Summary Background We report clinical safety and biochemical efficacy from a dose-ranging study of intravenously administered AVI-4658 phosphorodiamidate morpholino oligomer (PMO) in patients with ...Duchenne muscular dystrophy. Method We undertook an open-label, phase 2, dose-escalation study (0·5, 1·0, 2·0, 4·0, 10·0, and 20·0 mg/kg bodyweight) in ambulant patients with Duchenne muscular dystrophy aged 5–15 years with amenable deletions in DMD. Participants had a muscle biopsy before starting treatment and after 12 weekly intravenous infusions of AVI-4658. The primary study objective was to assess safety and tolerability of AVI-4658. The secondary objectives were pharmacokinetic properties and the ability of AVI-4658 to induce exon 51 skipping and dystrophin restoration by RT-PCR, immunohistochemistry, and immunoblotting. The study is registered, number NCT00844597. Findings 19 patients took part in the study. AVI-4658 was well tolerated with no drug-related serious adverse events. AVI-4658 induced exon 51 skipping in all cohorts and new dystrophin protein expression in a significant dose-dependent (p=0·0203), but variable, manner in boys from cohort 3 (dose 2 mg/kg) onwards. Seven patients responded to treatment, in whom mean dystrophin fluorescence intensity increased from 8·9% (95% CI 7·1–10·6) to 16·4% (10·8–22·0) of normal control after treatment (p=0·0287). The three patients with the greatest responses to treatment had 21%, 15%, and 55% dystrophin-positive fibres after treatment and these findings were confirmed with western blot, which showed an increase after treatment of protein levels from 2% to 18%, from 0·9% to 17%, and from 0% to 7·7% of normal muscle, respectively. The dystrophin-associated proteins α-sarcoglycan and neuronal nitric oxide synthase were also restored at the sarcolemma. Analysis of the inflammatory infiltrate indicated a reduction of cytotoxic T cells in the post-treatment muscle biopsies in the two high-dose cohorts. Interpretation The safety and biochemical efficacy that we present show the potential of AVI-4658 to become a disease-modifying drug for Duchenne muscular dystrophy. Funding UK Medical Research Council; AVI BioPharma.
A number of clinical studies have reported that diabetes mellitus (DM) is an independent risk factor for Atrial fibrillation (AF). After adjustment for other known risk factors including age, sex, ...and cardiovascular risk factors, DM remains a significant if modest risk factor for development of AF. The mechanisms underlying the increased susceptibility to AF in DM are incompletely understood, but are thought to involve electrical, structural, and autonomic remodeling in the atria. Electrical remodeling in DM may involve alterations in gap junction function that affect atrial conduction velocity due to changes in expression or localization of connexins. Electrical remodeling can also occur due to changes in atrial action potential morphology in association with changes in ionic currents, such as sodium or potassium currents, that can affect conduction velocity or susceptibility to triggered activity. Structural remodeling in DM results in atrial fibrosis, which can alter conduction patterns and susceptibility to re-entry in the atria. In addition, increases in atrial adipose tissue, especially in Type II DM, can lead to disruptions in atrial conduction velocity or conduction patterns that may affect arrhythmogenesis. Whether the insulin resistance in type II DM activates unique intracellular signaling pathways independent of obesity requires further investigation. In addition, the relationship between incident AF and glycemic control requires further study.
Abstract Registry-based randomized controlled trials are defined as pragmatic trials that use registries as a platform for case records, data collection, randomization, and follow-up. Recently, the ...application of registry-based randomized controlled trials has attracted increasing attention in health research to address comparative effectiveness research questions in real-world settings, mainly due to their low cost, enhanced generalizability of findings, rapid consecutive enrollment, and the potential completeness of follow-up for the reference population, when compared with conventional randomized effectiveness trials. However several challenges of registry-based randomized controlled trials have to be taken into consideration, including registry data quality, ethical issues, and methodological challenges. In this article, we summarize the advantages, challenges, and areas for future research related to registry-based randomized controlled trials.
Guidelines currently recommend ticagrelor over clopidogrel for patients with acute coronary syndrome (ACS) based on randomized clinical trial data in which ticagrelor reduced major adverse coronary ...events (MACE) vs clopidogrel but increased bleeding and dyspnea.
To compare the risk of MACE with ticagrelor vs clopidogrel in patients with ACS treated with percutaneous coronary intervention (PCI), to compare major bleeding and dyspnea, and to evaluate the association between P2Y12 inhibitor adherence and MACE.
Population-based cohort study using data of patients discharged alive after PCI for ACS from the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease registry from April 1, 2012, to March 31, 2016, with follow-up to 1 year. Analysis began April 2018.
Outpatient prescription for ticagrelor or clopidogrel within 31 days after PCI. Adherence was defined as a medication refill adherence value of 80% or higher.
Major adverse coronary events, a composite of all-cause death, hospitalization for ACS, unplanned coronary revascularization, or stent thrombosis within 365 days after index PCI. Secondary outcomes included hospitalization for major bleeding and emergency department visit for dyspnea.
Of 11 185 individuals who underwent PCI, the median (interquartile range) age was 61 (54-71) years, and 2760 (24.7%) were women. Ticagrelor users (4076 36.4%) were generally younger and had fewer cardiac and noncardiac comorbidities than clopidogrel users. Ticagrelor was not associated with lower risk of MACE (adjusted hazard ratio aHR, 0.97; 95% CI, 0.85-1.10); however, it was associated with an increased risk of major bleeding (aHR, 1.51; 95% CI, 1.29-1.78) and dyspnea (aHR, 1.98; 95% CI, 1.47-2.65). A total of 3328 ticagrelor users (81.6%) were adherent during the study vs 5256 of clopidogrel users (73.9%) (P < .001; χ2 = 86.4). In the full cohort, adherence was associated with a lower MACE risk (aHR, 0.79; 95% CI, 0.69-0.90 for adherence of ≥80% vs <80%). Differences in other secondary outcomes were not statistically significant. Sensitivity and subgroup analyses were consistent with primary analyses.
In this population-based cohort study of patients with ACS who underwent PCI, outpatient use of ticagrelor was not associated with a statistically significant reduction in MACE vs clopidogrel; however, it was associated with more major bleeding and dyspnea.
The importance of standard modifiable cardiovascular risk factors (SMuRFs) in preventing non-ST-segment elevation myocardial infarction (NSTEMI) is established. However, NSTEMI may present in the ...absence of SMuRFs, and little is known about their outcomes.
We analysed 176 083 adult (≥18 years) hospitalizations with NSTEMI using data from the United Kingdom (UK) Myocardial Infarction National Audit Project (MINAP). Clinical characteristics and all-cause in-hospital mortality were analysed according to SMuRF status, with 135 223 patients presenting with at least one of diabetes, hypertension, hypercholesterolaemia, or current smoking status and 40 860 patients without any SMuRFs. Those with a history of coronary artery disease were excluded. Patients without SMuRFs were more frequently older (median age 72 year vs. 71 years, P < 0.001), male (62% vs. 61%, P < 0.001), and Caucasian (95% vs. 92%, P < 0.001). Those without SMuRFs less frequently received statins (71% vs. 81%, P < 0.001), had their left ventricular (LV) function recorded (62% vs. 65%, P < 0.001) or for those with moderate or severe LV systolic dysfunction were prescribed angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (80% vs. 85%, P < 0.001). Following propensity score matching the odds of all-cause mortality odds ratio (OR): 0.85, 95% confidence interval (CI): 0.77-0.93, cardiac mortality (OR: 0.85, 95% CI: 0.76-0.94), and major adverse cardiovascular events (MACE) (OR: 0.85, 95% CI: 0.77-0.93) were lower in patients without SMuRFs.
More than one in five patients presenting with NSTEMI had no SMuRFs, who were less frequently received guideline-recommended management and had lower in-hospital (all-cause and cardiac) mortality and MACE than patients with SMuRFs.
This study aimed to determine 5-year efficacy of catheter ablation for persistent atrial fibrillation (AF) using AF termination as a procedural end point.
One hundred fifty patients (57±10 years) ...underwent persistent AF ablation using a stepwise ablation approach (pulmonary vein isolation, electrogram-guided, and linear ablation) with the desired procedural end point being AF termination. Repeat ablation was performed for recurrent AF or atrial tachycardia. AF was terminated by ablation in 120 patients (80%). Arrhythmia-free survival rates after a single procedure were 35.3%±3.9%, 28.0%±3.7%, and 16.8%±3.2% at 1, 2, and 5 years, respectively. Arrhythmia-free survival rates after the last procedure (mean 2.1±1.0 procedures) were 89.7%±2.5%, 79.8%±3.4%, and 62.9%±4.5%, at 1, 2, and 5 years, respectively. During a median follow-up of 58 (interquartile range, 43-73) months after the last ablation procedure, 97 of 150 (64.7%) patients remained in sinus rhythm without antiarrhythmic drugs. Another 14 (9.3%) patients maintained sinus rhythm after reinitiation of antiarrhythmic drugs, and an additional 15 (10.0%) patients regressed to paroxysmal recurrences only. Failure to terminate AF during the index procedure (hazard ratio 3.831; 95% confidence interval, 2.070-7.143; P<0.001), left atrial diameter≥50 mm (hazard ratio 2.083; 95% confidence interval, 1.078-4.016; P=0.03), continuous AF duration≥18 months (hazard ratio 1.984; 95% confidence interval, 1.024-3.846; P<0.04), and structural heart disease (hazard ratio 1.874; 95% confidence interval, 1.037-3.388; P=0.04) predicted arrhythmia recurrence.
In patients with persistent AF, an ablation strategy aiming at AF termination is associated with freedom from arrhythmia recurrence in the majority of patients over a 5-year follow-up period. Procedural AF nontermination and specific baseline factors predict long-term outcome after ablation.
To determine the accuracy of CHADS2 and CHA2DS2-VASc tools for predicting ischaemic stroke or transient ischaemic attack (TIA) and death in patients without a history of atrial fibrillation or ...flutter (AF).
The study included 20 970 patients without known AF enrolled in the Alberta Provincial Project for Outcomes Assessment in Coronary Heart disease (APPROACH) prospective registry who were discharged after an acute coronary syndrome (ACS) between 2005 and 2011. The outcome measures were incident ischaemic stroke, TIA or death from any cause.
Over a median follow-up of 4.1 years, 453 patients (2.2%) had a stroke (n=297) or TIA (n=156) and 1903 (9.0%) died. The incidence of stroke or TIA increased with increases in each risk score (p<0.001), with an absolute annual incidence ≥1% with CHADS2 ≥3 or CHA2DS2-VASc ≥4. Both CHADS2 and CHA2DS2-VASc scores had acceptable discrimination performance (C-statistic=0.68 and 0.71, respectively). The mortality rate was also greater in patients with higher CHADS2 and CHA2DS2-VASc scores (p<0.0001).
In patients with ACS but no AF, the CHADS2 and CHA2DS2-VASc scores predict ischaemic stroke/TIA events with similar accuracy to that observed in historical populations with non-valvular AF, but with lower absolute event rates. Further study of the utility of the CHADS2 and CHA2DS2-VASc scores for the assessment of thromboembolic risk and selection of antithrombotic therapy in patients without AF is warranted.
Whether the benefits observed with cardiac resynchronization therapy (CRT) are similar in patients with versus those without atrial fibrillation (AF) is unclear. Furthermore, whether patients with AF ...receiving CRT should undergo atrioventricular nodal (AVN) ablation remains uncertain.
The purpose of this study was to compare outcomes in patients with and those without AF receiving CRT and to evaluate the influence of AVN ablation on outcomes in patients with AF.
A systematic review and meta-analysis was performed. Outcomes included death, CRT nonresponse, and changes in left ventricular (LV) remodeling, quality of life (QoL), and 6-minute hall walk distance (6MWD).
Twenty-three observational studies were included and followed a total of 7,495 CRT recipients, 25.5% with AF, for a mean of 33 months. AF was associated with an increased risk of nonresponse to CRT (34.5% vs 26.7%; pooled relative risk RR 1.32; 95% confidence interval CI 1.12, 1.55; P = .001)) and all-cause mortality (10.8% vs 7.1% per year, pooled RR 1.50, 95% CI 1.08, 2.09; P = .015). The presence of AF was also associated with less improvement in QoL, 6-minute hall walk distance, and LV end-systolic volume but not LV ejection fraction. Among patients with AF, AVN ablation appeared favorable with a lower risk of clinical nonresponse (RR 0.40; 95% CI 0.28, 0.58; P <.001) and a reduced risk of death.
The benefits of CRT appear to be attenuated in patients with AF. The presence of AF is associated with an increased risk of clinical nonresponse and death than in patients without AF. AVN ablation may improve CRT outcomes in patients with AF.
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