PRODIGE: a randomized placebo-controlled trial of dalteparin low-molecular-weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma

Authors


  • The PRODIGE study of thromboprophylaxis using dalteparin in newly diagnosed brain tumor patients is an original, unpublished phase III trial. Preliminary results were presented at the 2007 Annual Meeting of the American Society of Clinical Oncology. J Clin Oncol 25:77s, 2007 (abstr 2011).

James R. Perry, Division of Neurology, Sunnybrook Health Science Centre, A402, 2075 Bayview Avenue, Toronto, Ontario, Canada.
Tel.: +1 416 480 4766; fax: 1+ 416 480 5054.
E-mail: james.perry@sunnybrook.ca

Abstract

Summary. Background and objectives: Venous thromboembolism (VTE) occurs in 20–30% of patients with malignant glioma per year of survival. We tested the efficacy of long-term dalteparin low-molecular-weight heparin (LMWH) for prevention of VTE in these patients. Patients/methods: Adults with newly diagnosed malignant glioma were randomized to receive dalteparin 5000 anti-Xa units or placebo, both subcutaneously once daily for 6 months starting within 4 weeks of surgery. Treatment continued for up to 12 months. The primary outcome was the cumulative risk of VTE over 6 months. The target sample size was 512 patients. Events were adjudicated by a committee unaware of treatment. Results: The trial began in 2002 and closed in May 2006 because of expiration of study medication. Ninety-nine patients were randomized to LMWH and 87 to placebo. Twenty-two patients developed VTE in the first 6 months: nine in the LMWH group and 13 in the placebo group [hazard ratio (HR) = 0.51, 95% confidence interval (CI): 0.19–1.4, P = 0.29]. At 6 months, there were three major bleeds on LMWH and none on placebo; at 12 months, 5 (5.1%) major bleeds on LMWH and 1 (1.2%) on placebo occurred (HR = 4.2, 95% CI: 0.48–36, P = 0.22). All major bleeds were intracranial and occurred while on study medication. The 12-month mortality rates were 47.8% for LMWH and 45.4% for placebo (HR = 1.2, 95% CI: 0.73–2.0, P = 0.48). Conclusions: Trends suggesting reduced VTE and increased intracranial bleeding were seen in the LMWH thromboprophylaxis group. The role of long-term anticoagulant thromboprophylaxis in patients with brain tumors remains uncertain.

Introduction

Patients with malignant brain tumors are at increased risk of venous thromboembolism (VTE). Cumulative 1-year rates of symptomatic VTE as high as 30% have been reported [1–6]. The etiology of thrombosis in these patients is multifactorial and includes stasis as a result of surgery and limb paresis, tissue-factor induced activation of coagulation, and vessel wall injury from chemotherapy and radiation [7–12].

Whereas antithrombotic prophylaxis is routinely used in patients undergoing general or orthopedic surgery and in hospitalized medical patients [13,14], it is not routinely used in ambulatory patients with malignant brain tumors because of the concern for anticoagulant-associated intracranial bleeding [15–18]. Compression stockings are commonly used to prevent deep vein thrombosis (DVT) in patients undergoing surgery for malignant brain tumors. However, mechanical methods of prophylaxis are not practical or proven to be effective in ambulatory outpatients. Experimental studies have suggested that low-molecular-weight heparin (LMWH) causes fewer hemorrhagic complications than unfractionated heparin (UFH) because it has less effect on platelet function [19]. The observation of less bleeding with LMWH has been confirmed in meta-analyses of trials comparing LMWH and UFH [20]. Furthermore, post-operative prophylaxis with short-term LMWH reduced the incidence of DVT compared with compression stockings alone in two trials in patients with brain tumors, and was found to be safe [21,22]. Based on these considerations, we conducted a double-blind randomized trial of prolonged thromboprophylaxis using LMWH in patients with malignant glioma who had completed surgery and were receiving further treatment and ongoing care.

Methods

Population

Subjects were eligible if they were over 18 years of age and had newly diagnosed, pathologically confirmed WHO Grade 3 or Grade 4 glioma (anaplastic astrocytoma, glioblastoma multiforme, gliosarcoma, anaplastic oligodendroglioma or anaplastic mixed glioma). Patients were excluded if they had: acute or chronic DVT demonstrated objectively, evidence of serious hemorrhage within 4 weeks of study entry, coagulopathy [i.e. International Normalized Ratio (INR) > 1.5 or platelet count < 100 × 109 per L], symptomatic intracranial or intratumoral bleeding, acute peptic ulcer disease, familial bleeding diathesis, a requirement for long-term anticoagulants, uncontrolled hypertension, significant renal failure (dependent on dialysis or creatinine of greater than three times upper limit of normal control), prior history of documented VTE, an allergy to anticoagulants, an expected lifespan of < 6 months and body weight < 40 kg; or if they were: pregnant, of childbearing potential and not using adequate contraception, geographically inaccessible for follow-up, or unable to commence study drug within 4 weeks of original surgery or biopsy.

Eligible patients underwent history and physical examination, routine blood work including complete blood count, platelet count, INR and activated partial thromboplastin time (APTT), creatinine and liver function tests. Written informed consent was obtained from all eligible patients. The study protocol was approved by the Institutional Review Board of each participating center.

Interventions

Consenting patients were randomized by contacting the Ontario Clinical Oncology Group (OCOG) Coordinating and Methods Centre at the Henderson Research Centre, Hamilton, Ontario. Treatment allocations were pre-determined using a computer-generated randomization list with random size permuted blocks, and stratified according to center, tumor grade (3 vs. 4), the Karnofsky Performance Status (KPS) (≤ 60 vs. 70 or more) and time from surgery to randomization (< 2 weeks vs. 2–4 weeks).

Patients were allocated to receive either the LMWH dalteparin sodium 5000 International Units or saline placebo, both administered subcutaneously once daily in prefilled syringes provided by Pfizer, Inc, (New York, NY, USA). The duration of therapy for the primary analysis of efficacy and safety was 6 months. The intention was for patients to continue study medication (dalteparin or placebo) for up to an additional 6 months. Therefore, secondary aims were to determine if the benefits of prophylaxis (if any) would continue beyond 6 months for long-term survivors and to provide insight into the safety and efficacy of long-term prophylaxis in this group of patients. The use of concurrent therapy with acetylsalicyclic acid (ASA), non-steroidal anti-inflammatory drugs and dextran was permitted but discouraged. Study medication was withheld if the platelet count dropped below a threshold of 50 x 109 per L and was restarted when the platelet count recovered to that level or above.

All patients were followed in clinic monthly for the first 6 months post-randomization and then at 9 and 12 months. At these visits they underwent history and physical examination. Between 6 and 12 months after study entry, patients had monthly telephone follow-up when there were no scheduled clinic visits. Compliance with study medication was assessed at each visit.

Outcomes

The primary outcome was objectively documented symptomatic DVT or pulmonary embolism (PE) occurring during the 6 months post-randomization. DVT was confirmed by an intraluminal filling defect on ascending venography or non-compressibility of the popliteal or more proximal segments of the deep veins of the lower limbs on compression ultrasound. Pulmonary embolism was confirmed by autopsy, a high probability ventilation-perfusion lung scan, conventional pulmonary angiogram, CT pulmonary angiogram, or objectively demonstrated DVT in patients with a clinical suspicion of PE and a non-high probability lung scan. All VTE events which occurred between randomization and 7 days after the last injection of study medication were considered outcomes. All suspected VTE events were adjudicated by a central committee unaware of the patient’s treatment assignment.

Secondary outcomes included bleeding (major and all bleeding), quality of life, cognition assessments and death. Bleeding was defined as major if it was clinically overt and satisfied one of the following criteria: a decrease in hemoglobin of 20 gm L−1 or more over a 48-h period, bleeding leading to transfusion of two or more units of packed red cells, retroperitoneal, intracranial, intraspinal, intraocular or pericardial bleeding documented by objective investigations or bleeding leading to an invasive intervention or death. All other overt bleeding events not meeting any of these criteria were classified as minor. All bleeding events which occurred between randomization and 48 h after the last injection of study medication were considered as safety outcomes. All bleeding episodes were adjudicated by the central adjudication committee. Overall mortality was ascertained over the 12 months from the time of randomization.

Statistical analysis

It was postulated that the cumulative risk of VTE at 6 months would be 13% for the placebo group. In order to detect a 60% relative reduction in VTE risk in the LMWH group with 80% power and a two-sided alpha of 5%, at least 40 events would be needed – therefore 217 patients per group would need to be enrolled in the study. Allowing for up to 15% of patients who withdrew consent or died during the 6-month follow-up, the final sample size was increased to 256 patients per arm.

Median duration of treatment was calculated with those treated beyond 6 months being censored (study drug use after 6 months was optional). The time-to-first-event for VTE, major bleeding and mortality were described using the Kaplan–Meier method, and the treatment arms were compared using the log rank test stratified for tumor grade, KPS, weeks from surgery to randomization and center. The primary analysis for efficacy was the comparison of the VTE rates between groups during the first 6 months. The safety analysis compared the cumulative risk of major bleeding between treatment arms during the first 6 months. The intention-to-treat principle was used in all analyses. For the primary analysis, patients who had not experienced an event by 6 months were censored as event-free at that point. A Cox regression model was used to examine the potential effect of baseline characteristics (treatment, extent of surgery, histology, age, KPS and days from surgery to randomization) on VTE and survival. An independent data safety monitoring committee met regularly to review the study progress and safety outcomes, but no formal interim analysis was planned or undertaken.

Results

The trial began in October 2002. Recruitment was lower than anticipated and the study was closed to recruitment in May 2006 as a result of expiration of the study drug.

Five hundred sixty-three patients were screened at 15 centers and 174 were excluded. The main reasons for exclusion were: unable to start treatment within 4 weeks of surgery (30%), geographical inaccessibility (24%) and expected lifespan < 6 months (18%). Of 389 eligible patients approached for consent, 186 agreed to be randomized; 99 to LMWH and 87 to placebo (Fig. 1). All patients randomized are included in the analysis. Two LMWH patients and one placebo patient never received treatment. The treatment groups were reasonably balanced for baseline characteristics (Table 1).

Figure 1.

 PRODIGE study flow diagram.

Table 1.   Baseline characteristics by treatment group
Baseline characteristicDalteparin (n = 99)Placebo (n = 87)
  1. *Patients can be included in more than one category.

Age: mean (min – max)57 (30–81)55 (26–77)
Gender: n (%)
 Male61 (62)50 (57)
 Female38 (38)37 (43)
Type of Surgery: n (%)
 Biopsy18 (18)16 (18)
 Partial resection26 (27)28 (32)
 Gross total resection55 (56)43 (49)
Histology: n (%)
 Anaplastic17 (17)14 (16)
 Other82 (83)73 (84)
 Paralysis or hemiparesis, n (%)7 (7)4 (5)
 Any weakness, n (%)24 (24)11 (13)
Pre-/peri-op DVT prophylaxis: n (%)
 Compression stockings*48 (48)40 (46)
 UFH*18 (18)7 (8)
 LMWH*15 (15)13 (15)
 No prophylaxis47 (47)37 (43)
Karnofsky Performance Status: n (%)
 60 or lower11 (11)3 (4)
 7020 (20)16 (18)
 8014 (14)14 (16)
 9034 (35)38 (44)
 10020 (20)16 (18)
 Radiotherapy (within first month), n (%)77 (78)78 (90)
Time from surgery to randomization:
 Days – mean (range)22 (5–39)23 (7–39)
 < 2 weeks, n (%)9 (9)7(8)

The median duration of treatment was 183 days in the LMWH group and 157 days in the placebo group. The number of patients on study drug for at least 1 month and 3 months was 82 and 69, respectively, in the LMWH arm, and 78 and 60 in the placebo arm. During the first 6 months after randomization, 29 LMWH patients and 35 placebo patients discontinued study medication early; this was not due to a study event or death. Beyond 6 months, 49 LMWH patients and 34 placebo patients continued treatment. Overall, 16 additional patients (6 LMWH, 10 placebo) discontinued treatment and withdrew consent for further follow-up.

During the first 6 months, there were nine LMWH patients who experienced VTE (seven DVT, one PE, one both) compared with 13 placebo patients (nine DVT, three PE, one both). The cumulative probability of VTE is shown in Fig. 2. The hazard ratio (HR) adjusted for strata is 0.51, 95% confidence interval (CI) 0.19–1.4. Beyond 6 months, two LMWH patients and one placebo patient experienced DVT. All but one of the LMWH patients had discontinued study drug prior to the event. In the Cox model, none of the factors examined were associated with VTE (Table 2).

Figure 2.

 Venous thromboembolism (VTE) during the first 6 months.

Table 2.   Multivariable models for VTE and overall survival during first 6 months
FactorVTE (22 events)Overall Survival (29 events)
HR (95% CI)P-valueHR (95% CI)P-value
  1. VTE, venous thromboembolism; HR, hazard ratio; CI, confidence interval; KPS, Karnofsky Performance Status.

Treatment:
 LMWH vs. placebo0.63 (0.26–1.49)0.291.26 (0.56–2.85)0.56
 KPS (per 10 unit)0.85 (0.61–1.20)0.360.54 (0.42–0.71)< 0.001
Time from surgery to:
 Randomization (per week)1.40 (0.88–2.22)0.150.94 (0.66–1.35)0.76
 Age (per 10 years)1.21 (0.75–1.95)0.451.61 (1.06–2.43)0.025
Extent of surgery:
 Biopsy vs. complete3.68 (1.18–11.4)0.084.64 (1.79–12.1)0.001
 Partial vs. complete1.86 (0.64–5.40) 1.05 (0.39–2.82) 
Histology:
 Glioblastoma vs. anaplastic2.59 (0.59–11.4)0.213.07 (0.86–10.9)0.08

During the first 6 months, three LMWH patients experienced major bleeding compared with none receiving placebo. Between 6 and 12 months, there were three more cases who had major bleeding on study drug: two LMWH and one placebo. Overall there were five major bleeds in the LMWH arm compared with one in the placebo arm (adjusted HR = 4.2, 95% CI: 0.48 to 36). The six major bleeding episodes were all intracranial (Table 3).

Table 3.   Details of patients with major bleeding events*
TreatmentDayEpisodeOutcome
  1. PE, pulmonary embolism; DVT, deep vein thrombosis. *All on study drug at time of the event.

Dalteparin1Fell at home.
Epidural hematoma
Surgical evacuation.
Drug stopped. PE on Day 83.
6Intratumoral bleed, FatalDeath.
19Asymptomatic epidural hematomaDrained.
187Intratumoral bleedDied of disease progression 5 days later.
245Intratumoral bleedDVT 3 weeks later.
Placebo220New seizures, subdural hematomaDrained. Remains alive.

Over the first 6 months, 18 LMWH patients died compared with 11 placebo patients (Fig. 3); adjusted HR = 1.4, 95% CI: 0.60 to 3.2. Over the 12 months, 45 LMWH patients died compared with 32 placebo patients (adjusted HR = 1.2, 95% CI: 0.73 to 2.0). In the Cox regression analysis, extent of surgery, histology, age and KPS were associated with overall survival (Table 2).

Figure 3.

 Overall survival during the first 6 months.

Discussion

After initial surgery, patients with malignant gliomas are usually treated with radiation and systemic anti-cancer therapy. Unfortunately, especially for patients with GBM, their clinical course is usually characterized by tumor progression and death within 1–2 years. While short term post-operative mechanical and anticoagulant prophylaxis has been shown to be safe, effective and is recommended for patients with newly resected malignant brain tumors [14], the risk of VTE remains high throughout the course of disease and the role of long-term thromboprophylaxis is unclear. The results of our study confirm, in the setting of a prospective randomized trial with objectively confirmed and adjudicated events, that the risk of thrombosis beyond the surgical period is substantial and consistent with rates reported in the literature.

We were unable to detect a statistically significant reduction in VTE with LMWH compared with placebo. The failure to detect a difference was most likely as a result of low statistical power related to low accrual. Nonetheless, there was a trend in favor of decreased VTE associated with LMWH.

There was no statistically significant difference in major bleeding detected between groups. However, there was a trend for increased major bleeding in patients who received anticoagulant prophylaxis. All of the major bleeds were intracranial and one was fatal.

Our study is the only phase III randomized trial of long-term thromboprophylaxis for brain tumor patients. Two small phase II studies reported encouraging results with LMWH and no episodes of intracranial bleeding [23,24]. In one of these studies, safety was the primary outcome and no intracranial bleeding was detected in 40 newly resected malignant glioma patients who, within 4 weeks of surgery, were given tinzaparin LMWH prophylaxis on a daily basis for up to 1 year [23]. In addition, only one of the 40 patients developed an objectively confirmed DVT during a median time on tinzaparin of 161 days. In another phase II study, 42 analyzable patients were treated with dalteparin 5000 IU daily; no grade 3 or 4 bleeding or episodes of VTE were observed over a median treatment period of 6.3 months [24]. The results of our larger randomized trial suggest that intracranial bleeding is an important safety concern in this patient population.

There is evidence in the literature that LMWH may have an anticancer effect possibly by inhibiting angiogenesis [25–27]. In our trial, no difference in survival was detected between groups.

The recruitment of patients was lower than anticipated in our study. We speculate that patients recently diagnosed with malignant brain tumors are overwhelmed with the implications of their disease and treatment decisions. The impression of the study nurses who often introduced the trial to patients was that discussing serious complications such as VTE was a barrier to the screening and enrollment process. We also had the impression that patients (and sometimes physicians) were more interested in enrolling their patients into trials of investigational new drugs which potentially had direct antitumor effects. At the time of our study the data concerning a putative survival advantage with LMWH was not clear and this potential advantage of study participation was not emphasized to patients. Finally, the injection of daily subcutaneous placebo for a long period also appeared to be a deterrent to study accrual. Even though our trial was appropriately designed to detect statistically significant differences in outcomes between treatment arms, study accrual was slower than anticipated. At the time of expiration of the study placebo supply the Steering Committee decided that continued efforts to accrue study subjects would not lead to the completion of the trial with adequate statistical power, so the study was closed prematurely.

In our study, investigators, patients and outcome assessors were blinded to treatment allocation. In addition, VTE and bleeding outcomes were adjudicated by a central committee unaware of treatment assignment. Screening compression ultrasounds to rule out silent DVT were not performed at study entry. This would have made the trial more complex for patients from the logistical point of view. We also felt that the number of silent thrombi should be equally balanced between treatment arms as a result of the randomization process. The original sample size determination allowed for a 15% loss as a result of discontinuation of study drug or death. In the trial, the loss was much higher likely reflecting how sick these patients were. Only 35 (19%) of patients were alive, event-free and still taking study drug for 12 months. These data, and the confirmed incidence of VTE, should help to inform any future clinical trials of thromboprophylaxis in this patient population.

Others [9,28] have reported various biomarkers or risk assessment tools to identify patients with systemic malignancies who are at high risk for VTE [29]. However, few biomarkers or risk factors are known for the brain tumor population despite having one of the highest risks for the development of VTE in cancer overall. Such biomarkers would obviously be helpful to detect patients at risk and to enrich future clinical trials such that a less ambitiously large study might be possible.

In our trial we found trends towards fewer thromboembolic events but more intracranial bleeding associated with LMWH. Venous thromboembolism therefore remains a significant cause of morbidity in patients with glioma. Continued research to find safe and effective methods of prophylaxis in this high-risk population is warranted.

Addendum

J.R. Perry: study PI, Steering Committee, study concept and design, provided patients, data interpretation, manuscript writing, final approval of manuscript.

J.A. Julian: Steering Committee, study concept and design, data collection and interpretation, manuscript writing, final approval of manuscript.

N.J. Laperriere: Steering Committee, study concept and design, provided patients, final approval of the manuscript.

W. Geerts: Steering Committee, study concept and design, manuscript writing, final approval of the manuscript.

G. Agnelli: Steering Committee, study concept and design, provided patients, final approval of the manuscript.

L.R. Rogers: Steering Committee, study concept and design, provided patients, final approval of the manuscript.

M.G. Malkin: Steering Committee, study concept and design, provided patients, final approval of the manuscript.

R. Sawaya: Steering Committee, study concept and design, final approval of the manuscript.

R. Baker: Steering Committee, study concept and design, provided patients, final approval of manuscript.

A. Falanga: Steering Committee, study concept and design, provided patients, final approval of the manuscript.

S. Parpia: data collection and statistical analysis, final approval of the manuscript.

T. Finch: study concept and design, data collection, administrative support, final approval of the manuscript.

M.N. Levine: Steering Committee, study funding, study concept and design, data interpretation, manuscript writing, final approval of the manuscript.

Acknowledgemets

The PRODIGE Steering Committee wishes to acknowledge all contributing investigators (Country, institution, name of site PI, n = accrued patients).

Canada (Canadian Brain Tumour Consortium Centres): Odette Cancer Centre, Toronto (J. Perry, n = 44), Princess Margaret Hospital, Toronto (N. Laperriere, n = 35), Queen Elizabeth II Clinical Research Centre, Halifax (D. Rheaume, n = 17), CancerCare Manitoba, Winnipeg (D. Eisenstat, n = 11), Ottawa Hospital Integrated Cancer Program, Ottawa (S. Gertler, n = 6), Cross Cancer Institute, Edmonton (D. Fulton, n = 5), Juravinski Cancer Centre, Hamilton (W. McMillan. n = 3), British Columbia Cancer Agency, Vancouver (B. Thiessen, n = 3).

Italy: Ospedali Riuniti Bergamo, Bergamo (A. Falanga, R. Merli, n = 23), Universita di Perugia (G. Agnelli, n = 6).

United States of America: Huntsman Cancer Institute, Salt Lake City (D. Blumenthal, W. Akerley, n = 13), Henry Ford Hospital, Detroit (L. Rogers, T. Mikkelsen, n = 10), Memorial-Sloan Kettering Cancer Center, New York (M. Malkin, n = 2), Evanston Northwestern Healthcare, Chicago (N. Paleologos, n = 1).

Australia: Sir Charles Gairdner Hospital, Perth (D. Joseph, n = 4), Royal Perth Hospital, Perth (R. Baker, n = 2), St George Hospital, Sydney (P. Graham, n = 1).

Disclosure of Conflict of Interests

Funding and research support by Pfizer Inc, Ontario Clinical Oncology Group, Crolla Chair in Brain Tumour Research (J.P.).

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