Effect of next-step antidepressant treatment on suicidal ideation: findings from the VAST-D trial.

BACKGROUND: Major depressive disorder (MDD) contributes to suicide risk. Treating MDD effectively is considered a key suicide prevention intervention. Yet many patients with MDD do not respond to their initial medication and require a 'next-step'. The relationship between next-step treatments and suicidal thoughts and behaviors is uncharted. METHOD: The VA Augmentation and Switching Treatments for Depression trial randomized 1522 participants to one of three next-step treatments: Switching to Bupropion, combining with Bupropion, and augmenting with Aripiprazole. In this secondary analysis, features associated with lifetime suicidal ideation (SI) and attempts (SA) at baseline and current SI during treatment were explored. RESULTS: Compared to those with SI only, those with lifetime SI + SA were more likely to be female, divorced, or separated, unemployed; and to have experienced more childhood adversity. They had a more severe depressive episode and were more likely to respond to 'next-step' treatment. The prevalence of SI decreased from 46.5% (694/1492) at baseline to 21.1% (315/1492) at end-of-treatment. SI during treatment was associated with baseline SI; low positive mental health, more anxiety, greater severity and longer duration of current MDD episode; being male and White; and treatment with S-BUP or C-BUP as compared to A-ARI. CONCLUSION: SI declines for most patients during next-step medication treatments. But about 1 in 5 experienced emergent or worsening SI during treatment, so vigilance for suicide risk through the entire 12-week acute treatment period is necessary. Treatment selection may affect the risk of SI.

Factors Affecting Antidepressant Response Trajectories: A Veterans Affairs Augmentation and Switching Treatments for Improving Depression Outcomes Trial Report.

Background: In this secondary analysis of the VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) study we used antidepressant response trajectories to assess the association of treatment and multiple clinical/demographic factors with the probability of response. Methods: Using data from VAST-D, a multi-site, randomized, single-blind trial with parallel-assignment to one of three treatment interventions in 1522 Veterans whose major depressive disorder was unresponsive to at least one antidepressant trial, we evaluated response patterns using group-based trajectory modeling (GBTM). A weighted multinomial logistic regression analysis with backward elimination and additional exploratory analyses were performed to evaluate the association of multiple clinical/demographic factors with the probability of inclusion into specific trajectories. Additional exploratory analyses were used to identify factors associated with trajectory group membership that could have been missed in the primary analysis. Results: GBTM showed the best fit for depression symptom change was comprised of six trajectories, with some trajectories demonstrating minimal improvement and others showing a high probability of remission. High baseline depression and anxiety severity scores decreased, and early improvement increased, the likelihood of inclusion into the most responsive trajectory in both the GBTM and exploratory analyses. Conclusion: While multiple factors influence responsiveness, the probability of inclusion into a specific depression symptom trajectory is most strongly influenced by three factors: baseline depression, baseline anxiety, and the presence of early improvement.

Childhood adversity and adulthood major depressive disorder.

OBJECTIVE: Examine how specific types of childhood adversity are associated with clinical features and treatment in adults with Major Depressive Disorder (MDD). METHOD: This is a secondary analysis of the 35-site VA Augmentation and Switching Treatments for Improving Depression Outcomes study. A 10-item Adverse Childhood Events (ACE) survey was administered at baseline. RESULTS: 83% experienced at least one of the 10 ACEs and 20.7% experienced 6 or more. Participants with childhood adversities were more likely to be younger, female, unemployed, single or divorced, and to have had more severe depression and anxiety, more lifetime episodes, a younger age of first diagnosed MDD, more comorbid PTSD, worse quality of life, and more suicidal ideation than those no or fewer adversities. Neither the overall number nor any of the specific types of adversities were associated with lower remission rates after administration of standard "next-step" treatment strategies, while histories of different specific types were associated with lower depression severity, better quality of life, and less suicidal ideation post-treatment. CONCLUSIONS: Attention to different forms of childhood adversity and to diverse clinical outcomes beyond remission and relapse are important considerations when treating individuals with MDD with histories of childhood maltreatment. CLINICALTRIALS: gov identifier: NCT01421342.

Continuation phase treatment outcomes for switching, combining, or augmenting strategies for treatment-resistant major depressive disorder: A VAST-D report.

BACKGROUND: This secondary analysis of the VA Augmentation and Switching Treatments for Depression study compared the continuation phase treatment outcomes of three commonly used second-step treatment strategies following at least one prior failed medication treatment attempt. METHODS: In total, 1522 outpatients with MDD were randomized to switching to bupropion-SR (S-BUP), combining with bupropion-SR (C-BUP), or augmenting with aripiprazole (A-ARI). Following 12 weeks of acute phase treatment, 725 entered the 24-week continuation treatment phase. Depressive symptom severity, relapse, "emergent" remission, anxiety, suicidal ideation, quality of life, health status, and side effects were compared. RESULTS: We did not find clinically significant differential treatment effects with the exception that A-ARI was associated with less anxiety than S-BUP or C-BUP. Participants who entered continuation treatment as remitters had milder depressive symptom severity and lower relapse rates than those not in remission; they also experienced more improvement on most other outcomes. A-ARI was associated with less anxiety, insomnia, and dry mouth but more somnolence, extrapyramidal effects, akathisia, abnormal laboratory values, and appetite and weight gain. CONCLUSIONS: Continuation treatment is a dynamic period. Regardless of the treatment, participants who entered continuation treatment at Week 12 in full remission continued to have better outcomes over the subsequent 24 weeks than those who were not in remission at the start of the continuation phase.

Impact of Concurrent Posttraumatic Stress Disorder on Outcomes of Antipsychotic Augmentation for Major Depressive Disorder With a Prior Failed Treatment: VAST-D Randomized Clinical Trial.

OBJECTIVE: To determine whether concurrent posttraumatic stress disorder (PTSD) should affect whether to augment or switch medications when major depressive disorder (MDD) has not responded to a prior antidepressant trial. METHODS: Patients at 35 Veterans Health Administration medical centers from December 2012 to May 2015 with nonpsychotic MDD (N = 1,522) and a suboptimal response to adequate antidepressant treatment were randomly assigned to 3 "next step" treatments: switching to bupropion, augmenting the current antidepressant with bupropion, and augmenting with the antipsychotic aripiprazole. Blinded ratings with the 16-item Quick Inventory of Depressive Symptomatology-Clinician Rated (QIDS-C16) determined remission and response by 12 weeks and relapse after remission. Survival analyses compared treatment effects in patients with concurrent PTSD diagnosed with the Mini-International Neuropsychiatric Interview (n = 717, 47.1%) and those without PTSD (n = 805, 52.9%). RESULTS: Patients diagnosed with PTSD showed more severe depressive symptoms at baseline and were less likely to achieve either remission or response by 12 weeks. Augmentation with aripiprazole was associated with greater likelihood of achieving response (68.4%) than switching to bupropion (57.7%) in patients with PTSD (relative risk [RR] = 1.26; 95% CI, 1.01-1.59) as well as in patients without PTSD (RR = 1.29; 95% CI, 1.05-1.97) (78.9% response with aripiprazole augmentation vs 66.9% with switching to bupropion). Treatment comparisons with the group receiving augmentation with bupropion were not significant. There was no significant interaction between treatment group and PTSD on remission (P = .70), response (P = .98), or relapse (P = .15). CONCLUSIONS: Although PTSD was associated with poorer overall outcomes, the presence of concurrent PTSD among Veterans in this trial did not affect the comparative effectiveness of medications on response, remission, or relapse after initial remission. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01421342.

Recurrent herpes zoster in the Shingles Prevention Study: Are second episodes caused by the same varicella-zoster virus strain?

Herpes zoster (HZ) is caused by reactivation of varicella zoster virus (VZV) that established latency in sensory and autonomic neurons during primary infection. In the Shingles Prevention Study (SPS), a large efficacy trial of live attenuated Oka/Merck zoster vaccine (ZVL), PCR-confirmed second episodes of HZ occurred in two of 660 placebo and one of 321 ZVL recipients with documented HZ during a mean follow-up of 3.13 years. An additional two ZVL recipients experienced a second episode of HZ in the Long-Term Persistence Substudy. All episodes of HZ were caused by wild-type VZV. The first and second episodes of HZ occurred in different dermatomes in each of these five participants, with contralateral recurrences in two. Time between first and second episodes ranged from 12 to 28 months. One of the five participants, who was immunocompetent on study enrollment, was immunocompromised at the onset of his first and second episodes of HZ. VZV DNA isolated from rash lesions from the first and second episodes of HZ was used to sequence the full-length VZV genomes. For the unique-sequence regions of the VZV genome, we employed target enrichment of VZV DNA, followed by deep sequencing. For the reiteration regions, we used PCR amplification and Sanger sequencing. Our analysis and comparison of the VZV genomes from the first and second episodes of HZ in each of the five participants indicate that both episodes were caused by the same VZV strain. This is consistent with the extraordinary stability of VZV during the replication phase of varicella and the subsequent establishment of latency in sensory ganglia throughout the body. Our observations also indicate that VZV is stable during the persistence of latency and the subsequent reactivation and replication that results in HZ.

Open versus Endovascular Repair of Abdominal Aortic Aneurysm.

BACKGROUND: Elective endovascular repair of an abdominal aortic aneurysm results in lower perioperative mortality than traditional open repair, but after 4 years this survival advantage is not seen; in addition, results of two European trials have shown worse long-term outcomes with endovascular repair than with open repair. Long-term results of a study we conducted more than a decade ago to compare endovascular repair with open repair are unknown. METHODS: We randomly assigned patients with asymptomatic abdominal aortic aneurysms to either endovascular repair or open repair of the aneurysm. All the patients were candidates for either procedure. Patients were followed for up to 14 years. RESULTS: A total of 881 patients underwent randomization: 444 were assigned to endovascular repair and 437 to open repair. The primary outcome was all-cause mortality. A total of 302 patients (68.0%) in the endovascular-repair group and 306 (70.0%) in the open-repair group died (hazard ratio, 0.96; 95% confidence interval [CI], 0.82 to 1.13). During the first 4 years of follow-up, overall survival appeared to be higher with endovascular repair than with open repair; from year 4 through year 8, overall survival was higher in the open-repair group; and after 8 years, overall survival was once again higher in the endovascular-repair group (hazard ratio for death, 0.94; 95% CI, 0.74 to 1.18). None of these trends were significant. There were 12 aneurysm-related deaths (2.7%) in the endovascular-repair group and 16 (3.7%) in the open-repair group (between-group difference, -1.0 percentage point; 95% CI, -3.3 to 1.4); most deaths occurred during the perioperative period. Aneurysm rupture occurred in 7 patients (1.6%) in the endovascular-repair group, and rupture of a thoracic aneurysm occurred in 1 patient (0.2%) in the open-repair group (between-group difference, 1.3 percentage points; 95% CI, 0.1 to 2.6). Death from chronic obstructive lung disease was just over 50% more common with open repair (5.4% of patients in the endovascular-repair group and 8.2% in the open-repair group died from chronic obstructive lung disease; between-group difference, -2.8 percentage points; 95% CI, -6.2 to 0.5). More patients in the endovascular-repair group underwent secondary procedures. CONCLUSIONS: Long-term overall survival was similar among patients who underwent endovascular repair and those who underwent open repair. A difference between groups was noted in the number of patients who underwent secondary therapeutic procedures. Our results were not consistent with the findings of worse performance of endovascular repair with respect to long-term survival that was seen in the two European trials. (Funded by the Department of Veteran Affairs Office of Research and Development; OVER ClinicalTrials.gov number, NCT00094575.).

General Predictors and Moderators of Depression Remission: A VAST-D Report.

OBJECTIVE: Almost two-thirds of patients with major depressive disorder do not achieve remission with initial treatments. Thus, identifying and providing effective, feasible, and safe "next-step" treatments are clinical imperatives. This study explores patient baseline features that might help clinicians select between commonly used next-step treatments. METHODS: The authors used data from the U.S. Department of Veterans Affairs (VA) Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) study, a multisite, randomized, single-blind trial of 1,522 Veterans Health Administration patients who did not have an adequate response to at least one course of antidepressant treatment meeting minimal standards for dosage and duration. For 12 weeks, participants received one of three possible next-step treatments: switch to another antidepressant-sustained-release bupropion; combination with another antidepressant-sustained-release bupropion; or augmentation with an antipsychotic-aripiprazole. Life table regression models were used to identify baseline characteristics associated with remission overall (general predictors) and their interaction with remission among the three treatment groups (moderators). RESULTS: Remission was more likely for individuals who were employed, less severely and chronically depressed, less anxious, not experiencing complicated grief symptoms, did not experience childhood adversity, and had better quality of life and positive mental health. Two features suggested specific next-step treatment selections: age ≥65 years (for whom augmentation with aripiprazole was more effective than switch to bupropion) and severe mixed hypomanic symptoms (for which augmentation with aripiprazole and combination with bupropion were more effective than switch to bupropion). CONCLUSIONS: If replicated, these preliminary findings could help clinicians determine which patients with depression requiring next-step treatment will benefit most from a specific augmentation, combination, or switching strategy.

Automated safety event monitoring using electronic medical records in a clinical trial setting: Validation study using the VA NEPHRON-D trial.

BACKGROUND/AIMS: Electronic medical records are now frequently used for capturing patient-level data in clinical trials. Within the Veterans Affairs health care system, electronic medical record data have been widely used in clinical trials to assess eligibility, facilitate referrals for recruitment, and conduct follow-up and safety monitoring. Despite the potential for increased efficiency in using electronic medical records to capture safety data via a centralized algorithm, it is important to evaluate the integrity and accuracy of electronic medical record-captured data. To this end, this investigation assesses data collection, both for general and study-specific safety endpoints, by comparing electronic medical record-based safety monitoring versus safety data collected during the course of the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) clinical trial. METHODS: The VA NEPHRON-D study was a multicenter, double-blind, randomized clinical trial designed to compare the effect of combination therapy (losartan plus lisinopril) versus monotherapy (losartan) on the progression of kidney disease in individuals with diabetes and proteinuria. The trial's safety outcomes included serious adverse events, hyperkalemia, and acute kidney injury. A subset of the participants (~62%, n = 895) enrolled in the trial's long-term follow-up sub-study and consented to electronic medical record data collection. We applied an automated algorithm to search and capture safety data using the VA Corporate Data Warehouse which houses electronic medical record data. Using study safety data reported during the trial as the gold standard, we evaluated the sensitivity and precision of electronic medical record-based safety data and related treatment effects. RESULTS: The sensitivity of the electronic medical record-based safety for hospitalizations was 65.3% without non-VA hospitalization events and 92.3% with the non-VA hospitalization events included. The sensitivity was only 54.3% for acute kidney injury and 87.3% for hyperkalemia. The precision of electronic medical record-based safety data was 89.4%, 38%, and 63.2% for hospitalization, acute kidney injury, and hyperkalemia, respectively. Relative treatment differences under the study and electronic medical record settings were 15% and 3% for hospitalization, 123% and 29% for acute kidney injury, and 238% and 140% for hyperkalemia, respectively. CONCLUSION: The accuracy of using automated electronic medical record safety data depends on the events of interest. Identification of all-cause hospitalizations would be reliable if search methods could, in addition to VA hospitalizations, also capture non-VA hospitalizations. However, hospitalization is different from a cause-specific serious adverse event that could be more sensitive to treatment effects. In addition, some study-specific safety events were not easily identified using the electronic medical records. This limits the effectiveness of the automated central database search for purposes of safety monitoring. Hence, this data captured approach should be carefully considered when implementing endpoint data collection in future pragmatic trials.

Predictability of Nonremitting Depression After First 2 Weeks of Antidepressant Treatment: A VAST-D Trial Report.

Objective: In this secondary analysis of data from the Veterans Affairs Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) study, the authors sought to determine the effectiveness of early improvement (or lack thereof) for predicting remission from depression with antidepressant therapy. Methods: This study used data from the VAST-D study, a multisite, randomized, single-blind trial with parallel assignment to one of three medication interventions for 1,522 veterans whose major depressive disorder was unresponsive to at least one course of antidepressant treatment meeting minimal standards for dosage and duration. The authors calculated the positive predictive value (PPV) and negative predictive value (NPV) of early improvement on remission, response, or greater than minimal improvement from depression for various degrees of improvement (10%-50%) on the Quick Inventory of Depressive Symptomatology-Clinician Rated (QIDS-C) at 1, 2, 4, and 6 weeks. Results: The end of week 2 of treatment was identified as the best time to evaluate early improvement. The presence of a ≥20% drop from the baseline QIDS-C score by the end of week 2 resulted in a PPV for remission of 38% and an NPV of 93% by week 12. Extending the observational window to week 6 minimally improved NPV (97%). This association did not differ across treatment groups. Conclusions: A lack of early improvement at the end of week 2 of antidepressant therapy can be used to inform clinical decisions on the likelihood of nonremission of depression during the subsequent 10 weeks, even when dosage optimization is incomplete.

Comparing Cost-Effectiveness of Aripiprazole Augmentation With Other "Next-Step" Depression Treatment Strategies: A Randomized Clinical Trial.

OBJECTIVE: To compare the cost-effectiveness of 3 common alternate treatments for depression. METHODS: The cost-effectiveness analysis was conducted as part of a randomized clinical trial, the Veterans Affairs Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) trial, in which patients were randomized from December 2012 to May 2015 and followed for 12 weeks in 35 Veterans Affairs medical centers. Depression diagnosis was based on ICD-9 codes. Patients were randomized to standard antidepressant therapy augmented with aripiprazole, standard antidepressant therapy augmented with bupropion, or switch to bupropion. Remission was measured using the 16-item Quick Inventory of Depressive Symptomatology-Clinican Rated. Outcomes included the incremental cost-effectiveness ratio (ICER) comparing costs per remission and costs per quality-adjusted life-year (QALY) with 12 weeks as the time horizon using the health care sector perspective. RESULTS: The mean age of participants enrolled in the trial (N = 1,522) was 54 years, and participants were predominantly male. The rate of remission at 12 weeks was highest for the aripiprazole augmentation arm (29%), followed by bupropion augmentation (27%), and lowest for switching to bupropion (22%). Switching to bupropion was strongly dominated by bupropion augmentation at an ICER of -$640/remission (95% CI, -$5,770 to $3,008). The ICER for the aripiprazole augmentation versus switching to bupropion was $1,074/remission (95% CI, $47 to $5,022), and the ICER for aripiprazole augmentation versus bupropion augmentation was $5,094/remission (95% CI, -$34,027 to $32,774). There were no significant differences in QALYs, mental health care costs, employment, or other work and social adjustment outcomes between treatment groups. CONCLUSIONS: In treatment of depression with less than optimal response, augmentation with either aripiprazole or bupropion was cost-effective relative to switching to bupropion. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01421342.

Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial.

IMPORTANCE: Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant. OBJECTIVE: To determine the relative effectiveness and safety of 3 common alternate treatments for MDD. DESIGN, SETTING, AND PARTICIPANTS: From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks. INTERVENTIONS: Switch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase). MAIN OUTCOMES AND MEASURES: The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects. RESULTS: Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain. CONCLUSIONS AND RELEVANCE: Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01421342.

Characteristics of U.S. Veteran Patients with Major Depressive Disorder who require "next-step" treatments: A VAST-D report.

OBJECTIVE: Finding effective and lasting treatments for patients with Major Depressive Disorder (MDD) that fail to respond optimally to initial standard treatment is a critical public health imperative. Understanding the nature and characteristics of patients prior to initiating "next-step" treatment is an important component of identifying which specific treatments are best suited for individual patients. We describe clinical features and demographic characteristics of a sample of Veterans who enrolled in a "next-step" clinical trial after failing to achieve an optimal outcome from at least one well-delivered antidepressant trial. METHODS: 1522 Veteran outpatients with nonpsychotic MDD completed assessments prior to being randomized to study treatment. Data is summarized and presented in terms of demographic, social, historical and clinical features and compared to a similar, non-Veteran sample. RESULTS: Participants were largely male and white, with about half unmarried and half unemployed. They were moderately severely depressed, with about one-third reporting recent suicidal ideation. More than half had chronic and/or recurrent depression. General medical and psychiatric comorbidities were highly prevalent, particularly PTSD. Many had histories of childhood adversity and bereavement. Participants were impaired in multiple domains of their lives and had negative self-worth. LIMITATIONS: These results may not be generalizable to females, and some characteristics may be specific to Veterans of US military service. There was insufficient data on age of clinical onset and depression subtypes, and three novel measures were not psychometrically validated. CONCLUSIONS: Characterizing VAST-D participants provides important information to help clinicians understand features that may optimize "next-step" MDD treatments.

The VA augmentation and switching treatments for improving depression outcomes (VAST-D) study: Rationale and design considerations.

Because two-thirds of patients with Major Depressive Disorder do not achieve remission with their first antidepressant, we designed a trial of three "next-step" strategies: switching to another antidepressant (bupropion-SR) or augmenting the current antidepressant with either another antidepressant (bupropion-SR) or with an atypical antipsychotic (aripiprazole). The study will compare 12-week remission rates and, among those who have at least a partial response, relapse rates for up to 6 months of additional treatment. We review seven key efficacy/effectiveness design decisions in this mixed "efficacy-effectiveness" trial.

Modeling the durability of ZOSTAVAX® vaccine efficacy in people ≥60 years of age.

Since 2006, the vaccine, ZOSTAVAX(®), has been licensed to prevent herpes zoster. Only limited clinical follow-up data are available to evaluate duration of protection, an important consideration when developing HZ vaccination policy recommendations. Four Poisson regression models were developed based on an integrated analysis of data from the Shingles Prevention Study and its Short Term Persistence extension to estimate the effects of years-since-vaccination and chronological-age on vaccine efficacy among people ≥60 years old. The models included number of HZ cases parsed into categories by chronological-age and time-since-vaccination as the dependent variable with different explanatory variables in each model. In all models, the interaction between vaccine-group and chronological-age was statistically significant indicating that vaccine efficacy decreases with the expected effects of advancing age but the interaction between vaccine-group and time-since-vaccination was not statistically significant indicating that much of the reduction in vaccine efficacy over time-since-vaccination can be explained by increasing age.

Long-term persistence of zoster vaccine efficacy.

BACKGROUND: The Shingles Prevention Study (SPS) demonstrated zoster vaccine efficacy through 4 years postvaccination. A Short-Term Persistence Substudy (STPS) demonstrated persistence of vaccine efficacy for at least 5 years. A Long-Term Persistence Substudy (LTPS) was undertaken to further assess vaccine efficacy in SPS vaccine recipients followed for up to 11 years postvaccination. Study outcomes were assessed for the entire LTPS period and for each year from 7 to 11 years postvaccination. METHODS: Surveillance, case determination, and follow-up were comparable to those in SPS and STPS. Because SPS placebo recipients were offered zoster vaccine before the LTPS began, there were no unvaccinated controls. Instead, SPS and STPS placebo results were used to model reference placebo groups. RESULTS: The LTPS enrolled 6867 SPS vaccine recipients. Compared to SPS, estimated vaccine efficacy in LTPS decreased from 61.1% to 37.3% for the herpes zoster (HZ) burden of illness (BOI), from 66.5% to 35.4% for incidence of postherpetic neuralgia, and from 51.3% to 21.1% for incidence of HZ, and declined for all 3 outcome measures from 7 through 11 years postvaccination. Vaccine efficacy for the HZ BOI was significantly greater than zero through year 10 postvaccination, whereas vaccine efficacy for incidence of HZ was significantly greater than zero only through year 8. CONCLUSIONS: Estimates of vaccine efficacy decreased over time in the LTPS population compared with modeled control estimates. Statistically significant vaccine efficacy for HZ BOI persisted into year 10 postvaccination, whereas statistically significant vaccine efficacy for incidence of HZ persisted only through year 8.

Factors associated with small abdominal aortic aneurysm expansion rate.

IMPORTANCE: Because of the high mortality rate after rupture of small abdominal aortic aneurysms (AAAs), surveillance is recommended to detect aneurysm expansion; however, the effects of clinical risk factors on long-term patterns of AAA expansion are poorly characterized. OBJECTIVE: To identify significant clinical risk factors associated with the AAA expansion rate for both constant and accelerated expansion trajectories. DESIGN, SETTING, AND PARTICIPANTS: A multivariate mixed-effects model was established to identify clinical risk factors associated with the AAA expansion rate. Separate shape factor analysis was used to characterize steady vs accelerated expansion over time. Five hundred sixty-seven patients hospitalized at Veterans Affairs medical centers were randomized to the surveillance arm of the Aneurysm Detection and Management (ADAM) study conducted by the Veterans Affairs Cooperative Studies Program from 1992 to 2000. The patients had an AAA with a maximum diameter from 3.0 to 5.4 cm, which was monitored until a 5.5-cm maximum diameter was reached or the aneurysm became symptomatic. Thirty-three participants were not included in this analysis owing to missing or extraneous values in key predictor variables. The mean (SD) follow-up time was 3.7 (2.0) years. MAIN OUTCOMES AND MEASURES: The primary outcome measure was the AAA expansion rate, determined by measurement of the maximum diameter by ultrasonography at regular intervals. The objective to assess the association of clinical variables with the expansion of the AAA was formulated after data collection. RESULTS: The mean (SD) linear expansion rate of AAAs was 0.26 (0.01) cm/y. Current smoking was associated with a 0.05 (0.01)-cm/y increase in the linear expansion rate (95% CI, 0.25-0.28; P < .001), diastolic blood pressure with a 0.02 (0.01)-cm/y increase per 10 mm Hg (95% CI, 0.01-0.04; P = .001), and diabetes mellitus with a 0.11 (0.02)-cm/y decrease (95% CI, 0.07-0.16; P < .001). Diastolic blood pressure and baseline AAA diameter were associated with accelerated AAA expansion (P = .001 and P < .001, respectively). CONCLUSIONS AND RELEVANCE: Smoking cessation and control of diastolic blood pressure are direct actions that should be taken to reduce the rate of AAA expansion. Other clinical risk factors, except for diabetes, were not associated with the AAA expansion rate. This study also provides evidence of differing trajectories in AAA expansion over time, a finding that merits further investigation.

Effect of age on survival between open repair and surveillance for small abdominal aortic aneurysms.

Randomized controlled trials have shown no significant difference in survival between immediate open repair and surveillance with selective repair for asymptomatic abdominal aortic aneurysms of 4.0 to 5.5 cm in diameter. This lack of difference has been shown to hold true for all diameters in this range, in men and women, but the question of whether patients of different ages might obtain different benefits has remained unanswered. Using the pooled patient-level data for the 2,226 patients randomized to immediate open repair or surveillance in the United Kingdom Small Aneurysm Trial (UKSAT; September 1, 1991, to July 31, 1998; follow-up 2.6 to 6.9 years) or the Aneurysm Detection and Management (ADAM) trial (August 1, 1992, to July 31, 2000; follow-up 3.5 to 8.0 years), the adjusted effect of age on survival in the 2 treatment groups was estimated using a generalized propensity approach, accounting for a comprehensive array of clinical and nonclinical risk factors. No significant difference in survival between immediate open repair and surveillance was observed for patients of any age, overall (p = 0.606) or in men (p = 0.371) or women separately (p = 0.167). In conclusion, survival did not differ significantly between immediate open repair and surveillance for patients of any age, overall or in men or women. Combined with the previous evidence regarding diameter, and the lack of benefit of immediate endovascular in trials comparing it with surveillance repair for small abdominal aortic aneurysms, these results suggest that surveillance should be the first-line management strategy of choice for asymptomatic abdominal aortic aneurysms of 4.0 to 5.5 cm.

Immediate open repair vs surveillance in patients with small abdominal aortic aneurysms: survival differences by aneurysm size.

OBJECTIVE: To assess whether survival differences exist between patients undergoing immediate open repair vs surveillance with selective repair for 4.0- to 5.4-cm abdominal aortic aneurysms (AAAs) and whether these differences vary by diameter, within sexes, or overall. PATIENTS AND METHODS: The study cohort included 2226 patients randomized to immediate repair or surveillance for the UK Small Aneurysm Trial (September 1, 1991, through July 31, 1998; follow-up, 2.6-6.9 years) or the Aneurysm Detection and Management trial (August 1, 1992, through July 31, 2000; follow-up, 3.5-8.0 years). Survival differences were assessed with proportional hazard models, adjusted for a comprehensive array of clinical and nonclinical risk factors. Interaction between treatment and AAA size was added to the model to assess whether the effect of immediate open repair vs surveillance varied by AAA size. RESULTS: The adjusted analysis revealed no statistically significant survival difference between immediate open repair and surveillance patients (hazard ratio [HR], 0.99; 95% CI, 0.83-1.18; mean follow-up time, 1921 days for both study groups). This lack of treatment effect persisted when men (HR, 1.01; 95% CI, 0.84-1.21) and women (HR, 0.96; 95% CI, 0.49-1.86) were examined separately and did not vary by AAA size (P=.39 for the entire cohort and P=.24 for women). CONCLUSION: Immediate open repair offered no significant survival benefit, even in patients with the largest AAAs and highest risk of rupture. Because recent trials failed to find a survival benefit of immediate endovascular repair over surveillance for small asymptomatic AAAs, our findings suggest that the gray area of first-line management for these patients should be resolved in favor of surveillance.