Laura Bonnett

Efficacy of Catheter Ablation for Persistent Atrial Fibrillation A Systematic Review and Meta-Analysis of Evidence From Randomized and Nonrandomized Controlled Trials

Background—Catheter ablation (CA) is commonly performed for persistent atrial fibrillation, but few high-quality randomized controlled trials (RCTs) exist, leading to funding restrictions being proposed in several countries. We performed a random-effects meta-analysis of RCTs and non-RCTs to assess the efficacy of CA for persistent atrial fibrillation. Methods and Results—We systematically searched PubMed, EMBASE, CENTRAL, OpenGrey, and clinicaltrials.gov for RCTs and non-RCTs reporting clinical outcomes after CA for persistent atrial fibrillation. Forty-six eligible studies were identified containing 3819 patients. After a single procedure, CA significantly reduced the risk of recurrent atrial fibrillation compared with medical therapy (odds ratio [OR], 0.32; 95% confidence interval [CI], 0.20–0.53; P<0.001). Outcomes were better if the pulmonary veins were encircled (OR, 0.26; 95% CI, 0.09–0.74; P=0.01), and electrical isolation reduced AF recurrence compared with purely anatomic encirclement (OR, 0.33; 95% CI, 0.13–0.86; P=0.02). Linear ablation within the left atrium (OR, 0.22; 95% CI, 0.10–0.49; P<0.001), but not complex fractionated atrial electrogram ablation (OR, 0.64; 95% CI, 0.35–1.18; P=0.15), significantly reduced AF recurrence. Results were not improved by performing more extensive linear lesion sets (OR, 0.77; 95% CI, 0.41–1.43; P=0.40) or from biatrial ablation (OR, 0.62; 95% CI, 0.31–1.24; P=0.17). Where data were available, the relative benefits seen held true both after a single or multiple procedure(s). Sensitivity analyses showed that inclusion of non-RCTs increased statistical power without biasing the calculated effect sizes. Conclusions—For patients with persistent atrial fibrillation, CA achieves significantly greater freedom from recurrent atrial fibrillation compared with medical therapy. The most efficacious strategy is likely to combine isolation of the pulmonary veins with limited linear ablation within the left atrium.Background— Catheter ablation (CA) is commonly performed for persistent atrial fibrillation, but few high-quality randomized controlled trials (RCTs) exist, leading to funding restrictions being proposed in several countries. We performed a random-effects meta-analysis of RCTs and non-RCTs to assess the efficacy of CA for persistent atrial fibrillation. Methods and Results— We systematically searched PubMed, EMBASE, CENTRAL, OpenGrey, and [clinicaltrials.gov][1] for RCTs and non-RCTs reporting clinical outcomes after CA for persistent atrial fibrillation. Forty-six eligible studies were identified containing 3819 patients. After a single procedure, CA significantly reduced the risk of recurrent atrial fibrillation compared with medical therapy (odds ratio [OR], 0.32; 95% confidence interval [CI], 0.20–0.53; P <0.001). Outcomes were better if the pulmonary veins were encircled (OR, 0.26; 95% CI, 0.09–0.74; P =0.01), and electrical isolation reduced AF recurrence compared with purely anatomic encirclement (OR, 0.33; 95% CI, 0.13–0.86; P =0.02). Linear ablation within the left atrium (OR, 0.22; 95% CI, 0.10–0.49; P <0.001), but not complex fractionated atrial electrogram ablation (OR, 0.64; 95% CI, 0.35–1.18; P =0.15), significantly reduced AF recurrence. Results were not improved by performing more extensive linear lesion sets (OR, 0.77; 95% CI, 0.41–1.43; P =0.40) or from biatrial ablation (OR, 0.62; 95% CI, 0.31–1.24; P =0.17). Where data were available, the relative benefits seen held true both after a single or multiple procedure(s). Sensitivity analyses showed that inclusion of non-RCTs increased statistical power without biasing the calculated effect sizes. Conclusions— For patients with persistent atrial fibrillation, CA achieves significantly greater freedom from recurrent atrial fibrillation compared with medical therapy. The most efficacious strategy is likely to combine isolation of the pulmonary veins with limited linear ablation within the left atrium. [1]: http://clinicaltrials.gov

Child development following in utero exposure Levetiracetam vs sodium valproate

Objective: Children born to women with epilepsy (WWE), exposed in utero to levetiracetam (LEV, n = 51), were assessed for early cognitive development and compared to children exposed to sodium valproate in utero (VPA, n = 44) and a group of children representative of the general population (n = 97). Methods: Children were recruited prospectively from 2 cohorts in the United Kingdom and assessed using the Griffiths Mental Development Scale (1996), aged <24 months. Information regarding maternal demographics were collected and controlled for. This is an observational study with researchers not involved in the clinical management of the WWE. Results: On overall developmental ability, children exposed to LEV obtained higher developmental scores when compared to children exposed to VPA (p < 0.001). When compared, children exposed to LEV did not differ from control children (p = 0.62) on overall development. Eight percent of children exposed to LEV in utero fell within the below average range (DQ score of <84), compared with 40% of children exposed to VPA. After controlling for maternal epilepsy and demographic factors using linear regression analysis, exposure to LEV in utero was not associated with outcome (p = 0.67). Conversely, when compared with VPA exposure, LEV exposure was associated with higher scores for the overall developmental quotient (p < 0.001). Conclusion: Children exposed to LEV in utero are not at an increased risk of delayed early cognitive development under the age of 24 months. LEV may therefore be a preferable drug choice, where appropriate, for WWE prior to and of childbearing age.

Prognostic factors for time to treatment failure and time to 12 months of remission for patients with focal epilepsy: post-hoc, subgroup analyses of data from the SANAD trial

BACKGROUND Epilepsy is a heterogeneous disorder, with outcomes ranging from immediate remission after taking a first antiepileptic drug to frequent unremitting seizures with multiple treatment failures. Few prognostic models enable prediction of outcome; we therefore aimed to use data from the SANAD study to predict outcome overall and for patients receiving specific treatments. METHODS The SANAD study was a randomised controlled trial in which standard antiepileptic drugs were compared with new treatments. Arm A included patients for whom carbamazepine was considered the first-line treatment, most of whom were newly diagnosed with focal epilepsy. Patients were randomly assigned to receive carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate. Outcomes were time to treatment failure overall, because of inadequate seizure control, and because of adverse events, and time to 12 months of remission from seizures. In this post-hoc study we used regression multivariable modelling to investigate how clinical factors affect the probability of treatment failure and the probability of achieving 12 months of remission. FINDINGS For time to treatment failure, we identified several significant risk factors: sex (male vs female, hazard ratio [HR] 0·86, 95% CI 0·75-0·99), treatment history (taking non-SANAD antiepileptic drugs [other than those listed above] vs treatment naive, 1·27, 1·05-1·53), age (eg, older than 71 years vs 10 years or younger, 0·68, 0·51-0·91), total number of seizures (eg, four to 11 seizures vs two or fewer, 1·08, 1·05-1·11), electroencephalogram results (epileptiform abnormality vs normal, 1·26, 1·07-1·50), seizure type (eg, secondary generalised vs simple or complex partial only, 0·78, 0·66-0·91), site of onset (not localised vs temporal lobe, 1·25, 1·06-1·47), and treatment (lamotrigine vs carbamazepine, 0·76, 0·61-0·95). Significant factors for time to 12 months of remission were sex (male vs female, 1·19, 1·05-1·35), treatment history (taking a non-SANAD antiepileptic drug vs treatment naive, 0·64, 0·52-0·78), age (eg, older than 71 years vs 10 years or younger, 1·60, 1·26-2·03), time from first seizure (60-239 months vs ≥2 months, 1·14, 1·01-1·29; >240 months vs ≤2 months, 1·39, 1·04-1·86), neurological insult (present vs absent, 0·75, 0·61-0·93), total number of seizures before randomisation (eg, four to 11 vs two or fewer, 0·87, 0·85-0·90), and treatment (gabapentin vs carbamazepine, 0·71, 0·59-0·86; topiramate vs carbamazepine, 0·81, 0·68-0·98). INTERPRETATION We present a thorough investigation of prognostic factors from a large randomised controlled trial in patients starting antiepileptic monotherapy. If validated, our models could aid in individual patient risk stratification and the design and analysis of epilepsy trials. FUNDING National Institute for Health Research (UK).

Ablation index, a novel marker of ablation lesion quality: prediction of pulmonary vein reconnection at repeat electrophysiology study and regional differences in target values

Aims Force-Time Integral (FTI) is commonly used as a marker of ablation lesion quality during pulmonary vein isolation (PVI), but does not incorporate power. Ablation Index (AI) is a novel lesion quality marker that utilizes contact force, time, and power in a weighted formula. Furthermore, only a single FTI target value has been suggested despite regional variation in left atrial wall thickness. We aimed to study AIs and FTIs relationships with PV reconnection at repeat electrophysiology study, and regional threshold values that predicted no reconnection. Methods and results Forty paroxysmal atrial fibrillation patients underwent contact force-guided PVI, and the minimum and mean AI and FTI values for each segment were identified according to a 12-segment model. All patients underwent repeat electrophysiology study at 2 months, regardless of symptoms, to identify sites of PV reconnection. Late PV reconnection was seen in 53 (11%) segments in 25 (62%) patients. Reconnected segments had significantly lower minimum AI [308 (252-336) vs. 373 (323-423), P < 0.0001] and FTI [137 (92-182) vs. 228 (157-334), P < 0.0001] compared with non-reconnected segments. Minimum AI and FTI were both independently predictive, but AI had a smaller P value. Higher minimum AI and FTI values were required to avoid reconnection in anterior/roof segments than for posterior/inferior segments (P < 0.0001). No reconnection was seen where the minimum AI value was ≥370 for posterior/inferior segments and ≥480 for anterior/roof segments. Conclusion The minimum AI value in a PVI segment is independently predictive of reconnection of that segment at repeat electrophysiology study. Higher AI and FTI values are required for anterior/roof segments than for posterior/inferior segments to prevent reconnection.

Seizure recurrence after antiepileptic drug withdrawal and the implications for driving: further results from the MRC Antiepileptic Drug Withdrawal Study and a systematic review

Background In the UK, patients with epilepsy in remission, who withdraw antiepileptic drug (AED) treatment, are advised not to drive during withdrawal and for 6 months thereafter, assuming the risk of recurrence in the next 12 months is below 20%. Those with a seizure recurrence currently have to be seizure-free for 12 months before returning to drive, whether treatment is restarted or not. New EU regulations recommend returning to driving 3 months after restarting treatment. Methods Regression modelling of data from the Medical Research Council AED withdrawal study was undertaken to estimate the risk of seizure recurrence in the next 12 months at various time points following: completion of drug withdrawal; AED reinstatement for those with a recurrence. A systematic review of prospective studies was also undertaken. Results Immediately following treatment withdrawal, the recurrence risk in the next 12 months was 30% (95% CI 25% to 35%) and at 3 months after withdrawal was 15% (95% CI 10% to 19%). At 3 months following the recommencement of treatment following a seizure recurrence, the risk of a seizure in the next 12 months was 26% (95% CI 17% to 35%), at 6 months 18% (95% CI 10% to 27%) and at 12 months 17% (95% CI 3% to 27%). Systematic review results were similar. Conclusion Current UK legislation concerning time off driving after withdrawing AED treatment may be too conservative. For those restarting treatment after a recurrence, current UK guidance may be too conservative but the new EU guidance too liberal.

Risk of recurrence after a first seizure and implications for driving: further analysis of the Multicentre study of early Epilepsy and Single Seizures.

Objective To determine for how long after a first unprovoked seizure a driver must be seizure-free before the risk of recurrence in the next 12 months falls below 20%, enabling them to regain their driving licence. Design Randomised controlled trial: Multicentre study of early Epilepsy and Single Seizures (MESS). Setting UK hospital outpatient clinics from 1 January 1993 to 31 December 2000. Participants People entered MESS if they had had one or more unprovoked seizures and both the participant and the clinician were uncertain about the need to start antiepileptic drug treatment. The subset of people used for this analysis comprised participants aged at least 16 years with a single unprovoked seizure. Main outcome measure Risk of seizure recurrence in the 12 months after a seizure-free period of 6, 12, 18, or 24 months from the date of the first (index) seizure. Regression modelling was used to investigate how antiepileptic treatment and several clinical factors influence the risk of seizure recurrence. Results At six months after the index seizure the risk of recurrence in the next 12 months for those who start antiepileptic drugs was significantly below 20% (unadjusted risk 14%, 95% confidence interval 10% to 18%). For patients who did not start treatment the risk estimate was less than 20% but the upper limit of the confidence interval was greater than 20% (18%, 13% to 23%). Multivariable analyses identified subgroups with a significantly greater than 20% risk of seizure recurrence in the 12 months after a six month seizure-free period, such as those with a remote symptomatic seizure with abnormal electroencephalogram results. Conclusion After a single unprovoked seizure this reanalysis of MESS provides estimates of seizure recurrence risks that will inform policy and guidance about regaining an ordinary driving licence. Further guidance is needed as to how such data should be utilised; in particular, whether a population approach should be taken with a focus on the unadjusted results or whether attempts should be made to individualise risk. Guidance is also required as to whether the focus should be on risk estimates only or on the confidence interval as well. If the focus is on the estimate only our unadjusted estimates suggest that treated and untreated patients are eligible to drive after being seizure-free for six months. If the focus is also on confidence intervals, direction is needed as to whether a conservative or liberal approach should be taken. Trial registration Current Controlled Trials ISRCTN98767960.

Liver Fibrosis by Transient Elastography and Virologic Outcomes After Introduction of Tenofovir in Lamivudine-Experienced Adults With HIV and Hepatitis B Virus Coinfection in Ghana

BACKGROUND Antiretroviral treatment (ART) programs in sub-Saharan Africa have for many years included lamivudine as the sole hepatitis B virus (HBV) inhibitor. Long-term outcomes and the effects of introducing tenofovir as part of ART in these populations have not been characterized. METHODS The study comprised a cross-sectional analysis of 106 human immunodeficiency virus (HIV)/HBV-coinfected subjects maintained on lamivudine, as well as a prospective analysis of 76 lamivudine-experienced subjects who introduced tenofovir. Patients underwent assessment of liver fibrosis by transient elastography (TE) and testing to characterize HIV type 1 (HIV-1) and HBV replication. RESULTS After a median of 45 months of lamivudine treatment, HIV-1 RNA and HBV DNA were detectable in 35 of 106 (33.0%) and 54 of 106 (50.9%) subjects, respectively, with corresponding drug resistance rates of 17 of 106 (16.0%) and 31 of 106 (29.2%), respectively. Median TE values were 5.7 kPa (interquartile range, 4.7-7.2 kPa) and independently associated with HBV DNA load, aspartate aminotransferase levels, and platelet counts; 13 of 106 (12.3%) subjects had TE measurements >9.4 kPa. Twelve months after the first assessment, and a median of 7.8 months after introducing tenofovir, HBV DNA levels declined by a mean of 1.5 log10 IU/mL (P < .001). TE values changed by a mean of -0.2 kPa (P = .097), and declined significantly in subjects who had pretenofovir HBV DNA levels >2000 IU/mL (mean, -0.8 kPa; P = .048) or TE values >7.6 kPa (mean, -1.2 kPa; P = .021). HIV-1 RNA detection rates remained unchanged. CONCLUSIONS A proportion of HIV/HBV-coinfected patients on long-term lamivudine-containing ART had poor HIV and HBV suppression, drug resistance, and TE values indicative of advanced liver fibrosis. Tenofovir improved HBV control and reduced liver stiffness in subjects with high HBV DNA load and TE values.

Improving Safety in Catheter Ablation for Atrial Fibrillation: A Prospective Study of the Use of Ultrasound to Guide Vascular Access

The most frequent complications of AF ablation (AFA) are related to vascular access, but there is little evidence as to how these can be minimized.

Prevalence of hepatitis D virus infection in sub-Saharan Africa: a systematic review and meta-analysis

Summary Background Hepatitis D virus (also known as hepatitis delta virus) can establish a persistent infection in people with chronic hepatitis B, leading to accelerated progression of liver disease. In sub-Saharan Africa, where HBsAg prevalence is higher than 8%, hepatitis D virus might represent an important additive cause of chronic liver disease. We aimed to establish the prevalence of hepatitis D virus among HBsAg-positive populations in sub-Saharan Africa. Methods We systematically reviewed studies of hepatitis D virus prevalence among HBsAg-positive populations in sub-Saharan Africa. We searched PubMed, Embase, and Scopus for papers published between Jan 1, 1995, and Aug 30, 2016, in which patient selection criteria and geographical setting were described. Search strings included sub-Saharan Africa, the countries therein, and permutations of hepatitis D virus. Cohort data were also added from HIV-positive populations in Malawi and Ghana. Populations undergoing assessment in liver disease clinics and those sampled from other populations (defined as general populations) were analysed. We did a meta-analysis with a DerSimonian-Laird random-effects model to calculate a pooled estimate of hepatitis D virus seroprevalence. Findings Of 374 studies identified by our search, 30 were included in our study, only eight of which included detection of hepatitis D virus RNA among anti-hepatitis D virus seropositive participants. In west Africa, the pooled seroprevalence of hepatitis D virus was 7·33% (95% CI 3·55–12·20) in general populations and 9·57% (2·31–20·43) in liver-disease populations. In central Africa, seroprevalence was 25·64% (12·09–42·00) in general populations and 37·77% (12·13–67·54) in liver-disease populations. In east and southern Africa, seroprevalence was 0·05% (0·00–1·78) in general populations. The odds ratio for anti-hepatitis D virus detection among HBsAg-positive patients with liver fibrosis or hepatocellular carcinoma was 5·24 (95% CI 2·74–10·01; p<0·0001) relative to asymptomatic controls. Interpretation Findings suggest localised clusters of hepatitis D virus endemicity across sub-Saharan Africa. Epidemiological data are needed from southern and east Africa, and from patients with established liver disease. Further studies should aim to define the reliability of hepatitis D virus testing methods, identify risk factors for transmission, and characterise the natural history of the infection in the region. Funding Wellcome Trust, Royal Society.

Treatment outcome after failure of a first antiepileptic drug

Objectives: We assessed the likelihood of 12-month seizure remission and treatment failure after failure of a first antiepileptic drug, and identified factors influencing these outcomes. Methods: SANAD (Standard and New Antiepileptic Drug) was a randomized controlled trial comparing monotherapy with standard and new antiepileptic drugs. Patients were followed up to study completion, even if they were switched from their randomized treatment. After a first treatment failure, we assessed the probability of 12-month seizure remission and treatment failure. Prognostic modeling identified predictors of these outcomes. Results: Forty-four percent of patients in the SANAD trial had a first treatment failure. Seventy-five percent of these subsequently achieved 12-month remission by 6 years of follow-up. Significant prognostic factors included sex, age at treatment failure, time on randomized treatment at treatment failure, neurologic insult, total number of tonic-clonic seizures at treatment failure, reason for treatment failure, seizure type, and CT/MRI scan result. After a first treatment failure, young patients without tonic-clonic seizures, with a normal CT/MRI scan and failing their treatment because of unacceptable adverse events, had the highest likelihood of 12-month remission. Approximately 50% of patients who failed a first treatment also failed their second. Significant prognostic factors included total number of tonic-clonic seizures at first treatment failure, reason for first treatment failure, and CT/MRI scan result. Patients with tonic-clonic seizures and failing because of inadequate seizure control had the highest risk of a second treatment failure. Conclusions: A high proportion of patients will achieve 12-month remission after a first treatment failure. Clinical factors can stratify patients according to likely outcome.