Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose-ranging study

Authors


Harry Buller, Department of Vascular medicine, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. Tel.: +31 205 665 966; fax: +31 206 968 833. E-mail: m.m.veendorp@amc.uva.nl

Abstract

Summary. Background: Apixaban, an oral potent reversible direct inhibitor of activated factor X, has shown promise in the prevention of venous thromboembolism following major orthopedic surgery. We conducted a dose-ranging study in patients with deep vein thrombosis. Methods: Consecutive patients with symptomatic deep vein thrombosis were included and randomized to receive 84–91 days of apixaban 5 mg twice-daily, 10 mg twice-daily, or 20 mg once-daily, or low molecular weight heparin (LMWH) followed by a vitamin K antagonist (VKA). The primary efficacy outcome was the composite of symptomatic recurrent venous thromboembolism and asymptomatic deterioration of bilateral compression ultrasound or perfusion lung scan. The principal safety outcome was the composite of major and clinically relevant, non-major bleeding. Results: The mean age of the 520 included patients was 59 years, and 62% were male. The primary outcome occurred in 17 of the 358 apixaban-treated patients [4.7%, 95% confidence interval (CI) 2.8–7.5%] and in five of the 118 LMWH/VKA-treated patients (4.2%, 95% CI  1.4–9.6%) who were evaluable. The incidence in all three apixaban groups was low and comparable without evidence of a dose response. The principal safety outcome occurred in 28 (7.3%) of the 385 apixaban-treated patients and in 10 (7.9%) of the 126 LMWH/VKA-treated patients. No dose response for apixaban was observed. Conclusion: These observations warrant further evaluation of apixaban in phase III studies. The attractive fixed-dose regimen of this compound may meet the demand to simplify anticoagulant treatment in patients with established venous thromboembolism.

Introduction

The aim of anticoagulant therapy in patients with symptomatic venous thromboembolism is to reduce the thrombotic burden and to prevent recurrent disease. The current standard treatment consists of 5–10 days of body weight-adjusted subcutaneous low molecular weight heparin (LMWH) followed by 3–12 months of vitamin K antagonists (VKAs) [1]. Although very effective, this therapy is cumbersome because of the need for injections initially and frequent laboratory monitoring and dose adjustments during the entire treatment period [2]. Presently, most patients with venous thromboembolism are admitted to the hospital for only 1 or 2 days or treated entirely at home. This further increases the demand for a simple, preferably oral, treatment strategy that can be given in a fixed dose [3,4].

Apixaban is a potent reversible direct inhibitor of activated factor X that can be administered orally. In the prevention of venous thromboembolism following major orthopedic surgery, this novel anticoagulant has recently shown great promise [5]. Therefore, apixaban might be an alternative to LMWH and VKAs in the treatment of patients with established venous thromboembolism. Hence, a dose-ranging study was conducted in patients with proven deep vein thrombosis (DVT), comparing the efficacy and safety of three dosage regimens of apixaban with that of LMWH combined with VKAs.

Materials and methods

Study population

Consecutive patients with acute symptomatic proximal DVT or extensive calf vein thrombosis, involving at least the upper third of the deep calf veins (trifurcation area) confirmed by compression ultrasonography (CUS) or venography, were potential candidates for the study.

Exclusion criteria included symptomatic pulmonary embolism (PE), calculated creatinine clearance below 30 mL min−1, impaired liver function [alanine aminotransferase (ALT) ≥ 3 times the upper limit of normal], bacterial endocarditis, life-expectancy < 6 months, thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent to treat the current episode of DVT, indications for VKAs other than DVT, more than 24 h of prerandomization treatment with therapeutic doses of unfractionated heparin, LMWH or fondaparinux or more than a single starting dose of VKA prior to randomization, active bleeding or high risk for bleeding contraindicating treatment with LMWH, fondaparinux or VKA, systolic blood pressure higher than 200 mmHg or diastolic blood pressure higher than 110 mmHg, use of more than 165 mg of acetylsalicylic acid per day, childbearing potential without adequate contraception, pregnancy, breast-feeding, and any other contraindication listed in the local labeling of enoxaparin, tinzaparin fondaparinux, warfarin, acenocoumarol, or phenprocoumon. Eligible patients were asked for written informed consent. The study complied with the Declaration of Helsinki, Good Clinical Practice guidelines and Therapeutic Products Program regulations, and all applicable Food and Drug Administration/Investigational New Drug regulations. The protocol was approved by the institutional review boards.

Study design

The Botticelli study was a veiled randomized, parallel group dose-ranging study that was double-blind for the different doses of apixaban and open-label for the LMWH /VKA comparator. All potential study outcomes [suspected thromboembolic complications, deaths, deteriorations on repeat ultrasound and perfusion lung scan (PLS), episodes of bleeding] were assessed by an independent committee, whose members were unaware of treatment assignment. A data safety monitoring board periodically reviewed the accumulated data.

An interactive voice response system was used for randomization, and patients were assigned to apixaban 5 mg twice-daily, 10 mg twice-daily, or 20 mg once-daily, or LMWH/VKA. The intended treatment duration was 84–91 days. For the initial treatment, tinzaparin 175 IU kg−1, enoxaparin 1.5 mg kg−1 once-daily or 1.0 mg kg−1 twice-daily and fondaparinux were allowed. The minimum duration of heparin treatment was 5 days, inclusive of a period of up to 24 h before randomization if a permitted LMWH was used. VKAs that could be used were warfarin, acenocoumarol, or phenprocoumon, which were started within 48 h after randomization. VKA treatment was adjusted to maintain the International Normalized Ratio (INR) within the therapeutic range (target 2.5, range 2.0–3.0). LMWH treatment was continued until a stable INR > 2 was observed on two measurements at least 24 h apart. Initially, the INR had to be measured every 2–3 days, but thereafter at least once monthly. VKA treatment was continued until day 84 + 7. The choice of LMWH /VKA was made per center.

Follow-up visits were scheduled at days 7, 14, 21, 49 and 84. At these visits, any symptoms of recurrent DVT or PE and bleeding were elicited. In addition, patients were instructed to report to the study site if any of these symptoms occurred between scheduled visits. Bilateral CUS and PLS were obtained at baseline and at the end of the intended study treatment period (days 84–91).

Efficacy outcomes

The primary efficacy outcome was the composite of symptomatic recurrent venous thromboembolism (i.e. recurrent DVT, fatal or non-fatal PE), and asymptomatic deterioration in the thrombotic burden as assessed by repeat bilateral CUS and PLS [6]. Symptomatic recurrent venous thromboembolism had to be confirmed by objective tests [7,8]. All deaths were evaluated for whether PE or bleeding were the cause. Deaths that could not be attributed to a known cause and for which PE could not be excluded were classified as being due to PE.

Deterioration on CUS was defined as an increase of ≥ 4 mm in the residual diameters of at least one of the veins (common femoral, superficial femoral, and popliteal) under full compression at day 84 as compared to baseline. Deterioration on PLS was defined as a decrease by more than 0.25 for any individual lobe at day 84 as compared to baseline.

Safety outcomes

The principal safety outcome was the composite of major and clinically relevant, non-major bleeding. Secondary safety outcomes were any bleeding and all-cause mortality. Major bleeding was defined as clinically overt bleeding that was fatal, was into a critical organ (intracranial, retroperitoneal, or pericardial), or led to a fall in hemoglobin ≥ 2 g dL−1, or transfusion of two or more units of packed red blood cells or whole blood [7].

Clinically relevant, non-major bleeding was defined as overt bleeding not meeting the criteria for major bleeding, but associated with medical intervention, unscheduled contact with a physician, (temporary) cessation of study treatment, or associated with any other discomfort for the patient, such as pain, or impairment of activities of daily life [9]. All other overt bleeding episodes were classified as minor bleeding.

Laboratory assessments

Blood samples for central assessment of hepatic function (total bilirubin and ALT) were collected at baseline and on days 21, 49, and 84.

Statistical analyses

Efficacy analyses were performed in the modified intention-to-treat (ITT) population (primary analysis) and in the per-protocol (PP) population. The modified ITT population comprised all randomized patients who had received at least one dose of study treatment, had objectively confirmed DVT at baseline, and in whom the primary efficacy outcome was evaluable. The PP population consisted of all patients valid for the ITT analysis without any major deviation from the protocol. Major deviations were prespecified and included receiving no study medication at all, poor compliance (< 80%) with intake of apixaban or bad control of INR after the first week of treatment (> 70% of measurements outside of the window 1.6–3.6), > 30 h of prerandomization treatment, and baseline perfusion scan performed more than 36 h after randomization. All safety analyses were performed in the safety population, defined as all patients who were randomized and received at least one dose of study drug.

For the primary efficacy analysis, the differences between apixaban groups and the control group were estimated using 95% exact confidence intervals (CIs).

It was calculated that a sample size of 130 patients per group, of whom 120 would qualify for the ITT analysis, would permit estimation of the differences between the apixaban and control groups to within approximately 10%, assuming primary efficacy outcome rates of approximately 5% and a 7% non-evaluable rate.

Results

Study population

From December 2005 to November 2006, 520 patients were randomized. The baseline characteristics of these patients are shown in Table 1. The mean age of the included patients was 59 years, and 62% were male. The groups had comparable baseline characteristics. The patient disposition is shown in Fig. 1: 476 patients (92%) were available for the primary efficacy analysis, whereas 511 patients (98%) were available for the safety analyses.

Table 1.   Baseline characteristics and treatment details of all patients who were randomized
 ApixabanLMWH/VKA (= 128)
5 mg twice-daily (= 130)10 mg twice-daily (= 134)20 mg once-daily (= 128)Any (= 392)
  1. *One patient received both enoxaparin 1.5 mg kg−1 once-daily s.c. and enoxaparin 1.0 mg kg−1 twice-daily s.c. during the course of initial treatment. LMWH, low molecular weight heparin; VKA, vitamin K antagonist; VTE, venous thromboembolism.

Age, years, mean (SD)56 (14)59 (17)60 (15)58 (15)59 (16)
Male gender, n (%)83 (64)76 (57)83 (65)242 (62)81 (63)
Body weight, kg85.8 (16.7)84.3 (18.0)84.5 (18.3)84.9 (17.7)80.7 (17.6)
 Range50–12949–13745–14345–14338–140
History of VTE, n (%)37 (28.5)28 (20.9)33 (25.8)98 (25.0)31 (24.2)
Documented active cancer, n (%)11 (8.5)6 (4.5)9 (7.0)26 (6.6)11 (8.6)
Surgery/trauma in previous 3 months, n (%)25 (19.2)29 (21.6)23 (18.0)77 (19.6)35 (27.3)
Treatment prerandomization, duration in hours, mean (SD)6.9 (7.3)6.4 (7.3)9.3 (8.3)7.5 (7.7)7.1 (13.7)
LMWH used for initial treatment
 Enoxaparin 1.5 mg kg−1 once-daily s.c.24 (19.0)*
 Enoxaparin 1.0 mg kg−1 twice-daily s.c.    72 (57.1)
 Tinzaparin 175 IU kg−1    31 (24.6)
Initial treatment, postrandomization,  Duration in days, mean (SD)    10.3 (5.9)
VKA used
 Warfarin88 (69.8)
 Phenprocoumon8 (6.3)
 Acenocoumarol30 (23.8)
Total duration of study drug exposure, days, mean (SD)80 (21)81 (20)77 (25)80 (22)82 (19)
Thrombotic burden at baseline
 Two or more locations of   non-compressibility68 (52.3)78 (58.2)71 (55.5)217 (55.4)80 (62.5)
 Perfusion defect present, n (%)87 (67)93 (69)86 (67)266 (68)88 (69)
Premature discontinuations and reasons
 Total number1712215010
 Bleeding complication, n22262
 Suspected VTE, n12141
 Death, n10010
 Other adverse event, n739192
 Comorbid condition and other reasons659205
Figure 1.

 Patient disposition. BID, twice-daily; QD, once daily; LMWH, low molecular weight heparin; VKA, vitamin K antagonist. *Symptomatic recurrent venous thromboembolism and asymptomatic deterioration of the ultrasound or perfusion lung scan.

Treatment and follow-up

Details of the initial and long-term study treatment are shown in Table 1. In the apixaban-treated patients, overall compliance was more than 80% in the majority of patients (96.9%, 99.2% and 99.2% in the 5 mg twice-daily, 10 mg twice-daily and 20 mg once-daily groups, respectively).

Among the LMWH/VKA-treated patients, time spent below, within and above the therapeutic range was 21%, 57% and 22% respectively. Treatment with study drug was not started or was discontinued prematurely in 60 patients (11.5%) (Table 1).

Efficacy outcomes

The primary outcome, symptomatic recurrent venous thromboembolism or asymptomatic deterioration of the CUS/PLS, occurred in 17 of the 358 apixaban-treated patients (4.7%, 95% CI  2.8–7.5%) and in five of the 118 LMWH/VKA-treated patients (4.2%, 95% CI  1.4–9.6%) who were evaluable. The incidence in all three apixaban groups was low and comparable, without evidence of a dose response (Table 2). Of the 12 symptomatic recurrences, 10 were recurrent DVT (two in the LMWH/VKA group), one was a non-fatal PE (in the LMWH/VKA group) and one was a patient (in the 20 mg once-daily apixaban group) in whom fatal PE could not be confidently excluded due to the absence of autopsy and the presence of clinical suspicion.

Table 2.   Efficacy in all evaluable patients and safety outcomes in all patients who received randomized treatment
OutcomeApixabanLMWH/VKA (= 128)
5 mg twice-daily (= 130)10 mg twice-daily (= 134)20 mg once-daily (= 128)Any (= 392)
  1. *Relative to the number of evaluable patients. Relative to the number of treated patients. LMWH, low molecular weight heparin; VKA, vitamin K antagonist; PE, pulmonary embolism; DVT, deep vein thrombosis.

Not treated or not evaluable139123410
Evaluable for primary outcome117125116358118
Primary outcome, n (%)*7 (6.0)7 (5.6)3 (2.6)17 (4.7)5 (4.2)
95% Confidence interval2.4–11.92.3–11.20.5–7.42.8–7.51.4–9.6
  Difference and 95% confidence   interval with LMWH/VKA group1.7 (− 4.4–8.2)1.4 (− 4.6–7.5)− 1.7 (− 7.3–3.6)
 Primary outcome sub-specified
  Fatal PE/unexplained death00110
  Symptomatic PE00001
  Symptomatic DVT34182
  Asymptomatic deterioration43182
Not treated21472
Included in safety analysis, bleeding128133124385126
Major and clinically relevant non-major bleeding, n (%)11 (8.6)6 (4.5)11 (8.9)28 (7.3)10 (7.9)
 95% Confidence interval[4.4–14.9][1.7–9.6][4.5–15.3][4.9–10.3][3.9–14.1]
Major bleeding10230
Clinically relevant non-major bleeding10692510
Minor bleeding41141910
Deaths, n (%)3 (2.3)1 (0.7)1 (0.8)5 (1.3)0 (0.0)
Deaths, sub-specified31150
 Fatal PE/unexplained death  110
 Major bleeding00000
 Other known cause31040

The PP analysis showed similar results (Fig. 1).

Safety outcomes

The incidences of bleeding events and deaths are shown in Table 2. Major and clinically relevant non-major bleeding occurred in 28 (7.3%) of the 385 apixaban-treated patients and in 10 (7.9%) of the 126 LMWH/VKA-treated patients. There were three non-fatal major bleeding events, one in the 5 mg apixaban twice-daily group and two in the 20 mg apixaban once-daily group. Again, no dose response for apixaban was observed.

In total, five patients, all with underlying malignant disease, died during the 3-month study period. All received apixaban. The direct causes of death were progressive malignant disease (= 3), possible PE (= 1), and suicide (= 1).

Other adverse events were equally distributed between the groups.

At week 3, 7 or 12, there was an increase greater than three times the upper limit of normal of ALT in five patients in the apixaban groups (1.3%) and in two patients (1.6%) in the LMWH/VKA group. An increase greater than two times the upper limit of normal for total bilirubin was seen in one apixaban recipient (0.3%) and in one LMWH/VKA recipient (0.8%). No concurrent increase greater than three times the upper limit of normal of ALT and greater than two times the upper limit of normal for total bilirubin occurred.

Discussion

The results of this dose-ranging study show that all three dose regimens of apixaban had an efficacy and safety profile similar to that of standard therapy with LMWH followed by VKAs. Overall, the primary efficacy outcome was observed in 4.7% of the apixaban recipients (range 2.6–6.0%) vs. 4.2% in the standard therapy group, whereas the incidences of the principal safety outcome were 7.4% (range 4.5–8.9%) and 7.9%, respectively (Table 2). Routine liver function testing revealed no evidence of liver toxicity.

Symptomatic episodes of recurrent venous thromboembolism during the 3-month study period occurred in 2.3% (range 1.6–3.0%) of apixaban-treated patients and in 2.3% with standard therapy (Table 2). This compares favorably with the 4.3% (95% CI  3.4–5.2%) of recurrent thrombosis with standard treatment reported in the Cochrane meta-analysis [10], as well as with the results from recent large trials of new anticoagulants in patients with symptomatic DVT [7–9].

The study was conducted according to current methodological standards; that is, consecutive patients were centrally randomized, the apixaban doses were double blind, strict criteria were defined a priori for diagnostic work-up of suspected outcome events, and all outcomes were evaluated by an adjudication committee unaware of treatment assignment. Furthermore, a high proportion of patients (92%) could be included in the primary efficacy analysis, and the results of the PP analyses were similar to those of the primary (ITT) efficacy analysis. Hence, the observed efficacy and safety of apixaban is likely to reflect its true clinical potential in the treatment of venous thromboembolism. On the basis of the overall low recurrence rate and excellent safety observed in the lowest dosage regimen (5 mg twice-daily), this dosing schedule could be used for long-term treatment, whereas, according to recent observations, a somewhat higher dosing schedule (e.g. 10 mg twice-daily) might be more appropriate for the initial treatment period [9].

In conclusion, our observations warrant further evaluation of apixaban in phase III studies. The attractive fixed-dose regimen of this compound may meet the demand to simplify anticoagulant treatment in patients with established venous thromboembolism.

Disclosure of Conflict of Interests

This study was sponsored by Bristol-Myers Squibb.

Appendix

Study Management and Coordination Committee: H. Büller (Chair), B. Brenner, T. Brighton, J. Chlumsky, B. Davidson, H. Decousus, H. Eriksson, B. Jacobson, J. Van Der Meer, E. Minar, F. Piovella, and W. Tomkowski. Central Independent Adjudication Committee: M. Prins (Chair), H. Baarslag, and D. Brandjes. Data Safety Management Board: D. Bergqvist (Chair), S. Laporte, and P. Mismetti. Investigators (principal investigators for each country): Australia – R. Baker, P. Blombery, B. Chong, A. Gallus, E. Gan, and H. Salem; Austria – M. Hirschl, E. Minar, and E. Pilger; Czech Republic – J. Chlumsky, K. Kovarova, J. Malý, P. Matoška, F. Patek, R. Spacek, M. Vitovec, and J. Zak; France – H. Decousus, J. Emmerich, P. Lacroix, D. Mottier, I. Quere, P. Roy, and J. Schmidt; Israel – M. Elias, D. Gavish, R. Hoffman, O. Hussein, M. Lishner, G. Lugassy, L. Schliamser, O. Shpilberg, D. Varon, and D. Zeltser; Italy – G. Ambrosio, A. Ghirarduzzi, D. Imberti, F. Piovella, E. Porreca, and P. Prandoni; Poland – A. Jawien, R. Nizankowski, M. Skorski, W. Tomkowski, W. Witkiewicz, and K. Zawilska; South Africa – J. Engelbrecht, B. Jacobson, J. v. Marle, and N. Wright; Sweden – J. Aagesen, A. Ågren, H. Eriksson, T. Jonson, G. Lärfars, and T. Wallen; the Netherlands – H. ten Cate, M. v. Marwijk Kooy, J. van der Meer, S. Middeldorp, J. Mol, and K. de Swart; USA – D. Garcia, R. Lyons, J. Rehm, and A. Spyropoulos.

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