Richard Buchsbaum

Warfarin and Aspirin in Patients with Heart Failure and Sinus Rhythm

BACKGROUND It is unknown whether warfarin or aspirin therapy is superior for patients with heart failure who are in sinus rhythm. METHODS We designed this trial to determine whether warfarin (with a target international normalized ratio of 2.0 to 3.5) or aspirin (at a dose of 325 mg per day) is a better treatment for patients in sinus rhythm who have a reduced left ventricular ejection fraction (LVEF). We followed 2305 patients for up to 6 years (mean [±SD], 3.5±1.8). The primary outcome was the time to the first event in a composite end point of ischemic stroke, intracerebral hemorrhage, or death from any cause. RESULTS The rates of the primary outcome were 7.47 events per 100 patient-years in the warfarin group and 7.93 in the aspirin group (hazard ratio with warfarin, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P=0.40). Thus, there was no significant overall difference between the two treatments. In a time-varying analysis, the hazard ratio changed over time, slightly favoring warfarin over aspirin by the fourth year of follow-up, but this finding was only marginally significant (P=0.046). Warfarin, as compared with aspirin, was associated with a significant reduction in the rate of ischemic stroke throughout the follow-up period (0.72 events per 100 patient-years vs. 1.36 per 100 patient-years; hazard ratio, 0.52; 95% CI, 0.33 to 0.82; P=0.005). The rate of major hemorrhage was 1.78 events per 100 patient-years in the warfarin group as compared with 0.87 in the aspirin group (P<0.001). The rates of intracerebral and intracranial hemorrhage did not differ significantly between the two treatment groups (0.27 events per 100 patient-years with warfarin and 0.22 with aspirin, P=0.82). CONCLUSIONS Among patients with reduced LVEF who were in sinus rhythm, there was no significant overall difference in the primary outcome between treatment with warfarin and treatment with aspirin. A reduced risk of ischemic stroke with warfarin was offset by an increased risk of major hemorrhage. The choice between warfarin and aspirin should be individualized. (Funded by the National Institute of Neurological Disorders and Stroke; WARCEF ClinicalTrials.gov number, NCT00041938.).

Comparison and predictors of rash associated with 15 antiepileptic drugs

Objective: To determine predictors and relative incidence of antiepileptic drug (AED)–related rash in patients taking all common AEDs. Methods: We reviewed 1,890 outpatients. Eighty-one variables were tested as potential predictors of rash. We compared the rate of rash attributed to each AED (AED rash) with the average rate of rash attributed to the other AEDs in all adults (aged ≥16 years; n = 1,649) when taking carbamazepine (CBZ), clobazam (CLB), felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), phenobarbital (PB), phenytoin (PHT), primidone (PRM), tiagabine (TGB), topiramate (TPM), vigabatrin (VGB), valproate (VPA), or zonisamide (ZNS). We repeated this analysis for patients with and without the identified nondrug predictors of AED rash. Results: The average rate of AED rash was 2.8%. The only nondrug predictor significant in multivariate analysis was occurrence of another AED rash (odds ratio 3.1, 95% CI 1.8 to 5.1; p < 0.0001); the rate of rash in this subgroup was 8.8%, vs 1.7% in those without another AED rash. Higher AED rash rates were seen with PHT (5.9% overall, p = 0.0008; 25.0% in those with another AED rash, p = 0.001), LTG (4.8%, p = 0.00095; 14.4%, p = 0.025), and CBZ (3.7%, not significant; 16.5%, p = 0.01). Lower rates were seen with LEV (0.6% overall; p = 0.00042), GBP (0.3%, p = 0.00035), and VPA (0.7%, p = 0.01). Rash rates were also low (<1% overall) with FBM, PRM, TPM, and VGB (not significant). These AED differences remained similar in patients with and without other AED rashes. There were four cases of Stevens–Johnson syndrome involving four AEDs. Conclusions: The rate of an antiepileptic drug (AED) rash is approximately five times greater in patients with another AED rash (8.8%) vs those without (1.7%). Rash rates were highest with phenytoin, lamotrigine, and carbamazepine and low (<1%) with several AEDs.

Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III

Amyotrophic lateral sclerosis (ALS) is a devastating, and currently incurable, neuromuscular disease in which oxidative stress and mitochondrial impairment are contributing to neuronal loss. Coenzyme Q10 (CoQ10), an antioxidant and mitochondrial cofactor, has shown promise in ALS transgenic mice, and in clinical trials for neurodegenerative diseases other than ALS. Our aims were to choose between two high doses of CoQ10 for ALS, and to determine if it merits testing in a Phase III clinical trial.

Phase IIB/III Trial of Tenecteplase in Acute Ischemic Stroke. Results of a Prematurely Terminated Randomized Clinical Trial

Background and Purpose— Intravenous alteplase (rtPA) remains the only approved treatment for acute ischemic stroke, but its use remains limited. In a previous pilot dose-escalation study, intravenous tenecteplase showed promise as a potentially safer alternative. Therefore, a Phase IIB clinical trial was begun to (1) choose a best dose of tenecteplase to carry forward; and (2) to provide evidence for either promise or futility of further testing of tenecteplase versus rtPA. If promise was established, then the trial would continue as a Phase III efficacy trial comparing the selected tenecteplase dose to standard rtPA. Methods— The trial began as a small, multicenter, randomized, double-blind, controlled clinical trial comparing 0.1, 0.25, and 0.4 mg/kg tenecteplase with standard 0.9 mg/kg rtPA in patients with acute stroke within 3 hours of onset. An adaptive sequential design used an early (24-hour) assessment of major neurological improvement balanced against occurrence of symptomatic intracranial hemorrhage to choose a “best” dose of tenecteplase to carry forward. Once a “best” dose was established, the trial was to continue until at least 100 pairs of the selected tenecteplase dose versus standard rtPA could be compared by 3-month outcome using the modified Rankin Scale in an interim analysis. Decision rules were devised to yield a clear recommendation to either stop for futility or to continue into Phase III. Results— The trial was prematurely terminated for slow enrollment after only 112 patients had been randomized at 8 clinical centers between 2006 and 2008. The 0.4-mg/kg dose was discarded as inferior after only 73 patients were randomized, but the selection procedure was still unable to distinguish between 0.1 mg/kg and 0.25 mg/kg as a propitious dose at the time the trial was stopped. There were no statistically persuasive differences in 3-month outcomes between the remaining tenecteplase groups and rtPA. Symptomatic intracranial hemorrhage rates were highest in the discarded 0.4-mg/kg tenecteplase group and lowest (0 of 31) in the 0.1-mg/kg tenecteplase group. Neither promise nor futility could be established. Conclusion— This prematurely terminated trial has demonstrated the potential efficiency of a novel design in selecting a propitious dose for future study of a new thrombolytic agent for acute stroke. Given the truncation of the trial, no convincing conclusions can be made about the promise of future study of tenecteplase in acute stroke.

Predictors of Lamotrigine‐associated Rash

Summary:  Purpose: To determine the predictors of lamotrigine‐associated rash (LTG‐rash) and the incidence of serious and benign LTG‐rash to individualize risk assessment in a given patient.

Cross-sensitivity of skin rashes with antiepileptic drug use

Objective: To determine rates of cross-sensitivity of rash among commonly used antiepileptic drugs (AEDs) in patients with epilepsy. Methods: The incidence of AED-related rash was determined in 1875 outpatients (≥12 years), taking carbamazepine (CBZ), clobazam (CLB), felbamate (FBM), gabapentin (GBP), levetiracetam (LEV), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), phenytoin (PHT), primidone (PRM), tiagabine (TGB), topiramate (TPM), vigabatrin (VGB), valproic acid (VPA), or zonisamide (ZNS). We compared rates of rash for each AED in patients with vs those without a rash to 1) another specific AED; 2) any other AED; 3) any two other AEDs; and 4) any non-epilepsy medication. Results: A total of 14.3% (269/1,875) of patients had a rash attributed to at least one AED; 2.8% had a rash to two or more AEDs. Of patients who had a rash to CBZ and were also prescribed PHT (n = 59), 57.6% had a rash to PHT (abbreviated as CBZ → PHT: 57.6%); of patients who had a rash to PHT and were also prescribed CBZ (n = 81), rate of rash was 42% (i.e., PHT → CBZ: 42%). Other results: CBZ → LTG: 20% (n = 50); LTG → CBZ: 26.3% (n = 38); CBZ → OXC: 33% (n = 15); OXC → CBZ: 71.4% (n = 7); CBZ → PB: 26.7% (n = 30); PB → CBZ: 66.7% (n = 12); LTG → PHT: 38.9% (n = 36); PHT → LTG: 18.9% (n = 74); PB → PHT: 53.3% (n = 15); PHT → PB: 19.5% (n = 41); OXC → LTG: 37.5% (n = 8); LTG → OXC: 20% (n = 15). There was evidence of specific cross-sensitivity between CBZ and PHT, and between CBZ and PB. Conclusion: Cross-sensitivity rates between certain antiepileptic drugs (AEDs) are high, especially when involving carbamazepine and phenytoin. Specific cross-sensitivity rates provided here may be useful for AED selection and counseling in individual patients.

Psychiatric and behavioral side effects of the newer antiepileptic drugs in adults with epilepsy

OBJECTIVE Psychiatric/behavioral side effects (PSEs) are common in patients taking antiepileptic drugs (AEDs). The objective of the study described here was to compare the PSE profiles of the newer AEDs. METHODS We examined the charts of 1394 adult outpatients seen at the Columbia Comprehensive Epilepsy Center who had taken one of the newer AEDs. We compared the rate of AED-related PSEs in patients newly started on the newer AEDs both before and after controlling for non-AED predictors of PSEs. RESULTS Overall, 221 of 1394 (16%) patients experienced PSEs. The average rate of AED-related PSEs for a single AED was 8.4%, with 6.1% resulting in dosage change and 4.3% resulting in AED discontinuation. Significantly fewer PSEs were attributed to gabapentin (n=160, 0.6% incidence, P<0.001) and lamotrigine (n=547, 4.8% incidence, P<0.001), and significantly more PSEs were attributed to levetiracetam (n=521, 15.7% incidence, P<0.001; 8.8% discontinued LEV because of PSEs). Vigabatrin, felbamate, and oxcarbazepine were associated with similarly low rates of PSEs in many analyses but with fewer of patients. Tiagabine was associated with high PSE rates (similar to those for levetiracetam), but was used much less commonly at our center. Intermediate rates of PSEs were attributed to topiramate and zonisamide (both nonsignificant). Psychiatric history was the most significant nondrug predictor of AED-related PSEs (PSEs occurred in 23% of patients with a psychiatric history vs 12% of patients without such a history, P<0.001). The relative rates of AED-related PSEs were similar when controlling for non-AED predictors and when analyzing only patients on monotherapy. CONCLUSIONS There are significant differences between the newer AEDs in terms of their PSE profiles. Patients taking levetiracetan experience significantly more PSEs than average, and patients taking gabapentin and lamotrigine experience significantly fewer PSEs. Even with the medication with the highest rate of PSEs (levetiracetam), less than 10% of patients discontinued it because of PSEs. A past psychiatric condition is the most significant nondrug predictor of AED-related PSEs.

Patient-reported cognitive side effects of antiepileptic drugs: predictors and comparison of all commonly used antiepileptic drugs.

Subjective cognitive side effects (CSEs) are common in patients taking antiepileptic drugs (AEDs). The objective of this study was to predict which patients are at risk for CSEs, and compare the CSE profiles of all commonly used AEDs. In this nonrandomized retrospective study, medical records of 1694 adult outpatients with epilepsy seen at our center over a 5-year period who had taken one or more AEDs were examined. Non-AED predictors of CSEs were investigated, and rates of AED-related CSEs were compared in 1189 patients (546 on monotherapy) newly started on an AED at our center. The average rate of AED-related intolerable CSEs (leading to dosage change or discontinuation) was 12.8%. On multivariate analysis, no significant non-AED predictors of CSEs were found. Significantly more intolerable CSEs were attributed to topiramate (21.5% of 130 patients) than to most other AEDs, including carbamazepine (9.9%), gabapentin (7.3%), levetiracetam (10.4%), lamotrigine (8.9%), oxcarbazepine (11.6%), and valproate (8.3%). CSE rates with zonisamide (14.9%) were significantly higher than those for gabapentin and lamotrigine. After exclusion of CSEs during the first 8 weeks of therapy, rates of CSEs were lower, but relative differences remained unchanged. In monotherapy, significantly more intolerable CSEs occurred with topiramate (11.1% of 18 patients) than with carbamazepine or valproate, and both phenytoin and zonisamide were associated with more CSEs than valproate. From this study, it can be concluded that intolerable patient-reported CSEs are most common with topiramate, followed by zonisamide, phenytoin, and oxcarbazepine. They are least likely to be reported with gabapentin, valproate, lamotrigine, carbamazepine, and levetiracetam.

A two-stage design for a phase II clinical trial of coenzyme Q10 in ALS

Background: The combination of a small pool of patients at any given time with the availability of many potential neuroprotective agents to be tested in ALS requires efficient phase II trial designs. Objective: To describe the design of the Clinical Trial of High Dose Coenzyme Q10 (CoQ10) in ALS (QALS study)—a phase II, randomized, placebo-controlled, double-blind, multicenter clinical trial. Methods: The study design features two stages. The first stage (dose selection) identifies which of two doses of CoQ10 (1800 mg or 2700 mg) is preferred using a selection procedure rather than a formal hypothesis test. The second stage (early efficacy test) compares the preferred dose of CoQ10 against placebo using a non-superiority or futility design. Data from patients assigned to the preferred dose of CoQ10 in the first stage are also used in the second stage. The primary outcome measure is the decline in Amyotrophic Lateral Sclerosis Functional Rating Scale–revised (ALSFRSr) score from baseline to 9 months. Results: The total sample size required is 185 patients, as compared to a much larger sample size estimated to be necessary using a conventional superiority design (total: 852 patients). The authors report a bias correction made necessary by the inclusion of patient data from the first stage in the second stage. Conclusions: Several features of the Clinical Trial of High Dose Coenzyme Q10 in ALS study design promote efficiency. These features may be beneficial in phase II trials in amyotrophic lateral sclerosis and other fields.

Correlating lamotrigine serum concentrations with tolerability in patients with epilepsy

Objective: To correlate lamotrigine (LTG) serum concentrations (levels) with tolerability in patients with epilepsy. Methods: The charts of 811 outpatients with epilepsy who had received LTG and were seen at the Columbia Comprehensive Epilepsy Center after January 1, 2000, were reviewed. Data gathered included levels, dosage, duration of use, concomitant antiepileptic drugs (AEDs), clinical toxicity, specific side effects, and efficacy. Rates of toxicity, specific side effects, and efficacy were calculated and correlated with serum levels. Results: In total, 3,731 LTG levels were recorded. A regimen was categorized as toxic if the patient experienced side effects that led to a dosage change or discontinuation of LTG. Of 3,919 AED regimens, 9.4% were toxic and 30.7% of patients had at least one toxic regimen. Toxicity increased with increasing LTG levels (p < 0.0001): With levels <5.0 μg/mL, 7% of patients were toxic; with levels of 5 to 10 μg/mL, 14%; with 10 to 15 μg/mL, 24%; with 15 to 20 μg/mL, 34%; and with >20 μg/mL, 59%. The correlation between levels and tolerability was independent of concurrent medication. Increasing efficacy, as measured by seizure freedom for a 6-month period, occurred up to levels of >20 μg/mL. Conclusions: There is a correlation between LTG serum level and tolerability, independent of the use of other AEDs. Adverse effects requiring a dose change are uncommon with the most frequently encountered LTG concentrations (<10 μg/mL) and occur in only 7.4% of patients at levels obtained during the majority of clinical trials (<5 μg/mL). An initial target range of 1.5 to 10 μg/mL is suggested, though higher levels, up to >20 μg/mL, are often tolerated and can lead to additional efficacy in refractory patients.