The risk of recurrent thromboembolic disorders in patients with unprovoked venous thromboembolism: New scenarios and opportunities

European Journal of Internal Medicine 25 (2014) 25–30

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European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim

Review article

The risk of recurrent thromboembolic disorders in patients with unprovoked venous thromboembolism: New scenarios and opportunities Paolo Prandoni ⁎, Sofia Barbar, Marta Milan, Valentina Vedovetto, Raffaele Pesavento Department of Medicine, Thromboembolism Unit, University of Padua, Italy

a r t i c l e

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Article history: Received 4 September 2013 Accepted 10 September 2013 Available online 9 October 2013 Keywords: Venous thromboembolism Deep venous thrombosis Pulmonary embolism Anticoagulation Thrombophilia

a b s t r a c t The risk of recurrent thromboembolic disorders in the 10-year period following an episode of unprovoked venous thromboembolism (VTE) ranges between 30 and 50%, the rate being higher in patients with primary deep venous thrombosis (DVT) than in those with primary pulmonary embolism (PE). The clinical presentation with primary PE increases by more than three times the risk of a new PE episode over that with isolated DVT. Baseline parameters that increase this risk are the proximal location of DVT, obesity, old age and male sex, whereas the role of thrombophilia is controversial. An increasing role is played by post-baseline parameters such as the ultrasound assessment of residual vein thrombosis and the determination of D-dimer. While the latest international guidelines suggest indefinite anticoagulation for most patients with the first episode of unprovoked VTE, new scenarios are being offered by the identification of risk stratification models and by strategies that have the potential to help identify patients in whom anticoagulation can be safely discontinued, such as those that incorporate the assessment of D-dimer and residual vein thrombosis. New opportunities are being offered by low-dose aspirin, which has recently been reported to decrease by more than 30% the risk of recurrent events without increasing the bleeding risk; and especially by a few emerging anti-Xa and anti-IIa oral compounds, which are likely to induce fewer haemorrhagic complications than vitamin K antagonists while preserving at least the same effectiveness, do not require laboratory monitoring, and can be used immediately after the thrombotic episode. © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction After discontinuing anticoagulation, a substantial proportion of patients with unprovoked deep venous thrombosis (DVT) and/or pulmonary embolism (PE) will develop recurrent venous thromboembolic (VTE) events. According to the findings from prospective cohort studies conducted at our Institution [1,2] and elsewhere [2–7], recurrent events are expected to develop in up to 50% of all such patients. This figure will not change after prolonging anticoagulation up to 6, 12 or 24 months [8–13]. Interestingly enough, while the risk is negligibly low after major surgery or trauma, it remains substantial in individuals whose thrombotic episode is triggered by “minor” transient risk factors, such as minor injury, knee arthroscopy, hormonal treatment, pregnancy or puerperium, and long trips [5]. Indeed, current strategies addressing the optimal duration of anticoagulation after a VTE episode tend to aggregate patients with unprovoked episodes and

⁎ Corresponding author at: Department of Medicine, Thromboembolism Unit, University of Padua, Via Giustiniani 2, 35128, Padua, Italy. Tel.: +39 049 8212656; fax: +39 049 8218731. E-mail address: [email protected] (P. Prandoni).

those whose events are associated with minor risk factors for venous thrombosis. 2. Baseline factors that increase the risk of recurrent VTE 2.1. Inherited thrombophilia and family history of VTE While inherited thrombophilia does not increase the risk of recurrent thromboembolism while on warfarin [14], whether and to which extent carriers of inherited thrombophilia exhibit a higher risk of recurrent VTE after discontinuing anticoagulation are controversial. It is generally accepted, although not conclusively demonstrated, that carriers of AT, protein C and S defects [15], carriers of hyperhomocysteinemia [16] and carriers of increased levels of factor VIII or IX [17–19], have a recurrence risk that is higher than that of control subjects. Whether carriers of factor V Leiden or prothrombin G20210A variant – including homozygous carriers and carriers of double heterozygosity – have a higher risk of recurrence as well is controversial, as there are data in favour and against this association [20,21]. Discrepancies among studies may be related to different selections of inception cohort, length of follow-up, initial treatment of the acute thrombotic disorder, duration of treatment, and changes in

0953-6205/$ – see front matter © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejim.2013.09.005

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general management of thrombotic patients. As a consequence, whether detection of these abnormalities, which are highly prevalent in western countries, has the potential to identify a subgroup of patients who might benefit from the adoption of individually adjusted prevention strategies following their first thrombotic episode, is virtually unknown. Surprisingly enough, two studies have consistently shown that the family history of VTE does not increase the risk of recurrent VTE [22,23]. 2.2. Male gender Following the observation that males exhibit a higher recurrence risk than females [24], a few meta-analyses of several studies confirmed the somewhat unexpected association between male sex and recurrent VTE [25,26]. Whether this finding is accounted for by sex-specific risk factors at time of first venous thrombosis is controversial [27,28]. 2.3. Presentation with primary DVT as compared to primary PE Patients with a first symptomatic unprovoked DVT are at higher risk of recurrent VTE than patients with a first unprovoked PE [2,29]. In addition, patients with clinically symptomatic PE have consistently been found to be at a higher risk of recurrent PE than those with DVT alone. These findings have recently been confirmed by a patient-level meta-analysis [30]. According to the same meta-analysis, the clinical presentation with PE (alone or associated with DVT) increases by more than three times the risk of a new PE episode over the clinical presentation with apparently isolated DVT [30]. 2.4. Old age Old age, which has long been regarded as a risk factor of venous thrombosis, has recently been identified as a predictive factor of recurrent VTE [31]. Thus, the common practice of administering old patients lower regimens or shorter periods of anticoagulation because of the fear of haemorrhagic complications should be reconsidered [32]. 2.5. Obesity and lipid lowering drugs Excess body weight was recently found to be a powerful and independent risk factor of recurrent VTE [33]. Obese patients should therefore be carefully educated, as decrease in body weight is likely to play a key role in reducing the risk of recurrent events. Interesting enough, a recent observation suggests that the use of fibrates may increase the risk of recurrent VTE [34].

contralateral DVT and of PE apparently not associated with DVT, suggesting that residual vein thrombosis should be regarded as a marker of hypercoagulability [42–44]. Whether the persistence of residual emboli after an episode of PE may predict the risk of recurrent PE as well is virtually unknown, although a recent small study failed to find this association [45]. 3.2. D-dimer A number of single studies [6,46–48] strongly suggest that the positivity of D-dimer at the time of warfarin discontinuation or soon after its interruption helps identify patients at a higher risk of developing recurrent VTE and, conversely, those in whom anticoagulation can be safely discontinued. These findings have recently been confirmed by a metaanalysis of available investigations [49]. 3.3. Post-thrombotic syndrome Another post-baseline factor potentially associated with an increased risk of recurrent VTE is the early development of post-thrombotic manifestations [50]. 4. Risk stratification models A novel approach for assessing risk of recurrent VTE consists of linking clinical patient characteristics with laboratory testing. Several such scoring models which can be used to assess the risk of recurrent VTE have been developed, but they await prospective validation before they can be applied in daily routine care [51–54]. In a Canadian model, women with idiopathic VTE and none or 1 of several parameters (age older than 65, obesity, D-dimer positivity at time of discontinuing anticoagulation and post-thrombotic manifestations) exhibited a considerably lower risk of recurrent VTE than the remaining patients [51]. Another prediction model enables the identification of the recurrence risk based on the combination of two baseline factors (sex and type of clinical presentation) and one post-baseline factor (D-dimer) [52]. In the last, based on a patient-level meta-analysis (the DASH score), D-dimer after stopping anticoagulation, age b 50 years, male sex and VTE not associated with hormonal therapy (in women) were found to be the main predictors of recurrence and were used to derive a prognostic recurrence score [53]. 5. Optimal duration of anticoagulation in patients with unprovoked VTE

2.6. Laboratory parameters The value of the activated partial thromboplastin time [35], high levels of hematocrit in men [36], elevated albuminuria [37], impaired tissue factor pathway inhibitor [38], and a number of global coagulation assays measuring thrombin generation have been reported to predict the risk of recurrent VTE [39–41]. All these observations show potential, but need confirmation. 3. Post-baseline factors that predict the risk of recurrent VTE 3.1. Residual vein thrombosis In a few cohort studies, the ultrasound persistence of residual thrombosis after an episode of proximal DVT was found to be an independent risk factor for recurrent thromboembolism [42,43]. A recent metaanalysis of available investigations suggest that, whichever the method used for measuring the thrombotic mass, residual vein thrombosis is a powerful and independent risk of recurrent VTE in patients with proximal vein thrombosis [44]. Interesting enough, residual vein thrombosis predicts not only the development of ipsilateral DVT, but also that of

Patients presenting with a first episode of unprovoked VTE should be offered at least 3 months of vitamin K antagonists, targeting an INR between 2.0 and 3.0 [55]. The decision as to go on or discontinue anticoagulation after the first conventional three months this period should be individually tailored and balanced against the haemorrhagic risk. While an indefinite anticoagulation can be considered in selected patients at very low bleeding risk, especially in those presenting with primary PE [55], in all other patients this decision requires caution. Indeed, the annual incidence of major bleeding from long-term anticoagulation is 1.5–2.0%, and the ‘case-fatality rate’ of an episode of major bleeding is considerably higher than that of an episode of recurrent VTE [56–58]. In addition, the development of major bleeding while on anticoagulation is, in turn, a powerful and independent risk of recurrent VTE and even of decreased life expectancy [59,60]. Whether low-dose warfarin, that is a dose that produces a targeted INR between 1.5 and 2.0, may offer a suitable option for patients requiring longer periods of anticoagulation has long been debated [61,62]. In agreement with the recent international guidelines, we believe that conventional warfarin regimen should be regarded as the first choice [55].

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Following the demonstration that a marker D-dimer can be helpful in the risk stratification, and thus ultimately therapeutic guidance, of individual patients with DVT [6,46–49], a randomized clinical trial showed that in patients who are left without anticoagulation as a consequence of a negative D-dimer – assessed one month after warfarin discontinuation – the rate of recurrent events is only slightly higher than in patients with positive D-dimer who continue anticoagulation [63]. In addition, repeating D-dimer testing after anticoagulation suspension has the potential to identify a number of individuals in whom D-dimer reverts to be positive and are, therefore, candidate to resume anticoagulation in order to prevent VTE recurrences [64]. In a few randomized clinical trials it has been shown that adjusting the duration of anticoagulation according to the persistence of residual thrombosis reduces the risk of recurrent VTE by approximately 40% [65,66]. Two prospective cohort studies, aimed at assessing the value of incorporating residual vein thrombosis with the D-dimer determination for identifying a subgroup of patients with unprovoked VTE in whom anticoagulation can be safely discontinued after an initial 3 to 12month period are currently ongoing in Italy. 6. New scenarios 6.1. Low-dose aspirin In a multicenter, double-blind study, more than 400 patients with unprovoked VTE who had completed 6 to 18 months of oral anticoagulant treatment were randomly assigned to aspirin, 100 mg daily, or placebo for at least two years [67]. VTE recurred in 28 of the 205 patients who received aspirin and in 43 of the 197 patients who received placebo (6.6% vs. 11.2% per year; HR, 0.58; 95% CI, 0.36 to 0.93). One patient in each treatment group had a major bleeding episode. The ASPIRE trial, which involved 822 patients, showed a nonsignificant decrease in the rate of recurrent VTE with aspirin (100 mg per day) as compared with placebo (rate of recurrence, 4.8% vs. 6.5% per year; hazard ratio, 0.74; 95% CI, 0.52 to 1.05; P = 0.09) [68]. However, since arterial thrombotic events occurred only about half as often in the aspirin-treated group as in the placebo group (10 events vs. 19 events), aspirin was associated with a significant reduction in the rate of major vascular events (hazard ratio, 0.66; 95% CI, 0.48 to 0.92; P = 0.01). Both studies used identical low-dose aspirin regimens and had similar enrolment criteria and outcome measures, making them amenable to meta-analysis. When data from these two trials were pooled, there was a 32% reduction in the rate of recurrence of VTE (hazard ratio, 0.68; 95% CI, 0.51 to 0.90; P = 0.007) and a 34% reduction in the rate of major vascular events (hazard ratio, 0.66; 95% CI, 0.51 to 0.86; P = 0.002). Moreover, these benefits were achieved with a low risk of bleeding. Hence, based on available evidence aspirin in low doses may offer a safe and highly cost-effective option for the long-term prevention of recurrent VTE. However, the degree by which aspirin reduces the rate of recurrent VTE is remarkably lower than that produced by old and new anticoagulants. In addition, in real practice the bleeding risk related to the use of even low doses of aspirin may not be as low as that observed in the WARFASA and in the ASPIRE studies [69]. Finally, for unknown reasons, aspirin does not seem to confer any appreciable protection against recurrent VTE in patients with symptomatic atherosclerosis [70,71]. An appealing perspective (to be tested in future investigations) may be replacing warfarin with aspirin in patients with unprovoked VTE in whom anticoagulation is discontinued as a result of early vein recanalisation and/or D-dimer negativity. 6.2. Emerging anti-thrombotic compounds New categories of oral antithrombotic drugs are emerging, which have the potential to simplify the long-term treatment of patients

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with VTE by obviating the need for periodic laboratory monitoring, while being associated with a favourable benefit-to-risk ratio. They include compounds that inhibit factor Xa, such as rivaroxaban, apixaban and edoxaban, and compounds that inhibit thrombin, such as dabigatran etexilate. Recently, the results of several randomized clinical trials, dealing with the initial and long-term treatment of VTE patients with dabigatran etexilate, rivaroxaban and apixaban have been reported. In the RE-COVER study, investigators enrolled patients with acute VTE who were initially given parenteral anticoagulation therapy, in a randomized, double-blind, non-inferiority trial, aimed to compare dabigatran etexilate, administered at a dose of 150 mg bid, with doseadjusted warfarin [72]. Thirty of the 1274 (2.4%) dabigatran patients, as compared with 27 of the 1265 (2.1%) warfarin patients, had recurrent VTE. Major bleeding complications occurred in similar proportions of patients allocated to dabigatran or placebo. In a confirmatory randomized, double-blind trial whose results have been recently presented (the RE-COVER 2 study), 2568 patients with acute VTE, treated with UFH, LMWH or fondaparinux for 5 to 11 days, were then randomized to receive dabigatran, 150 mg bid, or warfarin, dose-adjusted to an INR of 2.0 and 3.0, each given for 6 months [73]. Of 1279 patients randomized to dabigatran, 30 (2.4%) had recurrent VTE compared with 28 (2.2%) of 1289 patients randomized to warfarin; risk difference 0.2% (95% CI, − 1.0 to 1.5). The HR for dabigatran was 1.08 (95% CI, 0.64 to 1.80). Major bleeding complications occurred in similar proportions of patients allocated to dabigatran or placebo. Two subsequent clinical trials were designed to assess the efficacy and safety of dabigatran for the extended treatment of VTE [74]. In the RE-SONATE study, 1343 patients with VTE who had completed 6–18 months of anticoagulant therapy were randomized to dabigatran (150 mg bid) or placebo for an additional period of 6 months [74]. A 92% relative reduction in the relative risk for recurrent VTE was shown in favour of dabigatran, with a low risk for major bleeding (0.3% vs 0%). In the RE-MEDY study, 2856 patients treated for 6 months with vitamin K antagonists for a first VTE were randomized to dabigatran (150 mg bid) or warfarin (INR 2–3) for the long-term prevention of recurrent VTE [74]. Dabigatran was shown to be non-inferior to vitamin K antagonists (1.8% primary outcome events in dabigatran patients versus 1.3% in warfarin patients). Major bleeding complications occurred in 0.9% and 1.8% of patients, respectively (reduction in the relative risk, 48%). The EINSTEIN DVT and PE studies randomized 3449 patients with isolated DVT and 4832 patients with primary PE, respectively, to receive rivaroxaban (15 mg bid for 3 weeks followed by 20 mg once daily) or enoxaparin plus a vitamin K antagonist for 3, 6 or 12 months [75,76]. In the former study, rivaroxaban had non-inferior efficacy with respect to the primary outcome (2.1% vs. 3.0%; hazard ratio, 0.68; 95% CI, 0.44 to 1.04), while the principal safety outcome occurred in 8.1% of the patients in each group [75]. In the latter, the primary efficacy endpoint of symptomatic recurrent VTE occurred in 2.1% of patients receiving rivaroxaban and in 1.8% of patients receiving enoxaparin/VKA (hazard ratio 1.12; 95% CI, 0.75 to 1.68) [76]. The principal safety outcome of a first major or non-major clinically relevant bleeding event occurred in 10.3% and 11.4% of patients, respectively (hazard ratio, 0.90; 95% CI 0.76 to 1.07). Rates of major bleeding were significantly lower in patients receiving rivaroxaban (1.1% vs. 2.2%; HR 0.49; 95% CI, 0.31 to 0.79). The EINSTEIN Extension trial randomized 1197 patients who had completed 6 or 12 months of anticoagulant therapy for an acute index VTE event to an additional 6–12 months of therapy with either rivaroxaban, 20 mg once daily, or placebo [75]. Recurrent symptomatic VTE events were recorded in 1.3% of patients in the rivaroxaban group and 7.1% of patients in the placebo group (relative risk reduction, 82%). Major bleeding occurred in 4 (0.7%) rivaroxaban-treated patients as compared to none in the placebo group (P = 0.11).

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The efficacy of apixaban for VTE treatment, using a single drug approach, has recently been investigated in the AMPLIFY trial [77]. The AMPLIFY study was a randomized, double-blind trial comparing apixaban (10 mg twice a day for 7 days followed by 5 mg twice a day for six months) with enoxaparin followed by warfarin for the treatment of 5400 patients with acute VTE. Fifty-nine patients in the apixaban group (2.3%) and 71 patients (2.7%) in the conventional therapy group (RR, 0.84; 95% CI, 0.60 to 1.18) experienced an outcome event. Major bleeding occurred in 15 patients (0.6%) in the apixaban group and 49 patients (1.8%) in the conventional therapy group for a RR of 0.31 (95% CI, 0.17 to 0.55). Major and clinically relevant non-major bleeding occurred in 4.3% and 9.7% of patients in the apixaban and enoxaparin/warfarin groups, respectively (RR, 0.44; 95% CI, 0.36 to 0.55). The results of the study showed that apixaban was non-inferior in preventing recurrent VTE or VTE-related death and superior in avoiding major bleeding as well as the composite of major and clinically relevant non-major bleeding as compared to enoxaparin/warfarin. The AMPLIFY-Extension was a 12-month randomized clinical trial where apixaban 2.5 mg and 5 mg bid were compared with placebo for extended treatment to prevent recurrent VTE in approximately 2500 patients who had completed 6 to 12 months of treatment for DVT or PE [78]. Apixaban demonstrated superiority versus placebo in the reduction of the composite endpoint of symptomatic, recurrent VTE and death from any cause (p b 0.001). Apixaban was superior to placebo for the predefined secondary efficacy outcome of recurrent VTE and VTE-related death (8.8% in the placebo group, compared with 1.7% in both the apixaban 2.5 mg and 5 mg groups; p b 0.001). The rates of major bleeding were comparable for the 2.5 mg (0.2%), 5 mg (0.1%), and placebo (0.5%) treatment groups. The rate of the composite of major bleeding and clinically relevant non-major bleeding for the 5 mg treatment group (4.3%) was higher versus placebo group (2.7%), while 2.5 mg treatment group (3.2%) demonstrated similar rates to placebo. The results from a similar randomized clinical trial (HOKUSAI) addressing the value of edoxaban have recently become available [79]. In a randomized, double-blind, noninferiority study, 4921 patients with DVT and 3319 with PE (associated with right ventricular dysfunction in approximately one third) were allocated – after an initial treatment with parenteral drugs – to receive edoxaban at a dose of 60 mg once daily (30 in the case of moderate renal failure and/or a body weight below 60 kg), or warfarin for 3 to 12 months at discretion of attending physicians. Edoxaban was noninferior to warfarin with respect to the incidence of recurrent VTE, which occurred in 130 patients in the edoxaban group (3.2%) and 146 in the warfarin group (3.5%) (HR, 0.89; 95% CI, 0.70 to 1.13). Major and/or clinically relevant bleeding complications occurred in 349 patients (8.5%) in the edoxaban group and 423 (10.3%) in the warfarin group (HR, 0.81; 95% CI, 0.71 to 0.94). The rates of other adverse events were similar in the two groups. Interestingly enough, when the analysis was confined to the 938 patients with PE and right ventricular dysfunction, VTE complications were significantly less frequent in patients allocated to edoxaban than in those randomized to warfarin (3.3% vs 6.2%; HR, 0.52; 95% CI, 0.28 to 0.98). Overall, because of the potential to induce fewer bleeding complications the new drugs may open new scenarios for decisions on the duration of anticoagulation in patients with unprovoked VTE. 7. Learning points • Patients with the first episode of unprovoked VTE have a risk of recurrences over years that approach 50% of all such patients. The latest international guidelines suggest an indefinite anticoagulation in all those who are reputed to be at low bleeding risk.

• A number of models that help stratify the risk of recurrent events have recently been published; however, they need validation from prospective studies. • Algorithms that incorporate the ultrasound assessment of residual vein thrombosis and the serial determination of D-dimer have the potential to help identify individuals in whom anticoagulation can be safely discontinued. • Low doses of aspirin have recently shown to decrease the risk of recurrences by more than 30% after an initial period of conventional anticoagulation without increasing the haemorrhagic risk. • A few emerging anti-Xa and anti-IIa oral compounds, which seem to induce fewer haemorrhagic complications than vitamin K antagonists while preserving at least the same effectiveness, have the potential to replace conventional anticoagulants and can be used immediately after the thrombotic episode.

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