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. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke. With the exception of those with active malignancy, patients with VTE are often treated with Direct Oral Anticoagulant agents such as XARELTO® (Rivaroxaban) over vitamin K antagonists such as Warfarin because, Direct Oral Anticoagulant agents do not require routine laboratory monitoring or dose adjustment, have fewer interactions with food or other drugs and are associated with a lower risk of bleeding complications. Anticoagulation therapy is usually recommended for 3 months following an initial episode VTE in association with a transient risk factor such as surgery. In patients without reversible risk factors however, the risk of recurrent VTE is 10% or more during the first year, if anticoagulation therapy is discontinued. Extended anticoagulation therapy beyond 6 to 12 months even though effective is often not a common practice, for the fear of bleeding complications. Aspirin has been shown to reduce the risk of recurrent VTE when compared with placebo, but recurrence rate with this intervention is still significant at 5.1% per year.

The authors in this study compared the efficacy and safety of two doses of XARELTO® with Aspirin, in patients with Venous ThromboEmbolism, who had completed 6 to 12 months of anticoagulation therapy, and in whom there was uncertainty regarding the need for continued anticoagulation. In this randomized, double-blind, phase III trial, 3396 (N=3396) patients with Venous ThromboEmbolism were assigned, in a 1:1:1 ratio, to receive either XARELTO® 20 mg, XARELTO® 10 mg or Aspirin 100 mg given once daily. The primary efficacy outcome was symptomatic recurrent fatal or nonfatal Venous ThromboEmbolism, and the principal safety outcome was major bleeding. Secondary endpoints included whether the lower dose of XARELTO® was as effective as the higher dose and whether it was associated with less bleeding.

It was noted that after a median duration of treatment of 351 days, symptomatic recurrent fatal or nonfatal Venous ThromboEmbolism or unexplained death occurred in 1.5% of the patients assigned to XARELTO® 20 mg and 1.2% of the patients assigned to XARELTO® 10 mg compared with 4.4% among the patients assigned to the Aspirin group (P<0.001). Major or clinically relevant non-major bleeding occurred in 3.3%, 2.4%, and 2.0% of the patients, respectively.

It was concluded that among patients with Venous ThromboEmbolism for whom continued anticoagulation is a consideration, after an initial treatment course at usual therapeutic doses, the risk of a recurrent thromboembolic events were significantly lower with XARELTO® given at either a therapeutic dose (20 mg) or a prophylactic dose (10 mg), compared with Aspirin. There was no significant increase in bleeding rates. Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism. Weitz JI, Lensing AW, Prins MH, et al. for the EINSTEIN CHOICE Investigators. N Engl J Med 2017; 376:1211-1222

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 and may be unsafe and direct oral anticoagulants are ineffective in patients with mechanical heart valves. 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. The FDA in October 16, 2015, granted accelerated approval to Idarucizumab (PRAXBIND®), for the treatment of patients treated with Dabigatran (PRADAXA®), a direct thrombin inhibitor, when reversal of the anticoagulant effects of PRADAXA® is needed for emergency surgery/urgent procedures, or in life-threatening or uncontrolled bleeding. However, the other New Oral Anticoagulants approved in the United States for the treatment of Venous ThromboEmbolism such as XARELTO® (Rivaroxaban), ELIQUIS® (Apixaban), SAVAYSA® (Endoxaban), are Factor Xa inhibitors and do not have an antidote. As such, some Health Care Providers have discouraged their patients from taking these direct oral anticoagulants until an antidote became available, should their patients need urgent surgical intervention.

Andexanet alfa (AndexXa®) is a recombinant, modified human Factor Xa decoy protein without intrinsic catalytic activity, that binds Factor Xa inhibitors. In a previously published study, AndexXa® reversed the anticoagulant activity of ELIQUIS® and XARELTO® in older healthy participants within minutes after administration, and reduced both the unbound fraction of the plasma level of factor Xa inhibitor and anti-Factor Xa activity, with minimal clinical toxicity (N Engl J Med 2015; 373:2413-242). The AndexXa®, a Novel Antidote to the Anticoagulation Effects of FXA Inhibitors (ANNEXA-4) study is an ongoing, multicenter, prospective, open-label, single-group study designed to evaluate the use of AndexXa® in patients with acute major bleeding that was potentially life-threatening.

The authors in this interim report described the outcomes of 67 patients, for whom complete data was available. Patients in this study had acute major bleeding within 18 hours after the administration of one of four Factor Xa inhibitors – ELIQUIS®, XARELTO®, SAVAYSA®, or LOVENOX® (Enoxaparin). Acute major bleeding was defined as potentially life-threatening with signs or symptoms of hemodynamic compromise, decrease in hemoglobin of at least 2 gm/dl, symptomatic bleeding in a critical area or organ. The mean patient age was 77 years, and most patients had a history of cardiovascular disease and thrombotic events and bleeding was predominantly gastrointestinal or intracranial. An independent committee determined hemostatic efficacy on the basis of predetermined criteria. The baseline value for anti-Factor Xa activity was at least 75 ng/ml and 0.5 IU/ml or more for those receiving LOVENOX® and patients had confirmed bleeding severity. All patients received a bolus dose of AndexXa® within 3-6 hours following presentation to the ER followed by a 2-hour infusion of the drug. The two co-primary outcomes were the percent change in the anti-Factor Xa activity and the rate of excellent or good hemostatic efficacy, 12 hours after the AndexXa® infusion. Anti-Factor Xa activity was measured by means of a validated chromogenic assay of Factor Xa enzymatic activity.

It was noted that following the bolus dose of AndexXa®, the median anti-Factor Xa activity decreased by 89% from baseline, among patients receiving XARELTO® and by 93% among patients receiving ELIQUIS® and these levels remained the same during the 2-hour infusion. Four hours after the end of the infusion, the relative decrease in the anti-Factor Xa activity from baseline, among patients receiving XARELTO® was 39% and 30% among those receiving ELIQUIS®. Twelve hours after the AndexXa® infusion, hemostatic efficacy was adjudicated as excellent or good by the independent committee, in 79% of the patients and was consistent across all subgroups. During the 30-day follow up period, thrombotic events occurred in 18% of the patients.

The authors concluded that AndexXa® rapidly reversed anti-Factor Xa activity without significant toxicity, in 79% of the patients, 12 hours after an infusion of AndexXa®. This study also demonstrated that prolonged reversal of Factor Xa inhibition may not be necessary to achieve a good hemostatic response with AndexXa®. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. Connolly SJ, Milling TJ, Eikelboom JW, et al. N Engl J Med 2016; 375:1131-1141

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. Patients with unprovoked DVT and PE are two to four times more likely to be diagnosed with cancer within the ensuing 12 months compared to the general population. Approximately 20% of VTE events are related to underlying malignancy and patients with active malignancy have a five to six fold increased risk of VTE. In patients with cancer associated thrombosis, COUMADIN® (Warfarin) and XARELTO® (Rivaroxaban) are often prescribed, despite guidelines recommending Low Molecular Weight Heparin (LMWH) in this patient population. However, patients are less inclined to take LMWH as this is parenteral, expensive, inconvenient and carries the risk of Heparin-Induced Thrombocytopenia. Further, most patients with malignancy require indefinite anticoagulation and the safety and efficacy of LMWH in this setting is unknown. The efficacy and safety of oral, direct Factor Xa inhibitor such as XARELTO® is not well established in patients with VTE and active malignancy.

The authors in this study evaluated the risk and benefits of XARELTO® in this high-risk group of patients. In this case cohort study, the Mayo Thrombophilia Clinic Direct Oral Anticoagulants Registry included patients diagnosed with Deep Vein Thrombosis or Pulmonary Embolism, who were seen and treated with XARELTO® at the Thrombophilia Clinic, Gonda Vascular Center and Mayo Clinic in Rochester, Minn. These units work together and provide streamlined standardized care. Immediate anticoagulation therapy was provided for appropriate patients. Patients with symptomatic PE or extensive symptomatic iliofemoral Deep Vein Thrombosis were hospitalized. All patients with PE also had lower extremity duplex ultrasound to determine the source of embolism. Evaluation included upper extremity venous assessment, if a patient had symptoms suggestive of venous thrombosis or if a Central Venous Catheter was present.

Patients with acute VTE or asymptomatic PE suitable for outpatient anticoagulation therapy were counseled about the pros and cons of each anticoagulant currently approved by the FDA. Additionally, patients with active malignancy and VTE were counseled about the preferred first line of treatment with Low Molecular Weight Heparin, as well as the limited data for XARELTO® in cancer-associated VTE. Patients opting for XARELTO®, were started on treatment within the ensuing hour. Patients were evaluated every 3 months for efficacy and safety and followed prospectively from March 2013 and April 2015. The primary efficacy outcome was symptomatic venous or arterial thromboembolism occurring during the follow up period. The primary safety end point was major bleeding defined as overt bleeding plus a hemoglobin decrease of 2 or more grams/dL after the incident, transfusion of 2 or more units of packed red blood cells, or intracranial, intraspinal, intraocular, retroperitoneal, pericardial, or fatal bleeding.

Two hundred and ninety six (N=296) of the 404 patients in the registry with Venous ThromboEmbolism (VTE), received XARELTO® and had at least 3 months of follow up. Of these 296 patients on XARELTO®, 118 patients (40%) had active malignancy and 178 patients had no cancer. The 3 most common cancer locations were Genitourinary (23.6%), Gastrointestinal (20.3%) and Lung (13.5%). It was noted that there was no significant difference in VTE recurrence between the malignant (3.3%) and the nonmalignant (2.8%) VTE groups (P=0.533). Slightly higher rates for major bleeding (P=0.06) and non major clinically relevant bleeding (P=0.08) were noted in patients with cancer, but this was not statistically significant.

The authors concluded that the efficacy and safety of XARELTO® is similar for VTE patients with and without active malignancy. Efficacy and Safety of Rivaroxaban in Patients with Venous Thromboembolism and Active Malignancy: A Single-Center Registry. Bott-Kitslaar DM, Saadiq RA, McBane RD, et al. Am J Med. 2016; 129: 615-619

SUMMARY: Secondary hypogammaglobulinemia is a common immune defect in malignancies such as Chronic Lymphocytic Leukemia, Multiple Myeloma and Non-Hodgkin B cell lymphomas. Approximately 20-70% of these patients may experience hypogammaglobulinemia during the course of their illness. Secondary hypogammaglobulinemia generally correlates with duration and stage of the disease and there is a direct relationship between the frequency/severity of infections and low IgG levels. The infection risk may be further exacerbated by treatment induced hypogammaglobulinemia.

IntraVenous Immune globulin (IVIg) is a purified plasma fraction and contains more than 95% unmodified Immunoglobulin G (IgG). It is derived from large donor pools and is often recommended for patients with hypogammaglobulinemia, to reduce the risk of serious infection. With the recognition of serious IVIg-associated ThromboEmbolic Events (TEEs) dating back to the 1980’s, the FDA in 2013 mandated boxed warning for IVIg products. The TEE risk has been attributed to increased blood viscosity secondary to erythrocyte aggregation following administration of IVIg, resulting in stasis and thrombosis, platelet activation by exogenous IgG, arterial vasospasm and other plasma components such as coagulation factor XIa, that is not completely removed in some IVIg manufacturing processes. However, it is not clear if the TEEs are directly attributable to the IVIg itself or whether other risk factors such as patient’s age, disease state or other factors play a role.

The authors in this study conducted a retrospective review of data from the Surveillance, Epidemiology and End Results (SEER) cancer registries for Chronic Lymphocytic Leukemia (CLL) and Multiple Myeloma (MM) patients, linked to Medicare claims and enrollment data. This study included CLL and Myeloma patients (N=2724), 66 years or older, who were new users of IVIg and this group was propensity matched to non recipients of IVIg (N=8035). Propensity matching allowed comparison of groups across measured demographic and clinical characteristics and other variables. The primary endpoint was the occurrence of serious arterial ThromboEmbolic Event (TEE), defined as hospitalization for Acute Myocardial Infarction or Ischemic Stroke. Secondary endpoints included venous TEE (hospitalization for Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE). Based on previously published studies, the authors hypothesized that the prothrombotic effects of IVIg would most likely be acute but could last for as long as 1 month after an IVIg infusion.

It was noted that patients receiving IVIg were significantly more likely to develop a TEE such as Acute Myocardial Infarction or Stroke within the first 24 hours compared to IVIg nonrecipients (HR=3.40). This arterial thrombotic risk declined during the following 30 days. There was however, no significant increase in venous thrombotic events during the first 30 days after IVIg infusion. The risk for any ThromboEmbolic Events (TEEs) increased with age during the first 30 days following IVIg therapy (P=0.03), but was not associated with the type or duration of malignancy, history cardiovascular disease, history of venous thromboembolism or IVIg brand.

It was concluded that based on this study, arterial thrombotic events (Myocardial Infarction and Stroke) are likely to occur within the first 24 hours following IVIg administration, in patients with immunodeficiency, secondary to Chronic Lymphocytic Leukemia or Multiple Myeloma and this thrombotic risk is more common with increasing patient age. Clinicians should therefore weigh the risk/benefits with IVIg use and elderly patients should be well hydrated and closely monitored for the first 24 hours following IVIg infusion. Intravenous immune globulin and thromboembolic adverse events in patients with hematologic malignancy. Eric M. Ammann EM, Jones MP, Link BK, et al. Blood 2016; 127:200-207

SUMMARY: There are presently four Direct Oral AntiCoagulants (DOACs) 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 Vitamin K Antagonist COUMADIN® (Warfarin), the Direct 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. The FDA in October, 2015, granted accelerated approval to PRAXBIND® (Idarucizumab), for those patients treated with PRADAXA® (Dabigatran), when reversal of the anticoagulant effects of PRADAXA® is needed for emergency surgery/urgent procedures, or in life-threatening or uncontrolled bleeding. 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 other Direct Oral AntiCoagulants or for stopping the anticoagulant effects of these drugs, in patients who need urgent surgical intervention.

A recently published study has shown that the availability of Direct Oral AntiCoagulants has increased the number of doctor office visits, driven by new visits related to Direct Oral AntiCoagulant (DOAC) use in Atrial Fibrillation patients. It was noted that the utilization of DOAC’s was comparable to the use of COUMADIN® (Warfarin) for Atrial Fibrillation patients (Am J Med. 2015;128:1300-1305).

The discussion by the authors in this article, revolve around a 86-year old female weighing 55 kg, who presented to the ED with persistent Epistaxis. She had a history of Atrial Fibrillation and has been taking XARELTO® (Rivaroxaban) 20 mg, once daily, for stroke prevention for 1 year. She also had a history of peripheral arterial disease and was on Aspirin 80 mg, daily for primary prevention for 9 months. It was noted that the chromogenic anti–Factor Xa assay showed that her plasma concentration of XARELTO® was supratherapeutic. So, treatment with XARELTO® was discontinued. Nonetheless, two days later, the plasma XARELTO® concentration was still within the therapeutic range rather than subtherapeutic, suggesting slow drug elimination. The medical team discontinued her Aspirin and switched her from XARELTO® to COUMADIN® (Warfarin) and discharged her.

Several valuable recommendations made from this case are worth mentioning-

1) Older age and renal insufficiency are important factors contributing to bleeding while on DOACs. Because DOACs are partially excreted by the kidneys, dose reductions are recommended in the event of renal impairment. In a study evaluating the bleeding risk with PRADAXA® (Dabigatran) in the frail elderly, two thirds of patients were older than 80 years, and close to 60% of these patients had moderate or severe renal impairment.

2) Because patients with severe renal impairment have been excluded from phase III studies, DOACs should be avoided in this population along with those patients with extreme body weights.

3) Addition of Aspirin to oral anticoagulants is appropriate for up to 12 months after acute coronary syndromes, percutaneous coronary interventions, or stenting procedures. However, this combination therapy increases the risk of major bleeding by 50% compared with oral anticoagulant use alone.

4) For patients with mechanical heart valves, a combination of Aspirin plus oral anticoagulant may be appropriate. However, only a Vitamin K Antagonist (VKA) such as COUMADIN® should be used and DOACs are not recommended.

5) Although routine laboratory testing of patients taking a DOAC is not required, elderly patients should be closely monitored, with particular attention to renal function. A normal Prothrombin Time excludes supratherapeutic XARELTO® plasma levels, and XARELTO® levels can be measured using anti–Factor Xa chromogenic assays.

In conclusion, even though DOACs have several advantages compared with VKAs, DOACs should be avoided in frail elderly patients.

Optimizing the Safe Use of Direct Oral Anticoagulants in Older Patients – A Teachable Moment. Sennesael A, Dogné J and Spinewine A. JAMA Intern Med. 2015;175:1608-1609

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. The American College of Physicians in 2015 released pulmonary embolism guidelines after noting that there has been a dramatic increase in the testing for suspected acute Pulmonary Embolism (PE). There has also been an overuse of CT imaging and plasma d-Dimer measurement, without improvement in care, but rather harming the patient and increasing expenditure. The validated clinical decision tools, in addition to physician’s clinical judgment include the Wells and Geneva Scoring System. The PERC (see table) criteria includes 8 elements, which if absent in low risk patients rules out PE. These practice guidelines were developed to provide practical advice, based on the best available evidence.

Best Practice Advice 1: Clinicians should use validated clinical prediction tools to estimate pretest probability, in patients in whom acute PE is being considered. These clinical decision tools include physician’s clinical judgment as well as Wells and Geneva Scoring System.

Best Practice Advice 2: The PERC (see table) criteria includes 8 elements. Clinicians should not obtain d-Dimer measurements or imaging studies in patients with a low pretest probability of PE and who meet all Pulmonary Embolism Rule-Out (PERC) Criteria.

Best Practice Advice 3: For patients who have an intermediate pretest probability of PE or in patients with low pretest probability of PE who do not meet all PERC Criteria, clinicians should obtain a high-sensitivity d-Dimer measurement as the initial diagnostic test in patients. Clinicians should not use imaging studies as the initial test in patients who have a low or intermediate pretest probability of PE.

Best Practice Advice 4: Clinicians should use age-adjusted d-Dimer thresholds (age × 10 ng/mL rather than a generic 500 ng/mL) in patients older than 50 years because, normal d-Dimer levels increase with age.

Best Practice Advice 5: Clinicians should not obtain any imaging studies in patients with a d-Dimer level below the age-adjusted cutoff.

Best Practice Advice 6: Clinicians should obtain imaging with CT pulmonary angiography (CTPA) in patients with high pretest probability of PE. Clinicians should reserve ventilation–perfusion scans for patients who have a contraindication to CTPA or if CTPA is not available. Clinicians should not obtain a d-Dimer measurement in patients with a high pretest probability of PE because, a negative d-Dimer test will not preclude the need for imaging.

Evaluation of Patients with Suspected Acute Pulmonary Embolism: Best Practice Advice From the Clinical Guidelines Committee of the American College of Physicians. Raja AS, Greenberg JO, Qaseem A, et al. Ann Intern Med. 2015;163:701-711