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Tips from Other Journals
Use of Sildenafil as Treatment for Erectile Dysfunction
Sildenafil is the first oral drug approved by the U.S. Food and Drug Administration for treatment of erectile dysfunction. Although other drugs have been on the market for some time, they have met with mixed success because of the need for injection or insertion into the urethra. Sildenafil enhances the physiologic response that causes penile erection after sexual arousal. It inhibits the enzyme conversion that produces the contraction of the smooth muscle of the corpus cavernosum, allowing engorgement to be maintained. Medical Letter consultants reviewed the data on this drug.
Plasma concentrations of sildenafil reach a peak in about one hour. A fatty meal delays the peak by about one hour and decreases the peak concentration without affecting total absorption. The drug is actively metabolized in the liver and is excreted largely as metabolites in the stool. Both the parent drug and the active metabolite have a half-life of about four hours. In men older than 65 years and in men with hepatic or severe renal insufficiency, clearance is slower.
Only one published study of sildenafil using objective measurements has been conducted. Plethysmographic measurements were obtained in 12 men with erectile dysfunction in a randomized, controlled crossover study. The mean duration of erections was about one minute with placebo, four minutes with 10 mg of sildenafil, about eight minutes with 25 mg and eight to 11 minutes with 50 mg of active drug. The men were instructed to record erectile activity after taking 25 mg of sildenafil or placebo once daily for seven days. The number of erections within two hours after taking sildenafil was about five times greater with the active drug than with placebo.
Other unpublished studies evaluated men with erectile dysfunction who took 25, 50 or 100 mg of sildenafil or placebo at home for up to six months. The drug did not affect the frequency of attempted intercourse. However, in four fixed-dose trials, improvement in erections was reported by 63 percent of the 214 men taking 25 mg of sildenafil, 74 percent of the 391 men taking 50 mg and 82 percent of the 380 men taking 100 mg of the drug. Twenty-four percent of the 463 men taking placebo experienced improvement in erectile functioning. The effect was detectable as soon as 30 minutes after taking the drug and lasted up to four hours. Some men also reported increased erectile functioning the next day. Forty-three percent of men with radical prostatectomy reported improvement in erections after taking sildenafil compared with 15 percent after taking placebo.
Sildenafil lowers blood pressure slightly in normal patients and substantially in patients who are undergoing nitrate therapy for angina. The most common side effects are headache, flushing and dyspepsia. Transient abnormal vision, usually a color tinge or increased sensitivity to light, is uncommon and is usually dose-related. No incidence of priapism has been reported. Sildenafil should be used cautiously in patients taking cimetidine, erythromycin, rifampin and ketoconazole.
Sildenafil is available in 25-, 50- and 100-mg tablets. The manufacturer recommends an initial dosage of 50 mg (which can be increased to 100 mg if necessary) taken one hour before intercourse. Patients older than 65 years of age, those with hepatic or renal dysfunction and those who are taking a CYP3A4 inhibitor should start with a 25-mg dosage. Sildenafil should not be taken more than once a day. The cost to the pharmacist for 30 tablets of any size is about $263.
Medical Letter consultants conclude that sildenafil appears to be an effective oral drug for treatment of erectile dysfunction, although not all patients respond, and long-term safety has not been established. The hypotensive effects may be troublesome in some patients; persons using nitrates for treatment of angina should not take sildenafil.
BARBARA APGAR, M.D., M.S.
Medical Letter consultants. Sildenafil: an oral drug for impotence. Med Lett Drugs Ther May 8, 1998;40 (1026):51-2.
Dosage of Progesterone in Continuous Combined HRT
Continuous combined hormone replacement therapy usually consists of an estrogen combined with medroxyprogesterone acetate taken on a daily basis to counter the effects of unopposed estrogen on the endometrium. This form of hormone replacement therapy is increasingly prescribed to postmenopausal women who have not undergone hysterectomy in order to prevent vaginal bleeding during hormone therapy. Since vaginal bleeding is cited as the most common reason for discontinuation of hormone replacement therapy, establishing the optimal dosage of progesterone to achieve amenorrhea is important. Nand and colleagues compared the efficacy of three different dosages of medroxyprogesterone acetate in achieving amenorrhea when given with 1.25 mg of estrone sulfate.
In the multicenter trial, 557 postmenopausal patients were randomly assigned to receive one of three continuous hormone replacement regimens for two years. Menopausal status was evaluated on the basis of amenorrhea, symptoms and levels of follicle-stimulating hormone. Women were excluded from the study if they had hypertension or severe metabolic, endocrine or gastrointestinal disease. Women with a history of thromboembolism also were excluded. After a complete history, physical examination and baseline blood measurements, the patients began therapy with 1.25 mg of estrone sulfate plus medroxyprogesterone acetate in dosages of 2.5, 5.0 or 10.0 mg daily. Patients were given identical instructions and were followed every three months. Patients maintained a diary of symptoms, particularly of vaginal bleeding or spotting, which was recorded on a four-point scale. In addition to physical examinations, blood monitoring and compliance checks, the follow-up included endometrial sampling performed three times during the study and bone density measurements that were taken twice.
The three treatment groups were comparable in all respects at the beginning of the study. At the three-month stage, 42 percent of women reported some degree of vaginal bleeding. By six months, the percentage of women achieving amenorrhea was 76.5, 80.1 and 80.9 percent for the 2.5-, 5.0- and 10.0-mg dosages of medroxyprogesterone acetate. At one year, the amenorrhea figures were 80.0, 87.8 and 85.8 percent. At two years, 91.5, 89.9 and 94.3 percent of women reported amenorrhea. None of the differences between the three dosages reached statistical significance. Approximately 10 percent of women reported persistent bleeding, but this did not appear to be related to the dosage of medroxyprogesterone acetate. About 95 percent of the women had atrophic endometrium at baseline, and no endometrial hyperplasia was detected during the study.
The authors conclude that all three dosages of medroxyprogesterone acetate provided adequate endometrial protection and achieved amenorrhea in approximately 80 percent of women by six months of continuous therapy. Most women achieved amenorrhea or experienced only very slight bleeding or spotting within the first three months of therapy. Since the incidence of atrophic endometrium was so high at the beginning of the study, the authors do not believe baseline endometrial biopsy is necessary before hormone replacement therapy is initiated.
ANNE D. WALLING, M.D.
Nand SL, et al. Bleeding pattern and endometrial changes during continuous combined hormone replacement therapy. Obstet Gynecol May 1998;91:678-84.
Use of Ringer's Lactate with Emergency Blood Transfusion
Ringer's lactate solution has been shown to be an excellent initial intravenous fluid therapy for trauma resuscitation. Unfortunately, current guidelines mandate that only normal saline be administered with blood products because of the danger of creating emboli. In theory, the calcium in Ringer's lactate solution could overwhelm the chelating capacities of the citrate in stored blood, resulting in clot formation. These clots could be directly infused into the circulation, possibly under pressure in critically ill patients, and could lead to clinically significant emboli. Lorenzo and colleagues studied clot formation when blood products were administered with either normal saline, Ringer's lactate solution or Ringer's lactate solution with additional calcium chloride.
Twenty-five units of whole blood and 26 units of packed red blood cells were infused with one of five solutions: normal saline, standard Ringer's lactate solution or Ringer's lactate solution mixed with an additional 1, 2 or 5 g per L of calcium chloride. Using standard blood filter tubing, each mixture was infused at rates similar to those used in trauma resuscitation. Infusion time was noted, the appearance of gross clot in the filter was recorded, and the filter was weighed to determine the amount of clot formed.
In the whole-blood group, no differences were found in infusion times among any of the solutions. Filter weight did not differ between normal saline and standard Ringer's lactate but increased significantly with the solutions containing the additional 1 and 2 g per L of calcium chloride. In infusions with packed red blood cells, infusion times were significantly increased between normal saline and the highest calcium concentrations of Ringer's lactate. There was a trend toward increased filter weight as the calcium content increased, but this did not reach statistical significance. Some gross clot formation was observed in both whole blood and packed red blood cells with all solutions. The appearance of gross clot formation was significantly increased using Ringer's lactate with the highest concentration of calcium versus normal saline.
The authors conclude that Ringer's lactate containing the calcium concentrations in common usage does not cause increased coagulation when used in blood transfusion. In acute trauma situations, Ringer's lactate has proved to be an excellent initial intravenous fluid therapy because it is isotonic and has few side effects. Changing intravenous solution bags from Ringer's lactate to normal saline when blood is transfused can cause unwarranted delay and anxiety. The authors recommend amendments to standard blood bank recommendations to allow the use of Ringer's lactate with the transfusion of blood products at rapid infusion rates.
ANNE D. WALLING, M.D.
Lorenzo M, et al. Can Ringer's lactate be used safely with blood transfusions? Am J Surg April 1998;175:308-10.
Interferon-alfa in Children with Chronic Hepatitis C
Interferon-alfa is an accepted treatment for chronic hepatitis C in adults, with a response rate (defined as normalization of alanine aminotransferase [ALT] values) of about 50 percent and a relapse rate in the first year of 50 percent. Jonas and colleagues conducted an open-labeled prospective trial to determine the safety and efficacy of interferon-alfa-2a therapy in children with chronic hepatitis C virus.
A total of 21 children with at least two ALT determinations more than 1.5 times the upper limit for at least six months completed the study. Treatment consisted of 3 million U of interferon-alfa-2a administered subcutaneously three times weekly for six months. Treatment was extended to one year in patients found to be responding at six months.
Four children (19 percent) had complete response to treatment at the end of six months, with normal ALT values and no detectable RNA for hepatitis C virus. An additional eight children (38 percent) were partial responders, with at least a 50 percent improvement in ALT values. Two of the responders who received prolonged therapy remained RNAnegative for hepatitis C virus, with normal ALT values. Three of the partial responders who received 12 months of treatment became complete responders, and this response was sustained. There were no statistically significant factors associated with response; however, the small sample size limited the ability to detect differences in variables. Side effects of treatment included fever and malaise in virtually every child early in the treatment. Seven of the children participating in the study (33 percent) lost HCV RNA and had normalization of ALT; all of these children had sustained response for at least six months, and five had sustained response for 12 months.
The authors conclude that although the response rate of 33 percent for children is less than the 50 percent rate typically reported for adults at one year, treatment with interferon-alfa has some efficacy in children with chronic hepatitis C infection. Children who have complete or partial response at six months should undergo prolonged treatment. Side effects were minimal. The most worrisome side effect was weight loss, which occurred in one half of the children treated. All of these children regained the lost weight after the conclusion of therapy. No long-term effects of interferon-alfa therapy were noted in follow-up of up to 36 months' duration.
RICHARD SADOVSKY, M.D.
Jonas MM, et al. Interferon-alpha treatment of chronic hepatitis C virus infection in children. Pediatr Infect Dis J March1998;17:241-6.
Reduction in Low-Weight and Preterm Births by Intervention
Programs created to improve pregnancy outcomes have produced conflicting results. Most programs rely on screening questionnaires to identify patients at "high risk" for low-birth-weight infants or premature delivery. These high-risk patients are then enrolled in special programs, often involving clinic or home visits by nursing staff. Since the relationship between the nursing staff and the patients appears to be a crucial factor in determining pregnancy outcome, telephone counseling has been suggested as a cost-effective approach. One study found telephone support to be as effective as home uterine activity monitoring, but a second small study found no difference in pregnancy outcomes between the patients supported by telephone contact and the patients in the control group. Moore and colleagues conducted a randomized trial to assess the effect of regular telephone contact by nursing staff on preterm and low-birth-weight deliveries in women attending a public clinic.
All patients who spoke English and had access to a telephone were asked to participate in the study, beginning between 22 and 32 weeks' gestation. The 1,554 women who agreed to participate were randomly assigned to either the "phone" intervention group or the control group. Upon entering the study, all participants were given an extensive personal interview and received printed information on preventing preterm labor. Women in the phone group agreed to accept telephone contact three times per week, and arrangements were made to minimize the number of calls in which contact could not be established. Three trained nurses were responsible for placing all of the calls. The telephone calls did not follow a specified script but during each call, health status was assessed, appropriate health advice was given and patient concerns were addressed. Most of the calls focused on assessment of health status, including perceptions specific to pregnancy, and on more general topics, such as smoking, alcohol and drug use, and nutrition. The nurse gave recommendations specific to each patient based on the telephone assessment. Each call also allowed time for discussion of areas of concern to the patient. All data were collected by a nurse who did not know to which group the patients had been randomized. The primary outcome variable measured was the difference in the rates of premature and low-birth-weight infants.
The groups did not differ in any important variable (e.g., age, marital status, smoking, previous history of a low-birth-weight infant) at baseline. The median number of calls completed during the study ranged from 21 to 25, depending on the subgroup of patient when categorized by age and race. The median duration of each call ranged from 3.2 to 3.7 minutes. The rate of low birth weight (less than 2,500 g [5 lb, 8 oz]) was 10.9 percent in the intervention group, compared with 14.0 percent in the control group. Although this result did not reach statistical significance, the effect was most evident in black women 19 years of age or older. In these 759 women, the rate of low birth weight was 11.4 percent in the intervention group, compared with 17.3 percent in the control group. When analyzed by risk status, the reduction in low birth weight was most pronounced in women identified as low risk. For preterm births (less than 37 weeks' gestation), the overall rates were 9.7 in the intervention group and 11.0 in the control group but again, the effect was most pronounced in black women older than 19 years. In this group, the difference in preterm births (8.7 percent in the intervention group versus 15.4 percent in the control group) was statistically significant.
The authors conclude that although reductions in low-birth-weight and preterm births were achieved by the telephone intervention system, these reductions only reached statistical significance in black women 19 years of age or older. Much remains to be investigated on this topic. In particular, the optimal number and content of phone calls should be established, and the effect on large populations of women at relatively low risk should be studied.
ANNE D. WALLING, M.D.
Moore ML, et al. A randomized trial of nurse intervention to reduce preterm and low birth weight births. Obstet Gynecol May 1998;91:656-61.
EDITOR'S NOTE: The achievement of statistically significant improvement in only one group of patients should not detract from the clinical significance of the improved pregnancy outcomes in all women participating in this study. Even in low-risk women, a three-minute call approximately once per week reduced the number of low-birth-weight and preterm deliveries. The calls were not elaborate but focused on giving the women opportunities to talk about their concerns. If every physician who cares for pregnant patients arranged for office nurses to make similar calls, the potential impact on national birth statistics could be substantial. Such interventions would be even more impressive if a national system for primary care research could document the outcomes and appropriately attribute credit to primary care.
--A.D.W.
Role of Semen in the Sexual Transfer of Hepatitis Viruses
The sexual partners of men with hepatitis C virus (HCV) infection have a relatively low prevalence of the disease, yet cases of sexual transmission have been reported. With the discovery of a new HCV-related virus named hepatitis G (HGV) or GBV-C, the issue of sexual transmission has become more complicated. It is now recognized that HGV and GBV-C are two distinct isolates of the same virus, to be labeled HGV/GBV-C. Previous studies indicate that HGV/GBV-C infection may occur in up to 7 percent of the population and may infect up to 30 percent of persons at risk for bloodborne infections, such as intravenous drug users. Semprini and colleagues examined semen and serum samples from men infected with hepatitis C to determine whether HCV RNA and HGV/GBV-C RNA are present in semen.
The 90 men in the study were former intravenous drug users. All tested positive for anti-HCV antibodies. Of the group, 27 were also positive for human immunodeficiency virus (HIV) infection, and 10 were positive for hepatitis B surface antigen. All of the men were asymptomatic, and none were receiving antiviral medication. The semen and serum samples were tested for HCV and HGV/ GBV-C RNAs by polymerase chain reaction, hybridization and sequence analysis. Although 56 patients had detectable serum HCV RNA, none of the 90 men had HCV RNA in their semen.
HGV/GBV-C was detected in the serum of 28 of the 90 men. Seventeen of these 28 men were also HCV RNA positive; eight of the 17 were also HIV positive. HGV/GBV-C RNA sequences were detected in seminal plasma in six of 12 samples free from polymerase chain reaction inhibitors.
The authors suggest that reports of infection of sexual partners of men with hepatitis C may represent cases of HGV/GBV-C infection. Alternatively, hepatitis C could be transmitted during sexual activity by blood from minor abrasions or other lesions. Seminal fluid alone does not appear to pose a significant risk in the transmission of hepatitis C. The findings also suggest that a significant number of men infected with HCV may also be infected with HGV/GBV-C, which can pose a threat of sexual transmission.
ANNE D. WALLING, M.D.
Semprini AE, et al. Absence of hepatitis C virus and detection of hepatitis G virus/GB virus C RNA sequences in the semen of infected men. J Infect Dis April 1998;177:848-54.
Postexposure Varicella Vaccination in Siblings
The live attenuated varicella vaccine that was approved in 1995 is not currently recommended by the manufacturer for postexposure prophylaxis. The older varicella vaccine preparations were shown to be effective for postexposure prophylaxis in studies done in the 1970s and 1980s. Because the vaccine manufacturing process has since changed, no studies have been performed using the currently available Oka/Merck vaccine. Salzman and Garcia evaluated the efficacy of postexposure vaccination in siblings of children with active varicella virus infection.
Each time a patient presented with the varicella virus, varicella vaccination was offered to all family members with a negative history of varicella infection. Parents were instructed to count the number of lesions on their children on the fifth day of the rash. Phone contact during the following 10 to 30 days identified the vaccinated family members who had developed lesions. Ten vaccinated siblings (14 months to 12 years of age) of seven index case patients were followed. The mean numbers of lesions were 245 in the index case patients and 13.4 in the vaccinated siblings. Five of the vaccinated siblings did not develop lesions; the five patients who did develop lesions became symptomatic 12 to 13 days after vaccination.
Previous studies have shown the attack rate of varicella among susceptible household contacts to be as high as 87 percent, considerably higher than the rate of infection in patients who received the postexposure vaccination in this study. In susceptible persons who do develop active varicella virus infection, the disease appears to be attenuated. The authors conclude that varicella vaccination should be considered in all siblings of children with active varicella virus infection who have a negative history of varicella disease or vaccination.
RICHARD SADOVSKY, M.D.
Salzman MB, Garcia C. Postexposure varicella vaccination in siblings of children with active varicella. Pediatr Infect Dis J March 1998;17:256-7.
Long-Term Survival After Acute Myocardial Infarction
Studies of outcome following myocardial infarction showed that in suitable patients, fibrinolytic therapy typically prevents 20 to 30 deaths per 1,000 patients treated within the first month. Early aspirin therapy also showed the potential to prevent about 25 deaths and 10 to 15 non-fatal reinfarctions or strokes per 1,000 patients in the month following infarction. Baigent and colleagues conducted a randomized, placebo-controlled study to assess the long-term survival of patients with myocardial infarction receiving either or both of these therapies.
The authors used data from 17,187 patients with suspected acute myocardial infarction who were enrolled in the Second International Study of Infarct Survival from 1985 through 1987. These patients were randomly assigned to receive either 1.5 million IU of streptokinase or placebo for one hour, and either aspirin (162.5-mg, enteric-coated tablets) or placebo daily for one month. Compliance with the assigned treatments was high, and use of additional treatment was at the discretion of the physicians.
Follow-up data were available for about 95 percent of all patients up to 1990, and for 6,213 British patients up to mid-1997. In the overall population studied, there were 1,841 deaths recorded during the first 35 days; 991 deaths from day 36 through the end of year one; 1,478 deaths during years two through four; and 1,230 deaths during years five through 10. Patients receiving streptokinase had 29 fewer early deaths per 1,000 patients during the first 35 days of follow-up than those receiving placebo. This benefit persisted and resulted in 28 fewer deaths for 1,000 patients treated after four years and 23 fewer deaths for 1,000 patients treated after 10 years. The effect was not restricted to specific groups of patients. In particular, patients 70 years and older appeared to benefit as much as younger patients did. Over time there was no gain in survival or any evidence of a "catching up" in mortality following the initial improvement with early streptokinase therapy.
Compared with patients receiving placebo, patients treated with aspirin also showed a significant reduction in early mortality, with 26 fewer deaths per 1,000 patients treated during the first 35 days. As with streptokinase therapy, little further benefit or loss was observed during long-term follow-up. The benefits of the two treatments were additive. The early survival benefit of treatment with the combination of streptokinase plus aspirin resulted in approximately 55 fewer deaths per 1,000 patients by day 35. This benefit persisted in the longer term, with approximately 42 fewer deaths per 1,000 patients treated at 10 years.
The authors conclude that the early survival benefit produced by treatment with both forms of fibrinolytic therapy in patients with acute myocardial infarction appears to be maintained for at least 10 years.
ANNE D. WALLING, M.D.
Baigent C, et al. ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither. BMJ May 2, 1998;316:1337-43.
Smoking in Women and Risk of Myocardial Infarction
Approximately 40 percent of all deaths in Western countries are attributed to ischemic heart disease. Within the past 20 to 30 years, smoking has become more prevalent in women, and their smoking patterns have changed to more closely resemble those of men. Changes in the prevalence and patterns of smoking in women could have a dramatic impact on mortality rates. Prescott and colleagues conducted a large, population-based study in Denmark to compare the risk of myocardial infarction associated with smoking in men and women.
The authors pooled data from three large studies to obtain a cohort of 11,472 women and 13,191 men. These study participants were followed for a mean of 12.3 years. Risk factors for cardiovascular disease were assessed by using a self-administered questionnaire and laboratory tests. The type of tobacco smoked was recorded, and the patient's duration of smoking was measured. Alcohol consumption was classified according to total weekly intake. National hospital data systems and mortality registers were used to monitor hospital admissions for fatal and nonfatal myocardial infarctions.
During the follow-up period, 512 women and 1,251 men had myocardial infarctions. A total of 104 women and 274 men died as a result. The risk of myocardial infarction was strongly associated with elevated systolic blood pressure, body mass index, height, unfavorable lipoprotein profiles, education, diabetes, alcohol intake and physical inactivity during leisure time. Men had higher incidence rates of myocardial infarction than did women at all ages. The relative risk of myocardial infarction increased with tobacco use in both men and women. The relative risk of myocardial infarction in women who were current smokers was 2.24 compared with 1.43 in male smokers. This difference was significant and was unchanged after adjustment for other risk factors. Risks in ex-smokers were not increased, but in current smokers there was a clear dose-response relationship. Women were found to have a higher relative risk in each category. The risk increased with age and in smokers of both sexes who inhaled.
The authors conclude that the relative risk of myocardial infarction in women who smoke is approximately 50 percent greater than the risk in male smokers. This difference persisted after adjustment for multiple cardiovascular risk factors. The authors suggest that a possible cause may be the interaction of some hormonal factors with components of the inhaled smoke. There is growing epidemiologic evidence that women who smoke are relatively deficient in estrogen. Hormone replacement therapy may mitigate the risk of stroke to some extent, but clinical trials have not yet addressed this issue.
ANNE D. WALLING, M.D.
Prescott E, et al. Smoking and risk of myocardial infarction in women and men: longitudinal population study. BMJ April 4,1998;316:1043-7.
EDITOR'S NOTE: This study makes depressing reading, especially as it verifies what was suspected from earlier, smaller studies and clinical observations. Women do appear to be more vulnerable to the adverse cardiovascular effects of cigarette smoking than men. An onslaught of cardiovascular disease in women around menopause or even at younger ages has been anticipated (and appears to be happening) based purely on the increase in smoking and the change to more "male" patterns of smoking, such as completely smoking each cigarette and inhaling. We can now expect this epidemic to be exaggerated because of biologic vulnerability. Chronic obstructive pulmonary disease is now more common in women than in men. Must we simply document the gradual "feminization" of many smoking-related diseases? If every physician inquired about smoking cessation in every female patient at every visit, we would at least make a start toward reversing this trend.
--A.D.W.
Safety of Combined Therapy for Parkinson's Disease
One arm of a large British therapeutic trial comparing three treatment regimens for Parkinson's disease was terminated in 1995 because of unexpectedly high mortality rates in patients receiving combination therapy with a levodopa/dopa decarboxylase inhibitor and selegiline. Compared with patients receiving levodopa/dopa decarboxylase inhibitor alone, the relative mortality was increased by 60 percent, equivalent to one excess death for every 54 patients. Several explanations have been suggested for this finding, including cardiac rhythm disturbances, orthostatic hypotension, accelerated nigral cell death or an unanticipated drug interaction. Ben-Shlomo and colleagues conducted a randomized trial with blind comparison and reclassification to clarify the reasons for the excess mortality in patients who participated in the earlier trial and the safe use of selegiline alone or in combination with other drugs.
The clinical records of all patients who died during the earlier trial were studied. A panel of four investigators attempted to establish the most probable cause of death for each patient and assigned a confidence score to their conclusion, ranging from one (confident) to five (guessing). To check reliability, the cases of 20 randomly selected patients were reviewed again by the same panel three months after the original assessment. The panel was blind to the patient's death certificate and trial arm.
In the 249 patients treated with levodopa alone, 44 (17.7 percent) patients died, compared with 76 (28 percent) of the 271 patients receiving combined treatment with selegiline and levodopa. The panel reached a diagnosis in 90 of these deaths. For the remainder, data were insufficient to establish a confident cause of death, and the reason given on the death certificate was used.
The authors recalculated the excess mortality for patients treated with combined levodopa and selegiline to be approximately 35 percent or one excess death per 75 patients treated for one year. The only cause of death that showed significant excess was Parkinson's disease. There were more sudden deaths in the group receiving combined therapy, but this difference was not statistically significant. All groups had comparable proportions of unexpected and out-of-hospital deaths. Patients who received combined therapy with selegiline were more likely to have evidence of dementia, falls, postural dizziness and shortness of breath in the three months before death but did not have increased cardiovascular disease or report taking more cardiovascular medications. Patients in this group were also less likely to be taking antidepressant medication before death.
These results show a relatively increased mortality rate in patients treated with the drug combination that included selegiline, but the excess mortality is less than was first reported. The reasons for this excess mortality are not clear. Only mortality rates from Parkinson's disease were significantly different among the groups, but the disability data do not support the theory that this disease process was accelerated or exacerbated by therapy. The authors suggest that combination therapy with selegiline may be harmful to a subgroup of patients, but this group can only be crudely identified as those with confusion, dementia, falls and postural hypotension. Combination therapy with selegiline currently offers no advantage in patients with early, mild Parkinson's disease. It may be useful in selected patients with severe Parkinson's disease in order to improve quality of life, but it should be avoided in patients with dementia, postural hypotension, falls and confusion.
ANNE D. WALLING, M.D.
Ben-Shlomo Y, et al. Investigation by Parkinson's Disease Research Group of United Kingdom into excess mortality seen with combined levodopa and selegiline treatment in patients with early, mild Parkinson's disease: further results of randomised trial and confidential inquiry. BMJ April 18, 1998;316:1191-6.
Ipratropium Plus Albuterol for Treatment of Acute Asthma
The use of nebulized ipratropium in combination with beta agonists in the management of acute asthma in adults is controversial. The National Asthma Education Program Expert Panel's most recent guidelines, published in April 1997 by the National Institutes of Health, suggest only that anticholinergics may be considered in acute asthma management. Lin and associates conducted a double-blind, placebo-controlled study to evaluate the use of nebulized ipratropium bromide and albuterol compared with albuterol alone in the treatment of acute asthma in adults.
Fifty-five patients were included in the study. All patients were 18 years or older and had presented to the emergency department because of acute bronchospasm resulting from asthma. All of them had a peak expiratory flow rate (PEFR) of less than 200 L per minute. Patients were randomly assigned to receive either albuterol alone or albuterol plus ipratropium. Vital signs and symptomatic complaints were monitored during treatment. The treating physician was allowed to administer 125 mg of parenteral methylprednisolone if the patient's response to treatment was inadequate.
PEFR values were significantly higher in patients receiving ipratropium and albuterol. At 60 minutes, the median PEFR in patients who received combination therapy was 285 L per minute, compared with 240 L per minute in patients who received albuterol alone. In addition, the proportion of patients requiring hospital admission was significantly higher among the albuterol-only group. Ten of the 28 patients (36 percent) in the albuterol-only group required admission, compared with three of the 27 patients (11 percent) in the combination therapy group. Thirty-two percent of patients in the albuterol-only group required parenteral steroids compared with only 15 percent of patients receiving combination therapy. Patients in the two groups did not differ with respect to heart rate acceleration, tremor, agitation or accessory muscle use.
The authors conclude that initial treatment with ipratropium bromide and albuterol results in more bronchodilation than treatment with albuterol alone in adult patients with acute asthma.
RICHARD SADOVSKY, M.D.
Lin RY, et al. Superiority of ipratropium plus albuterol over albuterol alone in the emergency department management of adult asthma: a randomized clinical trial. Ann Emerg Med February 1998;31:208-13.
Antidepressants and Risk of Hip Fractures in the Elderly
The risk of falls and hip fractures in the elderly has been shown to increase with the use of psychotropic medications. This may be attributed to side effects of traditional antidepressant medications, such as sedation, orthostatic hypotension, confusion and cardiac irregularities. The selective serotonin reuptake inhibitors (SSRIs), which have rapidly replaced more traditional antidepressant medications for use in elderly patients, may have fewer hazardous side effects. Liu and colleagues studied the risk of hip fracture associated with the use of SSRIs compared with the risk of hip fracture associated with the use of traditional antidepressants in elderly patients.
Elderly Canadian patients hospitalized for treatment of hip fracture between April 1, 1994, and March 31, 1995, were included in the study. Patients who resided in long-term care facilities or had epilepsy, trauma or pathologic fracture were excluded from participation. Each case was matched by age and sex with five control subjects. Information about drugs prescribed for both study and control subjects was obtained from the drug benefit program, which serves all elderly Canadian residents.
Of the 8,239 study subjects, 6.6 percent had received a prescription for SSRIs, compared with 2.8 percent of the control subjects. A total of 11.6 percent of the study subjects and 7.7 percent of the control subjects were taking tricyclic antidepressants. The adjusted odds ratio for hip fracture was 2.4 for the patients taking SSRIs, compared with 1.5 to 2.2 for the patients taking traditional antidepressants. Risk was higher in new users of all antidepressant drugs. Patients taking antidepressants were more likely to take other drugs and to have undergone previous hospital admission for dementia.
The authors conclude that the use of any antidepressant medication in elderly patients increases the risk of hip fracture. SSRIs do not appear to offer an advantage over the traditional antidepressants. Treatment of depression in the elderly can have great benefit, but it must be balanced against the increased risk of hip fracture, which carries high rates of mortality and morbidity in elderly patients.
ANNE D. WALLING, M.D.
Liu B, et al. Use of selective serotonin-reuptake inhibitors or tricyclic antidepressants and risk of hip fractures in elderly people. Lancet May 2, 1998;351:1303-7.
Use of Prophylactic Aspirin in Preventing Preeclampsia
The use of prophylactic aspirin for the prevention of preeclampsia has been recommended on the basis of several small studies. The rationale for its recommendation is that aspirin inhibits thromboxane production more than prostacyclin production and therefore should prevent vasoconstriction and pathologic coagulation in the placenta. Caritis and colleagues conducted a randomized, double-blind, placebo-controlled trial to determine if aspirin reduced the incidence of preeclampsia in women at increased risk for developing this disease during pregnancy.
Women enrolled in the trial were screened at 13 different study sites. The researchers selected women in one of four high-risk groups. These groups included women with pregestational type 1 diabetes mellitus, women with multiple gestations, women with chronic hypertension and women who had had preeclampsia in a previous pregnancy. Patients were entered into the study between 13 and 26 weeks of pregnancy. They were given either 60 mg of aspirin or a placebo tablet once daily. Prenatal visits occurred every four weeks until week 28 of the pregnancy, then every two weeks until week 36, and then weekly until delivery. Patients were instructed to take their medication until delivery but were to discontinue it if preeclampsia developed. The primary outcome measured was preeclampsia, which was defined as the development of hypertension plus one of the following: proteinuria, thrombocytopenia or pulmonary edema. Hypertension was defined as a systolic blood pressure of 140 mm Hg or greater, or a diastolic blood pressure of 90 mm Hg or greater, on two occasions at least four hours apart. Proteinuria was defined as the excretion of 300 mg of protein in a 24-hour urine collection, or two dipstick test results that were 2+ or greater. Thrombocytopenia was defined as a platelet count of less than 100,000 per mm3 (100,000 3 109 per L).
Between 1991 and 1995, over 2,500 women were enrolled in the study, with one half of them receiving aspirin and the other half receiving placebo. There were no significant differences between the two groups in mean age, gravidity, mean week of gestation at entry into the study and race. At the end of the study, there was no difference in the incidence of preeclampsia between the aspirin group and the placebo group. This finding remained after each of the four risk groups were evaluated individually. The overall incidence of preeclampsia was quite high, at 20 percent for the placebo group and 18 percent for the aspirin group. Secondary outcomes, including incidence of preterm birth, infants born small for gestational age, perinatal deaths, abruptio placentae, postpartum hemorrhage and intraventricular hemorrhage, were not different between the two groups.
The researchers conclude from their study that low-dose aspirin does not prevent preeclampsia in high-risk women and therefore should not be administered to women in this group. On a positive note, the use of aspirin did not adversely affect the mothers or their infants.
JEFFREY T. KIRCHNER, D.O.
Caritis S, et al. Low-dose aspirin to prevent preeclampsia in women at high risk. N Engl J Med March 12, 1998; 338:701-5.
Prevalence Survey of Abuse in Women at Urgent Care Clinics
Violence against women is a significant public health problem, the prevalence of which is difficult to quantify. Surveys of women presenting to obstetric clinics and emergency departments indicate that up to 22 percent of female patients are victims of domestic violence. McGrath and colleagues administered a survey to determine the prevalence of physical and sexual abuse in women presenting to an urgent care clinic and the frequency with which they recalled being asked by their health care providers about abuse.
Women who presented to an urgent care clinic during an eight-month period were included in this study unless they were too ill to participate, had language or communication difficulties, or could not be interviewed alone. Interviews consisted of 22 questions asked by specially trained staff members. If abuse was disclosed, the patient was referred to a social worker for crisis intervention and counseling.
A total of 397 women were included in the study. Approximately 61 percent (242) were white, 18 percent (71) were black and 15 percent (61) were Hispanic. Forty-one percent (161) received Medicaid or had no insurance, and 56 percent (221) had at least a high school education. Sixty-four percent of the women were pregnant. A lifetime history of physical or sexual abuse was reported by 184 (46 percent) of the women. Recent physical or sexual abuse was reported by 10 percent (38). Recent abuse was significantly associated with young age and being uninsured or being insured with Medicaid. Pregnant patients included in this study reported lower rates of recent abuse than nonpregnant patients.
Only 18 percent of the women surveyed recalled being asked about abuse by a physician or nurse. Of the women who reported recent abuse, 71 percent reported never having been screened for abuse. This situation differed significantly by race. Fifty percent of recently abused women who were white recalled being screened for abuse, compared with only 10 percent of women who were not white. Insurance status did not appear to be associated with a history of being screened for abuse.
The authors conclude that women who presented to this urgent care clinic reported a high prevalence of physical and sexual abuse, including recent abuse. Although some studies have implicated pregnancy as a risk factor for violence, these authors found that young age was more highly associated with abuse. They urge health care professionals to routinely screen all women for physical and sexual abuse during routine visits.
ANNE D. WALLING, M.D.
McGrath ME, et al. A prevalence survey of abuse and screening for abuse in urgent care patients. Obstet Gynecol April 1998;91:511-4.
Effect of Growth Hormone Therapy in Short Normal Girls
Although growth hormone therapy has been available for more than 10 years, there are few data regarding its long-term effect on height or timing of onset of puberty in girls. A major concern is that any gain in prepubertal height could be lost in puberty if growth hormone therapy interferes with the size or duration of the pubertal growth spurt. McCaughey and colleagues conducted a randomized controlled trial to study the effect of growth hormone therapy on final height and pubertal development in girls.
The authors identified 40 girls who were at least two standard deviations below the mean height for their age and had no medical condition to account for their short stature. The parents of 18 girls consented to have their daughters participate in the study. The mean age of the girls at the start of the study was 8.07 years. Ten of these girls received 30 U of somatropin every week, given in daily subcutaneous injections. The remaining eight girls were assigned to a control group and received no treatment.
All 18 girls were intensively monitored. Height (both standing and sitting) and weight of study participants were measured every six months to assess body proportions. Bone age assessments, serum biochemical profiles, serum insulin and insulin-like growth factor 1 were measured annually. The 22 girls who declined to enter the study were monitored for standing height and weight every six months. Treatment lasted until the girls reached menarche and had at least stage 4 breast development (mean: 6.2 years).
The three groups had similar growth patterns at baseline; girls in the nonconsent group were slightly taller than girls in the other groups. During the trial, the girls receiving treatment grew significantly more than the girls in the two nontreatment groups. By 16 years of age, girls who received treatment were taller than those in the nontreatment group by 7.5 cm and were 6.0 cm taller than those who declined to participate in the study. All of the girls in the treatment group reached their target heights, compared with 38 percent of the girls who did not receive treatment. This difference was statistically significant. Age at menarche and other measures of puberty and development did not differ significantly between the groups.
The authors conclude that growth hormone therapy promotes height gain without compromising the process of puberty or its associated growth spurt. In considering the benefits of this therapy, the authors raise ethical and financial issues. Height gain and possible psychosocial benefits have to be balanced against cost. No significant psychosocial benefits have yet been shown. The authors estimate that each centimeter of height gained with the use of growth hormone therapy costs approximately $18,000.
ANNE D. WALLING, M.D.
McCaughey ES, et al. Randomised trial of growth hormone in short normal girls. Lancet March 28, 1998;351:940-4.
Spermicide-Coated Condoms and Urinary Tract Infections
Staphylococcus saprophyticus is responsible for up to 26 percent of urinary tract infections reported in young sexually active women. The risk factors for acquiring S. saprophyticus infection are not clear. Risk factors for acquiring a urinary tract infection from coliform bacteria are better understood and include the use of vaginal spermicide, spermicide-coated condoms or contraceptive diaphragms. Fihn and associates conducted a population-based, case-control study to determine if the same factors might predispose women to acute urinary tract infections caused by S. saprophyticus.
The case group comprised 96 sexually active women who had been diagnosed with a urinary tract infection caused by S. saprophyticus in the previous month. They were matched with 629 sexually active women who served as control subjects. Among the study population, condoms were the most common method of contraception and protection from sexually transmitted disease. In the case group, condoms were used during the previous year by 71 percent of the women and during the previous month by 53 percent. In the control group, condoms were used during the previous year by 31 percent of the women and during the previous month by 19 percent. Patients in the case group were slightly younger than patients in the control group and were significantly more likely to be unmarried, to have had multiple partners during the previous year and to have had frequent sexual intercourse and a history of urinary tract infections.
Exposure to spermicide-coated condoms during the previous month was associated with a statistically significant risk of urinary tract infection caused by S. saprophyticus, compared with no exposure to any type of condom. When women were exposed to even a lubricated condom, the risk of urinary tract infection was modestly increased. The risk of urinary tract infection associated with a spermicide-coated condom was highly significant. With more frequent use of spermicide-coated condoms during the prior month, the risk of acquiring a urinary tract infection with S. saprophyticus rose dramatically. The risk of urinary tract infection did not extend to exposure to uncoated condoms. This finding suggests that most of the excess risk of urinary tract infection among condom users was related to exposure to nonoxynol 9. There was no increased risk of urinary tract infection associated with S. saprophyticus among women who had used other contraceptive methods such as foam or jelly.
The authors conclude that the risk of a young sexually active woman acquiring a urinary tract infection after being exposed to condoms coated with nonoxynol 9 was three times higher than the risk for sexually active women who did not use coated condoms. The study suggests that vaginal spermicides damage normal vaginal flora in a manner that promotes colonization with S. saprophyticus. This association is supported by the consistency of these findings with earlier studies regarding spermicide exposure and urinary tract infection. Women who use coated condoms and have recurrent urinary tract infections, particularly infections caused by S. saprophyticus, should be advised to consider using other methods of contraception.
BARBARA APGAR, M.D., M.S.
Fihn SD, et al. Use of spermicide-coated condoms and other risk factors for urinary tract infection caused by Staphylococcus saprophyticus. Arch Intern Med February 9, 1998;158:281-7.
Evaluation and Management of Headache Symptoms
Headache evaluation is complicated by patients with overlapping symptoms and more than one type of headache. The major types of headache include migraine (with or without aura), tension-type headaches and drug-rebound (or chronic daily) headaches. Maizels reviewed the steps involved in evaluating and managing the patient with headache.
Migraine headaches are usually accompanied by nausea, photophobia or phonophobia. Auras, most commonly described as visual flashing lights, zig-zag lines or blind spots, may also be present. Migraine headaches are likely to have reliable triggers and patterns, and are usually relieved after sleep. Tension-type headaches may exist in a continuum with migraine headaches and are not directly related to muscle tenderness; rather, muscle tenderness is a secondary phenomenon. It is believed that migraines result from a disturbance of the serotonergic system of the midbrain and that all migraine abortive and prophylactic medications influence the serotonin pathway. Vascular changes are most likely secondary rather than causative. The etiology of the tension-type headache is less clear but is thought to be an integration of vascular, myofascial and supraspinal factors.
Drug-rebound headaches presenting as chronic daily headaches are common. The use of analgesic medications, even as little as 1,000 mg per day of aspirin or acetaminophen, can cause this type of headache. Any symptomatic headache remedy may cause drug rebound headache, but it is most likely with the use of ergotamines, narcotics and products that combine caffeine or butalbital with aspirin or acetaminophen. Many clinicians limit the use of all symptomatic medication to two days a week. Patients need much encouragement when attempting withdrawal from the causative medication and should be told they will feel worse for about two weeks. The addition of amitriptyline (10 to 25 mg) or a nonsteroidal anti-inflammatory drug (NSAID) such as naproxen may provide relief.
Treatment of acute headache should be based on the past experience of the patient, the headache severity, associated symptoms and the medication side-effect profile. Some choices are described in the accompanying table. Headaches accompanied by severe nausea may be treated by adding a dopamine antagonist anti-emetic such as metoclopramide. More severe headaches may require parenteral therapy with dihydroergotamine or a specific serotonin1 (5-HT1) receptor agonist such as sumatriptan or one of the newer triptans.
Headache prophylaxis includes resolution of trigger factors. Medication withdrawal should be considered. Prophylactic medication can be offered if severe attacks occur more than two or three times monthly or if attacks cannot be easily controlled with abortive medications. Prophylaxis may reduce migraine frequency by 50 to 60 percent. First-line agents are tricyclic antidepressants and beta blockers. Calcium-channel blockers and NSAIDS are less effective but may be tried before giving drugs that have greater side effects. Third-line agents include methysergide and monoamine oxidase inhibitors. Selective serotonin reuptake inhibitors should be considered for use in patients in whom depression is a significant factor of the headache symptoms. Divalproex sodium may be useful in reducing the frequency of migraine attacks.
In a discussion of worrisome headaches, the author concludes by discrediting the symptoms of the "classic" brain tumor headache. Neuroimaging is appropriate when the headache (1) is accompanied by unexpected neurologic signs or symptoms, (2) has new onset after age 50 or occurs in a patient with a history of cancer, (3) is triggered by cough, coitus or exertion, (4) is severe and sudden ("thunderclap headache"), (5) is different from a previously stable headache pattern or (6) is not diagnosable as a "primary" benign headache. Imaging is not necessary in the patient with a stable migraine pattern. There are no specific guidelines for the neuroimaging of tension-type headaches.
Medications for Symptomatic/Abortive Treatment of Headache Drug
Dosage
Remarks
Side effects/
contraindications
Mild headaches
Aspirin
NSAIDs (naproxen, ibuprofen, etc.)Use maximal tolerated doses at onset; e.g., naproxen at 775 mg, ibuprofen at 1,200 mg Side effects: gastrointestinal intolerance, bleeding, fluid retention
Contraindications: peptic ulcer disease, warfarin use; use with caution in patients with congestive heart failure, renal insufficiencyAspirin or acetaminophen with butalbital, caffeine One to two tablets at onset, repeated every four hours; maximum: four tablets per day Highly prone to drug rebound; limit use to two days per week Side effects: sedation, same as for aspirin (above) More severe headaches
Isometheptene, dichlorphenazone, acetaminophenTwo tablets at onset, then one every hour; maximum: five tablets per day Vasoconstrictor-sedative combination Side effects: dizziness;
Contraindications: glaucoma, severe renal or liver disease, coronary artery disease, hypertension, concomitant use of MAO inhibitorsErgotamine tartrate, caffeine One to two tablets orally at onset; may repeat within 30 minutes and every four hours; maximum: five tablets per day Highly prone to drug rebound: limit use to two days per week Side effects: nausea, abdominal pain, paresthesias, chest tightness; ergotism (ischemia of extremities)
Contraindications: coronary artery disease, peripheral vascular disease, hypertension, renal or liver diseases, sepsis, pregnancyMetoclopramide 10 mg orally, intramuscularly or intravenously Combine with any other agent to increase efficacy Side effects: dystonic reactions; avoid use in children Most severe headaches
Dihydroergotamine1 mg intramuscularly or subcutaneously, up to every eight hours; 2 mg intranasally; see also intravenous protocol Low rate of relapse; ideal for persistent headache Side effects and contraindications: same as for ergotamine, but does not cause drug rebound headache Sumatriptan succinate 6 mg subcutaneously; 25 to 100 mg orally; 5 to 20 mg intranasally; for relapse, may repeat one dose within 24 hours High rate of relapse; sumatriptan given subcutaneously is the drug of choice for severe migraine or rapid onset of symptoms Side effects: atypical sensations (tingling, numbness, warmth, cold, heaviness), flushing, chest pain, neck pain
Contraindications: coronary artery disease or Prinzmetal angina; hemiplegic or basilar migraine. Do not use within 24 hours of using ergots or MAO inhibitors
NSAIDs=nonsteroidal anti-inflammatory drugs; MAO inhibitors=monoamine oxidase inhibitors.
NOTE: All agents may be combined with anti-emetics for greater effect. Drugs are listed in groups of approximate order for increasing severity of headache
Reprinted with permission from Maizels M. The clinician's approach to the management of headache. West J Med 1998;168:203-12.
RICHARD SADOVSKY, M.D.
Maizels M. The clinician's approach to the management of headache. West J Med March 1998;168;203-12.
Estrogen Therapy After Surgery for Endometriosis
Endometriosis is a common disorder that may not respond to medical therapy. In patients who undergo total abdominal hysterectomy with bilateral salpingo-oophorectomy, there is disagreement about when to initiate estrogen replacement therapy. Some physicians advocate delaying estrogen replacement therapy for up to 18 months after surgery to avoid stimulating any residual implants or microscopic endometriosis tissue that surgery may have missed. Other physicians favor starting estrogen replacement therapy immediately following surgery. Hickman and colleagues conducted a retrospective cohort study to determine if the timing of estrogen replacement therapy following total abdominal hysterectomy with bilateral salpingo-oophorectomy for the treatment of endometriosis increased the incidence of symptom recurrence.
The authors reviewed the medical records of 60 women who began taking estrogen within the immediate postoperative period and 35 women who delayed taking estrogen for at least six weeks after surgery. All of the women reported pain as at least one indication for surgery; 63 percent (60 women) had previous medical therapy, and 78 percent (74 women) reported previous surgical therapy for endometriosis. The two groups were comparable in all respects except the timing of estrogen replacement therapy following surgery. Recurrent pain was reported by four women (7 percent) who began taking estrogen immediately following surgery compared with seven women (20 percent) who delayed taking estrogen for at least six weeks after surgery. This difference was not statistically significant. When factors such as age at time of hysterectomy, degree of endometriosis and adjunctive use of postoperative medroxyprogesterone were considered, the relative risk of pain recurrence following surgery was 5.7 for women who delayed taking estrogen.
The authors conclude that initiating estrogen replacement therapy immediately following total abdominal hysterectomy with bilateral salpingo-oophorectomy for the treatment of endometriosis does not increase the risk of recurrent symptoms.
ANNE D. WALLING, M.D.
Hickman TN, et al. Timing of estrogen replacement therapy following hysterectomy with oophorectomy for endometriosis. Obstet Gynecol May 1998;91:673-7.
Adult Psychiatric Status of Hyperactive Boys
Studies of adolescents and young adults who had been diagnosed with attention deficit hyperactivity disorder (ADHD) in childhood have shown that conduct problems, arrest records, poor academic histories and continuation of ADHD symptoms are common. Only two prospective, controlled studies of psychiatric status in adulthood have been performed. Mannuzza and associates prospectively followed boys of average intelligence with ADHD to gain further understanding of the course of this disorder.
The study subjects were referred to a child psychiatric clinic by teachers at an average age of 7.3 years. Eighty-five of the 104 subjects were interviewed at a mean age of 24.1 years. These probands were compared with 73 persons recruited from a nonpsychiatric clinic population. Interviewers were blinded to group status. The duration of follow-up ranged from 15 to 21 years.
The probands were significantly older and of lower social class than the comparison subjects. One third of the probands versus one fifth of the comparison subjects had ongoing mental disorders at the time of adult follow-up. The most common diagnoses in the probands were antisocial personality disorder and nonalcohol substance abuse.
Marijuana was abused by all of the probands with nonalcohol substance use disorder and in two of the three comparison subjects who had nonalcohol substance problems. Sixty percent of the probands with antisocial personality disorder versus 13 percent of those without antisocial personality disorder had comorbid substance use disorders. Only 4 percent of the probands (and none of the comparison subjects) had the full ADHD syndrome at follow-up, and no subject reported clinically impairing symptoms in the absence of the full syndrome. No evidence indicated that ADHD probands were at greater risk for having a current mood or anxiety disorder in adulthood.
The authors conclude that most cases of childhood ADHD remit by adulthood. They note that the study group was not entirely representative of children with ADHD, since other studies show that 30 to 50 percent of these children have comorbid conduct disorders. The authors view the absence of conduct disorder in the probands as a positive feature, noting that it is critical to examine the natural history of ADHD independently of the well-known consequences of conduct disorder, since 50 to 70 percent of children with ADHD do not have conduct disorder. It is relevant to note that even when conduct disorder is present, most affected children do not retain the disorder into adulthood.
BARBARA APGAR, M.D., M.S.
Mannuzza S, et al. Adult psychiatric status of hyperactive boys grown up. Am J Psychiatry April 1998;155:493-8.
Evaluation of Inappropriate Consumption of Sumatriptan
Sumatriptan accounted for the second highest outpatient drug expenditure in Denmark in 1995. Gaist and colleagues conducted a population-based interview study to investigate the appropriateness of sumatriptan use.
All patients who presented prescriptions for sumatriptan to pharmacists in a county in Denmark (population: 465,000) during a two-week period were included in the study. The patients were classified as high, intermediate or low users, based on the number of units of sumatriptan used in a 30-day period. Sumatriptan consumption was described as the defined daily dose unit (100 mg for oral sumatriptan and 6 mg for subcutaneous sumatriptan). High users were defined as those who took 60 U or more over a 30-day period; intermediate users were defined as those who took 30 to 59 U per 30-day period; and low users were defined as those who took less than 30 U over a 30-day period. Response rates varied greatly by level of usage. Only seven patients (33 percent) in the high-use group and 30 patients (47 percent) in the intermediate-use group agreed to be interviewed. Even within the groups, the highest users were least likely to agree to participate in the study.
Previous dependence on medications and chronic daily use of analgesics were commonly reported by patients in the high-use group.
The authors conclude that sumatriptan was widely used for inappropriate indications, particularly for tension and drug-induced headaches. They warn that a significant subgroup of patients are overusing sumatriptan, usually in substantial quantities.
ANNE D. WALLING, M.D.
Gaist D, et al. Inappropriate use of sumatriptan: population based register and interview study. BMJ May 1998;316:1352-3.
EDITOR'S NOTE: This study verifies a common observation in clinical practice that a few patients take sumatriptan in doses substantially in excess of recommendations. The drug was designed for use in migraine headaches--a condition that is characterized by episodic attacks--and was not intended for daily use or for use in dosages over 200 mg per day. Because only one third of the heaviest users participated in this study, the extent of overuse could be substantially higher than indicated in this study's results. Interestingly, the diagnosis of migraine or cluster headache was uncertain in many of the patients who overused the drug. Headache is a complex pain syndrome, and often drug dependency, and psychologic and social pathologies are intertwined with pathophysiology. Use of powerful medications must be monitored in all headache patients.
--A.D.W.
Work Environment and the Safety of Pregnant Workers
Workplace factors such as strenuous physical exertion and exposure to chemicals, infectious agents and stress can pose health risks to a pregnant woman and her developing fetus. Preconception exposures in both men (through sperm) and women (through ova) can affect the offspring. Physicians who may be asked to assess the risk of workplace exposure need skills to identify and quantify an exposure and to synthesize the information into an estimated risk. Feinberg and Kelley review employment issues related to pregnancy and provide an approach to identifying risk factors for pregnant workers.
The occupational and environmental history should include descriptions of past and current jobs along with exposures to chemicals (smoke, vapors or dust), infectious agents (viruses), physical elements (exertion, heat, lifting, noise or irradiation) and psychologic features (stress). Personal protection measures (such as the use of respirators, gloves or masks) and workplace controls (such as ventilation systems) should be considered. Community and home exposures must also be included.
Resources for Assessing Workplace
Exposure of Pregnant WomenNIOSH Pocket Guide to Chemical Hazards
Publications Dissemination DSDTT
National Institute for Occupational Safety and Health
4676 Columbia Parkway
Cincinnati, OH 45226
Telephone: 800-35-NIOSH
Web site: http://www.cdc.gov/nioshReproductive Toxicology Center (REPROTOX)
Columbia Hospital for Women Medical Center
2425 L St., N.W.
Washington, DC 20037
Telephone: 202-293-5137
E-mail: reprotox@erols.comTERAS
Department of Pathology
Brigham & Women's Hospital
75 Francis St.
Boston, MA 02115
Telephone: 617-732-6507
Fax: 617-732-7513TERIS
Teratogen Information System
University of Washington School of Medicine
Department of Pediatrics, Box 357920
Seattle, WA 98195
Telephone: 206-543-2465California Teratogen Information Service
and Clinical Research Program
University of California, San Diego, School of Medicine
Department of Pediatrics,
Division of Dysmorphology and Teratology
25 Dickinson St., Room 8446
San Diego, CA 92103-8447
Telephone: 619-543-2131
Fax 619-291-0946When evaluating a pregnant woman for work-related risks, areas of concern include exposure to chemicals and heavy metals, physical exertion and stress, exposure to infectious agents, radiation and electromagnetic materials. Many chemicals are associated with adverse pregnancy outcomes such as spontaneous abortions, low birth weight, congenital anomalies and impaired cognitive development. Although important data about chemicals and adverse outcomes may be difficult to obtain, employees can ask for copies of the "Material Safety and Data Sheet" from the employer; companies are required to provide this information. The physician can also contact the appropriate state agency. Interventions may include temporarily changing jobs, reducing the use of hazardous materials or using personal protective equipment.
The American Medical Association's Council of Scientific Affairs has developed guidelines for physical activity and continuation of work during pregnancy. These guidelines assume that the woman is healthy and the pregnancy is uncomplicated. Individualized evaluation of a pregnant worker is essential. Physicians should intervene when a pregnant worker's level of physical activity is excessive. Modification of physical exertion may include special safety training, lighter duty, reduced hours or a temporary job reassignment. Infectious exposures are common, especially among health care, school and institutional workers. Cytomegalovirus, parvovirus, rubella and varicella are the more common viruses that pose a risk to the fetus through maternal transmission. Pregnant workers should be advised to take appropriate precautions such as a transfer to another position or a temporary leave from work if harmful exposure is identified.
Pregnant women should avoid exposure to ionizing radiation and radioactive materials because of the risks of mental deficiency and malignancies in the newborn. Alternative work assignments or adequate protective measures are essential to prevent fetal exposure. Workplace stress and occupational fatigue may cause an increased incidence of preterm birth. Physicians may need to counsel patients on stress reduction and management.
The authors conclude that physicians need to be aware of the possible reproductive risks of pregnant workers in their practices and must be able to identify and quantify these risks and provide appropriate counseling for these patients. Resources for up-to-date information on hazardous exposures in the workplace are listed in the accompanying table. The use of consultants is appropriate in more complex cases.
RICHARD SADOVSKY, M.D.
Feinberg JS, Kelley CR. Pregnant workers. A physician's guide to assessing safe employment. West J Med February 1998;168:86-92.
Initial Evaluation of Melanoma with Chest X-Ray
Patients with stage I and stage II melanoma have a five-year survival rate that approaches 80 percent. Since the other 20 percent of patients have occult distant metastases, initial staging evaluations are often performed, although outcome data in asymptomatic patients are lacking. The most commonly performed procedure following a diagnosis of localized melanoma is chest radiography, because the lung is the most common visceral site for metastases. Terhune and associates retrospectively reviewed the medical records of consecutive asymptomatic patients with localized melanoma to assess the usefulness of an initial staging chest radiograph.
A total of 876 out of 1,032 patients (85 percent) in the study group had undergone an initial staging chest radiograph. Most of the tumors were of the superficial spreading type and occurred on the trunk. Only 5 percent could not be staged because the depth of invasion extended to the deep margins following a shave biopsy or because of misorientation of the biopsy specimen. Five percent of the biopsy samples revealed melanoma in situ, 62 percent showed stage I disease, 25 percent showed stage II disease of less than 4 mm and 5 percent showed stage II disease of 4 mm or more.
A total of 130 patients (15 percent) had a suspicious finding on chest radiograph necessitating further evaluation such as a repeat chest radiograph or a computed tomographic (CT) scan of the chest. In 35 patients, a combination of these modes was required to confirm the diagnosis. A total of 128 patients had no evidence of lung metastases. Only one patient underwent additional studies that suggested the presence of metastases. Subsequent histology revealed metastatic melanoma.
Silent pulmonary metastasis was found in only one patient. No metastatic lung disease was detected in cases of melanoma in situ and stage I disease, while lung metastasis was found in one of 258 patients with stage II disease. The frequency of false-positive results was 15 percent. Of the group for whom long-term follow-up data were available, 30 patients developed lung metastases and two developed a primary lung cancer. Seventeen cases of lung metastases occurred in patients with initial negative findings on chest radiograph, and five occurred in patients with initial suspicious findings on chest radiograph. This suggests that lung metastases occur more frequently in patients with suspicious false-positive radiographs. The authors suggest that these metastases were probably present at initial diagnosis and were not detected because of the limitations of chest radiography.
The authors conclude that initial chest radiographic screening in asymptomatic patients with stage I and intermediate-thickness stage II melanoma is highly unlikely to detect silent pulmonary metastases. In addition, the high false-positive rate can lead to costly subsequent investigations. The authors stress the importance of a thorough medical history and physical examination in the initial assessment of patients with cutaneous melanoma.
BARBARA APGAR, M.D., M.S.
Terhune MH, et al. Use of chest radiography in the initial evaluation of patients with localized melanoma. Arch Dermatol May 1998;134:569-72.
Antiretroviral Prophylaxis After Recent Sexual Exposure to HIV
Evidence confirming the value of postexposure antiretroviral therapy in reducing the risk of occupationally acquired human immunodeficiency virus (HIV) infection has led to recommendations that prophylaxis be considered in persons with a recent sexual exposure to HIV. Katz and Gerberding discuss the use of antiretroviral prophylaxis after recent sexual exposure to HIV.
The authors note that no direct evidence points to prevention of HIV infection with antiretroviral therapy after sexual exposure, but they believe prevention is biologically plausible, given the similarities between the immune responses to transcutaneous and transmucosal exposures. They state that primary care physicians must be prepared to evaluate, treat and counsel patients with a recent sexual exposure to HIV. On the initial visit, the physician must (1) identify persons who may be candidates for postexposure prophylaxis and offer antiretroviral treatment, (2) perform HIV antibody testing to identify already existing infection and (3) intervene to prevent future transmission of HIV. Potential candidates for prophylaxis include persons who have engaged in unprotected anal or vaginal intercourse with a partner who is likely to be HIV infected, although the average risk may not apply to a specific encounter because of variation in source and host factors. HIV infection may result from a few contacts or may not occur despite many contacts.
Testing for HIV infection is appropriate but immediate initiation of prophylaxis should not be delayed. Patients found to be HIV positive at baseline should be prescribed an appropriate drug regimen for primary or longstanding HIV infection. If the partner is willing to be tested, this should be done. Antiretroviral prophylaxis can be stopped if the partner's test results are negative. If the partner is infected, viral load quantitation can help determine the likelihood of HIV transmission, which is increased in persons with advanced disease and higher viral loads.
Postexposure prophylaxis should be initiated within 72 hours of exposure. The treatment regimen should be modeled after the one used for occupational exposures. Some HIV experts recommend triple therapy for prophylaxis after sexual exposure, but the authors believe that a single drug may be adequate to counter the very small viral inoculum present immediately after sexual exposure. All patients with sexual exposure to HIV should be tested for other sexually transmitted diseases.
Counseling the patient about ways to reduce the risk of HIV exposure is appropriate. During follow-up visits, adverse reactions to drug therapy should be monitored, and HIV antibody testing should be repeated at six weeks, three months and six months. The symptoms of acute HIV seroconversion warrant prompt treatment.
The authors state that public health messages that emphasize the use of condoms and the avoidance of high-risk behaviors are the most effective ways of preventing HIV infection. Postexposure treatment is only a back-up method. However, the availability of postexposure prophylaxis may motivate patients to seek medical care, providing an opportunity to counsel and educate them about prevention.
RICHARD SADOVSKY, M.D.
Katz MH, Gerberding JL. The care of persons with recent sexual exposure to HIV. Ann Intern Med February 15, 1998;128:306-12.
Prevention of High-Altitude Headache with Aspirin
Approximately 20 to 50 percent of skiers and mountaineers report headache at altitudes of 3,000 to 5,000 m (10,000 to 16,500 ft). Burtscher and colleagues conducted a double-blind study to evaluate the ability of aspirin to prevent altitude-related headache in volunteers traveling to high altitudes.
Twenty-nine volunteers with a history of altitude-related headache were randomly assigned to receive 320 mg of aspirin or an identical placebo every four hours, starting one hour before arrival at high altitude and continuing for 12 hours. Headache (measured on a four-point scale), heart rate, blood pressure and arterial oxygen saturation were measured one hour before and three, seven, 10 and 19 hours after arrival at high altitude. Gas exchange, heart rate and oxygen saturation were also assessed at low altitude and within five hours of arrival at high altitude, using a two-minute step-exercise program.
Only one of the volunteers who received aspirin developed headache at high altitude. Headache occurred in seven of the volunteers in the placebo group. This difference was statistically significant. The mean oxygen saturation did not differ between the treated and placebo groups, but individual values were predictive of the development of headache. Patients who received aspirin developed headache at lower oxygen saturations than did those who received placebo.
The authors conclude that aspirin prevents high-altitude headache without improving oxygenation. Aspirin appeared to raise the threshold for headache by improving the person's tolerance to lower oxygen saturation. They suggest that aspirin may enhance adaptation to high altitude by reducing sympathetic activity mediated by prostaglandins.
ANNE D. WALLING, M.D.
Burtscher M, et al. Aspirin for prophylaxis against headache at high altitudes: randomised, double blind, placebo controlled trial. BMJ April 4, 1998;316:1057-8.
Sibutramine Not Advised for Treatment of Obesity
Sibutramine hydrochloride monohydrate, a schedule IV controlled substance that is structurally related to amphetamine, has been approved by the U.S. Food and Drug Administration for the treatment of obesity. Medical Letter consultants reviewed current information about this new drug.
Sibutramine inhibits the reuptake of norepinephrine, serotonin and dopamine. Through this mechanism, concentrations of neurotransmitters are increased in the brain. The drug is rapidly absorbed from the gastrointestinal tract and is almost completely metabolized on its first pass through the liver. The active metabolites reach a peak concentration in serum in three to four hours, are primarily excreted in urine and partly in feces, and have a half-life of 14 to 16 hours. Results of an unpublished multicenter double-blind trial that placed 1,047 obese patients on a restricted-calorie diet demonstrated that patients taking placebo lost 0.9 kg. Patients taking 1-, 5-, 10-, 15-, 20- and 30-mg doses of sibutramine daily during the 24-week trial lost 1.8, 3.1, 4.4, 5.3, 5.8 and 6.5 kg, respectively. In other year-long unpublished studies, weight reduction reached a maximum by six months and was more or less maintained for another six months, with some regains by the end of one year.
The most common side effects of sibutramine were dry mouth, headache, insomnia and constipation. The drug caused dose-related increases in heart rate and blood pressure, some of which were clinically significant. No echocardiographic heart valve abnormalities were reported such as those that led to the removal of fenfluramine and dexfenfluramine from the market. Also, none of the patients developed pulmonary hypertension. Ketoconazole and erythromycin can increase serum concentrations of sibutramine, but the clinical significance of these elevations is unknown. Sibutramine should not be used with other serotonergic drugs including selective serotonin reuptake inhibitors, serotonin agonists for migraine, lithium, meperidine, fentanyl or dextromethorphan, or within two weeks of therapy with a monoamine oxidase inhibitor. The manufacturer states that the initial dosage of sibutramine, 10 mg daily, can be increased in four weeks to 15 mg daily if blood pressure and heart rate are stable. Sibutramine is available in 5-, 10- and 15-mg tablets; a 30-day supply of 15-mg tablets would cost a pharmacist about $113.
Medical Letter consultants advise against using sibutramine, although limited unpublished data indicate that it is modestly effective in reducing weight for six months. Dose-related increases in blood pressure and heart rate levels can occur, and long-term safety is unknown.
BARBARA APGAR, M.D., M.S.
Medical Letter consultants. Sibutramine for obesity. Med Lett Drugs Ther March 13, 1998;40(1022):32.
Using Inhaled Corticosteroids for Treatment of Patients with COPD
Because airway inflammation is associated with chronic obstructive pulmonary disease (COPD), corticosteroids could provide effective therapy. However, short-term trials of inhaled corticosteroids in patients with COPD have shown little effect on airway hyperresponsiveness or forced expiratory volume in one second (FEV1). Longer-term corticosteroid therapy has shown some beneficial effects on pulmonary function. Paggiaro and colleagues conducted a randomized, placebo-controlled multicenter trial to study the efficacy and safety of inhaled fluticasone propionate in patients with COPD.
A total of 281 patients with COPD were enrolled in the study. Patients were included in the study if they were current or former smokers, had experienced cough and excess sputum production for at least three months' duration in at least two consecutive years, had at least one exacerbation annually for the previous three years and were likely to have an exacerbation during the six-month treatment period. After a run-in period during which baseline symptoms were recorded, patients were randomly assigned to treatment with either two puffs of fluticasone propionate twice daily (1,000 mg daily) or placebo. The two groups of patients were matched for age, sex, smoking history, pulmonary function and severity of COPD. Assessment of treatment efficacy was performed after four, eight, 16 and 24 weeks of therapy. Patients were allowed to take short-acting beta agonists as required for relief of symptoms, and other medications, such as anticholinergics and xanthine derivatives, throughout the study without dosage changes.
Of the 142 patients initially assigned to the treatment group, 19 (13 percent) subsequently withdrew from the study because of adverse events (nine patients), treatment failure (four patients) or other reasons (six patients). Twenty-seven of the 139 patients (19 percent) initially assigned to the placebo group withdrew because of adverse events (16 patients), noncompliance or failure to return (four patients), treatment failure (one patient) or other reasons (six patients).
During the study period, at least one exacerbation occurred in 51 patients (37 percent) in the placebo group and in 45 patients (32 percent) in the treatment group. Although the total number of exacerbations was not significantly different in the two groups, patients who received fluticasone had significantly fewer exacerbations of a moderate or severe degree. Of the 51 patients in the placebo group who had exacerbations, 44 (86 percent) had moderate or severe exacerbations. In contrast, exacerbations were moderate or severe in 27 (60 percent) of the 45 patients experiencing exacerbations in the treatment group.
Compared with the placebo group, patients who received fluticasone showed significantly greater improvement in symptoms, peak expiratory flow rate, forced vital capacity, FEV1 and mid-expiratory flow rate. The patients in the treatment group also showed a significant increase in the distance they could walk for six minutes. After six months of treatment, the mean change in distance was 27 m in the treatment group and 8 m in the placebo group.
Patients who responded to inhaled fluticasone tended to be those with a longer duration of COPD; however, no other variables appeared to predict which patients would respond. Adverse effects were reported by a comparable proportion of patients in each group and were predominantly associated with COPD and respiratory infections. Few patients reported side effects attributable to steroids, such as hoarseness, dysphonia and candidiasis.
The authors conclude that six months of treatment with inhaled fluticasone propionate appears to be safe and effective in patients with COPD. The findings suggest that this therapy may improve pulmonary function but may not necessarily reduce the number of exacerbations in patients with long-established disease.
ANNE D. WALLING, M.D.
Paggiaro PL, et al. Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. Lancet March 14, 1998;351:773-80.
Metformin and Troglitazone for Type 2 Diabetes Mellitus
Until recently, the only treatments available in the United States for patients with type 2 diabetes were insulin or the sulfonylureas. Several new oral agents have been approved by the U.S. Food and Drug Administration, including metformin, troglitazone and alpha-glucosidase inhibitors such as acarbose. The advantage of these new products is that they have different mechanisms of action that help to reduce blood sugar levels. Inzucchi and colleagues evaluated the efficacy and physiologic effects of a combination of metformin and troglitazone in the treatment of type 2 diabetes.
Twenty-nine patients with type 2 diabetes were enrolled in this study. The patients had a mean age of 53 years, had had diabetes for an average of five years, had a mean body mass index of 33.8 and a mean glycosylated hemoglobin level of 9.5 percent. The patients underwent a drug washout period of two weeks. They were then randomly assigned to receive 1,000 mg of metformin twice daily or 400 mg of troglitazone once daily. Plasma glucose and glycosylated hemoglobin levels were measured at baseline and monthly thereafter. Routine hematologic and chemistry studies were also obtained. After three months, patients were given a combination of the originally assigned drug and the second oral agent. Monthly monitoring continued. The study participants were prescribed a special diet consisting of 50 percent carbohydrate, 34 percent fat and 16 percent protein.
After the first three months, the metformin group had a mean reduction in fasting plasma glucose levels of 58 mg per dL (3.20 mmol per L) and the troglitazone group had a mean reduction of 54 mg per dL (3.00 mmol per L). With the addition of the second drug, there was an additional mean reduction of 41 mg per dL (2.25 mmol per L) in the fasting plasma glucose levels. The total mean decrease for all patients during the six-month study period was 98 mg per dL (5.45 mmol per L), a 35 percent reduction from baseline. The mean glycosylated hemoglobin levels decreased 1.2 percent from month three to month six. There were no significant changes in body weight with either monotherapy or combination therapy. No adverse events were recorded in either study group, including increases in serum lactate levels or abnormalities in liver function tests. One patient developed diarrhea.
The authors conclude that metformin and troglitazone are equally effective in lowering plasma glucose concentrations in patients with type 2 diabetes. In addition, when used in combination, the two drugs are additive in their ability to help patients achieve better glycemic control.
JEFFREY T. KIRCHNER, D.O.
Inzucchi SE, et al. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med March 26, 1998;338:867-72.
EDITOR'S NOTE: Despite some of the hepatic problems recently attributed to troglitazone therapy, it is the opinion of many diabetologists that this agent alone (with or without metformin) should become the therapy of choice in most patients with type 2 diabetes. Historically, most physicians have first prescribed a sulfonylurea for these patients and switched to insulin when sulfonylureas failed. The problem with sulfonylureas is that they work by increasing endogenous insulin production. This may result in symptomatic hypoglycemia and also tends to result in weight gain. Hyperinsulinemia is also now thought to accelerate atherogenesis, and some older data have suggested that sulfonylurea therapy resulted in an increase in cardiovascular deaths. I believe that, once more clinical experience with the newer oral agents has been gained, the sulfonylureas will become third- or fourth-line drugs in the treatment of type 2 diabetes.
--J.T.K.
Meta-Analysis of Prednisone for Rheumatoid Arthritis
Although corticosteroids are effective in the treatment of rheumatoid arthritis, concerns about their safety have limited their use to intermittent therapy for acute exacerbations. Gøtzsche and Johansen conducted a meta-analysis of randomized trials of oral prednisone in the treatment of rheumatoid arthritis to compare the short-term efficacy of oral prednisone with that of nonsteroidal anti-inflammatory drugs (NSAIDs) and placebo.
Data were gathered from all trials published since 1966 in which low-dose prednisone (up to 15 mg daily) was compared with NSAIDs or placebo in the treatment of rheumatoid arthritis. Of the 28 randomized trials, 10 studies were included in the meta-analysis. The 10 studies included predominantly women (mean age: 55 years) with rheumatoid arthritis of approximately six years' duration. Most of the studies used the criteria established by the American Rheumatism Association for the disease and tended to involve patients with severe joint disease as assessed by the number of tender joints. All but one of the studies were double blind, and eight used a crossover design.
Data from these studies revealed that prednisone was significantly better than placebo in relieving joint tenderness, reducing pain and improving grip strength. Prednisone was also significantly better than NSAIDs in producing relief of pain and tenderness. Although prednisone was superior to NSAID therapy in improving grip strength, the difference in grip strength between patients treated with steroids and those treated with NSAIDs was not statistically significant.
The trials provided limited information on adverse effects. Five of the studies did not report on side effects, and one study reported that no side effects occurred. Of the remaining four studies, one reported "subjective reactions" in two patients, one reported acute psychosis in one patient, and two studies found no side effects with short-term therapy.
The authors conclude that low-dose prednisone therapy may be used intermittently in patients with rheumatoid arthritis.
ANNE D. WALLING, M.D.
Gotzsche PC, Johansen HK. Meta-analysis of short term low dose prednisolone versus placebo and non-steroidal anti-inflammatory drugs in rheumatoid arthritis. BMJ March 14, 1998;316:811-8.
Oral Contraceptive Use and Risk of Cardiovascular Disease
Oral contraceptives that contained more than 50 mg of estrogen were withdrawn from the market in the United States in 1989. The newer oral contraceptives have one fourth of the estrogen and one tenth of the progestogen of the original combination agents. The newer progestogens (desogestrel, gestodene and norgestimate) have fewer androgenic metabolic effects, do not adversely affect lipid levels and may be associated with a lower risk for cardiovascular disease. Chasan-Taber and Stampfer reviewed the epidemiologic studies of oral contraceptives and cardiovascular disease performed between 1967 and mid-1997, paying special attention to preparations that contain less than 50 mg of estrogen.
Case-control and cohort studies suggest that much of the excess risk for myocardial infarction in current users of oral contraceptives is attributable to cigarette smoking. Two separate studies showed that the relative risk of myocardial infarction was 39 and 30 in women who smoked 25 or more cigarettes daily and used oral contraceptives. This risk was four to eight times greater than the risk associated with smoking alone. Studies suggest that current users of oral contraceptives who are younger than 40 years and do not smoke have little or no increased risk for myocardial infarction. Data on the oral contraceptives that contain the newest progestogens are incomplete but suggest a lower relative risk for myocardial infarction than that associated with the earlier preparations. The data are sparse, however, and are based on fewer than 10 exposed cases. Data from epidemiologic studies consistently show that past use of oral contraceptives is not associated with an increased risk of myocardial infarction.
The authors note that previous studies of stroke (hemorrhagic and ischemic) in women using oral contraceptives often combined users of high- and low-dose formulations, which inflated the overall relative risks. Several studies suggest a positive interaction between oral contraceptive use, smoking and the risk of stroke. No studies suggest an increased risk for stroke among past users of oral contraceptives, with the exception of smokers. The studies in current users are inconsistent but probably demonstrate no increased risk for hemorrhagic stroke among women who use low-dose contraceptives and do not have risk factors. Studies of low-dose oral contraceptives indicate that these agents produce little increase in the risk for ischemic stroke, but the authors note that a two- to threefold increase in risk cannot be excluded.
Recent studies point to a potentially increased risk of thromboembolic disease with the newer progestogens. However, confounding variables and bias may account for some of the differences in the incidence of venous thromboembolism. Women who are carriers for the factor V Leiden mutation have been shown to have a sevenfold increase in thrombosis as compared with noncarriers. This observation suggests that the newest progestogens may be associated with a prothrombotic state similar to that induced by factor V Leiden.
The authors conclude that current use of oral contraceptives by women who do not smoke does not seem to increase the risk for myocardial infarction. The information about stroke risk is less definitive. There may be a small to moderate increase in the risk for ischemic stroke. The risk for thromboembolic disease may be modestly higher among users of preparations containing the newest progestogens than among users of other oral contraceptives. Clearly, the current preparations, including those with the newer progestogens, are associated with a lower risk for cardiovascular disease relative to the risk associated with the older, high-dose estrogen contraceptives and the risk associated with full-term pregnancy. Since cardiovascular disease among oral contraceptive users occurs mainly in those who smoke, smoking cessation should be strongly encouraged in women who use oral contraceptives.
RICHARD SADOVSKY, M.D.
Chasan-Taber L, Stampfer MJ. Epidemiology of oral contraceptives and cardiovascular disease. Ann Intern Med March 15, 1998;128:467-77.
"Tips from Other Journals" are written by the medical editors of American Family Physician.
Copyright © 1998 by the American Academy of Family Physicians.
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