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Screening for Depression in Terminally Ill Patients
Depression is a common occurrence in terminally ill patients. However, because much of the focus is on the primary medical condition, the depression may often go unrecognized by the treating clinician. Methods to screen for depression through patient self-reporting have been developed in an attempt to accurately and quickly identify such patients in the context of a routine office visit. The correlation of these screening interviews with clinician-administered interviews has been less than optimal. Chochinov and colleagues conducted a study to compare the performance of four brief screening measures for depression in a group of terminally ill patients.
A total of 197 patients who were receiving palliative care for advanced terminal cancer were included in the study. The four screening inventories used in the study included the Beck Depression Inventory--Short Form, a visual analog scale, a two-item interview assessing depressed mood and loss of interest or pleasure in activities and a single-item interview assessing depressed mood. The diagnostic interview used specific items pertaining to the diagnosis of major and minor depression from the Research Diagnostic Criteria. A total of 24 patients met the criteria for either major or minor depression (15 patients and nine patients).
The single-item inventory assessing depressed mood correctly identified the eventual diagnostic outcome of every patient in the study group. Whenever a patient acknowledged a depressed mood at a threshold level of severity, the probability of having major or minor depression based on the Research Diagnostic Criteria interview used by the examiners was 100 percent. Patients who did not admit to having a depressed mood were never diagnosed with depression based on the Research Diagnostic Criteria.
If the screening interview was extended to two items, all of the patients who were found to be depressed based on the Research Diagnostic Criteria were correctly identified; however, the two-item scale also identified four patients as depressed who were not classified as such on the basis of the full diagnostic interview. The Beck inventory short form correctly identified about 80 percent of depressed patients. The analog screen was even less accurate, identifying only 72 percent of clinically depressed patients and incorrectly labeling 50 percent of patients as depressed.
The authors conclude that a single-item interview that simply asks, "Are you depressed?" provides a very reliable and accurate screening tool when assessing depressed mood in terminally ill patients. The inclusion of an additional diagnostic criterion for depression such as a loss of interest or pleasure in activities did not improve the diagnostic accuracy of the screening examination. However, it may still be reasonable to include this piece of information in a brief screening interview, since it is considered a core criterion for depression. The overall performance of the one- or two-item interview was far superior to the Beck Depression Inventory and the visual analog scale for assessing depressed mood in terminally ill patients.
JEFFREY T. KIRCHNER, D.O.
Chochinov HM, et al. "Are you depressed?" Screening for depression in the terminally ill. Am J Psychiatry 1997; 154:674-6.
Vertical Transmission of Hepatitis C Virus Infection
Clear evidence exists documenting the perinatal vertical transmission of hepatitis C virus (HCV) infection. Maternal coinfection with HCV and human immunodeficiency virus (HIV) has been correlated with the probability of perinatal infection. The rate of vertical transmission of HCV appears to be low (ranging from zero to 6 percent). Bortolotti and associates conducted a multicenter study to investigate the features of hepatitis C infection in a group of infants who were born to mothers with hepatitis C antibodies and a group of children with chronic hepatitis C infection whose mothers were the only potential source of infection.
The first group included 14 infants who were seropositive for HCV who were born to mothers with hepatitis C antibodies and without HIV infection or hepatitis B surface antigen (HbsAg). The second group included 16 children with chronic HCV infection whose mothers had no HbsAg and who were chronic carriers of HCV. One mother had antibodies to HIV. The mothers were the only potential source of infection in this group. Both groups of children were followed for 12 to 48 months after birth.
All of the children in the first group had elevated alanine aminotransferase levels, ranging from 1.5 to 10.5 times normal during the first 12 months of life. RNA for HCV was detectable in all children at nine months of age and in some children as early as three months after birth.
All of the children in the second group came to observation after laboratory testing was performed because of intercurrent disease or after the detection of maternal antibodies to HCV. During a mean observation period of 18.7 months, alanine aminotransferase levels varied from normal to six times the upper limit of normal in these children, but exceeded twice the normal limit in only six children. RNA for HCV was detected in all of the children.
The authors conclude that HCV could have been vertically transmitted to the children even in the absence of a cofactor such as maternal HIV coinfection. These preliminary studies demonstrate that chronic infection acquired from mothers with HCV occurs in a high percentage of children, although liver disease appears to be asymptomatic during infancy and mild throughout childhood. Whether or not there is long-term recovery from HCV infection remains to be determined through longer follow-up studies.
In an accompanying editorial, Zein discusses the variability of vertical transmission of various genotypes of HCV and the lack of support for routine maternal screening. The failure to document transmission of HCV through breast feeding even in mothers whose breast milk showed RNA for HCV supports the likelihood of in utero vertical transmission of the virus. In the United States and Europe, the prevalence of HCV is approximately 1.2 percent of the general population. The incidence of vertical transmission is estimated to be up to 5 percent. The screening of 1,600 to 8,300 pregnant women would be needed for each case of vertical transmission diagnosed. The author concludes that since there is no specific means of intervention (i.e., either a vaccine or a successful treatment), routine screening for HCV cannot be performed at the present time.
RICHARD SADOVSKY, M.D.
Bortolotti F, et al. Hepatitis C virus infection and related liver disease in children of mothers with antibodies to the virus. J Pediatr 1997;130:990-3, and Zein NN. Vertical transmission of hepatitis C: to screen or not to screen [Editorial]. J Pediatr 1997;130:859-61.
Giant Cell Arteritis in Patients with Polymyalgia Rheumatica
Giant cell arteritis can occur as local vascular disease or as part of a systemic illness that includes fever, malaise, weight loss and/or polymyalgia rheumatica. Definitive diagnosis of giant cell arteritis requires a positive temporal artery biopsy, although false-negative results can occur because of the patchy distribution of lesions. Polymyalgia rheumatica is a syndrome affecting elderly patients and is characterized by proximal pain and stiffness of the shoulder, neck or pelvis. About one half of patients with giant cell arteritis have polymyalgia rheumatica, and from 10 to 15 percent of patients with polymyalgia rheumatica without local evidence of vasculitis have giant cell arteritis on biopsy. There are also shared immunologic abnormalities.
The distinction between these diseases is important because polymyalgia rheumatica is treated with low-dose corticosteroid therapy, whereas giant cell arteritis requires high doses of corticosteroids. Rodriguez-Valverde and colleagues conducted a retrospective study to identify predictors of a positive temporal artery biopsy and to define a predictive model for either a high or low probability of giant cell arteritis in patients with polymyalgia rheumatica.
Patients were defined as having polymyalgia rheumatica if they met the following criteria: age 50 years or greater at the onset of disease; erythrocyte sedimentation rate greater than 40 mm per hour (Westergren); bilateral moderate or severe pain involving at least two of the following areas: neck, shoulder and pelvic girdles; and rapid resolution of the syndrome (in less than seven days) with low-dose prednisone (5 mg twice daily in most cases).
Risk for an abnormal arterial biopsy was increased in patients who were 70 years of age or older at disease onset, had a new headache or abnormal temporal arteries on physical examination, and had jaw claudication. Raised liver enzymes also significantly increased the likelihood of a positive temporal artery biopsy.
The authors conclude that giant cell arteritis is especially likely in patients with polymyalgia rheumatica who are older than 70 years of age and who have a new headache, jaw claudication, raised liver enzymes and evidence of abnormal temporal arteries on physical examination. Because of the significant side effects of high-dose corticosteroid therapy, confirmation by temporal artery biopsy is still recommended in the elderly population to make a definitive diagnosis. Patients without these high-risk factors can be safely treated with low-dose corticosteroids without biopsy.
RICHARD SADOVSKY, M.D.
Rodriguez-Valverde V, et al. Risk factors and predictive models of giant cell arteritis in polymyalgia rheumatica. Am J Med 1997;90:331-6.
Zidovudine and Didanosine for HIV Infection in Children
Most children with human immunodeficiency virus (HIV) infection acquire the infection by perinatal exposure. Zidovudine has been the recommended treatment for symptomatic children. Englund and associates conducted a multicenter double-blind investigation of the use of zidovudine, didanosine or both in previously untreated children with HIV infection.
A total of 839 children were assigned to treatment with zidovudine alone, didanosine alone or a combination of both zidovudine and didanosine. Follow-up was performed for a minimum of 104 weeks. Eight children were excluded from analysis because of refusal to participate following randomization or because they had already received more than six weeks of zidovudine therapy. Ninety percent of the children completed the study. The primary end point was the length of time until the first progression of HIV disease or until death. Disease progression was defined as the development of cancer, evidence of growth failure, the occurrence of two or more opportunistic infections, or evidence of two or more abnormalities of the central nervous system.
At the time of entry into the study, 450 (54 percent) of the children were under 30 months of age. Over 90 percent had acquired HIV perinatally. Only 29 children were born to mothers who had received zidovudine therapy prenatally. After the study had been under way for 23 weeks, interim analysis showed that patients receiving zidovudine alone had a relative risk of 0.61 for progression of HIV disease or death, compared with children treated with didanosine alone or combination therapy. Primary end points had been reached by 27 percent of the children receiving zidovudine, compared with 19 percent of those receiving didanosine and 18 percent of those receiving combination therapy. Because of this finding, the study arm with zidovudine alone was discontinued.
At the end of the study, children treated with didanosine alone had outcomes similar to those treated with combination therapy. The median follow-up was 32 months. However, compared with patients who received didanosine alone, those who received combination therapy had a 0.66 relative risk of serious anemia or neutropenia. This difference was primarily due to a lower risk of hematologic toxicity in older children receiving didanosine. A significant difference was not found among younger patients. No laboratory or clinically significant adverse effects necessitated cessation of therapy after the interim analysis.
At four weeks, CD4+ counts had increased by a mean of 22 percent in the children receiving combination therapy, compared with an increase of 6 percent in those receiving didanosine alone. This improvement was not sustained, however. By week 96, the mean percentage of change in the CD4+ count was similar in the two treatment groups.
In patients who initially tested positive for p24 antigen, the p24 antigen level after four weeks of treatment was 52 percent lower in the combination therapy group than in the didanosine group, but this benefit was not maintained after 24 weeks. Among patients who tested negative for p24 at the time of entry into the study, the length of time until the test became positive was similar in both treatment groups.
The authors conclude that the superiority of didanosine alone or the combination of didanosine and zidovudine over zidovudine alone in symptomatic children with HIV infection is a new and clinically important finding. Although combination antiviral regimens, especially those that include a protease inhibitor, may delay disease progression and prolong survival in adults with HIV infection, their efficacy has not previously been assessed in children. At the present time, the authors recommend didanosine alone as the initial therapy for HIV-infected children who have not previously received antiretroviral therapy.
KATHRYN M. ANDOLESK, M.D., M.P.H.
Englund JA, et al. Zidovudine, didanosine, or both as the initial treatment for symptomatic HIV-infected children. N Engl J Med 1997;336:1704-12.
Use of Analgesic Cream for Neonatal Circumcision
Despite evidence that circumcision is intensely painful for newborns, many physicians are reluctant to administer analgesic medications. In addition to the immediate discomfort of the procedure, the neonate may be unsettled for several hours. Alterations in sleeping, feeding and crying patterns have been associated with the untreated pain of circumcision. In addition, circumcised infants have more pain during routine vaccination at four to six months of age than uncircumcised infants, suggesting that response to the perception of pain in the future may be altered. Taddio and colleagues assessed the effectiveness of a 5 percent lidocaine-prilocaine cream for analgesia during neonatal circumcision.
A total of 68 full-term neonates were enrolled in the double-blind, randomized controlled study. Thirty-eight infants received lidocaine-prilocaine cream for analgesia, and 30 infants received a placebo cream. One gram of lidocaine-prilocaine cream or placebo cream was applied to the penis under an occlusive dressing for 60 to 80 minutes before the procedure. Behavior and physiologic responses during the procedure were observed and measured. Blood samples were taken to measure serum levels of methemoglobin, plasma lidocaine, prilocaine and a metabolite of prilocaine.
Neonates in the lidocaine-prilocaine group demonstrated fewer facial grimaces during the procedure. They cried half as much, and their heartbeat increases were 10 beats per minute less on average. Serum levels of methemoglobin concentrations were similar for both groups. Lidocaine and prilocaine were detected in the plasma of most infants in the treatment group, but the levels were low and disappeared after 18 hours. Side effects were limited. Pallor at the application site was noted in 32 percent of the neonates in the lidocaine-prilocaine group, compared with 13 percent in the placebo group. One neonate in the lidocaine-prilocaine group had mild edema, and one had a local infection that was successfully treated with a topical antibiotic.
The authors conclude that neonates in the lidocaine-prilocaine group experienced pain during circumcision, although it was diminished. The relatively simple method of analgesia described in this study may increase the use of pain medications in infants who undergo circumcision.
KATHRYN M. ANDOLSEK, M.D., M.P.H.
Taddio A, et al. Efficacy and safety of lidocaine-prilocaine cream for pain during circumcision. N Engl J Med 1997;336:1197-201.
CurrentTherapies for the Management of Acne
Acne vulgaris is caused by obstruction of the sebaceous follicles of the face and the trunk. Acne affects 80 percent of the population at some time between the ages of 11 and 30 years and can cause scarring and permanent disfigurement in some patients. Leyden reviews the pathophysiology of acne and outlines currently available topical and systemic therapies.
Topical therapies have no effect on the production of sebum, so scrubbing with soaps, detergents and astringents, which only remove sebum from the skin surface, does not reduce sebum production. In fact, vigorous scrubbing and the use of abrasive cleaners and mechanical devices can exacerbate acne. Gentle nonabrasive cleaning is best for removing sebum. Diet does not influence sebum production, so dietary restriction is not part of management.
Sebum production can be altered by systemic medications, but noticeable improvement does not occur until two to four months after therapy begins. Since sebaceous glands are androgen-dependent, estrogens and antiandrogens are useful therapies. Because of their feminizing properties, they should be used only in women. The beneficial effects of ethinyl estradiol are most apparent at doses of 50 µg or more. Newer oral contraceptives that contain 35 µg or less of ethinyl estradiol are not as effective, although lower dose oral contraceptives that include a nonandrogenic progesterone such as norgestimate or desogestrel can be effective. Spironolactone may also be effective in reducing sebum production and improving acne, even in doses as low as 25 to 50 mg daily.
Isotretinoin, a natural metabolite of vitamin A, greatly reduces sebum production. A four- to five-month oral course of isotretinoin, 0.1 to 1.0 mg per kg, results in remission in most patients. Remission lasts longer in patients treated with higher doses. Unfortunately, its use is limited by side effects such as arthralgia, stiffness, tendinitis and elevated serum lipid levels. Because it is teratogenic, isotretinoin therapy can only be initiated in women who are proved not pregnant. Effective contraception is essential during isotretinoin use and for at least one month following its discontinuation.
Topical agents, such as tretinoin, isotretinoin and salicylic acid, can be effective in slowing the desquamation of follicular epithelial cells. Tretinoin is available in several concentrations and can be used in combination with topical or systemic antibiotics. The gel formulation is preferred in hot and humid climates and the cream in cold and dry climates. Salicylic acid is weaker but is available over the counter. Azelaic acid is a recently approved agent with some activity against comedogenesis.
Topical antibiotics, when applied once or twice daily, have a beneficial effect as well. Various antibiotics may be used, including formulations of erythromycin, clindamycin, metronidazole, azelaic acid, benzoyl peroxide, and a combination of benzoyl peroxide and erythromycin or glycolic acid. Benzoyl peroxide suppresses the growth of Propionibacterium acnes more effectively than clindamycin and erythromycin alone. However, it causes local irritation and allergic contact dermatitis more often than other topical antibiotics. Topical clindamycin is more effective than topical erythromycin in vivo, but their clinical efficacy is similar. The combination of benzoyl peroxide and erythromycin is probably the most effective topical therapy available.
Systemic antibiotics for acne therapy include tetracycline, erythromycin, minocycline, doxycycline, clindamycin and trimethoprim-sulfamethoxazole. Doxycycline, minocycline and trimethoprim-sulfamethoxazole are generally considered more effective and less potent than tetracycline and erythromycin. All tetracyclines should be avoided until children have their permanent teeth. Absorption of doxycycline and minocycline is not reduced by dairy products and food to the same degree as tetracycline. The dosage can be tapered after four to six weeks once the development of new inflammatory lesions has stopped. Minocycline may cause vertigo-like symptoms. Doxycycline can induce photosensitivity. Erythromycin, although much less expensive than minocycline or doxycycline, causes gastrointestinal upset. Resistance is uncommon.
For most patients, a combination of drugs that addresses the abnormal desquamation and reduces the proliferation of P. acnes is sufficient to control acne, depending on the patient's skin characteristics. Increased sebum production and abnormal desquamation of epithelial cells can occur in children younger than 13 years, but colonization with P. acnes has not yet occurred. Therefore, treatment for this age group includes topical tretinoin, adapalene, azelaic acid or salicylic acid. In young teenagers, a mild form of inflammatory acne develops. Most patients in this age group respond after two to four weeks of twice-daily application of a topical antibiotic, topical benzoyl peroxide or the combination of benzoyl peroxide and erythromycin or other topical antibiotics.
The author concludes that patients with inflammatory acne are best treated with benzoyl peroxide, benzoyl peroxide plus erythromycin, topical clindamycin, topical erythromycin and/or oral antibiotics. Patients with widespread nodular cystic lesions may respond to oral antibiotics but generally require therapy with systemic isotretinoin. Estrogens or antiandrogens are effective alternatives to systemic isotretinoin in women with persistent acne.
KATHRYN M. ANDOLSEK, M.D., M.P.H.
Leyden JJ. Therapy for acne vulgaris. N Engl J Med 1997;336:1156-62.
Quetiapine vs. Placebo in Patients with Schizophrenia
In the treatment of patients with schizophrenia, use of antipsychotic agents leads to fewer delusions, fewer hospitalizations and more self-reliance. However, the adverse effects of these antipsychotic agents temper complete enthusiasm for them. Newer antipsychotics, such as clozapine, may represent an advance since they have atypical pharmacologic features. Small and associates conducted a double-blind, placebo-controlled trial of quetiapine fumarate, a dibenzothiazepine antipsychotic drug that acts at multiple receptor sites, to determine its efficacy in the treatment of patients with schizophrenia.
Hospitalized adult patients with Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) criteria for acute exacerbation of chronic or subchronic schizophrenia were included in the study if they had no concomitant condition, such as mental retardation, and if they had not received injectable long-acting antipsychotic agents in the previous month. All psychotropic medications were discontinued, and patients were randomized to receive one of three treatment regimens: quetiapine in high dosages (up to 750 mg per day), quetiapine in low dosages (up to 250 mg per day) or placebo. The daily dosage was increased within the prescribed range until an adequate therapeutic effect was achieved. Extrapyramidal effects were evaluated and treated, if necessary. Symptoms of schizophrenia were assessed at baseline and weekly for six weeks. Adverse effects were assessed for severity and recorded.
A total of 96 patients were included in the placebo group, 94 patients were included in the low-dose quetiapine group and 96 patients were included in the high-dose quetiapine group. At least one half of the patients in each group withdrew before the end of the six-week study period, primarily because of treatment failure. At baseline, mean scores on the Brief Psychiatric Rating Scale (BPRS) were similar among the three groups. Patients in the high-dose group consistently showed improvements in BPRS scores compared with patients in the low-dose and placebo groups. Quetiapine was consistently effective in decreasing positive symptoms of schizophrenia. Mean Clinical Global Impression Severity of Illness scores were also significantly better (lower) in the high-dose group compared with the other two groups.
The patients taking high doses of quetiapine and the patients taking placebo received more treatment for extrapyramidal signs than did patients taking low doses of quetiapine. Agitation and somnolence were the most common adverse effects. Akathisia was most common in the patients receiving higher doses of quetiapine. Seventeen patients (seven in the high-dose group, seven in the low-dose group and three in the placebo group) withdrew from the study because of adverse effects. Hematologic test results were not significantly affected by the administration of quetiapine. Low-dose quetiapine was not shown to be more effective than placebo, leading the researchers to conclude that a daily dosage of more than 250 mg of quetiapine is optimum. Treatment with quetiapine was associated with clinically significant weight gain (an increase of more than 7 percent from baseline weight) in 25 percent of the patients in the high-dose group, compared with 16 percent of patients in the low-dose group and 5 percent in the placebo group.
The authors conclude that quetiapine, in dosages of more than 250 mg, was effective for the treatment of acute exacerbation of chronic or subchronic schizophrenia and may represent an advance in the treatment of patients with schizophrenia, especially treatment-resistant patients. Further studies of this drug, both in fixed doses and in comparison with other well-known antipsychotic medications, are warranted.
GRACE BROOKE HUFFMAN, M.D.
Small JG, et al. Quetiapine in patients with schizophrenia: a high- and low-dose double-blind comparison with placebo. Arch Gen Psychiatry 1997;54:549-57.
Treatment of Women with Hypothalamic Amenorrhea
Young women with hypothalamic amenorrhea and oligomenorrhea are likely to have reduced bone mineral density and are at greater risk of osteoporosis. Estrogen replacement therapy is known to reduce the risk of osteoporotic fractures in postmenopausal women. Hergenroeder and associates performed a randomized, controlled clinical trial comparing treatment with oral contraceptives, medroxyprogesterone acetate and placebo to determine which therapy might improve bone mineral density in young women with hypothalamic dysfunction.
A total of 24 white women ranging from 14 to 28 years of age with hypothalamic amenorrhea or oligomenorrhea were prospectively randomized to a 12-month regimen of either oral contraceptive pills, medroxyprogesterone or placebo if they were amenorrheic, or medroxyprogesterone or placebo if they were oligomenorrheic. Bone mineral density was measured by dual-energy x-ray absorptiometry at baseline and at six months and 12 months following therapy. Patients in the oral contraceptive group received 0.035 mg of ethinyl estradiol and 0.5 to 1.0 mg of norethindrone per day for 21 days of the 28-day cycle. Patients in the medroxyprogesterone group received 10 mg per day on the last 12 days of the calendar month. Those in the placebo group received one tablet per day on the same days as the medroxyprogesterone group.
The 15 women in the amenorrheic group had a lower mean baseline percentage body fat, compared with the nine women in the oligomenorrheic group. Total body mineral content and bone density of the amenorrheic group at 12 months were greater in the oral contraceptive group than in the medroxyprogesterone and placebo groups. At six and 12 months, no significant differences in the bone mineral content or density at any site were found between the medroxyprogesterone and placebo groups. In the patients with oligomenorrhea, total body bone mineral content at 12 months was greater in the placebo group than in the medroxyprogesterone group.
The changes in and the absolute measurements of bone mineral density and content at all bone sites were independent of weight change during the study. After adjusting for age, body weight and baseline measurements, treatment with oral contraceptives was associated with improved lumbar spine, total body bone mineral content and bone mineral density at 12 months in young women with hypothalamic amenorrhea. There was no apparent improvement of the bone mineral of the femoral neck in these women. Women in this study received approximately 3.5 times the conventional estrogen dosage used to treat postmenopausal women. Medroxyprogesterone did not appear to enhance bone mineral in women with either amenorrhea or oligomenorrhea.
The authors conclude that treatment with oral contraceptives was associated with an improvement in lumbar spine, total bone mineral content and bone mineral density in young women with hypothalamic amenorrhea. There was no evidence that oral medroxyprogesterone therapy produced the same beneficial results.
BARBARA APGAR, M.D., M.S.
Hergenroeder AC, et al. Bone mineral changes in young women with hypothalamic amenorrhea treated with oral contraceptives, medroxyprogesterone, or placebo over 12 months. Am J Obstet Gynecol 1997;176:1017-25.
Selegiline and Vitamin E for Alzheimer's Disease
Alzheimer's disease results in a loss of memory, cognition and judgment. Sano and associates investigated the use of selegiline (a monoamine oxidase inhibitor), alpha-tocopherol (vitamin E), or a combination of the two in patients with moderately severe Alzheimer's disease to evaluate the effect of these agents in functional deterioration.
A total of 341 patients were recruited for the two-year study from 23 centers participating in the Alzheimer's Disease Cooperative Study. Study subjects were randomly assigned to receive selegiline (5 mg twice daily), alpha-tocopherol (1,000 IU twice daily), a combination of selegiline and alpha-tocopherol, or placebo. The principal goal of the study was to monitor the time until one of the following primary outcomes occurred: death, institutionalization, inability to perform at least two of three basic activities of daily living such as eating or using the toilet, or severe dementia. A secondary goal was to monitor measures of cognition, function and behavior.
Despite random assignment, baseline scores on cognitive testing were slightly higher in the placebo group than in the selegiline group. After adjusting for this finding in the statistical analysis, delays in the time to a primary outcome were found for patients taking selegiline (655 days), alpha-tocopherol (670 days) and combination therapy (585 days), compared with the placebo group (440 days). Patients treated with alpha-tocopherol alone experienced a statistically significant delay in institutionalization. Patients in all of the treatment groups also had significant delays in deterioration of the performance of activities of daily living.
Cognition did not improve in any of the groups. Also, patients in the treatment groups, especially in the group receiving combination therapy, experienced falls and syncope more often than did patients in the placebo group. However, these findings did not necessitate the discontinuation of treatment. Combination therapy did not offer additional benefit beyond that achieved with either agent alone, nor was one agent clearly superior to the other.
The authors conclude that issues such as cost and convenience remain important factors when selecting medication for patients with Alzheimer's disease. Little is known about the efficacy of these agents in other patient groups, such as those with mild cognitive impairment or those with early- or late-stage Alzheimer's disease, since this study was confined to patients with moderately severe Alzheimer's disease.
KATHRYN M. ANDOLSEK, M.D., M.H.
Sano M, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. N Engl J Med 1997;336:1216-22.
Alendronate for Nonvertebral Fracture Prevention in Women
Nearly one half of postmenopausal women have osteoporosis. Vertebral body fractures represent the single most common osteoporotic fracture, but nonvertebral fractures account for the majority of morbidity, mortality and cost associated with this condition. Alendronate is a potent and specific inhibitor of osteoclast-mediated bone resorption and is known to increase bone mineral density in postmenopausal women with osteoporosis. Karpf and associates conducted a meta-analysis to determine what effect alendronate has on the incidence of nonvertebral fracture in women with osteoporosis.
Five trials were included in the study. The bone mineral density of each woman included in the study was measured at the lumbar spine, the trochanter and the femoral neck. Total body bone mineral density was also measured, and all symptomatic fractures were recorded.
Alendronate, 10 mg daily, was discovered to be the optimal dosage leading to increases in bone mineral density at all sites tested. The 5-mg dose of alendronate was approximately 70 percent as effective as the 10-mg dose in producing these increases. The 10-mg dose was the only dosage that did not reach a plateau in its effectiveness over the three-year period studied. Each dose of alendronate tested, however, led to improvements in body mass index when compared with placebo. The rate of nonvertebral fracture per 100 patient-years in the placebo group was 4.45, compared with a rate of 3.26 in the alendronate-treated group. These rates were lower (3.66 and 2.99, respectively) in women younger than age 65, and higher (5.34 and 3.57, respectively) in women older than age 65.
The authors conclude that, in postmenopausal women with osteoporosis, treatment with alendronate leads to increases in body mass index at all sites tested, including the hip and wrist, and decreases the risk of nonvertebral fracture for at least the first three years of treatment.
GRACE BROOKE HUFFMAN, M.D.
Karpf DB, et al. Prevention of nonvertebral fractures by alendronate: a meta-analysis. JAMA 1997;277:1159-64.
Ranitidine for Reflux During Pregnancy
More than one half of all pregnant women have symptoms of gastroesophageal reflux, particularly during the third trimester. Although conservative measures such as avoiding substances that precipitate or exacerbate symptoms and elevating the head of the bed may be successful, more than one third of pregnant women also report taking antacid medications with varying degrees of success in alleviating symptoms. Larson and colleagues investigated the ability of the histamine H2-receptor blocker ranitidine to relieve symptoms of gastroesophageal reflux during pregnancy.
Patients who were at more than 20 weeks of gestation attending a university prenatal clinic were asked to volunteer for the study if they had persistent heartburn despite use of conservative measures and antacid medications. Patients with known esophageal and gastric disease and liver conditions, and those requiring medication for chronic psychiatric conditions were excluded from the study. Patients were required to read and sign a statement concerning the testing of ranitidine in pregnant animals.
During the first week of the study, baseline data were collected, including an extensive questionnaire on gastrointestinal symptoms and general health, a symptom diary and a visual analog scale to evaluate the level of discomfort. Patients used only antacids during this initial week and then were randomly assigned to one of three treatment groups: placebo twice daily; placebo in the morning plus ranitidine, 150 mg, in the evening; and ranitidine, 150 mg twice daily. Diaries were collected each week. Patients also completed global assessments weekly and gave counts of pills and antacid medications used.
Complete data were available for 18 of the 20 women who completed the study. Patients reported significant improvement in heartburn symptoms when they took placebo, as well as when they took either regimen of ranitidine. The greatest improvement was reported with twice-daily ranitidine, which was associated with a 55.6 percent improvement over baseline and a 44.2 percent improvement compared with placebo. The improvement associated with the single daily dose of ranitidine was not statistically superior to either placebo or baseline. The number of antacid tablets consumed was significantly lower in patients receiving either of the ranitidine regimens. Only one patient reported the need for heartburn medication after delivery.
The authors conclude that ranitidine taken in a dosage of 150 mg twice daily provides effective relief of gastroesophageal reflux symptoms. They note the substantial placebo effect and the limited benefit provided by a single evening dose of 150 mg of ranitidine. Although ranitidine is a category B1 agent for pregnancy (indicating that no adequate studies have been performed in humans to assess pregnancy risk), it is available without a prescription as a 75-mg tablet, and no adverse effects have been reported in animal studies or case reports.
ANNE D. WALLING, M.D.
Larson JD, et al. Double-blind, placebo-controlled study of ranitidine for gastroesophageal reflux symptoms during pregnancy. Obstet Gynecol 1997;90:83-7.
Low-Molecular-Weight Heparin for Unstable Angina
The current standard of care for patients admitted to the hospital because of a nonQ-wave myocardial infarction or unstable angina consists of oral aspirin and intravenous administration of unfractionated heparin. However, this regimen is not consistently effective, since the anticoagulant response to heparin is unpredictable, and heparin may be neutralized by protein binding and platelets. Low-molecular-weight heparin has the advantage of being more predictable than unfractionated heparin in its therapeutic effect. Laboratory monitoring of anticoagulation is not required with low-molecular-weight heparin, and it is less commonly associated with thrombocytopenia. Cohen and colleagues compared the efficacy and safety of subcutaneous enoxaparin (a low-molecular-weight heparin) and intravenous heparin in patients with nonQ-wave coronary events.
The randomized multicenter trial, known as the Efficacy and Safety of Subcutaneous Enoxaparin in NonQ-Wave Coronary Events (ESSENCE) study, included 3,171 patients from Canada, Europe, South America and the United States. All of the patients had recent onset of angina, occurring within 24 hours of entry into the study and lasting at least 10 minutes. In addition, all of the patients had underlying ischemic heart disease manifested by one of the following: a previous history of myocardial infarction or bypass surgery, positive findings on an invasive or noninvasive diagnostic study, or definite electrocardiographic criteria, including ST-segment depression of at least 1 mm, new ST-segment elevation or T-wave changes in at least two leads.
Patients were randomized to receive either 1 mg per kg of enoxaparin subcutaneously every 12 hours plus intravenous placebo or intravenous heparin (usually a bolus infusion of 5,000 units) plus subcutaneous placebo injections. Treatment was continued for at least 48 hours, up to a maximum of eight days. In addition, aspirin was given in a daily dosage of 100 to 325 mg, depending on physician preference. The median duration of anticoagulant therapy was 2.6 days for both groups.
After 14 days of therapy, the risk of death, myocardial infarction and unstable angina was significantly lower among the patients who had received enoxaparin. This same pattern was seen at 30 days after treatment. The risk of the composite end point (death, myocardial infarction or recurrent angina) was 6 percent in the enoxaparin-treated patients, compared with 7.3 percent in the intravenous heparin group. Thirty days after randomization, the need for coronary revascularization was 27 percent in the enoxaparin group and 32 percent in the heparin group. No significant difference was apparent between the two groups in major hemorrhagic complications, but minor bleeding, most commonly ecchymosis at the injection site, occurred more frequently in the enoxaparin group.
The authors conclude that antithrombotic therapy with enoxaparin plus aspirin is more effective than intravenous heparin plus aspirin in reducing the incidence of ischemic events in patients with nonQ-wave myocardial infarction or unstable angina. A decrease in morbidity and mortality is seen for at least 30 days after initiation of therapy.
JEFFREY T. KIRCHNER, D.O.
Cohen M, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med 1997;337:447-52.
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