Feb 282012

For unclear reasons, people receiving chemotherapy for solid tumors are at particularly increased risk for deep venous thrombosis and pulmonary embolism (DVT/PE). Semuloparin is an ultra-low-molecular weight heparin with a long half life of 16-20 hours that (like enoxaparin) is renally excreted. Sanofi, makers of Lovenox, report in the February 16 New England Journal of Medicine that semuloparin significantly reduced rates of symptomatic DVT and PE in SAVE-ONCO, a large, Phase III randomized controlled trial, led by Giancarlo Agnelli et al.

What They Did:

Sanofi (who designed and managed the trial) randomized 3,172 patients undergoing chemotherapy for solid cancers (lung, pancreas, stomach, colon, rectal, bladder, or ovary), good performance status (ECOG 3+), and a life expectancy > 3 months to receive either semuloparin 20 mg or placebo subcutaneously once daily, for as long as patients were getting chemo.

The primary outcome was a combined endpoint of symptomatic DVT, any pulmonary embolism, or unexplained death. A co-primary safety outcome was major bleeding (hemoglobin drop >= 2 mg/dL or serious clinically).

Sanofi collected and analyzed all the data, but investigators report they had access to all data. Investigators wrote the first draft of the manuscript, and Sanofi's medical communications company (Excerpta Medica) edited it.

What They Found:
  • Semuloparin significantly reduced the rate of the composite endpoint, with 20 of 1,608 patients (1.2%) in the semuloparin group and 55 of 1,604 (3.4%) in the placebo group experiencing DVT, PE, or death compatible with undiagnosed PE.
  • This was an absolute difference of 2.2% and a relative reduction of 74%.
  • Number needed to treat to prevent one event in the composite endpoint would be 46.
  • There was no difference between the groups in overall survival (secondary endpoint) nor in the rate of fatal pulmonary embolism.
  • Semuloparin caused surprisingly little bleeding: there was no increased major bleeding in the semuloparin group overall (1.2% vs. 1.1%); there was a slight increase in minor bleeding (1.6% vs. 0.9%). Semuloparin did not produce an excess of adverse events over placebo, and there were no cases of heparin induced thrombocytopenia (HIT).

In a a 2011 Cochrane analysis of 9 randomized trials, Elie Aki and Holger Schunemann concluded that prophylactic heparin did improve overall survival at 2 years (but not at 1 year) in chemotherapy patients. They absorb the SAVE-ONCO data (which included more patients than all 9 previous trials) into a new analysis, and conclude in their associated NEJM editorial:

If 1000 patients with cancer were to use a prophylactic dose of low-molecular-weight heparin, over a period of 12 months death would be averted in approximately 30 patients, venous thromboembolism would be averted in 20, and 1 would have a major bleeding episode.

Those are pretty compelling numbers to me (which makes me think they'll be eye-popping miracles to most oncologists). This paper was initially presented at the ASCO meeting in June 2011, where it was selected for the "best of ASCO." Major specialty societies don't currently recommend prophylactic low-molecular weight heparin for all patients undergoing chemotherapy for solid tumors, but I wouldn't be surprised to see that change.

Agnelli G et al. Semuloparin for Thromboprophylaxis in Patients Receiving Chemotherapy for Cancer. N Engl J Med 2012;366:601-609.

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Semuloparin (a new LMWH) reduced DVT & PE in chemotherapy patients (RCT, NEJM)