F. Guercini

Low-molecular-weight heparin for the long-term treatment of symptomatic venous thromboembolism: meta-analysis of the randomized comparisons with oral anticoagulants

Summary.u2002 Background:u2002The management of venous thromboembolism (VTE) requires an initial treatment with unfractionated heparin (UFH) or low‐molecular‐weight heparin (LMWH), followed by oral anticoagulants (OA) for at least 3u2003months. OA treatment however, requires laboratory monitoring of anticoagulation, carries a definite risk of bleeding, and may be contraindicated in some patients. As an alternative to vitamin K antagonists, subcutaneous LMWH has been proposed and evaluated in randomized clinical trials, but they are all small studies that lack the power to establish if these two treatment modalities are equivalent in efficacy or safety. Objectives:u2002The objective of this review was to evaluate the efficacy (VTE recurrence) and safety (bleeds and deaths) of long‐term treatment of VTE with LMWH compared with OA. A secondary endpoint was to evaluate the effect of LMWH on cancer mortality. Methods:u2002Computerized searches of MedLine and EmBase were performed. In addition, randomized clinical trials were located through personal communication with colleagues, and through the manual scanning of meeting proceedings and reference lists of relevant studies. When necessary, the authors of the selected papers were called to obtain additional information. Two reviewers (AI and FG) reviewed and extracted data independently using a standard form. The primary analysis was performed for efficacy and safety endpoints on an intention‐to‐treat basis for the study period of randomized treatment. A meta‐regression analysis was used to investigate the relationship between daily dose and clinical outcome. Results:u2002Seven studies that fulfillled our predefined criteria were identified, for a total of 1379 patients. When all studies were combined, a statistically non‐significant reduction in the risk of VTE (OR 0.66; 95% confidence interval [CI] 0.41, 1.07) and in the risk of major bleeding (OR 0.45; 95% CI 0.18, 1.11) in favor of LMWH treatment was found. No difference in total mortality (OR 1.19; 95% CI 0.78, 1.83) or in cancer‐related mortality was observed between the LMWH and the OA treatment. Conclusions:u2002The results of this meta‐analysis indicate that a 3‐month course of LMWH is as effective and safe as a corresponding period of OA treatment, and may thus be considered as a valuable alternative option for patients in whom OA treatment appears contraindicated or problematic.

Cryptogenic stroke: time to determine aetiology

Summary.u2002 Strokes that remain without a definite cause even after extensive work‐up are classified as cryptogenic. These constitute about 30–40% of all strokes. Stroke aetiology may remain undetermined for the following reasons: (i) the cause of stroke is transitory or reversible and the diagnostic work‐out is not therefore performed at the appropriate time; (ii) all known causes of stroke are not fully investigated; (iii) some causes of stroke remain unknown. Recent studies have challenged the previous view that cryptogenic stroke is a relatively benign cerebrovascular event, and have shown that cryptogenic stroke is associated with a higher rate of recurrence and adverse outcome at long‐term follow‐up. The determination of stroke aetiology is a valuable procedure to avoid the risk of stroke recurrence, especially in young patients. In this review, we discuss new evidence on the aetiology of cryptogenic stroke, specifically focusing on patients with patent foramen ovale and atheroma of the aortic arch.

Low-molecular-weight heparin and cancer survival: review of the literature and pooled analysis of 1,726 patients treated for at least three months

Background: Heparin has been the main subject of intensive investigation and clinical use because of its therapeutic anticoagulant properties. It also exhibits many other biological activities, and it was claimed that it shows a beneficial effect on cancer spreading. Searching for papers investigating the effect of low-molecular-weight heparin (LMWH) on cancer mortality we found clinical trials and meta-analyses which showed a reduction in the mortality rate in cancer patients. However, the biological rationale of this effect for a short treatment with LMWH remains unclear. We wanted to check if similar results were achieved in cancer patients treated with LMWH for a longer period of time. Aim: To evaluate the effect on cancer mortality of a 3-month treatment with LMWH by performing a meta-analysis of published studies comparing LMWH and oral anticoagulants (OA) in the prevention of recurrent venous thromboembolism (VTE). Materials and Methods: Computerized searches of Medline and Embase were performed; clinical trials were also located through colleagues and hand scanning of meeting proceedings. Eligibility of the studies and extraction of data were performed by two authors using a standard form. The meta-analysis was performed assuming a fixed-effect model. Results: Eight studies were identified that fulfilled our predefined criteria for a total of 1,726 patients. After a mean of 8.6 months of follow-up, 327 patients had died of cancer, 160 in the LMWH group and 167 in the OA control group (OR 0.95, 95% CI 0.73–1.23; z = 0.42; p = 0.67). Considering cancer mortality in 948 cancer patients the figures were 160/472 in the LMWH group and 167/476 in the OA control group (OR 0.96, 95% CI 0.73–1.25; z = 0.33; p = 0.74). Conclusions: In 1,726 patients randomized to receive a long-term course of at least 3 months of LMWH or OA for the treatment of VTE, no effect on cancer mortality was found.

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 5xa0% 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 65xa0years 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 (1.3xa0%). Baseline 12-lead ECG showed no cases of silent AF. Holter monitoring was performed in 300 subjects, mean age 70xa0±xa04. 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 (10xa0%; 95xa0% confidence interval 6.4–13.5xa0%); AF was longer than 30xa0s in four of the subjects. In 56 additional subjects, Holter monitoring revealed excessive supraventricular ectopic activity (20xa0%; 95xa0% confidence interval 15.3–24.7xa0%). Holter monitoring was able to detect silent AF in about 10xa0% of subjects aged 65 or above with systemic arterial hypertension. The risk of stroke associated with screened silent AF should be carefully evaluated.

Influenza Vaccination and Vitamin K Antagonist Treatment: A Placebo-Controlled, Randomized, Double-blind Crossover Study

BACKGROUNDnAmong millions of persons vaccinated against influenza virus each year, many are older patients treated with several drugs, including vitamin K antagonists (VKAs), among which warfarin is the most commonly used. Due to high interpatient and intrapatient variability, the therapeutic dose of VKA has to be individualized by monitoring of international normalized ratio (INR) values. The objectives of this study were to evaluate variation in the INR and warfarin weekly dose variation after influenza vaccination administration and to follow up patients for related hemorrhagic and thrombotic events to evaluate the safety of the influenza vaccine and to assess the immunogenicity of the influenza vaccination in patients receiving VKAs.nnnMETHODSnOne hundred four patients on a stable VKA regimen and with an indication for influenza vaccination were randomized to receive influenza vaccination and subsequent placebo administration, or vice versa. All patients were tested for coagulation variables, clinical events, and antibody response against vaccine components.nnnRESULTSnSimilar mean prothrombin times, expressed as the INR and VKA weekly dose, were found in patients after receiving vaccine or placebo. The absence of any vaccination effect on VKA treatment was confirmed using a linear mixed-effects model. The percentages of time that patients were in therapeutic range were 70.7% after receiving vaccine and 72.4% after receiving placebo (P = .57). There were no fatal or major bleeding events and 11 minor mucocutaneous hemorrhagic events. After vaccination, the percentage of seroprotected patients ranged from 92.0% to 100.0% depending on the vaccine antigen examined.nnnCONCLUSIONSnInfluenza vaccination had no significant effect on INR values or warfarin sodium weekly doses. Close monitoring of INR values is not required after influenza vaccination in patients on stable long-term VKA regimens.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT00222638.

Safety and efficacy of ximelagatran: meta-analysis of the controlled randomized trials for the prophylaxis or treatment of venous thromboembolism.

BACKGROUNDnXimelagatran has been approved in Europe for VTE prophylaxis in orthopedic surgery at fixed doses and without laboratory monitoring. Aim of the study was to evaluate safety and efficacy of ximelagatran in a meta-analysis of prophylaxis and/or treatment randomized controlled trials.nnnMETHODSnAbsolute risk of events for ximelagatran and OR for its comparison with LMWH and coumarins were calculated. Subgroup analysis was performed for ximelagatran regimen, comparator agent, type of surgery, starting time of prophylaxis.nnnRESULTSnTwelve studies and 16,992 patients were meta-analysed. Ximelagatran showed an absolute risk of major VTE of 4.04% and 1.69% and of major bleedings of 1.68% and 1.03% in prophylaxis and treatment trials, respectively. In prophylaxis trials, a significant excess mortality (OR: 2.5; 95% CI: 1.02 - 6.13) and an excess in major bleedings (OR: 1.41; 95% CI: 0.93 - 2.14) was found in the whole ximelagatran group. No evidence of treatment effect for major VTE was seen in the comparison with LMWH (OR: 1.01; 95% CI: 0.52 - 1.97). The cohort of patients treated with 24 mg b.i.d. showed similar results. An increase in the absolute risk of bleeding (from 1.04% to 3.03%) was found between post and preoperative administration of ximelagatran. Major VTE risk was increased when ximelagatran was compared to b.i.d. LMWH.nnnCONCLUSIONSnXimelagatran can be considered for its potential advantages for prevention and treatment of VTE. Future efforts are needed by researchers to prospectively investigate the best postoperatively starting time and by clinicians to monitor overall mortality in prophylactic use.

The management of patients with venous thromboembolism in Italy: insights from the PREFER in VTE registry

Venous thromboembolism (VTE) is the third most common cardiovascular disease. Real-life data on the clinical presentation, risk factors, diagnosis, and treatment of VTE in Italy and Europe are required to optimize the management of this disease. The PREFER in VTE registry, a prospective non-interventional real-life study, was designed to assess clinical characteristics and management of patients with VTE, use of health care resources, and on-treatment patient quality of life. Eligible consecutive patients with objectively diagnosed VTE were enrolled in the registry and followed up for 12xa0months. Between January and December 2013, 816 Italian and 1027 patients from 6 European countries other than Italy (European patients) were enrolled in the registry, and followed up until December 2014. Italian patients were the oldest (mean age 65.7xa0years) among the European patients. The Italian patients with a history of cancer were 24.6xa0% of whom 63.2xa0% had an active cancer (18.2 and 57.0xa0%, respectively, in Europe). Parenteral heparin was given, as initial treatment, in 73.8xa0% of Italian patients (66.4xa0% in Europe); VKA in combination with other treatments in 45.8xa0% (34.7xa0% in Europe); and VKA as the only anticoagulant treatment in 24.4xa0% (17.2xa0% in Europe). Of the Italian patients, 43.2 and 90.6xa0% of patients were hospitalized for deep vein thrombosis and pulmonary embolism, respectively; 65.4xa0% were admitted to the hospital through the emergency department. Following a real world approach, PREFER in VTE shows that the Italian patients, among and compared to the European patients, are the oldest, have a history of cancer more commonly, receive an initial treatment with heparin more commonly, and are more commonly hospitalized, particularly if affected by PE.

Fatal Nocardia farcinica Bacteremia Diagnosed by Matrix-Assisted Laser Desorption-Ionization Time of Flight Mass Spectrometry in a Patient with Myelodysplastic Syndrome Treated with Corticosteroids

Nocardia farcinica is a Gram-positive weakly acid-fast filamentous saprophytic bacterium, an uncommon cause of human infections, acquired usually through the respiratory tract, often life-threatening, and associated with different clinical presentations. Predisposing conditions for N. farcinica infections include hematologic malignancies, treatment with corticosteroids, and any other condition of immunosuppression. Clinical and microbiological diagnoses of N. farcinica infections are troublesome, and the isolation and identification of the etiologic agent are difficult and time-consuming processes. We describe a case of fatal disseminated infection in a patient with myelodysplastic syndrome, treated with corticosteroids, in which N. farcinica has been isolated from blood culture and identified by Matrix-Assisted Laser Desorption-Ionization Time of Flight Mass Spectrometry. The patient died after 18 days of hospitalization in spite of triple antimicrobial therapy. Nocardia farcinica infection should be suspected in patients with history of malignancy, under corticosteroid therapy, suffering from subacute pulmonary infection,and who do not respond to conventional antimicrobial therapy. Matrix-Assisted Laser Desorption-Ionization Time of Flight Mass Spectrometry can be a valuable tool for rapid diagnosis of nocardiosis.