Risk of recurrent cerebrovascular events in patients with cryptogenic stroke or transient ischemic attack and patent foramen ovale: the FORI (Foramen Ovale Registro Italiano) study.

BACKGROUND: The optimal management of patients with cryptogenic ischemic stroke found to have a patent foramen ovale (PFO) at diagnostic workup remains unclear. The aims of this observational multicenter study were to evaluate: (1) the risk of recurrent cerebrovascular events in patients with cryptogenic minor ischemic stroke or transient ischemic attack (TIA) and PFO who either underwent percutaneous PFO closure or received only medical treatment, and (2) the risk factors associated with recurrent events. METHODS: Consecutive patients (aged 55 years or less) with first-ever cryptogenic minor ischemic stroke or TIA and PFO were recruited in 13 Italian hospitals between January 2006 and September 2007 and followed up for 2 years. RESULTS: 238 patients were included in the study (mean age 42.2 ± 10.0 years; 118 males); 117 patients (49.2%) received only antithrombotic therapy while 121 patients underwent percutaneous PFO closure (50.8%). Stroke as the qualifying event was more common in the medical treatment group (p = 0.01). The presence of atrial septal aneurysm and evidence of 20 bubbles or more on transcranial Doppler were more common in the PFO closure group (p = 0.002 and 0.02). Eight patients (6.6%) experienced a nonfatal complication during PFO closure. At the 2-year follow-up, 17 recurrent events (TIA or stroke; 3.6% per year) were observed; 7 of these events (2.9% per year) occurred in the percutaneous PFO closure group and 10 events (4.2% per year) in the medical treatment group. The rate of recurrent stroke was 0.4% per year in patients who underwent percutaneous closure (1 event) and 3.4% per year in patients who received medical treatment (8 events). On multivariate analysis, percutaneous closure was not protective in preventing recurrent TIA or stroke (OR = 0.1, 95% CI = 0.02-1.5, p = 0.1), while it was barely protective in preventing recurrent stroke (OR = 0.1, 95% CI = 0.0-1.0, p = 0.053). CONCLUSIONS: The results of this observational, nonrandomized study suggest that PFO closure might be superior to medical therapy for the prevention of recurrent stroke. Periprocedural complications were the trade-off for this clinical benefit. Controlled randomized clinical trials comparing percutaneous closure with medical management are required.

Vitamin K and non-vitamin K antagonist oral anticoagulants for non-valvular atrial fibrillation in real-life.

BACKGROUND: Current guidelines recommend vitamin K antagonists (VKAs) or non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in patients with non-valvular atrial fibrillation (AF). METHODS: We compared the clinical features of consecutive in- and out-patients with non-valvular AF newly-treated with NOACs or on treatment with VKAs. RESULTS: Overall, 1314 patients newly-treated with NOACs and 1024 on treatment with VKAs were included in the study. The mean CHA2DS2-VASc score was 4.3±1.5 and 4.0±1.5 and the mean HAS-BLED score was 2.8±1.2 and 2.2±1.1 in the two groups, respectively (both p<0.001). Hypertension, previous stroke, female gender, vascular diseases and previous bleeding were more prevalent in NOACs patients. Renal failure, age ≥75years and congestive heart failure were more prevalent in VKAs patients. Among NOACs patients, 438 were given dabigatran, 463 rivaroxaban and 413 apixaban (33%, 35% and 31%, respectively). The mean CHA2DS2-VASc and HAS-BLED scores were higher in rivaroxaban or apixaban patients compared with dabigatran (both p<0.001) and VKAs patients (both p<0.001). A lower mean age was observed in patients newly-treated with dabigatran. Patients newly-treated with reduced doses of NOACs (599 patients, 45.5%) had a higher CHA2DS2-VASc (4.8±1.4 vs. 3.9±1.5 vs. 4.0±1.5) and HAS-BLED (2.9±1.1 vs. 2.8±1.2 vs. 2.2±1.1) scores compared with those treated with regular doses of NOACs or VKAs. CONCLUSION: Patients given rivaroxaban and apixaban in clinical practice have a higher thrombotic and hemorrhagic risk in comparison with patients given dabigatran or VKAs. A considerable proportion of patients receive reduced doses of NOACs.

Holter monitoring to detect silent atrial fibrillation in high-risk subjects: the Perugia General Practitioner Study.

Atrial fibrillation (AF) is diagnosed for the first time in about 5 % of patients admitted for acute ischemic stroke. Advanced aged and arterial hypertension are risk factors for AF. We evaluated the prevalence of silent AF in subjects with advanced age and systemic arterial hypertension. Subjects of both gender, aged 65 years or more with systemic arterial hypertension were randomly identified from the patient lists of the participating general practitioners in the Perugia area, in Italy. Study subjects underwent baseline 12-lead ECG and, if this did not show AF, 48-h Holter monitoring was performed. AF was known and confirmed by 12-lead ECG in 4 out of the 308 evaluated subjects (1.3 %). Baseline 12-lead ECG showed no cases of silent AF. Holter monitoring was performed in 300 subjects, mean age 70 ± 4. Twenty-six recordings were not evaluable for the presence of artifacts; therefore, 274 subjects were included in the analysis. Holter monitoring showed AF in 27 out of 274 subjects (10 %; 95 % confidence interval 6.4-13.5 %); AF was longer than 30 s in four of the subjects. In 56 additional subjects, Holter monitoring revealed excessive supraventricular ectopic activity (20 %; 95 % confidence interval 15.3-24.7 %). Holter monitoring was able to detect silent AF in about 10 % of subjects aged 65 or above with systemic arterial hypertension. The risk of stroke associated with screened silent AF should be carefully evaluated.

Activation of blood coagulation in patients undergoing postoperative blood salvage and re-infusion of unwashed whole blood after total knee arthroplasty.

BACKGROUND: Perioperative blood salvage is commonly used in cardiovascular surgery and has been more recently introduced in major orthopedic surgery. Limited information is available on the influence of re-infused whole blood on the hemostatic system in orthopedic patients. MATERIALS AND METHODS: The aim of this study was to assess whether perioperative salvage and re-infusion of unwashed whole blood is associated with an activation of blood coagulation in patients undergoing total knee replacement. Consecutive patients receiving re-infusion were included in the study (n=13). Patients undergoing total knee replacement without perioperative blood salvage and re-infusion served as controls (n=6). In patients receiving re-infusion thrombin-antithrombin complexes (TAT), plasmin-antiplasmin complexes (PAP) and fibrinogen were assayed at the following times: before surgery (baseline), immediately before re-infusion (T0), immediately (T1), 2 h (T2) and 24 h (T3) after the end of re-infusion. In control patients blood samples were drawn at the average times corresponding to each of the sampling time in the patients receiving re-infusion. The first post-surgery LMWH dose was given within 12 h after surgery. RESULTS: TAT and PAP increased after surgery both in patients receiving re-infusion and controls. An increase of TAT and PAP was observed immediately after re-infusion with respect to baseline (TAT 513.1 +/- 259.1 microg/l vs. 5.3 +/- 4.9, p<0.0001; PAP 7408.0 +/- 1892.1 microg/l vs. 461.4 +/- 217.1, p<0.0001) and to controls (TAT 60.4 +/- 26.9 microg/l, p=0.002; PAP 2208.3 +/- 1446.4 microg/l, p<0.001). The levels of TAT and PAP in patients receiving re-infusion remained high at 2 h after re-infusion compared to those of the controls (TAT 124.1 +/- 38.3 microg/l vs. 38.08 +/- 18.9, p=0.016; PAP 5690.7 +/- 1435.5 microg/l vs. 1613.9 +/- 706.0, p<0.001) and decreased 24 h thereafter. Fibrinogen level was lower in patients receiving re-infusion compared to controls. CONCLUSIONS: Whole blood re-infusion is associated with an activation of blood coagulation in patients undergoing total knee replacement. The clinical relevance of this activation has to be tested in prospective studies with adequate sample size.

Prophylaxis of venous thromboembolism with low molecular weight heparin in bariatric surgery: a prospective, randomised pilot study evaluating two doses of parnaparin (BAFLUX Study).

BACKGROUND: The optimal dose of low molecular weight heparin (LMWH) to prevent venous thromboembolism (VTE) after bariatric surgery remains controversial. The aim of this multicentre, open-label, pilot study was to evaluate the efficacy and safety of two different doses of the LMWH parnaparin administered to patients undergoing bariatric surgery. METHODS: Patients were randomised to receive 4,250 IU/day (group A) or 6,400 IU/day (group B) of parnaparin s.c. for 7-11 days. Bilateral colour Doppler ultrasound of the lower limb was performed before surgery and at the end of the treatment period. The primary efficacy outcome was a composite of asymptomatic and symptomatic deep vein thrombosis, symptomatic pulmonary embolism and death from any cause during treatment. The primary safety endpoint was major and clinically relevant non-major bleeding. RESULTS: A total of 258 patients underwent randomization; 8 subjects were excluded following the safety analysis. One hundred thirty-one patients [106 females; mean age, 40.3 years (standard deviation (SD) ±9.6); mean body mass index (BMI), 44.6 kg/m(2) (SD ±5.4)] were assigned to group A and 119 patients [93 females; mean age, 41.5 years (SD ±9.9); mean BMI, 44.2 kg/m(2) (SD ±5.4)] were assigned to group B. The rate of the primary efficacy outcome was 1.5% (two cases; 95 % confidence interval (CI), 0.2-6.0%) in group A as compared with 0.8% (one case; 95% CI, 0.4-5.3%) in group B (p = ns). The composite incidence of major bleeding and clinically relevant non-major bleeding was 6.1% (eight cases; 95% CI, 2.9-12.1%) in group A and 5.0% (six cases; 95% CI, 2.1-11.1%) in group B (p = ns). CONCLUSIONS: A parnaparin dose of 4,250 IU/day seems suitable for VTE prevention in patients undergoing bariatric surgery.

Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review.

BACKGROUND: We aimed to determine the risk of recurrence for symptomatic venous thromboembolism (VTE) provoked by different transient risk factors. DATA SOURCES: MEDLINE, EMBASE, and Cochrane Collaboration Registry of Randomized Trials databases were searched. STUDY SELECTION: Prospective cohort studies and randomized trials of patients with a first episode of symptomatic VTE provoked by a transient risk factor and treated for at least 3 months were identified. DATA EXTRACTION: Number of patients and recurrent VTE during the 0- to 12-month and 0- to 24-month intervals after stopping therapy, study design, and provoking risk factor characteristics were extracted. DATA SYNTHESIS: Annualized recurrence rates were calculated and pooled across studies. At 24 months, the rate of recurrence was 3.3% per patient-year (11 studies, 2268 patients) for all patients with a transient risk factor, 0.7% per patient-year (3 studies, 248 patients) in the subgroup with a surgical factor, and 4.2% per patient-year (3 studies, 509 patients) in the subgroup with a nonsurgical factor. In the same studies, the rate of recurrence after unprovoked VTE was 7.4% per patient-year. The rate ratio for a nonsurgical compared with a surgical factor was 3.0 and for unprovoked thrombosis compared with a nonsurgical factor was 1.8 at 24 months. CONCLUSIONS: The risk of recurrence is low if VTE is provoked by surgery, intermediate if provoked by a nonsurgical risk factor, and high if unprovoked. These risks affect whether patients with VTE should undergo short-term vs indefinite treatment.

Small intestinal bacterial overgrowth and warfarin dose requirement variability.

The dose of warfarin needed to obtain a therapeutic anticoagulation level varies widely among patients and can undergo abrupt changes for unknown reasons. Drug interactions and genetic factors may partially explain these differences. Intestinal flora produces vitamin K2 (VK2) and patients with small intestinal bacterial overgrowth (SIBO) rarely present reduced INR values due to insufficient dietary vitamin K. The present study was undertaken to investigate whether SIBO occurrence may affect warfarin dose requirements in anticoagulated patients. Based on their mean weekly dose of warfarin while on stable anticoagulation, 3 groups of 10 patients each were defined: low dose (LD, or=70 mg/wk). Each patient underwent a lactulose breath test to diagnose SIBO. Plasma levels of warfarin and vitamin K-analogues were also assessed. Patients with an altered breath test were 50% in the VHD group, 10% in the HD group, and none in the LD group (P=0.01). Predisposing factors to SIBO were more frequent in the VHD group, while warfarin interfering variables were not. VHD patients were younger and had a higher plasma vitamin K1 (VK1) concentration (P>0.05). On the contrary, the plasma VK2 levels tended to be lower. This pilot study suggests that SIBO may increase a patient's warfarin dose requirement by increasing dietary VK1 absorption through the potentially damaged intestinal mucosa rather than increasing intestinal VK2 biosynthesis. Larger studies are needed to confirm these preliminary data and to evaluate the effects of SIBO decontamination on warfarin dosage.

Parnaparin versus aspirin in the treatment of retinal vein occlusion. A randomized, double blind, controlled study.

INTRODUCTION: Retinal vein occlusion (RVO) is a common cause of unilateral visual loss. Evidence based treatment recommendations for patients with RVO cannot be made because of the lack of adequate clinical trials. To compare the efficacy and safety of aspirin and of a low molecular weight heparin, parnaparin, in the treatment of RVO. MATERIALS AND METHODS: In a multicenter, randomized, double blind, controlled trial eligible patients with a delay between symptoms onset and objective diagnosis of less than 15 days were randomized to aspirin 100 mg/day for 3 months or to a fixed daily dose of parnaparin, 12.800 IU for 7 days followed by 6.400 IU for a total of 3 months. Primary end-point of the study was the incidence of functional worsening of the eye with RVO at 6 months, as assessed by fluorescein angiography, visual acuity, and visual field. Study end-points were adjudicated by an independent committee. RESULTS: Sixty-seven patients were enrolled in the study and 58 of them (28 treated with parnaparin, 30 with aspirin) were evaluable for the analysis. Baseline characteristics were well balanced between groups. Functional worsening was adjudicated in 20.7% of patients treated with parnaparin and in 59.4% of patients treated with ASA (p=0.002). Recurrent RVO was diagnosed in 3 patients, all treated with ASA (p=n.s.). Bleeding rates were similar between the two groups. CONCLUSIONS: Parnaparin appears to be more effective than aspirin in preventing functional worsening in patients with RVO. The results of this study need to be confirmed in a larger clinical trial.