Tag: Venous Thrombo Embolism

SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000 – 100,000 deaths. VTE is the third leading cause of cardiovascular mortality with a mortality rate of up to 25% in those with untreated acute pulmonary embolism. For decades, Unfractionated Heparin (UFH) also known as standard heparin along with Vitamin K antagonist (Warfarin) has been the established standard, for the treatment of Acute Venous ThromboEmbolism. Even though Low Molecular Weight Heparin (LMWH) preparations as well as new oral anticoagulants have been available for the treatment Venous ThromboEmbolism, there has been very little guidance for Health Care Providers on the use of these newer agents. The authors in this analysis compared the efficacy and safety outcomes associated with different anticoagulation regimens for treatment of Venous ThromboEmbolism (VTE). These anticoagulant regimens included Unfractionated Heparin (UFH), Low Molecular Weight Heparin (LMWH) or Fondaparinux in combination with Vitamin K antagonists, LMWH with Dabigatran (PRADAXA®), Rivaroxaban (XARELTO®), Apixaban (ELIQUIS®) or Edoxaban and LMWH alone. This meta analysis included 44,989 patients from 45 randomized trials which reported rates of recurrent VTE and major bleeding in patients with acute VTE. In these Acute Deep Vein Thrombosis and Pulmonary Embolism trials, Rivaroxaban and Apixaban were evaluated without the use of initial LMWH whereas both Dabigatran or Edoxaban were assessed following an initial 5 day treatment with LMWH. This analysis was therefore able to assess clinical and safety outcomes associated with different anticoagulation regimens. The followings findings were noted:

1) Standard Heparin–Vitamin K antagonist combination was associated with an increased risk of recurrent VTE compared with the LMWH–Vitamin K antagonist combination

2) Both new oral anticoagulants and LMWH–vitamin K antagonist combination had similar clinical outcomes. However, the newer oral anticoagulants were associated with a lower risk of major bleeding and this benefit was more pronounced with Rivaroxaban and Apixaban. Compared with LMWH-Dabigatran and LMWH-Edoxaban combinations, Apixaban was associated with a lower risk of bleeding.

This comprehensive analysis lead the authors to conclude that Unfractionated Heparin (Standard Heparin)–Vitamin K antagonist combination is the least effective strategy for the treatment of Acute Venous ThromboEmbolism and Rivaroxaban and Apixaban are associated with the lowest risk for bleeding. Castellucci LA, Cameron C, Le Gal G, et al. JAMA 2014;312:1122-1135

SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000 – 100,000 deaths. Even though Deep Vein Thrombosis (DVT) commonly occurs in the lower extremities, Non-Leg Deep Venous Thromboses (NLDVT) at other sites including the head and neck, trunk, and upper extremities can occur as well. Approximately one third of the patients with proximal Deep Vein Thrombosis (DVT) develop Post Thrombotic Syndrome which can be associated with pain and swelling in the extremity and if persistent, over time, can lead to skin pigmentation and ulceration, impacting the patients quality of life. Several small clinical studies have shown a decrease in the incidence of Post Thrombotic Syndrome, with Catheter Directed Thrombolysis (CDT), although safety outcomes from this intervention remained inconclusive. This had resulted in conflicting recommendations from the American Heart Association and American College of Chest Physicians. To address this further, the authors in this study compared safety outcomes in a group of patients with proximal and caval DVT who underwent CDT plus anticoagulation with another group treated with anticoagulation alone. In this propensity-matched analysis, 90,618 patients with a discharge diagnosis of proximal DVT over a 6 year period and 3,594 well-matched patients in each study group were identified from a Nationwide Inpatient Sample (NIS) database. The primary endpoint of this study was in-hospital mortality and secondary endpoints included incidence of pulmonary embolism, blood transfusion requirements, gastrointestinal bleeding, intracranial bleeding, IVC filter placement, procedure-related hematomas, length of hospital stay and hospital charges. This analysis did not demonstrate a significant difference in the in-hospital mortality between patients who had Catheter Directed Thrombolysis (CDT) plus anticoagulation group and the anticoagulation alone group (1.2% vs 0.9%). However, the rates of blood transfusion (11.1% vs 6.5%), pulmonary embolism (17.9% vs 11.4%), intracranial hemorrhage (0.9% vs 0.3%) and IVC filter placement (34.8% vs15.6%), were significantly higher in the CDT group compared to the anticoagulation alone group. Further, patients in the CDT group had a significantly longer hospital stay (7.2 vs. 5.0 days) and incurred significantly higher hospital expenses ($85,094 vs $28,164). More patients with private insurance had Catheter Directed Thrombolysis (CDT), compared to self-pay patients or those with Medicare or Medicaid (7.3% vs 2.8%, P<0.001). The authors concluded that Catheter Directed Thrombolysis (CDT) may not improve outcomes for patients with proximal Deep Vein Thrombosis but is associated with significantly higher adverse events and therefore warrants substantial justification, if this intervention is planned. Bashir R, Zack CJ, Zhao H, et al. JAMA Intern Med. 2014;174:1494-1501

SUMMARY: The CDC estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Even though Deep Vein Thrombosis (DVT) commonly occurs in the lower extremities, Non-Leg Deep Venous Thromboses (NLDVT) at other sites including the head and neck, trunk, and upper extremities can occur. The incidence, risk factors, management and outcomes in this patient group remains unclear. The authors therefore conducted a prospective cohort study in the ICU setting. This study is nested in a larger international trial in which 3746 patients, expected to remain in the med/surg Intensive Care Unit (ICU) for at least 3 days, were randomized to receive either Unfractionated (standard) heparin or Dalteparin (FRAGMIN®) for thromboprophylaxis. The authors characterized the NLDVT as Prevalent or Incident (depending on whether the thrombosis was identified within 72 hours of ICU admission or developed after the third ICU day) and whether they were catheter related or not. Risk factors for NLDVT and subsequent anticoagulant therapy, associated PE, and death were evaluated. Several important findings were noted from this study. Of the 3746 patients, 2.2% developed 1 or more Non-Leg Vein Thromboses (superficial or deep, proximal or distal). Majority of these thrombotic events (95%) occurred in the upper extremity and most of these occurred in the clinically important proximal and deep venous system. Further, these thrombotic episodes were more commonly Incident (2.0%) rather than Prevalent (0.2%) – P <0.001. It was noted that 1 in 7 patients with NLDVT developed PE. It appears that malignancy, hospitalization and Central Venous Catheters are risk factors for Upper Extremity Deep Vein Thrombosis (UEDVT), but the disproportionate increase in the incidence of UEDVT in hospitalized patients (30%-40% of hospital associated DVT’s) has been attributed to the increased use of CVC’s such as PICC (Peripherally Inserted Central Catheter). In this study, only 13% of the patients diagnosed with NLDVT received anticoagulation therapy. In an accompanying commentary by Dr. Greg Maynard, it was well pointed out that UEDVT is associated with similar rates of recurrence, PE and mortality as lower extremity DVT and as such UEDVT should be treated with anticoagulant therapy similar to Lower Extremity DVT. Dr. Maynard also noted that PICC associated DVT could be significantly reduced by appropriately choosing patients for a PICC line, proper PICC placement, early PICC removal, smaller diameter PICC and smaller number of lumens in the catheter. The authors concluded that despite universal prophylaxis with heparin, there was a high incidence of NLDVT in clinically important locations of the venous system, in critically ill patients and this calls for more structured preventive measures, as we learn more about this entity. Lamontagne F, McIntyre L, Dodek P, et al. JAMA Intern Med. 2014;174:689-696

SUMMARY: XARELTO® (Rivaroxaban) is an oral, direct inhibitor of Factor Xa. Two previously published randomized studies concluded that XARELTO® was noninferior to the standard anticoagulation therapy (administration of heparin overlapped and followed by Vitamin K Antagonist), for most patients with Venous ThromboEmbolism. Further, XARELTO® in these studies also had a better safety profile compared to standard anticoagulant therapy. The authors in this pooled analysis combined the data from 2 identically designed studies, EINSTEIN-DVT and EINSTEIN-PE in which XARELTO® was compared to standard anticoagulation therapy, in patients with DVT and PE respectively. The goal of this study was to provide a more accurate estimate of the efficacy and safety of XARELTO® in elderly patients and cancer patients in whom Vitamin K Antagonists (VKA) such as COUMADIN® (Warfarin) can be associated with a higher complication rate. In addition, the study included analysis of outcomes with XARELTO® in patients with previous VTE and in those presenting with extensive thrombosis. Of the 8282 patients with VTE randomized in the pooled analysis, 4151 patients received XARELTO® and 4131 patients received LOVENOX® (Enoxaparin) / Vitamin K Antagonists. In both pooled studies, patients in the XARELTO® group received a dose of 15 mg PO BID for 21 days, followed by 20 mg PO QD whereas patients assigned to the standard anticoagulation therapy group received LOVENOX® subcutaneous at a dose of 1.0 mg/kg BID and either oral Warfarin or Acenocoumarol started within 48 hours after randomization and patients continued treatment for 3, 6, or 12 months, as determined by the local Health Care Providers. INR was closely monitored and maintained between 2-3. On final review, the analysis suggested that XARELTO® resulted in efficacy similar to standard anticoagulation therapy, with a noninferiority P<0.001. The pre-specified principal safety outcome was clinically relevant bleeding and major bleeding was observed in 40 patients belonging to the XARELTO® group and in 72 patients belonging to the standard anticoagulation therapy group (HR=0.54; P= 0.002). Similar benefits in the efficacy and safety were seen in the key subgroups evaluated, which included elderly fragile patients, cancer patients, patients presenting with extensive thrombosis and those with a history of recurrent VTE. The authors concluded that the incidence of major bleeding with XARELTO® was significantly less, particularly in the high risk group of patients, when compared to standard anticoagulation therapy and may therefore have a safety advantage, without compromising efficacy. Prins MH, Lensing AW, Bauersachs R, et al. Thrombosis Journal 2013;11:21

 

 

SUMMARY: The American Society of Clinical Oncology (ASCO) recently provided recommendations for the prophylaxis and treatment of venous thromboembolism (VTE) in patients with cancer following a systematic review of 42 publications. They are as follows-

VTE prophylaxis in hospitalized patients

Majority of the hospitalized patients with active malignancy should receive VTE prophylaxis in the absence of contraindications. However there are no definitive data for VTE prophylaxis in patients admitted for short chemotherapy infusions, minor procedures or those undergoing stem-cell or bone marrow transplantation.

VTE prophylaxis in ambulatory patients

Routine VTE prophylaxis is not recommended although prophylaxis with low molecular-weight heparin can be considered in select group of outpatients with solid tumors who are receiving chemotherapy, after discussing the risk/benefits of such intervention. Patients with Myeloma receiving THALOMID® (Thalidomide) or REVLIMID® (Lenalidomide) should receive VTE prophylaxis with either aspirin or low molecular-weight heparin.

VTE prophylaxis in patients undergoing surgery

All cancer patients undergoing major surgical procedures should be considered for VTE prophylaxis with heparin unless there is a bleeding risk. This should be commenced preoperatively and can be complemented with mechanical methods to improve efficacy. This should be continued for at least 7-10 days and for up to 4 weeks postoperatively, in those undergoing major abdominal or pelvic surgery with restricted mobility, obesity, history of VTE or additional risk factors. Decision to consider prophylaxis, for patients undergoing low risk surgery, should be made on an individual basis.

Choice of Anticoagulation for cancer patients with VTE

For cancer patients who have a creatinine clearance of more than 30 ml/min and have newly diagnosed VTE , low molecular-weight heparin is preferred over unfractionated heparin for the initial 5 to 10 days. Low molecular-weight heparin, due to its superiority, is preferred over vitamin K antagonists for long term anticoagulation (6 months). Select cancer patients with metastatic disease or those receiving chemotherapy may be considered for anticoagulation with low molecular-weight heparin or vitamin K antagonists beyond the initial 6 months. A vena cava filter is indicated only for patients with contraindications to anticoagulant therapy and may be considered for those who progress despite optimal anticoagulation with low molecular-weight heparin. Patients with CNS malignancies and VTE should be anticoagulated like any other patient with VTE, monitoring closely for bleeding. Incidental VTE’s should be treated like symptomatic VTE. Decision to treat splanchnic or visceral vein thrombi diagnosed incidentally should be considered on an individual basis. The new novel oral anticoagulants are presently not recommended for prophylaxis or treatment of VTE.

Anticoagulation and survival benefit in patients without VTE

Cancer patients without VTE should not receive anticoagulants to improve survival, as there are no data to support this recommendation.

Predicting VTE in cancer patients using Risk Score

The risk score model below for VTE in cancer patients was developed and validated in multiple studies. The risk of VTE can be significantly reduced amongst these high risk patients by thromboprophylaxis
Lyman GH, Khorana AA, Kuderer NM, et al. J Clin Oncol 2013;31:2189-2204

 

 

 

 

SUMMARY: Apixaban (ELIQUIS®) is an oral, direct coagulation factor Xa inhibitor, similar to XARELTO® (Rivaroxaban). In this double blind study, ELIQUIS® was compared with conventional therapy, which included subcutaneous Enoxaparin (LOVENOX®) followed by Warfarin. Five thousand three hundred ninety five (5395) patients with acute deep vein thrombosis, pulmonary embolism or both, were randomly assigned to receive either ELIQUIS® 10 mg BID for one week followed by 5 mg BID for 6 months (n=2691) or conventional therapy with LOVENOX® followed by Warfarin (n=2704). The primary efficacy outcome was recurrent symptomatic venous thromboembolism or death, related to venous thromboembolism. ELIQUIS® was non inferior to conventional therapy (P<0.001). The risk of major bleeding was slightly lower in the ELIQUIS® group. This efficacy and safety of ELIQUIS® was demonstrable in all patient subgroups. ELIQUIS®, similar to XARELTO®, will very likely be approved for the treatment of Venous ThromboEmbolism. Unlike Vitamin K antagonists (Warfarin), the newer oral anticoagulants do not require coagulation monitoring as they have a rapid onset of action, relatively stable pharmacokinetics and are not associated with significant drug interactions. It is important to realize however, that there are no agents presently available to reverse bleeding associated with these new oral anticoagulants. Development of antidotes that bind to factor Xa inhibitors, in order to reverse bleeding complications, are underway. Agnelli G, Buller HR, Cohen A, et al. N Engl J Med 2013; 369:799-808