Role of cardiopulmonary exercise test in the prediction of hemodynamic impairment in patients with pulmonary arterial hypertension.

Periodic repetition of right heart catheterization (RHC) in pulmonary arterial hypertension (PAH) can be challenging. We evaluated the correlation between RHC and cardiopulmonary exercise test (CPET) aiming at CPET use as a potential noninvasive tool for hemodynamic burden evaluation. One hundred and forty-four retrospective PAH patients who had performed CPET and RHC within 2 months were enrolled. The following analyses were performed: (a) CPET parameters in hemodynamic variables tertiles; (b) position of hemodynamic parameters in the peak end-tidal carbon dioxide pressure (PETCO2) versus ventilation/carbon dioxide output (VE/VCO2) slope scatterplot, which is a specific hallmark of exercise respiratory abnormalities in PAH; (c) association between CPET and a hemodynamic burden score developed including mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index, and right atrial pressure. VE/VCO2 slope and peak PETCO2 significantly varied in mPAP and PVR tertiles, while peak oxygen uptake (peak VO2) and O2 pulse varied in the tertiles of all hemodynamic parameters. PETCO2 versus VE/VCO2 slope showed a strong hyperbolic relationship (R 2 = 0.7627). Patients with peak PETCO2 > median (26 mmHg) and VE/VCO2 slope < median (44) presented lower mPAP and PVR (p < 0.005) than patients with peak PETCO2 < median and VE/VCO2 slope > median. Multivariate analysis individuated peak VO2 (p = 0.0158) and peak PETCO2 (p = 0.0089) as hemodynamic score independent predictors; the formula 11.584 - 0.0925 × peak VO2 - 0.0811 × peak PETCO2 best predicts the hemodynamic score value from CPET data. A significant correlation was found between estimated and calculated scores (p < 0.0001), with a precise match for patients with mild-to-moderate hemodynamic burden (76% of cases). The results of the present study suggest that CPET could allow to estimate the hemodynamic burden in PAH patients.

Beta-blockers in pulmonary arterial hypertension: Time for a second thought?

Pulmonary arterial hypertension (PAH) is a heart failure syndrome characterized by right ventricular (RV) to pulmonary circulation uncoupling, counteracted by the sympathetic nervous system activation leading to ß1-receptors and α-myosin heavy chain downregulation, downregulation of the sarcoplasmic reticulum Ca2+ATPase, and ß-myosin heavy chain upregulation. Increased ventilation (VE) associated with VE inefficiency further characterizes PAH, as shown by an elevated VE versus carbon dioxide relationship slope during exercise, reflecting a specific behavior with progressive increase of dead space (VD) VE. The sympathetic system interacts with chemoreceptor-mediated VE control with increased VD leading to VE/perfusion mismatch. Growing evidence in the experimental models shows beneficial effects of different adrenoreceptor blockers on both right heart and pulmonary artery morphology and function. These effects can significantly change among ß-blockers according to their different pharmacokinetic and pharmacodynamic profiles. Since the first observation in the clinical setting, showing improvement associated with ß-blocker withdraw in PAH patients, recent studies suggest that the effects of ß-blockers in PAH might be related to the ß1-adrenergic receptors selectivity and α1- and ß3-related ancillary properties. While in the advanced stages of PAH ß-blockers may result deleterious as counteract the compensatory adrenergic-mediated effects of low cardiac output, in the early stages the modulation of the adrenergic system could ultimately improve VE efficiency and promote beneficial effects on heart failure gene expression and RV remodeling, particularly ß1-selective blockers and those associated with α- or ß3-activities. At present, all the above are physiologically sound but clinically unproven suggestions, and need to be tested in future randomized controlled trials.

The Coronary Sinus Reducer; 5-year Dutch experience.

BACKGROUND: Refractory angina is a growing and major health-care problem affecting millions of patients with coronary artery disease worldwide. The Coronary Sinus Reducer (CSR) is a device that may be considered for the relief of symptoms of refractory angina. It causes increased venous pressure leading to a dilatation of arterioles and reduced arterial vascular resistance in the sub-endocardium. This study describes the 5­year Dutch experience regarding safety and efficacy of the CSR. METHODS: One hundred and thirty-two patients with refractory angina were treated with the CSR. The primary efficacy endpoint of the study was Canadian Cardiovascular Society (CCS) class improvement between baseline and 6­month follow-up. The primary safety endpoint was successful CSR implantation in the absence of any device-related events. RESULTS: Eighty-five patients (67%) showed improvement of at least 1 CCS class and 43 patients (34%) of at least 2 classes. Mean CCS class improved from 3.17 ± 0.61 to 2.12 ± 1.07 after implantation (P < 0.001). The CSR was successfully implanted in 99% of the patients and only minor complications during implantation were reported. CONCLUSION: The CSR is a simple, safe, and effective option for most patients with refractory angina. However, approximately thirty percent of the patients showed no benefit after implantation. Future studies should focus on the exact underlying mechanisms of action and reasons for non-response to better identify patients that could benefit most from this therapy.

Direct comparison of predictive performance of PRECISE-DAPT versus PARIS versus CREDO-Kyoto: a subanalysis of the ReCre8 trial.

BACKGROUND: Multiple scores have been proposed to guide risk stratification after percutaneous coronary intervention. This study assessed the performance of the PRECISE-DAPT, PARIS and CREDO-Kyoto risk scores to predict post-discharge ischaemic or bleeding events. METHODS: A total of 1491 patients treated with latest-generation drug-eluting stent implantation were evaluated. Risk scores for post-discharge ischaemic or bleeding events were calculated and directly compared. Prognostic performance of both risk scores was assessed with calibration, Harrell's c­statistics net reclassification index and decision curve analyses. RESULTS: Post-discharge ischaemic events occurred in 56 patients (3.8%) and post-discharge bleeding events in 34 patients (2.3%) within the first year after the invasive procedure. C­statistics for the PARIS ischaemic risk score was marginal (0.59, 95% confidence interval (CI) 0.51-0.68), whereas the CREDO-Kyoto ischaemic risk score was moderate (0.68, 95% CI 0.60-0.75). With regard to post-discharge bleeding events, CREDO-Kyoto displayed moderate discrimination (c-statistic 0.67, 95% CI 0.56-0.77), whereas PRECISE-DAPT (0.59, 95% CI 0.48-0.69) and PARIS (0.55, 95% CI 0.44-0.65) had a marginal discriminative capacity. Net reclassification index and decision curve analysis favoured CREDO-Kyoto-derived bleeding risk assessment. CONCLUSION: In this contemporary all-comer population, PARIS and PRECISE-DAPT risk scores were not resilient to independent testing for post-discharge bleeding events. CREDO-Kyoto-derived risk stratification was associated with a moderate predictive capability for post-discharge ischaemic or bleeding events. Future studies are warranted to improve risk stratification with more focus on robustness and rigorous testing.

Randomised comparison of a balloon-expandable and self-expandable valve with quantitative assessment of aortic regurgitation using magnetic resonance imaging.

INTRODUCTION: Transcatheter aortic valve implantation (TAVI) is a safe and effective treatment for inoperable, intermediate- or high-risk patients with severe symptomatic aortic stenosis and has been associated with excellent clinical outcomes. A clinically relevant remaining problem is aortic regurgitation (AR) post-TAVI, which is associated with increased mortality. Therefore, we conducted a prospective randomised trial to assess the safety and efficacy of a first-generation self-expandable valve (SEV; CoreValve) and a third-generation balloon-expandable valve (BEV; Sapien 3) with respect to clinical outcomes and AR as determined quantitatively by magnetic resonance imaging (MRI). METHODS: The ELECT study was an investigator-initiated, single-centre trial involving patients with severe symptomatic aortic stenosis and with a clinical indication for transfemoral TAVI. Fifty-six patients were randomly assigned to the BEV or SEV group. RESULTS: AR determined quantitatively by MRI was lower in the BEV than in the SEV group [regurgitant fraction: 1.1% (0-8.0) vs 8.7% (3.0-14.8) for SEV; p = 0.01]. Secondary endpoints according to the criteria of the Second Valve Academic Research Consortium (VARC-2) showed BEV to have better early safety [0 (0%) vs 8 (30%); p = 0.002] at 30 days and a lower risk of stroke [0 (0%) vs 5 (21%); p = 0.01], major adverse cardiac and cerebrovascular events [0 (0%) vs 10 (38%); p < 0.001] or death [0 (0%) vs 5 (19%); p = 0.02] in the 1st year compared with SEV. CONCLUSIONS: The use of the latest generation of BEV was associated with less AR as quantitatively assessed by MRI. Although the use of MRI to quantify AR is not feasible in daily clinical practice, it should be considered as a surrogate endpoint for clinical outcomes in comparative studies of valves for TAVI. ClinicalTrials.gov number NCT01982032.

Appropriate use criteria for optical coherence tomography guidance in percutaneous coronary interventions : Recommendations of the working group of interventional cardiology of the Netherlands Society of Cardiology.

INTRODUCTION: Optical coherence tomography (OCT) enables detailed imaging of the coronary wall, lumen and intracoronary implanted devices. Responding to the lack of specific appropriate use criteria (AUC) for this technique, we conducted a literature review and a procedure for appropriate use criteria. METHODS: Twenty-one of all 184 members of the Dutch Working Group on Interventional Cardiology agreed to evaluate 49 pre-specified cases. During a meeting, factual indications were established whereupon members individually rated indications on a 9-point scale, with the opportunity to substantiate their scoring. RESULTS: Twenty-six indications were rated 'Appropriate', eighteen indications 'May be appropriate', and five 'Rarely appropriate'. Use of OCT was unanimously considered 'Appropriate' in stent thrombosis, and 'Appropriate' for guidance in PCI, especially in distal left main coronary artery and proximal left anterior descending coronary artery, unexplained angiographic abnormalities, and use of bioresorbable vascular scaffold (BVS). OCT was considered 'Rarely Appropriate' on top of fractional flow reserve (FFR) for treatment indication, assessment of strut coverage, bypass anastomoses or assessment of proximal left main coronary artery. CONCLUSIONS: The use of OCT in stent thrombosis is unanimously considered 'Appropriate' by these experts. Varying degrees of consensus exists on the appropriate use of OCT in other settings.

Evaluation of mitral regurgitation by an integrated 2D echocardiographic approach in patients undergoing transcatheter aortic valve replacement.

The purpose of this study was to evaluate mitral regurgitation (MR) severity in patients undergoing transcatheter aortic valve replacement (TAVR) by standardized assessment of two-dimensional (2D) transthoracic echocardiography (TTE) and 1-year echocardiographic and clinical outcomes. Pre- and post-procedural TTE's of patients undergoing TAVR between 2008 and 2014 were analyzed. MR was graded according to current guidelines with a systematic and integrated approach. Longitudinal echocardiographic and clinical results were analyzed. Regression analysis was performed for change in MR grade at follow-up, using pre-determined variables and confounders. Pre- and post-procedural TTE were available in 213 subjects. Significant MR was seen in 22% at baseline and 15% at follow-up; MR grade ≥ 3 in < 10%. Severity did not change in 61%, and decreased in 20% of the patients. Overall, the prevalence of MR grades pre- and post TAVR was not significantly different, nor influenced by MR etiology or TAVR prosthesis type. However, higher MR grades and pacemaker absence at baseline, were independently correlated to more improvement of MR after TAVR. Regarding clinical outcomes, NYHA class improved in two-thirds of the patients, irrespective of the baseline MR grade. Overall survival was not significantly different amongst MR grades post-TAVR. MR grading using an systematic 2D echocardiographic approach in patients undergoing TAVR is feasible in clinical practice. Our data revealed a relatively frequent prevalence of significant MR (although grade ≥ 3 was scarce), overall no change in the MR grade at 1 year follow-up, improvement of functional NYHA class, and no significant differences in long-term survival amongst the post-TAVR MR grades.

Veno-arterial extracorporeal membrane oxygenation in addition to primary PCI in patients presenting with ST-elevation myocardial infarction.

INTRODUCTION: Primary percutaneous coronary intervention (pPCI) in ST-elevation myocardial infarction (STEMI) can cause great haemodynamic instability. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) can provide haemodynamic support in patients with STEMI but data on outcome and complications are scarce. METHODS: An in-hospital registry was conducted enrolling all patients receiving VA-ECMO. Patients were analysed for medical history, mortality, neurological outcome, complications and coronary artery disease. RESULTS: Between 2011 and 2016, 12 patients underwent pPCI for STEMI and received VA-ECMO for haemodynamic support. The majority of the patients were male (10/12) with a median age of 63 (47-75) years and 4 of the 12 patients had a history of coronary artery disease. A cardiac arrest was witnessed in 11 patients. The left coronary artery was compromised in 8 patients and 4 had right coronary artery disease. All patients were in Killip class IV. Survival to discharge was 67% (8/12), 1­year survival was 42% (5/12), 2 patients have not yet reached the 1­year survival point but are still alive and 1 patient died within a year after discharge. All-cause mortality was 42% (5/12) of which mortality on ECMO was 33% (4/12). Patient-related complications occurred in 6 of the 12 patients: 1 patient suffered major neurological impairment, 2 patients suffered haemorrhage at the cannula site, 2 patients had limb ischaemia and 1 patient had a haemorrhage elsewhere. There were no VA-ECMO hardware malfunctions. CONCLUSION: VA-ECMO in pPCI for STEMI has a high survival rate and neurological outcome is good, even when the patient is admitted with a cardiac arrest.

The last frontier: transcatheter devices for percutaneous or minimally invasive treatment of chronic heart failure.

Heart failure has a high prevalence in the general population. Morbidity and mortality of heart failure patients remain high, despite improvements in drug therapy, implantable cardioverter-defibrillators and cardiac resynchronisation therapy. New transcatheter implantable devices have been developed to improve the treatment of heart failure. There has been a rapid development of minimally invasive or transcatheter devices used in the treatment of heart failure associated with aortic and mitral valve disease and these devices are being incorporated into routine clinical practice at a fast rate. Several other new transcatheter structural heart interventions for chronic heart failure aimed at a variety of pathophysiologic approaches are currently being developed. In this review, we focus on devices used in the treatment of chronic heart failure by means of left ventricular remodelling, left atrial pressure reduction, tricuspid regurgitation reduction and neuromodulation. The clinical evaluations of these devices are early-stage evaluations of initial feasibility and safety studies and additional clinical evidence needs to be gathered in appropriately designed clinical trials.

Effect of body mass index on clinical outcome and all-cause mortality in patients undergoing transcatheter aortic valve implantation.

OBJECTIVES: To assess the effect of body mass index (BMI) on outcome among patients with severe aortic stenosis (AS) admitted for transcatheter aortic valve implantation (TAVI). BACKGROUND: Being overweight or obese is associated with improved outcome following certain medical treatments, suggesting the existence of a BMI paradox. However, the relationship between BMI and mortality after TAVI remains controversial. METHODS: Patients were classified according to World Health Organisation criteria such as normal weight, overweight, or obesity according to their BMI (18.5 to 24.9 kg/m2, 25.0 to 29.9 kg/m2, and ≥30.0 kg/m2, respectively). RESULTS: A total of 549 consecutive patients (age: 80.2 ± 7.5 years; logistic European system for cardiac operative risk evaluation [EuroSCORE]: 17.3 ± 9.9%) who underwent TAVI for AS were included. Of these patients, 43% (n = 237) had normal weight, 36% (n = 200) were overweight, and 20% (n = 112) were obese. There were no differences in peri-operative bleeding or vascular complication rates between the groups. All-cause mortality after 30 days, and 1 year, were higher in normal weight patients compared with overweight and obese patients (7% vs. 5 and 4%, p = 0.383, and 19% vs. 9 and 10%, p = 0.006, respectively). After adjustment for several confounding factors, overweight was associated with a decreased 30-day and 1­year all-cause mortality outcome (hazard ratio [HR] 0.69; 95% confidence interval [CI] 0.47-0.99, and HR 0.65; 95% CI 0.45-0.94, respectively). CONCLUSIONS: Despite the well-documented adverse effects of increased body weight on health, being overweight is associated with improved survival following TAVI when compared with normal weight.

Rationale and design of the Edwards SAPIEN-3 periprosthetic leakage evaluation versus Medtronic CoreValve in transfemoral aortic valve implantation (ELECT) trial : A randomised comparison of balloon-expandable versus self-expanding transcatheter aortic valve prostheses.

BACKGROUND AND OBJECTIVES: Periprosthetic aortic regurgitation (PPR) after transcatheter aortic valve implantation (TAVI) remains an important issue associated with impaired long-term outcomes. The current randomised study aims to evaluate potential differences between the balloon-expandable Edwards SAPIEN-3 and the self-expanding Medtronic CoreValve system with the main focus on post-TAVI PPR by means of novel imaging endpoints, and an additional focus on other clinical endpoints. ENDPOINTS: The primary endpoint of this study is quantitative assessment of the severity of post-procedural PPR using cardiac magnetic resonance imaging. Several other novel imaging modalities (X-ray contrast angiography, echocardiography) are used as secondary imaging modalities for the assessment of PPR following TAVI. Secondary objectives of the study include clinical outcomes such as cerebral and kidney injury related to TAVI, and quality of life. METHODS AND DESIGN: The ELECT study is a single-centre, prospective, two-armed randomised controlled trial. For the purpose of this study, 108 consecutive adult patients suitable for transfemoral TAVI will be randomly allocated to receive the SAPIEN-3 (n = 54) or the CoreValve system (n = 54). DISCUSSION: The ELECT trial is the first randomised controlled trial to quantitatively compare the extent of post-TAVI PPR between the SAPIEN-3 and CoreValve. Furthermore, it will evaluate potential differences between the two prostheses with regard to mid-term clinical outcome and quality of life.

Safety and efficacy of a device to narrow the coronary sinus for the treatment of refractory angina: A single-centre real-world experience.

OBJECTIVE: The coronary sinus Reducer is a recently introduced device to treat patients with severe angina symptoms refractory to optimal medical therapy and not amenable for conventional revascularisation. We aimed to assess the safety and efficacy of the Reducer in a real-world cohort of patients with refractory angina. METHODS: This is a single-centre retrospective registry. Patients with severe angina symptoms, objective evidence of myocardial ischaemia using any adequate non-invasive modality and without options for conventional revascularisation were regarded eligible for Reducer implantation. RESULTS: Twenty-three patients (74 % male, mean age 70 ±â€¯8 years, 91.3 % previous bypass surgery, 82.6 % previous percutaneous intervention, 47.8 % previous myocardial infarction, 52.2 % diabetes mellitus) underwent Reducer implantation. The safety endpoint (successful implantation of the first device without device-related adverse events) was met in all patients. After a median follow-up of 9 (8-14) months the efficacy (any reduction in Canadian Cardiovascular Society (CCS) class and revascularisation-free survival) was reached in 17 patients (74 %): 8 patients (34.8 %) improved by 1 CCS class, 7 (30.4 %) by 2 CCS classes and 2 (8.7 %) by 3 CCS classes. One patient died 4 months after implantation because of progressive heart failure (not associated with Reducer implantation). CONCLUSION: In this single-centre real-world experience, Reducer implantation was safe and demonstrated excellent clinical efficacy in the treatment of refractory angina at mid-term follow-up.

The ethnicity-specific association of biomarkers with the angiographic severity of coronary artery disease.

BACKGROUND: Risk factor burden and clinical characteristics of patients with coronary artery disease (CAD) differ among ethnic groups. We related biomarkers to CAD severity in Caucasians, Chinese, Indians and Malays. METHODS: In the Dutch-Singaporean UNICORN coronary angiography cohort (n = 2033) we compared levels of five cardiovascular biomarkers: N-terminal pro-brain natriuretic peptide (NTproBNP), high-sensitivity C-reactive protein (hsCRP), cystatin C (CysC), myeloperoxidase (MPO) and high-sensitivity troponin I (hsTnI). We assessed ethnicity-specific associations of biomarkers with CAD severity, quantified by the SYNTAX score. RESULTS: Adjusted for baseline differences, NTproBNP levels were significantly higher in Malays than in Chinese and Caucasians (72.1 vs. 34.4 and 41.1 pmol/l, p < 0.001 and p = 0.005, respectively). MPO levels were higher in Caucasians than in Indians (32.8 vs. 27.2 ng/ml, p = 0.026), hsTnI levels were higher in Malays than in Caucasians and Indians (33.3 vs. 16.4 and 17.8 ng/l, p < 0.001 and p = 0.029) and hsTnI levels were higher in Chinese than in Caucasians (23.3 vs. 16.4, p = 0.031). We found modifying effects of ethnicity on the association of biomarkers with SYNTAX score. NTproBNP associated more strongly with the SYNTAX score in Malays than Caucasians (ß 0.132 vs. ß 0.020 per 100 pmol/l increase in NTproBNP, p = 0.032). For MPO levels the association was stronger in Malays than Caucasians (ß 1.146 vs. ß 0.016 per 10 ng/ml increase, p = 0.017). Differing biomarker cut-off levels were found for the ethnic groups. CONCLUSION: When corrected for possible confounders we observe ethnicity-specific differences in biomarker levels. Moreover, biomarkers associated differently with CAD severity, suggesting that ethnicity-specific cut-off values should be considered.

[Circulatory breathing abnormality: Clinical observation on exercise induced oscillatory breathing pattern].

OBJECTIVE: Exercise induced oscillatory ventilation (EIOB) during cardiopulmonary exercise testing (CPET) is associated with severity and prognosis of disease, but clinical approach for the character of EIOB due to circulatory dysfunction are seldom reported. METHODS: This retrospective analysis of symptom-limited maximum CPET data with an increment of 10-20 W/min in 38 patients with CHF. We calculated the duration, frequency, amplitude and other parameters of EIOB. RESULTS: There were 31 presenting with EIOB (82%) in all patients with CHF. In EIOB group, VE amplitude were (12.4 ± 4.4)L/min (accounting for 81% ± 30% of mean) and duration were (77.0 ± 20.0)s. The number of patients whose EIOB presenting at rest, exercise, recovery stage and the whole eriod were 24, 31, 4 and 4, respectively. Except VE, there were VO2, VCO2, RER and PETO2 presenting EIOB in all 31 patients; VE/VCO2, VO2/VE and breath frequency in 29 patients; PETCO2 in 26 patients; VT and VO2/HR in 25 patients; and HR in 2 patients. CONCLUSION: EIOB may occur in any period of CPET, mostly in severe patient with CHF, and presenting in many variables. Due to it is resulted from the circulatory dysfunction, we should call it circulatory (cardiac) oscillatory breathing abnormality.

Network meta-analysis on the comparative effectiveness and safety of transcatheter aortic valve implantation with CoreValve or Sapien devices versus surgical replacement.

INTRODUCTION: Surgical replacement for aortic stenosis is fraught with complications in high-risk patients. Transcatheter techniques may offer a minimally invasive solution, but their comparative effectiveness and safety is uncertain. We performed a network meta-analysis on this topic. METHODS: Randomized trials on transcatheter aortic valve replacement vs surgery were searched. The primary outcome was all cause death. Risk estimates were obtained with Bayesian network meta-analytic methods. RESULTS: Four trials with 1,805 patients were included. After a median of 8 months, risk of death and myocardial infarction was not different when comparing surgery versus transcatheter procedures, irrespective of device or access. Conversely, surgery was associated with higher rates of major bleeding (odds ratio vs CoreValve=3.03 [95% credible interval: 2.23-4.17]; odds ratio vs transfemoral Sapien =1.82 [1.21-2.70]; odds ratio vs transapical Sapien =2.08 [1.20-3.70]), and acute kidney injury (odds ratio vs CoreValve =2.08 [1.33-3.32]; odds ratio vs transapical Sapien =2.78 [2.21-99.80]), but lower rates of pacemaker implantation (odds ratio vs CoreValve =0.41 [0.28-0.59]), and moderate or severe aortic regurgitation (odds ratio vs CoreValve =0.06 [0.02-0.27]; odds ratio vs Sapien=0.17 [0.02-0.76]). Strokes were less frequent with CoreValve than with transfemoral Sapien (odds ratio =0.32 [0.13-0.73]) or transapical Sapien (odds ratio =0.33 [0.10-0.93]), whereas pacemaker implantation was more common with CoreValve (odds ratio vs surgery =2.46 [1.69-3.61]; odds ratio vs transfemoral Sapien =2.22 [1.27-3.85]). CONCLUSIONS: Survival after transcatheter or surgical aortic valve replacement is similar, but there might be differences in the individual safety and effectiveness profile between the treatment strategies and the individual devices used in transcatheter aortic valve implantation.

Comparative effectiveness of novel oral anticoagulants for atrial fibrillation: evidence from pair-wise and warfarin-controlled network meta-analyses.

INTRODUCTION: Novel oral anticoagulants have been tested against warfarin for atrial fibrillation, yet no direct comparison is available. We thus aimed to perform pair-wise (direct) and warfarin-adjusted network (i.e. indirect) meta-analyses of novel oral anticoagulants for atrial fibrillation. METHODS: Databases were searched for randomized warfarin-controlled trials of novel anticoagulants for non-valvular atrial fibrillation. The primary end-point was long-term stroke/systemic embolism. Odds ratios (95% intervals) were computed with RevMan and WinBUGS. RESULTS: Seven trials (52701 patients) were included, focusing on apixaban, dabigatran, edoxaban and rivaroxaban. Pair-wise meta-analysis showed that after a weighted average of 23 months these novel anticoagulants lead to significant reductions in the risk of stroke/systemic embolism (odds ratio=0.81 [0.71-0.92], I2=23%) and all cause death (odds ratio=0.88 [0.82-0.95], I2=0%) in comparison to warfarin. Network meta-analysis showed that apixaban and dabigatran proved similarly superior to warfarin in preventing stroke/systemic embolism (odds ratio=0.78 [0.62-0.96] for apixaban vs warfarin; odds ratio=0.66 [0.52-0.84] for high-dose dabigatran vs warfarin; odds ratio for apixaban vs high-dose dabigatran=1.17 [0.85-1.63]), but apixaban was associated with fewer major bleedings (odds ratio=0.73 [0.57-0.93]) and drug discontinuations (odds ratio=0.64 [0.52-0.78]) than dabigatran. Rivaroxaban did not reduce stroke/systemic embolism (odds ratio=0.87 [0.71-1.07]) or major bleedings in comparison to warfarin (odds ratio=0.87 [0.71-1.07]) and was associated with more major bleedings in comparison to apixaban (odds ratio=1.52 [1.19-1.92]). Data for edoxaban were inconclusive. CONCLUSIONS: Novel oral anticoagulants appear as a very promising treatment option for atrial fibrillation.