Tag: Venous Thrombo Embolism

SUMMARY: The FDA on October 16, 2015, granted accelerated approval to Idarucizumab (PRAXBIND®) for the treatment of patients treated with Dabigatran (PRADAXA®), when reversal of the anticoagulant effects of PRADAXA® is needed for emergency surgery/urgent procedures, or in life-threatening or uncontrolled bleeding. There are presently four New Oral Anticoagulants approved in the United States for the treatment of Venous ThromboEmbolism. They include PRADAXA® (Dabigatran), which is a direct thrombin inhibitor and XARELTO® (Rivaroxaban), ELIQUIS® (Apixaban), SAVAYSA® (Endoxaban), which are Factor Xa inhibitors. Compared to COUMADIN® (Warfarin), the New Oral Anticoagulants have a rapid onset of action, wider therapeutic window, shorter half-lives (7-14 hours in healthy individuals), no laboratory monitoring and fixed dosing schedule. The half life of these agents can however be prolonged in those with renal insufficiency. In several clinical studies, these New Oral Anticoagulants have been shown to reduce the rate of major bleeding by 28% and the rates of intracranial and fatal hemorrhage by 50%, when compared to COUMADIN®. Unlike bleeding caused by COUMADIN®, which can be reversed using Vitamin K or Fresh Frozen Plasma, there are no specific agents presently available, for reversing bleeding caused by the New Oral Anticoagulants or for stopping the anticoagulant effects of these drugs, in patients who need urgent surgical intervention.

To address this concern, the RE-VERSE AD study was conducted to evaluate the efficacy and safety of Idarucizumab, to reverse the anticoagulant effects of PRADAXA®, in patients who had serious bleeding (Group A) or required an urgent surgical procedure (Group B). PRAXBIND® (Idarucizumab) is a humanized monoclonal antibody fragment with high affinity for both free and thrombin-bound PRADAXA® and neutralizes the anticoagulant activity of PRADAXA®. In this prospective cohort study, results from the first 90 patients enrolled in the study were presented (Interim analysis). Group A included 51 patients and Group B included 39 patients and PRAXBIND® 5 grams IV was administered, to reverse the anticoagulant effects of PRADAXA®. The median age was 76 years and the median creatinine clearance was 58 ml/minute. The primary end point was the maximum percentage reversal of the anticoagulant effect of PRADAXA® within 4 hours after the administration of PRADAXA®, based on the dilute thrombin time or ecarin clotting time. An important secondary end point was the restoration of hemostasis. Among the patients with an elevated dilute thrombin time and ecarin clotting time at baseline, the median maximum percentage reversal was 100% and this benefit was seen within minutes after the first infusion with PRAXBIND®. The median time to restoration of hemostasis in Group A was 11.4 hours. In Group B, normal intraoperative hemostasis was reported in more than 90% of the patients who underwent procedures after the administration of PRAXBIND®.

The authors concluded that PRAXBIND® was, within minutes, able to completely reverse the anticoagulant effect of PRADAXA®. This reversal agent will fulfill an unmet need and with the availability soon of Factor Xa inhibitor antidotes, it is anticipated that Health Care Providers will be more willing to replace COUMADIN® with the Newer Oral Anticoagulants. Idarucizumab for Dabigatran Reversal. Pollack CV, Reilly PA, Eikelboom J, et al. N Engl J Med 2015; 373:511-520

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. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality. Clinicians are often confronted with the dilemma of using bridge therapy for patients with a history of VTE on Warfarin therapy, requiring invasive diagnostic or surgical procedures. Bridge therapy involves the use of rapid onset, short acting anticoagulant preparation such as Low Molecular Weight Heparin during the peri-procedural period (usually 5-10 days), to minimize the risk of subtherapeutic anticoagulation, during peri-procedure Warfarin withdrawal and reinitiation. Even though published studies have largely reviewed the risk of thrombotic events in patients with atrial fibrillation or mechanical heart valves, the risk for bleeding and VTE, associated with bridge therapy in patients receiving Warfarin for the secondary prevention of VTE, has remained unclear. Presently available guidelines that classify peri-procedural risk of recurrent VTE, off anticoagulant therapy, into high risk , medium risk and low risk, is based on indirect, low quality evidence and is not completely reliable. It is well established however, that anticoagulants stopped during the first four weeks of treatment, following diagnosis of VTE, predisposes an individual to increased risk of recurrent VTE.

To clarify the risk/benefits of bridge therapy, the authors conducted a retrospective cohort study, to assess the rates of clinically relevant bleeding and recurrent VTE, among patients in whom Warfarin therapy was interrupted for invasive procedures. They then compared the incidence of peri-procedure bleeding and recurrent VTE when a bridging strategy was used or not used. This study included 1178 patients and the most common indication for Warfarin therapy was DVT (56.3%). Majority of the patients (79%) were considered as low risk (acute VTE more than 12 months previously, with no other risk factors). The primary outcome of the study was clinically relevant bleeding resulting in hospitalization, ER visit or complicating the procedure in the first 30 days following the index procedure. Secondary outcomes included recurrent VTE, and all-cause mortality occurring in up to 30 days, following the index procedure.

It was noted that the 30-day rate of clinically relevant bleeding was significantly higher in the bridging group compared with the control group (2.7% versus 0.2%, HR=17.2; P=0.01). Further, there was no significant difference in the rate of recurrent VTE between the bridge and non-bridge therapy groups. No deaths occurred in either treatment groups. The authors concluded that bridge therapy for invasive procedures in patients receiving Warfarin for secondary VTE prevention, is associated with a significant increase in the incidence of bleeding complications, without any decrease in the rate of recurrent VTE. Warfarin can be safely interrupted in this patient group without bridge therapy. Further research is needed to address the value of bridge therapy in the medium and high risk groups. Bleeding, Recurrent Venous Thromboembolism, and Mortality Risks During Warfarin Interruption for Invasive Procedures. Clark NP, Witt DM, Davies LE, et al. JAMA Intern Med 2015;175:1163-1168.

SUMMARY: There are presently four New Oral Anticoagulants approved in the United States for the treatment of Venous ThromboEmbolism. They include PRADAXA® (Dabigatran), which is a direct thrombin inhibitor and XARELTO® (Rivaroxaban), ELIQUIS® (Apixaban), SAVAYSA® (Endoxaban), which are Factor Xa inhibitors. Compared to COUMADIN® (Warfarin), the New Oral Anticoagulants have a rapid onset of action, wider therapeutic window, shorter half-lives (7-14 hours in healthy individuals), no laboratory monitoring and fixed dosing schedule. The half life of these agents can however be prolonged in those with renal insufficiency. In several clinical studies, these New Oral Anticoagulants have been shown to reduce the rate of major bleeding by 28% and the rates of intracranial and fatal hemorrhage by 50%, when compared to COUMADIN®. Unlike bleeding caused by COUMADIN®, which can be reversed using Vitamin K or Fresh Frozen Plasma, there are no specific agents presently available, for reversing bleeding caused by the New Oral Anticoagulants or for stopping the anticoagulant effects of these drugs, in patients who need urgent s

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. Patients with unprovoked DVT and PE are two to four times more likely to be diagnosed with cancer within the following 12 months compared to the general population. It is however unknown if Splanchnic Venous Thrombosis (splanchnic veins carry blood through the liver and other abdominal organs) is a marker of occult cancer and a prognostic factor for cancer survival.

To address this question the authors from Denmark conducted a nationwide cohort study using Danish medical registries and included 1,191 patients with first time Splanchnic Venous Thrombosis (SVT) between 1994 and 2011, and followed them for subsequent cancer diagnosis, for a median of 1.6 years. They compared these results with the expected cancer risk in the general population. Additionally, to evaluate the impact of SVT on survival in those patients with cancer, the researchers compared survival in these cancer patients with a matched cohort of cancer patients without SVT. In the cohort of 1,191 patients with first time Splanchnic Venous Thrombosis (SVT), 183 patients were later diagnosed with cancer, of whom, 95 patients were diagnosed within 3 months of their SVT diagnosis. When compared to the general population, individuals diagnosed with SVT were 33 times more likely to be diagnosed with cancer within 3 months and their 3 month risk of developing cancer was 8%. The increased risk was for liver cancer, pancreatic cancer and myeloproliferative neoplasms and there was a continued twofold increase after one or more years of follow up. It was noted that Splanchnic Venous Thrombosis was also a poor prognostic factor for survival, in patients with liver and pancreatic cancer. The authors concluded that Splanchnic Venous Thrombosis (SVT) is a marker of occult malignancy, particularly liver cancer, pancreatic cancer and myeloproliferative neoplasms and SVT diagnosed in patients with liver or pancreatic cancer remains a poor prognostic factor. Therefore, patients presenting with Splanchnic Venous Thrombosis may require a more thorough diagnostic evaluation. Splanchnic venous thrombosis is a marker of cancer and a prognostic factor for cancer survival. Søgaard KK, Farkas DK, Pedersen L, et al. Blood, June 2015 DOI: 10.1182/blood-2015-03-631119

SUMMARY: The American Society of Clinical Oncology (ASCO) recently provided an update on recommendations, for the prophylaxis and treatment of Venous ThromboEmbolism (VTE) in patients with cancer, following a systematic review of 53 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 in patients with cancer because of limited data.

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.

Monitoring and patient counseling

Patients with cancer should be periodically assessed for VTE risk. Oncology professionals should educate patients about the signs and symptoms of VTE.

Predicting VTE in cancer patients using Risk Score

The risk score model 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, Bohlke K, Khorana AA, et al. J Clin Oncol 2015; 33:654-656

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. Even though the risk of recurrent VTE is high after anticoagulant treatment is discontinued in patients with a first unprovoked venous thromboembolism (10-30% risk of a recurrence within 5 years following cessation of anticoagulation), a significant number of these patients receive therapy for 6-12 months and are not routinely treated with long term anticoagulant therapy. This may be due to bleeding risks, cost of therapy and need for diligent monitoring while on long term anticoagulation. Aspirin is a non-selective, irreversible inhibitor of both COX-1 and COX-2 (Cyclooxygenases 1 and 2). It inhibits the production of Prostaglandins and Thromboxane A2 and there by decreases platelet aggregation. Both ASPIRE and WARFASA trials support the role of aspirin for the prevention of recurrent VTE in patients with an unprovoked VTE, after 6-18 months of anticoagulation therapy. These trials however were not individually powered to detect benefits of treatment for particular outcomes or subgroups of patients. The INSPIRE Collaboration involved further analysis of these trials to detect outcomes in pre-specified subgroups of patients. The intent-to-treat analysis included 1,224 patients and at a median follow up of 30.4 months, daily Aspirin given at a dose of 100mg reduced recurrent VTE events by 32% (HR=0.68; P=0.008) and this included reduction in recurrent Deep Vein Thrombosis by 34% (HR=0.66; P=0.01) and Pulmonary Embolism by 34% (HR=0.66; P=0.08), compared to Placebo. After adjustment for treatment adherence, recurrent VTE was reduced by 42% (HR=0.58; P=0.005). Subgroup analyses indicated similar relative, but larger absolute, risk reductions in men and older patients. Aspirin also reduced major vascular events by 44% (HR=0.66; P=0.002). The major bleeding rate was low at 0.5%/year for Aspirin and 0.4%/year for Placebo. The authors concluded that aspirin reduces the risk of recurrent VTE. Even though the efficacy of aspirin is inferior to that of Warfarin or the new oral anticoagulants, this data suggests that Aspirin should be strongly considered in patients with unprovoked VTE for whom long-term anticoagulation therapy with Warfarin or one of the new oral anticoagulants has to be discontinued or is not an appropriate option. Aspirin however, should not be considered a replacement option for conventional anticoagulation. Simes J, Becattini C, Agnelli G, et al. Circulation. 2014; 130:1062-1071

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