Michael K. Parides

Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial.

BACKGROUND The clinical benefit of preventive eradication of unruptured brain arteriovenous malformations remains uncertain. A Randomised trial of Unruptured Brain Arteriovenous malformations (ARUBA) aims to compare the risk of death and symptomatic stroke in patients with an unruptured brain arteriovenous malformation who are allocated to either medical management alone or medical management with interventional therapy. METHODS Adult patients (≥18 years) with an unruptured brain arteriovenous malformation were enrolled into this trial at 39 clinical sites in nine countries. Patients were randomised (by web-based system, in a 1:1 ratio, with random permuted block design [block size 2, 4, or 6], stratified by clinical site) to medical management with interventional therapy (ie, neurosurgery, embolisation, or stereotactic radiotherapy, alone or in combination) or medical management alone (ie, pharmacological therapy for neurological symptoms as needed). Patients, clinicians, and investigators are aware of treatment assignment. The primary outcome is time to the composite endpoint of death or symptomatic stroke; the primary analysis is by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00389181. FINDINGS Randomisation was started on April 4, 2007, and was stopped on April 15, 2013, when a data and safety monitoring board appointed by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health recommended halting randomisation because of superiority of the medical management group (log-rank Z statistic of 4·10, exceeding the prespecified stopping boundary value of 2·87). At this point, outcome data were available for 223 patients (mean follow-up 33·3 months [SD 19·7]), 114 assigned to interventional therapy and 109 to medical management. The primary endpoint had been reached by 11 (10·1%) patients in the medical management group compared with 35 (30·7%) in the interventional therapy group. The risk of death or stroke was significantly lower in the medical management group than in the interventional therapy group (hazard ratio 0·27, 95% CI 0·14-0·54). No harms were identified, other than a higher number of strokes (45 vs 12, p<0·0001) and neurological deficits unrelated to stroke (14 vs 1, p=0·0008) in patients allocated to interventional therapy compared with medical management. INTERPRETATION The ARUBA trial showed that medical management alone is superior to medical management with interventional therapy for the prevention of death or stroke in patients with unruptured brain arteriovenous malformations followed up for 33 months. The trial is continuing its observational phase to establish whether the disparities will persist over an additional 5 years of follow-up. FUNDING National Institutes of Health, National Institute of Neurological Disorders and Stroke.

Mitral-Valve Repair versus Replacement for Severe Ischemic Mitral Regurgitation

BACKGROUND Ischemic mitral regurgitation is associated with a substantial risk of death. Practice guidelines recommend surgery for patients with a severe form of this condition but acknowledge that the supporting evidence for repair or replacement is limited. METHODS We randomly assigned 251 patients with severe ischemic mitral regurgitation to undergo either mitral-valve repair or chordal-sparing replacement in order to evaluate efficacy and safety. The primary end point was the left ventricular end-systolic volume index (LVESVI) at 12 months, as assessed with the use of a Wilcoxon rank-sum test in which deaths were categorized below the lowest LVESVI rank. RESULTS At 12 months, the mean LVESVI among surviving patients was 54.6±25.0 ml per square meter of body-surface area in the repair group and 60.7±31.5 ml per square meter in the replacement group (mean change from baseline, -6.6 and -6.8 ml per square meter, respectively). The rate of death was 14.3% in the repair group and 17.6% in the replacement group (hazard ratio with repair, 0.79; 95% confidence interval, 0.42 to 1.47; P=0.45 by the log-rank test). There was no significant between-group difference in LVESVI after adjustment for death (z score, 1.33; P=0.18). The rate of moderate or severe recurrence of mitral regurgitation at 12 months was higher in the repair group than in the replacement group (32.6% vs. 2.3%, P<0.001). There were no significant between-group differences in the rate of a composite of major adverse cardiac or cerebrovascular events, in functional status, or in quality of life at 12 months. CONCLUSIONS We observed no significant difference in left ventricular reverse remodeling or survival at 12 months between patients who underwent mitral-valve repair and those who underwent mitral-valve replacement. Replacement provided a more durable correction of mitral regurgitation, but there was no significant between-group difference in clinical outcomes. (Funded by the National Institutes of Health and the Canadian Institutes of Health; ClinicalTrials.gov number, NCT00807040.).

Microvolt T-Wave Alternans Distinguishes Between Patients Likely and Patients Not Likely to Benefit From Implanted Cardiac Defibrillator Therapy A Solution to the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II Conundrum

Background—In 2003, the Centers for Medicaid and Medicare Services recommended QRS duration as a means to identify MADIT II–like patients suitable for implanted cardiac defibrillator (ICD) therapy. We compared the ability of microvolt T-wave alternans and QRS duration to identify groups at high and low risk of dying among heart failure patients who met MADIT II criteria for ICD prophylaxis. Methods and Results—Patients with MADIT II characteristics and sinus rhythm had a microvolt T-wave alternans exercise test and a 12-lead ECG. Our primary end point was 2-year all-cause mortality. Of 177 MADIT II–like patients, 32% had a QRS duration >120 ms, and 68% had an abnormal (positive or indeterminate) microvolt T-wave alternans test. During an average follow-up of 20±6 months, 20 patients died. We compared patients with an abnormal microvolt T-wave alternans test to those with a normal (negative) test, and patients with a QRS >120 ms with those with a QRS ≤120 ms; the hazard ratios for 2-year mortality were 4.8 (P=0.020) and 1.5 (P=0.367), respectively. The actuarial mortality rate was substantially lower among patients with a normal microvolt T-wave alternans test (3.8%; 95% confidence interval: 0, 9.0) than the mortality rate in patients with a narrow QRS (12.0%; 95% confidence interval: 5.6, 18.5). The corresponding false-negative rates are 3.5% and 10.2%, respectively. Conclusion—Among MADIT II–like patients, a microvolt T-wave alternans test is better than QRS duration at identifying a high-risk group and also better at identifying a low-risk group unlikely to benefit from ICD therapy.

Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression

BACKGROUND Ketamine is reported to have rapid antidepressant effects; however, there is limited understanding of the time-course of ketamine effects beyond a single infusion. A previous report including 10 participants with treatment-resistant major depression (TRD) found that six ketamine infusions resulted in a sustained antidepressant effect. In the current report, we examined the pattern and durability of antidepressant effects of repeated ketamine infusions in a larger sample, inclusive of the original. METHODS Participants with TRD (n = 24) underwent a washout of antidepressant medication followed by a series of up to six IV infusions of ketamine (.5 mg/kg) administered open-label three times weekly over a 12-day period. Participants meeting response criteria were monitored for relapse for up to 83 days from the last infusion. RESULTS The overall response rate at study end was 70.8%. There was a large mean decrease in Montgomery-Åsberg Depression Rating Scale score at 2 hours after the first ketamine infusion (18.9 ± 6.6, p < .001), and this decrease was largely sustained for the duration of the infusion period. Response at study end was strongly predicted by response at 4 hours (94% sensitive, 71% specific). Among responders, median time to relapse after the last ketamine infusion was 18 days. CONCLUSIONS Ketamine was associated with a rapid antidepressant effect in TRD that was predictive of a sustained effect. Future controlled studies will be required to identify strategies to maintain an antidepressant response among patients who benefit from a course of ketamine.

Two-Year Outcomes of Surgical Treatment of Severe Ischemic Mitral Regurgitation

BACKGROUND In a trial comparing coronary-artery bypass grafting (CABG) alone with CABG plus mitral-valve repair in patients with moderate ischemic mitral regurgitation, we found no significant difference in the left ventricular end-systolic volume index (LVESVI) or survival after 1 year. Concomitant mitral-valve repair was associated with a reduced prevalence of moderate or severe mitral regurgitation, but patients had more adverse events. We now report 2-year outcomes. METHODS We randomly assigned 301 patients to undergo either CABG alone or the combined procedure. Patients were followed for 2 years for clinical and echocardiographic outcomes. RESULTS At 2 years, the mean (±SD) LVESVI was 41.2±20.0 ml per square meter of body-surface area in the CABG-alone group and 43.2±20.6 ml per square meter in the combined-procedure group (mean improvement over baseline, -14.1 ml per square meter and -14.6 ml per square meter, respectively). The rate of death was 10.6% in the CABG-alone group and 10.0% in the combined-procedure group (hazard ratio in the combined-procedure group, 0.90; 95% confidence interval, 0.45 to 1.83; P=0.78). There was no significant between-group difference in the rank-based assessment of the LVESVI (including death) at 2 years (z score, 0.38; P=0.71). The 2-year rate of moderate or severe residual mitral regurgitation was higher in the CABG-alone group than in the combined-procedure group (32.3% vs. 11.2%, P<0.001). Overall rates of hospital readmission and serious adverse events were similar in the two groups, but neurologic events and supraventricular arrhythmias remained more frequent in the combined-procedure group. CONCLUSIONS In patients with moderate ischemic mitral regurgitation undergoing CABG, the addition of mitral-valve repair did not lead to significant differences in left ventricular reverse remodeling at 2 years. Mitral-valve repair provided a more durable correction of mitral regurgitation but did not significantly improve survival or reduce overall adverse events or readmissions and was associated with an early hazard of increased neurologic events and supraventricular arrhythmias. (Funded by the National Institutes of Health and Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00806988.).

Left Ventricular Assist Device as Destination for Patients Undergoing Intravenous Inotropic Therapy: A Subset Analysis From REMATCH (Randomized Evaluation of Mechanical Assistance in Treatment of Chronic Heart Failure)

Background—Left ventricular assist devices (LVADs) have improved survival in patients with end-stage heart failure. Compared with previous trials, the Randomized Evaluation of Mechanical Assistance in Treatment of Chronic Heart Failure (REMATCH) trial enrolled patients with more advanced heart failure and high prevalence of intravenous inotropic therapy. This study analyzes, on a post hoc basis, outcomes in patients undergoing inotropic infusions at randomization. Methods and Results—Of 129 patients randomized, 91 were receiving intravenous inotropic therapy at randomization to LVAD or optimal medical management (OMM). Mean systolic pressure was 100 versus 107 mm Hg in those not receiving inotropes, serum sodium was 134 versus 137 mEq/L, and left ventricular ejection fraction was 17% for both groups. LVADs improved survival throughout follow-up for patients undergoing baseline inotropic infusions (P=0.0014); for the LVAD group versus the OMM group, respectively, 6-month survival was 60% versus 39%, 1-year survival rates were 49% versus 24%, and 2-year survival rates were 28% versus 11%. For 38 patients not undergoing inotropic infusions, 6-month survival was 61% for those with LVADs and 67% for those with OMM, whereas 1-year rates were 57% and 40%, respectively (P=0.55). Quality-of-life scores for survivors improved. Median days out of hospital for patients on inotropic therapy at randomization were 255 with LVAD and 105 with OMM. Conclusions—Despite severe compromise, patients undergoing inotropic infusions at randomization derived major LVAD survival benefit with improved quality of life. Patients not undergoing inotropic infusions had higher survival rates both with and without LVAD, but differences did not reach significance. Future studies should prespecify analyses of inotropic and other therapies to determine how disease severity and parallel medical treatment influence the benefits offered by mechanical circulatory support.

Surgical treatment of moderate ischemic mitral regurgitation.

BACKGROUND Ischemic mitral regurgitation is associated with increased mortality and morbidity. For surgical patients with moderate regurgitation, the benefits of adding mitral-valve repair to coronary-artery bypass grafting (CABG) are uncertain. METHODS We randomly assigned 301 patients with moderate ischemic mitral regurgitation to CABG alone or CABG plus mitral-valve repair (combined procedure). The primary end point was the left ventricular end-systolic volume index (LVESVI), a measure of left ventricular remodeling, at 1 year. This end point was assessed with the use of a Wilcoxon rank-sum test in which deaths were categorized as the lowest LVESVI rank. RESULTS At 1 year, the mean LVESVI among surviving patients was 46.1±22.4 ml per square meter of body-surface area in the CABG-alone group and 49.6±31.5 ml per square meter in the combined-procedure group (mean change from baseline, -9.4 and -9.3 ml per square meter, respectively). The rate of death was 6.7% in the combined-procedure group and 7.3% in the CABG-alone group (hazard ratio with mitral-valve repair, 0.90; 95% confidence interval, 0.38 to 2.12; P=0.81). The rank-based assessment of LVESVI at 1 year (incorporating deaths) showed no significant between-group difference (z score, 0.50; P=0.61). The addition of mitral-valve repair was associated with a longer bypass time (P<0.001), a longer hospital stay after surgery (P=0.002), and more neurologic events (P=0.03). Moderate or severe mitral regurgitation was less common in the combined-procedure group than in the CABG-alone group (11.2% vs. 31.0%, P<0.001). There were no significant between-group differences in major adverse cardiac or cerebrovascular events, deaths, readmissions, functional status, or quality of life at 1 year. CONCLUSIONS In patients with moderate ischemic mitral regurgitation, the addition of mitral-valve repair to CABG did not result in a higher degree of left ventricular reverse remodeling. Mitral-valve repair was associated with a reduced prevalence of moderate or severe mitral regurgitation but an increased number of untoward events. Thus, at 1 year, this trial did not show a clinically meaningful advantage of adding mitral-valve repair to CABG. Longer-term follow-up may determine whether the lower prevalence of mitral regurgitation translates into a net clinical benefit. (Funded by the National Institutes of Health and the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00806988.).

A randomized controlled trial of intranasal ketamine in major depressive disorder.

BACKGROUND The N-methyl-D-aspartate glutamate receptor antagonist ketamine, delivered via an intravenous route, has shown rapid antidepressant effects in patients with treatment-resistant depression. The current study was designed to test the safety, tolerability, and efficacy of intranasal ketamine in patients with depression who had failed at least one prior antidepressant trial. METHODS In a randomized, double-blind, crossover study, 20 patients with major depression were randomly assigned, and 18 completed 2 treatment days with intranasal ketamine hydrochloride (50 mg) or saline solution. The primary efficacy outcome measure was change in depression severity 24 hours after ketamine or placebo, measured using the Montgomery-Åsberg Depression Rating Scale. Secondary outcomes included persistence of benefit, changes in self-reports of depression, changes in anxiety, and proportion of responders. Potential psychotomimetic, dissociative, hemodynamic, and general adverse effects associated with ketamine were also measured. RESULTS Patients showed significant improvement in depressive symptoms at 24 hours after ketamine compared to placebo (t = 4.39, p < .001; estimated mean Montgomery-Åsberg Depression Rating Scale score difference of 7.6 ± 3.7; 95% confidence interval, 3.9-11.3). Response criteria were met by 8 of 18 patients (44%) 24 hours after ketamine administration compared with 1 of 18 (6%) after placebo (p = .033). Intranasal ketamine was well tolerated with minimal psychotomimetic or dissociative effects and was not associated with clinically significant changes in hemodynamic parameters. CONCLUSIONS This study provides the first controlled evidence for the rapid antidepressant effects of intranasal ketamine. Treatment was associated with minimal adverse effects. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with major depression.

Neurological events during long-term mechanical circulatory support for heart failure ; the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) experience

Background—Progression of heart failure can lead to cardiac transplantation, but when patients are ineligible, long-term mechanical circulatory support may improve survival. The REMATCH trial showed that left ventricular assist devices (LVADs) prolonged survival in patients with end-stage disease, but with a significant number of adverse events. We report on the neurological outcomes in the REMATCH trial. Methods and Results—We examined new neurological events in the 129 patients randomized to either LVAD placement (n= 68) or medical management (n= 61), classified as stroke, transient ischemic attack, toxic-metabolic encephalopathy, and other. There were 46 neurological events: 42 in 30 LVAD patients and 4 in 4 patients in the medical arm (χ2, 30/68 versus 4/61, P < 0.001). Sixteen percent of the LVAD patients had a stroke, with a rate of 0.19 per year (95% CI, 0.10 to 0.33), many occurring in the postoperative period. The stroke rate in the medical arm was 0.052. A Kaplan-Meier survival analysis showed a 44% reduction in the risk of stroke or death in the LVAD group versus the optimal medical group (P = 0.002). The mean interval from implantation to stroke was 221.8 days (± 70.4 days). History of stroke, age, and sepsis were not stroke risk factors in the LVAD group. Conclusions—Fewer than half of the patients in the LVAD group had a neurological event, and there were few neurological deaths. Survival analysis combining stroke or death demonstrated a significant benefit for long-term circulatory support with an LVAD over medical therapy. Future trials will need to address prospectively all neurological outcomes, including neurocognitive function, and the role of long-term neuroprotection.

Surgical ablation of atrial fibrillation during mitral-valve surgery

BACKGROUND Among patients undergoing mitral-valve surgery, 30 to 50% present with atrial fibrillation, which is associated with reduced survival and increased risk of stroke. Surgical ablation of atrial fibrillation has been widely adopted, but evidence regarding its safety and effectiveness is limited. METHODS We randomly assigned 260 patients with persistent or long-standing persistent atrial fibrillation who required mitral-valve surgery to undergo either surgical ablation (ablation group) or no ablation (control group) during the mitral-valve operation. Patients in the ablation group underwent further randomization to pulmonary-vein isolation or a biatrial maze procedure. All patients underwent closure of the left atrial appendage. The primary end point was freedom from atrial fibrillation at both 6 months and 12 months (as assessed by means of 3-day Holter monitoring). RESULTS More patients in the ablation group than in the control group were free from atrial fibrillation at both 6 and 12 months (63.2% vs. 29.4%, P<0.001). There was no significant difference in the rate of freedom from atrial fibrillation between patients who underwent pulmonary-vein isolation and those who underwent the biatrial maze procedure (61.0% and 66.0%, respectively; P=0.60). One-year mortality was 6.8% in the ablation group and 8.7% in the control group (hazard ratio with ablation, 0.76; 95% confidence interval, 0.32 to 1.84; P=0.55). Ablation was associated with more implantations of a permanent pacemaker than was no ablation (21.5 vs. 8.1 per 100 patient-years, P=0.01). There were no significant between-group differences in major cardiac or cerebrovascular adverse events, overall serious adverse events, or hospital readmissions. CONCLUSIONS The addition of atrial fibrillation ablation to mitral-valve surgery significantly increased the rate of freedom from atrial fibrillation at 1 year among patients with persistent or long-standing persistent atrial fibrillation, but the risk of implantation of a permanent pacemaker was also increased. (Funded by the National Institutes of Health and the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00903370.).