Trial of Prazosin for Post-Traumatic Stress Disorder in Military Veterans.

BACKGROUND: In randomized trials, prazosin, an α1-adrenoreceptor antagonist, has been effective in alleviating nightmares associated with post-traumatic stress disorder (PTSD) in military veterans. METHODS: We recruited veterans from 13 Department of Veterans Affairs medical centers who had chronic PTSD and reported frequent nightmares. Participants were randomly assigned to receive prazosin or placebo for 26 weeks; the drug or placebo was administered in escalating divided doses over the course of 5 weeks to a daily maximum of 20 mg in men and 12 mg in women. After week 10, participants continued to receive prazosin or placebo in a double-blind fashion for an additional 16 weeks. The three primary outcome measures were the change in score from baseline to 10 weeks on the Clinician-Administered PTSD Scale (CAPS) item B2 ("recurrent distressing dreams"; scores range from 0 to 8, with higher scores indicating more frequent and more distressing dreams); the change in score from baseline to 10 weeks on the Pittsburgh Sleep Quality Index (PSQI; scores range from 0 to 21, with higher scores indicating worse sleep quality); and the Clinical Global Impression of Change (CGIC) score at 10 weeks (scores range from 1 to 7, with lower scores indicating greater improvement and a score of 4 indicating no change). RESULTS: A total of 304 participants underwent randomization; 152 were assigned to prazosin, and 152 to placebo. At 10 weeks, there were no significant differences between the prazosin group and the placebo group in the mean change from baseline in the CAPS item B2 score (between-group difference, 0.2; 95% confidence interval [CI], -0.3 to 0.8; P=0.38), in the mean change in PSQI score (between-group difference, 0.1; 95% CI, -0.9 to 1.1; P=0.80), or in the CGIC score (between-group difference, 0; 95% CI, -0.3 to 0.3; P=0.96). There were no significant differences in these measures at 26 weeks (a secondary outcome) or in other secondary outcomes. At 10 weeks, the mean difference between the prazosin group and the placebo group in the change from baseline in supine systolic blood pressure was a decrease of 6.7 mm Hg. The adverse event of new or worsening suicidal ideation occurred in 8% of the participants assigned to prazosin versus 15% of those assigned to placebo. CONCLUSIONS: In this trial involving military veterans who had chronic PTSD, prazosin did not alleviate distressing dreams or improve sleep quality. (Funded by the Department of Veterans Affairs Cooperative Studies Program; PACT ClinicalTrials.gov number, NCT00532493 .).

Cost-Effectiveness of Integrating Tobacco Cessation Into Post-Traumatic Stress Disorder Treatment.

INTRODUCTION: We examined the cost-effectiveness of smoking cessation integrated with treatment for post-traumatic stress disorder (PTSD). METHODS: Smoking veterans receiving care for PTSD (N = 943) were randomized to care integrated with smoking cessation versus referral to a smoking cessation clinic. Smoking cessation services, health care cost and utilization, quality of life, and biochemically-verified abstinence from cigarettes were assessed over 18-months of follow-up. Clinical outcomes were combined with literature on changes in smoking status and the effect of smoking on health care cost, mortality, and quality of life in a Markov model of cost-effectiveness over a lifetime horizon. We discounted cost and outcomes at 3% per year and report costs in 2010 US dollars. RESULTS: The mean of smoking cessation services cost was $1286 in those randomized to integrated care and $551 in those receiving standard care (P < .001). There were no significant differences in the cost of mental health services or other care. After 12 months, prolonged biochemically verified abstinence was observed in 8.9% of those randomized to integrated care and 4.5% of those randomized to standard care (P = .004). The model projected that Integrated Care added $836 in lifetime cost and generated 0.0259 quality adjusted life years (QALYs), an incremental cost-effectiveness ratio of $32 257 per QALY. It was 86.0% likely to be cost-effective compared to a threshold of $100 000/QALY. CONCLUSIONS: Smoking cessation integrated with treatment for PTSD was cost-effective, within a broad confidence region, but less cost-effective than most other smoking cessation programs reported in the literature.

The statin-iron nexus: anti-inflammatory intervention for arterial disease prevention.

OBJECTIVES: We postulated the existence of a statin-iron nexus by which statins improve cardiovascular disease outcomes at least partially by countering proinflammatory effects of excess iron stores. METHODS: Using data from a clinical trial of iron (ferritin) reduction in advanced peripheral arterial disease, the Iron and Atherosclerosis Study, we compared effects of ferritin levels versus high-density lipoprotein to low-density lipoprotein ratios (both were randomization variables) on clinical outcomes in participants receiving and not receiving statins. RESULTS: Statins increased high-density lipoprotein to low-density lipoprotein ratios and reduced ferritin levels by noninteracting mechanisms. Improved clinical outcomes were associated with lower ferritin levels but not with improved lipid status. CONCLUSIONS: There are commonalities between the clinical benefits of statins and the maintenance of physiologic iron levels. Iron reduction may be a safe and low-cost alternative to statins.

Longitudinal analysis of the relationship between PTSD symptom clusters, cigarette use, and physical health-related quality of life.

PURPOSE: Posttraumatic stress disorder (PTSD) symptoms, particularly numbing and hyperarousal symptoms, are related to poor physical health-related quality of life (HRQoL). Tobacco dependence is also associated with poor HRQoL, and individuals with PTSD may smoke at higher rates than the general population. Our study aimed to examine the impact of quitting smoking and changes in PTSD symptoms over time on changes in physical HRQoL. METHODS: The study used archival data from enrollees (N = 943) in a smoking cessation clinical trial for veterans with PTSD (VA Cooperative study #519). RESULTS: Two of the physical HRQoL domains were sensitive to changes in PTSD symptoms over time: General Health and Vitality. CONCLUSIONS: Our findings suggest that particular physical HRQoL domains may be subject to improvement if PTSD symptoms decrease over time.

Reduction of iron stores and clinical outcomes in peripheral arterial disease: outcome comparisons in smokers and non-smokers.

A prospective randomized trial suggested that iron (ferritin) reduction improved outcomes in smokers. The present study reanalyzed the trial results in smokers compared with non-smokers. Randomization of 1262 men with peripheral arterial disease (540 smokers and 722 non-smokers) to iron reduction (phlebotomy) or control groups permitted analysis of the effects of iron reduction and smoking on primary (all-cause mortality) and secondary (death plus non-fatal myocardial infarction or stroke) endpoints. Iron reduction resulted in significant improvement in the primary (hazard ratio [HR] 0.661, 95% confidence interval [CI] 0.45, 0.97; P = 0.036) and secondary (HR 0.64, 95% CI 0.46, 0.88; P = 0.006) endpoints compared with controls in smokers but not in non-smokers. Smokers required removal of a greater volume of blood to attain targeted ferritin reduction as compared with non-smokers (P = 0.003) and also exhibited differing characteristics from non-smokers, including significantly less statin use. Phlebotomy-related outcomes favored smokers over non-smokers. Biological linkages responsible for this unique effect offer promising lines for future iron reduction studies (ClinicalTrial.Gov Identifier: NCT00032357).

Smoking outcome expectancies in military veteran smokers with posttraumatic stress disorder.

INTRODUCTION: Smoking outcome expectancies were investigated in treatment-seeking military Veteran smokers with posttraumatic stress disorder (PTSD). The investigation of smoking outcome expectancies may enhance our understanding of the relationship between PTSD and cigarette smoking. METHODS: Participants were 943 military Veterans with a diagnosis of PTSD who were current smokers enrolled in a randomized multisite effectiveness trial to test whether the integration of smoking cessation treatment into mental health care (integrated care) improves prolonged abstinence rates compared with referral to specialized smoking cessation clinics (usual care). Using confirmatory factor analysis (CFA), we evaluated the conceptual model of smoking outcome expectancies measured on the Smoking Consequences Questionnaire-Adult (SCQ-A) version. The Kraemer method of mediation analysis was used to investigate the role of smoking outcome expectancies in mediating relationships between PTSD symptoms and smoking behavior, tobacco dependence, and abstinence self-efficacy. RESULTS: The CFA supported the 10-factor structure of the SCQ-A in smokers with PTSD. Relationships between measures of PTSD symptoms and tobacco dependence were mediated by the smoking outcome expectancy regarding negative affect reduction. This same smoking outcome expectancy mediated relationships between PTSD symptoms and smoking abstinence self-efficacy. CONCLUSIONS: The findings support the use of the SCQ-A as a valid measure of smoking outcome expectancies in military Veteran smokers with PTSD. Moreover, they suggest that smoking outcome expectancies may play an important role in explaining the relationship between PTSD and cigarette smoking.

Smoking intensity and severity of specific symptom clusters in posttraumatic stress disorder.

Smoking prevalence among patients with posttraumatic stress disorder (PTSD) is over 40%. Baseline data from the VA Cooperative Studies Program trial of integrated versus usual care for smoking cessation in veterans with PTSD (N = 863) were used in multivariate analyses of PTSD and depression severity, and 4 measures of smoking intensity: cigarettes per day (CPD), Fagerström Test for Nicotine Dependence (FTND), time to first cigarette, and expired carbon monoxide. Multivariate regression analysis showed the following significant associations: CPD with race (B = -7.16), age (B = 0.11), and emotional numbing (B =0 .16); FTND with race (B = -0.94), education (B = -0.34), emotional numbing (B = 0.04), significant distress (B = -0.12), and PHQ-9 (B = 0.04); time to first cigarette with education (B = 0.41), emotional numbing (B = -0.03), significant distress (B = 0.09), and PHQ-9 (B = -0.03); and expired carbon monoxide with race (B = -9.40). Findings suggest that among veterans with PTSD, White race and emotional numbing were most consistently related to increased smoking intensity and had more explanatory power than total PTSD symptom score. Results suggest specific PTSD symptom clusters are important to understanding smoking behavior in patients with PTSD.

Comparison of Prolonged Exposure vs Cognitive Processing Therapy for Treatment of Posttraumatic Stress Disorder Among US Veterans: A Randomized Clinical Trial.

Importance: Posttraumatic stress disorder (PTSD) is a prevalent and serious mental health problem. Although there are effective psychotherapies for PTSD, there is little information about their comparative effectiveness. Objective: To compare the effectiveness of prolonged exposure (PE) vs cognitive processing therapy (CPT) for treating PTSD in veterans. Design, Setting, and Participants: This randomized clinical trial assessed the comparative effectiveness of PE vs CPT among veterans with military-related PTSD recruited from outpatient mental health clinics at 17 Department of Veterans Affairs medical centers across the US from October 31, 2014, to February 1, 2018, with follow-up through February 1, 2019. The primary outcome was assessed using centralized masking. Tested hypotheses were prespecified before trial initiation. Data were analyzed from October 5, 2020, to May 5, 2021. Interventions: Participants were randomized to 1 of 2 individual cognitive-behavioral therapies, PE or CPT, delivered according to a flexible protocol of 10 to 14 sessions. Main Outcomes and Measures: The primary outcome was change in PTSD symptom severity on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) from before treatment to the mean after treatment across posttreatment and 3- and 6-month follow-ups. Secondary outcomes included other symptoms, functioning, and quality of life. Results: Analyses were based on all 916 randomized participants (730 [79.7%] men and 186 [20.3%] women; mean [range] age 45.2 [21-80] years), with 455 participants randomized to PE (mean CAPS-5 score at baseline, 39.9 [95% CI, 39.1-40.7] points) and 461 participants randomized to CPT (mean CAPS-5 score at baseline, 40.3 [95% CI, 39.5-41.1] points). PTSD severity on the CAPS-5 improved substantially in both PE (standardized mean difference [SMD], 0.99 [95% CI, 0.89-1.08]) and CPT (SMD, 0.71 [95% CI, 0.61-0.80]) groups from before to after treatment. Mean improvement was greater in PE than CPT (least square mean, 2.42 [95% CI, 0.53-4.31]; P = .01), but the difference was not clinically significant (SMD, 0.17). Results for self-reported PTSD symptoms were comparable with CAPS-5 findings. The PE group had higher odds of response (odds ratio [OR], 1.32 [95% CI, 1.00-1.65]; P < .001), loss of diagnosis (OR, 1.43 [95% CI, 1.12-1.74]; P < .001), and remission (OR, 1.62 [95% CI, 1.24-2.00]; P < .001) compared with the CPT group. Groups did not differ on other outcomes. Treatment dropout was higher in PE (254 participants [55.8%]) than in CPT (215 participants [46.6%]; P < .01). Three participants in the PE group and 1 participant in the CPT group were withdrawn from treatment, and 3 participants in each treatment dropped out owing to serious adverse events. Conclusions and Relevance: This randomized clinical trial found that although PE was statistically more effective than CPT, the difference was not clinically significant, and improvements in PTSD were meaningful in both treatment groups. These findings highlight the importance of shared decision-making to help patients understand the evidence and select their preferred treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT01928732.

Effect of controlled reduction of body iron stores on clinical outcomes in peripheral arterial disease.

BACKGROUND: Published results from a controlled clinical trial in patients with peripheral arterial disease found improved outcomes with iron (ferritin) reduction among middle-aged subjects but not the entire cohort. The mechanism of the age-specific effect was explored. METHODS: Randomization to iron reduction (phlebotomy, n = 636) or control (n = 641) stratified by prognostic variables permitted analysis of effects of age and ferritin on primary (all-cause mortality) and secondary (death, nonfatal myocardial infarction, and stroke) outcomes. RESULTS: Iron reduction improved outcomes in youngest age quartile patients (primary outcome hazard ratio [HR] 0.44, 95% CI 0.21-0.92, P = .028; secondary outcome HR 0.34, 95% CI 0.19-0.61, P < .001). Mean follow-up ferritin levels (MFFL) declined with increasing entry age in controls. Older age (P = .035) and higher ferritin (P < .001) at entry predicted poorer compliance with phlebotomy and rising MFFL in iron-reduction patients. Intervention produced greater ferritin reduction in younger patients. Improved outcomes with lower MFFL were found in iron-reduction patients (primary outcome HR 1.11, 95% CI 1.01-1.23, P = .028; secondary outcome HR 1.10, 95% CI 1.0-1.20, P = .044) and the entire cohort (primary outcome HR 1.11, 95% CI 1.01-1.23, P = .037). Improved outcomes occurred with MFFL below versus above the median of the entire cohort means (primary outcome HR 1.48, 95% CI 1.14-1.92, P = .003; secondary outcome HR 1.22, 95% CI 0.99-1.50, P = .067). CONCLUSIONS: Lower iron burden predicted improved outcomes overall and was enhanced by phlebotomy. Controlling iron burden may improve survival and prevent or delay nonfatal myocardial infarction and stroke.

The influence of posttraumatic stress disorder numbing and hyperarousal symptom clusters in the prediction of physical health status in veterans with chronic tobacco dependence and posttraumatic stress disorder.

Smoking and PTSD are predictors of poor physical health status. This study examined the unique contribution of PTSD symptoms in the prediction of the SF-36 physical health status subscales accounting for cigarette smoking, chronic medical conditions, alcohol and drug use disorders, and depression. This study examined baseline interview and self-report data from a national tobacco cessation randomized, controlled trial (Veterans Affairs Cooperative Study 519) that enrolled tobacco-dependent veterans with chronic PTSD (N = 943). A series of blockwise multiple regression analyses indicated that PTSD numbing and hyperarousal symptom clusters explained a significant proportion of the variance across all physical health domains except for the Physical Functioning subscale, which measures impairments in specific physical activities. Our findings further explain the impact of PTSD on health status by exploring the way PTSD symptom clusters predict self-perceptions of health, role limitations, pain, and vitality.

Design of the National Adaptive Trial for PTSD-related Insomnia (NAP Study), VA Cooperative Study Program (CSP) #2016.

There are currently no validated pharmacotherapies for posttraumatic stress disorder (PTSD)-related insomnia. The purpose of the National Adaptive Trial for PTSD-Related Insomnia (NAP Study) is to efficiently compare to placebo the effects of three insomnia medications with different mechanisms of action that are already prescribed widely to veterans diagnosed with PTSD within U.S. Department of Veterans Affairs (VA) Medical Centers. This study plans to enroll 1224 patients from 34 VA Medical Centers into a 12- week prospective, randomized placebo-controlled clinical trial comparing trazodone, eszopiclone, and gabapentin. The primary outcome measure is insomnia, assessed with the Insomnia Severity Index. A novel aspect of this study is its adaptive design. At the recruitment midpoint, an interim analysis will be conducted to inform a decision to close recruitment to any "futile" arms (i.e. arms where further recruitment is very unlikely to yield a significant result) while maintaining the overall study recruitment target. This step could result in the enrichment of the remaining study arms, enhancing statistical power for the remaining comparisons to placebo. This study will also explore clinical, actigraphic, and biochemical predictors of treatment response that may guide future biomarker development. Lastly, due to the COVID-19 pandemic, this study will allow the consenting process and follow-up visits to be conducted via video or phone contact if in-person meetings are not possible. Overall, this study aims to identify at least one effective pharmacotherapy for PTSD-related insomnia, and, perhaps, to generate definitive negative data to reduce the use of ineffective insomnia medications. NATIONAL CLINICAL TRIAL (NCT) IDENTIFIED NUMBER: NCT03668041.

Ferritin levels, inflammatory biomarkers, and mortality in peripheral arterial disease: a substudy of the Iron (Fe) and Atherosclerosis Study (FeAST) Trial.

BACKGROUND: This study delineated correlations between ferritin, inflammatory biomarkers, and mortality in a cohort of 100 cancer-free patients with peripheral arterial disease (PAD) participating in the Veterans Affairs (VA) Cooperative Study #410, the Iron (Fe) and Atherosclerosis Study (FeAST). FeAST, a prospective, randomized, single-blind clinical trial, tested the hypothesis that reduction of iron stores using phlebotomy would influence clinical outcomes in 1227 PAD patients randomized to iron reduction or control groups. The effects of statin administration were also examined in the Sierra Nevada Health Care (SNHC) cohort by measuring serum ferritin levels at entry and during the 6-year study period. No difference was documented between treatment groups in all-cause mortality and secondary outcomes of death plus nonfatal myocardial infarction and stroke. Iron reduction in the main study caused a significant age-related improvement in cardiovascular disease outcomes, new cancer diagnoses, and cancer-specific death. METHODS: Tumor necrosis factor (TNF)-alpha, TNF-alpha receptors 1 and 2, interleukin (IL)-2, IL-6, IL-10, and high-sensitivity C reactive protein (hs-CRP) were measured at entry and at 6-month intervals for 6 years. Average levels of ferritin and lipids at entry and at the end of the study were compared. The clinical course and ferritin levels of 23 participants who died during the study were reviewed. RESULTS: At entry, mean age of entry was 67 +/- 9 years for the SNHCS cohort, comparable to FeAST and clinical and laboratory parameters were equivalent in substudy participants randomized to iron reduction (n = 51) or control (n = 49). At baseline, 53 participants on statins had slightly lower mean entry-level ferritin values (114.06 ng/mL; 95% confidence interval [CI] 93.43-134.69) vs the 47 off statins (127.62 ng/mL; 95% CI, 103.21-152.02). Longitudinal analysis of follow-up data, after adjusting for the phlebotomy treatment effect, showed that statin use was associated with significantly lower ferritin levels (-29.78 ng/mL; Cohen effect size, -0.47 [t(df, 134) = 2.33, P = .02]). Mean follow-up average ferritin levels were higher in 23 participants who died (132.5 ng/mL; 95% CI, 79.36-185.66) vs 77 survivors (83.6 ng/mL; 95% CI, 70.34-96.90; Wilcoxon P = .05). Mean follow-up IL-6 levels were higher in dead participants (21.68 ng/mL; 95% CI, 13.71-29.66) vs survivors (12.61 ng/mL; 95% CI, 10.72-14.50; Wilcoxon P = .018). Ferritin levels correlated (Pearson) with average IL-6 levels (r = 0.1845; P = .002) and hsCRP levels (r = .1175; P = .04) during the study. CONCLUSION: These data demonstrate statistical correlations between levels of ferritin, inflammatory biomarkers, and mortality in this subset of patients with PAD.

Integrating tobacco cessation into mental health care for posttraumatic stress disorder: a randomized controlled trial.

CONTEXT: Most smokers with mental illness do not receive tobacco cessation treatment. OBJECTIVE: To determine whether integrating smoking cessation treatment into mental health care for veterans with posttraumatic stress disorder (PTSD) improves long-term smoking abstinence rates. DESIGN, SETTING, AND PATIENTS: A randomized controlled trial of 943 smokers with military-related PTSD who were recruited from outpatient PTSD clinics at 10 Veterans Affairs medical centers and followed up for 18 to 48 months between November 2004 and July 2009. INTERVENTION: Smoking cessation treatment integrated within mental health care for PTSD delivered by mental health clinicians (integrated care [IC]) vs referral to Veterans Affairs smoking cessation clinics (SCC). Patients received smoking cessation treatment within 3 months of study enrollment. MAIN OUTCOME MEASURES: Smoking outcomes included 12-month bioverified prolonged abstinence (primary outcome) and 7- and 30-day point prevalence abstinence assessed at 3-month intervals. Amount of smoking cessation medications and counseling sessions delivered were tested as mediators of outcome. Posttraumatic stress disorder and depression were repeatedly assessed using the PTSD Checklist and Patient Health Questionnaire 9, respectively, to determine if IC participation or quitting smoking worsened psychiatric status. RESULTS: Integrated care was better than SCC on prolonged abstinence (8.9% vs 4.5%; adjusted odds ratio, 2.26; 95% confidence interval [CI], 1.30-3.91; P = .004). Differences between IC vs SCC were largest at 6 months for 7-day point prevalence abstinence (78/472 [16.5%] vs 34/471 [7.2%], P < .001) and remained significant at 18 months (86/472 [18.2%] vs 51/471 [10.8%], P < .001). Number of counseling sessions received and days of cessation medication used explained 39.1% of the treatment effect. Between baseline and 18 months, psychiatric status did not differ between treatment conditions. Posttraumatic stress disorder symptoms for quitters and nonquitters improved. Nonquitters worsened slightly on the Patient Health Questionnaire 9 relative to quitters (differences ranged between 0.4 and 2.1, P = .03), whose scores did not change over time. CONCLUSION: Among smokers with military-related PTSD, integrating smoking cessation treatment into mental health care compared with referral to specialized cessation treatment resulted in greater prolonged abstinence. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00118534.

Iron reduction response and demographic differences between diabetics and non-diabetics with cardiovascular disease entered into a controlled clinical trial.

Iron-catalyzed oxygen-free radical-induced oxidative stress mediates the pathogenesis of diabetes and cardiovascular disease (CVD). Diabetics (n = 473) and non-diabetics (n = 804) with CVD entered into a randomized trial of iron (ferritin) reduction by calibrated phlebotomy (, Identifier NCT00032357) had comparable iron measures at entry but diabetics had a greater burden of CVD and comorbidities, lower hemoglobin and hematocrit levels, and higher glucose levels than non-diabetics. Entry iron measures were lower in diabetics on hypoglycemic therapy compared to previously untreated diabetics. Diabetics and non-diabetics had comparable iron measures during follow-up. The Loess analysis of paired ferritin and hemoglobin, and paired ferritin and glucose levels in diabetics randomized to phlebotomy showed higher ferritin levels associated with lower hemoglobin and higher glucose levels. Progressive ferritin reduction in diabetics correlated with increasing hemoglobin and decreasing glucose levels, neither of which reached levels observed in non-diabetics. We postulate that phlebotomy-triggered autophagy (ferritinophagy) released redox-active iron sequestered intracellularly, worsening anemia and glucose utilization that corrected partially with ferritin reduction. Intracellular redox-active iron levels contributory to disease, not reflected in peripheral iron measures, may persist because of glycation of iron transport proteins in diabetes. These findings suggest novel strategies for disease prevention and improving outcomes in diabetes and CVD.

Reduction of iron stores and cardiovascular outcomes in patients with peripheral arterial disease: a randomized controlled trial.

CONTEXT: Accumulation of iron in excess of physiologic requirements has been implicated in risk of cardiovascular disease because of increased iron-catalyzed free radical-mediated oxidative stress. OBJECTIVE: To test the hypothesis that reducing body iron stores through phlebotomy will influence clinical outcomes in a cohort of patients with symptomatic peripheral arterial disease (PAD). DESIGN, SETTING, AND PATIENTS: Multicenter, randomized, controlled, single-blinded clinical trial based on the Iron (Fe) and Atherosclerosis Study (FeAST) (VA Cooperative Study #410) and conducted between May 1, 1999, and April 30, 2005, within the Department of Veterans Affairs Cooperative Studies Program and enrolling 1277 patients with symptomatic but stable PAD. Those with conditions likely to cause acute-phase increase of the ferritin level or with a diagnosis of visceral malignancy within the preceding 5 years were excluded. Analysis was by intent-to-treat. INTERVENTION: Patients were assigned to a control group (n = 641) or to a group undergoing reduction of iron stores by phlebotomy with removal of defined volumes of blood at 6-month intervals (avoiding iron deficiency) (n = 636), stratified by hospital, age, and baseline smoking status, diagnosis of diabetes mellitus, ratio of high-density to low-density lipoprotein cholesterol level, and ferritin level. MAIN OUTCOME MEASURES: The primary end point was all-cause mortality; the secondary end point was death plus nonfatal myocardial infarction and stroke. RESULTS: There were no significant differences between treatment groups for the primary or secondary study end points. All-cause deaths occurred in 148 patients (23%) in the control group and in 125 (20%) in the iron-reduction group (hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.67-1.08; P = .17). Death plus nonfatal myocardial infarction and stroke occurred in 205 patients (32%) in the control group and in 180 (28%) in the iron-reduction group (HR, 0.88; 95% CI, 0.72-1.07; P = .20). CONCLUSION: Reduction of body iron stores in patients with symptomatic PAD did not significantly decrease all-cause mortality or death plus nonfatal myocardial infarction and stroke. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00032357.

Cognitive behavioral therapy for posttraumatic stress disorder in women: a randomized controlled trial.

CONTEXT: The prevalence of posttraumatic stress disorder (PTSD) is elevated among women who have served in the military, but no prior study has evaluated treatment for PTSD in this population. Prior research suggests that cognitive behavioral therapy is a particularly effective treatment for PTSD. OBJECTIVE: To compare prolonged exposure, a type of cognitive behavioral therapy, with present-centered therapy, a supportive intervention, for the treatment of PTSD. DESIGN, SETTING, AND PARTICIPANTS: A randomized controlled trial of female veterans (n=277) and active-duty personnel (n=7) with PTSD recruited from 9 VA medical centers, 2 VA readjustment counseling centers, and 1 military hospital from August 2002 through October 2005. INTERVENTION: Participants were randomly assigned to receive prolonged exposure (n = 141) or present-centered therapy (n = 143), delivered according to standard protocols in 10 weekly 90-minute sessions. MAIN OUTCOME MEASURES: Posttraumatic stress disorder symptom severity was the primary outcome. Comorbid symptoms, functioning, and quality of life were secondary outcomes. Blinded assessors collected data before and after treatment and at 3- and 6-month follow-up. RESULTS: Women who received prolonged exposure experienced greater reduction of PTSD symptoms relative to women who received present-centered therapy (effect size, 0.27; P = .03). The prolonged exposure group was more likely than the present-centered therapy group to no longer meet PTSD diagnostic criteria (41.0% vs 27.8%; odds ratio, 1.80; 95% confidence interval, 1.10-2.96; P = .01) and achieve total remission (15.2% vs 6.9%; odds ratio, 2.43; 95% confidence interval, 1.10-5.37; P = .01). Effects were consistent over time in longitudinal analyses, although in cross-sectional analyses most differences occurred immediately after treatment. CONCLUSIONS: Prolonged exposure is an effective treatment for PTSD in female veterans and active-duty military personnel. It is feasible to implement prolonged exposure across a range of clinical settings. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00032617.

Ferritin and Percent Transferrin Saturation Levels Predict Type 2 Diabetes Risk and Cardiovascular Disease Outcomes.

INTRODUCTION: Type 2 diabetes (T2D) and cardiovascular disease (CVD) risk associate with ferritin and percent transferrin saturation (%TS) levels. However, increased risk has been observed at levels considered within the "normal range" for these markers. OBJECTIVE: To define normative ferritin and %TS levels associated with T2D and CVD risk. METHODS: Six-monthly ferritin, %TS and hemoglobin levels from 1,277 iron reduction clinical trial participants with CVD (peripheral arterial disease, 37% diabetic) permitted pair-wise analysis using Loess Locally Weighted Smoothing plots. Curves showed continuous quantitative ferritin, hemoglobin (reflecting physiologic iron requirements), and %TS (reflecting iron transport and sequestration) levels over a wide range of values. Inflection points in the curves were compared to ferritin and %TS levels indicating increased T2D and CVD risk in epidemiologic and intervention studies. RESULTS: Increasing ferritin up to about 80 ng/mL and %TS up to about 25% TS corresponded to increasing hemoglobin levels, and minimal T2D and CVD risk. Displaced Loess trajectories reflected lower hemoglobin levels in diabetics compared to non-diabetics. Ferritin levels up to about 100 ng/mL paralleled proportionately increasing %TS levels up to about 55%TS corresponding to further limitation of T2D and CVD risk. Ferritin levels over 100 ng/mL did not associate with hemoglobin levels and coincided with increased T2D and CVD risk. CONCLUSIONS: Recognition of modified normal ranges for ferritin from about 15 ng/mL up to about 80- 100 ng/mL and %TS from about 15% up to about 25-55% may improve the value of iron biomarkers to assess and possibly lower T2D and CVD risk.

Racial Health Disparities, and Variant Red Cell and Iron Homeostasis.

Oxidative stress from excess iron may contribute to racial health disparities. Previously we reported improved clinical outcomes with lower ferritin and higher percent transferrin saturation (%TS) levels in White but not Black participants with peripheral arterial disease entered to a clinical trial. This report demonstrates racially variant interactions between hemoglobin, ferritin, and %TS levels. Lower hemoglobin and %TS levels, and higher ferritin levels were documented in Black compared with White participants within cardiovascular disease risk categories. Ferritin levels near 80 ng/mL related to higher hemoglobin levels in White but not Black participants. Higher %TS levels with ferritin levels above 80 ng/mL in White participants were blunted in Black participants. Ferritin/%TS ratios were significantly higher in Black than White participants. Iron incorporation into hemoglobin and scavenging by transferrin may buffer iron toxicity more effectively in White than in Black individuals. Metabolic vulnerability to iron excess may explain, in part, racial health disparities.

Cost-effectiveness of a conservative, ischemia-guided management strategy after non-Q-wave myocardial infarction: results of a randomized trial.

BACKGROUND: Use of coronary angiography after myocardial infarction has been controversial, with some physicians advocating routine use and others advocating selective use only after documentation of residual myocardial ischemia. The effects of these strategies on economic outcomes have not been established. METHODS AND RESULTS: We analyzed data from a randomized, controlled clinical trial conducted in 17 Department of Veterans Affairs hospitals that enrolled 876 clinically uncomplicated patients 24 to 72 hours after an acute non-Q-wave myocardial infarction. The routine invasive strategy included early coronary angiography with revascularization based on established guidelines. The conservative, ischemia-guided strategy included noninvasive testing with radionuclide ventriculography and exercise thallium scintigraphy, followed by coronary angiography in patients with objective evidence of myocardial ischemia. We measured the cost of hospitalization and outpatient visits and tests during follow-up and calculated the incremental cost-effectiveness ratio. The conservative, ischemia-guided strategy had lower costs than the routine invasive strategy, both during the initial hospitalization ($14 733 versus $19 256, P<0.001) and after a mean follow-up of 1.9 years ($39 707 versus $41 893, P=0.04). The hazard ratio for death was 0.72 (confidence limits, 0.51 to 1.01) in the conservative strategy. The conservative strategy had lower costs and better outcomes in 76% of 1000 bootstrap replications, and a cost-effectiveness ratio below $50 000 per year of life added in 96% of replications. CONCLUSIONS: A conservative, ischemia-guided strategy of selective coronary angiography and revascularization for patients who develop objective evidence of recurrent ischemia is more cost-effective than a strategy of routine coronary angiography after uncomplicated non-Q-wave myocardial infarction.

Issues in the design of multisite clinical trials of psychotherapy: VA Cooperative Study No. 494 as an example.

This article describes issues in the design of an ongoing multisite randomized clinical trial of psychotherapy for treating posttraumatic stress disorder (PTSD) in female veterans and active duty personnel. Research aimed at testing treatments for PTSD in women who have served in the military is especially important due to the high prevalence of PTSD in this population. VA Cooperative Study 494 was designed to enroll 384 participants across 12 sites. Participants are randomly assigned to receive 10 weekly sessions of individual psychotherapy: Prolonged Exposure, a specific cognitive-behavioral therapy protocol for PTSD, or present-centered therapy, a comparison treatment that addresses current interpersonal problems but avoids a trauma focus. PTSD is the primary outcome. Additional outcomes are comorbid problems such as depression and anxiety; psychosocial function and quality of life; physical health status; satisfaction with treatment; and service utilization. Follow-up assessments are conducted at the end of treatment and then 3 and 6 months after treatment. Both treatments are delivered according to a manual. Videotapes of therapy sessions are viewed by experts who provide feedback to therapists throughout the trial to ensure adherence to the treatment manual. Discussion includes issues encountered in multisite psychotherapy trials along with the rationale for our decisions about how we addressed these issues in CSP #494.