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 .).

Pallidal versus subthalamic deep-brain stimulation for Parkinson's disease.

BACKGROUND: Deep-brain stimulation is the surgical procedure of choice for patients with advanced Parkinson's disease. The globus pallidus interna and the subthalamic nucleus are accepted targets for this procedure. We compared 24-month outcomes for patients who had undergone bilateral stimulation of the globus pallidus interna (pallidal stimulation) or subthalamic nucleus (subthalamic stimulation). METHODS: At seven Veterans Affairs and six university hospitals, we randomly assigned 299 patients with idiopathic Parkinson's disease to undergo either pallidal stimulation (152 patients) or subthalamic stimulation (147 patients). The primary outcome was the change in motor function, as blindly assessed on the Unified Parkinson's Disease Rating Scale, part III (UPDRS-III), while patients were receiving stimulation but not receiving antiparkinsonian medication. Secondary outcomes included self-reported function, quality of life, neurocognitive function, and adverse events. RESULTS: Mean changes in the primary outcome did not differ significantly between the two study groups (P=0.50). There was also no significant difference in self-reported function. Patients undergoing subthalamic stimulation required a lower dose of dopaminergic agents than did those undergoing pallidal stimulation (P=0.02). One component of processing speed (visuomotor) declined more after subthalamic stimulation than after pallidal stimulation (P=0.03). The level of depression worsened after subthalamic stimulation and improved after pallidal stimulation (P=0.02). Serious adverse events occurred in 51% of patients undergoing pallidal stimulation and in 56% of those undergoing subthalamic stimulation, with no significant between-group differences at 24 months. CONCLUSIONS: Patients with Parkinson's disease had similar improvement in motor function after either pallidal or subthalamic stimulation. Nonmotor factors may reasonably be included in the selection of surgical target for deep-brain stimulation. (ClinicalTrials.gov numbers, NCT00056563 and NCT01076452.)

Detection and tracking of a novel genetically tagged biological simulant in the environment.

A variant of Bacillus thuringiensis subsp. kurstaki containing a single, stable copy of a uniquely amplifiable DNA oligomer integrated into the genome for tracking the fate of biological agents in the environment was developed. The use of genetically tagged spores overcomes the ambiguity of discerning the test material from pre-existing environmental microflora or from previously released background material. In this study, we demonstrate the utility of the genetically "barcoded" simulant in a controlled indoor setting and in an outdoor release. In an ambient breeze tunnel test, spores deposited on tiles were reaerosolized and detected by real-time PCR at distances of 30 m from the point of deposition. Real-time PCR signals were inversely correlated with distance from the seeded tiles. An outdoor release of powdered spore simulant at Aberdeen Proving Ground, Edgewood, MD, was monitored from a distance by a light detection and ranging (LIDAR) laser. Over a 2-week period, an array of air sampling units collected samples were analyzed for the presence of viable spores and using barcode-specific real-time PCR assays. Barcoded B. thuringiensis subsp. kurstaki spores were unambiguously identified on the day of the release, and viable material was recovered in a pattern consistent with the cloud track predicted by prevailing winds and by data tracks provided by the LIDAR system. Finally, the real-time PCR assays successfully differentiated barcoded B. thuringiensis subsp. kurstaki spores from wild-type spores under field conditions.

Considerations to increase rates of breast cancer screening across populations.

OBJECTIVES: COVID-19 has caused considerable drops in utilization of breast cancer screening services during the pandemic, especially among certain racial and ethnic groups. Members of the Community Oncology Alliance (COA)-including the COA president, South Carolina oncologist Kashyap Patel, MD-have reported increases in patients, particularly those of color, presenting with stage III and IV cancer at diagnosis. According to data released by the Biden administration, more than 9.5 million recommended cancer screenings had been missed in the United States as a result of the COVID-19 pandemic, as of February 2022. President Joe Biden and First Lady Jill Biden, EdD, aim to address this in the 2022 revitalized Cancer Moonshot Initiative. The findings made by COA as well as by Avalere also suggest that the pandemic has exacerbated existing health care disparities. METHODS: Using a multipayer database, we analyzed breast cancer screening rates for 2 periods-March 1 to September 30, 2019, and March 1 to September 30, 2020-among Medicare fee-for-service (FFS), managed Medicaid, and commercial insurance beneficiaries to understand the potential impact of the COVID-19 pandemic on adherence to the US Preventive Services Task Force breast cancer screening recommendations, which are currently undergoing review. Screening rates were evaluated across 5 racial/ethnic groups and by payer type. RESULTS: Mean monthly mammogram screening rates among eligible White Medicare FFS beneficiaries dropped to 0.6% in April 2020, but these screening rates recovered to 6.5% by June 2020. Screening rates for eligible Black Medicare FFS beneficiaries recovered on a pace slightly slower than that of White beneficiaries, but more rapidly than that of other groups. By comparison, American Indian/Alaska Native beneficiaries had a mean monthly screening rate of 0.5% in April 2020, which recovered to 3.1% in June 2020; these were below 2019 screening rates of 4.2% for April and 3.9% for June. Differences in screening rates by payer type were also observed. Patients with commercial insurance had higher screening rates compared with those covered by Medicare FFS and managed Medicaid. CONCLUSIONS: Our principal finding shows that mean breast cancer screening rates decreased in April 2020 across all payers, but recovery to prepandemic screening levels has occurred more slowly among certain racial and ethnic minority groups. Differences in recovery rates by payer type highlight a strong relationship between income level and screening utilization.

Optimal medical therapy with or without PCI for stable coronary disease.

BACKGROUND: In patients with stable coronary artery disease, it remains unclear whether an initial management strategy of percutaneous coronary intervention (PCI) with intensive pharmacologic therapy and lifestyle intervention (optimal medical therapy) is superior to optimal medical therapy alone in reducing the risk of cardiovascular events. METHODS: We conducted a randomized trial involving 2287 patients who had objective evidence of myocardial ischemia and significant coronary artery disease at 50 U.S. and Canadian centers. Between 1999 and 2004, we assigned 1149 patients to undergo PCI with optimal medical therapy (PCI group) and 1138 to receive optimal medical therapy alone (medical-therapy group). The primary outcome was death from any cause and nonfatal myocardial infarction during a follow-up period of 2.5 to 7.0 years (median, 4.6). RESULTS: There were 211 primary events in the PCI group and 202 events in the medical-therapy group. The 4.6-year cumulative primary-event rates were 19.0% in the PCI group and 18.5% in the medical-therapy group (hazard ratio for the PCI group, 1.05; 95% confidence interval [CI], 0.87 to 1.27; P=0.62). There were no significant differences between the PCI group and the medical-therapy group in the composite of death, myocardial infarction, and stroke (20.0% vs. 19.5%; hazard ratio, 1.05; 95% CI, 0.87 to 1.27; P=0.62); hospitalization for acute coronary syndrome (12.4% vs. 11.8%; hazard ratio, 1.07; 95% CI, 0.84 to 1.37; P=0.56); or myocardial infarction (13.2% vs. 12.3%; hazard ratio, 1.13; 95% CI, 0.89 to 1.43; P=0.33). CONCLUSIONS: As an initial management strategy in patients with stable coronary artery disease, PCI did not reduce the risk of death, myocardial infarction, or other major cardiovascular events when added to optimal medical therapy. (ClinicalTrials.gov number, NCT00007657 [ClinicalTrials.gov].).

Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT.

BACKGROUND: Knee osteoarthritis (OA) is a major cause of pain and functional limitation in older adults, yet longer-term studies of medical treatment of OA are limited. OBJECTIVE: To evaluate the efficacy and safety of glucosamine and chondroitin sulphate (CS), alone or in combination, as well as celecoxib and placebo on painful knee OA over 2 years. METHODS: A 24-month, double-blind, placebo-controlled study, conducted at nine sites in the US ancillary to the Glucosamine/chondroitin Arthritis Intervention Trial, enrolled 662 patients with knee OA who satisfied radiographic criteria (Kellgren/Lawrence grade 2 or 3 changes and baseline joint space width of at least 2 mm). This subset continued to receive their randomised treatment: glucosamine 500 mg three times daily, CS 400 mg three times daily, the combination of glucosamine and CS, celecoxib 200 mg daily, or placebo over 24 months. The primary outcome was a 20% reduction in Western Ontario and McMaster University Osteoarthritis Index (WOMAC) pain over 24 months. Secondary outcomes included an Outcome Measures in Rheumatology/Osteoarthritis Research Society International response and change from baseline in WOMAC pain and function. RESULTS: Compared with placebo, the odds of achieving a 20% reduction in WOMAC pain were celecoxib: 1.21, glucosamine: 1.16, combination glucosamine/CS: 0.83 and CS alone: 0.69, and were not statistically significant. CONCLUSIONS: Over 2 years, no treatment achieved a clinically important difference in WOMAC pain or function as compared with placebo. However, glucosamine and celecoxib showed beneficial but not significant trends. Adverse reactions were similar among treatment groups and serious adverse events were rare for all treatments.

Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis.

BACKGROUND: Glucosamine and chondroitin sulfate are used to treat osteoarthritis. The multicenter, double-blind, placebo- and celecoxib-controlled Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) evaluated their efficacy and safety as a treatment for knee pain from osteoarthritis. METHODS: We randomly assigned 1583 patients with symptomatic knee osteoarthritis to receive 1500 mg of glucosamine daily, 1200 mg of chondroitin sulfate daily, both glucosamine and chondroitin sulfate, 200 mg of celecoxib daily, or placebo for 24 weeks. Up to 4000 mg of acetaminophen daily was allowed as rescue analgesia. Assignment was stratified according to the severity of knee pain (mild [N=1229] vs. moderate to severe [N=354]). The primary outcome measure was a 20 percent decrease in knee pain from baseline to week 24. RESULTS: The mean age of the patients was 59 years, and 64 percent were women. Overall, glucosamine and chondroitin sulfate were not significantly better than placebo in reducing knee pain by 20 percent. As compared with the rate of response to placebo (60.1 percent), the rate of response to glucosamine was 3.9 percentage points higher (P=0.30), the rate of response to chondroitin sulfate was 5.3 percentage points higher (P=0.17), and the rate of response to combined treatment was 6.5 percentage points higher (P=0.09). The rate of response in the celecoxib control group was 10.0 percentage points higher than that in the placebo control group (P=0.008). For patients with moderate-to-severe pain at baseline, the rate of response was significantly higher with combined therapy than with placebo (79.2 percent vs. 54.3 percent, P=0.002). Adverse events were mild, infrequent, and evenly distributed among the groups. CONCLUSIONS: Glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee. Exploratory analyses suggest that the combination of glucosamine and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain. (ClinicalTrials.gov number, NCT00032890.).

Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial.

CONTEXT: Deep brain stimulation is an accepted treatment for advanced Parkinson disease (PD), although there are few randomized trials comparing treatments, and most studies exclude older patients. OBJECTIVE: To compare 6-month outcomes for patients with PD who received deep brain stimulation or best medical therapy. DESIGN, SETTING, AND PATIENTS: Randomized controlled trial of patients who received either deep brain stimulation or best medical therapy, stratified by study site and patient age (< 70 years vs > or = 70 years) at 7 Veterans Affairs and 6 university hospitals between May 2002 and October 2005. A total of 255 patients with PD (Hoehn and Yahr stage > or = 2 while not taking medications) were enrolled; 25% were aged 70 years or older. The final 6-month follow-up visit occurred in May 2006. INTERVENTION: Bilateral deep brain stimulation of the subthalamic nucleus (n = 60) or globus pallidus (n = 61). Patients receiving best medical therapy (n = 134) were actively managed by movement disorder neurologists. MAIN OUTCOME MEASURES: The primary outcome was time spent in the "on" state (good motor control with unimpeded motor function) without troubling dyskinesia, using motor diaries. Other outcomes included motor function, quality of life, neurocognitive function, and adverse events. RESULTS: Patients who received deep brain stimulation gained a mean of 4.6 h/d of on time without troubling dyskinesia compared with 0 h/d for patients who received best medical therapy (between group mean difference, 4.5 h/d [95% CI, 3.7-5.4 h/d]; P < .001). Motor function improved significantly (P < .001) with deep brain stimulation vs best medical therapy, such that 71% of deep brain stimulation patients and 32% of best medical therapy patients experienced clinically meaningful motor function improvements (> or = 5 points). Compared with the best medical therapy group, the deep brain stimulation group experienced significant improvements in the summary measure of quality of life and on 7 of 8 PD quality-of-life scores (P < .001). Neurocognitive testing revealed small decrements in some areas of information processing for patients receiving deep brain stimulation vs best medical therapy. At least 1 serious adverse event occurred in 49 deep brain stimulation patients and 15 best medical therapy patients (P < .001), including 39 adverse events related to the surgical procedure and 1 death secondary to cerebral hemorrhage. CONCLUSION: In this randomized controlled trial of patients with advanced PD, deep brain stimulation was more effective than best medical therapy in improving on time without troubling dyskinesias, motor function, and quality of life at 6 months, but was associated with an increased risk of serious adverse events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00056563.

Amiodarone versus sotalol for atrial fibrillation.

BACKGROUND: The optimal pharmacologic means to restore and maintain sinus rhythm in patients with atrial fibrillation remains controversial. METHODS: In this double-blind, placebo-controlled trial, we randomly assigned 665 patients who were receiving anticoagulants and had persistent atrial fibrillation to receive amiodarone (267 patients), sotalol (261 patients), or placebo (137 patients) and monitored them for 1 to 4.5 years. The primary end point was the time to recurrence of atrial fibrillation beginning on day 28, determined by means of weekly transtelephonic monitoring. RESULTS: Spontaneous conversion occurred in 27.1 percent of the amiodarone group, 24.2 percent of the sotalol group, and 0.8 percent of the placebo group, and direct-current cardioversion failed in 27.7 percent, 26.5 percent, and 32.1 percent, respectively. The median times to a recurrence of atrial fibrillation were 487 days in the amiodarone group, 74 days in the sotalol group, and 6 days in the placebo group according to intention to treat and 809, 209, and 13 days, respectively, according to treatment received. Amiodarone was superior to sotalol (P<0.001) and to placebo (P<0.001), and sotalol was superior to placebo (P<0.001). In patients with ischemic heart disease, the median time to a recurrence of atrial fibrillation was 569 days with amiodarone therapy and 428 days with sotalol therapy (P=0.53). Restoration and maintenance of sinus rhythm significantly improved the quality of life and exercise capacity. There were no significant differences in major adverse events among the three groups. CONCLUSIONS: Amiodarone and sotalol are equally efficacious in converting atrial fibrillation to sinus rhythm. Amiodarone is superior for maintaining sinus rhythm, but both drugs have similar efficacy in patients with ischemic heart disease. Sustained sinus rhythm is associated with an improved quality of life and improved exercise performance.

The evolving pattern of symptomatic coronary artery disease in the United States and Canada: baseline characteristics of the Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation (COURAGE) trial.

Major improvements in medical therapy and percutaneous coronary intervention for coronary artery disease (CAD) have emerged during the previous 2 decades, but no randomized trial in patients with stable CAD has been powered to compare these 2 strategies for the hard clinical end points of death or myocardial infarction (MI), and previous studies have not evaluated the effect of coronary stents and intensive medical therapy on cardiac events during long-term follow-up. Between 1999 and 2004, 2,287 patients with documented myocardial ischemia and angiographically confirmed CAD were randomized to the Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation (COURAGE) trial, with a principal hypothesis that a strategy of percutaneous coronary intervention plus intensive, guideline-driven medical therapy would be superior to a strategy of intensive medical therapy alone. The primary end point was a composite of all-cause mortality or acute MI (time to first event) during a 2.5- to 7-year (median 5) follow-up. Baseline characteristics were a mean age of 62 +/- 5 years, 85% men, and 86% Caucasian. Mean duration of angina before randomization was 26 months (average 10 episodes/week), and 29% of patients were smokers, 67% had hypertension, 38% had previous MI, 71% had dyslipidemia, 34% had diabetes, 27% had previous revascularization, and 69% had multivessel CAD. Approximately 55% of patients met established criteria for the metabolic syndrome. In conclusion, baseline characteristics of the COURAGE trial study population indicate a highly symptomatic group of patients with CAD who have a significant duration and frequency of antecedent angina pectoris and a high prevalence of cardiac risk factors.

Design and rationale of the Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation (COURAGE) trial Veterans Affairs Cooperative Studies Program no. 424.

BACKGROUND: Major improvements in medical therapy and percutaneous coronary intervention (PCI) for coronary heart disease have occurred during the past decade, but no randomized trial has compared these 2 strategies for the "hard" clinical end points of death or myocardial infarction nor have earlier studies incorporated the use of coronary stents and aggressive multifaceted medical therapy during long-term follow-up. METHODS: The COURAGE trial is a multicenter study of patients with documented myocardial ischemia and angiographically confirmed single or multivessel coronary artery disease who are randomized to a strategy of PCI plus intensive medical therapy or intensive medical therapy alone. Medical therapy in both groups is guideline-driven and includes: aspirin, clopidogrel, simvastatin (low-density lipoprotein cholesterol target 60-85 mg/dL), long-acting metoprolol and/or amlodipine, lisinopril or losartan, and long-acting nitrates, as well as lifestyle interventions. The primary end point is a composite of all-cause mortality or acute myocardial infarction, and there will be 85% power to detect an absolute 4.6% (relative 22%) difference between strategies. The principal hypothesis is that PCI plus aggressive medical therapy (projected event rate 16.4%) will be superior to aggressive medical therapy alone (projected event rate 21%) during a 2.5- to 7-year (median of 5 years) follow-up. CONCLUSIONS: COURAGE is the largest prospective randomized trial of PCI versus intensive medical therapy to date and will define the incremental benefits of PCI in the setting of contemporary optimal medical therapy for chronic coronary heart disease. A total of 2287 patients have been enrolled, and follow-up will conclude in June 2006.

GI risk factors and use of GI protective agents among patients receiving nonsteroidal antiinflammatory drugs.

BACKGROUND: Patient characteristics increase the risk of gastrointestinal (GI) complications associated with nonsteroidal antiinflammatory drugs (NSAIDs). Patients at risk may not be prescribed protective therapies that might mitigate their risk of NSAID-associated GI complications. OBJECTIVE: To assess GI risk among Veterans Affairs (VA) patients on NSAID therapy, determine whether therapy conformed to VA guidelines for lessening the risk of GI complications, and identify patient risk factors associated with conformance. METHODS: Using databases from 3 VA medical centers, we retrospectively identified patients receiving NSAIDs and obtained data regarding age, history of GI bleed over 8 years, GI adverse effects associated with NSAIDs, diagnoses, and medication history over one year. We inferred health status from age-adjusted Charlson comorbidity index values. Each patient's risk of developing GI complications over one year was calculated using these data. Among patients at significant or substantial risk, we assessed conformance to VA guidelines. We used logistic regression to identify risk factors associated with conformance and determine adjusted ORs (AORs) with 95% CIs for each risk factor. RESULTS: There were 19 122 patients receiving NSAIDs. Of 4589 patients at significant risk and 1246 at substantial risk, 1161 (25.3%) and 356 (28.6%), respectively, were prescribed guideline-conformant therapy. Risk factors associated with conformance (p < or = 0.001) among patients at significant risk were rheumatoid arthritis (AOR 1.34; 95% CI 1.13 to 1.58) and GI adverse effects (AOR 1.53; 95% CI 1.42 to 1.64). For substantial risk patients, risk factors associated with conformance (p < or = 0.031) were rheumatoid arthritis (AOR 1.65; 95% CI 1.37 to 1.98), concomitant corticosteroids (AOR 1.21; 95% CI 1.02 to 1.43), GI hospitalization (AOR 2.01; 95% CI 1.57 to 2.59), and GI adverse effects (AOR 1.79; 95% CI 1.47 to 2.18). CONCLUSIONS: Many patients at risk for GI adverse events do not receive guideline-conformant therapy. Educational interventions to improve conformance could focus on specific risk factors for GI complications.

Randomized trial of deep brain stimulation for Parkinson disease: thirty-six-month outcomes.

OBJECTIVES: Our objective was to compare long-term outcomes of deep brain stimulation (DBS) of the globus pallidus interna (GPi) and subthalamic nucleus (STN) for patients with Parkinson disease (PD) in a multicenter randomized controlled trial. METHODS: Patients randomly assigned to GPi (n = 89) or STN DBS (n = 70) were followed for 36 months. The primary outcome was motor function on stimulation/off medication using the Unified Parkinson's Disease Rating Scale motor subscale. Secondary outcomes included quality of life and neurocognitive function. RESULTS: Motor function improved between baseline and 36 months for GPi (41.1 to 27.1; 95% confidence interval [CI] -16.4 to -10.8; p < 0.001) and STN (42.5 to 29.7; 95% CI -15.8 to -9.4; p < 0.001); improvements were similar between targets and stable over time (p = 0.59). Health-related quality of life improved at 6 months on all subscales (all p values significant), but improvement diminished over time. Mattis Dementia Rating Scale scores declined faster for STN than GPi patients (p = 0.01); other neurocognitive measures showed gradual decline overall. CONCLUSIONS: The beneficial effect of DBS on motor function was stable and comparable by target over 36 months. Slight declines in quality of life following initial gains and gradual decline in neurocognitive function likely reflect underlying disease progression and highlight the importance of nonmotor symptoms in determining quality of life. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that improvement of motor symptoms of PD by DBS remains stable over 3 years and does not differ by surgical target. Neurology® 2012;79:55-65.

Intensive multifactorial intervention for stable coronary artery disease: optimal medical therapy in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial.

OBJECTIVES: This paper describes the medical therapy used in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial and its effect on risk factors. BACKGROUND: Most cardiovascular clinical trials test a single intervention. The COURAGE trial tested multiple lifestyle and pharmacologic interventions (optimal medical therapy) with or without percutaneous coronary intervention in patients with stable coronary disease. METHODS: All patients, regardless of treatment assignment, received equivalent lifestyle and pharmacologic interventions for secondary prevention. Most medications were provided at no cost. Therapy was administered by nurse case managers according to protocols designed to achieve predefined lifestyle and risk factor goals. RESULTS: The patients (n = 2,287) were followed for 4.6 years. There were no significant differences between treatment groups in proportion of patients achieving therapeutic goals. The proportion of smokers decreased from 23% to 19% (p = 0.025), those who reported <7% of calories from saturated fat increased from 46% to 80% (p < 0.001), and those who walked >or=150 min/week increased from 58% to 66% (p < 0.001). Body mass index increased from 28.8 +/- 0.13 kg/m(2) to 29.3 +/- 0.23 kg/m(2) (p < 0.001). Appropriate medication use increased from pre-randomization to 5 years as follows: antiplatelets 87% to 96%; beta-blockers 69% to 85%; renin-angiotensin-aldosterone system inhibitors 46% to 72%; and statins 64% to 93%. Systolic blood pressure decreased from a median of 131 +/- 0.49 mm Hg to 123 +/- 0.88 mm Hg. Low-density lipoprotein cholesterol decreased from a median of 101 +/- 0.83 mg/dl to 72 +/- 0.88 mg/dl. CONCLUSIONS: Secondary prevention was applied equally and intensively to both treatment groups in the COURAGE trial by nurse case managers with treatment protocols and resulted in significant improvement in risk factors. Optimal medical therapy in the COURAGE trial provides an effective model for secondary prevention among patients with chronic coronary disease. (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation; NCT00007657).

The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial.

OBJECTIVE: Osteoarthritis (OA) of the knee causes significant morbidity and current medical treatment is limited to symptom relief, while therapies able to slow structural damage remain elusive. This study was undertaken to evaluate the effect of glucosamine and chondroitin sulfate (CS), alone or in combination, as well as celecoxib and placebo on progressive loss of joint space width (JSW) in patients with knee OA. METHODS: A 24-month, double-blind, placebo-controlled study, conducted at 9 sites in the United States as part of the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT), enrolled 572 patients with knee OA who satisfied radiographic criteria (Kellgren/Lawrence [K/L] grade 2 or grade 3 changes and JSW of at least 2 mm at baseline). Patients with primarily lateral compartment narrowing at any time point were excluded. Patients who had been randomized to 1 of the 5 groups in the GAIT continued to receive glucosamine 500 mg 3 times daily, CS 400 mg 3 times daily, the combination of glucosamine and CS, celecoxib 200 mg daily, or placebo over 24 months. The minimum medial tibiofemoral JSW was measured at baseline, 12 months, and 24 months. The primary outcome measure was the mean change in JSW from baseline. RESULTS: The mean JSW loss at 2 years in knees with OA in the placebo group, adjusted for design and clinical factors, was 0.166 mm. No statistically significant difference in mean JSW loss was observed in any treatment group compared with the placebo group. Treatment effects on K/L grade 2 knees, but not on K/L grade 3 knees, showed a trend toward improvement relative to the placebo group. The power of the study was diminished by the limited sample size, variance of JSW measurement, and a smaller than expected loss in JSW. CONCLUSION: At 2 years, no treatment achieved a predefined threshold of clinically important difference in JSW loss as compared with placebo. However, knees with K/L grade 2 radiographic OA appeared to have the greatest potential for modification by these treatments.

Chondroitin product selection for the glucosamine/chondroitin arthritis intervention trial.

OBJECTIVE: To select a high-quality chondroitin dosage form and/or an appropriate source of sodium chondroitin for the National Institutes of Health's Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT). DESIGN: Controlled experimental trials. SETTING: Laboratory. PATIENTS OR PARTICIPANTS: Not applicable. INTERVENTIONS: Commercially available chondroitin products were reviewed, and purified sodium chondroitin from two suppliers was evaluated through tests (infrared and near-infrared identification, moisture content, pH, optical rotation, color and clarity of aqueous solutions prepared from the powders, protein contamination, total residue following ignition and nitrogen content, determination of sodium chondroitin molecular weight, disaccharide analysis, and measurement of chondroitin, sodium, and total glycosaminoglycan content) and an onsite supplier audit. MAIN OUTCOME MEASURES: Purity, potency, and quality of sodium chondroitin powders. RESULTS: No commercially available chondroitin product was deemed appropriate for use in GAIT. Samples of sodium chondroitin powder from two suppliers exhibited similar disaccharide and glycosaminoglycan content. Each contained approximately 2% hyaluronic acid and 8%-9% unsulfated disaccharide. Potency was inconsistent across groups, which might have resulted from different analytical methods and choice of reference standard. Mean potency obtained by five separate methods ranged from 82.2% to 95.5% for one supplier, 92.5% to 110.1% for another, and 95.1% to 112.5% for a commercially obtained reference standard. Critical issues raised by the results include choice of reference standard, selection of assay method, and the consistent appearance of an unidentifiable contaminant present in all three lots from one supplier. CONCLUSION: This blinded study determined methods to identify acceptable agents and provided results, which, in addition to regulatory compliance supplier audits, formed the basis for chondroitin product selection in GAIT.

Quality of life and exercise performance in patients in sinus rhythm versus persistent atrial fibrillation: a Veterans Affairs Cooperative Studies Program Substudy.

OBJECTIVES: The purpose of this study was to determine quality of life (QOL) and exercise performance (EP) in patients with persistent atrial fibrillation (AF) converted to sinus rhythm (SR) compared with those remaining in or reverting to AF. BACKGROUND: Restoration of SR in patients with AF improving QOL and EP remains controversial. METHODS: Patients with persistent AF were randomized double-blind to amiodarone, sotalol, or placebo. Those not achieving SR at day 28 were cardioverted and classified into SR or AF groups at 8 weeks (n = 624) and 1 year (n = 556). The QOL (SF-36), symptom checklist (SCL), specific activity scale (SAS), AF severity scale (AFSS), and EP were assessed. RESULTS: Favorable changes were seen in SR patients at 8 weeks in physical functioning (p < 0.001), physical role limitations (p = 0.03), general health (p = 0.002), and vitality (p < 0.001), and at 1 year in general health (p = 0.007) and social functioning (p = 0.02). Changes in the scores for SCL severity (p = 0.01), functional capacity (p = 0.003), and AFSS symptom burden (p < 0.001) at 8 weeks and in SCL severity (p < 0.01) and AF symptom burden (p < 0.001) at 1 year showed significant improvements in SR versus AF. Symptomatic patients were more likely to have improvement. The EP in SR versus AF was greater from baseline to 8 weeks (p = 0.01) and to 1 year (p = 0.02). The EP correlated with physical functioning and functional capacity except in the AF group at 1 year. CONCLUSIONS: In patients with persistent AF, restoration and maintenance of SR was associated with improvements in QOL measures and EP. There was a strong correlation between QOL measures and EP.