Venous thromboembolism is the second leading cause of death in patients with cancer, but compliance with routine prophylaxis remains a challenge.

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Studies continue to show that many at-risk patients with cancer are not receiving appropriate prophylaxis or any prophylaxis at all, even though many society guidelines call for routine prophylaxis. According to results from the Fundamental Research in Oncology and Thrombosis (FRONTLINE) survey published in 2003, just 52% of surgeons routinely used thromboprophylaxis for surgical patients with cancer, and routine prophylaxis was considered in less than 5% of medical oncology patients.

Similarly, data presented this year at the ASCO Annual Meeting and published in the Journal of Clinical Oncology revealed that 75.3% of patients with cancer did not receive anticoagulation during their hospital stays. None of these patients, identified from the Premier Perspective database and the Ingenix LabRx I3 database, had contraindications for anticoagulation. Within 30 days after hospital discharge, 97.9% of patients did not receive any prophylaxis.

“Venous thromboembolism prevention in this at-risk population has significant opportunities for improvement,” said Alpesh Amin, MD, FACP, executive director of the hospitalist program and medical director of the anticoagulation clinic at the University of California, Irvine, and lead author of the study presented at ASCO. “Only about one-quarter of providers are actually prophylaxing patients, based on the American College of Chest Physicians guidelines. There is a huge opportunity to actually improve the prevention, and other national societies such as ASCO are also on board in terms of appropriate venous thromboembolism prevention.”

Highlighting the issue

The low compliance numbers in these studies are an improvement over the numbers from a decade ago, but because the numbers are still high, the issue of prophylaxing patients with cancer has recently gained increased attention.

Alok A. Khorana, MD, associate professor at the James P. Wilmot Cancer Center at the University of Rochester School of Medicine and Dentistry in Rochester, N.Y., said compliance has improved since the 1990s, when surveys showed prophylaxis rates of 20% to 30%.

“Having said that, we are still having 30%, 40%, 50% of patients who aren’t getting prophylaxed, and it still continues to be a major issue,” Khorana told HemOnc Today. “We’ve known for a long time that patients with cancer are at high risk for getting blood clots, but this has become an increasing problem in the last decade or so. … There is a stronger association with mortality than we have previously understood.”

In addition, many of the newer chemotherapy agents, such as thalidomide (Thalomid, Celgene), bevacizumab (Avastin, Genentech) and lenalidomide (Revlimid, Celgene), are more strongly associated with developing clots, which “has really brought the issue to more of the front burner in terms of priority,” Khorana said.

Jeffrey Zwicker, MD, instructor in medicine at Beth Israel Deaconess Medical Center at Harvard University, said the problem of low compliance for VTE prophylaxis is not unique to patients with cancer.

“A lot of patients, both medical as well as patients with cancer, are not receiving the recommended prophylaxis,” he said. “It’s especially true in patients with cancer because of the perceived risks in this patient population — they’re perceived to have a higher risk for bleeding, and they’re on multiple other medications that could compound the issue … which just makes treating clinicians a bit more hesitant to add yet another medication to the mix.”

Explanations for low compliance

Experts cite a number of reasons for the low compliance numbers. Perhaps the most significant reason is the perception of an increased risk for bleeding with anticoagulants. “Physicians are fearful of side effects such as heparin-induced thrombocytopenia,” Amin said. “But now we have therapies, like enoxaparin (Lovenox, Sanofi-Aventis), for example, that has shown in studies compared head to head with unfractionated heparin, that it does have a decreased risk for bleeding and a significantly decreased risk for heparin-induced thrombocytopenia.”

Moreover, Amin said, his study and others have demonstrated low rates of prophylaxis in patients who did not have low platelet counts or other contraindications. Khorana said there are no data to suggest that bleeding rates are higher with prophylactic doses of anticoagulants as there are for therapeutic doses.

Gary H. Lyman, MD, MPH, FRCP, professor of medicine at Duke University and director of health services, effectiveness and outcomes research at the Duke Comprehensive Cancer Center in Durham, N.C., attributed the low numbers of compliance, in part, to a transition period between when guidelines are issued and when they affect clinical practice.

“Another aspect is that hospitalized cancer patients are often very sick, and there may be several things higher on the priority list for the treating physician,” said Lyman, who is also the panel chair on the ASCO Venous Thromboembolism guidelines. “In some instances, there probably is an intention to prophylax, but in others it simply gets overlooked and no one flags it.”

Michael B. Streiff, MD, director of anticoagulation management service and outpatient clinic at Johns Hopkins Comprehensive Hemophilia Treatment Center, agreed. “The problem is that inpatient medicine has become increasingly complex,” he said. “Venous thromboembolism prophylaxis is a preventive therapy, and all of the preventive therapies fall by the wayside if someone comes in with, for example, a new metastases or liver failure because of their metastases or bowel obstruction,” Streiff said. "All efforts are focused on trying to make those symptoms better. Unless people are prompted to think about the preventive therapies, like VTE prophylaxis, like flu vaccinations, those things drop off the radar screen.”

Khorana said it is not a provider issue but rather a health system issue. “Providers have a lot of things they need to do when a patient is admitted,” he said. “If it’s a patient with cancer who is admitted for pneumonia, you have to write the admission orders, IV fluids, pneumococcal vaccine, IV antibiotics and so on. Sometimes, the whole issue of prophylaxis goes to the end of the list of things that providers need to do — or they don’t think about it, or there’s a new intern who doesn’t think about it, and so on.”

Streiff, who is also a panel co-chair on the National Comprehensive Cancer Network’s guidelines on thromboprophylaxis, said some oncologists tend to view deep vein thrombosis or pulmonary embolism as “the price of business.”

“You’re trying to get the cancer under control, and if the patient develops a clot, [some oncologists think] that’s just a complication that’s going to happen to some people, and they don’t consider it something you can prevent,” he said.

Guideline consensus

Several medical organizations and societies, recognizing a need for consensus and improved prophylaxis in these patients, offer guidelines on prophylaxis, including the American College of Chest Physicians, which covers an array of situations, with a small section on patients with cancer; the European Society for Medical Oncology; the Italian Association of Medical Oncology; the French National Federation of the League of Centers Against Cancer; and most notably, ASCO and the NCCN.

Recently, a working group of members from these organizations — with the exception of the CHEST guidelines — wrote a consensus statement and call to action for thromboprophylaxis in patients with cancer. The statement was published online ahead of print in the Journal of Clinical Oncology on Aug. 31.

The working group reported broad consensus regarding the need for thromboprophylaxis in hospitalized patients with cancer and prolonged prophylaxis in high-risk surgical patients. They did not recommend prophylaxis for ambulatory patients with cancer, with the exceptions of those patients receiving thalidomide- or lenalidomide-based therapy and those patients with central venous catheters. When thromboprophylaxis is indicated, the guidelines recommend pharmacologic thromboprophylaxis, including low-dose unfractionated heparin, low–molecular-weight heparin or fondaparinux (Arixtra, GlaxoSmithKline) in those patients without contraindications, and all guidelines agree that heparins are preferred for long-term treatment of VTE.

The group also called for “a sustained research effort” to investigate the outstanding clinical issues to “reduce the burden of venous thromboembolism and its consequences in patients with cancer.” They noted the following as areas that require further research: prophylaxis in the ambulatory setting, the risk/benefit ratio of prophylaxis for hospitalized patients with cancer, an understanding of incidental VTE and the effect of anticoagulation on survival.

Ambulatory patients

One of the most significant unanswered questions in the guidelines is when to consider prophylaxis in ambulatory patients with cancer. According to Lyman, the ASCO panel felt that ambulatory patients in general do not have a sufficiently high risk for VTE to recommend routine prophylaxis after considering the risk for bleeding. And until recently, there was a lack of controlled clinical trials demonstrating significant risk reductions with prophylactic anticoagulation in these patients.

In a six-study meta-analysis presented at ASCO this year, Kuderer et al reported a 36% RR reduction in VTE in ambulatory patients with cancer who received a low–molecular-weight heparin. However, the researchers wrote in the abstract that the absolute risk reduction was small, and bleeding was still a concern.

In addition, the PROTECHT study, presented at the annual meeting of the American Society of Hematology and published in The Lancet on Sept. 1, also revealed a reduced incidence of thromboembolic events in ambulatory patients with metastatic or locally advanced cancer receiving the low–molecular-weight heparin nadroparin. Researchers found a 2% rate of thromboembolic events in patients receiving nadroparin compared with a 3.9% rate in those receiving placebo.

Most of the guidelines list exceptions to the recommendation for ambulatory patients, including patients with multiple myeloma who are receiving thalidomide or lenalidomide and chemotherapy or dexamethasone and corticosteroids. “These patients, historically, have been at extraordinarily high risk, ranging from 15% to 30% or 40% risk for these complications during the course of treatment,” Lyman said.

Additional exceptions to the ambulatory patient rule are also emerging. Data from the CONKO 004 trial, also presented at ASCO, suggested that ambulatory patients with advanced pancreatic cancer may benefit from thromboprophylaxis. Patients who received the low–molecular-weight heparin enoxaparin experienced risk reductions of up to 74% and experienced fewer bleeding events than the patients in the observation group (6.3% vs. 9.9%), although the difference was not significant.

“If benefit and safety are confirmed, [The CONKO 004 study findings] could be practice changing,” Lyman said. “For the first time, we have a study that shows a significant reduction in risk, as well as a high enough risk in the control patients to consider perhaps another high-risk setting — advanced pancreatic cancer.”

Extending outpatient prophylaxis

According to Streiff, many of the guidelines will likely incorporate data from Khorana and colleagues on an algorithm for identifying the patients at highest risk for VTE because it provides a starting point for considering prophylaxis in patients with cancer after hospital discharge. Published in Blood in May 2008, a multivariate risk model that incorporated five variables assisted in identifying patients with a nearly 7% short-term risk of VTE.

The five predictive variables included site of cancer (two points for a very high-risk site, one point for a high-risk site), platelet count of 350 × 10⁹/L or greater, hemoglobin < 100 g/dL, and/or use of erythropoiesis-stimulating agents, leukocyte count > 11 × 10⁹/L and BMI ≥ 35 (one point each). Khorana and colleagues reported that rates of VTE in a validation cohort were 0.3% for those with a low-risk score (0), 2% for those with an intermediate-risk score (1-2) and 6.7% in those with a high-risk score (≥3).

“This study has laid the groundwork, but I don’t think we have the evidence yet that people who are high risk, as identified by this scoring system, are people who will derive more benefit than harm from extended outpatient prophylaxis,” Streiff said.

Khorana said the ASCO panel will also discuss the current data on outpatient prevention. “I personally don’t think the data are sufficient enough for us to make that recommendation yet, but there’s at least much more data than we had even two years ago for the panel to consider and make a decision,” he said.

Another approach to targeting prophylaxis toward those patients at highest risk is the use of biomarkers. Data have also suggested that measuring levels of tissue factor, which is an initiator of coagulation, may also help to predict which patients are at risk for blood clots. Zwicker and colleagues have identified tissue factor-bearing microparticles that may be a risk factor for developing thrombosis and recently initiated a randomized, phase-3 trial evaluating primary prophylaxis in those patients who have elevated tissue factor-bearing microparticles.

Compliance with routine prophylaxis

In the meantime, the experts who spoke with HemOnc Today have a number of ideas for how to increase compliance. One way to prompt the health care team about these preventive measures is electronic alerts, which can be easily implemented at hospitals that already have electronic medical records in place, according to Lyman.

Streiff’s institution, Johns Hopkins, has already implemented smart-order sets, which make thromboprophylaxis a mandatory part of admission. With these order sets in place, physicians cannot order prescriptions or tests without assessing risk factors and prescribing risk-appropriate prophylaxis, he said.

The institution is currently looking at the effect these orders have had on compliance. “Preliminary data indicate that the order sets have improved compliance,” Streiff said. “Eventually everyone is getting to 95%+ within 24 hours of stratifying.”

Lyman said simply having nurses or pharmacists remind physicians about prophylaxis in the inpatient setting may improve compliance.

“While, ultimately, the physician is the one who has to take responsibility, I like to think the entire health care team has a responsibility to remind each other of the risk,” he said.

Khorana said it is important that health systems put protocols in place that concur or are somewhat similar to the national and international consensus of the guidelines.

“Wherever systems have put in electronic alerts, like a computer admission order entry alert or fact sheet protocols in the chart that remind providers to prophylax, we have seen compliance rates go up dramatically,” Khorana said.

Zwicker said one way to increase compliance is to obtain “buy-in” from oncologists, “that they in fact understand the problem and perceive it as a problem that needs to be addressed. A lot of the studies are initiated and implemented by hematologists, but it’s hard to disseminate the information when the hematologists are not controlling the patient population. Better buy-in and participation by the treating oncologists — both in study design and implementation and ultimately dissemination — would be helpful in making this common practice.” – by Tina DiMarcantonio

For more information:

• Agnelli G. Lancet. 2009;doi:10.1016/S1470-2045(09)70232-3.
• Amin A. #e17510. Presented at ASCO. J Clin Oncol. 2009;27(suppl):abstr e17510.
• Kakkar AK. Oncologist. 2003;8(4):381-388.
• Khorana AA. Blood. 2008;111:4902-4907.
• Khorana AA. J Clin Oncol. 2009;doi:10.1200/JCO.2009.22.3214.
• Kuderer NM. #9537. Presented at ASCO.J Clin Oncol. 2009;27(suppl):abstr 9537.
• Lyman GH. J Clin Oncol. 2007;25:5490-5505.
• Riess H. #LBA4506. Presented at ASCO. J Clin Oncol. 2009;27(suppl):abstr LBA4506.