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Updated ASCO guideline urges better recognition, management of VTE risk

Issue: August 25, 2013

ByDebbie Blamble, PharmD, BCOP

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Cancer and cancer therapies can increase a patient’s risk of developing venous thromboembolism.

ASCO recently updated its clinical practice guideline on VTE prophylaxis and treatment for patients with cancer.

The guidelines — published online in May by the Journal of Clinical Oncology — emphasize improved identification and management of patients based on VTE risk.

 

Debbie Blamble

Here’s a look at how new data from the past 6 years influenced the evolution of the guideline.

ASCO’s initial guideline, published in 2007, recommended that hospitalized patients with cancer be considered for pharmacologic VTE prophylaxis in the absence of any contraindication. The most recent guideline is a little more granular, with three recommendations for this patient population.

First, a more strongly worded recommendation suggests hospitalized patients with cancer and with acute medical illness or reduced mobility should receive pharmacologic VTE prophylaxis in the absence of any contraindication. The second recommendation suggests hospitalized patients with cancer but without additional risk factors may still be considered for pharmacologic VTE prophylaxis.

New data for these recommendations came from two primary prophylaxis trials that compared low–molecular-weight heparin (LMWH) to unfractionated heparin (UFH) in medically ill patients, as well as a systematic review that demonstrated the effectiveness of LMWH or UFH vs. placebo in decreasing deep vein thrombosis rates. The populations studied in all three of these publications were not limited to cancer patients.

Third, the guideline suggests that the data are inadequate to support routine VTE prophylaxis in the following hospitalized cancer populations: patients admitted for minor procedures, patients admitted for short chemotherapy infusions, or patients admitted to undergo stem cell or bone marrow transplantation. This last recommendation, due to insufficient data, was based on informal consensus among panel members. It will be an interesting recommendation to implement, as most institutions tend not to further risk-stratify cancer patients when assessing the need for pharmacologic VTE prophylaxis.

The updated guideline continues to recommend against routine pharmacologic VTE prophylaxis in outpatients with cancer, although most VTE occur in outpatients.

This recommendation was based on data from three systematic reviews and seven randomized controlled trials (RCTs).

One of the systematic reviews, published in the Cochrane Database of Systematic Reviews in 2012, showed fewer symptomatic VTE occurred in patients who received LMWH prophylaxis compared with placebo (RR=0.62; 95% CI, 0.41-0.99). Pharmacologic prophylaxis did not increase bleeding rates compared with placebo.

However, the absolute differences in VTE rates were less than 5% in all three systematic reviews. The number of patients needed to treat to prevent one symptomatic VTE event ranged from 36 to 67 patients. Based on the limited benefit in an unselected patient population, the ASCO panel chose not to recommend pharmacologic VTE prophylaxis in most outpatients with cancer.

A new recommendation indicates clinicians may consider LMWH prophylaxis on a case-by-case basis in highly selected outpatients with solid tumors who are receiving chemotherapy. In these cases, clinicians and patients should discuss the possible benefits and harms, as well as details of the regimen and anticipated duration of treatment.

This recommendation came from the evaluation of RCTs that compared LMWH with placebo or no prophylaxis in patients with cancer.

Two trials, one that involved patients with metastatic breast cancer and another of patients with newly diagnosed stage III/IV glioma, were stopped early and showed no difference between treatment arms. Three other trials — one in stage III/IV non–small cell lung cancer and two in advanced pancreatic cancer — demonstrated reductions in VTE with LMWH prophylaxis. Researchers observed no difference in major bleeding between groups in any of the trials. Given the heterogeneity of results, the panel worded its recommendation as a case-by-case consideration.

The final recommendation for outpatient VTE prophylaxis suggests patients with multiple myeloma who receive thalidomide (Thalomid, Celgene)- or lenalidomide (Revlimid, Celgene)-based regimens with chemotherapy and/or dexamethasone should receive pharmacologic VTE prophylaxis with LMWH if they are high risk, and either LWMH or aspirin if they are low risk.

The previous guideline recommended VTE prophylaxis with LMWH or adjusted-dose warfarin. Warfarin no longer appears in the recommendation. Also, the 2007 recommendation was based on extrapolation of data from other patient populations, not those with multiple myeloma. Since then, two RCTs compared aspirin, warfarin or LMWH to one another. Aspirin and LMWH performed comparably. Overall, warfarin performed similarly to the other agents, but it was shown to be less effective at preventing VTE among elderly patients receiving bortezomib (Velcade, Millennium Pharmaceuticals), melphalan, prednisone and thalidomide.

The panel made five recommendations regarding VTE prophylaxis in the perioperative setting, all of which are essentially unchanged from the previous guideline. In the interim, six meta-analyses and three RCTs added additional support for these recommendations.

• All patients with cancer undergoing major surgical intervention should be considered for pharmacologic VTE prophylaxis with either UFH or LMWH unless contraindicated because of active bleeding or high bleeding risk.
• Prophylaxis should start preoperatively (the previous guideline said preoperatively or as soon as possible in the postoperative period).
• Mechanical methods of VTE prophylaxis may be added to pharmacologic prophylaxis but should not be used alone for VTE prevention unless pharmacologic methods are contraindicated.
• A combined regimen on mechanical and pharmacologic VTE prophylaxis may improve efficacy, especially in the highest-risk patients.
• Pharmacologic VTE prophylaxis should be continued for at least 7 to 10 days after major surgery for cancer. Extended prophylaxis with LMWH for up to 4 weeks postoperatively should be considered for patients who undergo major abdominal or pelvic surgery for cancer who have high-risk features. In lower-risk surgical settings, the decision on the duration of VTE prophylaxis should be made on a case-by-case basis.

Seven recommendations fall within the category of VTE treatment and secondary prophylaxis. The last two are new to the guideline update.

• LMWH is preferred over UFH for the initial 5 to 10 days of anticoagulation for a patient with cancer and newly diagnosed VTE who does not have severe renal impairment. The clause about renal impairment was added, given the limited data in this patient population and some evidence that LMWH can accumulate in patients with impaired renal function.

In patients with renal impairment, the options are LMWH with Factor Xa monitoring, or UFH followed by vitamin K antagonist (VKA). For patients with — or who develop — heparin-induced thrombocytopenia (HIT), a direct thrombin inhibitor is preferred as initial anticoagulation. Based on limited data, the off-label use of fondaparinux may also be an option for those patients with HIT.

• For long-term anticoagulation, LMWH for at least 6 months is preferred because of improved efficacy over VKA. However, VKAs are acceptable if LMWH is not an option.
• Anticoagulation with LMWH or VKA beyond 6 months may be considered for select patients with active cancer, such as those with metastatic disease or those receiving chemotherapy. This last recommendation was based on consensus from the panel, as published studies do not exist. Factors for consideration include risk of VTE recurrence, risk of bleeding, cost of continuing therapy, quality of life, life expectancy and patient preference.
• Two recommendations regarding insertion of a vena cava filter and treatment of VTE in patients with central nervous system malignancies were essentially unchanged. There is moderate evidence at best for both of these recommendations, although the consensus of the panel was strong. Limited new data were available for review since the last guideline was published.
• The last two recommendations in this section are new.

First, the use of novel oral anticoagulants for either prevention or treatment of VTE in patients with cancer is not recommended. Data on the use of direct thrombin inhibitors and Factor Xa inhibitors in patients with cancer are limited. Larger trials are needed before they can be recommended.

The final recommendation — based on consensus of the panel, as literature support is insufficient — suggests incidental pulmonary embolism and DVT should be treated in the same manner as symptomatic VTE. In cohort studies, the rate of VTE events found incidentally was quite high, ranging from 35% to 50%. Regardless of how the VTE was found, no difference was seen in VTE recurrence, bleeding or survival.

These recommendations are essentially unchanged.

Anticoagulants are not recommended for the sole indication to improve survival in patients with cancer without VTE. These patients should be encouraged to participate in clinical trials designed to evaluate anticoagulant therapy as an adjunct to standard anticancer therapies.

Three systematic reviews and one RCT supported these recommendations. One meta-analysis demonstrated a lower mortality at 1 year with anticoagulation but a higher rate of bleeding. Two reviews that examined oral and parenteral anticoagulation found no survival advantage with warfarin but a higher rate of bleeding. A decrease in mortality was noted at 24 months for LMWH or UFH, with no increase in bleeding risk.

The RCT trial included patients with advanced cancer and a life expectancy of less than 6 months. Six weeks of LMWH had no effect on OS.

Based on the mixed results, more studies are necessary to determine the appropriate patients and preferred treatment plan for anticoagulation as an adjunct to anticancer therapy.

Both of these recommendations, based on consensus of panel members, are new for this guideline update.

First, patients with cancer should be assessed for VTE risk at the time of chemotherapy initiation and periodically thereafter. Individual risk factors such as cancer site or biomarkers do not reliably identify patients at high risk for VTE.

In the outpatient setting, there is a validated risk assessment tool — as described by Khorana and colleagues in Blood in 2008 — that can be used to perform VTE risk assessment. Five cohort studies were found that supported this recommendation; two reported on new risk assessment tools and three evaluated existing tools. Routine VTE prophylaxis of high-risk patients identified by the validated model is still an area of investigation, but these patients may benefit from increased education on the risk, signs and symptoms of VTE.

Second, the panel specifically recommended that oncologists educate patients regarding VTE, particularly in settings that increase risk, such as major surgery, hospitalization and receipt of systemic anticancer therapy.

ASCO recently published an update to its clinical practice guideline on VTE prophylaxis and treatment in patients with cancer, first published in 2007. Since 2007, several new oral anticoagulants have been approved; however, data with these agents in the cancer population are lacking.

Overall, the recommendations in the current guideline are similar to those made in 2007. The update emphasizes the importance of better identification and management of patients based on VTE risk.

Providers also should periodically reassess contraindications to VTE prophylaxis and treatment, as they may change over time. Further, providers are encouraged to educate patients about VTE and empower them to recognize and report signs and symptoms.

References:

Di Nisio M. Cochrane Database Syst Rev. 2012;2:CD008500.

Khorana AA. Blood. 2008;111:4902-4907.

Lyman GH. J Clin Oncol. 2013;31:2189-2204.

For more information:

Debbie Blamble, PharmD, BCOP, is an oncology clinical pharmacy specialist at The University of Texas MD Anderson Cancer Center. She can be reached at The University of Texas MD Anderson Cancer Center, Division of Pharmacy, 1515 Holcombe Blvd., Houston, TX 77030; email: dblamble@mdanderson.org.

Disclosure: Blamble reports no relevant financial disclosures.