Anticoagulation in Patients with Cancer- Associated Venous Thromboembolic Disease: Improving the Quality of Care with Rivaroxaban and Enoxaparin

Two studies presented at this year’s ASH annual meeting supported reducing the dose of enoxaparin in patients with chemotherapy-induced thrombocytopenia (CIT) and established the safety and efficacy of rivaroxaban to treat patients with cancer-associated thrombosis (CAT) – two areas in which there are few randomized clinical trials data to guide treatment decisions.

Modifying LMWH Dose in CIT

The first trial, examining enoxaparin dose adjustment in patients with CIT, was conducted by researchers at Memorial Sloan Kettering Cancer Center in New York, including Gerald Soff, MD, who discussed the study results in a press briefing.1 “Every day, in every cancer clinic around the world, the question comes up of how to manage blood thinners and how to manage cancer patients with severely reduced platelet counts,” he said, highlighting the importance of establishing a standard approach to anticoagulation dose modification for these patients.

The current approach to low-molecular-weight heparin (LMWH) dosing in the setting of CIT, which was adopted by Dr. Soff and colleagues at Memorial Sloan Kettering, is to reduce the LMWH dose depending on a patient’s platelet levels:

  • Administer full-dose LMWH (1 mg/kg subcutaneously every 12 hours or 1.5 mg/kg subcutaneously once-daily) for a platelet count >50,000/mcL
  • Administer a half dose for a platelet count 25,000-50,000/mcL
  • Hold LMWH temporarily for a platelet count <25,000/mcL

However, he said, this recommendation “is empirical, based on limited published experience, and has never been validated prospectively.” With this trial, investigators validated this recommendation in a cohort of 101 cancer patients who were on a therapeutic dose of enoxaparin for a VTE and who experienced at least one period of thrombocytopenia (platelet count ≤50,000 mcL) for at least seven days.

There were 144 episodes of thrombocytopenia, with an average duration of 21.3 days, among all patients. LMWH dose was modified in 137 of these episodes (95%), reflecting adherence to the guideline. Dose modifications were as follows: reduced in 20 episodes, held in 90 episodes, managed with combination of reduction/hold in 27 episodes, and unchanged in seven episodes.

“In general, the more severe thrombocytopenic episodes were managed with holding LMWH as opposed to dose reduction,” Dr. Soff and colleagues reported.

The mean platelet count during episodes varied depending on the type of dose modification; the mean platelet count during episodes of thrombocytopenia managed by holding LMWH was 27,000/mcL (standard deviation [STD] = 16,000) and it was 36,000/mcL (STD=15,000) in episodes managed by reducing LMWH dose.

Importantly, there were no recurrent VTEsor major bleeding episodes when LMWH was reduced or held. In this cohort, there was only one major bleeding episode (a trauma-associated retroperitoneal hemorrhage) that occurred prior to enoxaparin dose modification. There were also 14 clinically relevant non-major bleeding episodes; seven of these cases involved ecchymosis, epistaxis, or gingival bleeding. Ten patients died while experiencing an episode of thrombocytopenia.

“This Quality Assessment project supports the safety and efficacy of our guidelines for therapeutic LMWH dose modification in the setting of CIT,” Dr. Soff concluded. “These data support the conclusion that the current LMWH dose reduction approach provides safety and efficacy, balancing the risks of recurrent thrombosis and bleeding during periods of CIT in cancer patients.”

Though these data validated the dose modification approach for LMWH, these results could not be extrapolated to newer-generation oral anticoagulants, he added. “Their safe and acceptable use needs to be prospectively validated,” he said. “The highest-quality data are always in a randomized clinical trial; however, the nature of this kind of event in patients with thrombosis would not lend itself to a clinical trial.”

Safe and Effective Use of Rivaroxaban in Cancer-Associated Thrombosis

The second study, also conducted by researchers at Memorial Sloan Kettering, examined the use of the oral direct factor Xa inhibitor rivaroxaban among patients with CAT, finding that it was as safe and effective as, and more convenient than, LMWH.2

“For more than 10 years the gold standard for VTE in cancer patients has been injectable LMWH, which carries a lot of inconvenience for patients,” Simon Mantha, MD, MPH, said in an interview with ASH Clinical News. “Clearly there is a need for an alternative anticoagulant.”

In January 2014, Memorial Sloan Kettering established a Clinical Pathway to guide rivaroxaban use for CAT (including dosing guidelines in the setting of thrombocytopenia, advanced age, and hepatic dysfunction). They then began offering patients rivaroxaban as an alternative to enoxaparin, acknowledging that clinical trials had not established the superiority of either drug and that “the only reason to switch to rivaroxaban would be convenience,” Dr. Mantha explained.

Results from the first 100 patients (out of a planned 200) who had been treated for at least six months or had reached an endpoint (new or recurrent pulmonary embolism [PE], symptomatic proximal lower-extremity deep-vein thrombosis [DVT], major bleeding, clinically relevant non-major bleeding leading to discontinuation of rivaroxaban, or death), were presented.

Patients were not treated with rivaroxaban if they had active gastrointestinal or genitourinary lesions or had undergone gastric resection due to anticipated excess bleeding risk or reduced absorption – representing less than 5 percent of patients.

All patients had PE or symptomatic proximal DVT and a full course of anticoagulation with rivaroxaban (allowing up to 3 days of initial parenteral anticoagulation).
At six months, the cumulative incidences for study endpoints were:

  • Death: 14.4% (95% CI 6.8-21.4%)
  • New or recurrent VTE: 4.3% (95% CI 0.1-8.4%)
  • Major bleeding: 1.1% (95% CI 0-3.1%)
  • Clinically relevant non-major bleeding leading to rivaroxaban discontinuation: 7.9% (95% CI 2.1-13.3%)

“Major or life-threatening bleeding risk was only 1.1 percent at the six-month timepoint, which is quite low,” Dr. Mantha said. “The low rate of major bleeding is influenced likely by the exclusion of patients with active gastrointestinal or genitourinary lesions, who would be expected to have a high bleeding risk with an oral direct anticoagulant.”

Anticipating that older patients (≥75 years old) would have reduced drug clearance and an increased risk of bleeding with rivaroxaban, the investigators reduced the dose in these patients, which “did not appear to be associated with any loss in efficacy.”

The six-month follow-up of the remaining 100 patients was completed in December 2015, with the rates of major bleeding and recurrent VTE expected to remain non-inferior to LMWH, but with a lower burden of treatment. “It’s all about quality of life,” Dr. Mantha said.


References

  1. Miao Y, Soff GA, Parameswaran R, et al. Enoxaparin dose reduction for thrombocytopenia in patients with cancer: a quality assessment study. Abstract #429. Presented at the 2015 ASH Annual Meeting, December 7, 2015; Orlando, Florida.
  2. Mantha S, Miao Y, Sarasohn D, et al. Safe and effective use of rivaroxaban for treatment of cancer-associated venous thromboembolic disease: a quality improvement initiative. Abstract #431. Presented at the 2015 ASH Annual Meeting, December 7, 2015; Orlando, Florida.

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