Laurent Bertoletti

Prognostic factors of acute heart failure in patients with pulmonary arterial hypertension

Acute right ventricular failure in the setting of pulmonary arterial hypertension (PAH) often requires hospitalisation in intensive care units (ICU) to manage the subsequent low cardiac output and its consequences. There are very few data on these acute events. We recorded demographic, clinical and biological data and therapy in consecutive patients suffering from acute right heart failure requiring catecholamine treatment in the ICU of the French referral centre for pulmonary hypertension. These variables were analysed according to the survival status in ICU. 46 patients were included, the mean age was 50.3 yrs. ICU mortality was 41%. We found no difference in terms of demographics, clinical data, last haemodynamic measurements at admission. Systemic arterial pressure was significantly lower in the subgroup of patients whose clinical course was fatal. Plasma brain natriuretic peptide (BNP), C-reactive protein (CRP), serum sodium and creatinine at admission correlated with survival. Demonstration of an infection during the ICU stay was associated with a worse prognosis. These preliminary results underline the importance of some simple clinical and biological parameters in the prognostic evaluation of acute heart failure in the setting of PAH. Whether these parameters can guide therapy needs to be further investigated.

Survival effects of inferior vena cava filter in patients with acute symptomatic venous thromboembolism and a significant bleeding risk.

OBJECTIVES The purpose of this study was to investigate the survival effects of inferior vena cava filters in patients with venous thromboembolism (VTE) who had a significant bleeding risk. BACKGROUND The effectiveness of inferior vena cava filter use among patients with acute symptomatic VTE and known significant bleeding risk remains unclear. METHODS In this prospective cohort study of patients with acute VTE identified from the RIETE (Computerized Registry of Patients With Venous Thromboembolism), we assessed the association between inferior vena cava filter insertion for known significant bleeding risk and the outcomes of all-cause mortality, pulmonary embolism (PE)-related mortality, and VTE rates through 30 days after the initiation of VTE treatment. Propensity score matching was used to adjust for the likelihood of receiving a filter. RESULTS Of the 40,142 eligible patients who had acute symptomatic VTE, 371 underwent filter placement because of known significant bleeding risk. A total of 344 patients treated with a filter were matched with 344 patients treated without a filter. Propensity score-matched pairs showed a nonsignificant trend toward lower risk of all-cause death for filter insertion compared with no insertion (6.6% vs. 10.2%; p = 0.12). The risk-adjusted PE-related mortality rate was lower for filter insertion than no insertion (1.7% vs. 4.9%; p = 0.03). Risk-adjusted recurrent VTE rates were higher for filter insertion than for no insertion (6.1% vs. 0.6%; p < 0.001). CONCLUSIONS In patients presenting with VTE and with a significant bleeding risk, inferior vena cava filter insertion compared with anticoagulant therapy was associated with a lower risk of PE-related death and a higher risk of recurrent VTE. However, study design limitations do not imply a causal relationship between filter insertion and outcome.

Initial dual oral combination therapy in pulmonary arterial hypertension

Treatment for pulmonary arterial hypertension (PAH) has been underpinned by single-agent therapy to which concomitant drugs are added sequentially when pre-defined treatment goals are not met. This retrospective analysis of real-world clinical data in 97 patients with newly diagnosed PAH (86% in New York Heart Association functional class III−IV) explored initial dual oral combination treatment with bosentan plus sildenafil (n=61), bosentan plus tadalafil (n=17), ambrisentan plus tadalafil (n=11) or ambrisentan plus sildenafil (n=8). All regimens were associated with significant improvements in functional class, exercise capacity, dyspnoea and haemodynamic indices after 4 months of therapy. Over a median follow-up period of 30 months, 75 (82%) patients were still alive, 53 (71%) of whom received only dual oral combination therapy. Overall survival rates were 97%, 94% and 83% at 1, 2 and 3 years, respectively, and 96%, 94% and 84%, respectively, for the patients with idiopathic PAH, heritable PAH and anorexigen-induced PAH. Expected survival rates calculated from the French equation for the latter were 86%, 75% and 66% at 1, 2 and 3 years, respectively. Initial combination of oral PAH-targeted medications may offer clinical benefits, especially in PAH patients with severe haemodynamic impairment. Initial dual combination therapy may offer potential benefits in PAH patients with severe haemodynamic impairment http://ow.ly/YNxgk

Echocardiography and pulmonary embolism severity index have independent prognostic roles in pulmonary embolism

We analysed a cohort of patients with normotensive pulmonary embolism (PE) in order to assess whether combining echocardiography and biomarkers with the pulmonary embolism severity index (PESI) improves the risk stratification in comparison to the PESI alone. The PESI was calculated in normotensive patients with PE who also underwent echocardiography and assays of cardiac troponin I and brain natriuretic peptide. 30-day adverse outcome was defined as death, recurrent PE or shock. 529 patients were included, 25 (4.7%, 95% CI 3.2–6.9%) had at least one outcome event. The proportion of patients with adverse events increased from 2.1% in PESI class I–II to 8.4% in PESI class III–IV, and to 14.3% in PESI class V (p<0.001). In PESI class I–II, the rate of outcome events was significantly higher in patients with abnormal values of biomarkers or right ventricular dilatation. In multivariate analysis, the PESI (class III–IV versus I–II, OR 3.1, 95% CI 1.2–8.3; class V versus I–II, OR 5.5, 95% CI 1.5–25.5 and echocardiography (right ventricular/left ventricular ratio, OR (for an increase of 0.1) 1.3, 95% CI 1.1–1.5) were independent predictors of an adverse outcome. In patients with normotensive PE, biomarkers and echocardiography provided additional prognostic information to the PESI. In patients with normotensive PE, biomarkers and echocardiography provided additional prognostic information to the PESI http://ow.ly/lJ8pW

Pulmonary hypertension in patients with neurofibromatosis type I.

Neurofibromatosis type I (NF1) is a rare genetic disease caused by mutations in the NF1 gene, which codes for tumor suppressor neurofibromin. NF1 is transmitted as an autosomal dominant and fully penetrant trait with no sex predominance. Precapillary pulmonary hypertension (PH) is a severe complication of NF1, initially described in patients with advanced parenchymal lung disease, which may complicate the course of NF1. We conducted this study to describe clinical, functional, radiologic, and hemodynamic characteristics and outcome of patients with NF1-associated PH.We identified 8 new cases of NF1-associated PH in patients carrying a NF1 gene mutation. No bone morphogenic protein receptor 2 (BMPR2) point mutation or large size rearrangements were identified. Seven female patients and 1 male patient were reported, suggesting a possible female predominance. PH occurred late in the course of the disease (median age, 62 yr; range, 53-68 yr). Dyspnea and signs of right heart failure were the major symptoms leading to the diagnosis of PH. At diagnosis, patients had severe hemodynamic impairment with low cardiac index (median, 2.3 L/min per m2; range, 1.9-4.7) and elevated indexed pulmonary vascular resistance (median, 15.1 mm Hg/L/min per m2; range, 4.5-25.9). All patients were in New York Heart Association functional class III with severe exercise limitation (median 6-min walk distance, 180 m; range, 60-375 m). Most patients had associated parenchymal lung disease, but some had no or mild lung involvement with disproportionate pulmonary vascular disease. Overall, the impact of PH therapy was limited and outcomes were poor.In conclusion, PH represents a rare but severe complication of NF1, characterized by female predominance, late onset in the course of NF1, and severe functional and hemodynamic impairment. Because of poor outcome and limited impact of specific PH therapy, eligible patients require early referral for lung transplantation. Further studies are needed to better understand the pathophysiology and the role, if any, of neurofibromin in NF1-associated PH.Abbreviations: 6MWD = 6-minute walk distance, ACVRL1 = activin A receptor type II-like kinase-1, BMPR2 = bone morphogenic protein receptor 2, CI = cardiac index, CT = computed tomography, DLCO = diffusion capacity of carbon monoxide, FEV1 = forced expiratory volume in one second, FVC = forced vital capacity, GAP = GTPase-activating protein, GTP =guanosine triphosphate, GTPase = guanosine triphosphotase, HIV = human immunodeficiency virus, HRCT = high-resolution computed tomography, mPAP = mean pulmonary arterial pressure, mTOR = mammalian target of rapamycin, NF1 = neurofibromatosis type I, NIH = National Institutes of Health, NYHA: New York Heart Association, PAH = pulmonary arterial hypertension, PCWP = pulmonary capillary wedge pressure, PFT = pulmonary function test, PH = pulmonary hypertension, PVRi = indexed pulmonary vascular resistance, RAP = right atrial pressure, SpO2 = pulse arterial oxygen saturation, TLC = total lung capacity, TPRi = indexed total pulmonary resistance, VEGF = vascular endothelial growth factor, VSMC = vascular smooth muscle cells.

Consistency of Safety and Efficacy of New Oral Anticoagulants across Subgroups of Patients with Atrial Fibrillation

Aims The well-known limitations of vitamin K antagonists (VKA) led to development of new oral anticoagulants (NOAC) in non-valvular atrial fibrillation (NVAF). The aim of this meta-analysis was to determine the consistency of treatment effects of NOAC irrespective of age, comorbidities, or prior VKA exposure. Methods and Results All randomized, controlled phase III trials comparing NOAC to VKA up to October 2012 were eligible provided their results (stroke/systemic embolism (SSE) and major bleeding (MB)) were reported according to age (≤ or >75 years), renal function, CHADS2 score, presence of diabetes mellitus or heart failure, prior VKA use or previous cerebrovascular events. Interactions were considered significant at p <0.05. Three studies (50,578 patients) were included, respectively evaluating apixaban, rivaroxaban, and dabigatran versus warfarin. A trend towards interaction with heart failure (p = 0.08) was observed with respect to SSE reduction, this being greater in patients not presenting heart failure (RR = 0.76 [0.67–0.86]) than in those with heart failure (RR = 0.90 [0.78–1.04]); Significant interaction (p = 0.01) with CHADS2 score was observed, NOAC achieving a greater reduction in bleeding risk in patients with a score of 0–1 (RR 0.67 CI 0.57–0.79) than in those with a score ≥2 (RR 0.85 CI 0.74–0.98). Comparison of MB in patients with (RR 0.97 CI 0.79–1.18) and without (RR 0.76 CI 0.65–0.88) diabetes mellitus showed a similar trend (p = 0.06). No other interactions were found. All subgroups derived benefit from NOA in terms of SSE or MB reduction. Conclusions NOAC appeared to be more effective and safer than VKA in reducing SSE or MB irrespective of patient comorbidities. Thromboembolism risk, evaluated by CHADS2 score and, to a lesser extent, diabetes mellitus modified the treatment effects of NOAC without complete loss of benefit with respect to MB reduction.

Annual diagnosis rate of superficial vein thrombosis of the lower limbs: the STEPH community‐based study

The incidence of superficial vein thrombosis (SVT) in the general adult population remains unknown.

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.

Consistency of safety profile of new oral anticoagulants in patients with renal failure.

The use of new oral anticoagulants (NOACs) in patients with impaired renal function has raised major concerns, in particular the possibility of an increased risk of bleeding due to accumulation. The aims of this work were to assess the safety of NOACs in patients with renal failure and describe the relationship between clinical events and drug renal excretion magnitude.

Long-term treatment of venous thromboembolism with tinzaparin compared to vitamin K antagonists: A meta-analysis of 5 randomized trials in non-cancer and cancer patients☆

PURPOSE Due to its specific pharmacokinetic profile, tinzaparin, a low-molecular-weight heparin (LMWH), appears not to be associated with anti-factor Xa accumulation. Our meta-analysis aimed at determining whether long-term curative doses of tinzaparin is a valuable alternative to vitamin K antagonists (VKA) for the treatment of symptomatic venous thromboembolism (VTE), especially in patients with cancer who are at higher risk of recurrence and bleeding. MATERIALS AND METHODS A systematic literature search identified randomized studies on long-term tinzaparin compared to VKA in patients with VTE. Outcome measures were VTE recurrence, major bleeding, deaths and net clinical benefit combining the three endpoints during the treatment period and at one year. Pooled relative risk was estimated using the logarithm of the relative risk (RR) method based on a fixed-effect model in the overall population and cancer population. RESULTS Five randomized controlled studies were eligible. No difference between groups in VTE recurrence was found in the overall population (RR=0.85 [0.55; 1.31]). In cancer patients, a non-significant 38% VTE risk reduction in favor of tinzaparin was observed on treatment (RR=0.62 [0.30; 1.31]). The difference was significant at the end of follow-up at one year (RR=0.40 [0.19; 0.82], p<0.01). The incidence of major bleeding in the tinzaparin group was not significantly different from the VKA group in the overall population and cancer patients. CONCLUSIONS Tinzaparin appears as a valuable option for long-term treatment of patients in whom VKA are contraindicated or difficult to monitor. Tinzaparin may have a more favorable benefit-risk ratio than VKA in patients with cancer and VTE.