Journal of Thrombosis and Haemostasis, 13: 1028–1035
DOI: 10.1111/jth.12923
ORIGINAL ARTICLE
Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study C. W. FRANCIS,* C. M. KESSLER,† S. Z. GOLDHABER,‡ M. J. KOVACS,§ M. MONREAL,¶ M. V. HUISMAN,** D. BERGQVIST,†† A. G. TURPIE,‡‡ T. L. ORTEL,§§ A. C. SPYROPOULOS,* I . P A B I N G E R ¶ ¶ and A . K . K A K K A R * * * *University of Rochester Medical Center, Rochester, NY; †Georgetown University Hospital, Washington, DC; ‡Brigham and Women’s Hospital, Boston, MA, USA; §London Health Sciences Centre, London, Ontario, Canada; ¶Hospital Universitari Germans Trias i Pujol, Carretera de Canyet, Barcelona, Spain; **Leiden University Medical Center, Leiden, the Netherlands; ††University Hospital, Uppsala, Sweden; ‡‡Hamilton Health Sciences, McMaster University, Hamilton, ON, Canada; §§Duke University Medical Center, Durham, NC, USA; ¶¶Medical University of Vienna, Wien, Austria; and ***Barts and The London Queen Mary’s School of Medicine and Dentistry, London, UK
To cite this article: Francis CW, Kessler CM, Goldhaber SZ, Kovacs MJ, Monreal M, Huisman MV, Bergqvist D, Turpie AG, Ortel TL, Spyropoulos AC, Pabinger I, Kakkar AK. Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study. J Thromb Haemost 2015; 13: 1028–35.
Summary. Background: Treatment of venous thromboembolism (VTE) in patients with cancer has a high rate of recurrence and bleeding complications. Guidelines recommend low-molecular-weight heparin (LMWH) for at least 3–6 months and possibly indefinitely for patients with active malignancy. There are, however, few data supporting treatment with LMWH beyond 6 months. The primary aim of the DALTECAN study (NCT00942968) was to determine the safety of dalteparin between 6 and 12 months in cancer-associated VTE. Methods: Patients with active cancer and newly diagnosed VTE were enrolled in a prospective, multicenter study and received subcutaneous dalteparin for 12 months. The rates of bleeding and recurrent VTE were evaluated at months 1, 2–6 and 7–12. Findings: Of 334 patients enrolled, 185 and 109 completed 6 and 12 months of therapy; 49.1% had deep vein thrombosis (DVT); 38.9% had pulmonary embolism (PE); and 12.0% had both on presentation. The overall frequency of major bleeding was 10.2% (34/334). Major bleeding occurred in 3.6% (12/334) in the first month, and 1.1% (14/1237) and 0.7% (8/1086) per patientmonth during months 2–6 and 7–12, respectively. Recurrent VTE occurred in 11.1% (37/334); the incidence rate was 5.7% (19/334) for month 1, 3.4% (10/296) during months 2–6, and 4.1% (8/194) during months 7–12. One Correspondence: Charles Francis, University of Rochester Medical Center, 601 Elmwood Avenue, Box 704, Rochester, NY 14642, USA. Tel.: +1 585 275 3761; fax: +1 585 756 4446. E-mail: [email protected] Received 2 December 2014 Manuscript handled by: M. Cushman Final decision: M. Cushman, 22 March 2015
hundred and sixteen patients died, four due to recurrent VTE and two due to bleeding. Conclusion: Major bleeding was less frequent during dalteparin therapy beyond 6 months. The risk of developing major bleeding complications or VTE recurrence was greatest in the first month of therapy and lower over the subsequent 11 months. Keywords: cancer; dalteparin; deep vein thrombosis; low-molecular-weight heparin; pulmonary embolism; venous thromboembolism.
Introduction Venous thromboembolism (VTE) occurs frequently in patients with cancer and is routinely treated with anticoagulants. It is associated with a higher rate of recurrent VTE and bleeding complications than in VTE patients without cancer [1–3]. The risk of VTE is approximately four times higher in cancer than in non-cancer patients [4]. Cancer, recurrent VTE and major bleeding are independent risk factors for death in patients with VTE [5], and patients with cancer who develop VTE have a worse outcome than those without VTE [6,7]. Previous studies in patients with cancer and VTE have demonstrated the efficacy and safety of low-molecular-weight heparin (LMWH) as monotherapy for a period of 3 to 6 months [8–10]. The CLOT study was a multinational, prospective, randomized trial in a general cancer population and showed superior efficacy of LMWH monotherapy with dalteparin compared with initial LMWH followed by a vitamin K antagonist (VKA), with no significant increase in major bleeding [8]. Several guidelines, including those from the American College of Chest Physicians (ACCP) [11], the National © 2015 International Society on Thrombosis and Haemostasis
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Comprehensive Cancer Network (NCCN) [12] and the American Society of Clinical Oncology (ASCO) [13] recommend LMWH as monotherapy for 3 to 6 months in patients with cancer-associated thrombosis. The NCCN guidelines also recommend that anticoagulation be continued indefinitely in patients with active solid tumor malignancies or persistent risk factors [12]. There are, however, limited data on LMWH monotherapy beyond 6 months and it is critical to resolve this knowledge gap. Therefore, we conducted the DALTECAN study, an international, multicenter, single-arm, open-label study, to evaluate the safety of dalteparin in cancer patients receiving treatment with dalteparin for longer than 6 months and up to a year. Methods Study populations
Adult patients with active cancer and a newly diagnosed, symptomatic, proximal DVT of the lower extremity, or PE, or both, were screened for eligibility within 96 h of the diagnosis of VTE prior to the study baseline visit. Active cancer was defined as having a diagnosis of cancer (excluding basal cell or squamous cell carcinoma of the skin) within 6 months before enrollment, having received any treatment for cancer within the previous 6 months, or having documented recurrent or metastatic cancer. At baseline, proximal DVT was diagnosed on the basis of evidence of thrombosis in the popliteal or more proximal veins by computed tomography (CT) scan, compression ultrasonography or contrast venography. A diagnosis of PE required verification by ventilation-perfusion lung scanning, helical CT or pulmonary angiography. The study protocol was reviewed and approved by the institutional review boards of each participating center. Informed consent was obtained from all patients. An independent Data Safety Monitoring Committee reviewed safety-related findings every 3 months. Inclusion and exclusion criteria
Major inclusion criteria were ≥ 18 years of age with a newly diagnosed symptomatic proximal DVT, PE, or both. Subjects must have had active cancer diagnosed within 6 months before enrollment, or received chemotherapy within the previous 6 months, or had documented recurrent or metastatic cancer. Major exclusion criteria were a high risk of bleeding (e.g. recent neurosurgery within 30 days, history of intracranial hemorrhage or acute gastroduodenal ulcer), need for hemodialysis, prior placement of an inferior vena cava filter, known hypersensitivity or contraindication to LMWH, pregnancy, uncontrolled hypertension, therapeutic doses of heparin or LMWH for > 96 h or oral anticoagulant © 2015 International Society on Thrombosis and Haemostasis
therapy for > 48 h, or a condition that in the opinion of the investigator would preclude the patient from completing the study procedures. Treatment regimen
All patients received subcutaneous dalteparin (FragminÒ; Eisai Inc., Woodcliff Lake, NJ, USA) at an initial dose of 200 IU kg 1 day 1 with a maximal daily dose of 18 000 IU for the first 4 weeks. During months 2–12, prefilled syringes were supplied according to the patient’s weight: 7500 IU for those weighing 56 kg or less, 10 000 IU for 57 to 68 kg, 12 500 IU for 69–82 kg, 15 000 IU for 83–98 kg, and 18 000 IU for those over 99 kg. This amounted to a reduced dalteparin dose of approximately 150 IU kg 1 day 1. The patients or family members were taught to inject medication, but home care services were arranged if necessary. Treatment was continued for a maximum of 12 months or until any of the following occurred: (i) recurrent VTE; (ii) bleeding necessitating permanent discontinuation of anticoagulant therapy; (iii) other adverse event necessitating discontinuation of dalteparin; (iv) withdrawal of consent; or (v) removal of subject by principal investigator for any medical reason. Dose reduction or transient interruption in therapy was permitted if clinically indicated. During month 1, the recommended dose reduction was to 150 IU kg 1 (25% reduction), and during months 2–12 the recommended dose reduction was to the next lower available prefilled syringe dosage (i.e. step down one dose). Measurement of the anticoagulant effect using an antifactor Xa assay was discouraged, except for patients with clinically significant renal insufficiency either at baseline or developing during the study. For subjects whose CrCl declined to < 30 mL min 1, dalteparin was adjusted monthly to maintain a trough plasma anti-Xa level of < 0.4 IU mL 1 before the next injection. If the platelet count declined to between 50 000 and 100 000 mm 3, the dose of dalteparin was reduced to 150 IU kg 1 daily during month 1 or reduced to the next lower prefilled syringe during months 2–12, until the platelet count recovered to ≥ 100 000 mm 3. Dalteparin was withheld if the platelet count was < 50 000 mm 3 until the count recovered. Patients were permitted to receive non-investigational drugs as required. Follow-up
Patients without renal insufficiency underwent clinical evaluations for efficacy and safety at weeks 1, 4, 8, 12, 24, 36, 48 and 52. Patients with renal insufficiency at baseline were evaluated monthly throughout the study. Patients were contacted by phone in months when clinic visits were not scheduled. Clinical visits included assessment of history, physical examination, laboratory values,
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complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002; 100: 3484–8. Gussoni G, Frasson S, La Regina M, DiMicco P, Monreal M, RIETE Investigators. Three-month mortality rate and clinical predictors in patients with venous thromboembolism and cancer. Findings from the RIETE registry. Thromb Res 2013; 1: 24–30. Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 2007; 3: 632–4. Sorenson HT, Mellamkjaer L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism. N Engl J Med 2000; 25: 1846–50. Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M. Lowmolecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349: 146–53. Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, Wong T, Cook R, Solymoss S, Poon MC, Raskob G, LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med 2006; 119: 1062–72. Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, SolalCeligny P, LeMaignan C, Extra JM, Cotty P, Farge D. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med 2002; 162: 1729–35.
© 2015 International Society on Thrombosis and Haemostasis
11 Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schü nemann HJ. Executive summary: antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 2 (Suppl): 7S–47S. 12 National Comprehensive Cancer Network. NCCN Guidelines in oncology: venous thromboembolic disease. http://www.nccn.org/ professionals/physucuan_gls/pdf/vte.pdf; Version 2.2013. Accessed 15 October 2014. 13 Lyman GH, Bonike K, Khorana AA, Kuderer NM, Lee AY, Arcelus JI, Balaban EP, Clarke JM, Flowers CR, Francis CW, Gates LE, Kakkar AK, Key NS, Levine MN, Liebman HA, Tempero MA, Wong SL, Somerfield MR, Falanga A. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2013; 17: 2189–204. 14 Schulman S, Angeras U, Bergqvist D, Erikson B, Lassen MR, Fisher W, on behalf of the Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. J Thromb Haemost 2010; 8: 202–4. 15 Akl EA, Labedi N, Barba M, Terrenato I, Sperati F, Muti P, Schü nemann H. Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev 2011; (CD006650).
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with dalteparin at baseline (n = 334) had characteristics similar to those who completed the first 6 months and started the second 6 months of treatment (n = 185). Of the patients enrolled, 91.6% (306/334) had solid tumors, with lung (16.8%), colorectal (12%), breast (9.3%) and pancreatic (9.3%) cancers being the most common; 62.6% of subjects had metastatic solid tumors. The distribution of ECOG status at baseline was 29.6%, 48.8% and 20.7% for Stage 0, 1 and 2, respectively. The qualifying VTE event was a DVT, PE or both in 49.1%, 38.9% and 12.0%, respectively. Of the patients enrolled, 6.0% had moderate renal impairment (estimated CrCl 30– 50 mL min 1) and 1.3% had severe renal impairment (CrCl < 30 mL min 1) at baseline. The mean duration of dalteparin therapy was 210 days, with a mean of 205 once-daily doses administered. Overall study adherence was 96%; 95% of patients took at least 80% of the study medication. Outcomes
Major bleeding in months 1–12 occurred in 10.2% (34/ 334) of patients. The primary study endpoint was the incidence of major bleeding events during the 7–12-month (> 6 months and up to the end of study) study period. During the 7–12-month study period (1086 subjectmonths), eight subjects experienced a major bleeding
event for an incidence of 0.7% (95% CI, 0.3, 1.4%). This incidence was less than the incidence of major bleeding events during the initial 6 months of the study (1.7%; 95% CI, 1.1, 2.4%), and less than the incidence during every other analyzed time-period during months 1–6 (Table 2). When evaluated by month, the highest incidence of major bleeding events was during the first month of the study (3.6%, 95% CI [1.9, 6.2%]). From 2 to 6 months, the monthly incidence ranged from 0.8% to 1.8%, and from 7 to 12 months, it ranged from 0% to 1.4%. The most frequent sites of bleeding were the gastrointestinal tract [12], brain [6] and the genitourinary system [4]. The overall incidence of all bleeding was 36.5% (122/ 334) for months 1–12. The Kaplan–Meier probability estimate of major bleeding was 9.3% and 14.5% at 6 and 12 months, respectively (Fig. 1). No baseline risk factors were found to be predictive of bleeding when analyzed by Cox regression analysis, including presence of known cerebral metastatic disease. Over the 12-month observation period, recurrent VTE occurred in 11.1% (37/334) (Table 3). During the 7–12month period, eight subjects experienced a recurrent VTE, resulting in an incidence of 4.1% (95% CI, 1.8, 8.0), compared with 29 subjects with an incidence of 8.7% (95% CI, 5.9, 12.2), during the 1–6-month time-period. The incidence per patient-month was highest during the first month (5.7%; 19/334), as compared with months
Table 1 Baseline characteristics Table 2 Incidence of major bleeding* Characteristic Age, mean (years) Female, no. of patients (%) Weight, mean (kg) Hematologic, n (%) Solid tumor, n (%) Lung Colorectal Breast Pancreas ECOG score, n (%) 0 1 2 3 4 Qualifying event, n (%) DVT PE DVT + PE Renal dysfunction, n (%) Moderate renal impairment (CrCL 30–50 mL/min) Severe renal impairment (CrCI < 30 mL/min)
Total cohort (n = 334)
Second 6-month cohort* (n = 185)
63.8 171 (51.2) 79.1 28 (8.4) 306 (91.6) 56 (16.8) 40 (12.0) 31 (9.3) 31 (9.3)
64.5 87 (47.0) 81.9 24 (13.0) 161 (87.0) 25 (13.5) 28 (15.1) 17 (9.2) 7 (5.9)
99 163 69 1 0
(29.6) (48.8) (20.7) (0.5)
66 90 28 1 0
164 (49.1) 130 (38.9) 40 (12.0)
– – –
9 (6.0%) 2 (1.3%)
(35.7) (48.6) (15.1) (0.3)
17 (9.2) 6 (3.2%)
*This includes only patients who continued anticoagulant treatment beyond the initial 6 months. DVT, deep vein thrombosis; PE, pulmonary embolism. © 2015 International Society on Thrombosis and Haemostasis
Total (N = 334) Time period 1–6 months 7–12 months 1–12 months 2–6 months 2–12 months By month* 1st month 2nd month 3rd month 4th month 5th month 6th month 7th month 8th month 9th month 10th month 11th month 12th month+
Incidence n/subject months at riskb
%
95% confidence intervala
26/1571 8/1086 34/2657 14/1237 22/2323
1.7 0.7 1.3 1.1 0.9
1.1, 0.3, 0.9, 0.6, 0.6,
12/334 3/301 2/266 2/244 4/221 3/204 0/192 1/172 1/160 2/153 2/139 2/270
3.6 1.0 0.8 0.8 1.8 1.5
1.9, 6.2 0.2, 2.9 0.1, 2.7 0.1, 2.9 0.5, 4.6 0.3, 4.2 0, 1.6 0, 3.2 0, 3.4 0.2, 4.6 0.2, 5.1 0.1, 2.7
0.6 0.6 1.3 1.4 0.7
2.4 1.4 1.8 1.9 1.4
*Adjudicated events were events that had been reviewed and confirmed by the Central Adjudication Committee. Events recorded during the study but after 365 days of treatment are included in the 12th month counts. a95% confidence interval, two-tailed exact Clopb per-Pearson. Denominator was the total subject-months at
risk during the time period.
Censored
15 – 10 – 5– 0– 0
100
200 300 Time to event (Day)
400
500
Fig. 1. Time to major bleeding. The Kaplan–Meier estimate of the time to the first occurrence of major bleeding is shown. Open circles represent censored points and the numbers of patients at risk are indicated.
Table 3 Incidence of adjudicated new or recurrent venous thromboembolism (deep vein thrombosis/pulmonary embolism) Total (N = 334) Time period
Incidence n/N
(%)
95% confidence intervalb
1–6 months 7–12 months 1–12 months 2–6 months 2–12 months
29/334 8/194 37/334 10/296 18/296
8.7 4.1 11.1 3.4 6.1
5.9, 1.8, 7.9, 1.6, 3.6,
a
12.2 8.0 14.9 6.1 9.4
a b
20 –
Censored
15 – 10 – 5– 0– 0
100
200
300
400
500
Time to event (Day)
Denominator is the number of patients at risk for that period. 95% confidence interval, two-tailed exact Clopper-Pearson.
2–6 (3.4%; 10/296) and 7–12 (4.1%; 8/194). The Kaplan– Meier probability estimate for recurrent VTE was 7.2% and 9.3% at 6 and 12 months, with a mean time to first VTE of 294 days (Fig. 2). When conducting Cox regression analysis for recurrent VTE events, no risk factors at baseline were found to be predictive. Prognostic factors included age category, sex, previous history of VTE, and baseline tumor type, tumor stage, chemotherapy status, ECOG status and BMI. A total of 116 patients (33.8%) died during the 12month study and 2-month follow-up period, with deaths continuing throughout the study period (Fig. 3). The primary reason for death was underlying cancer (105), while four patients died as a result of recurrent PE and two patients died from bleeding. Renally impaired patients
A total of 34 subjects had moderate to severe renal impairment (estimated CrCl 30–50 mL min 1) either at baseline or that developed during the course of observation, and 19 subjects had severe renal impairment (CrCl < 30 mL min 1). Of patients with moderate to severe renal impairment, four (11.8%) had recurrent VTE and one (2.9%) had a major bleeding event. Of the 19 patients with severe renal impairment who had serial
Fig. 2. Time to venous thromboembolism (VTE). The Kaplan–Meier estimate of the time to first occurrence of new VTE is shown. Open circles represent censored points and the numbers of patients at risk are indicated.
80 – Kaplan – Meier % of event
Kaplan – Meier % of event
20 –
Kaplan – Meier % of event
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70 –
Censored
60 – 50 – 40 – 30 – 20 – 10 – 0– 0
50
100
150
200 250 300 Time to event (Day)
350
400
450
500
Fig. 3. Time to death. The Kaplan–Meier estimate of the time to death is shown. Censored points are indicated by the open circles and the numbers at risk are shown.
anti-Xa assessments, the mean trough anti-Xa level was 0.3 U mL 1. Three of these patients had at least one anti-Xa level over 1.0 U mL 1. In total, the median number of dose adjustments for these patients was 0.5. Discussion DALTECAN shows that extending treatment between 6 and 12 months has a similar rate of recurrence and of bleeding complications to that observed during months 2 to 6. The incidence of major bleeding in the first 6 months was 7.8% (1.7% per patient month), comparable to that in the CLOT study (6%), and most bleeding occurred in the first month (3.6%). The recurrence of VTE was a critical secondary endpoint in the DALTECAN study. The rate in months 7–12 was low (4.1%) and similar to that in months 2–6 (3.4%). The overall recurrence rate in months 1–6 was 9.1%, similar to that reported in the CLOT study (9%) [8]. The treatment of VTE in patients with cancer is challenging, and the outcomes are worse than in patients without cancer. The reasons for this may include the highly prothrombotic state induced by cancer, procoagulant effects of the pharmacologic agents used in cancer treatment, concomitant surgery and other procedures, the need for indwelling central venous catheters, and other © 2015 International Society on Thrombosis and Haemostasis
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medical procedures. Known risks for bleeding include cancer involvement of the mucosal surfaces, thrombocytopenia, surgery, and other procedures. Changes in the gastrointestinal tract caused by chemotherapy may also contribute. Outcomes are better if cancer-associated thrombosis is treated with LMWH monotherapy rather than with heparin or LMWH followed by VKA. This is supported by a meta-analysis showing a reduced rate of recurrent VTE with LMWH monotherapy [15]. The results of randomized controlled trials also support the use of LMWH monotherapy. In the CLOT study [8], the probability of recurrent VTE at 6 months was 17% in the VKA-treated group and 9% in the dalteparin group (P = 0.002). The rate of major bleeding was 6% in the dalteparin-treated group and 4% in the VKA-treated group, which was not significantly different. The LITE trial reported that the LMWH tinzaparin was more effective in preventing recurrent VTE in cancer patients with VTE than combined therapy using initial heparin followed by VKA [9]. Meyer et al. [10] also reported that fewer patients with cancer and VTE experienced recurrent VTE or major bleeding when enoxaparin was used, compared with warfarin, for 3 months. Based on these studies, several guidelines recommend that patients with cancer and VTE be treated for 6 months with dalteparin monotherapy [11–13]. However, recommendations for treatment beyond 6 months are equivocal as there have been no data from clinical trials reporting recurrence and bleeding rates for longer periods of LMWH therapy prior to this trial. Cancer patients with VTE are heterogeneous, with varying tumor types, treatments and other characteristics that could influence the risk of thrombosis and response to treatment. The baseline characteristics of the subjects enrolled in the DALTECAN study were similar to those in the CLOT study, with comparable age, tumor types and distribution of DVT and PE. However, none of these characteristics contributed significantly to the risk of bleeding or thrombosis. Impaired renal function was considered likely to have an impact on bleeding risk and was a prespecified co-variable for analysis, but did not contribute significantly to bleeding rates. The DALTECAN study has important strengths. All subjects had objectively documented VTE and received a standard regimen of dalteparin monotherapy. The compliance was high and follow-up complete at 12 months in 63.2% of patients. All new VTE and bleeding events were adjudicated by expert independent committees. A limitation of the study is the open-label, single-arm design. Given the nature of a population comprised of cancer patients with VTE, the lack of published clinical data pertaining to this patient population, and the equivocal nature of national guidelines pertaining to the duration of anticoagulation with LMWH in patients with cancer and VTE, there was insufficient clinical equipoise to conduct a randomized trial with one group receiving limited-dura© 2015 International Society on Thrombosis and Haemostasis
tion anticoagulation for 3–6 months. The lack of a control group, however, limits the interpretation of our results. The DALTECAN cohort may have been less ill than patients who may be encountered in the general cancer population with symptomatic VTE. This may contribute to a relatively favorable prognosis being obtained for bleeding risk. Also, the high death rate resulted in only 32% of initially enrolled patients remaining on anticoagulation for the entire 12 months. DALTECAN highlights the ongoing challenges of treating cancer patients with acute DVT and PE. First, more than a decade after publication of the CLOT trial, the failure rate of full-dose LMWH monotherapy remains high, with 24 patients presenting with recurrent PE. Second, the rate of major bleeding remains high during the first months, with intracranial hemorrhage a complication in six patients, or 2% of the enrolled study population. Thus, alternative anticoagulant strategies need to be considered and these might include the use of new oral targeted agents. Third, the high mortality rate of the study cohort was due almost exclusively to cancer, with VTE adjudicated as the cause of death in only four patients. Thus, DALTECAN raises the question of whether the risk of extended-duration anticoagulation outweighs the benefit when factoring in cause of death and major bleeding complications. This mortality confounder also raised several analytic challenges. First, does this survival bias naturally select those who would bleed or have recurrent events? In order to account for this, the per-patient month analysis strategy was selected. This strategy accounts not only for the number of patients at any given study time-point, but also normalizes the analysis for the total number of observation months. Answering these questions will require additional clinical trials in this population, which is complicated by the impending mortality of advanced-cancer patients, for whom prevention of recurrent VTE with LMWH monotherapy must be balanced against its impact on major bleeding and quality of life. Addendum C. Francis contributed to the study design and data analysis, and wrote and approved the final manuscript. C. Kessler, S. Z. Goldhaber, M. Kovacs, A. Kakkar, A. C. Spyropoulos, I. Pabinger, M. Monreal, M. V. Huisman, D. Bergqvist, A. G. Turpie and T. Ortel contributed to the study design, data analysis and revision of the manuscript, and approved the final manuscript. Disclosure of Conflict of Interests This study was funded by Eisai. Eisai provided funding for editorial support in the development of this paper. C. McQueen of NSCI Group, Inc. provided writing support based on input from all authors. Eisai reviewed and
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provided feedback on the paper to the authors. The authors had full editorial control of the paper and gave their final approval of all content. A. Kakkar reports grants and personal fees from Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer and Sanofi S.A, outside the submitted work. M. Kovacs reports honorarium from Pfizer, LEO Pharma and Bayer; and grants from Pfizer, Bayer and Daiichi Sankyo, outside the submitted work. M. Monreal reports grants from Sanofi and Bayer Pharma AG; and personal fees from Daiichi Sankyo, Pfizer, Bayer Pharma AG and Boehringer Ingelheim, outside the submitted work. T. Ortel reports consultancy fees and research support from Instrumental Laboratory, during the conduct of the study; consultancy fees from Daiichi Sankyo; and research support for a clinical trial from Pfizer, outside the submitted work. I. Pabinger reports giving educational lectures for Pfizer, during the conduct of the study. A. C. Spyropoulos reports personal fees from Sanofi, during the conduct of the study; and personal fees from Boehringer Ingelheim, Jansen and Daiichi Sankyo, outside the submitted work. A. G. Turpie was Chair of a study for The Data and Safety Monitoring Board, outside the submitted work. Appendix List of Steering Committee Lord Ajay Kakkar, Barts and The London Queen Mary’s School of Medicine and Dentistry Alex C Spyropoulos, University of Rochester Medical Center Ingrid Pabinger, Medical University of Vienna Manuel Monreal, Hospital Universitari Germans Trias i Pujol Samuel Z. Goldhaber, Brigham and Women’s Hospital Craig Kessler, Georgetown University Hospital Menno V. Huisman, Leiden University Medical Center David Bergqvist, University Hospital, Uppsala, Sweden Thomas Ortel, Duke University Medical Center Michael Kovacs, London Health Sciences Centre Charles Francis, University of Rochester Medical Center Adjudication Committee Alexander G. Turpie, Hamilton Health Sciences, McMaster University (Chair) Michael Streiff, Johns Hopkins University Howard Leibman, University of Southern California List of sites Ruby Deveras, Halifax Health Carmelita Escalante, Anderson Cancer Center Charles Francis, University of Rochester Medical Center Craig Kessler, Georgetown University Hospital Vinay Shah, Henry Ford Hospital
Mandeep Dhami, Eastern CT Hematology and Oncology Associates Antonios Gasparis, Stony Brook University Gail Macik, University of Virginia Thomas Ortel, Duke University Medical Center Jean Connors, Brigham and Women’s Hospital Darrell Harrington, Harbor-UCLA Medical Center Robert Robles, Bay Area Cancer Research Group Steven Ades, Vermont Cancer Center at Fletcher Allen Health Care Vijay Rao Phooshkooru, MidDakota Clinic David Henry, Pennsylvania Oncology Hematology Associates Goetz Kloecker, James Graham Brown Cancer Center Ira Oliff, Orchard Healthcare Jeffrey Cilley, Hematology Oncology Associates of Illinois Jeffrey Wasser, University of Connecticut Health Center Alison Stopeck, Arizona Cancer Center at UMC North Michael Kovacs, London Health Sciences Centre Sudeep Shivakumar, Queen Elizabeth II Health Sciences Centre Marc Carrier, Ottawa Hospital Research Institute Vicky Tagalakis, Sir Mortimer B. Davis Jewish General Hospital Erik Yeo, University Health Network Agnes Lee, Vancouver General Hospital Thrombosis Clinic Bruce Ritchie, University of Alberta Jeannine Kassis, Hopital Maisonneuve-Rosemont Ernst Pilger, LKH Graz Universit€ atstklinik f€ ur Innere Medizin Ingrid Pabinger, Medizinische Universit€ at Wien Ernst Rechberger, KH der Barmherzigen Schwestern Peter Balcke, Landesklinikum St P€ olten Michael Steurer, Medizinische Universit€ at Innsbruck Josef Koenig, KH d. Elisabethinen Linz GmbH Frans Erdkamp, Orbis Medisch Centrum Jitske Smit, Gelre ziekenhuizen Ram on Lecumberri, Clinica Universitaria de Navarra Javier Trujillo-Santos, Hospital Universitario Santa Lucıa Antoni Castro, Hospital Universitari Dr Josep Trueta Vladimir Salazar, Hospital Virgen de la Arrixaca Juan Carlos Reverter, Hospital Clinic i Provincial References 1 Lee AY, Levine MN. Venous thromboembolism and cancer: risks and outcomes. Circulation 2003; 23(Suppl 1): I17–21. 2 Lee A, Peterson E. Treatment of cancer-associated thrombosis. Blood 2013; 14: 2310–7. 3 Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood 2013; 10: 1712–23. 4 Prandoni P, Lensing AW, Piccioli A, Bernardi E, Simioni P, Girolami B, Marchori A, Sabbion P, Prins MH, Norenta F, Girolami A. Recurrent venous thromboembolism and bleeding
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complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002; 100: 3484–8. Gussoni G, Frasson S, La Regina M, DiMicco P, Monreal M, RIETE Investigators. Three-month mortality rate and clinical predictors in patients with venous thromboembolism and cancer. Findings from the RIETE registry. Thromb Res 2013; 1: 24–30. Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 2007; 3: 632–4. Sorenson HT, Mellamkjaer L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism. N Engl J Med 2000; 25: 1846–50. Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M. Lowmolecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349: 146–53. Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, Wong T, Cook R, Solymoss S, Poon MC, Raskob G, LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med 2006; 119: 1062–72. Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, SolalCeligny P, LeMaignan C, Extra JM, Cotty P, Farge D. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med 2002; 162: 1729–35.
© 2015 International Society on Thrombosis and Haemostasis
11 Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schü nemann HJ. Executive summary: antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 2 (Suppl): 7S–47S. 12 National Comprehensive Cancer Network. NCCN Guidelines in oncology: venous thromboembolic disease. http://www.nccn.org/ professionals/physucuan_gls/pdf/vte.pdf; Version 2.2013. Accessed 15 October 2014. 13 Lyman GH, Bonike K, Khorana AA, Kuderer NM, Lee AY, Arcelus JI, Balaban EP, Clarke JM, Flowers CR, Francis CW, Gates LE, Kakkar AK, Key NS, Levine MN, Liebman HA, Tempero MA, Wong SL, Somerfield MR, Falanga A. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2013; 17: 2189–204. 14 Schulman S, Angeras U, Bergqvist D, Erikson B, Lassen MR, Fisher W, on behalf of the Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. J Thromb Haemost 2010; 8: 202–4. 15 Akl EA, Labedi N, Barba M, Terrenato I, Sperati F, Muti P, Schü nemann H. Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev 2011; (CD006650).
DOI: 10.1111/jth.12923
ORIGINAL ARTICLE
Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study C. W. FRANCIS,* C. M. KESSLER,† S. Z. GOLDHABER,‡ M. J. KOVACS,§ M. MONREAL,¶ M. V. HUISMAN,** D. BERGQVIST,†† A. G. TURPIE,‡‡ T. L. ORTEL,§§ A. C. SPYROPOULOS,* I . P A B I N G E R ¶ ¶ and A . K . K A K K A R * * * *University of Rochester Medical Center, Rochester, NY; †Georgetown University Hospital, Washington, DC; ‡Brigham and Women’s Hospital, Boston, MA, USA; §London Health Sciences Centre, London, Ontario, Canada; ¶Hospital Universitari Germans Trias i Pujol, Carretera de Canyet, Barcelona, Spain; **Leiden University Medical Center, Leiden, the Netherlands; ††University Hospital, Uppsala, Sweden; ‡‡Hamilton Health Sciences, McMaster University, Hamilton, ON, Canada; §§Duke University Medical Center, Durham, NC, USA; ¶¶Medical University of Vienna, Wien, Austria; and ***Barts and The London Queen Mary’s School of Medicine and Dentistry, London, UK
To cite this article: Francis CW, Kessler CM, Goldhaber SZ, Kovacs MJ, Monreal M, Huisman MV, Bergqvist D, Turpie AG, Ortel TL, Spyropoulos AC, Pabinger I, Kakkar AK. Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study. J Thromb Haemost 2015; 13: 1028–35.
Summary. Background: Treatment of venous thromboembolism (VTE) in patients with cancer has a high rate of recurrence and bleeding complications. Guidelines recommend low-molecular-weight heparin (LMWH) for at least 3–6 months and possibly indefinitely for patients with active malignancy. There are, however, few data supporting treatment with LMWH beyond 6 months. The primary aim of the DALTECAN study (NCT00942968) was to determine the safety of dalteparin between 6 and 12 months in cancer-associated VTE. Methods: Patients with active cancer and newly diagnosed VTE were enrolled in a prospective, multicenter study and received subcutaneous dalteparin for 12 months. The rates of bleeding and recurrent VTE were evaluated at months 1, 2–6 and 7–12. Findings: Of 334 patients enrolled, 185 and 109 completed 6 and 12 months of therapy; 49.1% had deep vein thrombosis (DVT); 38.9% had pulmonary embolism (PE); and 12.0% had both on presentation. The overall frequency of major bleeding was 10.2% (34/334). Major bleeding occurred in 3.6% (12/334) in the first month, and 1.1% (14/1237) and 0.7% (8/1086) per patientmonth during months 2–6 and 7–12, respectively. Recurrent VTE occurred in 11.1% (37/334); the incidence rate was 5.7% (19/334) for month 1, 3.4% (10/296) during months 2–6, and 4.1% (8/194) during months 7–12. One Correspondence: Charles Francis, University of Rochester Medical Center, 601 Elmwood Avenue, Box 704, Rochester, NY 14642, USA. Tel.: +1 585 275 3761; fax: +1 585 756 4446. E-mail: [email protected] Received 2 December 2014 Manuscript handled by: M. Cushman Final decision: M. Cushman, 22 March 2015
hundred and sixteen patients died, four due to recurrent VTE and two due to bleeding. Conclusion: Major bleeding was less frequent during dalteparin therapy beyond 6 months. The risk of developing major bleeding complications or VTE recurrence was greatest in the first month of therapy and lower over the subsequent 11 months. Keywords: cancer; dalteparin; deep vein thrombosis; low-molecular-weight heparin; pulmonary embolism; venous thromboembolism.
Introduction Venous thromboembolism (VTE) occurs frequently in patients with cancer and is routinely treated with anticoagulants. It is associated with a higher rate of recurrent VTE and bleeding complications than in VTE patients without cancer [1–3]. The risk of VTE is approximately four times higher in cancer than in non-cancer patients [4]. Cancer, recurrent VTE and major bleeding are independent risk factors for death in patients with VTE [5], and patients with cancer who develop VTE have a worse outcome than those without VTE [6,7]. Previous studies in patients with cancer and VTE have demonstrated the efficacy and safety of low-molecular-weight heparin (LMWH) as monotherapy for a period of 3 to 6 months [8–10]. The CLOT study was a multinational, prospective, randomized trial in a general cancer population and showed superior efficacy of LMWH monotherapy with dalteparin compared with initial LMWH followed by a vitamin K antagonist (VKA), with no significant increase in major bleeding [8]. Several guidelines, including those from the American College of Chest Physicians (ACCP) [11], the National © 2015 International Society on Thrombosis and Haemostasis
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Comprehensive Cancer Network (NCCN) [12] and the American Society of Clinical Oncology (ASCO) [13] recommend LMWH as monotherapy for 3 to 6 months in patients with cancer-associated thrombosis. The NCCN guidelines also recommend that anticoagulation be continued indefinitely in patients with active solid tumor malignancies or persistent risk factors [12]. There are, however, limited data on LMWH monotherapy beyond 6 months and it is critical to resolve this knowledge gap. Therefore, we conducted the DALTECAN study, an international, multicenter, single-arm, open-label study, to evaluate the safety of dalteparin in cancer patients receiving treatment with dalteparin for longer than 6 months and up to a year. Methods Study populations
Adult patients with active cancer and a newly diagnosed, symptomatic, proximal DVT of the lower extremity, or PE, or both, were screened for eligibility within 96 h of the diagnosis of VTE prior to the study baseline visit. Active cancer was defined as having a diagnosis of cancer (excluding basal cell or squamous cell carcinoma of the skin) within 6 months before enrollment, having received any treatment for cancer within the previous 6 months, or having documented recurrent or metastatic cancer. At baseline, proximal DVT was diagnosed on the basis of evidence of thrombosis in the popliteal or more proximal veins by computed tomography (CT) scan, compression ultrasonography or contrast venography. A diagnosis of PE required verification by ventilation-perfusion lung scanning, helical CT or pulmonary angiography. The study protocol was reviewed and approved by the institutional review boards of each participating center. Informed consent was obtained from all patients. An independent Data Safety Monitoring Committee reviewed safety-related findings every 3 months. Inclusion and exclusion criteria
Major inclusion criteria were ≥ 18 years of age with a newly diagnosed symptomatic proximal DVT, PE, or both. Subjects must have had active cancer diagnosed within 6 months before enrollment, or received chemotherapy within the previous 6 months, or had documented recurrent or metastatic cancer. Major exclusion criteria were a high risk of bleeding (e.g. recent neurosurgery within 30 days, history of intracranial hemorrhage or acute gastroduodenal ulcer), need for hemodialysis, prior placement of an inferior vena cava filter, known hypersensitivity or contraindication to LMWH, pregnancy, uncontrolled hypertension, therapeutic doses of heparin or LMWH for > 96 h or oral anticoagulant © 2015 International Society on Thrombosis and Haemostasis
therapy for > 48 h, or a condition that in the opinion of the investigator would preclude the patient from completing the study procedures. Treatment regimen
All patients received subcutaneous dalteparin (FragminÒ; Eisai Inc., Woodcliff Lake, NJ, USA) at an initial dose of 200 IU kg 1 day 1 with a maximal daily dose of 18 000 IU for the first 4 weeks. During months 2–12, prefilled syringes were supplied according to the patient’s weight: 7500 IU for those weighing 56 kg or less, 10 000 IU for 57 to 68 kg, 12 500 IU for 69–82 kg, 15 000 IU for 83–98 kg, and 18 000 IU for those over 99 kg. This amounted to a reduced dalteparin dose of approximately 150 IU kg 1 day 1. The patients or family members were taught to inject medication, but home care services were arranged if necessary. Treatment was continued for a maximum of 12 months or until any of the following occurred: (i) recurrent VTE; (ii) bleeding necessitating permanent discontinuation of anticoagulant therapy; (iii) other adverse event necessitating discontinuation of dalteparin; (iv) withdrawal of consent; or (v) removal of subject by principal investigator for any medical reason. Dose reduction or transient interruption in therapy was permitted if clinically indicated. During month 1, the recommended dose reduction was to 150 IU kg 1 (25% reduction), and during months 2–12 the recommended dose reduction was to the next lower available prefilled syringe dosage (i.e. step down one dose). Measurement of the anticoagulant effect using an antifactor Xa assay was discouraged, except for patients with clinically significant renal insufficiency either at baseline or developing during the study. For subjects whose CrCl declined to < 30 mL min 1, dalteparin was adjusted monthly to maintain a trough plasma anti-Xa level of < 0.4 IU mL 1 before the next injection. If the platelet count declined to between 50 000 and 100 000 mm 3, the dose of dalteparin was reduced to 150 IU kg 1 daily during month 1 or reduced to the next lower prefilled syringe during months 2–12, until the platelet count recovered to ≥ 100 000 mm 3. Dalteparin was withheld if the platelet count was < 50 000 mm 3 until the count recovered. Patients were permitted to receive non-investigational drugs as required. Follow-up
Patients without renal insufficiency underwent clinical evaluations for efficacy and safety at weeks 1, 4, 8, 12, 24, 36, 48 and 52. Patients with renal insufficiency at baseline were evaluated monthly throughout the study. Patients were contacted by phone in months when clinic visits were not scheduled. Clinical visits included assessment of history, physical examination, laboratory values,
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complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002; 100: 3484–8. Gussoni G, Frasson S, La Regina M, DiMicco P, Monreal M, RIETE Investigators. Three-month mortality rate and clinical predictors in patients with venous thromboembolism and cancer. Findings from the RIETE registry. Thromb Res 2013; 1: 24–30. Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 2007; 3: 632–4. Sorenson HT, Mellamkjaer L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism. N Engl J Med 2000; 25: 1846–50. Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M. Lowmolecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349: 146–53. Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, Wong T, Cook R, Solymoss S, Poon MC, Raskob G, LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med 2006; 119: 1062–72. Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, SolalCeligny P, LeMaignan C, Extra JM, Cotty P, Farge D. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med 2002; 162: 1729–35.
© 2015 International Society on Thrombosis and Haemostasis
11 Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schü nemann HJ. Executive summary: antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 2 (Suppl): 7S–47S. 12 National Comprehensive Cancer Network. NCCN Guidelines in oncology: venous thromboembolic disease. http://www.nccn.org/ professionals/physucuan_gls/pdf/vte.pdf; Version 2.2013. Accessed 15 October 2014. 13 Lyman GH, Bonike K, Khorana AA, Kuderer NM, Lee AY, Arcelus JI, Balaban EP, Clarke JM, Flowers CR, Francis CW, Gates LE, Kakkar AK, Key NS, Levine MN, Liebman HA, Tempero MA, Wong SL, Somerfield MR, Falanga A. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2013; 17: 2189–204. 14 Schulman S, Angeras U, Bergqvist D, Erikson B, Lassen MR, Fisher W, on behalf of the Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. J Thromb Haemost 2010; 8: 202–4. 15 Akl EA, Labedi N, Barba M, Terrenato I, Sperati F, Muti P, Schü nemann H. Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev 2011; (CD006650).
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with dalteparin at baseline (n = 334) had characteristics similar to those who completed the first 6 months and started the second 6 months of treatment (n = 185). Of the patients enrolled, 91.6% (306/334) had solid tumors, with lung (16.8%), colorectal (12%), breast (9.3%) and pancreatic (9.3%) cancers being the most common; 62.6% of subjects had metastatic solid tumors. The distribution of ECOG status at baseline was 29.6%, 48.8% and 20.7% for Stage 0, 1 and 2, respectively. The qualifying VTE event was a DVT, PE or both in 49.1%, 38.9% and 12.0%, respectively. Of the patients enrolled, 6.0% had moderate renal impairment (estimated CrCl 30– 50 mL min 1) and 1.3% had severe renal impairment (CrCl < 30 mL min 1) at baseline. The mean duration of dalteparin therapy was 210 days, with a mean of 205 once-daily doses administered. Overall study adherence was 96%; 95% of patients took at least 80% of the study medication. Outcomes
Major bleeding in months 1–12 occurred in 10.2% (34/ 334) of patients. The primary study endpoint was the incidence of major bleeding events during the 7–12-month (> 6 months and up to the end of study) study period. During the 7–12-month study period (1086 subjectmonths), eight subjects experienced a major bleeding
event for an incidence of 0.7% (95% CI, 0.3, 1.4%). This incidence was less than the incidence of major bleeding events during the initial 6 months of the study (1.7%; 95% CI, 1.1, 2.4%), and less than the incidence during every other analyzed time-period during months 1–6 (Table 2). When evaluated by month, the highest incidence of major bleeding events was during the first month of the study (3.6%, 95% CI [1.9, 6.2%]). From 2 to 6 months, the monthly incidence ranged from 0.8% to 1.8%, and from 7 to 12 months, it ranged from 0% to 1.4%. The most frequent sites of bleeding were the gastrointestinal tract [12], brain [6] and the genitourinary system [4]. The overall incidence of all bleeding was 36.5% (122/ 334) for months 1–12. The Kaplan–Meier probability estimate of major bleeding was 9.3% and 14.5% at 6 and 12 months, respectively (Fig. 1). No baseline risk factors were found to be predictive of bleeding when analyzed by Cox regression analysis, including presence of known cerebral metastatic disease. Over the 12-month observation period, recurrent VTE occurred in 11.1% (37/334) (Table 3). During the 7–12month period, eight subjects experienced a recurrent VTE, resulting in an incidence of 4.1% (95% CI, 1.8, 8.0), compared with 29 subjects with an incidence of 8.7% (95% CI, 5.9, 12.2), during the 1–6-month time-period. The incidence per patient-month was highest during the first month (5.7%; 19/334), as compared with months
Table 1 Baseline characteristics Table 2 Incidence of major bleeding* Characteristic Age, mean (years) Female, no. of patients (%) Weight, mean (kg) Hematologic, n (%) Solid tumor, n (%) Lung Colorectal Breast Pancreas ECOG score, n (%) 0 1 2 3 4 Qualifying event, n (%) DVT PE DVT + PE Renal dysfunction, n (%) Moderate renal impairment (CrCL 30–50 mL/min) Severe renal impairment (CrCI < 30 mL/min)
Total cohort (n = 334)
Second 6-month cohort* (n = 185)
63.8 171 (51.2) 79.1 28 (8.4) 306 (91.6) 56 (16.8) 40 (12.0) 31 (9.3) 31 (9.3)
64.5 87 (47.0) 81.9 24 (13.0) 161 (87.0) 25 (13.5) 28 (15.1) 17 (9.2) 7 (5.9)
99 163 69 1 0
(29.6) (48.8) (20.7) (0.5)
66 90 28 1 0
164 (49.1) 130 (38.9) 40 (12.0)
– – –
9 (6.0%) 2 (1.3%)
(35.7) (48.6) (15.1) (0.3)
17 (9.2) 6 (3.2%)
*This includes only patients who continued anticoagulant treatment beyond the initial 6 months. DVT, deep vein thrombosis; PE, pulmonary embolism. © 2015 International Society on Thrombosis and Haemostasis
Total (N = 334) Time period 1–6 months 7–12 months 1–12 months 2–6 months 2–12 months By month* 1st month 2nd month 3rd month 4th month 5th month 6th month 7th month 8th month 9th month 10th month 11th month 12th month+
Incidence n/subject months at riskb
%
95% confidence intervala
26/1571 8/1086 34/2657 14/1237 22/2323
1.7 0.7 1.3 1.1 0.9
1.1, 0.3, 0.9, 0.6, 0.6,
12/334 3/301 2/266 2/244 4/221 3/204 0/192 1/172 1/160 2/153 2/139 2/270
3.6 1.0 0.8 0.8 1.8 1.5
1.9, 6.2 0.2, 2.9 0.1, 2.7 0.1, 2.9 0.5, 4.6 0.3, 4.2 0, 1.6 0, 3.2 0, 3.4 0.2, 4.6 0.2, 5.1 0.1, 2.7
0.6 0.6 1.3 1.4 0.7
2.4 1.4 1.8 1.9 1.4
*Adjudicated events were events that had been reviewed and confirmed by the Central Adjudication Committee. Events recorded during the study but after 365 days of treatment are included in the 12th month counts. a95% confidence interval, two-tailed exact Clopb per-Pearson. Denominator was the total subject-months at
risk during the time period.
Censored
15 – 10 – 5– 0– 0
100
200 300 Time to event (Day)
400
500
Fig. 1. Time to major bleeding. The Kaplan–Meier estimate of the time to the first occurrence of major bleeding is shown. Open circles represent censored points and the numbers of patients at risk are indicated.
Table 3 Incidence of adjudicated new or recurrent venous thromboembolism (deep vein thrombosis/pulmonary embolism) Total (N = 334) Time period
Incidence n/N
(%)
95% confidence intervalb
1–6 months 7–12 months 1–12 months 2–6 months 2–12 months
29/334 8/194 37/334 10/296 18/296
8.7 4.1 11.1 3.4 6.1
5.9, 1.8, 7.9, 1.6, 3.6,
a
12.2 8.0 14.9 6.1 9.4
a b
20 –
Censored
15 – 10 – 5– 0– 0
100
200
300
400
500
Time to event (Day)
Denominator is the number of patients at risk for that period. 95% confidence interval, two-tailed exact Clopper-Pearson.
2–6 (3.4%; 10/296) and 7–12 (4.1%; 8/194). The Kaplan– Meier probability estimate for recurrent VTE was 7.2% and 9.3% at 6 and 12 months, with a mean time to first VTE of 294 days (Fig. 2). When conducting Cox regression analysis for recurrent VTE events, no risk factors at baseline were found to be predictive. Prognostic factors included age category, sex, previous history of VTE, and baseline tumor type, tumor stage, chemotherapy status, ECOG status and BMI. A total of 116 patients (33.8%) died during the 12month study and 2-month follow-up period, with deaths continuing throughout the study period (Fig. 3). The primary reason for death was underlying cancer (105), while four patients died as a result of recurrent PE and two patients died from bleeding. Renally impaired patients
A total of 34 subjects had moderate to severe renal impairment (estimated CrCl 30–50 mL min 1) either at baseline or that developed during the course of observation, and 19 subjects had severe renal impairment (CrCl < 30 mL min 1). Of patients with moderate to severe renal impairment, four (11.8%) had recurrent VTE and one (2.9%) had a major bleeding event. Of the 19 patients with severe renal impairment who had serial
Fig. 2. Time to venous thromboembolism (VTE). The Kaplan–Meier estimate of the time to first occurrence of new VTE is shown. Open circles represent censored points and the numbers of patients at risk are indicated.
80 – Kaplan – Meier % of event
Kaplan – Meier % of event
20 –
Kaplan – Meier % of event
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70 –
Censored
60 – 50 – 40 – 30 – 20 – 10 – 0– 0
50
100
150
200 250 300 Time to event (Day)
350
400
450
500
Fig. 3. Time to death. The Kaplan–Meier estimate of the time to death is shown. Censored points are indicated by the open circles and the numbers at risk are shown.
anti-Xa assessments, the mean trough anti-Xa level was 0.3 U mL 1. Three of these patients had at least one anti-Xa level over 1.0 U mL 1. In total, the median number of dose adjustments for these patients was 0.5. Discussion DALTECAN shows that extending treatment between 6 and 12 months has a similar rate of recurrence and of bleeding complications to that observed during months 2 to 6. The incidence of major bleeding in the first 6 months was 7.8% (1.7% per patient month), comparable to that in the CLOT study (6%), and most bleeding occurred in the first month (3.6%). The recurrence of VTE was a critical secondary endpoint in the DALTECAN study. The rate in months 7–12 was low (4.1%) and similar to that in months 2–6 (3.4%). The overall recurrence rate in months 1–6 was 9.1%, similar to that reported in the CLOT study (9%) [8]. The treatment of VTE in patients with cancer is challenging, and the outcomes are worse than in patients without cancer. The reasons for this may include the highly prothrombotic state induced by cancer, procoagulant effects of the pharmacologic agents used in cancer treatment, concomitant surgery and other procedures, the need for indwelling central venous catheters, and other © 2015 International Society on Thrombosis and Haemostasis
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medical procedures. Known risks for bleeding include cancer involvement of the mucosal surfaces, thrombocytopenia, surgery, and other procedures. Changes in the gastrointestinal tract caused by chemotherapy may also contribute. Outcomes are better if cancer-associated thrombosis is treated with LMWH monotherapy rather than with heparin or LMWH followed by VKA. This is supported by a meta-analysis showing a reduced rate of recurrent VTE with LMWH monotherapy [15]. The results of randomized controlled trials also support the use of LMWH monotherapy. In the CLOT study [8], the probability of recurrent VTE at 6 months was 17% in the VKA-treated group and 9% in the dalteparin group (P = 0.002). The rate of major bleeding was 6% in the dalteparin-treated group and 4% in the VKA-treated group, which was not significantly different. The LITE trial reported that the LMWH tinzaparin was more effective in preventing recurrent VTE in cancer patients with VTE than combined therapy using initial heparin followed by VKA [9]. Meyer et al. [10] also reported that fewer patients with cancer and VTE experienced recurrent VTE or major bleeding when enoxaparin was used, compared with warfarin, for 3 months. Based on these studies, several guidelines recommend that patients with cancer and VTE be treated for 6 months with dalteparin monotherapy [11–13]. However, recommendations for treatment beyond 6 months are equivocal as there have been no data from clinical trials reporting recurrence and bleeding rates for longer periods of LMWH therapy prior to this trial. Cancer patients with VTE are heterogeneous, with varying tumor types, treatments and other characteristics that could influence the risk of thrombosis and response to treatment. The baseline characteristics of the subjects enrolled in the DALTECAN study were similar to those in the CLOT study, with comparable age, tumor types and distribution of DVT and PE. However, none of these characteristics contributed significantly to the risk of bleeding or thrombosis. Impaired renal function was considered likely to have an impact on bleeding risk and was a prespecified co-variable for analysis, but did not contribute significantly to bleeding rates. The DALTECAN study has important strengths. All subjects had objectively documented VTE and received a standard regimen of dalteparin monotherapy. The compliance was high and follow-up complete at 12 months in 63.2% of patients. All new VTE and bleeding events were adjudicated by expert independent committees. A limitation of the study is the open-label, single-arm design. Given the nature of a population comprised of cancer patients with VTE, the lack of published clinical data pertaining to this patient population, and the equivocal nature of national guidelines pertaining to the duration of anticoagulation with LMWH in patients with cancer and VTE, there was insufficient clinical equipoise to conduct a randomized trial with one group receiving limited-dura© 2015 International Society on Thrombosis and Haemostasis
tion anticoagulation for 3–6 months. The lack of a control group, however, limits the interpretation of our results. The DALTECAN cohort may have been less ill than patients who may be encountered in the general cancer population with symptomatic VTE. This may contribute to a relatively favorable prognosis being obtained for bleeding risk. Also, the high death rate resulted in only 32% of initially enrolled patients remaining on anticoagulation for the entire 12 months. DALTECAN highlights the ongoing challenges of treating cancer patients with acute DVT and PE. First, more than a decade after publication of the CLOT trial, the failure rate of full-dose LMWH monotherapy remains high, with 24 patients presenting with recurrent PE. Second, the rate of major bleeding remains high during the first months, with intracranial hemorrhage a complication in six patients, or 2% of the enrolled study population. Thus, alternative anticoagulant strategies need to be considered and these might include the use of new oral targeted agents. Third, the high mortality rate of the study cohort was due almost exclusively to cancer, with VTE adjudicated as the cause of death in only four patients. Thus, DALTECAN raises the question of whether the risk of extended-duration anticoagulation outweighs the benefit when factoring in cause of death and major bleeding complications. This mortality confounder also raised several analytic challenges. First, does this survival bias naturally select those who would bleed or have recurrent events? In order to account for this, the per-patient month analysis strategy was selected. This strategy accounts not only for the number of patients at any given study time-point, but also normalizes the analysis for the total number of observation months. Answering these questions will require additional clinical trials in this population, which is complicated by the impending mortality of advanced-cancer patients, for whom prevention of recurrent VTE with LMWH monotherapy must be balanced against its impact on major bleeding and quality of life. Addendum C. Francis contributed to the study design and data analysis, and wrote and approved the final manuscript. C. Kessler, S. Z. Goldhaber, M. Kovacs, A. Kakkar, A. C. Spyropoulos, I. Pabinger, M. Monreal, M. V. Huisman, D. Bergqvist, A. G. Turpie and T. Ortel contributed to the study design, data analysis and revision of the manuscript, and approved the final manuscript. Disclosure of Conflict of Interests This study was funded by Eisai. Eisai provided funding for editorial support in the development of this paper. C. McQueen of NSCI Group, Inc. provided writing support based on input from all authors. Eisai reviewed and
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provided feedback on the paper to the authors. The authors had full editorial control of the paper and gave their final approval of all content. A. Kakkar reports grants and personal fees from Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer and Sanofi S.A, outside the submitted work. M. Kovacs reports honorarium from Pfizer, LEO Pharma and Bayer; and grants from Pfizer, Bayer and Daiichi Sankyo, outside the submitted work. M. Monreal reports grants from Sanofi and Bayer Pharma AG; and personal fees from Daiichi Sankyo, Pfizer, Bayer Pharma AG and Boehringer Ingelheim, outside the submitted work. T. Ortel reports consultancy fees and research support from Instrumental Laboratory, during the conduct of the study; consultancy fees from Daiichi Sankyo; and research support for a clinical trial from Pfizer, outside the submitted work. I. Pabinger reports giving educational lectures for Pfizer, during the conduct of the study. A. C. Spyropoulos reports personal fees from Sanofi, during the conduct of the study; and personal fees from Boehringer Ingelheim, Jansen and Daiichi Sankyo, outside the submitted work. A. G. Turpie was Chair of a study for The Data and Safety Monitoring Board, outside the submitted work. Appendix List of Steering Committee Lord Ajay Kakkar, Barts and The London Queen Mary’s School of Medicine and Dentistry Alex C Spyropoulos, University of Rochester Medical Center Ingrid Pabinger, Medical University of Vienna Manuel Monreal, Hospital Universitari Germans Trias i Pujol Samuel Z. Goldhaber, Brigham and Women’s Hospital Craig Kessler, Georgetown University Hospital Menno V. Huisman, Leiden University Medical Center David Bergqvist, University Hospital, Uppsala, Sweden Thomas Ortel, Duke University Medical Center Michael Kovacs, London Health Sciences Centre Charles Francis, University of Rochester Medical Center Adjudication Committee Alexander G. Turpie, Hamilton Health Sciences, McMaster University (Chair) Michael Streiff, Johns Hopkins University Howard Leibman, University of Southern California List of sites Ruby Deveras, Halifax Health Carmelita Escalante, Anderson Cancer Center Charles Francis, University of Rochester Medical Center Craig Kessler, Georgetown University Hospital Vinay Shah, Henry Ford Hospital
Mandeep Dhami, Eastern CT Hematology and Oncology Associates Antonios Gasparis, Stony Brook University Gail Macik, University of Virginia Thomas Ortel, Duke University Medical Center Jean Connors, Brigham and Women’s Hospital Darrell Harrington, Harbor-UCLA Medical Center Robert Robles, Bay Area Cancer Research Group Steven Ades, Vermont Cancer Center at Fletcher Allen Health Care Vijay Rao Phooshkooru, MidDakota Clinic David Henry, Pennsylvania Oncology Hematology Associates Goetz Kloecker, James Graham Brown Cancer Center Ira Oliff, Orchard Healthcare Jeffrey Cilley, Hematology Oncology Associates of Illinois Jeffrey Wasser, University of Connecticut Health Center Alison Stopeck, Arizona Cancer Center at UMC North Michael Kovacs, London Health Sciences Centre Sudeep Shivakumar, Queen Elizabeth II Health Sciences Centre Marc Carrier, Ottawa Hospital Research Institute Vicky Tagalakis, Sir Mortimer B. Davis Jewish General Hospital Erik Yeo, University Health Network Agnes Lee, Vancouver General Hospital Thrombosis Clinic Bruce Ritchie, University of Alberta Jeannine Kassis, Hopital Maisonneuve-Rosemont Ernst Pilger, LKH Graz Universit€ atstklinik f€ ur Innere Medizin Ingrid Pabinger, Medizinische Universit€ at Wien Ernst Rechberger, KH der Barmherzigen Schwestern Peter Balcke, Landesklinikum St P€ olten Michael Steurer, Medizinische Universit€ at Innsbruck Josef Koenig, KH d. Elisabethinen Linz GmbH Frans Erdkamp, Orbis Medisch Centrum Jitske Smit, Gelre ziekenhuizen Ram on Lecumberri, Clinica Universitaria de Navarra Javier Trujillo-Santos, Hospital Universitario Santa Lucıa Antoni Castro, Hospital Universitari Dr Josep Trueta Vladimir Salazar, Hospital Virgen de la Arrixaca Juan Carlos Reverter, Hospital Clinic i Provincial References 1 Lee AY, Levine MN. Venous thromboembolism and cancer: risks and outcomes. Circulation 2003; 23(Suppl 1): I17–21. 2 Lee A, Peterson E. Treatment of cancer-associated thrombosis. Blood 2013; 14: 2310–7. 3 Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood 2013; 10: 1712–23. 4 Prandoni P, Lensing AW, Piccioli A, Bernardi E, Simioni P, Girolami B, Marchori A, Sabbion P, Prins MH, Norenta F, Girolami A. Recurrent venous thromboembolism and bleeding
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