Amr F. Barakat

Cardiovascular outcomes with sodium–glucose cotransporter-2 inhibitors in patients with type II diabetes mellitus: A meta-analysis of placebo-controlled randomized trials

BACKGROUND The impact of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on cardiovascular outcomes in patients with type II diabetes mellitus (DM) is not well established. METHODS We searched electronic databases from inception through July 2016 for randomized, placebo-controlled trials, involving SGLT-2 inhibitors. Fixed-effects summary odds ratios (OR) were constructed using Peto model. RESULTS Eighty-one trials with a total of 37,195 patients were included. The mean follow-up was 89weeks. Compared with placebo, SGLT-2 inhibitors were associated with a lower risk of all-cause mortality (OR 0.72; 95% CI 0.59-0.86; P<0.001), cardiovascular mortality (OR 0.67; 95% CI 0.53-0.84; P=0.001), and heart failure (OR 0.67; 95% CI 0.51-0.87; P=0.003), but a similar risk of myocardial infarction (OR 0.89; 95% CI 0.74-1.09; P=0.29) and stroke/transient ischemic attack (OR 1.09; 95% CI 0.87-1.37; P=0.47). The reduction in all-cause mortality was noticed with empagliflozin (OR 0.66; 95% CI 0.54-0.81; P<0.001), but not with other SGLT-2 inhibitors (ORdapagliflozin 1.37; 95% CI 0.71-2.62; P=0.35; ORcanagliflozin 0.82; 95% CI 0.41-1.68; P=0.59; ORluseogliflozin 4.6; 95% CI 0.07-284.25; P=0.47; and ORipragliflozin 4.73; 95% CI 0.08-283.14; P=0.46) (Pinteraction=0.19). Potential harm was observed with dapagliflozin on cardiovascular mortality (OR 2.15, 95% CI 0.92-5.04, P=0.08). CONCLUSIONS In patients with type II DM, SGLT-2 inhibitors appeared to reduce both all-cause and cardiovascular mortality, primarily due to reduction in the risk of heart failure. The benefit was only seen with empagliflozin. There was suggestion of potential harm with dapagliflozin, thus future trials are needed to ascertain the cardiovascular safety of other agents in this class.

Long-Term Efficacy and Safety of Everolimus-Eluting Bioresorbable Vascular Scaffolds Versus Everolimus-Eluting Metallic Stents: A Meta-Analysis of Randomized Trials.

Background— Data regarding the long-term efficacy and safety of everolimus-eluting bioresorbable vascular scaffolds (BVS) compared with everolimus-eluting stents are limited. This meta-analysis aimed to compare the long-term outcomes with both devices. Methods and Results— Randomized trials reporting clinical outcomes beyond 1 year and comparing BVS with everolimus-eluting stents were included. Summary estimates risk ratios (RRs) were constructed. The primary efficacy outcome was target lesion failure, defined as cardiac death, target vessel myocardial infarction, and ischemia-driven target lesion revascularization, and the primary safety outcome was definite or probable stent/scaffold thrombosis. Six trials with 5392 patients were included (mean follow-up, 25 months). BVS had a higher rate of target lesion failure (RR, 1.33; 95% confidence interval [CI], 1.11–1.58) driven by the higher rates of target vessel myocardial infarction (RR, 1.65; 95% CI, 1.26–2.17) and target lesion revascularization (RR, 1.39; 95% CI, 1.08–1.78). The risk of definite or probable stent/scaffold thrombosis (RR, 3.22; 95% CI, 1.89–5.49) and very late stent/scaffold thrombosis (>1 year; RR, 4.78; 95% CI, 1.66–13.8) was higher with BVS. The risk of cardiac and all-cause mortality was similar in both groups. Conclusions— Compared with everolimus-eluting stents, BVS is associated with increased risk of target lesion failure driven by the increased rates of target vessel myocardial infarction and ischemia-driven target lesion revascularization in these studies (mean follow-up, 25 months). The risk of definite or probable stent/scaffold thrombosis and very late stent/scaffold thrombosis seems to be higher with BVS. Further information from randomized trials is critical to evaluate clinical outcomes with BVS on complete resolution of the scaffold.

Radiofrequency Ablation of Persistent Atrial Fibrillation Diagnosis-to-Ablation Time, Markers of Pathways of Atrial Remodeling, and Outcomes

Background—Various ablation strategies of persistent atrial fibrillation (PersAF) have had disappointing outcomes, despite concerted clinical and research efforts, which could reflect progressive atrial fibrillation–related atrial remodeling. Methods and Results—Two-year outcomes were assessed in 1241 consecutive patients undergoing first-time ablation of PersAF (2005–2012). The time intervals between the first diagnosis of PersAF and the ablation procedures were determined. Patients had echocardiograms and measures of B-type natriuretic peptide and C-reactive protein before the procedures. The median diagnosis-to-ablation time was 3 years (25th–75th percentiles 1–6.5). With longer diagnosis-to-ablation time (based on quartiles), there was a significant increase in recurrence rates in addition to an increase in B-type natriuretic peptide levels (P=0.01), C-reactive protein levels (P<0.0001), and left atrial size (P=0.03). The arrhythmia recurrence rates over 2 years were 33.6%, 52.6%, 57.1%, and 54.6% in the first, second, third, and fourth quartiles, respectively (Pcategorical<0.0001). In Cox Proportional Hazard analyses, B-type natriuretic peptide levels, C-reactive protein levels, and left atrial size were associated with arrhythmia recurrence. The diagnosis-to-ablation time had the strongest association with the ablation outcomes which persisted in multivariable Cox analyzes (hazard ratio for recurrence per +1Log diagnosis-to-ablation time 1.27, 95% confidence interval 1.14–1.43; P<0.0001; hazard ratio fourth versus first quartile 2.44, 95% confidence interval 1.68–3.65; Pcategorical<0.0001). Conclusions—In patients with PersAF undergoing ablation, the time interval between the first diagnosis of PersAF and the catheter ablation procedure had a strong association with the ablation outcomes, such as shorter diagnosis-to-ablation times were associated with better outcomes and in direct association with markers of atrial remodeling.

Migraine and the risk of cardiovascular and cerebrovascular events: a meta-analysis of 16 cohort studies including 1 152 407 subjects

Objectives To perform an updated meta-analysis to evaluate the long-term cardiovascular and cerebrovascular outcomes among migraineurs. Setting A meta-analysis of cohort studies performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data sources The MEDLINE, Web of Science and Cochrane Central Register of Controlled Trials databases were searched for relevant articles. Participants A total of 16 cohort studies (18 study records) with 394 942 migraineurs and 757 465 non-migraineurs were analysed. Primary and secondary outcome measures Major adverse cardiovascular and cerebrovascular events (MACCE), stroke (ie, ischaemic, haemorrhagic or non-specified), myocardial infarction (MI) and all-cause mortality. The outcomes were reported at the longest available follow-up. Data analysis Summary-adjusted hazard ratios (HR) were calculated by random-effects Der-Simonian and Liard model. The risk of bias was assessed by the Newcastle-Ottawa Scale. Results Migraine was associated with a higher risk of MACCE (adjusted HR 1.42, 95% confidence interval [CI] 1.26 to 1.60, P<0.001, I2=40%) driven by a higher risk of stroke (adjusted HR 1.41, 95% CI 1.25 to 1.61, P<0.001, I2=72%) and MI (adjusted HR 1.23, 95% CI 1.03 to 1.43, P=0.006, I2=59%). There was no difference in the risk of all-cause mortality (adjusted HR 0.93, 95% CI 0.78 to 1.10, P=0.38, I2=91%), with a considerable degree of statistical heterogeneity between the studies. The presence of aura was an effect modifier for stroke (adjusted HR aura 1.56, 95% CI 1.30 to 1.87 vs adjusted HR no aura 1.11, 95% CI 0.94 to 1.31, P interaction=0.01) and all-cause mortality (adjusted HR aura 1.20, 95% CI 1.12 to 1.30 vs adjusted HR no aura 0.96, 95% CI 0.86 to 1.07, Pinteraction<0.001). Conclusion Migraine headache was associated with an increased long-term risk of cardiovascular and cerebrovascular events. This effect was due to an increased risk of stroke (both ischaemic and haemorrhagic) and MI. There was a moderate to severe degree of heterogeneity for the outcomes, which was partly explained by the presence of aura. PROSPERO registration number CRD42016052460.

Persistent Atrial Fibrillation Ablation With or Without Contact Force Sensing

Arrhythmia recurrences remain common after ablation of persistent atrial fibrillation (PersAF). Contact force (CF)‐sensing catheters have been introduced for objective assessment of contact during radiofrequency application and have been suggested to improve outcomes in ablation of paroxysmal AF, but little is known about their role in PersAF ablation. We aimed to compare the procedural profiles and outcomes of (PersAF) ablation with or without using CF‐sensing catheters.

Primary prevention implantable cardioverter defibrillator in patients with non-ischaemic cardiomyopathy: a meta-analysis of randomised controlled trials

Objectives The objective of this meta-analysis of randomised controlled trials (RCTs) is to evaluate the role of primary prevention implantable cardioverter defibrillator (ICD) in patients with non-ischaemic cardiomyopathy (NICM). Setting A meta-analysis of RCTs performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Data sources The PubMed, MEDLINE, Embase and Cochrane Central Register of Controlled Trials databases were searched for relevant articles. Participants A total of 5 RCTs with 2573 patients with NICM were included. Intervention Primary prevention ICD, compared with medical therapy alone. Primary and secondary outcome measures All-cause mortality (primary outcome) and sudden cardiac death (SCD, secondary outcome). Data analysis Summary estimate HR were constructed using the random-effect DerSimonian and Laird’s model. Multiple study-level subgroup analyses were performed, and interaction was tested using random-effect analysis. Results Compared with medical therapy alone, ICD placement was associated with lower risk of all-cause mortality (HR 0.79; 95% CI 0.64 to 0.93; p<0.001; I2=0%) at a mean follow-up of 4.2 years. The risk of SCD was also lower with ICD placement (RR 0.47; 95% CI 0.30 to 0.73; p=0.001; I2=0%) compared with control. On subgroup analyses, there was a suggestion of possible effect modification by age, in which benefit was observed in age group <60 years (HR 0.64; 95% CI 0.47 to 0.89), but not with age ≥60 years (HR 0.82; 95% CI 0.65 to 1.03) (Pinteraction=0.058), but not with other study-level variables. Conclusions Compared with medical therapy alone, primary prevention ICD therapy in patients with NICM is associated with a significant reduction in all-cause mortality, especially in younger patients. Future dedicated studies are needed to investigate the role of primary prevention ICD in the elderly population. PROSPEROregistrationnumber PROSPERO CRD42016052010.

Meta-Analysis of Safety and Efficacy of Uninterrupted Non–Vitamin K Antagonist Oral Anticoagulants Versus Vitamin K Antagonists for Catheter Ablation of Atrial Fibrillation

This meta-analysis sought to assess the safety and efficacy of uninterrupted non-vitamin K antagonist oral anticoagulants (NOACs) versus uninterrupted vitamin K antagonists in atrial fibrillation (AF) patients undergoing catheter ablation. Electronic databases were searched for randomized trials (RCTs) and observational studies that compared uninterrupted NOACs versus uninterrupted vitamin K antagonists in the catheter ablation of AF. Safety outcomes included major bleeding, total bleeding, minor bleeding, and cardiac tamponade. Efficacy outcomes were symptomatic thromboembolism and symptomatic stroke/transient ischemic attack. Summary estimate risk ratios (RRs) were constructed primarily with a DerSimonian-Laird model. Thirteen studies (3 RCTs and 10 observational studies) with 4,878 patients were included. The risk of major bleeding (RR 0.83, 95% confidence interval [CI] 0.46 to 1.50, p = 0.53), total bleeding (RR 0.90, 95% CI 0.71 to 1.15, p = 0.41), minor bleeding (RR 0.98, 95% CI 0.80 to 1.21, p = 0.85), cardiac tamponade (RR 0.85, 95% CI 0.43 to 1.69, p = 0.65), symptomatic thromboembolism (RR 0.92, 95% CI 0.26 to 3.31, p = 0.90), and symptomatic stroke/transient ischemic attack (RR 1.03, 95% CI 0.29 to 3.65, p = 0.97) was similar in both groups. The quality of evidence for both major bleeding and symptomatic thromboembolism was moderate for RCTs and very low for observational studies. In conclusion, the use of uninterrupted NOACs in AF catheter ablation appears to be safe and efficacious. The evidence is not of high quality; thus, further high-quality RCTs are needed to confirm these findings.

Initial Experience With High-Risk Patients Excluded From Clinical Trials: Safety of Short-Term Anticoagulation After Left Atrial Appendage Closure Device.

Background—The implantation of left atrial appendage closure device (WATCHMAN, Boston Scientific, Natick, MA) is an alternative option to oral anticoagulation (OAC) for stroke prevention in atrial fibrillation. Patients require short-term OAC after implantation to avoid device thrombosis. The 2 clinical trials that assessed this device excluded patients thought not to be candidates for OAC. As such, little is known about the safety of this strategy in patients with previous major bleeding events. Methods and Results—All 20 consecutive patients with history of spontaneous major bleeding while on OAC who had subsequently undergone WATCHMAN device implantation at our institution were included. A newly conceived multidisciplinary Atrial Fibrillation Stroke Prevention Center evaluated patients for candidacy for device implantation and subsequent antithrombotic therapy. The primary outcome was spontaneous major bleeding while receiving short-term postprocedural OAC. Median CHA2DS2-VASc and HAS-BLED scores were 5 (quartiles 5–6) and 5 (quartiles 4–5), respectively. Previous major bleeding events were major gastrointestinal bleeding, intracranial bleeding, spontaneous hemopericardium with cardiac tamponade, and hemarthrosis in 11, 7, 1, and 1 patients, respectively. None of the patients had spontaneous major bleeding during the course of OAC after device implantation. In 1 patient, OAC was discontinued after 40 days because of mechanical fall with head trauma resulting in subdural hematoma with no associated neurological deficits; this was managed conservatively. Conclusions—With careful multidisciplinary evaluation, a short course of OAC after WATCHMAN device implantation in patients with previous spontaneous major bleeding events is associated with low risk of recurrent spontaneous major bleeding.

Safety and efficacy of second-generation drug-eluting stents compared with bare-metal stents: An updated meta-analysis and regression of 9 randomized clinical trials

The efficacy of second‐generation drug‐eluting stents (DES; eg, everolimus and zotarolimus) compared with bare‐metal stents (BMS) in patients undergoing percutaneous coronary intervention was challenged recently by new evidence from large clinical trials. Thus, we aimed to conduct an updated systematic review and meta‐analysis of randomized clinical trials (RCTs) evaluating the efficacy and safety of second‐generation DES compared with BMS. Electronic databases were systematically searched for all RCTs comparing second‐generation DES with BMS and reporting clinical outcomes. The primary efficacy outcome was major adverse cardiac events (MACE); the primary safety outcome was definite stent thrombosis. The DerSimonian and Laird method was used for estimation of summary risk ratios (RR). A total of 9 trials involving 17 682 patients were included in the final analysis. Compared with BMS, second‐generation DES were associated with decreased incidence of MACE (RR: 0.78, 95% confidence interval [CI]: 0.69‐0.88), driven by the decreased incidence of myocardial infarction (MI) (RR: 0.67, 95% CI: 0.48‐0.95), target‐lesion revascularization (RR: 0.47, 95% CI: 0.42‐0.53), definite stent thrombosis (RR: 0.57, 95% CI: 0.41‐0.78), and definite/probable stent thrombosis (RR: 0.54, 95% CI: 0.38‐0.80). The incidence of all‐cause mortality was similar between groups (RR: 0.94, 95% CI: 0.79‐1.10). Meta‐regression showed lower incidences of MI with DES implantation in elderly and diabetic patients (P = 0.026 and P < 0.0001, respectively). Compared with BMS, second‐generation DES appear to be associated with a lower incidence of MACE, mainly driven by lower rates of target‐lesion revascularization, MI, and stent thrombosis. However, all‐cause mortality appears similar between groups.

Outcomes and Management of Patients With Severe Pulmonary Vein Stenosis From Prior Atrial Fibrillation Ablation

Background: Pulmonary vein (PV) stenosis remains a feared complication of atrial fibrillation ablation. Little is known about outcomes in patients with severe PV stenosis, especially about repeat ablations. Methods: In 10 368 patients undergoing atrial fibrillation ablation (2000–2015), computed tomography scans were obtained 3 to 6 months after ablation. The clinical outcomes in severe PV stenosis were determined. Results: Severe PV stenosis was diagnosed in 52 patients (0.5%). This involved mostly the left superior PV (51% of severely stenosed veins). Percutaneous interventions were performed in 43 patients, and complications occurred in 5: 3 PV ruptures, 1 stroke, and 1 phrenic injury. Over a median follow-up of 25 months, 41 (79%) patients remained arrhythmia free. Repeat ablation was performed in 15 patients (7 from the main series and 8 from prior ablation at other institutions); of whom 10 had PV stents in place. Conduction recovery was noted in all but 2 of the stenosed or stented PVs, and areas with recovery were targeted with antral ablation. Lasso entrapment within stents occurred in 2 patients but eventually freed without complications. After redo ablation, preplanned stenting was performed in 3 patients and computed tomographic scans showed progression of concomitant stenoses in 1 patient (moderate to severe). No procedure-related deaths occurred. Conclusions: The incidence of severe PV stenosis is low but remains associated with significant morbidity. In patients with recurrent arrhythmia, conduction recovery at the stenosed or stented veins is common. Care must be taken to ablate antrally to avoid stenosis progression. In patients with prior PV stents, we suggest to avoid using Lasso.