Giovanni Nante

Effectiveness of fixed minidose warfarin in the prevention of thromboembolism and vascular death in nonrheumatic atrial fibrillation

Adjusted-dose warfarin is effective for stroke prevention in patients with nonrheumatic atrial fibrillation (AF), but the risk of bleeding is high, especially among the elderly. Fixed minidose warfarin is effective in preventing venous thromboembolism with low risk of bleeding and no need for frequent clinical monitoring. Patients > 60 years with nonrheumatic AF were randomized in an open-labeled trial to receive fixed minidose warfarin (1.25 mg/day) or standard adjusted-dose warfarin (International Normalized Ratio [INR] between 2.0 and 3.0). Primary outcome events were ischemic stroke, peripheral or visceral embolism, cerebral or fatal bleeding, and vascular death. Secondary end points were major bleeding, myocardial infarction, and death. This study was discontinued before completion in light of publication of the Stroke Prevention in Atrial Fibrillation III trial, which indicated that low-intensity fixed-dose warfarin treatment (i.e., INR < 1.5) was insufficient for stroke prevention in high-risk patients with nonrheumatic AF. From a total of 1,209 considered patients, 303 were randomized to be studied (150 in the minidose group and 153 in the adjusted-dose group). Mean follow-up was 14.5 months. The rate of cumulative primary events was 11.1% (95% confidence intervals [CI] 4.0 to 18.2) in the fixed minidose group and 6.1% (95% CI 1.1 to 11.1) in the adjusted-dose group (p = 0.29). The rate of ischemic stroke was significantly higher in the minidose group (3.7% vs 0% per year, p = 0.025). Major bleedings were more frequent in standard treatment group (2.6% vs 1% per year, p = 0.19). Most thromboembolic complications occurred at INRs < 1.2, whereas the majority of hemorrhages occurred at INRs > 3.0. No significant difference in primary outcome events was observed in the abbreviated study. However, the significantly increased occurrence of ischemic stroke in the fixed minidose warfarin group suggests that this regimen does not protect patients with nonrheumatic AF.

Facioscapulohumeral Muscular Dystrophy and Occurrence of Heart Arrhythmia

Background: Subjects with facioscapulohumeral muscular dystrophy (FSHD) do not generally suffer from significant cardiac symptoms. Although with heterogeneous results, studies reported to date indicate that heart alterations unrelated to cardiomyopathy are possible in FSHD. Patients and Methods: We describe the findings of a multicenter investigation aimed at detecting cardiac abnormalities in 83 FSHD patients, 44 males and 39 females with a mean age of 47 years. All patients underwent clinical heart examination, 12-lead electrocardiography and 24-hour Holter monitoring; echocardiography was also performed on most patients. Results: Among the 83 patients, 62 with no cardiovascular risk factors were identified. Ten of them manifested clinical or subclinical cardiac involvement: 5 reported symptoms represented mostly by frequent palpitations secondary to supraventricular arrhythmia and another 5 exhibited electrocardiographic signs of short runs of supraventricular paroxysmal tachycardia. In the absence of cardiovascular risk factors, we found symptoms or signs of heart involvement of mainly arrhythmic origin in 10 of our 83 FSHD patients (12%). Conclusions: Considering our data and those available in the literature as a whole, arrhythmic alterations seem to be detected more frequently than expected in FSHD patients.

Thromboembolic Prevention in Frail Elderly Patients With Atrial Fibrillation: A Practical Algorithm

Atrial fibrillation is a common condition in the elderly, and the incidence of thromboembolic events secondary to atrial fibrillation increases with age. Antithrombotic therapy effectively prevents stroke and systemic embolism but also exposes patients to the risk of bleeding. Because the risk of bleeding also increases with age, clinicians tend to withhold anticoagulation in the elderly. Anticoagulation is particularly complex in the frail elderly patient, who presents additional risk factors affecting both efficacy and safety of thromboembolic prevention. The main clinical trials rarely include frail elderly patients and, consequently, the guidelines do not provide guidance for their management. In the absence of clear indications for this class of patients, we identified some areas that should be taken into account both before starting and when discontinuing anticoagulation: comorbidities, polypharmacotherapy, adherence, cognitive impairment, mobility and monitoring barriers, nutritional status and swallowing disorders, risk of falls, and reduced life expectancy. We also suggest a multidimensional algorithm covering both a standard ischemic and bleeding risk assessment and an additional anticoagulation-focused frailty assessment. This is of particular relevance given the recent introduction of the oral direct inhibitors, as they are likely to widen the treatment options for the frail elderly. Depending on which aspect of frailty is present, anticoagulation can now be tailored accordingly.

Reasons for and consequences of vitamin K antagonist discontinuation in very elderly patients with non-valvular atrial fibrillation

Essentials Anticoagulation in the elderly is still a challenge and suspension of warfarin is common. This is an observational study reporting reasons and consequences of warfarin suspension. Vascular disease, age, time in therapeutic range, and bleedings are associated with suspension. After suspension for bleeding or frailty, patients remain at high‐risk of death or complications.

Impact of residual pulmonary obstruction on the long-term outcome of patients with pulmonary embolism

The impact of residual pulmonary obstruction on the outcome of patients with pulmonary embolism is uncertain. We recruited 647 consecutive symptomatic patients with a first episode of pulmonary embolism, with or without concomitant deep venous thrombosis. They received conventional anticoagulation, were assessed for residual pulmonary obstruction through perfusion lung scanning after 6 months and then were followed up for up to 3 years. Recurrent venous thromboembolism and chronic thromboembolic pulmonary hypertension were assessed according to widely accepted criteria. Residual pulmonary obstruction was detected in 324 patients (50.1%, 95% CI 46.2–54.0%). Patients with residual pulmonary obstruction were more likely to be older and to have an unprovoked episode. After a 3-year follow-up, recurrent venous thromboembolism and/or chronic thromboembolic pulmonary hypertension developed in 34 out of the 324 patients (10.5%) with residual pulmonary obstruction and in 15 out of the 323 patients (4.6%) without residual pulmonary obstruction, leading to an adjusted hazard ratio of 2.26 (95% CI 1.23–4.16). Residual pulmonary obstruction, as detected with perfusion lung scanning at 6 months after a first episode of pulmonary embolism, is an independent predictor of recurrent venous thromboembolism and/or chronic thromboembolic pulmonary hypertension. Residual pulmonary obstruction after PE is an independent predictive factor of VTE recurrences and/or CTEPH http://ow.ly/XK49308SDTd

A Randomized Trial of Pharmacogenetic Warfarin Dosing in Naïve Patients with Non-Valvular Atrial Fibrillation

Genotype-guided warfarin dosing have been proposed to improve patient’s management. This study is aimed to determine whether a CYP2C9- VKORC1- CYP4F2-based pharmacogenetic algorithm is superior to a standard, clinically adopted, pharmacodynamic method. Two-hundred naïve patients with non-valvular atrial fibrillation were randomized to trial arms and 180 completed the study. No significant differences were found in the number of out-of-range INRs (INR<2.0 or >3.0) (p = 0.79) and in the mean percentage of time spent in the therapeutic range (TTR) after 19 days in the pharmacogenetic (51.9%) and in the control arm (53.2%, p = 0.71). The percentage of time spent at INR>4.0 was significantly lower in the pharmacogenetic (0.7%) than in the control arm (1.8%) (p = 0.02). Genotype-guided warfarin dosing is not superior in overall anticoagulation control when compared to accurate clinical standard of care. Trial Registration ClinicalTrials.gov NCT01178034

A new D-dimer cutoff in bedridden hospitalized elderly patients.

Asymptomatic deep vein thrombosis (DVT) and pulmonary embolism are leading causes of morbidity following the hospitalization of elderly people. The diagnosis of DVT is supported by the D-dimer laboratory assay. The concentration of D-dimer increases in patients with DVT, but may be high in other conditions too (i.e. cancer, infections and inflammation). Old age coincides with a physiological increase in D-dimer values, and that is why D-dimer assay in the elderly is characteristically highly sensitive but scarcely specific. The aim of our study was to explore the reliability of different D-dimer cutoffs for the diagnosis of asymptomatic DVT in a population of bedridden hospitalized elderly patients. We studied 199 patients who were a mean 86.3 ± 6.7 years old. All participants underwent lower limb Doppler ultrasound (DUS) and D-dimer venous blood sampling on admission. In our cohort, the usual cutoff proved highly sensitive (100%), but its specificity was very poor (20.1%). To find a higher cutoff that could improve the methods specificity, we analyzed our data using a receiver operating characteristic curve analysis. The resulting D-dimer cutoff of 492 &mgr;g/l enabled us to retain the same sensitivity while improving the tests specificity to 39.1%, with a consequent improvement in its positive predictive value and accuracy. In addition to improving the methods reliability, this result may be helpful in clinical practice, in both medical wards and nursing homes. By adopting a cutoff of 492 &mgr;g/l, clinicians could significantly increase the proportion of older patients in whom DVT can be safely ruled out, reducing referrals for DUS and administration of heparin, with consequent clinical, practical and economic advantages.

Consequences of warfarin suspension after major bleeding in very elderly patients with non valvular atrial fibrillation

Consequences of warfarin suspension after major bleeding in very elderly patients with non valvular atrial fibrillation -

Point of Care Testing (POCT) to assess drug concentration in patients treated with non-vitamin K antagonist oral anticoagulants (NOACs)

BACKGROUND Non-vitamin K antagonist oral anticoagulants (NOACs) do not need routine laboratory monitoring but measurement of drug concentration is important in emergency conditions. Specific laboratory tests are not readily available or not implemented in every hospital. Point-of-Care Tests (POCT) may bridge this gap and be used as a bedside solution. OBJECTIVES Feasibility of POCT to assess plasma levels of dabigatran, rivaroxaban and apixaban. PATIENTS/METHODS Activated Coagulation Time-Low Range (ACT - LR) using a portable Hemochron Signature Elite for dabigatran and prothrombin time (expressed as INR) by Coaguchek XS Pro for rivaroxaban and apixaban were obtained at trough and peak in 136 consecutive patients taking NOACs (70 on dabigatran, 45 on rivaroxaban and 20 on apixaban). Using a paired study design, drug concentrations were concurrently determined by functional specific tests. RESULTS AND CONCLUSIONS The correlation between NOACs concentration and the values obtained using the POCTs was high for dabigatran and rivaroxaban (r = 0.80 and r = 0.82, respectively) and low for apixaban (r = 0.21). ACT-LR ≤ 188 s better detected dabigatran levels ≤ 50 ng/ml, with a sensitivity of 87.5% and a specificity of 84.1%. ACT-LR values > 217 s better discriminated value of dabigatran > 200 ng/ml, with a sensitivity of 86.7% and a specificity of 81.4%. INR Coaguchek values ≤ 1.2 better identified patients with rivaroxaban values < 100 ng/ml, with sensitivity of 90%, specificity of 88.5%. This analysis was not possible for apixaban. CONCLUSION In emergency situations POCT use may provide useful immediate information on dabigatran and rivaroxaban concentration.

Short article: Relapsing Whipple's disease: a case report and literature review.

Whipple’s disease is a rare infection caused by Tropheryma whipplei, a Gram-negative Bacillus usually found in macrophages of the lamina propria of the small intestine. The typical clinical manifestations of classic Whipple’s disease are diarrhea, weight loss, malabsorption, abdominal pain, and arthralgia. The disease’s laboratory diagnosis is currently based on duodenal biopsy. Treatment generally includes primary therapy for 2 weeks with intravenous antibiotics capable of reaching high levels in the cerebrospinal fluid, such as ceftriaxone, usually followed by treatment with oral cotrimoxazole for 1 year. Early diagnosis should enable appropriate treatment and improves the prognosis, and prolonged antibiotic treatment often leads to complete remission. Our case report focuses on a 72-year-old man who had been passing watery stools for 1–2 months, accompanied by low-grade fever. He reported profound asthenia, a weight loss of about 3 kg, and loss of appetite. Thirty years earlier (in 1984), he had been working as a horse keeper at a University Department of Agricultural and Veterinary Studies, where he had contracted Whipple’s disease. Laboratory tests and microbiological studies led to a diagnosis of recurrent Whipple’s disease. Esophagogastroduodenoscopy was performed under deep sedation. Biopsy samples obtained from the stomach and duodenum were stained with hematoxylin and eosin, Giemsa, and periodic acid–Schiff to identify any accumulation of typical periodic acid–Schiff-positive macrophages in the lamina propria. A specific quantitative real-time PCR assay using specific oligonucleotide probes for targeting repeated sequences of Tropheryma whipplei was also performed to detect its DNA in the duodenum samples.