[ECRIN standard requirements for good clinical practices-compliant data management in multinational clinical trials]. / Référentiel ECRIN pour la conformité aux bonnes pratiques de gestion des données des essais cliniques multinationaux.

CONTEXT: Clinical studies involve an increasing amount of data collection and management. However, there is no specific quality standard sufficiently practical, in free access, and open for data management and the underlying IT-infrastructure in academic units. European Clinical Research Infrastructures Network (ECRIN) published standard requirements for certified data management units. We present a French version of these standards. METHODS: A group of experts produced the standards, by consensus. The first version was revised after two pilot audits for data centre certification were performed. RESULTS: The revised version includes 21 lists of five to ten standards, in three groups: information technologies, data management (DM) and "general". CONCLUSIONS: These standards offer a clear description of DM and IT requirements for clinical studies. Initially created for ECRIN certification purposes, they offer a very useful reference for academic DM structures.

Effect of a retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial.

IMPORTANCE: Although retrievable inferior vena cava filters are frequently used in addition to anticoagulation in patients with acute venous thromboembolism, their benefit-risk ratio is unclear. OBJECTIVE: To evaluate the efficacy and safety of retrievable vena cava filters plus anticoagulation vs anticoagulation alone for preventing pulmonary embolism recurrence in patients presenting with acute pulmonary embolism and a high risk of recurrence. DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label, blinded end point trial (PREPIC2) with 6-month follow-up conducted from August 2006 to January 2013. Hospitalized patients with acute, symptomatic pulmonary embolism associated with lower-limb vein thrombosis and at least 1 criterion for severity were assigned to retrievable inferior vena cava filter implantation plus anticoagulation (filter group; n = 200) or anticoagulation alone with no filter implantation (control group; n = 199). Initial hospitalization with ambulatory follow-up occurred in 17 French centers. INTERVENTIONS: Full-dose anticoagulation for at least 6 months in all patients. Insertion of a retrievable inferior vena cava filter in patients randomized to the filter group. Filter retrieval was planned at 3 months from placement. MAIN OUTCOMES AND MEASURES: Primary efficacy outcome was symptomatic recurrent pulmonary embolism at 3 months. Secondary outcomes were recurrent pulmonary embolism at 6 months, symptomatic deep vein thrombosis, major bleeding, death at 3 and 6 months, and filter complications. RESULTS: In the filter group, the filter was successfully inserted in 193 patients and was retrieved as planned in 153 of the 164 patients in whom retrieval was attempted. By 3 months, recurrent pulmonary embolism had occurred in 6 patients (3.0%; all fatal) in the filter group and in 3 patients (1.5%; 2 fatal) in the control group (relative risk with filter, 2.00 [95% CI, 0.51-7.89]; P = .50). Results were similar at 6 months. No difference was observed between the 2 groups regarding the other outcomes. Filter thrombosis occurred in 3 patients. CONCLUSIONS AND RELEVANCE: Among hospitalized patients with severe acute pulmonary embolism, the use of a retrievable inferior vena cava filter plus anticoagulation compared with anticoagulation alone did not reduce the risk of symptomatic recurrent pulmonary embolism at 3 months. These findings do not support the use of this type of filter in patients who can be treated with anticoagulation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00457158.

Two-year outcome of patients after a first hospitalization for heart failure: A national observational study.

BACKGROUND: National population-based management and outcome data for patients of all ages hospitalized for heart failure have rarely been reported. AIM: National population-based management and outcome of patients of all ages hospitalized for heart failure have rarely been reported. The present study reports these results, based on 77% of the French population, for patients hospitalized for the first time for heart failure in 2009. METHODS: The study population comprised French national health insurance general scheme beneficiaries hospitalized in 2009 with a principal diagnosis of heart failure, after exclusion of those hospitalized for heart failure between 2006 and 2008 or with a chronic disease status for heart failure. Data were collected from the national health insurance information system (SNIIRAM). RESULTS: A total of 69,958 patients (mean age, 78 years; 48% men) were studied. The hospital mortality rate was 6.4%, with 1-month, 1-year and 2-year survival rates of 89%, 71% and 60%, respectively. Heart failure and all-cause readmission-free rates were 55% and 43% at 1 year and 27% and 17% at 2 years, respectively. Compared with a reference sample of 600,000 subjects, the age- and sex-standardized relative risk of death was 29 (95% confidence interval [CI] 28-29) at 2 years, 82 (95% CI 72-94) in subjects aged<50 years and 3 (95% CI 3-3) in subjects aged ≥ 90 years. For subjects aged < 70 years who survived 1 month after discharge, factors associated with a reduction in the 2-year mortality rate were: female sex; age < 55 years; absence of co-morbidities; and use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers, lipid-lowering agents or oral anticoagulants during the month following discharge. Poor prognostic factors were treatment with a loop diuretic before or after hospitalization and readmission for heart failure within 1 month after discharge. CONCLUSIONS: This large population-based study confirms the severe prognosis of heart failure and the need to promote the use of effective medications and management designed to improve survival.

First hospitalization for heart failure in France in 2009: patient characteristics and 30-day follow-up.

BACKGROUND: The incidence of heart failure (HF) is stable in industrialized countries, but its prevalence continues to increase, especially due to the ageing of the population, and mortality remains high. OBJECTIVE: To estimate the incidence in France and describe the management and short-term outcome of patients hospitalized for HF for the first time. METHOD: The study population comprised French national health insurance general scheme beneficiaries (77% of the French population) hospitalized in 2009 with a principal diagnosis of HF after exclusion of those hospitalized for HF between 2006 and 2008 or with a chronic disease status for HF. Data were collected from the national health insurance information system (SNIIRAM). RESULTS: A total of 69,958 patients (mean age 78 years; 48% men) were included. The incidence of first hospitalization for HF was 0.14% (≥ 55 years, 0.5%; ≥ 90 years, 3.1%). Compared with controls without HF, patients more frequently presented cardiovascular or other co-morbidities. The hospital mortality rate was 6.4% and the mortality rate during the 30 days after discharge was 4.4% (3.4% without readmission). Among 30-day survivors, all-cause and HF 30-day readmission rates were 18% (< 70 years, 22%; ≥ 90 years, 13%) and 5%, respectively. Reimbursements among 30-day survivors comprised at least a beta-blocker in 54% of cases, diuretics in 85%, angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in 67%, a diuretic and ACEI/ARB combination in 23% and a beta-blocker, ACEI/ARB and diuretic combination in 37%. CONCLUSION: Patients admitted for HF presented high rates of co-morbidity, readmission and death at 30 days, and there remains room for improvement in their drug treatments; these findings indicate the need for improvement in return-home and therapeutic education programmes.

Clinical relevance of symptomatic superficial-vein thrombosis extension: lessons from the CALISTO study.

The clinical relevance of symptomatic extension of spontaneous, acute, symptomatic, lower-limb superficial-vein thrombosis (SVT) is debated. We performed a post hoc analysis of a double-blind trial comparing fondaparinux with placebo. The main study outcome was SVT extension by day 77, whether to ≤ 3 cm or > 3 cm from the sapheno-femoral junction (SFJ). All events were objectively confirmed and validated by an adjudication committee. With placebo (n = 1500), symptomatic SVT extension to ≤ 3 cm or > 3 cm from the SFJ occurred in 54 (3.6%) and 56 (3.7%) patients, respectively, inducing comparable medical resource consumption (eg, anticoagulant drugs and SFJ ligation); subsequent deep-vein thrombosis or pulmonary embolism occurred in 9.3% (5/54) and 8.9% (5/56) of patients, respectively. Fondaparinux was associated with lower incidences of SVT extension to ≤ 3 cm (0.3%; 5/1502; P < .001) and > 3 cm (0.8%; 12/1502; P < .001) from the SFJ and reduced related use of medical resources; no subsequent deep-vein thrombosis or pulmonary embolism was observed in fondaparinux patients. Thus, symptomatic extensions are common SVT complications and, whether or not reaching the SFJ, are associated with a significant risk of venous thromboembolic complications and medical resource consumption, all reduced by fondaparinux.

Epidemiology, diagnosis, treatment and management of superficial-vein thrombosis of the legs.

Recent data on lower-limb superficial-vein thrombosis (SVT) may substantially impact its clinical management. Particularly, the clear confirmation that SVT is closely linked to deep-vein thrombosis (DVT) or pulmonary embolism (PE) highlights the potential severity of the disease. DVT or PE is diagnosed in 20-30% of SVT patients. Moreover, clinically relevant symptomatic thromboembolic events complicate isolated SVT (without concomitant DVT or PE at diagnosis) in 4-8% of patients. For the first time, an anticoagulant treatment, once-daily 2.5 mg fondaparinux for 45 days, was demonstrated to be effective and safe for preventing these symptomatic thromboembolic events in patients with lower-limb isolated SVT in the randomized, placebo-controlled CALISTO study. More recent data from another randomized trial support these findings. New recommendations on the management of SVT patients, including complete ultrasonography examination of the legs and, in patients with isolated SVT, prescription of once-daily 2.5 mg fondaparinux subcutaneously for 45 days on top of symptomatic treatments, may be proposed, wherever the cost of fondaparinux is acceptable. Superficial-vein thrombosis (SVT) of the lower limbs has long been regarded as a benign, self-limiting disease, expected to resolve spontaneously and rapidly, and requiring only symptomatic treatments [1,2]. However, the perception of this disease is now changing with the recent publication of data indicating its potential severity [3] and showing for the first time the benefit of a therapeutic strategy based on the administration of an anticoagulant treatment [4]. The overall management of this frequent disease therefore needs to be reconsidered.

Superficial venous thrombosis and compression ultrasound imaging.

BACKGROUND: A current debate concerning suspected superficial vein thrombosis (SVT) focuses on the need of performing a compression ultrasound (CUS) exploration for confirming the diagnosis of SVT. This study was conducted to determine the clinical relevance and optimal CUS exploration in patients with symptomatic SVT. METHODS: We analyzed the characteristics of SVT and concomitant deep vein thrombosis (DVT) in patients included in the Prospective Observational Superficial Thrombophlebitis (POST) multicenter, observational prospective study. All patients underwent complete bilateral lower limb CUS, exploring both the superficial and deep venous systems. RESULTS: A total of 844 patients with clinical symptoms of SVT were recruited, of which 99 isolated SVTs (21.4%) had saphenofemoral/popliteal junction involvement, and 198 (23.5%) had a concomitant DVT, with 41.8% of them proximal DVTs. In 83 patients (41.9%), DVT and SVT were not contiguous. Five of 639 patients (1%) had an isolated contralateral DVT (ie, not bilateral). Age ≥ 75 years (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.6-3.4), inpatient status (OR, 5.4; 95% CI, 3.4-8.7), a personal history of DVT or pulmonary embolism (OR, 1.8; 95% CI, 1.2-2.8), and SVT on nonvaricose veins (OR, 3.3; 95% CI, 2.1-5.0) were significantly and independently associated with an increased risk of concomitant DVT. Half of the patients exhibited none of these risk factors, and the prevalence of concomitant DVT dropped to 11%. CONCLUSIONS: In patients with symptomatic SVT, a CUS exploration screening the whole venous system of the affected limb is useful because it provides information that has important consequences for the management of these patients.

A randomized double-blind trial of upward progressive versus degressive compressive stockings in patients with moderate to severe chronic venous insufficiency.

BACKGROUND: The present randomized double-blind multicenter study was designed to assess the efficacy of a progressive compressive stocking (new concept with maximal pressure at calf), compared to a degressive compressive stocking graded 30 mm Hg, evaluating the improvement of lower leg symptoms of chronic venous insufficiency (CVI) in ambulatory patients with moderate to severe chronic venous disease. METHODS: Both gender outpatients presenting symptomatic moderate to severe CVI were eligible for a treatment by compressive stockings. Patients were randomly assigned to receive either degressive compressive stockings (30 mm Hg at ankle, 21 mm Hg at upper calf) or progressive compressive stockings (10 mm Hg at ankle, 23 mm Hg at upper calf). The primary outcome, evaluated after 3 months, was a composite success outcome, including improvement of pain or heavy legs without onset of either ulcer, deep or superficial vein thrombosis of the lower limbs, or pulmonary embolism. The ease of application of the compressive stockings reported by patients was one of secondary outcome. RESULTS: Overall, 401 patients (199 in the progressive compressive stocking group and 202 in the degressive compressive stocking group) were randomized by 44 angiologists in France. Among them, 66% were classified in the C3 CEAP category. The rate of success was significantly higher in the progressive compressive stocking group compared to the degressive compressive stocking group (70.0% vs 59.6%; relative risk, 1.18; 95% confidence interval, 1.02-1.37; P = .03). This was mainly due to more frequent symptom improvement in the progressive compressive stocking group. The compressive stockings were considered easy to apply by 81.3% of patients in the progressive compressive stocking group vs 49.7% of patients in the degressive compressive stocking group (P < .0001). The rate of related serious adverse events was low and similar in both groups. CONCLUSIONS: This trial has demonstrated that progressive compressive stockings are more effective than usual degressive compressive stockings in the improvement of pain and lower leg symptoms in patients with CVI. Moreover, progressive compressive stockings were easier to apply, raising no safety concern at 3 months.

Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients.

BACKGROUND: The efficacy and safety of prolonging prophylaxis for venous thromboembolism in medically ill patients beyond hospital discharge remain uncertain. We hypothesized that extended prophylaxis with apixaban would be safe and more effective than short-term prophylaxis with enoxaparin. METHODS: In this double-blind, double-dummy, placebo-controlled trial, we randomly assigned acutely ill patients who had congestive heart failure or respiratory failure or other medical disorders and at least one additional risk factor for venous thromboembolism and who were hospitalized with an expected stay of at least 3 days to receive apixaban, administered orally at a dose of 2.5 mg twice daily for 30 days, or enoxaparin, administered subcutaneously at a dose of 40 mg once daily for 6 to 14 days. The primary efficacy outcome was the 30-day composite of death related to venous thromboembolism, pulmonary embolism, symptomatic deep-vein thrombosis, or asymptomatic proximal-leg deep-vein thrombosis, as detected with the use of systematic bilateral compression ultrasonography on day 30. The primary safety outcome was bleeding. All efficacy and safety outcomes were independently adjudicated. RESULTS: A total of 6528 subjects underwent randomization, 4495 of whom could be evaluated for the primary efficacy outcome--2211 in the apixaban group and 2284 in the enoxaparin group. Among the patients who could be evaluated, 2.71% in the apixaban group (60 patients) and 3.06% in the enoxaparin group (70 patients) met the criteria for the primary efficacy outcome (relative risk with apixaban, 0.87; 95% confidence interval [CI], 0.62 to 1.23; P=0.44). By day 30, major bleeding had occurred in 0.47% of the patients in the apixaban group (15 of 3184 patients) and in 0.19% of the patients in the enoxaparin group (6 of 3217 patients) (relative risk, 2.58; 95% CI, 1.02 to 7.24; P=0.04). CONCLUSIONS: In medically ill patients, an extended course of thromboprophylaxis with apixaban was not superior to a shorter course with enoxaparin. Apixaban was associated with significantly more major bleeding events than was enoxaparin. (Funded by Bristol-Myers Squibb and Pfizer; ClinicalTrials.gov number, NCT00457002.).

The risk of subsequent cancer and arterial cardiovascular events in patients with superficial vein thrombosis in the legs.

Although it has been clearly demonstrated that venous thromboembolism is associated with an increased risk of subsequent overt cancer and arterial cardiovascular events in comparison with control populations, whether this association also applies to patients with isolated (ie, without concomitant involvement of the deep vein system) superficial vein thrombosis (SVT) in the legs is unknown. In 737 consecutive patients with isolated SVT not involving the sapheno-femoral junction, we conducted a retrospective investigation to assess the rate of cancer and that of arterial cardiovascular events occurring during follow-up. The event rates were compared with those occurring in 1438 controls having comparable characteristics. Both cases and controls were followed-up for an average period of 26 ± 8 months (range, 3-45). Malignancy was diagnosed in 26 cases (3.5%) and 56 controls (3.9%), leading to a hazard ratio of 0.86 (95% confidence interval, 0.55%-1.35%). Arterial cardiovascular events occurred in 32 cases (4.3%) and 63 controls (4.4%), leading to a hazard ratio of 0.97 (95% confidence interval, 0.63%-1.50%). We conclude that the occurrence of isolated SVT in the legs does not place patients at an increased risk of malignancies or arterial cardiovascular events. Whether this conclusion also applies to patients whose thrombosis involves the sapheno-femoral junction remains to be demonstrated.

Safety profile of tinzaparin versus subcutaneous unfractionated heparin in elderly patients with impaired renal function treated for acute deep vein thrombosis: the Innohep® in Renal Insufficiency Study (IRIS).

INTRODUCTION: Trials comparing the use of full dose unfractionated heparin (UFH) or low molecular weight heparins (LMWHs) in very elderly patients with impaired renal function are lacking. IRIS aimed to assess whether LMWH is at least as safe as UFH in this population. MATERIALS AND METHODS: The study included renally impaired patients ≥70 years with acute symptomatic lower limb deep vein thrombosis (DVT). Patients were randomized to initial treatment with either tinzaparin 175 IU/kg once daily (n=269) or activated partial thromboplastin time-adjusted UFH twice daily (n=270). After acute management both groups received vitamin K antagonist to day 90. RESULTS: The trial was stopped prematurely due to a difference in mortality favoring the UFH group (11.5 vs. 6.3%; p=0.035). Rates of clinically relevant bleedings by day 90 were similar in the tinzaparin (11.9%) and UFH (11.9%) groups, as were rates of confirmed recurrent venous thromboembolism (VTE) (2.6 vs. 1.1%; p=0.34). As the mortality difference could not be explained by bleedings or recurrent VTE, a post-hoc analysis was performed. This identified six baseline characteristics significantly correlated with mortality, of which five were over-represented in the tinzaparin group. CONCLUSION: The IRIS study was a challenging study involving patients (mean age 83 years) usually excluded from clinical studies, but its early termination has left questions unanswered. The mortality difference observed with tinzaparin vs. UFH in elderly, renally-impaired patients with DVT cannot be explained on the basis of bleedings or recurrent VTE, and may reflect an imbalance of mortality risk factors at baseline.

Recent findings in the epidemiology, diagnosis and treatment of superficial-vein thrombosis.

Recent data on lower-limb superficial-vein thrombosis (SVT) may substantially impact its clinical management. Thus, the clear confirmation that SVT is closely linked to deep-vein thrombosis (DVT) or pulmonary embolism (PE) highlights the potential severity of the disease. DVT or PE are diagnosed in 20-30% of SVT patients. Moreover, clinically relevant symptomatic thromboembolic events complicate isolated SVT (without concomitant DVT or PE at diagnosis) in 4-8% of patients. For the first time, an anticoagulant treatment, once-daily 2.5 mg fondaparinux for 45 days, was demonstrated to be effective and safe for preventing these symptomatic thromboembolic events in patients with lower-limb isolated SVT in the randomized placebo-controlled CALISTO study. Based on these recent findings, new recommendations on the management of SVT patients, including complete ultrasonography examination of the legs, and in patients with isolated SVT, prescription of once-daily 2.5 mg fondaparinux subcutaneously for 45 days on top of symptomatic treatments, may be proposed.

[Epidemiologic and therapeutic advances in superficial venous thrombosis of the legs]. / Epidémiologie et traitement des thromboses veineuses superficielles des membres inférieurs.

Thromboses affecting venous superficial system have been considered as benign diseases. Recent studies demonstrate that they might be associated with more severe venous events (as deep venous thrombosis [DVT] or pulmonary embolism [PE]), initially or during 3-month followup. The POST study presents clinical evolution of 844 patients with superficial venous thrombosis (SVT) of lower limbs. Of note, concomitant DVT and/or symptomatic PE were initially found in one quarter of them. Among the 586 patients with isolated SVT (i. e. without DVT or symptomatic PE, and at more than 3 cm of the saphenofemoral junction), 10% presented with DVT, PE, recurrent or extensive SVT during the 3-month follow-up. These results, as the heterogeneous therapeutic management, were confirmed by another cohort study (OPTIMEV). In the CALISTO study, Fondaparinux, at a dose of 2.5 mg once a day for 45 days was effective in the treatment of patients with isolated SVT of the legs and did not have serious side effects. In absence of contra-indication, this treatment may be preferred in patients with confirmed isolated SVT of lower limb.

Fondaparinux for the treatment of superficial-vein thrombosis in the legs.

BACKGROUND: The efficacy and safety of anticoagulant treatment for patients with acute, symptomatic superficial-vein thrombosis in the legs, but without concomitant deep-vein thrombosis or symptomatic pulmonary embolism at presentation, have not been established. METHODS: In a randomized, double-blind trial, we assigned 3002 patients to receive either fondaparinux, administered subcutaneously at a dose of 2.5 mg once daily, or placebo for 45 days. The primary efficacy outcome was a composite of death from any cause or symptomatic pulmonary embolism, symptomatic deep-vein thrombosis, or symptomatic extension to the saphenofemoral junction or symptomatic recurrence of superficial-vein thrombosis at day 47. The main safety outcome was major bleeding. The patients were followed until day 77. RESULTS: The primary efficacy outcome occurred in 13 of 1502 patients (0.9%) in the fondaparinux group and 88 of 1500 patients (5.9%) in the placebo group (relative risk reduction with fondaparinux, 85%; 95% confidence interval [CI], 74 to 92; P<0.001). The incidence of each component of the primary efficacy outcome was significantly reduced in the fondaparinux group as compared with the placebo group, except for the outcome of death (0.1% in both groups). The rate of pulmonary embolism or deep-vein thrombosis was 85% lower in the fondaparinux group than in the placebo group (0.2% vs. 1.3%; 95% CI, 50 to 95; P<0.001). Similar risk reductions were observed at day 77. A total of 88 patients would need to be treated to prevent one instance of pulmonary embolism or deep-vein thrombosis. Major bleeding occurred in one patient in each group. The incidence of serious adverse events was 0.7% with fondaparinux and 1.1% with placebo. CONCLUSIONS: Fondaparinux at a dose of 2.5 mg once a day for 45 days was effective in the treatment of patients with acute, symptomatic superficial-vein thrombosis of the legs and did not have serious side effects. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT00443053.)

Superficial venous thrombosis and venous thromboembolism: a large, prospective epidemiologic study.

BACKGROUND: Superficial venous thrombosis (SVT) is perceived to have a benign prognosis. OBJECTIVE: To assess the prevalence of venous thromboembolism in patients with SVT and to determine the 3-month incidence of thromboembolic complications. DESIGN: National cross-sectional and prospective epidemiologic cohort study. (ClinicalTrials.gov registration number: NCT00818688) SETTING: French office- and hospital-based vascular medicine specialists. PATIENTS: 844 consecutive patients with symptomatic SVT of the lower limbs that was at least 5 cm on compression ultrasonography. MEASUREMENTS: Incidence of venous thromboembolism and extension or recurrence of SVT in patients with isolated SVT at presentation. RESULTS: Among 844 patients with SVT at inclusion (median age, 65 years; 547 women), 210 (24.9%) also had deep venous thrombosis (DVT) or symptomatic pulmonary embolism. Among 600 patients without DVT or pulmonary embolism at inclusion who were eligible for 3-month follow-up, 58 (10.2%) developed thromboembolic complications at 3 months (pulmonary embolism, 3 [0.5%]; DVT, 15 [2.8%]; extension of SVT, 18 [3.3%]; and recurrence of SVT, 10 [1.9%]), despite 540 patients (90.5%) having received anticoagulants. Risk factors for complications at 3 months were male sex, history of DVT or pulmonary embolism, previous cancer, and absence of varicose veins. LIMITATION: The findings are from a specialist referral setting, and the study was terminated before the target patient population was reached because of slow recruitment. CONCLUSION: A substantial number of patients with SVT exhibit venous thromboembolism at presentation, and some that do not can develop this complication in the subsequent 3 months. PRIMARY FUNDING SOURCE: GlaxoSmithKline, sanofi-aventis, and the Ministère Francais de la Santé et des Sports (Programme Hospitalier de Recherche Clinique).

Left atrial radiofrequency ablation during mitral valve surgery: a prospective randomized multicentre study (SAFIR).

BACKGROUND: Randomized studies evaluating left atrial radiofrequency ablation (RFA) in patients with persistent atrial fibrillation undergoing mitral valve surgery are scarce and monocentric. AIM: To evaluate the efficacy of left atrial RFA concomitant with mitral valve surgery to restore and maintain sinus rhythm. METHODS: The SAFIR is a multicentre, double-blinded, centrally randomized study involving four university hospitals. Between December 2002 and September 2005, 43 patients with mitral valve disease and long-standing, persistent atrial fibrillation (duration>6 months) were included. We compared valvular surgery alone (n=22) or with left atrial RFA (n=21). The main endpoint was sinus rhythm at 12 months without recurrence of arrhythmia during follow-up. Secondary endpoints were surgical adverse events, atrial fibrillation relapses, stroke and echocardiographic measurements after three and 12 months' follow-up. Analyses of the efficacy criteria were performed on an intention-to-treat basis. RESULTS: The primary endpoint occurred significantly more often in the RFA group than in the control group (respectively, 12/21 patients [57%] vs 1/22 patients [4%]; p=0.004). There were more patients with sinus rhythm in the RFA group than in the control group at discharge (72.7% vs 4.8%; p<0.005), 3-month follow-up (85.7% vs 23.8%; p<0.01) and 12-month follow-up (95.2% vs 33.3%; p<0.005). The patients in the RFA group had similar rates of postoperative complications and stroke during follow-up as those in the control group. CONCLUSIONS: This multicentre study suggests that left atrial RFA is effective and safe in patients with chronic atrial fibrillation and mitral valve disease.

New insights on the relation between untreated and treated outcomes for a given therapy effect model is not necessarily linear.

BACKGROUND AND OBJECTIVES: A relation between the size of treatment efficacy and severity of the disease has been postulated and observed as linear for a few therapies. We have called this relation the effect model. Our objectives were to demonstrate that the relation is general and not necessarily linear. STUDY DESIGN AND SETTING: We extend the number of observed effect model. Then we established three numerical models of treatment activity corresponding to the three modes of action we have identified. Using these models, we simulated the relation. RESULTS: Empirical evidence confirms the effect model and suggests that it may be linear over a short range of event frequency. However, it provides an incomplete understanding of the phenomenon because of the inescapable limitations of data from randomized clinical trials. Numerical modeling and simulation show that the real effect model is likely to be more complicated. It is probably linear only in rare instances. The effect model is general. It depends on factors related to the individual, disease and outcome. CONCLUSION: Contrarily to common, assumption, since the effect model is often curvilinear, the relative risk cannot be granted as constant. The effect model should be taken into account when discovering and developing new therapies, when making, health care policy decisions or adjusting clinical decisions to the patient risk profile.

Epidemiology of post-operative venous thromboembolism in Asian patients. Results of the SMART venography study.

BACKGROUND AND OBJECTIVES: The rate of post-operative asymptomatic deep-vein thrombosis in Asian patients remains uncertain. The aim of this study was to estimate the rate of venous thromboembolism, including asymptomatic deep-vein thrombosis, undergoing hip or knee surgery and not receiving pharmacological thromboprophylaxis. DESIGN AND METHODS: This was a prospective observational study of a cohort of consecutive Asian patients. The primary study outcome was the composite of venographically detected asymptomatic, or confirmed symptomatic venous thromboembolism, or sudden death at hospital discharge. Bilateral venography was to be performed in all patients between days 5 and 14 after surgery. Follow-up lasted 1 month. RESULTS: A total of 386 patients (median age: 65 years, female: 63.7%, body-mass index > or = 30 kg/m2: 15.4%) undergoing hip (n=160) or knee (n=226) replacement surgery satisfied the study selection criteria and 326 (84.5%) had evaluable venograms. The rate of the primary outcome was 36.5% (119 patients, 99% confidence interval: 29.7 to 43.7). The rate of symptomatic venous thromboembolism was 0.9% (3 patients, 99% confidence interval: 0.1 to 3.3). During follow-up (358 patients for a median duration of 33 days after surgery), two additional episodes of symptomatic venous thromboembolism occurred. Multivariate analysis identified that knee replacement surgery, duration of surgery and treatment with antibiotics within 1 week before surgery were independent risk factors (p<0.05) for venous thromboembolism or sudden death at hospital discharge. INTERPRETATION AND CONCLUSIONS: In Asian patients, the incidence of asymptomatic and symptomatic venous thromboembolism after major orthopedic surgery is high. These results suggest that thromboprophylaxis should be considered in these patients.

Predictors of cardiovascular events in patients with end-stage renal disease: an analysis from the Fosinopril in dialysis study.

BACKGROUND: Cardiovascular events (CVE) are a major cause of morbidity and mortality in end-stage renal disease (ESRD) patients. These patients are often excluded from CV clinical trials, and the prognostic factors associated with CVE in patients with ESRD have not been fully explored. A risk prediction model was created from the FOSIDIAL trial to identify factors predictive of CVE and to evaluate the relative strength of known predictors when considered together in a multivariate model. METHODS: FOSIDIAL was a prospective, randomized, double-blind study with 2-year follow-up and CVE adjudication. The study enrolled 397 patients with ESRD and left ventricular hypertrophy (LVH). CVE included cardiovascular death, non-fatal myocardial infarction, unstable angina, stroke, revascularization, heart failure hospitalization, resuscitated cardiac arrest and confirmed stroke. The model was built using a forward selection of all baseline variables. A structural equation model (SEM) was used to identify factors with an indirect association with CVE. RESULTS: CV history was the most important prognostic factor, followed by C-reactive protein (CRP), left ventricular mass index, diabetes and age. Smoking, low HDL, female gender and Kt/V were indirectly associated with CVE. CONCLUSION: Prior CV disease, elevated CRP, LVH, diabetes or advanced age identifies patients at the highest risk for CVE. These data may be useful to detect high risk patients, to define potential targets for pharmacologic intervention, and to plan future studies in ESRD. Further research is needed to identify effective approaches that reduce the rate of CVE in these patients.

Thromboprophylaxis with dalteparin in medical patients: which patients benefit?

It is unclear whether thromboprophylaxis produces a consistent risk reduction in different subgroups of medical patients at risk from venous thromboembolism. We performed a retrospective, post hoc analysis of 3706 patients enrolled in the PREVENT study. Patients were at least 40 years old with an acute medical condition requiring hospitalization for at least 4 days and had no more than 3 days of immobilization prior to enrolment. Patients received either subcutaneous dalteparin (5000 IU) or placebo once daily. The primary end point was the composite of symptomatic deep vein thrombosis (DVT), pulmonary embolism, asymptomatic proximal DVT, or sudden death. Primary diagnosis subgroups were acute congestive heart failure, acute respiratory failure, infectious disease, rheumatological disorders, or inflammatory bowel disease. All patients, except those with congestive heart or respiratory failure, had at least one additional risk factor for venous thromboembolism. A risk reduction was shown in patients receiving dalteparin versus placebo. The relative risk (RR) was 0.73 in patients with congestive heart failure, 0.72 for respiratory failure, 0.46 for infectious disease, and 0.97 for rheumatological disorders. The RR was 0.52 in patients aged > or = 75 years, 0.64 in obese patients, 0.34 for patients with varicose veins, and 0.71 in patients with chronic heart failure. No subgroup had a significantly different response from any other. Importantly, multivariate analysis showed that all patient groups benefited from thromboprophylaxis with dalteparin. Our findings, therefore, support the broad application of thromboprophylaxis in acutely ill hospitalized medical patients.