients had been treated for at least 3 months with a VKA after the index event. The main predictors of recurrence in this study were abnormal D-dimer after stopping anticoagulation, age <50 years, male sex, and VTE not associated with hormonal therapy (in women), which were used to develop the DASH prognostic recurrence score. A score of 1 predicts an annualized recurrence risk for 3.1%; a score of 2, 6.4%; and a score 3, 12.3%. The low recurrence at a score of 1 could potentially serve to identify patients in whom indefinite anticoagulation may not be necessary after an initial treatment of 3 months. The use of risk prediction scores like the Vienna Risk Prediction Model and the DASH score will help to simplify recurrent VTE risk assessment and stratification, but prospective validation of these scoring systems is warranted before they can be adopted into clinical practice.

A 78-year-old man presents for secondary prophylaxis after a VTE episode. His medical history is significant for uncontrolled hypertension, asthma, and coronary heart disease. He had a stent placed 3 months ago. His current medications included dual antiplatelet therapy (DAPT), an antihypertensive, and a long-acting -agonist. Which of the following is likely to increase his risk for bleeding if he is prescribed an oral anticoagulant?
Concomitant long-acting -agonist and DAPT usage

Concomitant hypertension and asthma

His advanced age and concomitant DAPT usage

His advanced age and concomitant antihypertensive therapy usage

Assessing the Risk for Bleeding

All anticoagulants are associated with a risk for bleeding by virtue of their mechanism of action, although the new oral anticoagulants appear to have a lower risk for major bleeding compared with the traditional agents as seen in the VTE treatment and extension trials.[37,50,58-60] These trials, however, excluded patients with some comorbidities and clinical conditions that increase the risk for bleeding. In addition, concomitant use of antiplatelet therapy was discouraged. Thus, the true benefit-risk ratio of the new agents in real-life anticoagulant users who are likely to be elderly and have various disorders that may affect the bleeding risk remains to be clarified. As all 4 new oral anticoagulants are eliminated renally to some extent, there is a concern for increased drug exposure in patients with renal impairment. In pharmacokinetic studies comparing healthy subjects with normal renal function with subjects with varying degrees of renal impairment, the clearance of dabigatran and rivaroxaban was found to decrease and their exposure increased as renal function decreased.[87,88] Rivaroxaban and apixaban undergo partial metabolism in the liver via the CYP450 pathway.[61,62,89] There are 2 potential issues related to hepatic metabolism. Firstly, the clearance of these agents may be reduced in patients with hepatic impairment. Compared with healthy subjects with normal hepatic function, significant increases in rivaroxaban exposure were observed in subjects with moderate hepatic impairment.[90] Second, as various medications are metabolized via the CYP450 pathway, there is the potential for drug interactions that

may affect rivaroxaban or apixaban exposure. As rivaroxaban is also a substrate of the transporter Pglycoprotein (P-gp), drugs that are combined P-gp and strong inhibitors of CYP3A4 (such as ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan) have been shown to cause significant increases in rivaroxaban exposure. Coadministration of these drugs with rivaroxaban should, thus, be avoided.[48] Although dabigatran does not undergo hepatic metabolism, it is a substrate of P-gp and drugs that inhibit P-gp can also increase the exposure of dabigatran. Clinically significant increases in dabigatran exposure occur when the P-gp inhibitor dronedarone or systemic ketoconazole is coadministered in patients with moderate renal impairment.[56] The concomitant use of the new anticoagulants with drugs that interfere with hemostasis (eg, aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDS], and antiplatelet agents) can also potentially increase the risk for bleeding. This was shown to be the case in clinical trials of patients with acute coronary syndrome on DAPT where coadministration of dabigatran, rivaroxaban, or apixaban were generally found to increase the risk for major and any bleeding in a dose-dependent manner.[91-95] Other factors such as elderly age (>75 years), comorbid conditions (hypertension, cerebrovascular disease, ischemic stroke, heart disease [atrial fibrillation, recent myocardial infarction], peptic ulcer disease, and cancer), and short duration of anticoagulant therapy have also been shown to be associated with an increased risk for bleeding.[96] Some of the comorbid conditions (hypertension, cancer, and ischemic stroke) that increase the risk for bleeding also increase the risk for thrombosis, and further complicate the decision to initiate or extend anticoagulant therapy. To guide physicians on anticoagulant therapy decisions, the RIETE Registry bleeding risk score was developed and validated in patients with acute VTE.[97] Utilizing 6 independent risk factors for bleeding identified at baseline, age >75 years, recent major bleeding, cancer, creatinine levels >1.2 mg/dL, anemia, and PE, the RIETE risk score (Table 4) predicts the risk for major bleeding within 3 months of anticoagulant therapy. A score of 0 predicts low risk, a score of 1-4 indicates intermediate risk, and a score of >4 predicts high risk for major bleeding. It should be emphasized that this risk score is only a guide and physicians should not rely solely on it to make therapy decisions. The risk score should be used in conjunction with other assessments, particularly the risk for thrombosis, to arrive at a more comprehensive evaluation of the benefit-risk for anticoagulation. Table 4. REITE Risk Score[97]

Risk Factor Recent major bleeding Creatinine levels >1.2 mg/dL Anemia Cancer Clinically overt PE Age >75 years Maximum Score

Score 2 1.5 1.5 1 1 1 8

Managing Bleeding Complications With the New Oral Anticoagulants

There are currently no approved antidotes to rapidly reverse the anticoagulant effect of the new oral agents in the event of a life-threatening bleeding complication, which is a limitation of the new agents. However, because the new agents have a shorter half-life compared with the traditional agents, their anticoagulant effects wear off more rapidly than those of traditional agents. One could argue that for many clinical scenarios, the need for an

antidote is more of a theoretical concern rather than a real clinical concern. On the other hand, one could also argue that the half-lives of the new agents are still relatively long, between 8 to 15 hours depending on the agent, and that strategies to manage acute and severe potentially life- threatening bleeding episodes are necessary. The management of bleeding episodes while on dabigatran or rivaroxaban will depend on the severity of the event.[98,99] In all cases, the initial step is the discontinuation of the anticoagulant. This should be followed by interventions to identify and treat the source of bleeding. Supportive measures such as mechanical compression, fluid replacement, blood transfusion, and hemodynamic support may be needed to stabilize the patient depending on the severity of bleeding. Diuresis may also help facilitate renal elimination of the anticoagulants. In the event of uncontrolled bleeding despite these measures or in the event of life-threatening bleeding, the use of hemostatic procoagulant agents, such as activated prothrombin complex concentrate or recombinant factor VIIa, may be considered for rapid reversal of anticoagulation effects.[48,56] In a randomized, placebo-controlled, crossover study, prothrombin complex concentrate was shown to immediately and completely reverse the anticoagulant effect of rivaroxaban in healthy subjects but had no influence on the anticoagulant effect of dabigatran at the dose tested.[100] In an ex-vivo study, the nonspecific hemostatic procoagulant agents recombinant factor VIIa and FEIBA (Factor VIII Inhibitor Bypassing Activity) appeared to reverse the anticoagulant activity of rivaroxaban or dabigatran in healthy subjects.[101] Although the results of these studies are promising, there are no clinical data on the use of these agents in hemorrhagic situations. Because about 35% of dabigatran is bound to plasma proteins, hemodialysis may also be considered in the event of severe bleeding with dabigatran. Dialysis eliminates about 60% of dabigatran over 2 to 3 hours but data supporting this approach are limited.[56] Rivaroxaban is not considered to be dialyzable because 92% to 95% is plasma bound.[48]

Managing Oral Anticoagulants in the Perioperative Setting

Patients who undergo surgical or invasive procedures while on anticoagulant therapy are at risk for increased bleeding. To reduce the risk for bleeding, dabigatran or rivaroxaban need to be temporarily discontinued prior to surgery. The timing of discontinuation will depend on the patients degree of renal impairment, the half-life of the anticoagulant, and the anticipated risk for bleeding associated with the surgery (Table 5).[99] For example, in patients with normal renal function and a standard risk for bleeding, dabigatran or rivaroxaban should be discontinued at least 24 hours prior to surgery, which would be sufficient for drug clearance. With declining renal function and a higher risk for bleeding, a longer duration of interruption may be needed (Table 5). During this period, the use of bridging therapy with parenteral heparin or LMWH should be unnecessary, but may be considered for longer periods of discontinuation, depending on the patients risk for thrombosis. After surgery, dabigatran and rivaroxaban can be reinstated as soon as hemostasis is established and if clinically indicated. When oral medication is not possible, for example, in bowel paralysis, parenteral anticoagulants (heparin, LMWH, fondaparinux) may be necessary. Table 5. Suggested Timing of Dabigatran or Rivaroxaban Discontinuation Prior to Surgery.[99]

Renal Function (CrCL, ml/min)

Half-Life (h, range)

Timing of Discontinuation After Last Dose Before Surgery Standard Risk for High Risk for Bleedinga Bleedingb

Dabigatran > 80 > 50 to 80 > 30 to 50 30 13 (11-22) 15 (12-34) 18 (13-23) 27 (22-35) 24 h 24 h 2d 4d 2d 2d 4d 6d

Rivaroxaban > 30 < 30 12 (11-13) Unknown 24 h 2d 2d 4d

a Examples are cardiac catheterization, ablation therapy, colonoscopy without removal of large polyps, and uncomplicated laparoscopic procedures, such as cholecystectomy. b Examples are major cardiac surgery, insertion of pacemakers or defibrillators (resulting from the risk for pocket hematoma), neurosurgery, large hernia surgery, and major cancer/urologic/vascular surgery. Republished from Schulman S, Crowther MA. Blood. 2012;119:3016-3023. [99] Routine monitoring of the anticoagulation effect of the new oral agents is not required because of their predictable pharmacokinetic response and their wide therapeutic window. However, in certain clinical situations assessment of the level of anticoagulation or drug concentration may be useful; for example, in patients with a thrombotic or hemorrhagic event, prior to emergent surgery, in patients with deteriorating renal function, potential overdose, or to monitor adherence to therapy. Several assays are available for this purpose; the activated partial thromboplastin time (aPTT), thrombin clotting time (TCT), and the ecarin clotting time (ECT) assays for dabigatran and the prothrombin time (PT), aPTT, and antifactor Xa chromogenic assays for rivaroxaban.[98,102] The aPTT, TCT, and ECT are prolonged in the presence of dabigatran.[98] The TCT and ECT tests are highly sensitive at measuring the anticoagulant effect of dabigatran and show a linear relationship to dabigatran plasma concentrations of up to 400 ng/mL. The aPTT assay, in contrast, is relatively insensitive for the plasma concentration range of dabigatran encountered after administration of therapeutic doses. In addition, the type of coagulometer and sensitivity of the reagents used can also affect aPTT measurements. Thus, the aPTT assay does not reliably measure dabigatran levels in plasma. However, aPTT may still be useful as a qualitative measure of the presence or absence of anticoagulation effect of dabigatran. In the presence of rivaroxaban, PT and aPTT are prolonged in a dose-dependent manner.[103] However, the results, can vary depending on the thromboplastin reagents used. Attempts to standardize the variability in results obtained with different reagents using the INR conversion system developed for warfarin should not be undertaken because of a lack of correlation between rivaroxaban-induced PT prolongation and the international sensitivity indices of the various thromboplastin reagents. Given their limitations, PT and aPTT may be useful as qualitative rather than quantitative measures of rivaroxabans anticoagulation effect. For example, normal values of PT (measured in seconds) using rivaroxaban-sensitive agents such as Neoplastin Plus (Diagnostica Stago), would suggest an absence of clinically relevant anticoagulation effects of rivaroxaban. Like PT and aPTT, the antifactor Xa chromogenic assays also exhibit a concentration-dependent relationship with rivaroxaban, but only the assay calibrated with rivaroxaban reliably measures rivaroxaban levels in plasma. Chromogenic assays used to measure the activity of heparin or LMWH (which also inhibit factor Xa) may not be as accurate as a rivaroxaban-calibrated assay. Patients taking warfarin who have problems maintaining their INRs in the therapeutic range and those who have tolerability issues with warfarin may be candidates for switching to the new oral anticoagulants. In addition, patients who are stabilized on warfarin may prefer to switch to the new oral agents because of the convenience of therapy. When switching from warfarin to a new agent, 2 factors need to be taken into consideration during the transition period when warfarin is discontinued and the new agent is initiated. If the new agent is initiated too soon after discontinuing warfarin, the risk for bleeding increases due to an overlap of anticoagulation effect. Also, if initiation of the new agent is delayed, then the risk for thrombosis increases. Thus, the timing of initiation of the new agent is very important. To ensure safe and effective anticoagulation, dabigatran may be initiated when the INR is less than 2.3, which is based on the study protocols of RE-LY, REMEDY, and RE-SONATE.[36,57, 60,99] Rivaroxaban may be initiated when the INR is 3.0, based on the

ROCKET AF study.[49] However, most clinicians would prefer the INR to be 2.5 and falling prior to commencing rivaroxaban. When switching patients from dabigatran or rivaroxaban to warfarin, warfarin needs to be initiated before discontinuing the new oral agent because it takes approximately 5 days for the onset of the anticoagulation effect of warfarin. The timing of initiation of warfarin may depend on the renal function of the patient as well as the half-life of the new agent (Table 6).[99] In patients with declining renal function, a shorter overlap period would be required. Because rivaroxaban has a shorter half-life compared with dabigatran, a longer overlap period with warfarin would be required with rivaroxaban. It is important to note that both dabigatran and rivaroxaban may affect the INR; thus, for a reliable determination of INR, measuring should be performed at least 2 to 3 days after discontinuing the new oral agent. Table 6. Suggested Strategy for Conversion From Dabigatran or Rivaroxaban to Warfarin

Calculated CrCL, mL/min >50 31-50 15-30

Dabigatran: Start Day With Warfarin* Day 3 Day 2 Day 1

Rivaroxaban: Start Day With Warfarin* Day 4 Day 3 Day 2

*Dabigatran/rivaroxaban is stopped on day 0. The longer overlap with rivaroxaban is justified by its half-life being shorter than that of dabigatran. Republished from Schulman S, Crowther MA. Blood. 2012;119:3016-3023. [99] Secondary prevention of VTE is an important consideration in all patients who have had a VTE event. However, as the magnitude of the risk for recurrence varies widely among patients, secondary prevention needs to be individualized. Warfarin has been the mainstay oral anticoagulant for secondary prevention of VTE for the past 50 years, but it is notoriously challenging to administer. The newer oral agents (dabigatran and rivaroxaban) have been demonstrated to be as effective as warfarin in reducing the risk for recurrence and also appear to have a better bleeding profile than warfarin. In addition, compared with warfarin, the newer agents have a wide therapeutic window, a shorter half-life, a predictable anticoagulant response, very few drug interactions, and no requirement for routine monitoring for dose adjustment. Also, they can be prescribed in fixed doses. Given these benefits, the newer agents are expected to simplify VTE management.

This article is a CME certified activity. To earn credit for this activity visit: http://www.medscape.org/viewarticle/776729
AMPLIFY = Efficacy and Safety Study of Apixaban for the Treatment of Deep Vein Thrombosis or Pulmonary Embolism AMPLIFY-EXTENSION = Efficacy and Safety Study of Apixaban for Extended Treatment of Deep Vein Thrombosis or Pulmonary Embolism APPRAISE = Apixaban for Prevention of Acute Ischemic and Safety Events aPTT = activated partial thromboplastin time ASPIRE = Aspirin to Prevent Recurrent Venous Thromboembolism CrCL = creatinine clearance CTEPH = chronic thromboembolic pulmonary hypertension DAPT = dual antiplatelet therapy DASH = D-dimer, Age, Sex, Hormonal therapy DVT = deep vein thrombosis ECT = ecarin clotting time FEIBA = Factor VIII Inhibitor Bypassing Activity INR = international normalization ratio

LMWH = low-molecular-weight heparin MI =myocardial infarction NR = not reported NS = not significant NSAID = nonsteroidal anti-inflammatory drug PE = pulmonary embolism PEP = Pulmonary Embolism Prevention P-gp = P-glycoprotein PT = prothrombin time PTS = post-thrombotic syndrome RECORD1 = Rivaroxaban Versus Enoxaparin for Thromboprophylaxis After Hip Arthroplasty RECORD2 = Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial RECORD3 = Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism RE-COVER = versus Warfarin in the Treatment of Acute Venous Thromboembolism RE-COVER II = Randomized Trial of Dabigatran Versus Warfarin in the Treatment of Acute Venous Thromboembolism RE-LY = Randomized Evaluation of Long-Term Anticoagulation Therapy RE-MEDY = Dabigatran or Warfarin for Extended Maintenance Therapy of Venous Thromboembolism RE-NOVATE = Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial RE-SONATE = Twice-daily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the Long-term Prevention of Recurrent Symptomatic Proximal Venous Thromboembolism in Patients With Symptomatic Deep-vein Thrombosis or Pulmonary Embolism RIETE = Computerized Registry of Patients with Venous Thromboembolism ROCKET AF = Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation STARS = Studying Thrombosis After Replacement Surgery TCT = thrombin clotting time UFH = unfractionated heparin VKA = vitamin K antagonist VTE = venous thromboembolism WARFASA = Warfarin and Aspirin

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