Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

MEDICAL FRONTIERS - XXII Congress of the International Society on Thrombosis and Haemostasis

Boston, Massachusetts / July 11-16, 2009

Cancer-associated Thrombosis

Factors that promote venous thromboembolism (VTE) in patients with cancer are prolonged bed rest, vascular injury via direct tumour invasion into the vasculature and chemotherapy-induced endothelial damage, together with a hypercoagulability state that characterizes many cancers. “All intravenous (i.v.) chemotherapy turns on blood clotting factors and the more cycles a patient receives, the worse it gets,” confirmed Dr. Fred Rickles, Professor of Medicine, Pediatrics, Pharmacology and Physiology, The George Washington University, Washington, D.C. Evidence now indicates that activation of blood coagulability pathways is directly linked to malignant transformation of the tumour and in turn is associated with angiogenesis, tumour growth and metastasis. Indeed, VTE is a negative prognostic sign in cancer and may be the first sign of an occult malignancy, as he noted.

Whether or not thromboprophylaxis prolongs survival in cancer patients via mechanisms other than VTE prevention remains an intriguing research question. The occurrence of VTE in malignancy even when treated has a high 30-day mortality rate: 6% following deep vein thrombosis (DVT) and 12% following pulmonary embolism (PE). Regardless of the type of malignancy, symptomatic VTE reduces survival odds. Men with prostate, colon, brain and lung cancers are particularly vulnerable to thromboembolic complications as are women with breast, ovarian and lung cancers.

According to Dr. Craig Kessler, Georgetown University Medical Center, Washington, D.C., in-hospital mortality rates have been shown to be virtually identical among patients who have concomitant VTE, regardless of whether the patient has metastatic or non-metastatic disease.

A post-hoc analysis of the CLOT (Randomized Comparison of Low Molecular Weight Heparin Versus Oral Anticoagulant Therapy for the Prevention of Recurrent VTE in Patients with Cancer) trial presented here by Dr. Agnes Lee, McMaster University, Hamilton, Ontario, and colleagues also showed that adenocarcinoma of unknown primary site and lung cancer confer a 3.5-fold greater risk of patients developing recurrent VTE compared with colorectal cancer with a relative risk of one.

The seminal CLOT trial specifically addressed the rate of recurrent VTE in cancer patients with acute DVT or PE. Some 210 days’ post-randomization, the risk of recurrent VTE was 52% lower in the dalteparin arm compared with those on an oral anticoagulant and the risk of major bleeding was only slightly higher in the low molecular-weight heparin (LMWH) arm at 5.6% vs. 3.6% in the oral anticoagulant arm (not significant) (Figure 1). Recurrent VTE in the setting of malignancy was also significantly lower in two other trials in which enoxaparin and tinzaparin were each compared with oral anticoagulant therapy.

As a result of these findings, the new standard of care for the treatment and secondary prevention of VTE in patients consists of a LMWH, given at therapeutic doses for a minimum of three to six months, according to American College of Chest Physicians (ACCP) recommendations. As Dr. Kessler pointed out, as of May 2007, dalteparin was the only LMWH approved for both the treatment and secondary prevention of VTE in cancer, with oral anticoagulant therapy to follow for as long as the disease is active.

Figure 1.

Thromboprophylaxis of Hospitalized and Surgical Oncology Patients

The most recent recommendations from the American Society of Clinical Oncology (ASCO) indicate that hospitalized cancer patients should be considered for VTE prophylaxis in the absence of bleeding or other contraindications. It also recommends all cancer patients undergoing major surgery be considered for thromboprophylaxis, as should those undergoing laparotomy, laparoscopy or thoracotomy lasting longer than 30 minutes. Prophylaxis should be continued for at least seven to 10 days’ post-operatively and prolonged prophylaxis (up to four weeks) may be considered following surgery in patients with high-risk features.

For both the prophylaxis and treatment of thromboembolic disease, current options include unfractionated heparin, LMWH and fondaparinux. The new oral anticoagulants, direct Xa inhibitors, may also play a role. Results from a number of VTE prophylaxis studies consistently support a relative risk reduction of approximately 50% (range, 44% to 63%) with either LMWH or fondaparinux in medical patients. Similarly, prophylaxis in surgical patients with either unfractionated heparin or a LMWH was shown to reduce VTE rates from 16.9% to 13.9% in the Canadian Colorectal DVT Prophylaxis trial and bleeding rates remained low. In the FAME study, dalteparin was given for either seven or 28 days following major abdominal surgery. The cumulative incidence of VTE was again reduced from 16.3% with short-term thromboprophylaxis to 7.3% with prolonged thromboprophylaxis, for a relative risk reduction of 55% in favour of the four-week regimen. There was no increase in bleeding risk in the extended prophylaxis arm.

According to ASCO guidelines, VTE prophylaxis is not routinely recommended for ambulatory patients with cancer. However, as Dr. Kessler observed, VTE risk is highly variable in oncology patients, often the consequence of the treatment involved. Multiple myeloma patients receiving thalidomide plus chemotherapy, for example, have a VTE incidence of 28% while bevacizumab increases the risk of symptomatic VTE by 33%, according to a meta-analysis (JAMA 2008;300:274-6).There is also some indication that LMWHs possess anti-tumour effects with survival odds at one year being suggestively higher for patients in CLOT without metastases receiving dalteparin vs. those on oral antico
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Figure 2.

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In a study involving 84 patients with small cell lung cancer, Altinbas et al. (J Thromb Haemost 2004;2(8):1266-71) demonstrated that at one year, 51.3% of patients on chemotherapy plus dalteparin were still alive vs. 29.5% on chemotherapy alone with median survival of 13 months vs. eight months, respectively.

VTE Prophylaxis: A Key Patient Safety Priority

Abundant data exist supporting thromboprophylaxis for most hospital patients, including patients with cancer as well as those requiring surgery for cancer, yet VTE prophylaxis remains largely underused in patients at risk. As cited by Dr. William Geerts, Professor of Medicine, University of Toronto, Ontario, according to a FRONTLINE survey carried out in 2003, 52% of cancer patients undergoing surgical procedures compared with only 5% of those treated medically received appropriate prophylaxis. A Canadian study involving 29 hospitals found that of 90% of consecutive medical admissions meeting the criteria required for prophylaxis, 23% received some prophylaxis
the recommended prophylaxis, he reported (Figure 3).

Figure 3.

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According to readmission rates among patients who had been in hospital within the previous month, Swiss investigators found that fewer than half of medical patients readmitted with a symptomatic VTE received prophylaxis. Even partial prophylaxis is associated with poorer outcomes.

In an analysis involving 83,794 discharges (Amin et al. J Oncol Pract 2009;5(4):159-64), researchers found only 16% of the cohort had received appropriate prophylaxis and that partial prophylaxis conferred a significantly higher risk in hospital-acquired VTE, in-hospital death and 30-day VTE readmission rates. “This represents missed opportunities to prevent complications,” Dr. Geerts remarked, “and we have to ask what [we] can do to try and improve adherence to prophylaxis.”

Excellent quality guidelines represent a “big step forward,” Dr. Geerts noted, making necessary decisions about prophylaxis relatively easy. Endorsement by a national organization such as ASCO and the Society of Hospital Medicine is another “giant step forward” in the implementation of appropriate prophylaxis, he added. Other strategies that may be helpful on a national level are public reporting of quality of care adopted by the Surgical Care Improvement Project; since hospitals have been encouraged to provide recommended prophylaxis to the vast majority of surgical patients in the US, “rates of adherence have been steadily increasing since this initiative began,” confirmed Dr. Geerts.

Canada has adopted the World Health Organization Surgical Safety Checklist, where healthcare workers must note if DVT prophylaxis is indicated, if it has been ordered and if it is has been administered—“another huge step forward for patient safety,” as Dr. Geerts told delegates. More local strategies include having a written hospital policy on prophylaxis. The use of “order sets” that have prophylaxis recommendations embedded among other admission or post-operative orders is “the single most effective strategy,” in Dr. Geerts’ opinion, for improving prophylaxis rates because they save time, they can be used in every patient group and they can be used to audit adherence to prophylaxis use.

“Decisions about prophylaxis have to be mandatory as well—you don’t have to do it, but you have to make a conscious decision for every patient as to whether they should get DVT prophylaxis or not,” Dr. Geerts remarked, “and I cannot emphasize strongly enough the role of collecting data and providing feedback to hospitals.” In his own institution, for example, administrators have adopted a “one drug at one dose” policy for everybody at risk for thrombosis, except where the bleeding risk is high; for these patients, “we give obsessive mechanical prophylaxis and daily reassessment looking for the time when they can get prophylaxis based on evidence,” Dr. Geerts related. Having initiated audits a while ago, the hospital recently found that 87% of surgical patients received appropriate or recommended prophylaxis as did 77% of medical patients and 97% of patients in the ICU.

“Thromboprophylaxis is the highest ranked safety intervention for hospitalized patients,” Dr. Geerts stated, “but only when it is incorporated into the culture of routine care will every hospitalized patient receive thromboprophylaxis that is appropriate to their thromboembolic and bleeding risk.”

LMWH and Special Populations

According to Edith Nutescu, PharmD, Clinical Professor of Pharmacy Practice, University of Illinois College of Pharmacy, Chicago, it would be imprudent to group all LMWHs together as a class and make few distinctions between the different agents. She presented an analysis of recent clinical trials involving the various LMWHs which showed that there were differences in the agents’ tendencies to bioaccumulate in renally impaired patients. Tincani et al. (Haematologica 2006;91:976-9) found no evidence of bioaccumulation following six days of a dalteparin regimen, regardless of renal function. Nor was there any correlation between degree of renal impairment and peak anti-Factor Xa levels on day 6.

Regarding critically ill patients with a creatinine clearance (CrCl) <30 mL/min, Douketis et al. (Arch Intern Med 2008;168:1805-12) found no evidence of dalteparin bioaccumulation in patients with a ³1 trough anti-Factor Xa level. In contrast, Mahe et al. (Drugs Aging 2007;24:63-71) found that enoxaparin levels were significantly enhanced in elderly patients with a CrCl 20 to 50 mL/min, although not in those who received tinzaparin. “Obviously, if a drug accumulates and we don’t adjust the dose, bleeding risk will increase and patient safety is compromised,” stated Dr. Nutescu, “so we need to recognize that there are differences in these agents and adjust the doses appropriately for agents that accumulate.”

UK-based investigators under lead author Dr. Victoria M.A. Simpson, University College London Hospitals, identified 16 women, mean age 32, who had acute VTE during pregnancy and nine others who were on long-term anticoagulation. In order to maintain mean anti-Xa levels, investigators found it was necessary to increase the dose of dalteparin by a mean of 20% over initial daily doses by the third trimester. “The required increase in dose could not be accounted for by increasing weight alone, as the dose/kg also increased,” investigators observed. The mean daily dose required to maintain therapeutic anti-Xa levels during the third trimester was significantly greater than the dose of 200 U/kg a day, suggesting that anti-Xa levels should be monitored in women who require prophylaxis or treatment of VTE during pregnancy.

Questions and Answers

The following section is based on discussions with Edith Nutescu, PharmD, Clinical Professor of Pharmacy Practice, University of Illinois College of Pharmacy, Chicago, and Dr. William Geerts, Professor of Medicine, University of Toronto, Ontario, during the scientific sessions at the XXII Congress of the International Society on Thrombosis and Haemostasis.

Q: How do you explain the difference between dalteparin and tinzaparin which do not seem to bioaccumulate vs. enoxaparin, which does?

Dr. Nutescu: I think it goes back to the differences in the pharmacokinetic and the pharmacodynamic characteristics of the various agents. Their molecular weights are slightly different; their anti-Factor Xa:IIa ratios are slightly different; and it appears that agents that have a higher Xa:IIa ratio, such as enoxaparin, tend to accumulate more vs. dalteparin and tinzaparin, which have more of a IIa effect and they have less tendency to accumulate or perhaps not at all.

Q: Most patients who are admitted to hospital are acutely ill. How many hospitalized patients do not meet the criteria for thromboprophylaxis?

Dr. Geerts: In our hospital, only about 15% would be considered low risk, so 85% would meet the criteria for thromboprophylaxis and you have to ask, is it worth a huge effort to try and find patients who are too low-risk to warrant prophylaxis? The entire concept of prevention means you have to give immunization or make seat belts mandatory for everybody to prevent those at higher risk from getting complications. We can make the patient selection process pretty simple.

Note: At press time, in Canada, LMWHs are not indicated for the treatment or prevention of VTE during pregnancy nor for the primary thromboprophylaxis of ambulatory oncology patients.