Serum Cathepsin S and Mortality in Older Adults. 9/21/2011. Background: The aim of this study was to investigate associations between circulating cathepsin S levels and mortality. Methods: Serum samples were used to measure cathepsin S in this prospective study of 2 community-based cohorts, the Uppsala Longitudinal Study of Adult Men (ULSAM) which consists of 1009 men at mean age 71 years and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) which consists of 987 women at mean age 70 years. Results: 413 participants died in the ULSAM cohort (incidence rate: 3.59/100 person-years at risk) and 100 participants died in the PIVUS cohort (incidence rate: 1.32/100 person-years at risk). In multivariable Cox regression models adjusted for age, systolic blood pressure, diabetes, smoking status, body mass index, total cholesterol, high-density lipoprotein cholesterol, antihypertensive treatment, lipid-lowering treatment, and history of cardiovascular disease, higher serum cathepsin S was associated with an increased risk for mortality (ULSAM cohort: HR for 1-unit increase of cathepsin S, 1.04 [95% CI, 1.01-1.06], p=0.009; PIVUS cohort: HR for 1-unit increase of cathepsin S, 1.03 [95% CI, 1.00-1.07], p=0.04). Author's Conclusion: Higher serum cathepsin S levels were associated with increased mortality risk. Source: JAMA


Response-Guided Telaprevir Combination Treatment for Hepatitis C Virus Infection. 9/15/2011. Background: to compare rates of sustained virologic response among chronic hepatitis C virus (HCV) patients receiving two treatment durations of peginterferon-ribavirin. Methods: In this noninferiority trial 540 patients with chronic infection with HCV genotype 1 who had not previously received treatment, received telaprevir at a dose of 750 mg every 8 hours, peginterferon alfa-2a at a dose of 180 μg per week, and ribavirin at a dose of 1000 to 1200 mg per day, for 12 weeks (T12PR12), followed by peginterferon-ribavirin. Patients who had an extended rapid virologic response (undetectable HCV RNA levels at weeks 4 and 12) were randomly assigned after week 20 to receive the dual therapy for 4 more weeks (T12PR24) or 28 more weeks (T12PR48). Patients without an extended rapid virologic response were assigned to T12PR48.Results: 65% of patients had an extended rapid virologic response. The overall rate of sustained virologic response was 72%. Among the 322 patients with an extended rapid virologic response who were randomly assigned to a study group, 149 (92%) in the T12PR24 group and 140 (88%) in the T12PR48 group had a sustained virologic response (absolute difference, 4 percentage points; 95% confidence interval, −2 to 11), establishing noninferiority. Author's Conclusion: A regimen of peginterferon-ribavirin for 24 weeks, with telaprevir for the first 12 weeks, was noninferior to the same regimen for 48 weeks in patients with undetectable HCV RNA at weeks 4 and 12, with an extended rapid virologic response achieved in nearly two thirds of patients. Source: NEJM


Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis. 9/15/2011. Background: This trial compared percutaneous transluminal angioplasty and stenting (PTAS) with medical management in preventing recurrent stroke associated with atherosclerotic intracranial arterial stenosis. Methods: In this randomized trial, 451 patients who had a recent transient ischemic attack or stroke attributed to stenosis of 70 to 99% of the diameter of a major intracranial artery were randomly assigned to aggressive medical management alone or aggressive medical management plus PTAS with the use of the Wingspan stent system. Results: 30-day rate of stroke or death was 14.7% in the PTAS group (nonfatal stroke, 12.5%; fatal stroke, 2.2%) and 5.8% in the medical-management group (nonfatal stroke, 5.3%; non-stroke-related death, 0.4%) (p=0.002). Beyond 30 days, stroke in the same territory occurred in 13 patients in each group. Author's Conclusion: Aggressive medical management was superior to PTAS with the use of the Wingspan stent system, both because the risk of early stroke after PTAS was high and because the risk of stroke with aggressive medical therapy alone was lower than expected. Source: NEJM


Apixaban versus Warfarin in Patients with Atrial Fibrillation. 9/15/2011. Background: This trial compared Apixaban, a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of stroke in patients with atrial fibrillation, with warfarin. Methods: In this randomized, double-blind trial, apixaban (at a dose of 5 mg twice daily) was compared with warfarin (target international normalized ratio, 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. Results: The rate of ischemic or hemorrhagic stroke or systemic embolism was 1.27% per year in the apixaban group, as compared with 1.60% per year in the warfarin group (HR with apixaban, 0.79; 95% CI, 0.66 to 0.95; p<0.001 for noninferiority; p=0.01 for superiority). The rate of major bleeding was 2.13% per year in the apixaban group, as compared with 3.09% per year in the warfarin group (HR, 0.69; 95% CI, 0.60 to 0.80; p<0.001), and the rates of death from any cause were 3.52% and 3.94%, respectively (HR, 0.89; 95% CI, 0.80 to 0.99; p=0.047). Author's Conclusion: Apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality. Source: NEJM


Analgesic Use and Risk of Renal Cell Cancer. 9/12/2011. Background: This study investigated the association between analgesic use and renal cell cancer (RCC). Methods: Use of aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen was ascertained in 1990 in the Nurses' Health Study and in 1986 in the Health Professionals Follow-up Study, and every 2 years thereafter. Baseline and duration of use of analgesics were evaluated. Results: During follow-up of 16 years among 77,525 women and 20 years among 49,403 men, 333 RCC cases were documented. Aspirin and acetaminophen use were not associated with RCC risk, however, regular use of nonaspirin NSAIDs was associated with an increased RCC risk. The pooled multivariate relative risk was 1.51 (95% CI, 1.12-2.04) at baseline. There was a dose-response relationship between duration of nonaspirin NSAID use and RCC risk; compared with nonregular use, the pooled multivariate relative risks were 0.81 (95% CI, 0.59-1.11) for use less than 4 years, 1.36 (0.98-1.89) for 4 to less than 10 years, and 2.92 (1.71-5.01) for use for 10 or more years (p<0.001 for trend). Author's Conclusion: Longer duration of use of nonaspirin NSAIDs may increase the risk of RCC. Source: AMA


Azithromycin for COPD. 8/25/2011. Background: This trial sought to determine whether azithromycin decreased the frequency of exacerbations in participants with COPD who had an increased risk of exacerbations but no hearing impairment, resting tachycardia, or apparent risk of prolongation of the corrected QT interval. Methods: In this randomized trial 1,142 patients were randomly assigned to receive azithromycin, at a dose of 250 mg daily, or placebo for 1 year in addition to their usual care. Results: The median time to the first exacerbation was 266 days (95% CI, 227 to 313) among participants receiving azithromycin, as compared with 174 days (95% CI, 143 to 215) among participants receiving placebo (p<0.001). The frequency of exacerbations was 1.48 exacerbations per patient-year in the azithromycin group, as compared with 1.83 per patient-year in the placebo group (p=0.01). Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P=0.04). Author's Conclusion: Azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of COPD exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects. Source: NEJM


Apixaban with Antiplatelet Therapy after Acute Coronary Syndrome. 8/25/2011. Background: This trial sought to determine whether apixaban, an oral, direct factor Xa inhibitor, would reduce the risk of recurrent ischemic events when added to antiplatelet therapy after an acute coronary syndrome. Methods: This randomized, double-blind, placebo-controlled trial compared apixaban, at a dose of 5 mg twice daily, with placebo, in addition to standard antiplatelet therapy, in patients with a recent acute coronary syndrome and at least two additional risk factors for recurrent ischemic events. Results: The trial was terminated prematurely because of an increase in major bleeding events with apixaban in the absence of a counterbalancing reduction in recurrent ischemic events. With a median follow-up of 241 days, the primary outcome of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 of the 3705 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 of the 3687 patients (7.9%) assigned to placebo (14.0 events per 100 patient-years) (hazard ratio with apixaban, 0.95; 95% CI, 0.80 to 1.11; p=0.51). Author's Conclusion: The addition of apixaban, at a dose of 5 mg twice daily, to antiplatelet therapy in high-risk patients after an acute coronary syndrome increased the number of major bleeding events without a significant reduction in recurrent ischemic events. Source: NEJM


Soy Isoflavones in the Prevention of Menopausal Bone Loss and Other Symptoms. 8/22/2011. Background: This trial sought to determine the efficacy of soy isoflavone tablets in preventing bone loss and menopausal symptoms. Methods: In this single-center, randomized, placebo-controlled, double-blind clinical trial, women aged 45 to 60 years within 5 years of menopause and with a bone mineral density T score of -2.0 or higher in the lumbar spine or total hip were randomly assigned to receive daily soy isoflavone tablets, 200 mg, or placebo. Results: After 2 years, no significant differences were found between the participants receiving soy tablets (n = 122) and those receiving placebo (n = 126) regarding changes in bone mineral density in the spine (-2.0% and -2.3%, respectively), the total hip (-1.2% and -1.4%, respectively), or the femoral neck (-2.2% and -2.1%, respectively). A significantly larger proportion of participants in the soy group experienced hot flashes and constipation compared with the control group. Author's Conclusion: The daily administration of tablets containing 200 mg of soy isoflavones for 2 years did not prevent bone loss or menopausal symptoms. Source: AMA


Risperidone for Antidepressant-Resistant Symptoms of PTSD. 8/03/2011. Background: This trial sought to determine the efficacy of the second-generation antipsychotic risperidone as an adjunct to ongoing pharmacologic and psychosocial treatments for veterans with chronic military-related PTSD. Methods: In this 6-month, randomized, double-blind, placebo-controlled multicenter trial, 247 patients with military-related PTSD and ongoing symptoms despite at least 2 adequate serotonin reuptake-inhibiting (SRI) antidepressant treatments were given up to 4 mg of risperidone or placebo daily. Results: Change in Clinician-Administered PTSD Scale (CAPS) scores from baseline to 24 weeks in the risperidone group was −16.3 (95% CI, −19.7 to −12.9) and in the placebo group, −12.5 (95% CI, −15.7 to −9.4); the mean difference was 3.74 (95% CI, −0.86 to 8.35; t=1.6; p=0.11). Risperidone did not reduce symptoms of depression (MADRS mean difference, 1.19; 95% CI, −0.29 to 2.68; p=0.11) or anxiety (HAMA mean difference, 1.16; 95% CI, −0.18 to 2.51; p=0.09; patient-rated CGI mean difference, 0.20; 95% CI, −0.06 to 0.45; p=0.14; observer-rated CGI mean difference, 0.18; 95% CI, 0.01 to 0.34; p=0.04). Author's Conclusion: In patients with SRI-resistant symptoms, 6-month treatment with risperidone compared with placebo did not reduce PTSD symptoms. Source: JAMA


3 Doses of Intermittent Preventive Treatment With Sulfadoxine-Pyrimethamine for the Prevention of Malaria During Pregnancy. 8/01/2011. Background: compare the efficacy and safety of 3-dose versus 2-dose intermittent preventive therapy in pregnancy (ITPp) with sulfadoxine-pyrimethamine (SP) for the prevention of placental malaria and associated low birth weight (LBW). Methods: In this parallel-group, open-label, individually randomized controlled superiority trial 814 women were seen at least 3 times and received either 2 or 3 doses of IPTp-SP. Results: The prevalence of placental malaria was 2-fold lower in the 3-dose group (8.0%) than in the 2-dose group (16.7%); the adjusted prevalence ratio (APR) was 0.48 (CI, 0.32-0.71). The prevalence of LBW was 6.6% in the 3-dose group versus 13.3% in the 2-dose group (APR, 0.50; 95% CI, 0.32-0.79), and the prevalence of preterm births was 3.2% versus 8.9% (APR, 0.37; 95% CI, 0.19-0.71). Author's Conclusion: Adding a third dose of ITPp-SP halved the risk of placental malaria, LBW, and preterm births in all gravidae. Source: CID

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July 2011

Cranberries or Antibiotics in Recurrent UTI Prevention.7/25/2011. Background: This study compares the efficacy of cranberries versus antibiotics in preventing recurrent urinary tract infections (UTIs). Methods: In this double-blind, double-dummy noninferiority trial, 221 premenopausal women with recurrent UTIs were randomized to 12-month prophylaxis use of trimethoprim-sulfamethoxazole (TMP-SMX), 480 mg once daily, or cranberry capsules, 500 mg twice daily. Results: After 12 months, the mean number of patients with at least 1 symptomatic UTI was higher in the cranberry than in the TMP-SMX group (4.0 vs 1.8; p=0.02), and the proportion of patients with at least 1 symptomatic UTI was higher in the cranberry than in the TMP-SMX group (78.2% vs 71.1%). Author's Conclusion: TMP-SMX, 480 mg once daily, is more effective than cranberry capsules, 500 mg twice daily, to prevent recurrent UTIs. Source: AMA


Albuterol, Placebo, or No Intervention in Asthma Patients. 7/14/2011. Background: This study compared the effects of a bronchodilator, two placebo interventions, and no intervention on outcomes in patients with asthma. Methods: In this double-blind, crossover pilot study, 46 patients with asthma were randomly assigned to active treatment with an albuterol inhaler, a placebo inhaler, sham acupuncture, or no intervention using a block design, in which one each of these four interventions was administered in random order during sequential visits. The procedure was repeated in two more blocks for a total of 12 visits. Results: Albuterol resulted in a 20% increase in maximum forced expiratory volume in 1 second (FEV1), as compared with approximately 7% with each of the other three interventions (p<0.001). Patients' reports of improvement after intervention was 50% with the albuterol inhaler, 45% with placebo inhaler, 46% with sham acupuncture, and 21%with no-intervention control (p<0.001). Author's Conclusion: Albuterol as compared with the two placebo interventions improved FEV1 in these patients with asthma, but provided no incremental benefit with respect to the self-reported outcomes. Source: NEJM

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June 2011

Telaprevir for Previously Untreated Chronic Hepatitis C Virus Infection. 6/23/2011. Background: This study sought to compare the efficacy of telaprevir, a hepatitis C virus (HCV) genotype 1 protease inhibitor, in combination with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, and evaluate the potential for shortening the duration of treatment. Methods: In this international, phase 3, randomized, double-blind, placebo-controlled trial, 1,088 patients with HCV genotype 1 infection who had not received previous treatment for the infection were assigned to receive either telaprevir combined with peginterferon alfa-2a and ribavirin for 12 weeks (T12PR group), followed by peginterferon-ribavirin alone for 12 weeks if HCV RNA was undetectable at weeks 4 and 12 or for 36 weeks if HCV RNA was detectable at either time point, telaprevir with peginterferon-ribavirin for 8 weeks and placebo with peginterferon-ribavirin for 4 weeks (T8PR group), followed by 12 or 36 weeks of peginterferon-ribavirin on the basis of the same HCV RNA criteria, or placebo with peginterferon-ribavirin for 12 weeks, followed by 36 weeks of peginterferon-ribavirin (PR group). Results: Significantly more patients in the T12PR or T8PR group than in the PR group had a sustained virologic response (75% and 69%, respectively, vs. 44%; p<0.001 for the comparison of the T12PR or T8PR group with the PR group). A total of 58% of the patients treated with telaprevir were eligible to receive 24 weeks of total treatment. Author's Conclusion: The addition of Telaprevir to peginterferon-ribavirin treatment was associated with significantly improved rates of sustained virologic response with only 24 weeks of therapy administered in the majority of patients. Source: NEJM


Acid-Suppressive Medication Use and the Risk for Nosocomial Gastrointestinal Tract Bleeding. 6/13/2011. Background: This study defined the incidence of nosocomial GI bleeding outside of the intensive care unit and examined the association between acid-suppressive medication use and this complication. Methods: A pharmacoepidemiologic cohort study was conducted of 78,394 patients admitted to an academic medical center from 2004 through 2007, at least 18 years of age, and hospitalized for 3 or more days excluding admissions with a primary diagnosis of GI bleeding. Results: Acid-suppressive medication was ordered in 59% of admissions, and nosocomial GI bleeding occurred in 0.29% of admissions. The adjusted odds ratio for nosocomial GI bleeding in the group exposed to acid-suppressive medication relative to the unexposed group was 0.63 (95% CI, 0.42-0.93). The number needed to treat to prevent 1 episode of nosocomial GI bleeding was 770. Author's Conclusion: Nosocomial GI bleeding outside of the intensive care unit was rare. The number needed to treat to prevent 1 case of nosocomial GI bleeding was relatively high. Source: AMA


Exemestane for Breast-Cancer Prevention in Postmenopausal Women. 6/23/2011. Background: This trial evaluated the efficacy of exemestane, an aromatase inhibitor for the prevention of breast cancer. Methods: In this randomized, placebo-controlled, double-blind trial 4,560 eligible postmenopausal women 35 years of age or older who had at least one of specified risk factors were assigned to either exemestane or placebo. Results: At a median follow-up of 35 months, 11 invasive breast cancers were detected in those given exemestane and in 32 of those given placebo, with a 65% relative reduction in the annual incidence of invasive breast cancer (0.19% vs. 0.55%; hazard ratio, 0.35; 95% CI, 0.18 to 0.70; p=0.002). The annual incidence of invasive plus noninvasive (ductal carcinoma in situ) breast cancers was 0.35% on exemestane and 0.77% on placebo (hazard ratio, 0.47; 95% CI, 0.27 to 0.79; p=0.004). Author's Conclusion: Exemestane significantly reduced invasive breast cancers in postmenopausal women who were at moderately increased risk for breast cancer and was associated with no serious toxic effects at 3 years. Source: NEJM


Telaprevir for Retreatment of HCV Infection. 6/23/2011. Background: This trial evaluated the addition of telaprevir to peginterferon alfa-2a plus ribavirin in patients with HCV genotype 1 infection who had no response or a partial response to previous therapy or who had a relapse after an initial response. Methods: In this randomized, phase 3 trial, 663 patients were assigned to either the T12PR48 group, which received telaprevir for 12 weeks and peginterferon plus ribavirin for a total of 48 weeks, the lead-in T12PR48 group, which received 4 weeks of peginterferon plus ribavirin followed by 12 weeks of telaprevir and peginterferon plus ribavirin for a total of 48 weeks, or the control group (PR48), which received peginterferon plus ribavirin for 48 weeks. Results: Rates of sustained virologic response among patients who had a previous relapse were 83% in the T12PR48 group, 88% in the lead-in T12PR48 group, and 24% in the PR48 group; among patients who had a partial response were 59%, 54%, and 15%, respectively; and among patients who had no response were 29%, 33%, and 5%, respectively (p<0.001 for all comparisons).Author's Conclusion: Telaprevir combined with peginterferon plus ribavirin significantly improved rates of sustained virologic response. Source: NEJM


Proton Pump Inhibitor Use and the Antifracture Efficacy of Alendronate. 6/13/2011. Background: This study related risk of hip fracture to recent pharmacy records of refill of prescriptions for alendronate. Methods: In this population-based, national register-based, open cohort study, risk of hip fracture was related to recent pharmacy records of refill of prescriptions for alendronate in 38,088 patients. Results: For hip fractures, there was statistically significant interaction with alendronate for PPI use (p<0.05). The treatment response associated with complete refill compliance to alendronate was a 39% risk reduction (HR, 0.61; 95% CI, 0.52-0.71; p<0.001) in patients who were not PPI users, while the risk reduction in concurrent PPI users was not significant (19%; HR, 0.81; 95% CI, 0.64-1.01; p=0.06). Author's Conclusion: Concurrent PPI use was associated with a dose-dependent loss of protection against hip fracture. Source: AMA


Melanoma Vaccine Plus Interleukin. 6/02/2011. Background: This trial evaluated whether the addition of a melanoma vaccine to interleukin-2, an immune activating agent, would stimulate an immune response against cancer more successfully than interleukin alone. Methods: In this randomized, phase 3 trial, 185 patients at 21 centers with stage IV or locally advanced stage III cutaneous melanoma, expression of HLA*A0201, an absence of brain metastases, and suitability for high-dose interleukin-2 therapy, were randomly assigned to receive interleukin-2 alone (720,000 IU per kilogram of body weight per dose) or gp100:209-217(210M) plus incomplete Freund's adjuvant (Montanide ISA-51) once per cycle, followed by interleukin-2. Results: The vaccine-interleukin-2 group, as compared with the interleukin-2-only group, had a significant improvement in centrally verified overall clinical response (16% vs. 6%, p=0.03), as well as longer progression-free survival (2.2 months; 95% CI, 1.7 to 3.9 vs. 1.6 months; 95% CI, 1.5 to 1.8; p=0.008). Author's Conclusion: The response rate was higher and progression-free survival longer with vaccine and interleukin-2 than with interleukin-2 alone. Source: NEJM

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May 2011

Bevacizumab for Neovascular Age-Related Masculaar Degeneration. 5/19/2011. Background: This trial evaluates the efficacy of bevacizumab as compared to that of ranibizumab in the treatment of neovascular age-related macular degeneration (AMD). Methods: In this multicenter, single-blind, noninferiority trial, 1,208 neovascular AMD patients were randomly assigned to receive intravitreal injections of ranibizumab or bevacizumab on either a monthly schedule or as needed with monthly evaluation. Results: The mean change in visual acuity at 1 year was 8 letters gained in the monthly-administered Bevacizumab group as compared to 8.5 letters gained in the monthly-administered ranibizumab. The proportion of patients with serious systemic adverse events was higher with bevacizumab than with ranibizumab (24.1% vs. 19.0%; risk ratio, 1.29; 95% CI, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern. Author's Conclusion: At 1 year, bevacizumab and ranibizumab had equivalent effects on visual acuity when administered according to the same schedule. Differences in rates of serious adverse events require further study. Source: NEJM


Alemtuzumab Induction in Renal Transplantation. 5/19/2011. Background: This study compares induction therapy involving alemtuzumab with the most commonly used induction regimens in patient populations at either high immunologic risk or low immunologic risk. Methods: In this prospective study, 139 high-risk patients were randomly assigned to receive alemtuzumab (one dose of 30 mg) or rabbit antithymocyte globulin (a total of 6 mg per kilogram of body weight given over 4 days), and 335 low-risk patients received alemtuzumab (one dose of 30 mg) or basiliximab (a total of 40 mg over 4 days). All patients received tacrolimus and mycophenolate mofetil and underwent a 5-day glucocorticoid taper in a regimen of early steroid withdrawal. Results: The rate of biopsy-confirmed acute rejection was significantly lower in the alemtuzumab group than in the conventional-therapy group at both 6 months (3% vs. 15%, p<0.001) and 12 months (5% vs. 17%, p<0.001). At 3 years, the rate of biopsy-confirmed acute rejection in low-risk patients was lower with alemtuzumab than with basiliximab (10% vs. 22%, p=0.003), but among high-risk patients, no significant difference was seen between alemtuzumab and rabbit antithymocyte globulin (18% vs. 15%, p=0.63). Author's Conclusion: By the first year after transplantation, biopsy-confirmed acute rejection was less frequent with alemtuzumab than with conventional therapy. Source: NEJM


Selenium in Mild Graves' Orbitopathy. 5/19/2011. Background: This trial sought to determine the effect of selenium (an antioxidant agent) or pentoxifylline (an antiinflammatory agent) in patients with mild Graves' orbitopathy. Methods: In this randomized, double-blind, placebo-controlled trial, 159 patients with mild Graves' orbitopathy were given selenium (100 μg twice daily), pentoxifylline (600 mg twice daily), or placebo (twice daily) orally for 6 months and were then followed for 6 months after treatment was withdrawn. Results: At the 6-month evaluation, treatment with selenium was associated with an improved quality of life, (p<0.001) less eye involvement, (p=0.01) and slowed progression of Graves' orbitopathy (p=0.01), as compared with placebo. Treatment with pentoxifylline did not have this result. The Clinical Activity Score decreased in all groups, but the change was significantly greater in the selenium-treated patients. Author's Conclusion: Selenium administration significantly improved quality of life, reduced ocular involvement, and slowed progression of the disease in patients with mild Graves' orbitopathy. Source: NEJM


Lactobacillus crispatus Probiotic for Prevention of Recurrent Urinary Tract Infection. 5/04/2011. Background: Depletion of vaginal lactobacilli is associated with UTI risk. This trial assessed whether repletion by Lactobacillus crispatus intravaginal suppository probiotic (Lactin-V; Osel) is beneficial. Methods: In this double-blind placebo-controlled trial, 100 women with a history of recurrent UTI received antimicrobials for acute UTI and then were randomly assigned to receive either Lactin-V or placebo daily for 5 days and then once weekly for 10 weeks. Results: Recurrent UTI occurred in 15% of women receiving Lactin-V compared with 27% of women receiving placebo (RR, 0.5; 95% CI, 0.2-1.2). Author's Conclusion: Lactin-V after treatment for cystitis is associated with a reduction in recurrent UTI. Source: CID

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April 2011

Sirolimus in Patients with Lymphangioleiomyomatosis. 4/28/2011. Background: Sirolimus (also called rapamycin) inhibits mTOR and has shown promise in phase 1-2 trials involving patients with Lymphangioleiomyomatosis (LAM) a progressive, cystic lung disease in women. Methods: In this two-stage, 12-month randomized, double-blind trial, 89 patients with LAM who had moderate lung impairment received either sirolimus or placebo, and were observed for another 12 months. Results: During the treatment period, the FEV1 slope was −12±2 ml per month in the placebo group versus 1±2 ml per month in the sirolimus group (p<0.001). After discontinuation of sirolimus, the decline in lung function resumed in the sirolimus group and paralleled that in the placebo group. Author's Conclusion: Sirolimus stabilized lung function, reduced serum VEGF-D levels, and was associated with a reduction in symptoms in patients with LAM. Source: NEJM


Dalteparin Not Superior to Unfractionated Heparin in Critically Ill Patients. 4/07/2011. Background: This study tested the superiority of dalteparin over unfractionated heparin on venous thromboembolism in critically ill patients. Methods: In this multicenter trial 3764 patients were randomly assigned to receive either subcutaneous dalteparin (at a dose of 5000 IU once daily) plus placebo once daily (for parallel-group twice-daily injections) or unfractionated heparin (at a dose of 5000 IU twice daily) while they were in the intensive care unit. proximal leg deep-vein thrombosis, was diagnosed on compression ultrasonography performed within 2 days after admission, twice weekly, and as clinically indicated. Results: There was no significant difference in the rate of proximal leg deep-vein thrombosis, which occurred in 96 of 1873 patients (5.1%) receiving dalteparin versus 109 of 1873 patients (5.8%) receiving unfractionated heparin (hazard ratio in the dalteparin group, 0.92; 95% CI, 0.68 to 1.23; p=0.57). Author's Conclusion: Among critically ill patients, dalteparin was not superior to unfractionated heparin in decreasing the incidence of proximal deep-vein thrombosis. Source: NEJM

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March 2011

Tiotropium versus Salmeterol in COPD.3/24/2011. Background: This trial investigated whether the anticholinergic drug tiotropium is superior to the β2-agonist salmeterol in preventing exacerbations of moderate-to-very-severe chronic obstructive pulmonary disease (COPD). Methods: In this randomized, double-blind, double-dummy, parallel-group trial, 7376 patients with moderate-to-very-severe COPD were treated with 18 μg of tiotropium once daily or 50 μg of salmeterol twice daily, and evaluated for the incidence of moderate or severe exacerbations. Results: Tiotropium, as compared with salmeterol, increased the time to the first severe exacerbation (hazard ratio, 0.72; 95% CI, 0.61 to 0.85; P<0.001), reduced the annual number of moderate or severe exacerbations (0.64 vs. 0.72; rate ratio, 0.89; 95% CI, 0.83 to 0.96; P=0.002), and reduced the annual number of severe exacerbations (0.09 vs. 0.13; rate ratio, 0.73; 95% CI, 0.66 to 0.82; P<0.001). Author's Conclusion: Tiotropium is more effective than salmeterol in preventing exacerbations.Source: NEJM


Pioglitazone for Diabetes Prevention.3/24/2011. Background: This study sought to examine whether pioglitazone can reduce the risk of type 2 diabetes mellitus in adults with impaired glucose tolerance. Methods: In this randomized, double-blind, placebo-controlled study 602 patients were randomly assigned to receive pioglitazone or placebo. Fasting glucose was measured quarterly, and oral glucose tolerance tests were performed annually. Results: Annual incidence rates for type 2 diabetes mellitus were 2.1% in the pioglitazone group and 7.6% in the placebo group, and conversion to normal glucose tolerance occurred in 48% of the patients in the pioglitazone group and 28% of those in the placebo group (P<0.001). Author's Conclusion: Pioglitazone reduced the risk of conversion of impaired glucose tolerance to type 2 diabetes mellitus by 72% but was associated with significant weight gain and edema. Source:NEJM


Early Start Dialysis May Be Harmful.3/14/2011. Background: This study sought to determine whether early initiation of hemodialysis is associated with a survival benefit or harm. Methods: Demographics such as year of dialysis initiation, primary etiology of renal failure, and body mass index, hemoglobin, and serum albumin levels of 81,176 nondiabetic, 20- to 64-year-old, in-center incident hemodialysis patients with no reported comorbidity besides hypertension, were examined. A healthiest Group (HG) was identified, and a piecewise proportional hazards model was used to estimate covariate-adjusted mortality hazard ratios (HRs) for eGFR at the time of initiation of dialysis. Results: Compared with the reference group, the HR for the HG was 1.27 (eGFR, 5.0-9.9 mL/min/1.73 m2), 1.53 (eGFR, 10.0-14.9 mL/min/1.73 m2), and 2.18 (eGFR 15.0 mL/min/1.73 m2) and ranged from 1.50 to 3.53 mL/min/1.73 m2 in the first year of dialysis for the early-start group. Author's Conclusion: The increased HR during hemodialysis associated with early start in the healthiest group of patients undergoing dialysis indicates that early start of dialysis may be harmful. Source:AMA


Olmesartan for the Delay or Prevention of Microalbuminuria in Type 2 Diabetes. 3/10/2011. Background: This trial aimed to determine whether treatment with an angiotensin-receptor blocker (ARB) would delay or prevent the occurrence of microalbuminuria in patients with type 2 diabetes and normoalbuminuria. Methods: randomized, double-blind, multicenter, controlled trial, 4447 patients with type 2 diabetes were assigned to receive 40 mg olmesartan or placebo once daily for a median of 3.2 years. Results: The target blood pressure (<130/80 mm Hg) was achieved in 80% of the patients taking olmesartan as compared to 71% taking placebo, and blood pressure was lower by 3.1/1.9 mm Hg in the olmesartan group than in the placebo group. Microalbuminuria developed in 8.2% of the patients in the olmesartan and 9.8% in the placebo group. Author's Conclusion: Olmesartan was associated with a delayed onset of microalbuminuria, but the higher rate of fatal cardiovascular events with olmesartan among patients with preexisting coronary heart disease is of concern. Source: NEJM


Irbesartan Ineffective in Patients with Atrial Fibrillation. 3/10/2011. Background: This trial evaluated whether irbesartan, an angiotensin-receptor blocker, would reduce the risk of cardiovascular events among patients with atrial fibrillation. Methods: 9016 patients with a history of risk factors for stroke and a systolic blood pressure of at least 110 mm Hg were randomly assigned to receive either irbesartan at a target dose of 300 mg once daily or double-blind placebo. Results: Stroke, myocardial infarction, or death from vascular causes occurred at a rate of 5.4% per 100 person-years in both groups (hazard ratio with irbesartan, 0.99; 95% CI, 0.91 to 1.08; p=0.85), and hospitalization for heart failure occurred at a rate of 7.3% per 100 person-years among patients receiving irbesartan and 7.7% per 100 person-years among patients receiving placebo (hazard ratio, 0.94; 95% CI, 0.87 to 1.02; p=0.12). Author's Conclusion: Irbesartan did not reduce cardiovascular events in patients with atrial fibrillation. Source: NEJM


Loop Diuretic Use in Patients with Acute Decompensated Heart Failure. 3/03/2011. Background: This study sought to collect data regarding diuretic therapy to guide its use. Methods: In this prospective, double-blind, randomized trial, 308 patients with acute decompensated heart failure were assigned to receive furosemide administered intravenously by means of either a bolus every 12 hours or continuous infusion and at either a low dose (equivalent to the patient's previous oral dose) or a high dose (2.5 times the previous oral dose). Results: There was no significant difference in patients' global assessment of symptoms or in the mean change in the creatinine level, between the bolus and continuous infusion groups or the high- and low-dose groups. The high-dose strategy was associated with greater diuresis and more favorable outcomes in some secondary measures but also with transient worsening of renal function. Author's Conclusion: Among patients with acute decompensated heart failure, there were no significant differences in patients' global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose. Source: NEJM


Long-Term Effects of Intensive Glucose Lowering. 3/03/2011. Background: This trial assessed the 5-year outcome of intensive glucose-lowering on mortality and cardiovascular events.Methods: Participants with type 2 diabetes and cardiovascular disease or additional cardiovascular risk factors were randomly assigned to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level of 7 to 7.9%). Intensive therapy was terminated and all participants began receiving standard therapy due to an increased mortality rate in the intensive-therapy group. Results: Before the intensive therapy was terminated, the intensive-therapy group did not differ significantly from the standard-therapy group in the rate of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes (p=0.13) but had more deaths from any cause (hazard ratio, 1.21; 95% CI, 1.02 to 1.44) and fewer nonfatal myocardial infarctions (hazard ratio, 0.79; 95% CI, 0.66 to 0.95). These trends persisted during the entire follow-up period and other adverse events were similar in the two groups. Author's Conclusion: As compared with standard therapy, the use of intensive therapy for 3.7 years to target a glycated hemoglobin level below 6% reduced 5-year nonfatal myocardial infarctions but increased 5-year mortality and should not be recommended for high-risk patients with advanced Type 2 Diabetes. Source: NEJM


Apixaban Alternative to Vitamin K Antagonist Therapy. 3/03/2011. Background: This study evaluated whether Apixaban, a novel factor Xa inhibitor, may be an alternative treatment to vitamin K antagonist therapy in patients with atrial fibrillation. Methods: In this double-blind study, 5599 patients with atrial fibrillation who were at increased risk for stroke and for whom vitamin K antagonist therapy was unsuitable, were randomly assigned to to receive 5 mg of apixaban twice daily or 81 to 324 mg of aspirin per day. Results: There were 51 occurrences of stroke or systemic embolism among patients assigned to apixaban and 113 among those assigned to aspirin (hazard ratio with apixaban, 0.45; 95% CI, 0.32 to 0.62; p<0.001). The data and safety monitoring board recommended early termination of the study because of the clear benefit in favor of apixaban. Author's Conclusion: apixaban reduced the risk of stroke or systemic embolism without significantly increasing the risk of major bleeding or intracranial hemorrhage, and is therefore a suitable alternative treatment to vitamin K antagonist therapy. Source: NEJM


Long-Acting Injectable Risperidone in Unstable Schizophrenia. 3/03/2011. Background: This study evaluated the long-term use of long-acting injectable risperidone, a second-generation antipsychotic agent, in patients with unstable schizophrenia. Methods: 369 patients in the Veterans Affairs (VA) system who had schizophrenia or schizoaffective disorder and who were at risk for hospitalization were randomly assigned to receive 25 to 50 mg of long-acting injectable risperidone every two weeks or a psychiatrist's choice of an oral antipsychotic. Results: The rate of hospitalization after randomization was not significantly lower among patients who received long-acting injectable risperidone than among those who received oral antipsychotics (39% after 10.8 months vs. 45% after 11.3 months; hazard ratio, 0.87; 95% CI, 0.63 to 1.20). Author's Conclusion: Long-acting injectable risperidone was not superior to a psychiatrist's choice of oral treatment in patients with schizophrenia and schizoaffective disorder, and it was associated with more local injection-site and extrapyramidal adverse effects. Source: NEJM

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February 2011

Proton Pump Inhibitor Use and Efficacy of Alendronate. 2/14/2011. Background: This study assessed the relationship of increased hip fractures with alendronate use. Methods: This population-based, national register-based, open cohort study related risk of hip fracture to recent pharmacy records of refill of prescriptions of alendronate for 38,088 patients with a mean duration of follow-up of 3.5 years. Results: For hip fractures, there was statistically significant interaction with alendronate for PPI use (p<0.05). The treatment response associated with complete refill compliance to alendronate was a 39% risk reduction (HR, 0.61; 95% CI, 0.52-0.71; p<0.001) in patients who were not PPI users, while the risk reduction in concurrent PPI users was not significant (19%; HR, 0.81; 95% CI, 0.64-1.01; p=0.06). Author's Conclusion: Concurrent PPI use was associated with a dose-dependent loss of protection against hip fracture with alendronate in elderly patients. Source:AMA


Dietary Fiber Intake and Reduced Mortality. 2/14/2011. Background: This study evaluated the effect of dietary fiber intake on mortality. Methods: Dietary fiber intake was assessed using a food-frequency questionnaire at baseline and then compared to total mortality and death from specific causes in the NIH (National Institutes of Health)-AARP Diet and Health Study. Results: Dietary fiber intake was associated with a significantly lowered risk of total death (multivariate relative risk comparing the highest with the lowest quintile, 0.78 [95% CI, 0.73-0.82; p<0.001] in men and 0.78 [95% CI, 0.73-0.85; p<0.001] in women) and death from cardiovascular, infectious, and respiratory diseases by 24% to 56% in men and by 34% to 59% in women. Author's Conclusion: Dietary fiber may reduce the risk of death from cardiovascular, infectious, and respiratory diseases. Source: AMA


Acid-Suppressive Medication Use and Nosocomial Gastrointestinal Tract Bleeding. 2/14/2011. Background: This study assessed the incidence of GI bleeding outside of the intensive care unit and its association with acid-suppressive medication use. Methods: This was a pharmacoepidemiologic cohort study of 78,394 patients hospitalized for 3 or more days excluding a primary diagnosis of GI bleeding. Results: Acid-suppressive medication was ordered in 59% of admissions, and nosocomial GI bleeding occurred in 0.29% of admissions. The number needed to treat to prevent 1 episode of nosocomial GI bleeding was 770. Author's Conclusion: Nosocomial GI bleeding outside of the intensive care unit was rare and the number needed to treat to prevent 1 case of nosocomial GI bleeding was relatively high. Source:AMA

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January 2011

Iniparib Addition to Chemotherapy in Metastatic Triple-Negative Breast Cancer. 1/20/2011. Background: The goal of this study was to compare the efficacy and safety of gemcitabine and carboplatin with or without iniparib, a small molecule with PARP-inhibitory activity, in patients with metastatic triple-negative breast cancer. Methods: In this open-label, phase 2 study, 123 patients were randomly assigned to receive gemcitabine (1000 mg per square meter of body-surface area) and carboplatin (at a dose equivalent to an area under the concentration-time curve of 2) on days 1 and 8 either with or without iniparib (at a dose of 5.6 mg per kilogram of body weight) on days 1, 4, 8, and 11 every 21 days. Results: In those receiving the addition of iniparib had improved rates of clinical benefit from 34% to 56% (p=0.01) and overall response from 32% to 52% (p=0.02). The addition of iniparib also prolonged the median progression-free survival from 3.6 months to 5.9 months (hazard ratio for progression, 0.59; p=0.01) and the median overall survival from 7.7 months to 12.3 months (hazard ratio for death, 0.57; p=0.01). Author's Conclusion: The addition of iniparib to chemotherapy improved the clinical benefit and survival of patients with metastatic triple-negative breast cancer without significantly increased toxic effects. Source: NEJM


Escitalopram for Menopausal Hot Flashes. 1/19/2011. Background: This trial sought to determine the efficacy and tolerability of 10 to 20 mg/d escitalopram, a selective serotonin reuptake inhibitor, in alleviating menopausal hot flashes. Methods: In this randomized, double-blind, placebo-controlled, parallel group trial 205 women received either 10 to 20 mg/d of escitalopram or a matching placebo for 8 weeks. Results: The mean difference in hot flash frequency reduction was 1.41 (95% CI, 0.13-2.69) fewer hot flashes per day at week 8 among women taking escitalopram (p<0.001), with mean reductions of 4.60 (95% CI, 3.74-5.47) and 3.20 (95% CI, 2.24-4.15) hot flashes per day in the escitalopram and placebo groups, respectively. Fifty-five percent of women in the escitalopram group, as compared to 36% in the placebo group, reported a decrease of at least 50% in hot flash frequency (p=0.009) at the 8-week follow-up. Author's Conclusion: The use of escitalopram (10-20 mg/d) compared with placebo resulted in fewer and less severe menopausal hot flashes at 8 weeks of follow-up. Source: AMA

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December 2010

Comparative Safety for Opioids. 12/27/2010. Background: This study sought to compare the safety of opioids commonly used for nonmalignant pain. Methods: This propensity-matched cohort analysis compared 6275 patients taking one of 5 opioids, odeine phosphate, hydrocodone bitartrate, oxycodone hydrochloride, propoxyphene hydrochloride, and tramadol hydrochloride for nonmalignant pain. Results: The risk of cardiovascular events was similar across opioid groups 30 days after the start of opioid therapy, but it was elevated for codeine (RR, 1.62; 95% CI, 1.27-2.06) after 180 days. Compared with hydrocodone, after 30 days of opioid exposure the risk of fracture was significantly reduced for tramadol (RR, 0.21; 95% CI, 0.16-0.28) and propoxyphene (0.54; 0.44-0.66) users. The risk of gastrointestinal safety events did not differ across opioid groups. All-cause mortality was elevated after 30 days for oxycodone (RR, 2.43; 95% CI, 1.47-4.00) and codeine (2.05; 1.22-3.45) users compared with hydrocodone users. Author's Conclusion: The rate of safety events among patients taking opioids for nonmalignant pain varies significantly by agent, but should prompt caution and further study. Source: AMA


Wait-and-See Therapy Versus Antibiotic Treatment for Nontuberculous Mycobacterial Cervicofacial Lymphadenitis in Children. 12/10/2010. Background: This study assessed the time for all infected lymph nodes to heal in children with microbiologically confirmed nontuberculous mycobacterial cervicofacial lymphadenitis after the nonantibiotic, wait-and-see treatment, compared with patients after a 12-week course of clarithromycin and rifabutin.Methods: Fifty children with a polymerase chain reaction (PCR)- or cultureconfirmed diagnosis of cervicofacial nontuberculous mycobacterial infection were randomized to receive antibiotic therapy or to be given a wait-and-see approach. Results: The median time to resolution of the disease for the antibiotic group was 36 weeks, compared with 40 weeks for the wait-and-see group. Author's Conclusion: No significant differences in median healing time between the wait-and-see group and the group receiving clarithromycin and rifabutin antibiotic therapy were observed. Source: CID


Posaconazole for Chronic Pulmonary Aspergillosis. 12/15/2010. Background: This trial tested the efficacy and safety of posaconazole when used in patients with Chronic pulmonary aspergillosis (CPA), a severe, progressive respiratory infection characterized by multiple pulmonary cavities and increased levels of antibodies to Aspergillus species. Methods: In this retrospective study 79 patients received 400 mg of posaconazole twice per day, and a composite clinical and radiological evaluation was used to assess response to posaconazole after 6 and 12 months of therapy. Results: Kaplan‐Meier plots revealed that in some patientsthe first response was not observed until approximately one year of treatment and covariates were not significant. Adverse reactions including nausea, rash, headache, and lethargy were observed in 12 patients. Aspergillus species were recovered from 22 patients. Author's Conclusion: Posaconazole is a safe but only partially effective treatment for CPA. Source: CID

 

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November 2010

Serum a-Carotene Concentrations. 11/22/2010. Background: This study assessed the role of a-carotene in the development of CVD or cancer. Methods: In this study Cox proportional hazard regression analyses were used to estimate the relative risk for death from all causes and selected causes associated with serum -carotene concentrations among 15,318 adults 20 years and older who participated in the Third National Health and Nutrition Examination Survey Follow-up Study. Results: Participants with serum levels higher than 1 µg/dL had a lower risk of death from all causes (p<0.001 for linear trend); for those with a-carotene concentrations of 2 to 3 µg/dL, the relative risk for death was 0.77 (95% CI, 0.65-0.83), 0.73 (0.65-0.83) among those with concentrations of 4 to 5 µg/dL, 0.66 (0.55-0.79) among those with concentrations of 6 to 8 µg/dL, and 0.61 (0.51-0.73) among those with concentrations of 9 µg/dL or higher. Author's Conclusion: Serum a-carotene concentrations are inversely associated with the risk of death from all causes, supporting the increase of fruit and vegetable consumption. Source: AMA

Metformin Use Among Patients with Diabetes and Atherothrombosis. 11/22/2010. Background: This study evaluated the safety of Metformin use in patients with atherthrombosis. Methods: Using multivariable adjustment and propensity score to account for baseline differences, mortality rates were assessed among 19, 691 patients having diabetes with established atherothrombosis and participating in the Reduction of Atherothrombosis for Continued Health (REACH) Registry. Results: The mortality rates were 6.3% (95% CI, 5.2%-7.4%) with metformin and 9.8% (8.4%-11.2%) without metformin. Author's Conclusion: Metformin use may decrease mortality among patients with diabetes when used as a means of secondary prevention, but should be tested prospectively in this population to confirm its effect on survival. Source: AMA

Adjuvant Docetaxel for Node-Negative Breast Cancer. 12/02/2010. Background: This trial assessed the value of docetaxel, doxorubicin, and cyclophosphamide (TAC) and fluorouracil, doxorubicin, and cyclophosphamide (FAC) regimens in the treatment of node-negative disease. Methods: 1,060 women with axillary-node-negative breast cancer and at least one high-risk factor for recurrence to treatment with TAC or FAC every 3 weeks for six cycles after surgery. Results: At a median follow-up of 77 months, the proportion of patients alive and disease-free was higher among the TAC group (87.8%) than among the FAC group (81.8%), representing a 32% reduction in the risk of recurrence with TAC (hazard ratio, 0.68; 95% CI, 0.49 to 0.93; p=0.01 by the log-rank test). Author's Conclusion: As compared with adjuvant FAC, adjuvant TAC improved the rate of disease-free survival among women with high-risk, node-negative breast cancer. Source: NEJM

Omega-3 Fatty Acids for the Prevention of Recurrent Symptomatic Atrial Fibrillation. Background: This study evaluated the possibility that omega-3 polyunsaturated fatty acids may provide a safe, effective treatment option for Atrial Fibrillation (AF) patients. Methods: In this prospective, randomized, double-blind, placebo-controlled, parallel-group multicenter trial, 663 US outpatient participants with confirmed symptomatic paroxysmal or persistent AF were given prescription omega-3 (8 g/d) or placebo for the first 7 days and prescription omega-3 (4 g/d) or placebo thereafter through week 24. Results: At 24 weeks, in the paroxysmal AF stratum, 48% of the participants in the placebo group and 52% of the participants in the prescription group had a recurrent symptomatic AF or flutter event.Author's Conclusion: 24-week treatment with prescription omega-3 compared with placebo did not reduce recurrent AF over 6 months. Source: AMA

Safety of Recombinant Activated Factor VII. 11/04/2010. Background: This analysis assessed the thromboembolic risk of the off-label use of recombinant activated factor VII (rFVIIa). Methods: Data from 35 randomized clinical trials were analyzed to determine the frequency of thromboembolic events. Results: Among 4468 subjects, 498 or 11.1% had thromboembolic events. 5.5% of arterial thromboembolic events occurred among those who received rFVIIa as compared to 3.2% among those who received placebo (p=0.003). Rates of venous thromboembolic events were similar among both groups of subjects (5.3% vs. 5.7%). Author's Conclusion: Treatment with high doses of rFVIIa on an off-label basis significantly increased the risk of arterial but not venous thromboembolic events, especially among the elderly. Source: NEJM

Everolimus for Subependymal Giant-Cell Astrocytomas in Tuberous Sclerosis. 11/04/2010. Background: This trial assessed the efficacy of everolimus, which inhibits the mammalian target of rapamycin, as treatment for subependymal giant-cell astrocytomas in patients with the tuberous sclerosis complex. Methods: 28 patients 3 years or older withserial growth of f subependymal giant-cell astrocytomas were given everolimus orally, at a dose of 3.0 mg per square meter of body-surface area, to achieve a trough concentration of 5 to 15 ng per milliliter. Results: Everolimus therapy was associated with a clinically meaningful reduction in volume of the primary subependymal giant-cell astrocytoma, as assessed on independent central review (p<0.001 for baseline vs. 6 months), with a reduction of at least 30% in 21 patients (75%) and at least 50% in 9 patients (32%). Author's Conclusion: Everolimus therapy was associated with reduction in the volume of subependymal giant-cell astrocytomas and related seizure frequency. Source: NEJM

 

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October 2010

Tanezumab for Pain Relief from Osteoarthritis. 10/14/2010. Background: This trial was conducted to evaluate the safety and analgesic efficacy of tanezumab. Methods: 450 patients with osteoarthritis of the knee were randomly assigned to receive varying doses of tanezumab or placebo and assessed for pain, stiffness, and physical function of the knee over a 16 week period. Results: The mean reduction in knee pain from baseline ranged from 45% to 62% with respect to tanezumab dose, as compared to 22% reduction with placebo (p<0.001). The use of tanezumab over placebo was also associated with greater response to therapy. Author's Conclusion: Tanezumab administration was associated with a decrease in joint pain, an improvement in function, and a slightly increased rate of adverse events such as headache (9% of patients), upper respiratory tract infection (7% of patients), and paresthesia (7% of patients). Source:NEJM


Tiotropium Bromide for Uncontrolled Asthma. 10/28/2010. Background: This trial evaluated the efficacy of the addition of tiotropium bromide, a long-acting anticholinergic agent approved for the treatment of chronic obstructive pulmonary disease, to an inhaled glucocorticoid in treating asthma. Methods: In this three-way, double-blind, triple-dummy crossover trial, 210 asthma patients were treated with a tiotropium bromide and inhaled glucocorticoid combination, a doubled dose of inhaled glucocorticoid, or inhaled glucocorticoid with the addiction of the long-acting beta-agonist (LABA) salmeterol. Results: The addition of tiotropium appeared to be equivalent to the addition of salmeterol and superior to doubling the inhaled glucocorticoid dose, with a morning peak expiratory flow (PEF) mean difference of 25.8 liters per minute (p<0.001), an evening PEF difference of 35.3 liters per minute (p<0.001), and a proportion of asthma-control days difference of 0.079 (p=0.01). Author's Conclusion: The addition of tiotropium to inhaled glucocorticoid improved symptoms and lung function in patients with inadequately controlled asthma. Source:NEJM


Anaplastic Lymphoma Kinase Inhibition in Lung Cancer. 10/28/2010. Background: This clinical trial evaluated the therapeutic efficacy of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the anaplastic lymphoma kinase (ALK) tyrosine kinase found in a subgroup of non-small-cell lung cancers. Methods: 82 patients with advanced ALK-positive disease were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Results: At a mean treatment duration of 6.4 months, the overall response rate was 57%; 27 patients (33%) had stable disease. Grade 1 or 2 (mild) gastrointestinal side effects were observed. Author's Conclusion: Inhibition of ALK, by the use of crizotinib, in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients.Source:NEJM

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September 2010.

Anti-inflammatory Drug Use Associated with Atrial Fibrillation. 9/13/2010. Background: This study sought to determine the existence of an association between the use of non-steroidal anti-inflammatory drugs (NSAIDs) and the risk of atrial fibrillation (AF). Methods: Two separate nested case-control analyses were performed to estimate the risk of first-time chronic and paroxysmal AF among users of SAIDs and NSAIDs using patients between the ages of 40 and 89 years. Results: An association was found between the current use of SAIDs and chronic AF (RR, 2.49; 95% CI, 1.56-3.97) as well as the current use of NSAIDs and an increased risk of chronic AF (RR, 1.44; 95% CI, 1.08-1.91). Author's Conclusion: The use of NSAIDs, as for SAIDs, is associated with an increased risk of chronic AF. Source:AMA


Efficacy of the Use of Neuromuscular Blockers in Early Acute Respiratory Distress Syndrome. 9/16/2010. Background: This trial evaluated the clinical outcomes after therapy with neuromuscular blocking agents in patients with early, severe acute respiratory distress syndrome (ARDS). Methods: A multicenter, double-blind trial was performed in which 340 patients presenting to the intensive care unit (ICU) with an onset of severe ARDS were randomly assigned to receive either cisatracurium besylate or placebo. Results: The hazard ratio for death at 90 days in the cisatracurium group, as compared with the placebo group, was 0.68 (95% CI, 0.48 to 0.98; p=0.04). Author's Conclusion: In patients with severe ARDS, early administration of a neuromuscular blocking agent improved the adjusted 90-day survival and increased the time off the ventilator without increasing muscle weakness. Source:NEJM


Emergency Department Visits Associated with Chronic Opioid Therapy. 9/13/2010. Background: This study was performed to determine the association between opioid prescribing and adverse outcomes. Methods: Regression analysis was used to examine risk factors for emergency department visits (EDVs) and alcohol- or drug-related encounters (ADEs) in the 12 months following 90 days or more of prescribed opioids. Results: Headache, back pain, mental health disorders, and preexisting substance use disorders were significantly associated with EDVs and ADEs. Opioid dose per day was not consistently associated with EDVs but doubled the risk of ADEs at morphine-equivalent doses over 120 mg/d. Author's Conclusion: Use of Schedule II opioids, headache, back pain, and substance use disorders are associated with EDVs and ADEs among adults prescribed opioids for 90 days or more. Source:AMA


Effect of Sibutramine on Cardiovascular Outcomes. 9/02/2010. Background: The purpose of this trial was to assess the long-term effects of sibutramine treatment on the rate of cardiovascular events and related death among subjects at high risk. Methods: After a 6-week, single-blind, lead-in period of sibutramine treatment and participation in a weight management, 9804 overweight or obese subjects, 55 years of age or older, with preexisting cardiovascular disease, type 2 diabetes mellitus, or both, were randomly assigned to receive sibutramine or placebo until the first occurrence of a primary outcome event. Results: The risk of a primary outcome event was 11.4% in the sibutramine group as compared with 10.0% in the placebo group (hazard ratio, 1.16; 95% CI, 1.03 to 1.31; p=0.02). The rates of nonfatal myocardial infarction and nonfatal stroke were 4.1% and 2.6% in the sibutramine group and 3.2% and 1.9% in the placebo group, respectively (hazard ratio for nonfatal myocardial infarction, 1.28; 95% CI, 1.04 to 1.57; p=0.02; hazard ratio for nonfatal stroke, 1.36; 95% CI, 1.04 to 1.77; p=0.03). The rates of death were not increased. Author's Conclusion: Subjects with preexisting cardiovascular conditions who were receiving long-term sibutramine treatment had an increased risk of nonfatal myocardial infarction and nonfatal stroke but not of death. Source: NEJM


Once- and Twice-Daily budesonide/formoterol in Asthma Treatment. 8/16/2010. Background: The objective of this study was to assess the efficacy of once-daily budesonide/formoterol pressurized metered-dose inhaler (pMDI) versus budesonide pMDI (primary) and twice-daily budesonide/formoterol (secondary) in children/adolescents with asthma stabilized with twice-daily budesonide/formoterol. Methods: This was a 12-week multicenter, double-blind randomized controlled study in which 521 patients between 6 and 15 years received twice-daily budesonide/formoterol pMDI 40/4.5 µg x 2 inhalations (160/18 µg daily), once-daily budesonide/formoterol pMDI 80/4.5 µg x 2 inhalations (160/9 µg daily; evening), or once-daily budesonide pMDI 80 µg x 2 inhalations (160 µg daily; evening). Results: Once- or twice-daily budesonide/formoterol was more effective than budesonide for evening peak expiratory flow at the end of the 24-hour once-daily dosing interval (p=0.027). Twice-daily budesonide/formoterol was more effective than once-daily treatments for evening predose forced expiratory volume in 1 second (P =0.011), versus budesonide for daytime/nighttime rescue medication (p=0.023), and versus once-daily budesonide/formoterol for daytime rescue medication (last 12 hours of once-daily dosing) (p=0.032). Author's Conclusion: Once-daily budesonide/formoterol was significantly more effective than once-daily budesonide for most pulmonary-function variables, and twice-daily budesonide/formoterol (160/18 µg daily) maintenance therapy was more effective than once-daily dosing (160/9 µg daily). Source: AAP


Lactobacillus reuteri Effect on Infantile Colic. 9/03/2010. Background: This study assessed the efficacy of Lactobacillus reuteri on infantile colic. Methods: Fifty exclusively breastfed colicky infants, were randomly assigned to receive either Lactobacillus reuteri DSM 17 938 (108 colony-forming units) or placebo daily for 21 days. Results: The median of daily crying times in minutes/day were 370 vs 300 (p = .127) on day 0 and 35.0 vs 90.0 (p = .022) on day 21, in the Lactobacillus reuteri and placebo groups, respectively. Author's Conclusion: Lactobacillus reuteri DSM 17 938 at a dose of 108 colony-forming units per day in early breastfed infants improved symptoms of infantile colic and was well tolerated and safe. Source:AAP


Dose Comparisons of Clopidogrel and Aspirin. 9/02/2010. Background: Clopidogrel and aspirin, used for patients with acute coronary syndromes and those undergoing percutaneous coronary intervention (PCI), do not have evidence-based guidelines for dosing. Methods: 25,086 patients with an acute coronary syndrome who were referred for an invasive strategy were randomly assigned to receive either double-dose clopidogrel (a 600-mg loading dose on day 1, followed by 150 mg daily for 6 days and 75 mg daily thereafter) or standard-dose clopidogrel (a 300-mg loading dose and 75 mg daily thereafter) and either higher-dose aspirin (300 to 325 mg daily) or lower-dose aspirin (75 to 100 mg daily). Results: A primary outcome of cardiovascular death, myocardial infarction, or stroke at 30 days occurred in 4.2% of patients assigned to double-dose clopidogrel as compared with 4.4% assigned to standard-dose clopidogrel (hazard ratio, 0.94; 95% CI, 0.83 to 1.06; p=0.30). Author's Conclusion: There was no significant difference between a 7-day, double-dose clopidogrel regimen and the standard-dose regimen, or between higher-dose aspirin and lower-dose aspirin, with respect to the primary outcome of cardiovascular death, myocardial infarction, or stroke. Source:NEJM

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August 2010.

Ipilimumab Effective in Treating Metastatic Melanoma Patients. 8/19/2010. Background:This phase 3 study was conducted to evaluate the efficacy of ipilimumab, which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response, in combination with a glycoprotein 100 (gp100) vaccine as a treatment for patients with metastatic melanoma. Methods: 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned to receive ipilimumab and gp100, ipilimumab alone, or gp100 alone. Results: The median of overall survival time was 10 months in the combination group taking ipilimumab and gp100, 6.4 months in those taking gp100 alone, and 10.1 months in those taking ipilimumab alone. Author's Conclusion: Treatment with ipilimumab improved overall survival regardless of the addition of gp100. Source: NEJM


Renal Safety of Tenofovir Disoproxil Fumarate in HIV‐Infected Patients. 9/01/2010. Background: This study was conducted to determine the renal safety of tenofovir disoproxil fumarate (TDF)‐containing ART regimens for HIV‐infected individuals due to the increasing number of case reports suggesting an association with significant nephrotoxicity. Methods: Data on study characteristics, participant characteristics, therapeutic interventions, renal function, bone density, and fracture rates were extracted from prospective studies comparing TDF‐containing with non-TDF containing ART regimens. Results: A significantly greater loss of kidney function (mean difference in calculated creatinine clearance, 3.92 mL/min; 95% CI, 2.13-5.70 mL/min) and a greater risk of acute renal failure (risk difference, 0.7%; 95% CI, 0.2-1.2) were observed among the TDF recipients as compared with control subjects. Author's Conclusion: Although TDF use was associated with a statistically significant loss of renal function, the clinical magnitude of this effect does not support the need to restrict TDF use in jurisdictions where regular monitoring of renal function and serum phosphate levels is impractical. Source: CID


Pegylated Interferon Alfa‐2a Monotherapy for Hemodialysis Patients with Acute Hepatitis C. 9/01/2010. Background: The purpose of this study was to evaluate the efficacy and safety of pegylated interferon (IFN) therapy for hemodialysis patients with acute hepatitis C. Methods: 35 hemodialysis patients with acute hepatitis C who did not have spontaneous clearance of HCV by 16 weeks were treated with 135 μg pegylated IFN alfa‐2a weekly for 24 weeks, while 7 patients with clearance of HCV by 16 weeks were simply under observation. Thirty‐six hemodialysis patients from 2002-2005 who had acute hepatitis C but did not receive treatment served as historical controls. Results: The rate of sustained virologic response in the treatment group was 88.6% in comparison to the 16.7% rate of spontaneous HCV clearance in the control group. Author's Conclusion: Pegylated IFN alfa‐2a monotherapy is safe and extremely effective in treating hemodialysis patients with acute hepatitis C. Source: CID


Sildenafil Use in Advanced Idiopathic Pulmonary Fibrosis. 8/12/2010. Background: This study was conducted to determine if use of sildenafil, a phosphodiesterase-5 inhibitor, in advanced idiopathic pulmonary fibrosis patients, would improve blood flow to well-ventilated regions of the lungs. Methods: A 12-week, double-blind, randomized, placebo-controlled trial of sildenafil, including 180 patients, was conducted with the hypothesis that successful treatment would result in an increase of patients' 6-minute walk distance of 20% or more. A second 12-week period consisted of an open-label evaluation involving all patients receiving sildenafil. Results: 9 of 89 patients (10%) in the sildenafil group as opposed to 6 of 91 (7%) in the placebo group had an increase in 6-minute walk distance of 20% or more (p=0.39). Small but significant differences in arterial oxygenation, carbon monoxide diffusion capacity, degree of dyspnea, and quality of life favoring the sildenafil group were observed while serious adverse events were similar for both study groups. Author's Conclusion: Silendafil did not result in the expected benefits, however, other positive results suggest a basis for further research. Source: NEJM


Reduced Intensity Treatment for Early-stage Hodgkin's Lymphoma. 8/12/2010. Background: The purpose of this study was to determine whether it is possible to reduce the intensity of treatment in early stage I or II Hodgkin's lymphoma while maintaining a favorable prognosis. Methods: During this 5 year, multicenter, randomized trial, 1,370 newly diagnosed, early-stage Hodgkin's lymphoma patients were randomly assigned to one of four different treatment regimens, which consisted of either two or four cycles of ABVD followed by either 20 or 30 Gy of radiation therapy. Results: Rates of freedom from treatment failure were 93.0% (95% CI, 90.5 to 94.8) in the four-cycle ABVD regimen group and 91.1% (95% CI, 88.3 to 93.2) in the two-cycle regimen group. No significant differences between the 20 Gy and 30Gy doses of radiation therapy in either freedom from treatment failure (P=1.00) or overall survival (P=0.61) were observed. Author's Conclusion: In early-stage Hodgkin's lymphoma patients with a favorable prognosis, treatment with two cycles of ABVD followed by 20 Gy of involved-field radiation therapy and four cycles of ABVD followed by 30 Gy of involved-field radiation therapy are equally effective. Source: NEJM


Increase in Seizure Risk Not Associated with DTaP Vaccine. 7/19/2010. Background: This analysis was performed to assess the risk of seizures associated with the receipt of the diphtheria-tetanus-acellular pertussis vaccine (DTaP). Methods: Risk-interval cohort and self-controlled case series (SCCS) analyses were conducted on Vaccine Safety Datalink (VSD) information of children aged 6 weeks to 23 months who had not received DTP during the study period. The risk-interval cohort method compared the incidence of seizures that occurred within the 4 days after each DTaP dose to those that occurred outside of this period. In the SCCS method, the comparison was performed between the seizure incidences of the each patient that occurred within and outside of the 4 day period. Results: 7,191 seizure events were noted among 433,654 children, resulting in a 0.87 adjusted incidence rate ratio of seizures across all dosesin the cohort analysis, and a 0.91 incidence rate ratio in the SCCS analysis. Author's Conclusion: An increased risk of seizures after the DTap vaccination was not apparent in children between 6 weeks and 23 months of age. Source: AAP


Length of Intravenous Antibiotic Therapy in Infant Urinary Tract Infections. 7/12/2010. Background: This study was conducted to compare the efficacy of short-duration (3 days or less) and long-duration (4 days or more) of intravenous antibiotic therapy in infants hospitalized with urinary tract infections (UTIs). Methods: Data concerning infants younger than 6 months who were hospitalized with UTIs over a 5 year period, was collected from hospitals in the Pediatric Health Information System and adjusted for all covariates, propensity scores, and clustering according to hospital before being evaluated. Results: Of 12,333 infants, the treatment failure rates were 1.6% with short-duration therapy and 2.2% with long-duration therapy. After multivariate adjustment the odds ratio for long versus short treatment was 1.02 (95% CI: 0.77-1.35). Author's Conclusion: Treatment failure for infant UTIs was uncommon and showed no significant association with the duration of intravenous antibiotic therapy. Source: AAP

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July 2010

Progression of Retinopathy in Type 2 Diabetes. 7/15/2010. Background: Previous data suggest that intensive glycemic control, combination therapy for dyslipidemia, and intensive blood-pressure control may limit the development and progression of diabetic retinopathy. Methods: 2,856 type 2 diabetes patients at high risk for cardiovascular disease were evaluated for the progression of diabetic retinopathy 4 years after receiving either intensive or standard treatment for glycemia (target glycated hemoglobin level, <6.0% or 7.0 to 7.9%, respectively) and also for dyslipidemia (160 mg daily of fenofibrate plus simvastatin or placebo plus simvastatin) or for systolic blood-pressure control (target, <120 or <140 mm Hg). Results: The rates of progression were 7.3% with intensive glycemia treatment, versus 10.4% with standard therapy (adjusted odds ratio, 0.67; 95% CI, 0.51 to 0.87; p=0.003); 6.5% with fenofibrate for intensive dyslipidemia therapy, versus 10.2% with placebo (adjusted odds ratio, 0.60; 95% CI, 0.42 to 0.87; p=0.006); and 10.4% with intensive blood-pressure therapy, versus 8.8% with standard therapy (adjusted odds ratio, 1.23; 95% CI, 0.84 to 1.79; p=0.29). Author's Conclusion: The rate of progression of diabetic retinopathy was reduced by intensive glycemic control and intensive combination treatment of dyslipidemia, but not intensive blood-pressure control. Source: NEJM

Rituximab Therapy for Remission Induction In Severe ANCA-Associated Vasculitis. 7/15/2010. Background: Uncontrolled studies suggest that rituximab is effective and may be safer for remission-induction therapy for severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis than a cyclophosphamide-based regimen. Methods: A multicenter, randomized, double-blind, double-dummy, noninferiority trial was conducted to compare the induction of remission with rituximab and cyclophosphamide without the use of prednisone at 6 months. Results: 64% of the rituximab group reached the primary end point, as compared with 53% of the control group, a result that met the criterion for noninferiority (p<0.001). In inducing remission of relapsing disease, 67% of the rituximab group as opposed to 42% of the control group reached the primary end point (p=0.01). Author's Conclusion: Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. Source: NEJM

Increase in Mortality Not Associated with Cefepime. 8/15/2010. Background: Concern has been raised that cefepime is associated with increased mortality compared with other B-lactam antibiotics. Methods: A meta-analyisis was performed comparing 88 trials concerning cefepime use. Results: 30-day mortality rates in cefepime patients were 6.21% compared to 6.00% in comparator patients (adjusted risk difference (ARD) per 1000 population, 5.38; 95%CI, -1.53 to 12.28).  Furthermore, a sensitivity analysis was performed on 24 clinical trials involving febrile neutropenia and did not show a statistically significant increase in mortality while on cefepime (ARD per 1000 population, 9.67; 95%CI, -2.87 to 22.21). Author's Conclusion: The difference in mortality rates was not determined to be significant enough to signal a threat. Source: CID

Lorcaserin Used for Weight Loss. 7/15/2010. Background: Lorcaserin, a serotonin 2C receptor agonist may aid weight loss. Methods: This was a randomized, double-blind trial in which 3,182 were assigned to receive 10 mg of lorcaserin, or a placebo, two times a day for a year. At one year lorcaserin patients were randomly reassigned to receive either a placebo or continue on lorcaserin. Results: At 1 year, 47.5% of patients in the lorcaserin group and 20.3% in the placebo group had lost an average loss of 5.8±0.2 kg with lorcaserin and 2.2±0.1 kg with placebo during year 1 (p<0.001). This loss was maintained in 67.9% patients who continued to receive lorcaserin during the second year, and 50.3% (p<0.001) in patients who received placebo. Author's Conclusion: Lorcaserin was associated with increased weight loss and maintenance, as compared with placebo. Source: NEJM

NCG in Propionic Acidemia Patients. 7/20/2010. Background: This study was performed to determine whether N-carbamylglutamate (NCG) reduces plasma levels of ammonia and glutamine and increases the rate of ureagenesis in patients with propionic acidemia (PA). Methods: Blood samples were taken and analyzed before and after a 3-day trial of oral NCG in 7 patients with PA. Results: Peak [13C]urea increased after treatment with NCG (from 2.2 to 3.8 µM; p< .0005). There were concomitant decreases in mean plasma ammonia (59-43 µM; p< .018) and glutamine (552-331 µM; p< .0005). Author's Conclusion: NCG augments ureagenesis and decreases plasma ammonia and glutamine in patients with PA. Source: AAP

 

Homocysteine Levels Not Associated with Vascular Outcomes. 6/23/2010. Background: The objective of this study was to assess the effects of the reduction of homocysteine blood levels on cardiovascular disease outcomes. Methods: This was a double-blind, randomized, controlled trial in which 12,064 survivors of myocardial infarction were given either 2 mg of folic acid with 1 mg of vitamin b12 or a matching placebo daily. Results: During 6.7 years of follow-up, major vascular events occurred in 1,537 of the participants (25.5%) who were allocated folic acid plus vitamin B12, and in 1,493 of the participants (24.8%) who were allocated the placebo (RR, 1.04; 95% CI, 0.97-1.12; p= 0.28). Author's Conclusion: Long term reduction in blood homocysteine levels was not associated with a beneficial effect on vascular outcomes. Source: JAMA 

Trimethoprim-Sulfamethoxazole-Induced Hyperkalemia. 6/28/2010. Background: The objective of this study was to assess the risk of hospitalization due to hyperkalemia in elderly patients receiving treatment of a Trimethoprim-Sulfamethoxazole along with either an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB). Methods: This was a population based, nested, case control study conducted over a 14 year period, in which Odds ratios were determined for the association between hyperkalemia-associated hospitalization and previous antibiotic use in patients 66 years and older, receiving continuous therapy with either an ACEI or an ARB. Results: In cases of hospitalization for hyperkalemia occurring within 14 days of antibiotic exposure, the use of trimethoprim-sulfamethoxazole was associated with a risk of hyperkalemia-associated hospitalization 6.7 times that of amoxicillin (95% CI, 4.5-10.0). Author's Conclusion: The use of trimethoprim-sulfamethoxazole in elderly patients receiving ACEIs or ARBs is associated with a significant risk of hyperkalemia-associated hospitalization. Source: Arch Intern Med

 

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June 2010

Fluoroquinolones for Extensively Drug-Resistant Tuberculosis. 6/20/2010. Background: Extensively Drug-Resistant Tuberculosis (XDR TB) is resistant to most second-line antimycobacterial drugs which tend to be toxic and costly. Methods: A meta-analysis combined studies reporting on XDR TB treatment outcomes from PubMed and EMBASE through May 2009. Results: Of 560 patients in 13 studies, 43.7% (95% CI, 32.8% - 54.5%) experienced favorable outcomes and 20.8% (95% CI, 14.2%-27.3%) died. A study in which higher proportion of patients received a later-generation fluoroquinolone also had a higher proportion of favorable outcomes (p=0.012). Author's Conclusion: This meta-analysis provides the first empirical evidence that later-generation fluoroquinolones improve treatment outcomes. Source: CID 

Valproic Acid in First Trimester Associated with Congenital Malformations. 6/10/2010. Background: The risk of congenital malformations associated with the use of valproic acid during the first trimester of pregnancy is largely unknown, apart from that of spina bifida. Methods: Data was combined from eight previous studies to identify 14 congenital malformations common in infants who were exposed to valproic acid during the first trimester. A case-control study was then performed using 180 registrations from the European Surveillance of Congenital Anomalies (EUROCAT) antiepileptic-study database, comparing a case group of pregnancy outcomes with any of these 14 malformations with control groups of infants with malformations not previously associated with valproic acid exposure and infants with chromosomal abnormalities. Results: Of the 180 registrations, 122 were in the case group, 45 in control group 1 with previously unassociated malformations, and 13 in control group 2 with chromosomal abnormalities. Occurrence of 6 of the specified malformations associated with valproic acid was greatly increased as displayed by the adjusted odds ratios: spina bifida, 12.7 (95% CI, 7.7 to 20.7); atrial septal defect, 2.5 (95% CI, 1.4 to 4.4); cleft palate, 5.2 (95% CI, 2.8 to 9.9); hypospadias, 4.8 (95% CI, 2.9 to 8.1); polydactyly, 2.2 (95% CI, 1.0 to 4.5); and craniosynostosis, 6.8 (95% CI, 1.8 to 18.8). Author's Conclusion: The use of valproic acid monotherapy in the first trimester was associated with significantly increased risks of several congenital malformations, as compared with no use of antiepileptic drugs or with use of other antiepileptic drugs. Source: NEJM 

Nilotinib Superior Over Imatinib in Treating Chronic Myeloid Leukemia. 6/17/2010. Background: This study assessed the efficacy and safety of Nilotinib, which is known to be a more potent inhibitor of BCR-ABL than Imatinib. Methods: This was a phase 3, randomized, open-label, multicenter study, in which 846 chronic-phase Philadelphia chromosome-positive CML patients were assigned to receive a dose of either 300 mg or 400 mg of nilotinib twice a day or 400 mg of imatinib once daily for 12 months. Results: At 12 months, the rates of major molecular response were 44% and 43% for nilotinib and 22% for imatinib. Author's Conclusion: Treatments of nilotinib at either dose twice daily was twice as effective as that of imatinib in newly diagnosed chronic-phase Philadelphia chromosome-positive CML patients. Source: NEJM


Use of Antiretroviral Drugs to Reduce HIV-1 Transmission While Breastfeeding. 6/17/2010. Background: This study assessed the efficacy of a maternal triple-drug antiretroviral regimen and an infant nevirapine prophylaxis in reducing postnatal transmission of HIV-1. Methods: 2369 HIV-1-positive, breast-feeding mothers with a CD4+ lymphocyte count of at least 250 cells per cubic millimeter and their infants received perinatal prophylaxis with single-dose nevirapine and 1 week of zidovudine plus lamivudine, and were randomly assigned to receive either a maternal antiretroviral regimen, infant nevirapine, or no extended postnatal antiretroviral regimen. Results: 5% of the infants were HIV-1-positive at 2 weeks of life. The estimated risk of transmission between 2 and 28 weeks was 5.7% in the control group with no extended antiretroviral regimen, 2.9% in the maternal-regimen group (p=0.009), and 1.7% in the infant-regimen group (p<0.001). Author's Conclusion: Both the maternal antiretroviral regimen and the infant nevirapine were effective in reducing HIV-1 transmission while breast-feeding. Source: NEJM


Dasatinib Superior Over Imatinib in Treating Chronic Myeloid Leukemia. 6/17/2010. Background: This study assessed the efficacy and safety of Dasatinib, a potent BCR-ABL kinase inhibitor commonly used after the failure of imatinib treatment, as a first-line treatment of chronic-phase Chronic Myeloid Leukemia. Methods: 519 chronic-phase CML patients were randomly assigned to receive either a 100 mg dose of dasatinib or a 400 mg dose of imatinib once daily for 12 months. Results: Complete cytogenetic response was assessed after a follow-up of 12 months at 77% with dasatinib and 66% with imatinib (p<0.007). Major molecular responses were also achieved in a shorter time with dasatinib (p<0.0001). Author's Conclusion: Dasatinib, as compared with imatinib, resulted in higher and faster rates of complete cytogenetic response and major molecular response, and may therefore improve long-term outcomes among newly diagnosed chronic-phase CML patients. Source: NEJM

Higher Serum Levels of B6 and Methionine Associated with Lower Risk of Lung Cancer. 6/16/2010. Background: B Vitamins and 1-carbon metabolism factors maintain DNA integrity and regulate gene expression. The European Prospective Investigation into Cancer and Nutrition (EPIC) investigated its affect on cancer risk. Methods: 519,978 people were recruited from 10 different countries of whom 385,747 gave blood. 1770 people were chosen according to country, sex, age, and date of blood dontation. Over 14 years, 899 cases of lung cancer were identified, the incidence rates of cancer among smokers were accounted for, and the odds ratios of lung cancer by various vitamin B serum levels were analyzed. Results: A lower risk for lung cancer was seen for elevated serum levels of B6 (fourth vs first quartile OR, 0.44; 95% CI, 0.33-0.60; p for trend <0.000001), as well as for serum methionine (fourth vs first quartile OR, 0.52; 95% CI, 0.39-0.69; p for trend <0.000001). Similar decreases in risk were similar and consistent in respect to never, former, and current smokers and length of follow-up, indicating that they were not confounded by smoking or preclinical disease. Author's Conclusion: Increased serum levels of B6 and methionine were associated with a decreased risk of lung cancer. Source: JAMA

Breast Cancer Survival in Relation to Chemotherapy Regimens. 6/03/2010. Background: Chemotherapy regimens that combine anthracyclines and taxanes result in improved disease-free and overall survival of women with operable lymph-node-positive breast cancer. This study compared the efficacy of these treatments. Methods: 5,351 patients with operable, node-positive, early-stage breast cancer were randomly assigned to one of the following three treatments: sequential ACT (four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel), concurrent ACT (four cycles of doxorubicin, cyclophosphamide, and docetaxel), or doxorubicin-docetaxel (four cycles of doxorubicin and docetaxel). Results: At 73 months, the overall survival rates were 83%, 79%, and 79% for the Sequential ACT, Concurrent ACT, and doxorubicin-docetaxel groups, respectively; disease-free survival rates were 74%, 69%, and 69%. Author's Conclusion: Sequential ACT improved disease-free survival as compared with doxorubicin-docetaxel or concurrent ACT, and it improved overall survival as compared with doxorubicin-docetaxel. Source: NEJM 

Ongoing Safety Review of Benicar (olmesartan). 6/11/2010. Two long-term clinical trials designed to determine Benicar's effect on the progression of kidney disease in type 2 diabetes patients revealed an unexpected finding in which there was a greater number of deaths from a cardiovascular cause in the Benicar-treated patients compared to placebo. The FDA has NOT yet concluded that Benicar increases the risk of death however, and currently believes that Benicar's benefits in high blood pressure patients still outweighs its potential risks. Source: FDA 

 

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May 2010

Bisphosphonates and Subtrochanteric or Diaphyseal Femur Fractures. 05/13/2010. Bisphosphonates have been used for many years for the prevention and/or treatment of osteoporosis in a number of populations. Methods: A secondary analyses using the results of three large, randomized bisphosphonate trials: the Fracture Intervention Trial (FIT), the FIT Long-Term Extension (FLEX) trial, and the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial (PFT) was done to evaluate if there were atypical fractures of the femoral shaft associated with the use of bisphosphonates. Results: There were 284 records for hip or femur fractures among 14,195 women reviewed in these trials with a total of 12 fractures in 10 patients being classified as occurring in the subtrochanteric or diaphyseal femur thereby resulting in a combined rate of 2.3 per 10,000 patient-years. When compared to placebo, the relative hazard was 1.03 (95% CI, 0.06 to 16.46) for alendronate use in the FIT trial, 1.50 (95% CI, 0.25 to 9.00) for zoledronic acid use in the HORIZON-PFT trial, and 1.33 (95% CI, 0.12 to 14.67) for continued alendronate use in the FLEX trial. Authors Conclusion: The occurrence of fracture of the subtrochanteric or diaphyseal femur was rare and there was no significant increase in risk associated with bisphosphonate use, however the study was underpowered for definitive conclusions. Source: N Engl J Med

The Impact of Maternal Vitamin A Supplementation on Pulmonary Function in Offspring. 05/13/2010.  Vitamin A is important in regulating the early development of lung formation. Methods: This was a cohort study involving rural Nepali children 9 to 13 years of age whose mothers from a chronically malnourished population had participated in a placebo-controlled, double-blind, cluster-randomized trial of vitamin A or beta-carotene supplementation between 1994 and 1997. Results: A total of 1658 (88%) were eligible to participate in this study in which spirometry was performed in 83% of those eligible between October 2006 and March 2008. Children whose mothers had received vitamin A supplementation had an adjusted forced expiratory volume in 1 second (FEV1) and a forced vital capacity (FVC) that were significantly higher than those of children whose mothers had received placebo (FEV1, 46 ml higher with vitamin A; 95% CI, 6 to 86; FVC, 46 ml higher with vitamin A; 95% CI, 8 to 84). In children whose mothers had received beta carotene supplementation the adjusted FEV1 and FVC values that were similar to those of children whose mothers had received placebo (FEV1, 14 ml higher with beta carotene; 95% CI, -24 to 54; FVC, 17 ml higher with beta carotene, 95% CI, -21 to 55). Conclusion: Maternal repletion with vitamin A in a chronic malnourished population with recommended dietary levels before, during, and after pregnancy was able to improve lung function in offspring. Source: N Engl J Med


High Dose Oral Vitamin D Once-a-Year in Older Women was Associated with Increase Falls and Fractures. 05/12/2010. Methods: This was a randomized, double-blind, placebo controlled trial involving 2,256 women ≥ 70 years of age who were to receive either cholecalciferol (vitamin D) 500,000 IU annually for 3 to 5 years or placebo. Results: Women in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2,892 times (rate, 83.4 per 100 person-years) while 769 women in the placebo group fell 2,512 times (rate, 72.7 per 100 person-years; incidence rate ratio (RR), 1.15; 95% CI, 1.02-1.30; P = .03). The incidence RR for fracture in the vitamin D group was 1.26 (95% CI, 1.00-1.59; P = .047) vs the placebo group (rates per 100 person-years, 4.9 vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02). Conclusion: The annual administration of high dose vitamin D in older women increased the risk of falls and fractures. Source: JAMA


High Dose vs. Regular Dose PPI Use for Bleeding Peptic Ulcers. 05/10/2010. Background: Even though high dose proton pump inhibitors (PPIs) (80-mg bolus, followed by 8-mg/h continuous infusion for 72 hours) have been widely studied and used there is no definitive evidence that high dose is more effective. Methods: This was a systematic review and meta-analysis of randomized controlled trials that compared the use of high-dose PPIs vs non-high-dose PPIs in patients with bleeding peptic ulcer. Results: A total of 1,157 patients from 7 high-quality randomized studies were included in this meta-analysis. High dose PPIs and regular dose PPIs did not differ in their effects on the rates of rebleeding (7 studies and 1157 patients; OR, 1.30; 95% CI, 0.88-1.91), surgical intervention (6 studies and 1052 patients; 1.49; 0.66-3.37), or mortality (6 studies and 1052 patients; 0.89; 0.37-2.13). In addition, a post hoc subgroup analyses further revealed that these outcome measures were unaffected by severity of signs of recent hemorrhage at initial endoscopy, route of PPI administration, or PPI dose. Conclusion: The use of high dose PPIs does not further reduce the rates of rebleeding, surgical intervention, or mortality after endoscopic treatment in patients with bleeding peptic ulcer when compared to regular dosing. Source: Arch Intern Med 

Azithromycin Use in Cystic Fibrosis Patients Not Infected with Pseudomonas aeruginosa. 05/05/2010. Main Objective: Change in FEV1. Methods: This was a multicenter, randomized, double-blind, placebo-controlled trial that was conducted in 260 cystic fibrosis patients ages 6 to 18 years who were to either receive weight based azithromycin (250 to 500 mg) three times per week for 168 days or placebo. Results: There was no difference in the change in FEV1 between the azithromycin and placebo groups was 0.02 L (95% CI, -0.05 to 0.08; P = .61). In addition, none of the exploratory pulmonary function end points were statistically significant. However, pulmonary exacerbations occurred in 21% of the azithromycin group vs 39% of the placebo group. Patients in the azithromycin group had a 50% reduction in exacerbations (95% CI, 31%-79%) and an increase in body weight of 0.58 kg (95% CI, 0.14-1.02) compared with placebo participants. There were no significant differences between groups in height, use of intravenous or inhaled antibiotics, or hospitalizations. Conclusions: Azithromycin use in cystic fibrosis patients not infected with Pseudomonas aeruginosa did not have any improvements in pulmonary function testing. Source: JAMA  

 

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April 2010

Dutasteride and Risk of Prostate Cancer: 04/01/2010. Dutasteride (Duagen) is a 5-alpha reductase inhibitor used in the management of benign prostatic hyperplasia. Methods: This was a 4-year, multicenter, randomized, double-blind, placebo-controlled, parallel-group study involving 6,729 men between the ages of 50-75 years, a PSA level of 2.5-10 ng/mL and a negative biopsy of prostate that compared dutasteride, at a dose of 0.5 mg daily to placebo. Results: Prostate cancer was detected in 659/3305 of men taking dutasteride versus 858/3424 of men on placebo thereby representing a relative risk reduction 22.8% with dutasteride (95% CI, 15.2 to 29.8; p<0.001). Furthermore, dutasteride when compared to placebo, resulted in a 77.3% relative reduction in the rate of acute urinary retention (1.6% vs. 6.7%). Comment: While these results are interesting and certainly worth following, it is not known if dutasteride is simply slowing the growth of cancer already present but not detected on a biopsy. In addition, there was a statistically significant increase in cardiac failure noted in the study that warrants additional consideration. Source: N Engl J Med


Oseltamivir with Hand Sanitization and Surface Contamination Helpful in Camp Settings. 04/04/2010. Main Objective: To describe the effectiveness of containment of novel influenza A (H1N1) infection at a summer camp. Methods: A total of 171 campers, 48 camp counselors, and 27 camp staff were studied. Any campers with confirmed influenza received oseltamivir and were immediately isolated and sent home. In addition, all boys and counselors in the infected child's adjoining cabins received prophylactic oseltamivir x 10 days, including 8 campers at higher risk for influenza infection (eg, those with asthma, seizure disorder, or diabetes). Alcohol-based hand sanitizer was provided at each of the daily activities, in the boys' cabins, and in the dining hall, and counselors were educated by the medical staff on the spread of influenza and its prevention through good hand hygiene. Furthermore, all cabins, bathrooms, and community sports equipment were sprayed or wiped down with disinfectant each day. Results: Three of the 171 campers tested positive for influenza A during the course of the 2-week fourth session, which resulted in an attack rate of 1.8%. The probability of observing 3 or fewer infected campers if the attack rate was 12% is less than 1 in 10,000,000 (P < .0000001). No campers tested positive for influenza A after returning home at the end of the camp session. Comment: While oseltamivir does confer a benefit in prevention, it is important to note the extensive amount of hand sanitization and surface decontamination that was implemented. Source: Arch Pediatr Adolsec Med

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March 2010

Pharmacogenetics: Carbamazepine and MRP2 Transport into the Brain. 03/20/2010. The cell membrane transporter, multidrug resistance protein 2 (MRP2) is known to be upregulated in brain tissue from patients with epilepsy and involved in the transport of antiepileptic drugs. Methods: This was a case-controlled study that evaluated 146 patients being treated with carbamazepine for the treatment of epilepsy. They were evaluated for the presence of single nucleotide polymorphisms to the gene coding for MRP2 and the development of neurologic adverse reactions associated with the carbamazepine. Results: A nonsynonymous polymorphism, c.1249G>A (p.V417I, rs2273697), showed a strong association by carbamazepine (p=0.005). Logistic regression analysis with multiple clinical variables indicated that the presence of A allele at the MRP2 c.1249G>A locus was an independent determinant of central nervous system ADR caused by carbamazepine. Source: Pharmacogenet Genomics


Rosuvastatin Demonstrates Similar Risk Reduction for Primary Prevention of CVD in Women as Men. 03/09/2010. A group from Harvard Medical School sought to assess the impact of statin therapy in women without cardiovascular disease (CVD). Methods: This was determined by comparing the results from the JUPITER study with a meta-analysis of predominately primary prevention trials. The JUPITER trial included 6,801 women ≥60 years of age and 11,001 men ≥50 years of age with high-sensitivity C-reactive protein ≥2 mg/L and low-density lipoprotein cholesterol <130 mg/dL randomized to rosuvastatin versus placebo. The meta-analysis included women (20,147 women; >276 CVD events; mean age, 63 to 69 years) and sex-specific outcomes. Results: The absolute CVD rates in JUPITER women for rosuvastatin and placebo (0.57 and 1.04 per 100 person years, respectively) were lower than for men (0.88 and 1.54 per 100 person years, respectively), with similar relative risk reduction in women (hazard ratio (HR), 0.54; 95% confidence interval (CI), 0.37 to 0.80; p=0.002) and men (HR, 0.58; 95% CI, 0.45 to 0.73; p<0.001). Conclusion: The authors reported that the JUPITER trial demonstrated the relative risk reduction for the primary prevention of CVD was similar to that seen in men. Source: Circulation


Dopamine versus Norepinephrine in the Treatment of Shock. 03/04/2010. Methods: This was a multicenter, randomized trial in 1,679 patients with shock who received either dopamine at 20 mcg/kg/min or norepinephrine 0.19 mcg/kg/min as first-line vasopressor therapy to restore and maintain blood pressure. Endpoints: The primary outcome was the rate of death at 28 days after randomization; secondary end points included the number of days without need for organ support and the occurrence of adverse events. Results: There was no significant between-group difference in the rate of death at 28 days (52.5% in the dopamine group and 48.5% in the norepinephrine group; odds ratio with dopamine, 1.17; 95% CI, 0.97 to 1.42; P=0.10). However, patients treated with dopamine had more arrhythmic events than among those treated with norepinephrine (24.1% vs. 12.4%, P<0.001). Conclusions: While there were no significant differences in the rate of death between dopamine and norepinephrine, there were more adverse drug events with dopamine. Source: NEJM


Ethosuximide and Valproic Acid Better Than Lamotrigine for Childhood Absence Epilepsy. 03/04/2010. Methods: This was a double-blind, randomized, controlled clinical trial in 453 children to test the efficacy, tolerability, and neuropsychological effects of 16 weeks of therapy with either ethosuximide (n=156), valproic acid (n=148), or lamotrigine (n=149) in children with newly diagnosed childhood absence epilepsy. Endpoint: The primary outcome was freedom from treatment failure after 16 weeks of therapy. Results: The freedom from treatment failure rates for ethosuximide and valproic acid were similar (53% and 58%, respectively; odds ratio (OR) with valproic acid vs. ethosuximide, 1.26; 95% CI, 0.80 to 1.98; P=0.35) and were higher than the rate for lamotrigine (29%; OR with ethosuximide vs. lamotrigine, 2.66; 95% CI, 1.65 to 4.28; OR with valproic acid vs. lamotrigine, 3.34; 95% CI, 2.06 to 5.42; P<0.001 for both comparisons). Conclusion: Ethosuximide and valproic acid are more effective than lamotrigine. Source: NEJM


Inactivated Whole-Cell Mycobacterial Vaccine Prevents TB in HIV Infected Patients Primed with Bacille Calmette-Guerin (BCG).  03/04/2010.  Methods: The DarDar trial was a randomized, placebo-controlled, double-blind trial in 2,013 patients (1,006 received mycobacterium vaccine and 1,007 received placebo) and were followed up every 3 months for 3.3 years.  The study was carried in an outpatient facility in Dar es Salaam, Tanzania.  The main outcome measures were disseminated (primary endpoint), definite, and probable tuberculosis (secondary endpoints). Results: The trial was terminated early because of slow accrual of cases of disseminated tuberculosis and significant protection against definite tuberculosis. Hazard ratios were disseminated tuberculosis 0.52 (95% confidence interval 0.21-1.34; seven cases with mycobacterium vaccine, 13 cases in placebo; p = 0.16), definite tuberculosis 0.61 (95% confidence interval 0.39-0.96; 33 cases with mycobacterium vaccine, 52 cases in placebo; p = 0.03), and probable tuberculosis 1.17 (95% confidence interval 0.76-1.80; 48 cases with mycobacterium vaccine, 40 cases in placebo; p = 0.46).  Conclusion: These results provide evidence that immunization with a whole cell mycobacterial vaccine is a viable strategy for the prevention of HIV-associated tuberculosis in adults who had childhood BCG immunization. Source:  AIDS


Aspirin Not Protective in Prevention of Cardiovascular Events in Patients with Low Ankle Brachial Index. 03/02/2010. Methods: This was an intention-to-treat, double-blind, randomized controlled trial conducted from April 1998 to October 2008 in which 28,980 men and women aged 50 to 75 years living in central Scotland, free of clinical cardiovascular disease, recruited from a community health registry, and had an ABI screening test of ≤0.95 were either given enteric coated aspirin 100 mg or placebo. Endpoint: The primary end point was a composite of initial fatal or nonfatal coronary event or stroke or revascularization. Results: After a mean follow-up of 8.2 years, there was no statistically significant difference between groups (13.7 events per 1000 person-years in the aspirin group vs. 13.3 in the placebo group; hazard ratio [HR], 1.03; 95% CI, 0.84-1.27). Conclusion: In patients no known clinical cardiovascular disease and a low ABI, the administration of aspirin compared with placebo did not result in a significant reduction in vascular events. Source: JAMA

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February 2010


Patients Presenting to the ED with Sickle Cell Disease Have Delays in Treatment Despite Greater Pain. 02/20/2010. Objectives: To determine whether there is a difference in time to initial analgesic for patients with acute pain from sickle cell disease (SCD) versus renal colic (RC) and to identify factors contributing to variance in time to analgesic. Methods: A retrospective cohort study of the adult emergency department (ED) patients with acute pain from SCD and RC in an urban ED. Results: Median time to initial analgesic was 80 minutes for patients with SCD (interquartile range, 48 to 145) versus 50 minutes for patients with RC (interquartile range: 30 to 96). In addition, patients presenting with SCD reported a higher pain score on admission as compared with RC patients and were more frequently assigned a higher triage priority level (p=0.05). Covariates that contributed the most delays to the model were afternoon arrival (HR: 0.35, p<0.01), low acuity triage level (HR: 0.42, p<0.01), SCD diagnosis (HR: 0.61, p<0.01), and inability to obtain intravenous access (HR: 0.71, p=0.01). The concluded that despite SCD patients presenting to the ED with higher admission pain scores and triage acuity levels, these patients experienced longer delays in the administration of the initial analgesic compared with RC patients. Source: Clin J Pain


Botulinum toxin type A (Botox) and Migraine Relief Evaluated.  02/15/2010.  Population studied:  Patients coming to the dermatologist for Botox injections for cosmetic reasons but also reported history of migraine headaches.  Methods:  Nonrandomized, single-center, non-comparative trial in 25 patients (of which several were lost to follow up leaving only 18 patients with data).  Results: Of the remaining patients who completed the study (n=18), the authors report that the majority with imploding and ocular migraines experienced a significant reduction in headache frequency.  Comment:  It is important to note that this study was funded by the company who makes Botox (Allergan, Inc.) and that the headache specialist who evaluated the patients in this study not only knew the patients had received Botox but also reported being a consultant, speaker and researcher for Allergan, Inc.)  Furthermore, appropriate blinding or comparative analysis took place.  Nor was a power analysis performed a-priori.  The results of this study warrant caution and need for validation in a well designed study.  Source:  Arch Dermatol


The Safety and Efficacy of Latrepirdine in the Treatment of Huntington Disease.  02/08/2010.  Huntington's disease (HD) is an uncurable and devastating neurodegenerative genetic disorder due to CAG repeats and that is clinical characterized by abnormal involuntary movements or chorea.  Later in the disease other psychological and cognitive changes are apparent.  The proposed mechanism for latrepirdine is thought to be related to stabilization or improved mitochondrial function in a way that prevents neurons from damage and dysfunction.  Methods:  This was a Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial in 91 patients with mild to moderate HD were to either receive latrepirdine, 20 mg 3 times daily (n = 46), or matching placebo (n = 45) for a 90-day treatment period.  Results: Treatment with latrepirdine resulted in improved mean MMSE scores compared with stable performance in the placebo group (treatment effect, 0.97 points; 95% confidence interval, 0.10-1.85; P = .03), however no significant treatment effects were seen on the UHDRS or the ADAS-cog.  Latrepirdine was well tolerated (87% of the patients given latrepirdine completed the study vs 82% in the placebo group), and adverse event rates were comparable in the 2 groups.   Comment:  Latrepirdine is not currently FDA approved and is also being evaluated in the treatment of Alzheimer's disease  Sponsor: Medivation, Inc.   Source(s): Arch Neurol   Clinical Trials.gov


Fixed Combination of Latanoprost and Timolol vs. Individual Components in Primary Open-Angle Gluacoma or Ocular Hypertension.  02/08/2010.  Methods: This was a 12-week, randomized, double-masked, parallel-group trial in patients with open-angle glaucoma or ocular hypertension treated with a β-blocker and with baseline intraocular pressure (IOP) of 26 through 36 mm Hg.  After a washout period, patients were randomized to once-daily fixed combination of latanoprost and timolol in the evening, latanoprost in the evening, or timolol in the morning.  Main endpoint: Postbaseline intraocular pressure (IOP) assessments at 8 AM, 10 AM, and 4 PM at weeks 2, 6, and 12.  Results:  The fixed combination given once-daily was statistically superior to latanoprost at 7 of 9 time points and at all 9 time points when compared with timolol, resulted in greater percentage reductions in diurnal IOP levels, and a greater likelihood of achieving lower mean diurnal IOP levels. Diurnal IOP reductions of 30% or more from baseline to week 12 were achieved by 73.5%, 57.5%, and 32.8% of those treated with the fixed combined dose, latanoprost, and timolol, respectively (P = .007 for fixed combined dose vs timolol; P < .001 for fixed combined dose vs latanoprost).  All treatments were well tolerated.  Sponsor:  This study was funded by Pfizer.  Source(s): Arch Ophthalmol   Clinical Trials.gov


Oral Fingolimod vs. Intramuscular Interferon for Multiple Sclerosis. 02/04/2010. Fingolimod is a sphingosine-1-phosphate-receptor modulator that has been shown to prevent lymphocyte egress from lymph nodes in patients with multiple sclerosis. Methods: This was a 12-month, double-blind, double-dummy study, randomized trial in which 1,292 patients with relapsing-remitting multiple sclerosis who had a recent history of at least one relapse received either oral fingolimod at 1.25 or 0.5 mg daily or interferon beta-1a (an established therapy for multiple sclerosis) at a weekly dose of 30 µg IM. A total of 1153 patients (89%) completed the study. Results: The annualized relapse rate was significantly lower in both groups receiving fingolimod - 0.20 (95% confidence interval [CI], 0.16 to 0.26) in the 1.25-mg group and 0.16 (95% CI, 0.12 to 0.21) in the 0.5-mg group - than in the interferon group (0.33; 95% CI, 0.26 to 0.42; P<0.001 for both comparisons). MRI findings supported the primary results however, there were no significant differences seen in progression of disability. Unfortunately, there were two fatal infections that occurred in the group that received the 1.25-mg dose of fingolimod: disseminated primary varicella zoster and herpes simplex encephalitis. Other noted side effects with fingolimod were nonfatal herpesvirus infections, bradycardia and atrioventricular block, hypertension, macular edema, skin cancer, and elevated liver-enzyme level. Conclusion: The authors concluded that this trial showed the superior efficacy of oral fingolimod with respect to relapse rates and MRI outcomes in patients with multiple sclerosis, as compared with intramuscular interferon beta-1a, but that longer studies were still needed to determine the safety and efficacy beyond 1-year. Source: NEJM


GFR, Proteinuria and Risk of Mortality, MI and Progression to Kidney Failure.  02/03/2010.  Methods: JAMA published a community-based cohort study with 920,985 adult participants identified from a province-wide laboratory registry that includes eGFR and proteinuria measurements from Alberta, Canada, between 2002 and 2007. Results: The majority of individuals (89.1%) had an eGFR of 60 mL/min/1.73 m2 or greater. The adjusted rate of all-cause mortality was higher in study participants with lower eGFRs or heavier proteinuria. Adjusted mortality rates were more than 2-fold higher among individuals with heavy proteinuria measured by urine dipstick and eGFR of 60 mL/min/1.73 m2 or greater, as compared with those with eGFR of 45 to 59.9 mL/min/1.73 m2 and normal protein excretion (rate, 7.2 [95% CI, 6.6-7.8] vs 2.9 [95% CI, 2.7-3.0] per 1000 person-years, respectively; rate ratio, 2.5 [95% CI, 2.3-2.7]). Conclusion: The risks of mortality, myocardial infarction, and progression to kidney failure associated with a given level of eGFR are independently increased in patients with higher levels of proteinuria.  Source:  JAMA

Metformin for the Treatment of Adolescent Obesity.  02/01/2010.   Methods: A multicenter, randomized, double-blind, placebo-controlled clinical trial of obese adolescents (aged 13-18 years) studied the ability of metformin XR 2000 mg once daily for 48 weeks to reduce body mass index.  Results: Mean (SE) adjusted BMI increased 0.2 (0.5) in the placebo group and decreased 0.9 (0.5) in the metformin XR group (P = .03). This difference persisted for 12 to 24 weeks after cessation of treatment, but with no significant effects of metformin on body composition, abdominal fat, or insulin indices were observed.  Source:  Arch Pediatr Adolesc Med 

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January 2010

Efficacy & Safety of Varenicline for Smoking Cessation in Patients with Cardiovascular Disease (CVD).  01/19/2010.  Methods: Varenicline 1 mg twice daily for 12 weeks was compared to placebo in a multicenter, randomized, double-blind clinical trial in 714 smokers with stable CVD.  Results: Carbon-monoxide verified continuous abstinence rates were higher for varenicline from weeks 9 through 12 was 47.0% vs. 13.9%; OR, 6.11; 95% CI, 4.18 to 8.93) and weeks 9 through 52 weeks was 19.2% vs. 7.2%; OR, 3.14; 95%CI, 1.93 to 5.11).  There was no difference in CV mortality, all-cause mortality, CV events or serious adverse events.  However, more patients in the varenicline group (9.6%) discontinued the drug versus placebo (4.3%).  Comment: While this data shows varenicline to be effective and safe in patients with CVD in the short term, the long-term safety is not known.  It is also worth noting that as in other smoking cessation trials that many patients start to smoke again despite early beneficial results and stopped the drug due to adverse events.  Source:  AHA  

Omega-3 Fatty Acid Levels Decrease the Rate of Telomere Shortening.  01/20/2010.  A prospective cohort study of 608 patients with stable coronary artery disease (CAD) and who were followed for a median of 6 years found that the rate of telomere shortening was fastest in patients with the lowest levels of omega-3 fatty acids (DHA and EPA), whereas patients with the highest levels had the slowest rates or telomere shortening.  Comment: The telomere is an area at the end of a chromosome that compensate for incomplete DNA replication.  Their presence helps to prevent chromosomal deterioration that is associated with aging.  Their rate of shortening directly affects that cells ability to replicate appropriately.   Source: JAMA  

A High Number of Nursing Home Patients Get Prescribed Antipsychotics Without a Clinical Indication.  01/11/2010:  According to the Archives of Internal Medicine, a study assessing the prescribing characteristics of a nationwide, cross-sectional population of patients admitted to the nursing home showed that more than 29% (n = 4818) received at least 1 antipsychotic medication and of those, 32% (n=1545) had no clinical indication.  Of no real surprise, prescribing rates of the facility were also found to be independently associated with antipsychotic use.  Source:  Arch Intern Med


Rapid Screening and Decolonization of Nasal Carriers of Staphylococcus aureus Reduces Surgical-Site Infections.  01/05/2010.  A randomized, double-blind, placebo-controlled, multicenter trial from October 2005 - June 2007 on a total of 6,771 patients who were received nasal swab screening upon admission.  1251 of these patients were positive for S. aureus and all were susceptible to methicillin and mupirocin.  808 of these patients went on to have surgery.  Of those nasal swab +, 3.4% of patients who received mupirocin nasal ointment and chlorhexidine soap developed surgical-site S. aureus infections versus 7.7% of those in the placebo; relative risk of infection, 0.42; 95% CI, 0.23 to 0.75).  There was no significant difference in all-cause in-hospital mortality. Comment:  It is worth noting that only 18.5% of the poplulation sampled were nasal swab positive and all were methicillin sensitive rather than methicillin resistant.   Source: N Engl J Med


H1N1 Vaccine 15-mcg dose is Immunogenic in Infants and Children with Mild-Moderate Side Effects.  01/05/2010.  A randomized, observer-blind, age-stratified, parallel group assessed two doses (15 mcg vs. 30 mcg given in a 2 dose regimen administered 21 days apart) in 370 healthy infants and children aged 6 months less than 9 years of living in Australia.  After the first dose, 92.5% of patients receiving the 15 mcg dose had antibody titers of 1:40 or greater and 97.7% of children who received the 30 mcg shot had antibody titers of 1:40 or greater.  After the second shot of either dose, all children demonstrated antibodies production or titers greater than 1:40.  Comment:  This data shows that the monovalent H1N1 vaccine is not only effective at generating antibodies but appears to be without significant adverse events. Source: JAMA

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Depression Care in the United States - 1 in 4 Patients with Depression Receives Treatment Consistent with Guidelines.  01/05/2010.  The Collaborative Psychiatry Epidemiology Surveys (CPES; n = 15,762) published their results in the Archives of General Psychiatry today.  Their findings show that only 50% of Americans with clinical depression receive any treatment for it and that the lowest rates being found among Mexian American and African American individuals.  The researchers indicate that this reveals the disparity in access to health care and may be overlooked.  Source: Arch Gen Psychiatry 

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December 2009

The STAR*D Trial Updates.  12/04/2009.  The American Psychiatric Association (APA) released a commentary today regarding the importance of findings that have come out of the STAR*D Trial and its impact, not only on patient care, but also on health care reform.  STAR*D stands for "Sequenced Treatment Alternatives to Relieve Depression" and was funded by the National Institute of Mental Health (NIMH).  The sequence in the study name means that patients who failed initial therapy with citalopram for 12 weeks where then given an alternative antidepressant.  Important findings include: 1) No clear winner as it relates to an antidpressant; 2) Only 1 in 3 patients achieved remission after 14 weeks on citalopram (initial drug therapy), however after 1-year of multi-step or sequential medication about 70% of patients achieved remission; 3) The likelihood of remission after two vigorous trials of medications was substantially decreased; 4) Primary-care clinicians and specialty-care clinicians achieved similar patient outcomes in the first treatment step.  Source(s):  APA  Psychiatric Services   STAR*D.org 

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November 2009

Early Communication:  Sibutramine (Meridia) & the Sibutramine Cardiovascular Morbidity/Mortality Outcomes in Overweight or Obese Subjects at Risk of a Cardiovascular Event (SCOUT) Trial.  11/20/2009:  The FDA is investigating a review of preliminary analysis from this trial that is suggesting that those taking sibutramine have a higher number of cardiovascular events (heart attack, stroke, resusicated cardiac arrest, or death) than patients taking placebo.  While the FDA made no formal recommendations to healthcare professionals at this time, they did remind clinicians that sibutramine should be avoided in patients with a history of coronary artery disease, heart failure, arrhythmias, or stroke as currently recommended in the product labeling.  Source: FDA



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