About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants. This study compared the efficacy and safety of switching patients with ...treatment-resistant depression from an ineffective antidepressant to flexibly dosed esketamine nasal spray plus a newly initiated antidepressant or to a newly initiated antidepressant (active comparator) plus placebo nasal spray.
This was a phase 3, double-blind, active-controlled, multicenter study conducted at 39 outpatient referral centers. The study enrolled adults with moderate to severe nonpsychotic depression and a history of nonresponse to at least two antidepressants in the current episode, with one antidepressant assessed prospectively. Confirmed nonresponders were randomly assigned to treatment with esketamine nasal spray (56 or 84 mg twice weekly) and an antidepressant or antidepressant and placebo nasal spray. The primary efficacy endpoint, change from baseline to day 28 in Montgomery-Åsberg Depression Rating Scale (MADRS) score, was assessed by a mixed-effects model using repeated measures.
Of 435 patients screened, 227 underwent randomization and 197 completed the 28-day double-blind treatment phase. Change in MADRS score with esketamine plus antidepressant was significantly greater than with antidepressant plus placebo at day 28 (difference of least square means=-4.0, SE=1.69, 95% CI=-7.31, -0.64); likewise, clinically meaningful improvement was observed in the esketamine plus antidepressant arm at earlier time points. The five most common adverse events (dissociation, nausea, vertigo, dysgeusia, and dizziness) all were observed more frequently in the esketamine plus antidepressant arm than in the antidepressant plus placebo arm; 7% and 0.9% of patients in the respective treatment groups discontinued study drug because of an adverse event. Adverse events in the esketamine plus antidepressant arm generally appeared shortly after dosing and resolved by 1.5 hours after dosing.
Current treatment options for treatment-resistant depression have considerable limitations in terms of efficacy and patient acceptability. Esketamine is expected to address an unmet medical need in this population through its novel mechanism of action and rapid onset of antidepressant efficacy. The study supports the efficacy and safety of esketamine nasal spray as a rapidly acting antidepressant for patients with treatment-resistant depression.
IMPORTANCE: Approximately one-third of patients with major depressive disorder (MDD) do not respond to available antidepressants. OBJECTIVE: To assess the efficacy, safety, and dose-response of ...intranasal esketamine hydrochloride in patients with treatment-resistant depression (TRD). DESIGN, SETTING, AND PARTICIPANTS: This phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study was conducted in multiple outpatient referral centers from January 28, 2014, to September 25, 2015. The study consisted of 4 phases: (1) screening, (2) double-blind treatment (days 1-15), composed of two 1-week periods, (3) optional open-label treatment (days 15-74), and (4) posttreatment follow-up (8 weeks). One hundred twenty-six adults with a DSM-IV-TR diagnosis of MDD and history of inadequate response to 2 or more antidepressants (ie, TRD) were screened, 67 were randomized, and 60 completed both double-blind periods. Intent-to-treat analysis was used in evaluation of the findings. INTERVENTIONS: In period 1, participants were randomized (3:1:1:1) to placebo (n = 33), esketamine 28 mg (n = 11), 56 mg (n = 11), or 84 mg (n = 12) twice weekly. In period 2, 28 placebo-treated participants with moderate-to-severe symptoms were rerandomized (1:1:1:1) to 1 of the 4 treatment arms; those with mild symptoms continued receiving placebo. Participants continued their existing antidepressant treatment during the study. During the open-label phase, dosing frequency was reduced from twice weekly to weekly, and then to every 2 weeks. MAIN OUTCOMES AND MEASURES: The primary efficacy end point was change from baseline to day 8 (each period) in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. RESULTS: Sixty-seven participants (38 women, mean SD age, 44.7 10.0 years) were included in the efficacy and safety analyses. Change (least squares mean SE difference vs placebo) in MADRS total score (both periods combined) in all 3 esketamine groups was superior to placebo (esketamine 28 mg: −4.2 2.09, P = .02; 56 mg: −6.3 2.07, P = .001; 84 mg: −9.0 2.13, P < .001), with a significant ascending dose-response relationship (P < .001). Improvement in depressive symptoms appeared to be sustained (−7.2 1.84) despite reduced dosing frequency in the open-label phase. Three of 56 (5%) esketamine-treated participants during the double-blind phase vs none receiving placebo and 1 of 57 participants (2%) during the open-label phase had adverse events that led to study discontinuation (1 event each of syncope, headache, dissociative syndrome, and ectopic pregnancy). CONCLUSIONS AND RELEVANCE: In this first clinical study to date of intranasal esketamine for TRD, antidepressant effect was rapid in onset and dose related. Response appeared to persist for more than 2 months with a lower dosing frequency. Results support further investigation in larger trials. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01998958
IMPORTANCE: Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established. OBJECTIVE: To assess the efficacy ...of esketamine nasal spray plus an oral antidepressant compared with an oral antidepressant plus placebo nasal spray in delaying relapse of depressive symptoms in patients with TRD in stable remission after an induction and optimization course of esketamine nasal spray plus an oral antidepressant. DESIGN, SETTING, AND PARTICIPANTS: In this phase 3, multicenter, double-blind, randomized withdrawal study conducted from October 6, 2015, to February 15, 2018, at outpatient referral centers, 705 adults with prospectively confirmed TRD were enrolled; 455 entered the optimization phase and were treated with esketamine nasal spray (56 or 84 mg) plus an oral antidepressant. After 16 weeks of esketamine treatment, 297 who achieved stable remission or stable response entered the randomized withdrawal phase. INTERVENTIONS: Patients who achieved stable remission and those who achieved stable response (without remission) were randomized 1:1 to continue esketamine nasal spray or discontinue esketamine treatment and switch to placebo nasal spray, with oral antidepressant treatment continued in each group. MAIN OUTCOMES AND MEASURES: Time to relapse was examined in patients who achieved stable remission, as assessed using a weighted combination log-rank test. RESULTS: Among the 297 adults (mean age SD, 46.3 11.13 years; 197 66.3% female) who entered the randomized maintenance phase, 176 achieved stable remission; 24 (26.7%) in the esketamine and antidepressant group and 39 (45.3%) in the antidepressant and placebo group experienced relapse (log-rank P = .003, number needed to treat NNT, 6). Among the 121 who achieved stable response, 16 (25.8%) in the esketamine and antidepressant group and 34 (57.6%) in the antidepressant and placebo group experienced relapse (log-rank P < .001, NNT, 4). Esketamine and antidepressant treatment decreased the risk of relapse by 51% (hazard ratio HR, 0.49; 95% CI, 0.29-0.84) among patients who achieved stable remission and 70% (HR, 0.30; 95% CI, 0.16-0.55) among those who achieved stable response compared with antidepressant and placebo treatment. The most common adverse events reported for esketamine-treated patients after randomization were transient dysgeusia, vertigo, dissociation, somnolence, and dizziness (incidence, 20.4%-27.0%), each reported in fewer patients (<7%) treated with an antidepressant and placebo. CONCLUSIONS AND RELEVANCE: For patients with TRD who experienced remission or response after esketamine treatment, continuation of esketamine nasal spray in addition to oral antidepressant treatment resulted in clinically meaningful superiority in delaying relapse compared with antidepressant plus placebo. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02493868
The RIFLE (risk, injury, failure, loss of kidney function, and end-stage renal failure) classification for acute kidney injury (AKI) was recently modified by the Acute Kidney Injury Network (AKIN). ...The two definition systems differ in several aspects, and it is not clearly determined which has the better clinical accuracy.
In a retrospective observational study we investigated 4,836 consecutive patients undergoing cardiac surgery with cardiopulmonary bypass from 2005 to 2007 at Mayo Clinic, Rochester, MN, USA. AKI was defined by RIFLE and AKIN criteria.
Significantly more patients were diagnosed as AKI by AKIN (26.3%) than by RIFLE (18.9%) criteria (P < 0.0001). Both definitions showed excellent association to outcome variables with worse outcome by increased severity of AKI (P < 0.001, all variables). Mortality was increased with an odds ratio (OR) of 4.5 (95% CI 3.6 to 5.6) for one class increase by RIFLE and an OR of 5.3 (95% CI 4.3 to 6.6) for one stage increase by AKIN. The multivariate model showed lower predictive ability of RIFLE for mortality. Patients classified as AKI in one but not in the other definition set were predominantly staged in the lowest AKI severity class (9.6% of patients in AKIN stage 1, 2.3% of patients in RIFLE class R). Potential misclassification of AKI is higher in AKIN, which is related to moving the 48-hour diagnostic window applied in AKIN criteria only. The greatest disagreement between both definition sets could be detected in patients with initial postoperative decrease of serum creatinine.
Modification of RIFLE by staging of all patients with acute renal replacement therapy (RRT) in the failure class F may improve predictive value. AKIN applied in patients undergoing cardiac surgery without correction of serum creatinine for fluid balance may lead to over-diagnosis of AKI (poor positive predictive value). Balancing limitations of both definition sets of AKI, we suggest application of the RIFLE criteria in patients undergoing cardiac surgery.
Objective A proportion of patients experience a decrease in left ventricular (LV) ejection fraction (EF) after mitral valve repair; however, predictors and long-term consequences remain unclear. ...Methods A study of 1705 patients with severe, degenerative mitral valve regurgitation and normal preoperative EF (>60%) undergoing mitral valve repair from 1993 to 2012 was performed. Multivariate logistic regression and Cox proportional hazards models were used to determine the predictors of early postoperative LV dysfunction (EF < 50%) and long-term survival, respectively. Results Postoperative outcomes were comparable between patients; however, those with an EF of <50% (n = 314, 18.4%) had significantly greater enlargement in systolic dimension (left ventricular end-systolic diameter, −0.6 vs 4.3 mm; P < .001) and decrease in right ventricular systolic pressure (−2.7 vs −7.8 mm Hg; P < .001) immediately after repair. On longitudinal follow-up, early LV impairment persisted, with EF recovering to preoperative levels (>60%) in only one third of patients with postrepair EF <50% versus two thirds of those with an EF of ≥50% ( P < .001). The overall survival at 5, 10, and 15 years of follow-up was 95%, 85%, and 70.8%, respectively. Although early postoperative EF < 50% was not a significant determinant of late survival, when adjusting for older age (hazard ratio HR, 1.09), hypertension (HR, 1.38), New York Heart Association class III or IV (HR, 1.71), and preoperative atrial fibrillation (HR, 2.33), postoperative EF < 40% conferred a 70% increase in the hazard of late death (HR, 1.74; 95% confidence interval, 1.03-2.92; P = .037). A preoperative right ventricular systolic pressure >49 mm Hg and left ventricular end-systolic diameter >36 mm were independently associated with a 4.4- and 6.5-fold increased risk of developing a postoperative EF < 40% ( P < .001, for both). Conclusions De novo postoperative LV dysfunction is not uncommon in patients with “normal” preoperative EF undergoing mitral valve repair. LV dysfunction can persist, impairing recovery of LV size, function, and survival. The consideration of mitral repair before the onset of excessive LV dilation or pulmonary hypertension, even in those with preserved EF, seems warranted.
Objective:Ketamine, an N-methyl-d-aspartate glutamate receptor antagonist, has demonstrated a rapid-onset antidepressant effect in patients with treatment-resistant depression. This study evaluated ...the efficacy of twice- and thrice-weekly intravenous administration of ketamine in sustaining initial antidepressant effects in patients with treatment-resistant depression.Method:In a multicenter, double-blind study, adults (ages 18–64 years) with treatment-resistant depression were randomized to receive either intravenous ketamine (0.5 mg/kg of body weight) or intravenous placebo, administered over 40 minutes, either two or three times weekly, for up to 4 weeks. Patients who discontinued double-blind treatment after at least 2 weeks for lack of efficacy could enter an optional 2-week open-label phase to receive ketamine with the same frequency as in the double-blind phase. The primary outcome measure was change from baseline to day 15 in total score on the Montgomery-Åsberg Depression Rating Scale (MADRS).Results:In total, 67 (45 women) of 68 randomized patients received treatment. In the twice-weekly dosing groups, the mean change in MADRS score at day 15 was −18.4 (SD=12.0) for ketamine and −5.7 (SD=10.2) for placebo; in the thrice-weekly groups, it was −17.7 (SD=7.3) for ketamine and −3.1 (SD=5.7) for placebo. Similar observations were noted for ketamine during the open-label phase (twice-weekly, −12.2 SD=12.8 on day 4; thrice-weekly, −14.0 SD=12.5 on day 5). Both regimens were generally well tolerated. Headache, anxiety, dissociation, nausea, and dizziness were the most common (≥20%) treatment-emergent adverse events. Dissociative symptoms occurred transiently and attenuated with repeated dosing.Conclusions:Twice-weekly and thrice-weekly administration of ketamine at 0.5 mg/kg similarly maintained antidepressant efficacy over 15 days.
Frailty is recognized as a major prognostic indicator in heart failure. There has been interest in understanding whether pre-operative frailty is associated with worse outcomes after implantation of ...a left ventricular assist device (LVAD) as destination therapy.
Patients undergoing LVAD implantation as destination therapy at the Mayo Clinic, Rochester, Minnesota, from February 2007 to June 2012, were included in this study. Frailty was assessed using the deficit index (31 impairments, disabilities and comorbidities) and defined as the proportion of deficits present. We divided patients based on tertiles of the deficit index (>0.32 = frail, 0.23 to 0.32 = intermediate frail, <0.23 = not frail). Cox proportional hazard regression models were used to examine the association between frailty and death. Patients were censored at death or last follow-up through October 2013.
Among 99 patients (mean age 65 years, 18% female, 55% with ischemic heart failure), the deficit index ranged from 0.10 to 0.65 (mean 0.29). After a mean follow-up of 1.9 ± 1.6 years, 79% of the patients had been rehospitalized (range 0 to 17 hospitalizations, median 1 per person) and 45% had died. Compared with those who were not frail, patients who were intermediate frail (adjusted HR 1.70, 95% CI 0.71 to 4.31) and frail (HR 3.08, 95% CI 1.40 to 7.48) were at increased risk for death (p for trend = 0.004). The mean (SD) number of days alive out of hospital the first year after LVAD was 293 (107) for not frail, 266 (134) for intermediate frail and 250 (132) for frail patients.
Frailty before destination LVAD implantation is associated with increased risk of death and may represent a significant patient selection consideration.
Objective Clinicians may give greater consideration to medical management versus coronary artery bypass grafting (CABG) for coronary artery disease (CAD) at the time of aortic valve intervention. We ...evaluated the prognostic impact of revascularization strategy during aortic valve replacement (AVR). Methods We studied 1308 consecutive patients with significant CAD (≥50% stenosis) undergoing AVR with or with out CABG between 2001 and 2010. Late mortality and its determinants were analyzed using multivariable Cox models. Results Patients undergoing CABG (n = 1043; 18%) had more frequent angina (50% vs 26%; P < .001), left ventricular dysfunction (22% vs 14%; P = .003), advanced (>70% stenosis) CAD (85% vs 48%; P < .001), and incidence of triple-vessel/left-main CAD (44% vs 8%; P < .001). Whereas operative mortality was comparable between patients undergoing AVR plus CABG versus isolated AVR (2.9% vs 3.0%; P = .90), 5-year (72% vs 64%) and 8-year (50% vs 39%) survival was higher following CABG ( P = .007). Adjusting for older age (hazard ratio HR, 1.28 per 5 years), female sex (HR, 1.23), peripheral vascular disease (HR, 1.71), New York Heart Association functional class III to IV (HR, 1.48), and diabetes (HR, 1.50) concomitant CABG at AVR reduced late mortality risk by more than one-third (HR, 0.62, 95% confidence interval, 0.49-0.79; P < .001). CABG continued to confer a survival advantage in patients with moderate (50%-70%) (HR, 0.62; P = .02) and severe (>70%) CAD (HR, 0.62; P = .002). Conclusions In patients undergoing AVR with coexistent CAD, concomitant CABG reduces risk of late death by more than one-third, without augmenting operative mortality. This survival advantage persists in moderate (50% to 70%) and severe (>70%) CAD. These findings underline the prognostic importance of revascularization in this population and should influence decisions regarding revascularization strategy in patients undergoing transcatheter valve therapy.
Background The timing of valve repair or replacement in patients with severe aortic valve regurgitation (AR) is controversial. We investigated the effect of left ventricular (LV) function on survival ...and recovery of LV performance and dimensions after correction of chronic severe AR. Methods We reviewed 530 consecutive patients who underwent aortic valve repair or replacement for severe AR between January 1, 2004, and June 30, 2014. Results The 30-day mortality was 0.75%. In multivariate analysis, older age (hazard ratio HR = 1.02, p = 0.03), preoperative LV ejection fraction (EF) <60% (HR = 1.78, p = 0.04), previous myocardial infarction (HR = 2.53, p = 0.01), and previous cardiac operation (HR = 1.82, p = 0.03) were associated with all-cause mortality. Ejection fraction was reduced before hospital discharge but then improved and was greater than preoperative levels at all subsequent intervals. The LV dimensions decreased early postoperatively and continued to decrease thereafter. In multivariate analysis, factors associated with LV dysfunction (EF <60%) 1 year after aortic valve replacement were preoperative LV end-systolic dimension ≥40 mm (odds ratio OR = 5.39, p < 0.01) and previous myocardial infarction (OR = 3.62, p = 0.04). Conclusions Preoperative LV dysfunction (EF <60%) had an adverse effect on overall survival after correction of chronic severe AR. Because survival is improved in patients with greater preoperative LVEF and because reverse LV remodeling is more complete with smaller LV dimensions, surgical intervention should be considered promptly in patients with chronic severe AR and deterioration of these indicators during echocardiographic surveillance.
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