Prasugrel vs. clopidogrel in acute coronary syndrome patients treated with prasugrel.

WHAT IS KNOWN AND OBJECTIVE: Current guidelines recommend a combination of clopidogrel and aspirin for management of patients who have experienced an acute coronary syndrome (ACS). Additional antiplatelet agents have been recently approved. Few comparative effectiveness studies are available for these new agents. Accordingly, we evaluated effect on time to hospital admission and resource utilization (number of hospitalizations, ER visits and outpatient visits) of prasugrel vs. clopidogrel in prasugrel-treated patients as assessed in a matched cohort. METHODS: Based on the Truven Health Analytics MarketScan database from 01 January 2009 through 31 July 2012, a retrospective prasugrel-clopidogrel matched cohort was created. Inferences for average treatment effect over 1 and 12 months on time to hospitalization and resource utilization were performed by (i) frequentist Kaplan-Meier estimation with a Cox proportional hazard model and Lin's cost history method for censored resource utilization outcomes and (ii) Bayesian discrete-time hazard and negative binomial models. RESULTS AND DISCUSSION: The 10,963 matched pairs were well balanced on baseline characteristics. Frequentist analyses of time to hospital admission over 365 days and mean all-cause resource utilization over 30 and 365 days showed no statistical differences between prasugrel and clopidogrel (P-values > 0·05). Based on Bayesian analysis of time to admission over 12 months, there was positive evidence of equivalence (0·987 probability of equivalence at a 10% equivalence margin and a Bayes factor of 0·611). Although the frequentist analyses for number of all-cause hospitalizations showed a lack of a significant difference at Months 1 and 12, the Bayesian data analysis showed positive evidence of superiority of clopidogrel at Month 1 (Bayes factor: 5·369); however, at Month 12, there was little evidence of superiority of one treatment over the other (Bayes factor: 0·422). WHAT IS NEW AND CONCLUSION: Using frequentist and Bayesian data analyses, in prasugrel-treated patients, clopidogrel was equivalent to prasugrel for time to hospital admission over 12 months and there was positive evidence that it was superior to prasugrel for number of hospitalizations over the first month of treatment.

Time course of adverse events most commonly associated with topiramate for migraine prevention.

The efficacy, safety and tolerability of topiramate has been demonstrated in three large multicenter, randomized, double-blind, placebo-controlled trials. To characterize the time course of adverse events (AEs) that led to treatment discontinuation in >/=2% of patients who received topiramate 100 mg/day during three pivotal, multicenter, randomized, double-blind, placebo-controlled, and 26-week trials. The pooled population comprised all randomized patients who reported safety data during the double-blind phase (topiramate 100 mg/day, n = 386; placebo n = 372), which consisted of a 4-week titration period and a 22-week maintenance period. Incidence, time to onset, and cumulative mean rate of AEs were assessed. Overall, AEs led to treatment discontinuation in 24.9% of patients receiving topiramate 100 mg/day and 11.0% receiving placebo (P < 0.001). AEs leading to discontinuation during the double-blind phase in > or =2% of patients included paresthesia (8.0% discontinued), any cognitive symptoms (7.3% discontinued), fatigue (4.7% discontinued), insomnia (3.4% discontinued), nausea (2.3% discontinued), loss of appetite, anxiety, and dizziness (2.1% discontinued because each AE). Most AEs began during the titration period. Paresthesia, any cognitive symptoms, nausea, and loss of appetite occurred at a higher rate in the topiramate group than in the placebo group (P < 0.01). AEs leading to discontinuation of topiramate are probably to occur during dose titration. If a patient has not experienced one of these AEs within the first 6 weeks of initiating topiramate 100 mg/day, these AEs are unlikely to occur.

Detection of atrial fibrillation and flutter by a dual-chamber implantable cardioverter-defibrillator. For the Worldwide Jewel AF Investigators.

BACKGROUND: To distinguish prolonged episodes of atrial fibrillation (AF) that require cardioversion from self-terminating episodes that do not, an atrial implantable cardioverter-defibrillator (ICD) must be able to detect AF continuously for extended periods. The ICD should discriminate between atrial tachycardia/flutter (AT), which may be terminated by antitachycardia pacing, and AF, which requires cardioversion. METHODS AND RESULTS: We studied 80 patients with AT/AF and ventricular arrhythmias who were treated with a new atrial/dual-chamber ICD. During a follow-up period lasting 6+/-2 months, we validated spontaneous, device-defined AT/AF episodes by stored electrograms in all patients. In 58 patients, we performed 80 Holter recordings with telemetered atrial electrograms, both to validate the continuous detection of AT/AF and to determine the sensitivity of the detection of AT/AF. Detection was appropriate in 98% of 132 AF episodes and 88% of 190 AT episodes (98% of 128 AT episodes with an atrial cycle length <300 ms). Intermittent sensing of far-field R waves during sinus tachycardia caused 27 inappropriate AT/AF detections; these detections lasted 2.6+/-2.0 minutes. AT/AF was detected continuously in 27 of 28 patients who had spontaneous episodes of AT/AF (96%). The device memory recorded 90 appropriate AT/AF episodes lasting >1 hour, for a total of 2697 hours of continuous detection of AT/AF. During Holter monitoring, the sensitivity of the detection of AT/AF (116 hours) was 100%; the specificity of the detection of non-AT/AF rhythms (1290 hours) was 99.99%. Of 166 appropriate episodes detected as AT, 45% were terminated by antitachycardia pacing. CONCLUSIONS: A new ICD detects AT/AF accurately and continuously. Therapy may be programmed for long-duration AT/AF, with a low risk of underdetection. Discrimination of AT from AF permits successful pacing therapy for a significant fraction of AT.

Electron microscopic comparison of the sequences of single-stranded genomes of mammalian parvoviruses by heteroduplex mapping.

The sequence homologies among the linear single-stranded genomes of several mammalian parvoviruses have been studied by electron microscopic analysis of the heteroduplexes produced by reannealing the complementary strands of their DNAs. The genomes of Kilham rat virus, H-1, minute virus of mice and LuIII, which are antigenically distinct non-defective parvoviruses, have considerable homology: about 70% of their sequences are conserved. The homologous regions map at similar locations in the left halves (from the 3' ends) of the genomes. No sequence homology, however, is observed between the DNAs of these nondefective parvoviruses and that of bovine parvovirus, another non-defective virus, or that of defective adenoassociated virus, nor between the genomes of bovine parvovirus and adenoassociated virus. This suggests that only very short, if any, homologous regions are present. From our results, we predict an evolutionary relationship among Kilham rat virus, H-1, minute virus of mice and LuIII. It is interesting to note that, although LuIII was originally isolated from a human cell line and is specific for human cells in vitro, its genome has sequences in common only with the rodent viruses Kilham rat virus, minute virus of mice and H-1, and not with the other two mammalian parvoviruses tested.

Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in women with hypothalamic amenorrhea and osteopenia: an open-label extension of a double-blind, placebo-controlled study.

OBJECTIVE: The effects of long-term triphasic oral contraceptive administration on bone mineral density (BMD) were investigated in premenopausal women with hypothalamic amenorrhea (HA) and osteopenia. METHODS: After completing three 28-day cycles in the double-blind phase of a placebo-controlled trial, women (mean age, 26.7 years) who received norgestimate 180-250 microg/ethinyl estradiol 35 microg (NGM/EE, n = 15) or placebo (n = 12) in the double-blind phase were to receive open-label NGM/EE for 10 additional cycles. RESULTS: For subjects completing > or =10 NGM/EE treatment cycles, mean posteroanterior total lumbar spine BMD (L1-L4) increased from 0.881+/-0.0624 g/cm2 at baseline (last visit prior to NGM/EE) to 0.894+/-0.0654 g/cm2 at final visit (p = .043); no significant changes in hip BMD occurred. Decreases in N-telopeptide, osteocalcin, procollagen type I propeptide and bone-specific alkaline phosphatase levels indicated effects on bone metabolism. CONCLUSIONS: Long-term administration of triphasic NGM/EE to osteopenic women with HA may increase total lumbar spine BMD.

Effects of a triphasic combination oral contraceptive containing norgestimate/ethinyl estradiol on biochemical markers of bone metabolism in young women with osteopenia secondary to hypothalamic amenorrhea.

This multicenter, double-blind, placebo-controlled, randomized study of 45 patients evaluated the short-term effects of an oral contraceptive [Ortho Tri-Cyclen, 180-250 micro g of norgestimate (NGM) and 35 microg of ethinyl estradiol (EE)] on biochemical markers of bone resorption, formation, and osteoprotegerin in young women (mean age +/- SD, 26.5 +/- 6.3 yr) with hypothalamic amenorrhea and osteopenia. Body fat, endocrine, and cognitive function were evaluated as secondary endpoints. Biomarkers of bone metabolism were measured at baseline and after three cycles of NGM/EE or placebo. There were significant decreases in mean values of N-telopeptide [mean (SD), -13.4 (13.4) vs. 1.2 (23.8) nmol bone collagen equivalents (BCE)/mmol creatinine (Cr); P = 0.001] and deoxypyridinoline [-1.2 (2.9) vs. -0.5 (1.5) nmol deoxypyridinoline/mmol Cr; P = 0.021] as well as significant decreases in bone specific alkaline phosphatase [-5.1 (3.5) vs. 0.4 (3.1) ng/ml; P < 0.001], osteocalcin [-5.9 (3.6) vs. -2.9 (3.7); P = 0.016], and procollagen of type I propeptide [-35.2 (44.6) vs. -0.2 (30.0) ng/ml; P = 0.025], but not osteoprotegerin [0.39 (1.46) vs. -0.2 (0.49) pmol/liter; P = 0.397] in the NGM/EE vs. placebo group. There were no significant differences between groups with respect to changes in cognitive function, mood, body weight, body mass index, body fat, percentage of body fat, and all endocrine levels except FSH, [-3.7 (3.8) vs. -0.6 (2.1) IU/liter; P < 0.001, NGM/EE vs. placebo]. No serious adverse events were reported in either group. These results suggest that NGM/EE decreases bone turnover in osteopenic premenopausal women with hypothalamic amenorrhea. Further studies are needed to determine whether estrogen will increase bone density in this population.

Therapeutic trial of tilorone in ALS: lack of benefit in a double-blind, placebo-controlled study.

Sixteen patients with amyotrophic lateral sclerosis (ALS) participated in a double-blind, placebo-controlled study using tilorone hydrochloride, a drug active against a variety of DNA and RNA viruses in animals. On the basis of neurologic examination, pulmonary function studies, quantitative muscle examination, speech recording, and periodic filming of functional muscle strength, it was concluded that at a dose of 1 gm per week, tilorone did not alter the course of ALS.

Imipramine-serotonin induced myopathy.

Imipramine and serotonin (5-HT) were used to produce a myopathy in rats. Imipramine was used to stimulate a defect in transport of 5-HT observed in the platelets of Duchenne's dystrophy patients. The most effective dosage schedule was imipramine, 10 mg per kilogram, for 7 days followed by 5-HT, 100 mg per kilogram, 6 hours after the final imipramine dose. A single series of injections produced focal groups of necrotic and regenerating muscle fibers. In some rats, multiple series of injections resulted in a chronic myopathy with a predilection for proximal muscles, particularly quadriceps. In addition to skeletal muscle lesions, focal areas of myocardial damage were seen. The affected rats had a marked elevation of plasma creatine phosphokinase (including MB isoenzyme), serum glutamic oxaloacetic transaminase, and lactic dehydrogenase. Femoral nerve section did not affect the development of muscle lesions.

An improved method for examination of cerebrospinal fluid cells.

A new collection technique allows cytologic examination up to 2 weeks after lumbar puncture without loss of cells or morphologic detail. Cerebrospinal fluid (CSF) was allowed to flow directly from a lumbar puncture needle into a solution of Carbowax in ethanol and was then processed with a cytocentrifuge. Two groups of patients were studied -- those undergoing spinal anesthesia and those having myelography for low back pain. Lymphocytes, polymorphonuclear neutrophils, and ependymal cells were regularly found in the CSF; a definite difference was found in the quantity and cell types in the two patient populations. The proposed method may be sensitive enough to aid in the identification of other neurologic diseases with low cell counts.

Gabapentin for parkinsonism: a double-blind, placebo-controlled, crossover trial.

PURPOSE: Gabapentin is a recently available anticonvulsant whose mechanism of action remains unknown. We suspected efficacy from serendipitous observations of gabapentin in patients with parkinsonism. This led us to a double-blind, placebo-controlled, crossover trial. PATIENTS AND METHODS: We administered gabapentin in a placebo-controlled, double-blind, crossover trial to 19 subjects with advanced parkinsonism. We measured the effect of placebo and gabapentin on subjects' symptoms with the Unified Parkinson's Disease Rating Scale, the Webster Scale, and the Hoehn and Yahr Scale. We assessed tremor with surface-recorded electromyography. RESULTS: Total Unified Parkinson's Disease Rating Scale improved with gabapentin compared with placebo (P = 0.0005). Likewise, activities of daily living and examination subscore of the Unified Parkinson's Disease Rating Scale improved with gabapentin compared with placebo but did not achieve statistical significance. Webster Scale showed improvement but neither Hoehn and Yahr Scale nor Webster Scale changes reached statistical significance. Tremor as measured by the Unified Parkinson's Disease Rating Scale improved with gabapentin but the use of the root mean square of the rectified electromyography as a measure of tremor activity was not statistically significant. CONCLUSIONS: This study demonstrates that gabapentin improves rigidity, bradykinesia, and tremor of parkinsonism including both Parkinson's disease and Parkinson's syndrome. The rigidity and bradykinesia of parkinsonism improve on the drug even when the effects of gabapentin on tremor are discounted.

Positive (99mTc) diphosphonate and 67 Ga-citrate scans in ameloblastoma: case report.

Technetium-99m-diphosphonate scintigrams and 67Ga citrate bone scans were performed in a patient with known ameloblastoma of the right mandible. The tumor concentrated both radionuclides avidly. The lesion was larger on the gallium scans, presumably due to inflammation of adjacent soft tissue and to poorer instrument resolution for 67Ga than for technitium. If a single radionuclide is to be selected for evaluating the extent of tumor in ameloblastoma, the bone-imaging agent is preferable.

Positive Ga-67 citrate scan in retroperitoneal fibrosis.

A patient with retroperitoneal fibrosis was evaluated by Ga-67 citrate imaging. The radionuclide study accurately demonstrated the location and extent of the disease.

Norgestimate and ethinyl estradiol in the treatment of acne vulgaris: a randomized, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy of a triphasic, combination oral contraceptive (OC), (norgestimate-ethinyl estradiol), in comparison with placebo in the treatment of moderate acne vulgaris. METHODS: Two hundred fifty women were enrolled in a multicenter, randomized, double-blind, placebo-controlled clinical trial to evaluate the effectiveness of norgestimate-ethinyl estradiol in the treatment of acne vulgaris. Subjects were 15-49 years old and had moderate acne vulgaris. Each month for 6 months, subjects received either 3 consecutive weeks of active OC treatment followed by 1 week of inactive drug, or 4 consecutive weeks of color-matched placebo tablets. Efficacy was assessed by facial acne lesion counts, the investigator's global assessment, and the subject's self-assessment. Hormone levels were also measured. RESULTS: Despite the large placebo effect inherent in an acne trial (due to, for example, careful skin care, frequent office visits, regression to the mean), of the 164 subjects who completed the study without major protocol deviations, the OC group was significantly better than the placebo group for all primary efficacy measures: inflammatory lesions (mean reduction, 51.4% compared to 34.6%; P = .01), total lesions (mean reduction, 46.4% compared to 33.9%; P = .001); investigator's global assessment (83.3% compared to 62.5%; P = .001). Free testosterone decreased significantly and sex hormone-binding globulin increased significantly in the OC group, but remained unchanged in the placebo group. CONCLUSION: A triphasic combination of norgestimate and ethinyl estradiol is an effective treatment for moderate acne vulgaris in women with no known contraindication to OC therapy.

Maintenance of the long-term effectiveness of tramadol in treatment of the pain of diabetic neuropathy.

OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of tramadol in a 6-month open extension following a 6-week double-blind randomized trial. RESEARCH DESIGN AND METHODS: Patients with painful diabetic neuropathy who completed the double-blind study were eligible for enrollment in an open extension of up to 6 months. All patients received tramadol 50-400 mg/day. Self-administered pain intensity scores (scale 0-4; none to extreme pain) and pain relief scores (scale -1-4; worse to complete relief) were recorded the first day of the open extension (last day of the double-blind phase) and at 30, 90, and 180 days. RESULTS: A total of 117 patients (56 former tramadol and 61 former placebo) entered the study. On the first day of the study, patients formerly treated with placebo had a significantly higher mean pain intensity score (2. 2+/-1.02 vs. 1.4+/-0.93, P<0.001) and a lower pain relief score (0. 9+/-1.43 vs. 2.2+/-1.27, P<0.001) than former tramadol patients. By Day 90, both groups had mean pain intensity scores of 1.4, which were maintained throughout the study. Mean pain relief scores (2. 4+/-1.09 vs. 2.2+/-1.14) were similar after 30 days in the former placebo and former tramadol groups, respectively and were maintained for the duration of the study. Four patients discontinued therapy due to ineffective pain relief; 13 patients discontinued due to adverse events. The most common adverse events were constipation, nausea, and headache. CONCLUSIONS: Tramadol provides long-term relief of the pain of diabetic neuropathy.

Automatic measurement of long-term heart rate variability by implanted single-chamber devices.

Heart rate variability (HRV) measurement is an established technology for the assessment of cardiac autonomic status. Recently 24 h HRV has been shown to correlate with disease severity in heart failure. This potentially makes continuous 24 h HRV measurement suitable for monitoring of heart-failure patients. Day-to-day 24 h measurement of HRV is, in principle, feasible when implemented using implanted devices (pacemakers and defibrillators) used in patients who are predominantly in the sinus rhythm. However, a number of such devices used in heart-failure patients are single-chamber devices, in which the distinction between sinus rhythm beats and ectopic beats is problematic. The study investigates whether a reasonably accurate 24 h HRV measurement can be achieved by automatic algorithms, suitable for implementation using implanted devices, without the need for identification of ectopic beats. A set of 5321 nominal 24 h Holter recordings of cardiac patients are used. Each of the recordings contains at least one ectopic beat; approximately 30% of the recordings have more than 1% of ectopic beats. Conventional 24 h measures of HRV, that is the SDNN, HRV index, and SDANN indices, are obtained from each recording after elimination of the ectopic beats and are approximated by HRV measures computed by the same formulas without exclusion of the ectopic beats. The SDANN values are also approximated by the standard deviation of 5 min medians of all RR intervals (SDMRR measure). The errors introduced by including the ectopic beats in the HRV computation were evaluated using the Bland-Altman statistics and by Cohen's kappa statistics investigating the precision of identifying patients with depressed and preserved 24 h HRV. The SDNN measure is very sensitive to the quality of the RR interval sequence and cannot be reasonably used without distinction between sinus rhythm and ectopic beats. The HRV index measure is marginally more acceptable when used without ectopic elimination. The SDANN is rather insensitive, and its replacement by SDMRR values leads to relative errors in the region of 2-5% that are almost independent of the number of ectopic beats included. Even in recordings with a substantial proportion of ectopic beats, a practically acceptable (kappa > 0.9) identification of depressed and preserved SDANN values is possible without ectopic elimination. Thus, continuous monitoring of 24 h HRV is technically feasible within implanted devices, provided the SDANN measure is monitored and either computed from the sequence of all RR intervals or, potentially preferably, replaced by the SDMRR measure.

The duration of response to norgestimate and ethinyl estradiol in the treatment of acne vulgaris.

OBJECTIVE: This was a postmarketing, retrospective, exploratory analysis to investigate the duration of response to a triphasic combination oral contraceptive (OC) (Ortho Tri-Cyclen; Ortho-McNeil Pharmaceutical, Raritan, NJ) [norgestimate-ethinyl estradiol]) in the treatment of moderate acne vulgaris. PROCEDURES: Healthy women with moderate acne vulgaris were enrolled in two 6-month, multicenter, randomized, double-blind, placebo-controlled clinical trials. Subjects received either 3 weeks of active OC treatment (i.e., 0.035 mg ethinyl estradiol plus increasing doses of norgestimate [0.180 mg, 0.215 mg, 0.250 mg]) and 1 week of inactive tablets, or 4 weeks of color-matched placebo tablets. RESULTS: A total of 507 subjects were enrolled in the study. Duration of response was analyzed in subjects with at least slight improvement in global progress of treatment from the earliest cycle showing response (n = 305) and in subjects with at least slight improvement at or before cycle 3 (n = 276); the duration of response was statistically significant in favor of the norgestimate-ethinyl estradiol group in both cases (P < or = .001). The variability of mean percent change in lesions was also statistically significantly greater in the placebo group than in the OC group for total lesions (P < or = .001) and inflammatory lesions (P < or = .001). CONCLUSION: A triphasic combination of norgestimate and ethinyl estradiol lengthens the time interval to recurrence of acne lesions.

In-hospital risk of venous thromboembolism and bleeding and associated costs for patients undergoing total hip or knee arthroplasty.

OBJECTIVE: Benefits of anti-coagulation for venous thromboembolism (VTE) prevention in total hip and knee arthroplasty (THA/TKA) may be offset by increased risk of bleeding. The aim was to assess in-hospital risk of VTE and bleeding after THA/TKA and quantify any increased costs. METHODS: Healthcare claims from the Premier Perspective(TM) Comparative Hospital Database (January 2000-September 2008) were selected for subjects ≥ 18 years with ≥ 1 diagnosis code for THA/TKA. VTE was defined as ≥ 1 code for deep vein thrombosis or pulmonary embolism. Bleeding was classified as major/non-major. Incremental in-hospital costs associated with VTE and bleeding were calculated as cost differences between inpatients with VTE or bleeding matched 1:1 with inpatients without VTE or bleeding. RESULTS: A total of 820,197 inpatient stays were identified: 8042 had a VTE event and 7401 a bleeding event (2740 major bleeding). The risks of VTE, any bleeding, and major bleeding were 0.98, 0.90, and 0.33/100 inpatient stays, respectively. Mean incremental in-hospital costs per inpatient were $2663 for VTE, $2028 for bleeding, and $3198 for major bleeding. LIMITATIONS: These included possible inaccuracies or omissions in procedures, diagnoses, or costs of claims data; no information on the amount of blood transfused or decreases in the hemoglobin level to evaluate bleeding event severity; and potential biases due to the observational design of the study. CONCLUSIONS: In-hospital risk and incremental all-cause costs with THA/TKA were higher for VTE than for bleeding. Despite higher costs, major bleeding occurred less frequently than VTE, suggesting a favorable benefit/risk profile for VTE prophylaxis in THA/TKA.