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Results of a Nationwide Veterans Administration Cooperative Study Comparing the Efficacy and Toxicity of Carbamazepine, Phenobarbital, Phenytoin, and Primidone

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Results of a Nationwide Veterans Administration Cooperative Study Comparing the Efficacy and Toxicity of Carbamazepine, Phenobarbital, Phenytoin, and Primidone Epilepsin, 28(Suppl. 3):SSO-S58, 1987 Raven Press, Ltd., New York 0 International League Against Epilepsy Results of a Nationwide Veterans Administration Cooperative Study Comparing the Efficacy and Toxicity of Carbamazepine, Phenobarbital, Phenytoin, and Primidone Dennis B. Smith, "Richard H. Mattson, ?Joyce A. Cramer, $Joseph F. Collins, §Robert A. Novelly, [[BruceCraft, and the Weterans Administration Epilepsy Cooperative Study Group Good Samaritan Hospital & Medical Center, Portland Oregon; *Yale University School of Medicine, New Haven, Connecticut; $Veterans Administration Cooperative Studies Program, Perry Point, Maryland; *f§Veterans Administration Hospital, West Haven, Connecticut; and llNeurology Service, Veterans Administration Medical Center, Augusta, Georgia, U.S.A. Summary: In 1985 a 5-year multicenter Veterans Admin- sociated with significantly lower incidences of intolerable istration Cooperative Study was completed that com- side effects than were primidone or phenobarbital. A be- pared the efficacy and toxicity of phenobarbital, car- havioral toxicity battery was performed whenever pos- bamazepine, phenytoin, and primidone in a double-blind sible prior to administration of any antiepileptic drug and prospective study design. A total of 622 patients, either at 1, 3, 6, and 12 months after initiation of monotherapy. previously untreated or undertreated, were entered into Significant differences in performance on all subtests of the study. Strict exclusion criteria limited confounding the battery were found between patients with epilepsy factors such as drug or alcohol abuse. Results showed and a control group matched by age, sex, and education. that each of the four drugs used as monotherapy were When the differential effects of all four drugs on behav- similarly effective in the treatment of generalized tonic- ioral toxicity were compared, few statistically significant clonic seizures, but carbamazepine was significantly differences emerged. However, carbamazepine consis- more effective in the treatment of complex partial sei- tently produced fewer adverse effects on tests of atten- zures as measured by 100% control. When the results for tionkoncentration and motor performance than did the all four drugs were combined, the data showed that ap- other three antiepileptic drugs. Key Words: Epilepsy- proximately 80% of the patients were adequately man- Seizures-Therapy -Anticonvulsants- Controlled clin- aged on monotherapy. Differences in toxicity were the ical trials-Drug-induced abnormalities-carbarnaze- most significant factor that discriminated between these pine -Phenobarbital-Phenytoin- Primidone. four drugs. Both carbamazepine and phenytoin were as- In 1985 a nationwide multicenter study spon- generalized seizures (Mattson et al., 1985). The sored by the Veterans Administration (V.A.) was study was initiated in order to overcome short- completed. The study was a 5-year prospective, comings of previous studies of the comparative ef- double-blind trial comparing the efficacy and tox- ficacy and toxicity of antiepileptic drugs. icity of carbamazepine, phenobarbital, phenytoin, Coatsworth (1971) reviewed the literature from and primidone in adults with partial or secondarily 1920 through 1971 reporting on studies of the clin- ical efficacy of marketed antiepileptic drugs and found that a total of 250 case reports on the efficacy Address correspondence and reprint requests to Dr. D. B. and toxicity of these agents had been published. In Smith at Good Samaritan Hospital & Medical Center, 1015 N.W. 22nd Avenue, Suite 400, Portland, OR 97210, U.S.A. addition, results of 110 clinical trials were pub- 1 Includes Antonio V. Delgado-Escueta, Thomas R. Browne, lished during this same reporting period. Of the Peter D. Williamson, David M. Treirnan, James 0. McNamara, clinical trials, only three involved a single- or Charlotte B. McCutchen, Richard W. Homan, Wayne E. Crill, Michael F. Lubozynski, N. Paul Rosenthal, and Assa Mayers- double-blind protocol, 25 included an electroen- dorf. cephalogram (EEG) profile, five included a psycho- 5'50 V.A. COOPERATIVE STUDY RESULTS S5 1 TABLE 1. Studies comparing major antiepileptic drugs for partial and generalized tonic-clonic seizures (1966- 1979) Comparison of Relative efficacy Comments Study Goal drug toxicity of seizure control (duration; patients) White et al., 1966 Show PRM equals PHT All drugs equal All drugs equal 2 weeks; 20 or PB institutionalized patients Millichap and Aymat, Compare PRM with PHT more toxic than Both drugs equal 8 months; 20 outpatient I968 PHT PRM children; no drug levels Cereghino et al., 1974 Show CBZ equals PHT CBZ more toxic than All drugs equal 3 weeks; 45 or PB PHT or PB (equal institutionalized behavior for all drugs) patients Troupin et al., 1975 Show CBZ equals PHT All drugs equal Both drugs equal 4 weeks; 20 outpatients Cereghino et al., 1975 Best combination of Combinations including PHT + PB 3 weeks; 41 two or three drugs CBZ more toxic than combination is best institutionalized (PHT, PB, CBZ) PB and PHT patients Rodin et al., 1976 Best drug (PRM or CBZ more toxic than All combinations equal 3 months; 45 CBZ) to add to PHT PRM; CBZ fewer outpatients; if PB fails behavioral deficits behavioral testing; no than PRM drug levels Kosteljanetz et al., 1979 Show CBZ equals PHT All drugs equal, but Both drugs equal 6 months; 19 PHT more difficult to outpatients; triple- adjust dose blind CBZ, carbamazepine; PB, phenobarbital; PHT, phenytoin; PRM, primidone. logical evaluation, and only three included any kind tial, and generalized tonic clonic seizures.” (Anti- of statistical analysis. From 1972 to 1979, results of epileptic drugs, 2nd ed. Raven Press, 1982.) an additional seven clinical trials were reported, These conflicting recommendations emphasize but because of a variety of shortcomings (failure to the problems that existed in interpreting the com- use a double-blind randomized protocol, failure to parative literature on antiepileptic drugs. It was compare all four drugs and to monitor serum con- against that background that the V.A. Cooperative centration of the drugs, inclusion of institutional- Study was conceived. The study was designed to ized refractory patients and patients with mixed overcome shortcomings in previous trials by (1) seizure types, and insufficient sample size for sta- studying newly diagnosed patients with epilepsy tistical analysis), these studies failed to reveal any not currently receiving antiepileptic drug therapy, clear differences in the clinical effectiveness or rel- (2) utilizing a homogeneous, noninstitutionalized ative toxicities of carbamazepine, phenobarbital, population that would be representative of a typical phenytoin, and primidone (Table 1). outpatient seizure population, (3) documenting eti- It was thus apparent that despite a wealth of liter- ology by EEG and imaging studies, (4) quantifying ature dating back nearly 50 years, no convincing the frequency and severity of seizures, (5) moni- scientific evidence had been developed that could toring serum concentrations of the antiepileptic be used to justify the selection of any single anti- drugs, (6) comparing all four drugs simultaneously epileptic drug for any specific seizure type (with the by a randomized, double-blind study design, (7) exception of generalized absence seizures) in using each drug singly as monotherapy until proven adults. Despite the inconclusiveness of these unsatisfactory, and (8) using a sufficiently large studies, there was no dearth of dogmatic state- population base to allow meaningful statistical anal- ments recommending one drug over another, as ex- ysis on completion. emplified by the following quotations from three These objectives were achieved, and the results commonly used textbooks in neurology. of that study for the first time provide a scientific For the treatment of major and focal epilepsy, “it is rationale for recommending specific antiepileptic usual to begin in an adult with phenobarbi- drugs for specific seizure types. In this paper, some tone. , . .” (Brain’s Diseases of the nervous of the results of that study are summarized. system, 8th ed. Oxford University Press, 1977.) “The treatment of grand ma1 seizures in adults METHODS always begins with phenytoin. .” (Modern practical neurology. Raven Press, 1977.) Enrolled in the study were 622 patients newly “Carbamazepine is a major antiepileptic drug for diagnosed as having simple or complex seizures or the treatment of complex partial, elementary par- primarily or secondarily generalized tonic-clonic Epilepsia, Vol. 28, Suppl. 3, 1987 S52 D.B. SMiTH ET AL. seizures. All patients were previously untreated or Newly Diagnosed Epilepsy Patient undertreated. A double-blind prospective study de- sign was used. Patients were followed for as long as Evaluated as Primary or Secondarily 6 years (average, 3 years) at 10 V.A. medical Generalized Tonic-Clonic centers (Augusta, GA; Boston, MA; Dallas, TX; Durham, NC; Los Angeles, CA; Minneapolis, MN; Complex or Elementary San Diego, CA; Seattle, WA; Sepulveda, CA; and Partial Seizures West Haven, CT, U.S.A.). The study population included men and women (age range, 18 to 70 I Randomize to Studv Druq I years). Nonveterans were also entered into the Does Patient Ha& study. Exclusion criteria were strict (Table 2). Inadequate Seizure Control? I Study design No Details of the study design have been described Yes r elsewhere (Delgado-Escueta et al., 1983; Mattson Does Patient Have et al., 1983; Cramer et al., 1983). Figure
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