Erik Cobo

Thrombectomy within 8 Hours after Symptom Onset in Ischemic Stroke

BACKGROUND We aimed to assess the safety and efficacy of thrombectomy for the treatment of stroke in a trial embedded within a population-based stroke reperfusion registry. METHODS During a 2-year period at four centers in Catalonia, Spain, we randomly assigned 206 patients who could be treated within 8 hours after the onset of symptoms of acute ischemic stroke to receive either medical therapy (including intravenous alteplase when eligible) and endovascular therapy with the Solitaire stent retriever (thrombectomy group) or medical therapy alone (control group). All patients had confirmed proximal anterior circulation occlusion and the absence of a large infarct on neuroimaging. In all study patients, the use of alteplase either did not achieve revascularization or was contraindicated. The primary outcome was the severity of global disability at 90 days, as measured on the modified Rankin scale (ranging from 0 [no symptoms] to 6 [death]). Although the maximum planned sample size was 690, enrollment was halted early because of loss of equipoise after positive results for thrombectomy were reported from other similar trials. RESULTS Thrombectomy reduced the severity of disability over the range of the modified Rankin scale (adjusted odds ratio for improvement of 1 point, 1.7; 95% confidence interval [CI], 1.05 to 2.8) and led to higher rates of functional independence (a score of 0 to 2) at 90 days (43.7% vs. 28.2%; adjusted odds ratio, 2.1; 95% CI, 1.1 to 4.0). At 90 days, the rates of symptomatic intracranial hemorrhage were 1.9% in both the thrombectomy group and the control group (P=1.00), and rates of death were 18.4% and 15.5%, respectively (P=0.60). Registry data indicated that only eight patients who met the eligibility criteria were treated outside the trial at participating hospitals. CONCLUSIONS Among patients with anterior circulation stroke who could be treated within 8 hours after symptom onset, stent retriever thrombectomy reduced the severity of post-stroke disability and increased the rate of functional independence. (Funded by Fundació Ictus Malaltia Vascular through an unrestricted grant from Covidien and others; REVASCAT ClinicalTrials.gov number, NCT01692379.).

Oral citicoline in acute ischemic stroke: an individual patient data pooling analysis of clinical trials.

Background and Purpose— No single neuroprotective agent has been shown to influence outcome after acute stroke. Citicoline has been studied worldwide in many clinical trials with positive findings, but only 1 trial has obtained significant results in the primary efficacy variables. Our objective was to evaluate the effects of oral citicoline in patients with acute ischemic stroke by a data pooling analysis of clinical trials. The primary efficacy end point chosen was the common evaluation of recovery, combining National Institutes of Health Stroke Scale ≤1, modified Rankin Scale score ≤1, and Barthel Index ≥95 at 3 months using the generalized estimating equations analysis. Methods— A systematic search of all prospective, randomized, placebo-controlled, double-blind clinical trials with oral citicoline (MEDLINE, Cochrane, and Ferrer Group bibliographic databases) was undertaken. Individual patient data were extracted from each study and pooled in a single data file. The main inclusion criteria included compatible neuroimaging with ischemic stroke, National Institutes of Health Stroke Scale ≥8, and prior modified Rankin Scale score ≤1. Four clinical trials using various doses of oral citicoline (500, 1000, and 2000 mg) were identified. Results— Of 1652 randomized patients, 1372 fulfilled the inclusion criteria (583 received placebo, 789 received citicoline). Recovery at 3 months was 25.2% in citicoline-treated patients and 20.2% in placebo-treated patients (odds ratio [OR], 1.33; 95% CI, 1.10 to 1.62;P =0.0034). The dose showing the largest difference with placebo was 2000 mg, with 27.9% of patients achieving recovery (OR, 1.38; 95% CI, 1.10 to 1.72;P =0.0043). The overall safety of citicoline was similar to placebo. Conclusions— Treatment with oral citicoline within the first 24 hours after onset in patients with moderate to severe stroke increases the probability of complete recovery at 3 months.

Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial)

BACKGROUND Citicoline is approved in some countries for the treatment of acute ischaemic stroke. The drug has shown some evidence of efficacy in a pooled analysis. We sought to confirm the efficacy of citicoline in a larger trial. METHODS We undertook a randomised, placebo-controlled, sequential trial in patients with moderate-to-severe acute ischaemic stroke admitted at university hospitals in Germany, Portugal, and Spain. Using a centralised minimisation process, patients were randomly assigned in a 1:1 ratio to receive citicoline or placebo within 24 h after the onset of symptoms (1000 mg every 12 h intravenously during the first 3 days and orally thereafter for a total of 6 weeks [2×500 mg oral tablets given every 12 h]). All study participants were masked. The primary outcome was recovery at 90 days measured by a global test combining three measures of success: National Institutes of Health Stroke Scale ≤1, modified Rankin score ≤1, and Barthel Index ≥95. Safety endpoints included symptomatic intracranial haemorrhage in patients treated with recombinant tissue plasminogen activator, neurological deterioration, and mortality. This trial is registered, NCT00331890. RESULTS 2298 patients were enrolled into the study from Nov 26, 2006, to Oct 27, 2011. 37 centres in Spain, 11 in Portugal, and 11 in Germany recruited patients. Of the 2298 patients who gave informed consent and underwent randomisation, 1148 were assigned to citicoline and 1150 to placebo. The trial was stopped for futility at the third interim analysis on the basis of complete data from 2078 patients. The final randomised analysis was based on data for 2298 patients: 1148 in citicoline group and 1150 in placebo group. Global recovery was similar in both groups (odds ratio 1·03, 95% CI 0·86-1·25; p=0·364). No significant differences were reported in the safety variables nor in the rate of adverse events. INTERPRETATION Under the circumstances of the ICTUS trial, citicoline is not efficacious in the treatment of moderate-to-severe acute ischaemic stroke. FUNDING Ferrer Grupo.

Effect of using reporting guidelines during peer review on quality of final manuscripts submitted to a biomedical journal: masked randomised trial

Objective To investigate the effect of an additional review based on reporting guidelines such as STROBE and CONSORT on quality of manuscripts. Design Masked randomised trial. Population Original research manuscripts submitted to the Medicina Clínica journal from May 2008 to April 2009 and considered suitable for publication. Intervention Control group: conventional peer reviews alone. Intervention group: conventional review plus an additional review looking for missing items from reporting guidelines. Outcomes Manuscript quality, assessed with a 5 point Likert scale (primary: overall quality; secondary: average quality of specific items in paper). Main analysis compared groups as allocated, after adjustment for baseline factors (analysis of covariance); sensitivity analysis compared groups as reviewed. Adherence to reviewer suggestions assessed with Likert scale. Results Of 126 consecutive papers receiving conventional review, 34 were not suitable for publication. The remaining 92 papers were allocated to receive conventional reviews alone (n=41) or additional reviews (n=51). Four papers assigned to the conventional review group deviated from protocol; they received an additional review based on reporting guidelines. We saw an improvement in manuscript quality in favour of the additional review group (comparison as allocated, 0.25, 95% confidence interval –0.05 to 0.54; as reviewed, 0.33, 0.03 to 0.63). More papers with additional reviews than with conventional reviews alone improved from baseline (22 (43%) v eight (20%), difference 23.6% (3.2% to 44.0%), number needed to treat 4.2 (from 2.3 to 31.2), relative risk 2.21 (1.10 to 4.44)). Authors in the additional review group adhered more to suggestions from conventional reviews than to those from additional reviews (average increase 0.43 Likert points (0.19 to 0.67)). Conclusions Additional reviews based on reporting guidelines improve manuscript quality, although the observed effect was smaller than hypothesised and not definitively demonstrated. Authors adhere more to suggestions from conventional reviews than to those from additional reviews, showing difficulties in adhering to high methodological standards at the latest research phases. To boost paper quality and impact, authors should be aware of future requirements of reporting guidelines at the very beginning of their study. Trial registration and protocol Although registries do not include trials of peer review, the protocol design was submitted to sponsored research projects (Instituto de Salud Carlos III, PI081903).

Dual-chamber defibrillators reduce clinically significant adverse events compared with single-chamber devices: results from the DATAS (Dual chamber and Atrial Tachyarrhythmias Adverse events Study) trial.

AIMS This randomized trial evaluated clinically significant adverse events (CSAEs), in patients implanted with dual-chamber (DC) vs. single-chamber (SC) implantable cardioverter defibrillator (ICD). DC-ICD had atrial tachyarrhythmia (AT) therapy capabilities. Strict programming recommendations were reinforced. METHODS AND RESULTS Patients with conventional SC-ICD indication were randomized to DC-ICD, SC-ICD, or a DC-ICD programmed as an SC-ICD (SC-simulated) and followed for 16 months. Patients in the DC and SC-simulated groups crossed over after 8 months. The primary endpoint was a composite of CSAE: all-cause mortality; invasive intervention; hospitalization (> 24 h) for cardiovascular causes; inappropriate shocks (two or more episodes); and sustained symptomatic AT lasting > 48 h. The outcome variable was a pre-specified score that corrected for clinical severity and follow-up duration. Three hundred and thirty-four patients were analysed (DC-ICD, n = 112; SC-ICD, n = 111; SC-simulated, n = 111). The mean left ventricular ejection fraction was 0.36 +/- 0.13, 69% were in functional class > or = II. CSAE occurred in 65 DC-ICD, 82 SC-ICD, and 84 SC-simulated patients. The outcome variable was 33% lower in the DC-ICD group (OR 0.31; 95% CI 0.14-0.67; P = 0.0028). Mortality was 4% in DC, 9% in SC, and 10% in SC-simulated. CONCLUSION In patients with a standard SC-ICD indication, DC-ICD was associated with less CSAE when compared with SC-ICD.

REVASCAT: A Randomized Trial of Revascularization with Solitaire FR® Device vs. Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight-Hours of Symptom Onset

REVASCAT is a prospective, multicenter, randomized trial seeking to establish whether subjects meeting following main inclusion criteria: age 18–80, baseline National Institutes of Health Stroke Scale ≥6, evidence of intracranial internal carotid artery or proximal (M1 segment) middle cerebral artery occlusion, Alberta Stroke Program Early Computed Tomography score of >7 on non-contrast CT or >6 on diffusion-weighted magnetic resonance imaging, ineligible for or with persistent occlusion after intravenous alteplase and procedure start within 8 hours from symptom onset, have higher rates of favorable outcome when treated with the SolitaireTM FR embolectomy device compared to standard medical therapy alone The primary end-point, based on intention-to-treat criteria is the distribution of modified Rankin Scale scores at 90 days. Projected sample size is 690 patients. Estimated common odds ratio is 1•615. Randomization is performed under a minimization process using age, baseline NIHSS, therapeutic window, occlusion location and investigational center. The study follows a sequential analysis (triangular model) with the first approach to test efficacy at 174 patients and subsequent analyses (if necessary) at 346, 518, and 690 subjects. Secondary end-points are infarct volume evaluated on CT at 24 h, dramatic early favorable response, defined as NIHSS of 0–2 or NIHSS improvement ≥8 points at 24 h and successful recanalization in the Solitaire arm according to the thrombolysis in cerebral infarction (TICI) classification defined as TICI 2b or 3. Safety variables are mortality at 90 days, symptomatic intracranial haemorrhage rates at 24 hours and procedure related complications.

Preventing ventricular dysfunction in pacemaker patients without advanced heart failure: results from a multicentre international randomized trial (PREVENT-HF)

Previous experimental and clinical studies have consistently suggested that right ventricular (RV) apical pacing has important adverse effects. Ventricular pacing (VP), however, is required, and cannot be reduced in many patients with atrioventricular (AV) block. The PREVENT‐HF study was an international randomized trial that explored differences in left ventricular (LV) remodelling during RV apical vs. biventricular (BIV) pacing in patients with AV block.

Statistical Reviewers Improve Reporting in Biomedical Articles: A Randomized Trial

Background Although peer review is widely considered to be the most credible way of selecting manuscripts and improving the quality of accepted papers in scientific journals, there is little evidence to support its use. Our aim was to estimate the effects on manuscript quality of either adding a statistical peer reviewer or suggesting the use of checklists such as CONSORT or STARD to clinical reviewers or both. Methodology and Principal Findings Interventions were defined as 1) the addition of a statistical reviewer to the clinical peer review process, and 2) suggesting reporting guidelines to reviewers; with “no statistical expert” and “no checklist” as controls. The two interventions were crossed in a 2×2 balanced factorial design including original research articles consecutively selected, between May 2004 and March 2005, by the Medicina Clinica (Barc) editorial committee. We randomized manuscripts to minimize differences in terms of baseline quality and type of study (intervention, longitudinal, cross-sectional, others). Sample-size calculations indicated that 100 papers provide an 80% power to test a 55% standardized difference. We specified the main outcome as the increment in quality of papers as measured on the Goodman Scale. Two blinded evaluators rated the quality of manuscripts at initial submission and final post peer review version. Of the 327 manuscripts submitted to the journal, 131 were accepted for further review, and 129 were randomized. Of those, 14 that were lost to follow-up showed no differences in initial quality to the followed-up papers. Hence, 115 were included in the main analysis, with 16 rejected for publication after peer review. 21 (18.3%) of the 115 included papers were interventions, 46 (40.0%) were longitudinal designs, 28 (24.3%) cross-sectional and 20 (17.4%) others. The 16 (13.9%) rejected papers had a significantly lower initial score on the overall Goodman scale than accepted papers (difference 15.0, 95% CI: 4.6–24.4). The effect of suggesting a guideline to the reviewers had no effect on change in overall quality as measured by the Goodman scale (0.9, 95% CI: −0.3–+2.1). The estimated effect of adding a statistical reviewer was 5.5 (95% CI: 4.3–6.7), showing a significant improvement in quality. Conclusions and Significance This prospective randomized study shows the positive effect of adding a statistical reviewer to the field-expert peers in improving manuscript quality. We did not find a statistically significant positive effect by suggesting reviewers use reporting guidelines.

Association Between Time to Reperfusion and Outcome Is Primarily Driven by the Time From Imaging to Reperfusion

Background and Purpose— A progressive decline in the odds of favorable outcome as time to reperfusion increases is well known. However, the impact of specific workflow intervals is not clear. Methods— We studied the mechanical thrombectomy group (n=103) of the prospective, randomized REVASCAT (Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset) trial. We defined 3 workflow metrics: time from symptom onset to reperfusion (OTR), time from symptom onset to computed tomography, and time from computed tomography (CT) to reperfusion. Clinical characteristics, core laboratory-evaluated Alberta Stroke Program Early CT Scores (ASPECTS) and 90-day outcome data were analyzed. The effect of time on favorable outcome (modified Rankin scale, 0–2) was described via adjusted odds ratios (ORs) for every 30-minute delay. Results— Median admission National Institutes of Health Stroke Scale was 17.0 (14.0–20.0), reperfusion rate was 66%, and rate of favorable outcome was 43.7%. Mean (SD) workflow times were as follows: OTR: 342 (107) minute, onset to CT: 204 (93) minute, and CT to reperfusion: 138 (56) minute. Longer OTR time was associated with a reduced likelihood of good outcome (OR for 30-minute delay, 0.74; 95% confidence interval [CI], 0.59–0.93). The onset to CT time did not show a significant association with clinical outcome (OR, 0.87; 95% CI, 0.67–1.12), whereas the CT to reperfusion interval showed a negative association with favorable outcome (OR, 0.72; 95% CI, 0.54–0.95). A similar subgroup analysis according to admission ASPECTS showed this relationship for OTR time in ASPECTS<8 patients (OR, 0.56; 95% CI, 0.35–0.9) but not in ASPECTS≥8 (OR, 0.99; 95% CI, 0.68–1.44). Conclusions— Time to reperfusion is negatively associated with favorable outcome, being CT to reperfusion, as opposed to onset to CT, the main determinant of this association. In addition, OTR was strongly associated to outcome in patients with low ASPECTS scores but not in patients with high ASPECTS scores. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01692379.

Impact of anti-tachycardia pacing on atrial fibrillation burden when added on top of preventive pacing algorithms: results of the prevention or termination (POT) trial

AIMS The efficacy of preventive pacing algorithms (PPA) and anti-tachycardia pacing (ATP) in reducing atrial fibrillation (AF) burden remains controversial. The aim of this study was to assess whether ATP on top of PPA decreases AF burden. METHODS AND RESULTS A series of 199 consecutive patients, with conventional indications for pacing, and documented AF, received a DDDR (rate adaptive dual chamber pacemaker) pacemaker with ATP capabilities (AT 500 Medtronic). After 3 months of conventional DDDR pacing at 70 b.p.m., AF burden was analysed. If patients had >30 min/week of AF, they were randomized to PPA or to PPA+ATP for 3 months (period 1). They were then crossed to the alternative therapy (period 2) and followed three additional months with a 1-month wash out period in-between. A group of 85 patients were randomized. Mean age 68 +/- 8 years, 61% men. Both groups showed a significant decrease in AF burden at the end of period 1 (64 and 81%, respectively). CONCLUSIONS Atrial pacing with PPA decreases AF burden in patients with pacing indication. We did not observe a further decrease in AF burden or in the number of episodes when adding ATP on top of PPA.