AGE, Vol. 18, 5-9, 1995

HYDERGINE REVISITED: A STATISTICAL ANALYSIS OF STUDIES SHOWING EFFICACY IN THE TREATMENT OF COGNITIVELY IMPAIRED ELDERLY

Ronald Ammon, Rehka Sharma, Steven R. Gambert* and Krishan Lal Gupta

New York Medical College Department of Medicine Division of Gerontology and Geriatrics Munger Pavilion Valhalla, NY 10595

ABSTRACT

The pharmacologic treatment of dementia has received much attention in recent years. Hyder- gine, one of only two drugs approved by the Food and Drug Administration (FDA) for the treatment of dementia, was largely abandoned in the t980's due to the uncertainty of its degree of clinical ef- ficacy. The purpose of our study was to more precisely define the effect of Hydergine on cogni- tive function in elderly demented patients by combining the results of multiple weighted stud- ies using similar methodology. All data came from randomized placebo controlled trials on a total of 271 subjects.

Our results show that Hydergine had a statis- tically significant effect on global functional status compared to placebo, with the most sig- nificant improvement demonstrated on symptoms of depression, emotional lability, and indifference to surroundings. Further studies using Hydergine in the treatment of dementia appear to be justi- fied.

INTRODUCTION Dementia is a major health issue and will most cer- tainly become more prevalent as the worldwide elderly population increases. The prevalence of Alz- helmet's disease has currently been estimated to be between 5%-i 0% in those over age 65 and 20%-40% of those over 85 years old (1,43,44,45). A variety of pharmacologic agents have been examined, including cerebral vasodilators, cholinergic agents, and central nervous system stimulants for the purpose of either slowing or even stopping the progression of demen- tia. One of the most extensively studied classes of compounds has been the ergot alkaloids. Hydergine, a preparation containing three dihydrogenated ergot alkaloids, has been one of the most widely used drugs in the treatment of cognitive decline caused by dementia, and only one of two drugs that have been

*To whom all correspondence should be addressed: Steven R. Gambert, New York Medical College, De- partment of Medicine, Munger Pavilion, Valhalla, NY 10595, USA.

approved by the FDA for use in "senility states" or in the treatment of Alzheimer's disease (2).

Hydergine, marketed by Sandoz Pharmaceuticals, was first introduced in Europe in 1949 and later in the United States in 1954 for the treatment of hyperten- sion and peripheral vascular disease (3). Physicians in Europe who were originally using Hydergine to treat elderly patients for hypertension reported im- provement in symptoms of dementia. This led to early clinical trials of Hydergine to treat dementia in the 1950's. These trials were generally favorable but were limited by inadequate research design. It was not until the early 1970's when reports of better de- signed placebo control studies supported its efficacy (3).

The beneficial effect of Hydergine was originally thought to be due to its action as a cerebral vasodila- tor. Animal studies have shown that Hydergine functions as a metabolic enhancer, effects brain neurotransmission, and may act as a central alpha blocker as well as a dopamine and serotonin agonist (4). Interpretation of early studies using Hydergine as compared to placebo, the degree of improvement was difficult to quantify. In addition, rating scales that were used were not developed specifically for geriat- ric patients. In 1974, a scale specifically designed to quantify the degree of cognitive impairment in geriat- ric subjects was introduced. This scale, called the Sandoz Clinical Assessment-Geriatric (SCAG), con- sisted of 18 symptom areas rated on a seven point format (5). This scale was used in the measurement of outcome in many Hydergine trials in the 1970's and 1980's. Over the past two decades, more than twenty randomized controlled trials have included components of the SCAG scale to measure clinical improvement. Despite this standardization in meas- urement of effect, however, individual trials have included only a small number of subjects and for a limited duration of treatment. Since precise determi- nation of the clinical efficacy of Hydergine required larger sample sizes, we decided to review the com- bined results of several individual trials that used comparable methodology.

METHODS

Study Identification: The medical literature was searched to obtain all human trials using Hydergine in the treatment of dementia. Using MEDLINE from 1966 to 1993, we searched key words Hydergine and dementia, Hydergine and cerebrovascular insuffi- ciency, Hydergine and multi infarct dementia, Hyder- gine and Alzheimefs disease, Hydergine, Ergot alkaloids, and Ergoloid mesylates. 20 trials (6-25) and 11 reviews (26-36) were obtained from MED-

LINE. An additional 6 (37-42) trials were obtained from the bibliographies of the individual articles. A total of 26 individual trials were obtained. Attempts were also made to obtain unpublished trials using Hydergine for the treatment of dementia by contacting the manufacturer of Hydergine directly, but none were available.

Study Selection: Our analysis included studies that were randomized, double-blind, placebo controlled. All studies used components of the SCAG scale to assess clinical efficacy and used 3 mg. Hydergine daily for a period of at least 12 weeks. Studies were excluded if fewer than ten individual SCAG compo- nents were not reported, or if pretreatment SCAG scores and average improvement in score were not reported. Of the 26 studies identified, four were ex- cluded due to failure to include the SCAG scale (11,12,37,41). Another 10 trials were excluded be- cause the data on individual SCAG scores was not provided (6,14,15,20,22,25,38,39,40,42). Five excluded trials reported pre-treatment and post- treatment results but failed to report mean pre- and post-treatment SCAG scores (10,17,18,19, 24). One trial was excluded because it used a dose of Hyder- gine other than 3 mg. a day (21) and one excluded trial measured fewer than ten SCAG components (8). Thus, only five individual trials fulfilled our inclusion criteria (7,9,13,16,23). Unfortunately, in none of the studies was there a standardized determination of the degree of dementia, in all cases, subjects were insti- tutionalized. Although specific age ranges were reported in four of the five studies, one case only specified "geriatric".

Statistical Method: The effect of Hydergine on indi- vidual SCAG components was determined using a calculation of mean improvements weighted by the number of subjects in each study. Mean improve- ments in individual SCAG component scores were combined from the five trials. Weighted averages for each SCAG component were calculated in order to allow assessment of studies having variable sample size. The Student T test was applied to the weighted averages.

RESULTS

Study Characteristics: Study characteristics of the five included trials are summarized in Table 1. All five studies compared the effect of Hydergine, 3mg a day on SCAG scores at 12 weeks. A total of 271 patients were enrolled in trials. 134 subjects were treated with Hydergine and 137 were treated with placebo, all over the age of 65. A total of ten individual SCAG components were measured. In one trial, papaverine was used as a comparison compound. Three trials measured 15 individual SCAG components; one trial measured 14 SCAG variables, and another trial measured 12 variables.

Table 1 Study Characteristics of Included Trials

Study, year Patients Enrolled (reference) Country (completed)

Bazo, 1973 USA 70 (7) (66)

Ditch, 1971 USA 40 (9) (39)

Jennings, 1972 USA 50 (13) (50)

Rao, 1971 USA 60 (16) (57)

Triboletti, 1969 USA 59 (23) (59)

Analysis of Pooled Data: Analysis of pooled data re- vealed that the mean improvement for each SCAG variable improved to a greater degree in the Hyder- gine treated group, as compared to the control group. For each of the ten SCAG components, the improve- ment in the Hydergine-treated group was statistically greater. When a comparison of the individual SCAG scores was made, the greatest percent improvements were rated in the following groups for those treated with Hydergine vs. placebo: depression (10.4%), emotional lability (6.2%), and indifference to surroundings (5.4%). The data are summarized in Table 3.

Table 2 SCAG Symptom Areas Studied

1. Depression 2. Motivation 3. Irritability 4. Hostility 5. Indifference to surroundings 6. Unsociability 7. Uncooperativeness 8. Emotional lability 9. Appetite 10. Dizziness

DISCUSSION

Quantitative review of the available literature demon- strates that Hydergine improves global functional status to a greater degree than a placebo. All ten SCAG components improved significantly in those subjects treated with Hydergine. Although the degree of improvement was statistically significant, it is im- possible from available data to evaluate the degree of

Hydergine: A Statistical Analysis of Studies

Table 3 Results of Pooled Data

SCAG Component

Depression

Average Improvement Hydergine Group

Irritability

Average Improvement Placebo Group

Student T Test

.970"* .245"* .052"

Initiative .799"* .460"* .028"

.534** .273"* .033*

Sociability

Hostility .492"* .221 **

Indifference .599"* .218**

.554** .262"*

.040*

.042"

.038"

Cooperativeness .386"* .147"* .041"

Emotional lability .725"* .288** .042"

Appetite .456"* .172** .048"

Dizziness .805** .615** .016* *Significant at p less than .05

**Based on a 0-7 SCAG rating scale

meaningful functional improvement. The available trials are limited by their relatively short duration of treatment, small sample size, relatively low dose of Hydergine used, and poorly defined patient popula- tion. Larger studies lasting for more than 12 weeks and additional outcomes assessment would need to be conducted in order to determine the effect of Hydergine on cerebral function in demented persons and clinical relevance of improvement.

Many of these studies were conducted prior to 1980 before the availability of computerized tomogra- phy and magnetic resonance imaging. Therefore it was extremely difficult to precisely define the etiology of the cognitive dysfunction. Although our studies claimed to evaluate cognitively impaired patients, other etiologies for cognitive decline were still possi- ble. Future studies should evaluate treatment in patients with Alzheimer's disease, multi infarct dementia, as well as those with combined illness.

There is a great deal of difficulty comparing individual studies due to a lack of standardization of measurement of outcome. While the SCAG score was one of the most widely used scales in the literature, many trials failed to measure more than a few individual SCAG variables, thus limiting our available sample size.

In the included studies, Hydergine was not asso- ciated with significant side effects. Transient nausea and gastric disturbances have been reported in sev- eral. As other agents continue to be developed and tested to treat AIzheimer's disease, side effect profiles and cost are two major considerations beyond effi- cacy alone that will need further evaluation.

Unfortunately, we could only evaluate those ten components of the SCAG scale that were common to all studies being evaluated. While the original SCAG scale did attempt to evaluate other areas of clinical effectiveness including "overall improvement", we

were unable to evaluate this measure. Given the limited pharmacologic options available in the treat- ment of dementia and the relatively low incidence of adverse effects of Hydergine, it is out conclusion that further evaluation of Hydergine in the treatment of dementia is warranted. While improvements in global function and sociability may be achieved with Hyder- gine, however, clinical impact on individual patients, family members, and caregivers remains the most important outcome to explore.

In recent years there have been a number of papers that combine previous studies in an attempt to evaluate and quantify treatment effect. These studies are referred to as either meta-analysis, a term first coined by Glass in 1976 (46,47), or post-hoc analysis. These types of analyses are useful in clinical research since data from multiple small trials can be combined to increase the statistical power and to more precisely quantify treatment effect. Meta studies are most useful when disparity exists among smaller multiple studies; however these require the most data; post-hoc analysis is the preferred method if all studies do not provide statistical data for pooling. Both methods are well suited for analysis of the effect of Hydergine on aspects of global functional status since most of the available studies measured different clinical outcomes.

There are a number of concerns associated with the pooling of data from multiple trials. If the pooled data are derived from poor quality studies, the com- bined results may be misleading (48). This effect can be minimized by applying inclusion criteria prior to undertaking a quantitative review (49), as was the case in our study. In our study the use of inclusion criteria attempted to include only those studies with similar methodology. Trials using the same dose of Hydergine with identical length of treatment and similar measurements of clinical outcome were

included. One of the unfortunate limitations of our study was poorly defined study group characteristics. The precise cause of cognitive impairment was not stated in the included studies. Another potential criti- cism is the issue of publication bias. The exclusion of unpublished data may adversely affect final analysis. In our study, attempts were made to obtain any un- published data by contacting the manufacturer of Hydergine; no unpublished data were available for our use.

R E F E R E N C E S

1. Evans D: Prevalence of Alzheimers disease in a community population of older persons. Journal of the American Medical Association, 262:2551- 2556, 1989.

2. Cole J: Drug therapy of senile organic brain syn- dromes. Psychiatric Journal of the University of Ottawa, 5:41-52, 1980.

3. Goldstein M: Ergot compounds and brain func- tion: neuroendocrine and neuropsychiatric aspects, New York, Raven Press, 1980. Hollister L: Ergoloid mesylates for senile demen- tias, unanswered questions. Annals of Internal Medicine, 100:894-898, 1984.

5. Shader R: A new scale for clinical assessment in geriatric populations: Sandoz clinical assessment- geriatric (SCAG). Journal of the American Geriat- ric Society, 22:107-113, 1974. Arrigo A: Effects of intravenous high dose co- dergocrine mesylate (Hydergine) in elderly patients with severe multi-infarct dementia: a double-blind, placebo-controlled trial. Current Medical Research and Opinion, 11:491-500, 1989. Bazo A: An ergot alkaloid preparation (Hydergine) versus papaverine in treating com- mon complaints of the aged: double-blind study. Journal of the American Geriatrics Society 21:63- 71, 1973. Banen D: An ergot preparation (Hydergine) for relief of symptoms of cerebrovascular insuffi- ciency. Journal of the American Geriatric Society, 20:22-24, 1972. Ditch M: An ergot preparation (Hydergine) in the treatment of cerebrovascular disorders in the geriatric patient: double-blind study. Journal of the American Geriatric Society, 19:208-217, 1971.

10. Gaitz C: Pharmacotherapy for organic brain syn- drome in late life. Archives of General Psychiatry, 34:839-845, 1977.

11. Gerin J: Symptomatic treatment of cerebrovascu- lar insufficiency with Hydergine. Current Therapeutic Research, 11:539-546, 1969.

12. Hindmarch I: The effect of an ergot alkaloid de- rivative (Hydergine) on aspects of psychomotor performance, arousal, and cognitive processing ability. Journal of Clinical Pharmacology, 6:726- 732, 1979.

4.

.

7.

8.

.

13. Jennings W: An ergot alkaloid preparation (Hydergine) versus placebo for the treatment of symptoms of cerebrovascular insufficiency: dou- ble-blind study. Journal of the American Geriatric Society, 20:407-412, 1972.

14. Matejcek M: Electroencephalographic and clinical changes as correlated in geriatric patients treated three months with an ergot alkaloid preparation. Journal of the American Geriatric Society, 27:198- 202, 1979.

15. McConnachie R: A clinical trial comparing Hydergine with placebo in the treatment of cere- brovascular insufficiency in elderly patients. Current Medical Research and Opinion, 1:463- 468, 1973.

16. Rao D: A double-blind investigation of Hydergine in the treatment of cerebrovascular insufficiency in the elderly. Hopkins Medical Journal, 130:317- 324, 1971.

17. Rehman S: Two trials comparing Hydergine with placebo in the treatment of patients suffering from cerebrovascular insufficiency. Current Medical Research and Opinion, 1:456-462, 1973.

18. Rosen H: Mental decline in the elderly: pharma- cotherapy (ergot alkaloids versus papaverine). Journal of the American Geriatric Society, 23:169- 174, 1975.

19. Roubicek J: An ergot preparation (Hydergine) in geriatric therapy. Journal of the American Geriat- ric Society, 20:222-229, 1972.

20. Rouy J: Ergot mesylates (Hydergine) in the treatment of mental deterioration in the elderly: a six month double-blind placebo-controlled trial. Current Medical Research and Opinion, 11:380- 388, 1989.

21.Thibault A: A double-blind evaluation of Hyder- gine and placebo in the treatment of patients with organic brain syndrome and cerebral arterioscle- rosis in a nursing home. Current Medical Research and Opinion, 2:482-487, 1974.

22.Thienhaus O: A controlled double-blind study of high-dose dihydroergotoxine mesylate (Hyder- gine) in mild dementia. Journal of the American Geriatric Society, 35:219-223, 1987.

23.Triboletti F: Hydergine for the treatment of symptoms of cerebrovascular insufficiency. Cur- rent Therapeutic Research, 11:609-620, 1969.

24. Van Loveren-Huyben C: Double-blind clinical and psychologic study of ergoloid mesylates (Hydergine) in subjects with senile mental deterio- ration. Journal of the American Geriatric Society, 32:584-588, 1984.

25. Yesavage J: Dihydroergotoxine: 6 mg. versus 3 mg. dosage in the treatment of senile dementia. Preliminary report. Journal of the American Geri- atric Society, 27:80-82, 1979.

26. McDonald R: Hydergine: a review of 26 clinical studies. Pharmakopsychiatr-Neuropsychophar- makol, 12:407-422, 1979.

Hydergine: A Statistical Analysis of Studies

27. Hydergine helpful for Alzheimer's disease. Geri- atrics, 34:23, 1979.

28. Hofmann A: Historical view on ergot alkaloids. Pharmacology, 16 Supp:l-4, 1978.

29. Hughes J: An ergot alkaloid preparation (Hydergine) in the treatment of dementia: critical review of the clinical literature. Journal of the American Geriatric Society, 24:490-497, 1976.

30. Hydergine for cerebral arteriosclerosis. Medical Letter of Drugs and Therapeutics, 16:21-22, 1974.

31.Dihydrogenated ergot alkaloids (Hydergine) and cerebrovascular insufficiency. Medical Letter of Drugs and Therapeutics, 12:27-28, 1970.

32. Goodnick P: Chemotherapy of cognitive disorders in geriatrics subjects. Journal of Clinical Psychia- try 45:196-209, 1984.

33. Koberle S: Long-term study with co-dergocrine mesylate (Hydergine) in health pensioners. Results after three years. Gerontology, 30 Supp:3-52, 1984.

34. Spiegel R: A controlled long-term study with ergo- Ioid mesylates (Hydergine) in healthy, elderly volunteers: results after three years. Journal of the American Geriatric Society, 31:549-555, 1983.

35. Loew D: Hydergine in senile mental impairment. Gerontology, 28:54-74, 1982.

36. Yesavage J: Senile dementia: combined pharma- cologic and psychologic treatment. Journal of the American Geriatric Society, 29:164-171, 1981.

37. Forster W: Combined hydrogenated alkaloids of ergot in senile and arteriosclerotic psychoses. Geriatrics, 1:26-30, 1955.

38. Hollingsworth S: Response of geriatric patients from the satellite nursing homes of Maricopa county to Hydergine therapy: a double-blind study. Therapeutic Research, 27:401-411, 1980.

39. Lazzari R: Multicenter double-blind placebo-con- trolled long-term clinical trial of Hydergine in chronic senile cerebral insufficiency: an interim report. Aging, 23:347-371, 1983.

40. Nelson J: Relieving select symptoms of the eld- erly. Geriatrics, 3:133-142, 1975.

41. Spiegel R: A controlled long-term study with ergo- Ioid mesylates (Hydergine) in healthy, elderly volunteers: results after three years. Journal of the American Geriatrics Society, 31:549-55, 1983.

42. Soni S: Dihydrogenated alkaloids of ergotoxine in non-hospitalized elderly patients. Current Medical Research and Opinion, 3:464-468, 1975.

43. Brodie J: An epidemiologist views senile demen- tia facts and fragments. American Journal of Epidemiology, 115:155-162, 1982.

44. Small G: Diagnosis and treatment of dementia in the aged. Western Journal of Medicine, 135:469- 481, 1981.

45. Larson E: Cognitive impairment: dementia and Alzheimer's disease. Annual Review of Public Health, 13:431-449, 1992.

46. Glass G: Primary, secondary, and meta-analysis of research. Education Research, 5:3-8, 1976.

47. Sacks H: Meta-analysis of randomized controlled trials. New England Journal of Medicine, 8:450- 455, 1987.

48. Dichersin K: Meta-analysis: state of the science. Epidemiologic Reviews, 14:154-175, 1992.

49. Chalmers T: A method for assessing the quality of a randomized controlled trial. Controlled Clini- cal Trials. Elsevier, North Holland, 31-49, 1981.

9