Low molecular weight heparins for secondary prevention of symptomatic venous thromboembolism in patients with cancer

22 Oct 2007 Low molecular weight heparins for secondary prevention 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 bleeding time. Low molecular weight heparins (LMWHs) have fewer drug interactions and do not require monitoring of bleeding time. The Therapeutics Initiative has systematically reviewed Dalteparin for this indication.⁽²⁾ However, other LMWHs have also been studied in clinical trials in this population and are known to be in common use in British Columbia. Therefore, a systematic review of all randomized clinical trials comparing all LMWHs vs. OAC was conducted.

Drug  [Product monograph]⁽³⁾

Categorization: LMWHs are categorized as antithrombotic-anticoagulant compounds.

Mechanism of Action: LMWHs 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: Dalteparin is the only LMWH licensed by Health Canada for the secondary prevention of VTE in patients with cancer⁽⁴⁾. It can be administrated by subcutaneous or IV infusion (the recommended dose for other LMWHs is not known).

Duration of therapy: 6 months for dalteparin.

Methodology of the systematic review

Research question: In randomized controlled trials (RCTs), do low molecular-weight heparins provide a therapeutic advantage compared with oral anti-coagulants (warfarin, acenocoumarol) for secondary prevention of VTE in patients with cancer?

Assessment principles: RCTs comparing any LMWH with oral anticoagulants for the extended treatment of VTE in patients with cancer will be critically appraised according to the following hierarchy of health outcomes 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 bleedings thrombocytopenia; and asymptomatic deep venous thrombosis.

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

Search findings:
Four open-label RCTs comparing LMWHs (dalteparin, enoxaparin and tinazaparin) vs. oral anticoagulants were identified.^(5–8)

Results

1,124 cancer patients with objectively documented VTE were randomized to LMWH or OAC treatment for a duration of 3 to 6 months with maximum follow-up up to 1 year.

The pooled estimate yielded no statistically significant difference between LMWHs vs. OAC in,

• total serious adverse events (2 trials; N=778 patients; RR 1.08, 95%CI 0.93-1.25, p=NS)
• all cause mortality (4 trials; N=1,124 patients; RR 0.97, 95%CI 0.86-1.08, p=NS),
• fatal bleeding (3 trials; N=1,022 patients; RR 0.71, 95%CI 0.27-1.88, p=NS),
• major bleeding (4 trials; N=1,124 patients): RR 1.10, 95%CI (0.69-1.75, p=NS) or
• total withdrawals (2 trials; N=778 patients; RR 0.92, 95%CI 0.80-1.06, p=NS).

“Mortality on treatment” was significantly higher in the LMWH as compared with OAC (2 trials; N=778 patients; RR 2.21, 95%CI 1.45-3.39, p=0.0002), ARI= 9%, NNH=12 during 6 months of treatment. It was not possible to calculate a pooled estimate of the risk of thrombocytopenia as trials defined it differently.
The incidence of recurrent venous thromboembolism (VTE) varied across the 4 trials. At the end of treatment it was (8%, 3%, 6.5%, 6%, respectively) for LMWH groups and (16%, 4%, 10%, 10%, respectively) for OAC groups. We did not calculate a pooled estimate of the risk of recurrent VTE due to attrition bias and other factors that affected the censoring of this outcome measure.

• The risk of death in these trials was about 3 to 6 times the risk of recurrent VTE, which made the censoring less accurate. It was not possible to ascertain VTE at the time of death in most of the cases.
• The criteria used to define recurrent VTE varied across the trials.
• In all trials the counting of these recurrent events were actually made per protocol and not on ITT analysis as not all patients could be evaluated (death 30-50%, other withdrawals, loss of follow-up, patients not assessed for efficacy etc).
• The method of assessment of recurrent “symptomatic” VTE varied across studies. For example, in the Lee 2003 trial⁽⁸⁾, it was unclear if the assessment of the recurrent VTE was by schedule or driven by the patients symptoms. In the Deitcher 2006 trial⁽⁵⁾, the recurrence VTE could be symptomatic extension within the same venous segment or detection of new thrombosis within a venous segment not previously involved without specifying if the latter had to be symptomatic.
• In one trial it was not possible to distinguish deep venous thrombosis from pulmonary embolism since it was reported as a composite outcome measure.
• The timing of measuring VTE was different across trials. Two of the trials did not measure VTE after the treatment period.
• A robust treatment benefit related to a reduction in the risk of recurrent VTE might also be suggested by reduction in hospitalization. This was not seen in the trials where there was a VTE benefit and where hospitalizations were reported.

Conclusions:

• There is insufficient evidence that LMWHs provide a therapeutic advantage in terms of mortality or morbidity (particularly pulmonary embolism, major bleeding or minor bleeding) compared with oral anticoagulants for up to 6 months treatment of symptomatic venous thromboembolism (VTE) in patients with cancer.
• There is sufficient evidence that “mortality on treatment“ were statistical significantly higher with LMWH treatment as compared with OAC (ARI= 9%, NNH=12) during 6 months of treatment.
• There is insufficient evidence that LMWHs reduced the incidence of recurrence of VTE as compared with oral anticoagulants in patients with cancer due to major flaws in VTEs censoring which consequently precludes an accurate interpretation of results.

References

1. Prandoni P, Anthonie WA. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002;100:3484-8.
2. Therapeutics Initiative. Drug Assessments. http://www.ti.ubc.ca/DrugAssessments
3. Product Monograph. Heparins: Low Molecular Weight Pr. Compendium of Pharmaceuticals and Specialties (CPS) . 1-10-2006.  Canadian Pharmacists Association (CPhA).
   Ref Type: Serial (Book,Monograph)
4. Pfizer. Product Monograph. Fragmin® Pr (Dalteparin Sodium). CPS.  26-7-2006.  Canadian Pharmacists Association (CPhA).
   Ref Type: Serial (Book,Monograph)
5. Deitcher SR, Kessler CM, Merli G, Rigas JR, Lyons RM, Fareed J, et al. Secondary prevention of venous thromboembolic events in patients with active cancer: enoxaparin alone versus initial enoxaparin followed by warfarin for a 180-day period. Clinical & Applied Thrombosis/Hemostasis 2006 Oct;12(4):389-96.
6. Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, et al. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. American Journal of Medicine 2006 Dec;119(12):1062-72.
7. Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study.[see comment]. Arch Intern Med 2002;162(15):1729-35.
8. Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer.[see comment]. N Engl J Med 2003;349(2):146-53.