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Renal Insufficiency
Treatment of VTE remains a challenge in the setting of renal insufficiency as patients with renal insufficiency have both an increased rate of bleeding and VTE. In the Registro Informatizado de Enfermedad TromboEmbólica (RIETE) study, 10,526 patients with VTE were followed prospectively to examine the effect of renal failure on the incidence of fatal pulmonary embolism (PE) and fatal bleeding within 15 days of diagnosis. Seven hundred and four (6.7%) patients had a creatinine clearance (CrCl) between 30 and 60 ml/min and 588 (5.6%) patients had a CrCl <30 ml/min. Compared with patients with a CrCl >60 ml/min, patients with a CrCl <30 ml/min had a 6.6-fold greater risk of fatal PE (1.0 vs 6.6%) and sixfold greater risk of fatal bleeding (0.2 vs 1.2%). The majority of patients were treated with LMWH (93% of patients with CrCl >60 ml/min and 89% of patients with a CrCl <30 ml/min).
Because LMWH and fondaparinux are excreted renally, these drugs may accumulate, leading to an increased risk of bleeding. However, there is considerable variability in drug accumulation among different LMWHs in patients with renal insufficiency. Data suggest that dalteparin may be safe at prophylactic doses in critically ill patients with severe renal failure (CrCl <30 ml/min). The use of tinzaparin has not been associated with an increased risk of bleeding but has an unexplained increased mortality in older patients. Treatment dose of any LMWH is contraindicated in the setting of severe renal failure and UFH is not well-studied in the long-term treatment of VTE. Therefore, VKA remains the treatment of choice for patients with severe renal insufficiency.
Unsuspected PE & PE Location
A PE detected on computed tomography (CT) in the absence of clinical suspicion is described as an unsuspected PE (UPE). With the increasingly widespread use of multiple-row detector CT (MDCT), the rate of reported UPEs has increased. MDCT improves visualization of pulmonary vasculature in the middle and peripheral lung zones, and has thereby improved the detection of PE. The overall rate of UPE in cancer patients on MDCT scan is reported to be 2.6% with an increased incidence in patients who are hospitalized and with advanced disease. Although this category of PE is often termed 'asymptomatic' or 'incidental', there is evidence to suggest that many of these patients are in fact symptomatic. Furthermore, in a retrospective chart review of 70 cancer patients with UPE, those who reported PE-related symptoms had significantly poorer survival compared with those who were truly asymptomatic. By contrast, in another retrospective review of 51 cancer patients with UPE, there was no difference in 12-month mortality rate between patients with UPE and those with symptomatic PE (52.9 and 53.3%, respectively). These varying results underscore the importance of prospective studies addressing the implication of UPE in cancer patients in order to guide appropriate treatment.
The management of subsegmental PE (SSPE) is particularly controversial because available data suggest that SSPE may not affect survival, yet the majority of patients are treated. In a retrospective cohort of 94 patients found to have an SSPE on MDCT pulmonary angiography, there was no recurrent VTE, hemorrhage or death reported at 3 months in the 24% of patients who were not treated. Of the 76% who were treated, 97% were treated with anticoagulant alone or anticoagulant in combination with an IVC filter, resulting in five major bleeding complications, one VTE recurrence and two deaths (neither from PE). This study suggests that the bleeding risk associated with anticoagulation may not outweigh the risk of VTE recurrence given the favorable short-term outcome in patients who were not treated for their SSPE.
Importantly, the favorable outcome data of untreated SSPE are derived from studies of the general population, and less is known about the natural history of untreated SSPE in cancer patients. In a retrospective chart review of 70 cancer patients with UPE, there was no significant difference in survival among UPE patients with isolated SSPE and matched controls (HR: 1.04; 95% CI: 0.44–2.39; p = 0.92). However, UPE identified more proximal to the subsegmental arterial branches has a significantly negative impact on survival with an associated HR of 2.28 at 6 months (95% CI: 1.20–4.33; p = 0.011). Although SSPE may not affect mortality, from a recent survey of 47 physician members of Thrombosis Interest Group of Canada, the presence of metastatic cancer was more likely to prompt physicians to treat SSPE than SSPE in a patient who did not have cancer.
Although the ACCP guidelines recommend treating a PE the same regardless of its location or whether it was unsuspected, more prospective research is needed to delineate the clinical relevance of these different types of PE in cancer patients.
Brain Metastases
Anticoagulation therapy is contraindicated in patients with active intracranial bleeding. Spontaneous intracranial hemorrhage is more common in patients with brain lesions as a result of metastatic disease as compared with patients with primary brain tumor, occurring in 14% of patients with brain metastases versus 0.8% of patients with gliomas. The use of dalteparin for long-term thromboprophylaxis in patients with malignant glioma was shown to increase intracranial bleeding resulting in closure of the PRODIGE trial. Among metastatic brain lesions, thyroid cancer, melanoma, renal cell carcinoma and choriocarcinoma have been associated with high rates of spontaneous hemorrhage. However, the majority of CNS metastases arise from lung and breast cancers and have a relatively low risk of intracranial hemorrhage (1–5%).
Massive PE
Although the majority of patients with PE are candidates for treatment with anticoagulation therapy, the recommended treatment of patients with massive PE is systemic thrombolysis. The rationale for thrombolytic therapy is that it leads to short-term resolution of emboli and improves hemodynamic instability. Despite this recommendation, in a study of 108 patients with massive PE, two-thirds of the patients did not receive thrombolysis or embolectomy. Interestingly, of those patients who received thrombolysis, mortality or recurrent PE at 90 days was not reduced. The role of IVC filters, catheter-based interventions and surgical embolectomy in massive PE is yet to be fully established.
Bleeding Patient
The only indications for an IVC filter are for those patients who have a contraindication to anticoagulation and those with recurrent VTE despite adequate anticoagulation therapy. These recommendations are set forth in the setting of relatively limited evidence. In a study of 400 patients with newly diagnosed proximal DVT comparing anticoagulation with UFH or LMWH alone versus in combination with an IVC filter, the patients treated with IVC had a lower incidence of PE at 12 days but a higher rate of DVT at 2 years, with no difference in mortality. As the patients in the IVC group of this study were also treated with anticoagulation, the benefits of an IVC for patients in whom anticoagulation is contraindicated remains unclear. No randomized trial or prospective cohort study has evaluated IVC filters as monotherapy in patients with DVT without concurrent use of anticoagulation. For this reason, in patients with a DVT in whom an IVC filter has been placed, anticoagulation should be initiated once the bleeding or bleeding risk has resolved. Removal of the IVC filter is generally recommended as soon as it is safe to do so in patients with a good prognosis.
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