Robert D. McBane

Management of Antithrombotic Therapy in Patients Undergoing Invasive Procedures

When patients receiving anticoagulation therapy undergo invasive procedures, management requires an individualized assessment of the risk of bleeding versus the risk of thrombosis. This review explains management, including bridging anticoagulation for patients receiving warfarin.

Effectiveness and Safety of Dabigatran, Rivaroxaban, and Apixaban Versus Warfarin in Nonvalvular Atrial Fibrillation

Background The introduction of non–vitamin K antagonist oral anticoagulants has been a major advance for stroke prevention in atrial fibrillation; however, outcomes achieved in clinical trials may not translate to routine practice. We aimed to evaluate the effectiveness and safety of dabigatran, rivaroxaban, and apixaban by comparing each agent with warfarin. Methods and Results Using a large US insurance database, we identified privately insured and Medicare Advantage patients with nonvalvular atrial fibrillation who were users of apixaban, dabigatran, rivaroxaban, or warfarin between October 1, 2010, and June 30, 2015. We created 3 matched cohorts using 1:1 propensity score matching: apixaban versus warfarin (n=15 390), dabigatran versus warfarin (n=28 614), and rivaroxaban versus warfarin (n=32 350). Using Cox proportional hazards regression, we found that for stroke or systemic embolism, apixaban was associated with lower risk (hazard ratio [HR] 0.67, 95% CI 0.46–0.98, P=0.04), but dabigatran and rivaroxaban were associated with a similar risk (dabigatran: HR 0.98, 95% CI 0.76–1.26, P=0.98; rivaroxaban: HR 0.93, 95% CI 0.72–1.19, P=0.56). For major bleeding, apixaban and dabigatran were associated with lower risk (apixaban: HR 0.45, 95% CI 0.34–0.59, P<0.001; dabigatran: HR 0.79, 95% CI 0.67–0.94, P<0.01), and rivaroxaban was associated with a similar risk (HR 1.04, 95% CI 0.90–1.20], P=0.60). All non–vitamin K antagonist oral anticoagulants were associated with a lower risk of intracranial bleeding. Conclusions In patients with nonvalvular atrial fibrillation, apixaban was associated with lower risks of both stroke and major bleeding, dabigatran was associated with similar risk of stroke but lower risk of major bleeding, and rivaroxaban was associated with similar risks of both stroke and major bleeding in comparison to warfarin.

Survival and recurrence in patients with splanchnic vein thromboses.

BACKGROUND & AIMS Hepatic, splenic, portal, and mesenteric veins are confluent elements within the splanchnic system. It is therefore unclear whether thromboses of isolated segments represent unique entities. We compared etiologies, recurrence, and survival of patients with thromboses of different splanchnic venous segments. METHODS An inception cohort of individuals was identified with first lifetime incident of splanchnic vein thrombosis between 1980 and 2000. We performed a case-controlled comparison of recurrent thrombosis and survival data with those of patients with deep venous thrombosis (DVT). RESULTS The study (832 patients; mean age, 53 +/- 17 years; 42% women) included patients with isolated portal (n = 329), mesenteric (n = 76), splenic (n = 62), and hepatic (n = 45) vein thrombosis and patients with multisegment involvement (n = 320). Malignancy (27%) and cirrhosis (24%) were the most common etiologies. Recurrence-free survival 10 years after splanchnic vein thrombosis (76%) was comparable with that after DVT (68%) and not improved by anticoagulant therapy. Hormone therapy was the only independent predictor of recurrence (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.09-4.45; P = .03). Major bleeding was 6.9/100 patient-years. Gastroesophageal varices (HR, 2.63; 95% CI, 1.72-4.03; P < .001) and warfarin therapy (HR, 1.91, 95% CI, 1.25-2.92; P = .003) were independent predictors of bleeding. The 10-year survival rate of patients with splanchnic vein thrombosis (60%) was lower than that of patients with DVT (68%, P < .05). Older age (HR, 1.03; 95% CI, 1.02-1.03), active cancer (HR, 2.23; 95% CI, 1.78-2.78), and myeloproliferative disorder (HR, 1.92; 95% CI, 1.41-2.61) were independent determinants of mortality (P < .001). CONCLUSIONS Splanchnic vein thrombosis depends on the pathology of the organ supplied. On the basis of the low rate of recurrence and substantial rate of major hemorrhage, prolonged anticoagulant therapy does not appear to be justified.

Cerebral venous sinus thrombosis Incidence of venous thrombosis recurrence and survival

Objective: To determine whether treatments guidelines for lower extremity venous thrombosis (DVT) could be applied to patients with cerebral venous sinus thrombosis (CVST), the rates of recurrent venous thrombosis and survival for these two diseases were compared. Methods: The authors studied all patients diagnosed with CVST at the Mayo Clinic between 1978 and 2001. Survival and recurrent venous thrombosis rates (cerebral or noncerebral) were compared with those from patients with DVT. Survival rates were also compared with white US residents. Results: One hundred fifty-four patients (age 40 ± 19 years) were included (58% women). Warfarin, prescribed in 50% of patients, was continued for an average of 9 months. During a mean of follow up of 36 ± 47 months (464 patient-years), 20 patients experienced 23 recurrent venous thrombi for an event rate of 5.0/100 patient-years. This recurrence rate was similar to patients with lower extremity DVT (3.8/100 patient-years). Mortality rates were lower for CVST (2.8/100 patient-years) compared with DVT (6.2/100 patient-years; p = 0.001) patients but higher than expected for white US residents (p = 0.001). Increasing age and active malignancy were the only predictors of poor survival. Neither recurrent thrombosis nor survival was influenced by warfarin therapy. Conclusions: The likelihood of recurrent venous thrombosis is similar after cerebral venous sinus thrombosis (CVST) and lower extremity deep venous thrombosis (DVT). Compared with DVT, survival rates are higher following CVST but are adversely influenced by malignancy and older age.

Periprocedural anticoagulation management of patients with nonvalvular atrial fibrillation.

OBJECTIVE To estimate the 3-month cumulative incidence of thromboembolism (TE), bleeding, and death among consecutive patients with nonvalvular atrial fibrillation (AF) who were receiving long-term anticoagulation therapy and were referred to the Thrombophilia Center at Mayo Clinic for periprocedural anticoagulation management. PATIENTS AND METHODS In a prospective cohort study of consecutive patients receiving long-term anticoagulation therapy who were referred to the Thrombophilia Center for periprocedural anticoagulation management over the 7-year period, January 1, 1997, to December 31, 2003, 345 patients with nonvalvular AF were eligible for inclusion. Warfarin was stopped 4 to 5 days before and was restarted after surgery as soon as hemostasis was assured. The decision to provide bridging therapy with heparin was individualized and based on the estimated risks of TE and bleeding. RESULTS The 345 patients with AF (mean +/- SD age, 74+/-9 years; 33% women) underwent 386 procedures. Warfarin administration was not interrupted for 44 procedures. Periprocedural heparin was provided for 204 procedures. Patients receiving heparin were more likely to have prior TE (43% vs 24%; P<.001) and a higher CHADS2 (congestive heart failure, hypertension, age, diabetes, stroke) score (2.2 vs 1.9; P=.06). Four patients had 6 episodes of TE (3 strokes and 3 acute coronary episodes; TE rate, 1.1%; 95% confidence interval, 0.0%-2.1%). Nine patients had 10 major bleeding events (major bleeding rate, 2.7%; 95% confidence interval, 1.0%-4.4%). There were no deaths. Neither bleeding nor TE rates differed by anticoagulant management strategy. CONCLUSION The 3-month cumulative incidence of TE and bleeding among patients with AF in whom anticoagulation was temporarily interrupted for an invasive procedure was low and was not significantly influenced by bridging therapy.

Herpes esophagitis: clinical syndrome, endoscopic appearance, and diagnosis in 23 patients

The unexpected diagnosis of herpetic esophagitis in a patient with nausea led us to review our experience with this disease. Review of our records from 1979 to 1989 produced 23 cases proven by endoscopic culture or microscopic examination (Cowdry-type A inclusions), the largest such series reported to date. Twenty-two of the 23 patients were immunocompromised. Odynophagia and chest pain were each present in half of the cases, but 26% of patients had neither. Gastrointestinal bleeding was attributable to herpetic esophagitis in 30%. Thirty percent of patients had disseminated herpes simplex infection and 70% had simultaneous infections with other organisms. Endoscopic findings included nonspecific inflammation, discrete ulcers, coalescent ulcers, and pseudomembranous esophagitis. Herpes virus was not suspected endoscopically as the cause of esophagitis in 30% of cases. Culture was slightly more sensitive than microscopic examination for diagnosis (89% vs. 76%), but both methods should be employed in any immunocompromised patient with esophagitis.

Comparison of PFA-100 testing and bleeding time for detecting platelet hypofunction and von Willebrand disease in clinical practice

The PFA-100 instrument (Platelet Function Analyzer, Dade Behring) has been reported to be superior to the bleeding time (BT) as a screening test of primary hemostasis. However evaluation of this device has been principally limited to selected populations. The studys aim was to determine testing performance in clinical practice, by comparing the PFA-100 to the BT for the identification of von Willebrand disease (VWD) and intrinsic platelet hypofunction. From 1998-2000, PFA-100 closure time (CT) for epinephrinecollagen (EPI) and ADP-collagen (ADP) cartridges and modified Ivy BTs were performed on outpatients referred for testing for suspected or known hemorrhagic diathesis (n = 346). Evaluation included assays of von Willebrand factor and platelet aggregometry in addition to platelet flow cytometry and electron microscopy when indicated. The normal distribution of PFA-100 CTs was determined using blood samples from 61 normal donors studied on 155 occasions. Results show that thirty-four patients met the diagnostic criteria for VWD and 31 patients were diagnosed with congenital or acquired intrinsic platelet hypofunction. The sensitivity of the PFA-100 for identification of VWD was significantly better (p < 0.01) than the BT with similar specificity. In contrast, the PFA-100 was comparable, but not superior to the BT for detecting platelet hypofunction. We conclude that the PFA-100 performance compares favorably to the BT for the identification of intrinsic platelet hypofunction in clinical practice with superior sensitivity for detecting VWD. Therefore, the PFA-100 could replace the BT for purposes of screening for VWD and intrinsic platelet hypofunction. When clinical suspicion is strong, testing should be supplemented with assays of von Willebrand factor and platelet aggregometry.

Acute venous disease: Venous thrombosis and venous trauma

Acute venous disorders include deep venous thrombosis, superficial venous thrombophlebitis, and venous trauma. Deep venous thrombosis (DVT) most often arises from the convergence of multiple genetic and acquired risk factors, with a variable estimated incidence of 56 to 160 cases per 100,000 population per year. Acute thrombosis is followed by an inflammatory response in the thrombus and vein wall leading to thrombus amplification, organization, and recanalization. Clinically, there is an exponential decrease in thrombus load over the first 6 months, with most recanalization occurring over the first 6 weeks after thrombosis. Pulmonary embolism (PE) and the post-thrombotic syndrome (PTS) are the most important acute and chronic complications of DVT. Despite the effectiveness of thromboembolism prophylaxis, appropriate measures are utilized in as few as one-third of at-risk patients. Once established, the treatment of venous thromboembolism (VTE) has been defined by randomized clinical trials, with appropriate anticoagulation constituting the mainstay of management. Despite its effectiveness in preventing recurrent VTE, anticoagulation alone imperfectly protects against PTS. Although randomized trials are currently lacking, at least some data suggests that catheter-directed thrombolysis or combined pharmaco-mechanical thrombectomy can reduce post-thrombotic symptoms and improve quality of life after acute ileofemoral DVT. Inferior vena caval filters continue to have a role among patients with contra-indications to, complications of, or failure of anticoagulation. However, an expanded role for retrievable filters for relative indications has yet to be clearly established. The incidence of superficial venous thrombophlebitis is likely under-reported, but it occurs in approximately 125,000 patients per year in the United States. Although the appropriate treatment remains controversial, recent investigations suggest that anticoagulation may be more effective than ligation in preventing DVT and PE. Venous injuries are similarly under-reported and the true incidence is unknown. Current recommendations include repair of injuries to the major proximal veins. If repair not safe or possible, ligation should be performed.

Predictors of major bleeding in peri-procedural anticoagulation management

Summary.  Background: Appropriate periprocedural management for chronically anticoagulated patients requires assessment of patient‐specific thrombosis and bleeding risks. However, predictors of post‐procedure bleeding are unknown. Objectives: To determine the 3‐month cumulative incidence and independent predictors of peri‐procedural bleeding in chronically anticoagulated patients requiring temporary warfarin interruption for an invasive procedure. Methods: In a protocol driven, cohort study design, all patients referred to the Mayo Clinic Thrombophilia Center for peri‐procedural anticoagulation management (1997–2007; n = 2182), were followed forward in time to determine the 3‐month cumulative incidence of peri‐procedural bleeding (Kaplan–Meier product limit) and potential predictors of bleeding (Cox proportional hazards). Decisions to ‘bridge’ with low‐molecular‐weight heparin were based on estimated thromboembolism and bleeding risk. Results: Indications for chronic anticoagulation included venous thromboembolism (38%), atrial fibrillation (30%) and mechanical heart valves (27%). Of these, 1496 (69%) patients received bridging therapy. The 3‐month cumulative incidence rates of major and overall bleeding were 2.1% and 5.1%, respectively. Major bleeding occurred more frequently in patients receiving bridging therapy (3% vs. 1%; P = 0.017). Independent predictors (hazard ratio; 95% confidence interval) of major bleeding included mitral mechanical heart valve (2.2; 1.1–4.3), active cancer (1.8; 1.0–3.1), prior bleeding history (2.6; 1.5–4.5) and re‐initiation of heparin therapy within 24 h after the procedure (1.9; 1.1–3.4). Conclusion: Factors predisposing to peri‐procedural bleeding are primarily patient‐specific. Premature heparin re‐initiation is an avoidable provider‐specific variable to consider.

Surgical Pathology of Nonbacterial Thrombotic Endocarditis in 30 Patients, 1985–2000

OBJECTIVE To describe the causes, complications, and histological appearance of nonbacterial thrombotic endocarditis (NBTE) in a surgical population compared with those in previously reported autopsy series. PATIENTS AND METHODS Cases were identified by reviewing the surgical pathology reports for all cardiac valvular specimens removed at Mayo Clinic, Rochester, Minn., between 1985 and 2000. Archived microscopic slides and medical records were reviewed for each study patient. RESULTS The study group consisted of 30 patients (20 female and 10 male), with a mean age of 49 years (range, 15-89 years). Of these 30 patients, 28 had single valve involvement (19 mitral, 8 aortic, and 1 tricuspid), and 2 had involvement of both their mitral and aortic valves. An underlying immune-mediated disorder was identified in 18 patients (60%), including primary antiphospholipid syndrome (in 8), rheumatic heart disease (in 6), systemic lupus erythematosus (in 2), and rheumatoid arthritis (in 2), 15 (83%) of whom were women. Of the remaining 12 patients with no autoimmune disease, only 5 (42%) were women. No patient had metastatic malignant disease or disseminated intravascular coagulopathy. Systemic embolization was documented in 10 patients (33%), 8 of whom had cerebral involvement. Valvular vegetations were visualized by echocardiography before surgery in 8 patients and were suspected but not confirmed preoperatively in 1 patient. All vegetations consisted primarily of platelets and fibrin. The site and appearance of vegetations did not vary with the underlying disease state. CONCLUSIONS In contrast to previously reported autopsy series, NBTE in a surgical population was more commonly associated with autoimmune disorders than malignancy or disseminated intravascular coagulopathy. Women were affected twice as often as men. Systemic embolization, particularly to the brain, was prominent in both surgical and autopsy series. Vegetations had a similar appearance regardless of the specific underlying disease. An antemortem diagnosis of NBTE in a patient with no known risk factors should prompt a search not only for occult malignancy, as suggested by autopsy studies, but also for autoimmune or rheumatic diseases, particularly the antiphospholipid syndrome.