Case study 133.1
A 54-year-old male presents with a worsening chronic cough. Chest imaging and subsequent needle biopsy reveal the presence of metastatic lung adenocarcinoma. The patient has no prior history of venous thromboembolism (VTE), remains active, and has a normal Body Mass Index (BMI) and complete blood count (CBC). Systemic chemotherapy with a bevacizumab-containing regimen is planned.
1. Is pharmacologic VTE prophylaxis indicated for this patient? If so, what is the preferred agent?
- Yes, therapeutic low-molecular-weight heparin (LMWH)
- Yes, therapeutic warfarin
- Yes, prophylactic LMWH
- No; prophylaxis is not indicated
The use of VTE prophylaxis in ambulatory cancer patients receiving chemotherapy has demonstrated efficacy in the past, and has recently been studied in large, industry-sponsored trials using LMWH. While these studies have found decreased event rates in patients receiving prophylaxis compared with placebo, overall event rates are low. Risk assessment scores have been developed to identify those patients at increased risk who might derive greater benefit from prophylaxis.
The risk for a VTE event varies among patients. Data from a prospective observational study involving approximately 2700 cancer patients were used to derive a risk model for VTE (shown in Table 133.1).
Table 133.1 Khorana Risk Assessment Score.
Patient characteristic |
OR (95% CI) |
Risk score |
|---|
Stomach or pancreas site |
4.3 (1.2–15.6) |
2 points |
Lung, lymphoma, GYN, bladder, or testicular site |
1.5 (0.9–2.7) |
1 point |
Platelet count ≥350,000 per μl |
1.8 (1.1–3.2) |
1 point |
Hemoglobin <10 g/dL |
2.4 (1.4–4.2) |
1 point |
WBC count >11,000 per μl |
2.2 (1.2–4) |
1 point |
BMI ≥35 kg/mg2 |
2.5 (1.3–4.7) |
1 point |
The study authors found that the total risk score correlated with VTE risk in a separate validation cohort. The incidence of VTE was 0.3% in low-risk patients (0 points), 2% in intermediate-risk patients (1–2 points), and 6.7% in high-risk patients (≥3 points) over a median of 2.5 months. The baseline risk of VTE in a given patient with cancer can be estimated using this straightforward metric.
This Khorana risk-scoring model was applied to the patient population in the SAVE-ONCO trial, the largest VTE prophylaxis study in this setting to date. Approximately 3200 ambulatory patients receiving chemotherapy for locally advanced or metastatic cancer were randomized to receive semuloparin 20 mg daily versus placebo. The overall incidence of VTE in the semuloparin group was 1.2%, versus 3.4% in the placebo group (HR: 0.36; P < 0.001). In the subset analyses reported at ASH 2011, patients with a Khorana risk score of >3 receiving prophylaxis had a VTE rate of 1.5% compared to 5.4% for the placebo group (HR: 0.27; 95% CI: 0.09–0.82). Overall bleeding rates were comparable between the semuloparin arm and placebo; however, bleeding rate increased with corresponding increase in Khorana risk score. The overall VTE event rate in the general ambulatory cancer patient population is low, and no survival benefit has been demonstrated. In summary, while the relative risk reduction with prophylactic anticoagulation is significant, the absolute risk difference is small.
One trial was recently reported that employed apixaban, a new oral anticoagulant, for VTE prophylaxis. This trial demonstrated that apixaban has a good safety profile compared with placebo, with increased risk of bleeding as dose increases, but was not powered to demonstrate efficacy. Insufficient data currently exist to recommend the use of any new oral anticoagulant for VTE prophylaxis in oncology patients, especially since the utility of prophylactic anticoagulation in this setting has not been demonstrated.
Current ACCP guidelines suggest against the use of prophylaxis except in those patients with additional risk factors. We reserve empiric prophylaxis for ambulatory patients treated with highly thrombogenic myeloma regimens, history of prior unprovoked or life-threatening VTE, or strong inherited thrombophilias (such as homozygous factor V Leiden). The patient in this case has no past history of thrombosis and no other VTE risks. His Khorana risk score is 1, with a VTE incidence rate of 2%. The contribution of bevacizumab to thrombotic risk is not clear, given conflicting reports. There are no data to support the routine use of prophylactic anticoagulation with bevacizumab-containing regimens. Additional studies are needed to better prospectively identify ambulatory cancer patients at high risk for VTE who may benefit from such prophylactic anticoagulation.
The efficacy and safety of prophylactic anticoagulation in the hospitalized cancer patient and in patients undergoing oncology surgery, who have a higher risk of post-op VTE than non-oncology patients, have been clearly demonstrated. We have not covered these indications in this chapter. As in all situations where anticoagulation treatment is considered, the risks and benefits need to be carefully evaluated and understood for each individual patient.
After two cycles of chemotherapy, restaging computed tomography (CT) scan is performed. Incidental pulmonary embolus is found in a right lower lobe segmental artery. Although the patient is fatigued and has an infrequent nonproductive cough, his heart rate is 85 beats per minute, his blood pressure is 128/72, and room air oxygen saturation is 96%. Brain natriuretic peptide is within normal limits, and there is no evidence of right heart strain on physical exam. CT also suggests a response to therapy, and plans are to continue with the current treatment regimen.
2. Which of the following agents would be preferred for initial treatment?
- Warfarin
- Intravenous (IV) unfractionated heparin (UFH)
- Dalteparin
- Dabigatran
- Rivaroxaban
This patient presents with an apparently asymptomatic pulmonary embolism (PE). In a retrospective study, however, 75% of cancer patients who were diagnosed with unexpected PE did in fact have symptoms, including fatigue and dyspnea, that had been previously attributed to the cancer or its treatment. Clinicians need to have a high index of suspicion for VTE in the evaluation of new symptoms in the cancer patient. Treatment of incidental VTE is warranted. A study comparing recurrent VTE, bleeding, and mortality rates in oncology patients with incidentally detected versus symptomatic PE found no difference in outcome for either group, suggesting that the incidental PE group had just as high a risk of adverse events associated with VTE as symptomatic patients. Regardless of symptoms, the presence of thrombus serves as an indicator for true hypercoagulable state. In our experience, when patients with asymptomatic VTE are observed and re-imaged, there is a high rate of extension or development of new thrombus in other locations.
Initial treatment of acute VTE requires the use of rapid-acting agents to prevent clot propagation. Use of warfarin alone is associated with an unacceptably high rate of thrombus extension and is not appropriate initial therapy in this patient or any patient with acute VTE. Intravenous UFH, LMWH, fondaparinux, and, recently, rivaroxaban have all been demonstrated to have good efficacy and safety in the initial treatment of VTE in the general population. LMWH has many pharmacokinetic advantages over UFH, including fixed weight-based dosing with no need for monitoring. There would be no reason to hospitalize this ambulatory patient for treatment with UFH. Although the current standard of care of PE in many institutions is to admit patients for treatment and observation, we have found that many reliable patients who have an unexpected finding of PE can be treated in the outpatient setting. Clinical judgment incorporating an assessment of clot burden, degree of symptoms, oxygen saturation, and hemodynamic function can be used to determine the need for hospitalization. A recent meta-analysis of 13 studies with a total of 2458 patients supports outpatient treatment in low-risk patients. Despite the use of different risk stratification schemes, the risk of recurrent VTE, fatal PE, and major bleeding was low.
Based on the results of multiple trials, LMWH is the standard of care for initial treatment of cancer-associated VTE in ambulatory patients. The largest study of acute VTE treatment in oncology patients to date is the Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) trial. Approximately 700 patients who were actively receiving chemotherapy were randomized to treatment with dalteparin 200 units/kg/day for one month followed by a decrease in dose to 150 units/kg/day for 5 months, or initial dalteparin for 5–7 days followed by warfarin for 6 months. The probability of recurrent VTE was 9% for those treated with dalteparin alone versus 17% for warfarin (P = 0.002). There was no difference in risk of bleeding.
As a result of these findings, LMWH has been widely recommended as the preferred treatment for acute VTE in the cancer patient, without transition to warfarin. Guidelines from American Society of Clinical Oncology (ASCO), National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO), and American College of Chest Physicians (ACCP) endorse the use of LMWH as monotherapy for 3–6 months in this population. While oncology patients have sometimes failed therapeutic warfarin, warfarin management itself in this population is difficult due to drug–drug interactions, hepatotoxicity from chemotherapy, and absorption issues due to the significant gastrointestinal impact of chemotherapy. It should be noted that the CLOT trial had a warfarin time in therapeutic range (TTR) of only 46%, reflecting the management difficulty in this population. Most of the recurrent events occurred during the first month of anticoagulation treatment, when optimal warfarin dose is being defined. Almost half of the recurrent events in the warfarin arm occurred when the international normalized ratio (INR) was <2.0, which may account for some of the differences seen between the treatment arms. For certain patients, however, transitioning to warfarin after initial therapy with LMWH may be appropriate or unavoidable. The cost of LMWH can be prohibitive for many patients, and the once- or twice-daily subcutaneous injections can be difficult to tolerate. In addition, LMWH should be used with caution in the setting of renal insufficiency.
Dabigatran, which directly inhibits thrombin, and rivaroxaban and apixaban, which target factor Xa, are oral anticoagulants that have been developed as alternatives to warfarin and are available for prescribed use. While most trials so far show equivalent efficacy and possibly improved safety compared with warfarin, these drugs have only been studied in highly selected patient populations. Experience and data for use outside these populations is limited or nonexistent. Dabigatran and apixaban are approved for stroke prophylaxis in patients with nonvalvular atrial fibrillation, but not for treatment of acute VTE. Rivaroxaban is now also approved by the US Food and Drug Administration (FDA) for the treatment of DVT and PE. Dabigatran labeling was recently changed to list use in patients with mechanical valves as an absolute contraindication, based on the early termination of the RE-ALIGN trial due to increased events with dabigatran compared to warfarin. This unexpected result demonstrates that caution is warranted when prescribing new anticoagulants for patients with high-risk thrombotic indications that have not been specifically validated. In addition to having a high risk for thrombosis, cancer patients are also commonly prescribed medications (including certain antibiotics, antifungals, antivirals, and seizure medications) that affect plasma concentrations of these oral anticoagulants. These interactions occur via p-glycoprotein transport in the case of dabigatran, or both p-glycoprotein and CYP3A4 for rivaroxaban and apixaban.
Rivaroxaban, or use of the other new oral anticoagulants, would not be considered first-line therapy for a cancer patient on cytotoxic chemotherapy.
3. After 6 months of treatment, this patient is hospitalized with acute kidney injury related to volume depletion and ibuprofen use. Recent restaging scans showed partial recanalization of subsegmental pulmonary emboli. Metastatic disease remains present but stable. Chemotherapy is currently on hold for a number of months. Initial labs show a creatinine clearance of 20 ml/min and a partial thromboplastin time (PTT) of 80 seconds. Anti-Xa level is 3.8 units per mL (drawn 4 hours after his last injection). How should the patient’s anticoagulation be managed?
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