Dalteparin for extended treatment of symptomatic venous thromboembolism in patients with cancer

Dalteparin for extended treatment of symptomatic venous thromboembolism in patients with cancer

Background information of the condition

Venous thromboembolism (VTE) in patients with cancer: Cancer is a major risk factor for VTE with the 12-month cumulative incidence of recurrent VTE three times higher than patients without cancer [20.7% vs. 6.8%, respectively] (1).  Oral anticoagulants (OAC) – warfarin and acenocoumarol, are the standard long-term (3-6 month) therapy for secondary prevention of VTE, regardless of the underlying morbidity. However, in cancer patients, OACs have higher potential for drug interactions resulting in an increased need to monitor INR. Low molecular weight heparins (LMWHs) have fewer drug interactions and do not require monitoring INR. Dalteparin is the only LMWH that has Health Canada approval for extended treatment of VTE in patients with cancer.

Drug [Product monograph](2)

Categorization: Dalteparin sodium is an anti-thrombotic compound.

Mechanism of action: It acts by enhancing the inhibition of Factor Xa and thrombin (IIa) by antithrombin.  It preferentially inhibits coagulation Factor Xa, while only slightly affecting clotting time, e.g., activated partial thromboplastin time (APTT)”

Dose: subcutaneous or IV infusion

Duration of therapy: 6 months

Methodology of the systematic review

Research question: In randomized controlled trials (open label, single blind or double blind), does dalteparin sodium monotherapy provide a therapeutic advantage compared with oral anti-coagulants (warfarin, acenocoumarol) for the extended treatment to prevent recurrence of VTE in patients with cancer?

Assessment principles: RCTs comparing dalteparin sodium with oral anti-coagulants (warfarin, acenocoumarol) for the extended treatment of VTE in patients with cancer will be critically appraised according to the following hierarchy of health outcome measures – all cause mortality including fatal pulmonary embolism and fatal bleeding; non-fatal serious adverse events (including major bleeding, and pulmonary embolism); symptomatic deep vein thrombosis; drug tolerability (including withdrawal due to adverse events), minor bleeding and asymptomatic deep venous thrombosis.

Search strategy: Databases searched were – Medline (1966- March 2007), EMBASE (1966- March 2007), Cochrane database (issue 1, 2007) and the FDA website.

Search findings: Lee et al, 2003 was the only RCT identified (3).  It was of 6 months duration in 676 adult patients with cancer, comparing dalteparin sodium (N = 338) with oral anticoagulants (N = 338).  In August 2006, the FDA released additional information(4) on this trial, leading to re-analysis of data on withdrawals due to adverse events.

Results: Patients with newly diagnosed symptomatic proximal DVT and/or PE were included in this study.  The majority of patients in this trial had solid tumours and 67% had metastatic disease at the time of entry; 18-20% had a recent history of major surgery; 12-14% had central venous catheters; and 69-77% were receiving cancer treatment.

Data provided in the publication by Lee et al, 2003 (3)

  • There was no significant difference in all-cause mortality, fatal and non-fatal pulmonary embolism, fatal bleeding or major bleeding with dalteparin as compared with oral anticoagulants.  One case of major bleeding was fatal in the dalteparin group as compared to none in the oral anticoagulant group.
  • The primary outcome measure, the composite of DVT and/or pulmonary embolism or both, was significantly decreased in the dalteparin group as compared with oral anticoagulant group [27(8%) vs. 53(16%), ARR=8%, NNT=13].  This was mainly due to significant reduction in proximal symptomatic DVT recurrence [14(4.1%) vs. 37(10.9%), ARR=6.8%, NNT=15].

Critical appraisal of Lee et al, 2003 publication

The trial did not report of total serious adverse events, thrombocytopenia, or withdrawal due to adverse events.  The total number of patients investigated for VTE recurrence in each treatment group is not reported.  This is important to determine bias in an open label trial (ascertainment and adjudication bias).  Information on distribution of pharmacological co-interventions among the groups was not reported.  Additional information is needed regarding long-term VTE recurrence after stopping dalteparin or oral anticoagulant therapy in all randomized patients.

Data obtained through the FDA website(4;5)

The FDA website reported on the number of deaths in both treatment groups each month and whether patients died “on treatment” or after stopping treatment, therefore the following analysis according to full intention-to-treat analysis was possible:

Mortality at 6 months Dalteparin
N=338
OAC
N=338
ARR/NNT
ARI/NNH
Total Mortality 131 (38.8%) 137 (40.5%) p = NS
Mortality on treatment* 59 (17.4%) 21 (6.2%) ARI = 11.2, NNH =9
Mortality after discontinuing treatment** 72 (21.3%) 116 (34.3%) ARR= 13.0, NNT =8

* death on treatment or within 24 hours of discontinuing treatment
** death after 24 hours of discontinuing treatment

  • The total rate of Serious Adverse Events (SAE) was not statistically significantly different between dalteparin (47.2%) and OAC group (44.4%).
  • Fatal bleeding was the cause of death in three patients in dalteparin group (one hemoptysis, one cerebellar hemorrhage and one gastrointestinal hemorrhage) and one in the OAC group (reported as melena).
  • Although total mortality was not significantly different between dalteparin and OAC groups at the end of six months [38.8% vs. 40.5% respectively] or at the end of 1 year of follow-up [190 (56.2%) vs. 194 (57.9%), respectively];
    • The mortality rate “on treatment” was numerically higher at each month in the dalteparin group as compared to OAC group [(5.4% vs. 3.7% at month 1); (5.8% vs. 1.3% at month 2); (4% vs. 1.9% at month 3); (1.9% vs. 1.6% at month 4); (4.5% vs. 0% at month 5); and (2.8% vs.0% at month 6)].  At 6 months there was a significant increase in mortality “on treatment” with dalteparin as compared with OAC [ARI=11.2%, NNH=9]
    • The mean duration of survival (days) at the end of 6 months of treatment and at 1 year in both treatment groups needs to be reported.
  • The incidence of severe thrombocytopenia (≤ 50,000/mm3was statistically significantly higher in the dalteparin group as compared to the OAC group [21(6.2%) vs. 9(2.6%), ARI =3.6%, NNH=28].  Dose modification of the study drug or interruption due to thrombocytopenia was significantly higher in the dalteparin group as compared to OAC group [27(7.9%) 5 (1.4 %), ARI =6.5%; NNH=16].

Summary and rationale for conclusions

The goal of therapy in adult patients with cancer, who had symptomatic VTE, is to prevent recurrence of VTE without increasing mortality and/or hospitalization.  Based on one open label trial Lee et al, of 6 months duration, 1 in 11 patients had a significant increased risk of dying “on treatment” with dalteparin as compared to “on treatment” with OAC.  Although the total mortality rate at month 6 and 12 was not significantly different between the treatment groups, for proper interpretation, the mean duration of survival needs to be reported.

The primary outcome, recurrent VTE is susceptible to misinterpretation due to the competing risk of ‘death and VTE’ and the inaccuracy in VTE diagnosis at the time of death.  The benefit due to significant reduction in VTE (ARR=8%) in the dalteparin group is not reflected in the rate of hospitalization (30.8% vs. 28.1%), non- fatal serious adverse events (8.4% vs. 3.9%) or total serious adverse events (47.2% vs. 44.4%) at 6 months, which were numerically higher in the dalteparin group as compared to OAC group.  The presence of VTE predicted poor prognosis: 20 out of 21 patients who discontinued dalteparin due to VTE died after the event as compared to 40 out of 47 patients who discontinued OAC due to VTE.  Thus, no benefit can be claimed for dalteparin in terms of VTE rates.

Conclusions

  • Total mortality was not significant different between the two groups during the 6-month treatment period. However, mortality “on treatment” was statistical significantly higher in those patients receiving dalteparin (17.4%) as compared to those receiving OAC (6.2%) [ARI=11.2%, NNH=9].
  • There was a significant increase in severe thrombocytopenia (ARI=3.6% and NNH=28) and study drug modification or interruption due to thrombocytopenia (ARI=6.5% and NNH=16) in the dalteparin group as compared with oral anticoagulant group.
  • A reduction in total VTE in the dalteparin group cannot be claimed due to the opposing risk in death (3 times more than risk of VTE) and the inaccuracy in diagnosis of VTE at the time of death. Furthermore, there were differences in VTE censoring for dalteparin group due to statistically significant greater withdrawals due to death in this group as compared to the OAC group. These limitations are exemplified by the similar rate on total hospitalizations for both groups.
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