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Outcomes in Patients With Primary Raynaud Phenomenon
Reversible vasospasm of the extremities occurs as an isolated symptom in the absence of underlying disease (primary Raynaud phenomenon) or in association with other disorders (secondary Raynaud phenomenon). It has been reported that Raynaud phenomenon is associated with connective tissue diseases, but the frequency and types of diseases that eventually develop are not well established. Spencer-Green conducted a systematic literature search to assess the rates and predictors of transition to secondary disease after a primary diagnosis of Raynaud phenomenon.
A total of 639 patients with primary Raynaud phenomenon were identified from 10 studies. The average length of study follow-up was four years. The average duration of Raynaud phenomenon in the study subjects was 12.3 years. During follow-up, 12.6 percent (81 patients) developed a secondary disorder. Eighty of these cases were connective tissue diseases. Two thirds of the cases of connective tissue disease were attributed to systemic sclerosis. Systemic lupus erythematosus, rheumatoid arthritis or mixed connective tissue disease each occurred in fewer than nine patients.
Transitions to specific connective tissue diseases were infrequent, occurring at a mean rate of 3.2 per 100 patient-years of observation. The mean time from onset of Raynaud phenomenon until development of systemic sclerosis was 10.1 years in patients who developed the disorder. This was no different from the development time for any other secondary disorder. The detailed analysis noted that the best predictor of transition from primary to secondary disease was an abnormal nailfold capillary pattern (positive predictive value: 47 percent). Antinuclear antibody levels in the study subjects had a positive predictive value of only 30 percent. Other diagnostic features such as pulmonary function, presence of digital ulcers and esophageal dysfunction were not statistically predictive of transition.
The author concludes that the analysis was limited by variable entry criteria of diagnostic clinical findings and substantial variation in rates of transition to secondary disease. Despite these limitations, the author notes that, in a clinical practice, the rate and frequency with which secondary connective tissue diseases develop in patients with primary Raynaud phenomenon are low. The best predictor of transition to secondary disease is the presence of abnormalities of the nailfold capillary bed.
BARBARA APGAR, M.D., M.S.
Spencer-Green G. Outcomes in primary Raynaud phenomenon. A meta-analysis of the frequency, rates, and predictors of transition to secondary diseases. Arch Intern Med March 23, 1998;158:595-600.
Incidence and Risk Factors of Clostridium difficile Colitis
Clostridium difficile colitis is often a hospital-acquired infection that produces discomfort and, occasionally, severe illness in patients with unrelated medical or surgical conditions. The spectrum of disease ranges from asymptomatic colonization to fulminant, life-threatening infection. The mildest form presents without pseudomembranous formation, producing diarrhea and mild abdominal discomfort. More severe colitis involves profuse diarrhea, abdominal pain, distention, fever and an elevated white blood cell count. Occasionally, patients develop fulminant toxic colitis that may result in death. Risk factors for development of C. difficile colitis include transfer from a nursing home, increased age, renal failure, chemotherapy and antibiotic therapy. Environmental contamination remains the primary cause. Kent and associates performed a prospective study to evaluate the incidence, risk factors and clinical course of C. difficile colitis in patients admitted to a surgical service.
Over a five-month period, 374 patients were prospectively evaluated for symptomatic C. difficile colitis. Patients found to have C. difficile colitis as the reason for admission were excluded, as were patients who would be in the hospital for fewer than two days. Rectal cultures were obtained, and all patients had a thorough history and abdominal examination.
Twenty-one patients developed symptomatic C. difficile colitis, with no clustering of cases. Ten patients had diarrhea without systemic illness, 10 patients had diarrhea accompanied by fever, abdominal pain or distention, and one patient developed toxic colitis. Stool softeners appeared to protect against the development of C. difficile colitis, but the association was not statistically significant. Three variables were identified as independently increasing the risk of developing C. difficile colitis: (1) admission from a nursing home or rehabilitation center, (2) use of the antibiotic cefoxitin and (3) an operative procedure for bowel obstruction.
The authors conclude that the 5.6 percent incidence of symptomatic C. difficile infection in these patients compares with the range of 2.3 to 7.8 percent noted in other studies. Cefoxitin, a prophylactic antibiotic commonly used before surgical procedures, was associated with the infection. Intestinal operations were associated with the greatest frequency of infections, especially colectomy and surgery for acute large- or small-bowel obstruction. Functional and mechanical intestinal obstruction appears to predispose patients to the development of C. difficile colitis. Treatment should be withheld in postoperative patients who have mild to moderate symptoms until a positive cytotoxin titer is obtained. Empiric treatment is appropriate when symptoms suggest a severe form of C. difficile colitis.
RICHARD SADOVSKY, M.D.
Kent KC, et al. The impact of Clostridium difficile on a surgical service. Ann Surg February 1998;227:296-301.
Two New Treatments for Male Androgenetic Alopecia
The U.S. Food and Drug Administration (FDA) recently approved two new formulations of drugs for the treatment of male androgenetic alopecia: finasteride (1 mg) for oral treatment of male pattern baldness and minoxidil (5 percent), a topical solution for over-the-counter use. A lower strength of topical minoxidil (2 percent) is currently marketed for use in both men and women. Consultants for The Medical Letter on Drugs and Therapeutics reviewed the data on the new formulations.
Finasteride is a specific inhibitor of type II 5*-reductase, preventing the conversion of testosterone to a more potent metabolite, dihydrotestosterone. It is known that male pseudohermaphrodites with genetic deficiency of 5*-reductase do not lose their hair. After a 1-mg dose of finasteride, serum concentrations of dihydrotestosterone decrease by 65 percent within 24 hours. Finasteride is well absorbed and has a half-life of five to six hours. The 5-mg tablets have been reported to cause erectile dysfunction, gynecomastia, severe myopathy and loss of libido in older men. Adverse events are reduced with the 1-mg tablets.
Because of teratogenic effects in animals, women of reproductive age are warned not to handle crushed or broken tablets. To date, no clinical studies of finasteride for treatment of hair loss have been published, although the results of three double-blind trials have been presented as abstracts. In two studies, 1,553 men with male pattern baldness took 1 mg of finasteride or placebo for one year. After one year, men taking the active drug had an average of 107 more hairs (a 12 percent increase) in a one-inch diameter circle on the scalp than did those who took placebo. Hair counts were maintained up to 24 months in the men who continued active drug therapy. In the other study of 326 men, those who took finasteride had significantly higher hair counts in the frontal area. However, 30 percent of the men taking placebo said they believed their appearance had improved.
Although its mechanism is not completely understood, minoxidil appears to have a direct effect on hair follicles, which increase in size with treatment. Serum concentrations are much lower after topical application than with use of oral minoxidil. Four unpublished studies presented to the FDA compared preparations of 2 percent and 5 percent minoxidil with placebo. The studies in women found no difference in net hair gain between the two active drugs. In men, new hairs increased by five per cm2 in the placebo group, 30 per cm2 with 2 percent minoxidil and 39 per cm2 with 5 percent minoxidil. When the drug therapy was stopped, the newly regrown hairs were shed. In one double-blind study, topical use of 2 percent minoxidil caused significant increases in left-ventricular end-diastolic volume, cardiac output and left ventricular mass. No studies on the safety of 5 percent minoxidil have been published. Local reactions such as erythema have been reported. Oral minoxidil is associated with hypertrichosis of the fetus and multiple congenital anomalies.
A one-month supply of finasteride in 1-mg tablets costs the pharmacist $46.88. The 5-mg tablets cost $63.23. A one-month supply (60 mL) of 2 percent minoxidil costs the pharmacist $22.56. Generic formulations of the same drug cost an average of $10.82. Five percent minoxidil costs $28.32 for 60 mL.
Medical Letter consultants conclude that both 5 percent minoxidil topical solution and 1 mg oral finasteride can produce a modest increase in hair in young men with mild to moderate hair loss, but both medications must be continued indefinitely to maintain the effect. The long-term safety of either formulation has not been determined. The slight difference in new hair growth between the old 2 percent minoxidil solution and the new 5 percent minoxidil solution does not justify the higher cost and the increased risk of adverse events.
BARBARA APGAR, M.D., M.S.
Medical Letter consultants. Propecia and Rogaine Extra Strength for alopecia. Med Lett Drugs Ther February 27, 1998;40(1021):25-7.
Exercises Reduce Incontinence During and After Pregnancy
Vaginal birth is believed to be a major etiologic factor in urinary incontinence in women. Pelvic muscle exercises have been shown to decrease urine loss in nonpregnant women with incontinence, but data on pregnant women have not been adequately addressed. Sampselle and colleagues studied the effect of a program of pelvic muscle exercises on incontinence symptoms and pelvic muscle strength up to one year post delivery.
The authors studied primiparous patients with no history of incontinence. At 20 weeks of gestation, 34 expectant mothers were randomly assigned to a treatment group that received standardized instruction in pelvic muscle exercises; 38 women were assigned to the control group. Data on urinary incontinence and pelvic muscle strength were collected at 20 and 35 weeks of gestation and at six weeks, six months and 12 months postpartum in both groups.
The two groups were comparable at baseline in terms of age, level of education, symptoms of urinary incontinence and maximum voluntary contraction force. By 35 weeks of gestation, the treatment group demonstrated significantly less urinary incontinence. These differences were also measured in late pregnancy and at six months postpartum. At one year following birth, the differences between the groups had disappeared. Adherence to the exercise program at least 75 percent of the time was reported by 85 percent of the treatment group at 35 weeks of gestation. Adherence ranged from 62 to 90 percent during the postpartum year.
The authors conclude that pelvic muscle exercises reduce symptoms of urinary incontinence in late pregnancy and up to six months postpartum. They speculate that the exercise group experienced more rapid rehabilitation because of improved muscle tone and functional reserve. The authors recommend that women who are pregnant or who are planning an eventual pregnancy be offered instruction in pelvic muscle exercises, particularly those in whom pelvic muscle weakness is detected.
ANNE D. WALLING, M.D.
Sampselle CM, et al. Effect of pelvic muscle exercise on transient incontinence during pregnancy and after birth. Obstet Gynecol March 1998;91:406-12.
Significance of Asymptomatic Carotid Bruits in the Elderly
Although auscultation for carotid bruits is easily performed and noninvasive, its utility for identifying asymptomatic elderly patients at high risk for stroke is not known. Shorr and colleagues retrospectively studied the association between asymptomatic carotid bruits and stroke in elderly patients with isolated systolic hypertension.
The study group consisted of 4,442 participants in the Systolic Hypertension in the Elderly Program who were followed for an average of 4.5 years. Patients were excluded if they had a history of stroke with resultant paresis, transient ischemic attack plus carotid bruit, two transient ischemic attacks in the same distribution, atrial fibrillation or flutter, or if they took insulin, lived in a nursing home or were diagnosed with dementia. The presence of carotid bruits was noted on the physical examination. Medical records were reviewed to determine whether patients developed symptoms of transient ischemic attack or stroke. If these symptoms were present, type and location were noted.
Carotid bruits were found in 284 patients and were more common in older and nonwhite patients. Patients with bruits tended to have a higher systolic blood pressure and were more likely to be smokers. A total of 231 strokes were identified in 18,488 person-years of follow-up. Twenty-one strokes occurred in the 1,129 person-years of follow-up in patients with carotid bruits. This event rate was 1.86 per 100 person-years, compared with 1.21 for those without bruits. Those with unilateral bruits had an event rate of 2.21, compared with a rate of 1.40 per 100 person-years for those with bilateral bruits. For patients aged 60 to 69 years, there was a trend toward increased stroke risk. However, for patients aged 70 years and older, the presence of carotid bruits was not related to the risk of subsequent stroke.
The authors conclude that carotid bruit is not a useful clinical marker of increased stroke risk. Bruits are, however, a sign of generalized atherosclerosis. Therefore, high-risk management strategies should not be undertaken in elderly patients with isolated systolic hypertension who have asymptomatic bruits.
In an accompanying editorial, Aronson and Landefeld concur that carotid auscultation cannot be recommended in patients who are asymptomatic. Instead, efforts should be made to identify and treat known risk factors for stroke. Such treatment should include anticoagulation in patients with atrial fibrillation, blood pressure control in patients with hypertension and cholesterol lowering with statins in patients with coronary artery disease.
GRACE BROOKE HUFFMAN, M.D.
Shorr RI, et al. The prognostic significance of asymptomatic carotid bruits in the elderly. J Gen Intern Med February 1998;13:86-90, and Aronson L, Landefeld CS. Examining older people for carotid bruits. Listen to your patient, not her neck. J Gen Intern Med February 1998;13:140-1.
Impact of Job Satisfaction on Chronic Low Back Pain
Low back pain is one of the most common workplace injuries in the United States. Progression from acute injury to chronic pain and disability is dependent on a variety of factors. Previous studies have found that various psychosocial factors predispose patients to disability from low back pain. Williams and colleagues assessed the issue of job satisfaction as an independent predictor of low back pain outcomes such as pain, disability and distress.
Patients included in the study were men 18 to 50 years of age who had experienced daily acute low back pain for a period of six to 10 weeks. Patients were admitted to the study if back pain had been their only pain problem and if they were in good health otherwise. Reasons for exclusion included a prior back injury or surgery, major medical illnesses or the use of mood-changing medications. The 82 patients who were eligible for the study were reassessed six months after the injury. Job satisfaction was measured by the Job Descriptive Index, which measures six components of the job: the nature of the work, present pay, opportunities for promotion, supervision, co-workers and overall satisfaction. The modified Work Apgar test was used to obtain a single overall evaluation of job satisfaction. Pain, disability, psychologic distress and orthopedic impairment were also measured.
Patients with disability or chronic low back pain scored below the 25th percentile on their satisfaction with the actual work they performed in their job. They also scored between the 25th and 50th percentiles regarding satisfaction with supervisors and co-workers.
The authors conclude that job satisfaction is a factor in the transition from acute to chronic low back pain and disability. Job satisfaction was associated with better overall clinical outcomes at the end of six months. The type of work or social position had no impact on the outcome of acute low back pain. Interventions that focus on job satisfaction, rather than pain relief, may reduce the likelihood that acute low back pain will progress to chronic low back pain. Intervention could also reduce the number of injuries that result in long-term disability.
KARL MILLER, M.D.
Williams RA, et al. The contribution of job satisfaction to the transition from acute to chronic low back pain. Arch Phys Med Rehabil April 1998;79:366-74.
Identification and Treatment of Kawasaki Disease
Kawasaki disease, also known as mucocutaneous lymph node syndrome, is a multisystem vasculitis that occurs in children. Minimally, it presents with mucocutaneous symptoms and fever, but it also may damage the coronary arteries and result in fatal myocardial infarction. Prompt treatment is imperative. Bradley and Glodé reviewed the identification and treatment of this disease.
The incidence of Kawasaki disease in Japan is about 100 per 100,000 children under five years of age -- about 10 times of that in the United States. In North America, people of Asian and African descent are more likely to be diagnosed with the disease. Patients are usually under 10 years of age, with the peak age of occurrence at one year. The disease is more common and more commonly fatal in boys. Death occurs in about 0.5 percent of patients, most of whom are under three years of age.
The specific etiology of Kawasaki disease is uncertain. The high fevers and evidence of acute phase reactants on laboratory testing indicate an infectious etiology. No single agent has yet been identified. The clinical aspects of this disease mimic those of a toxin-mediated disease, as does the fact that intravenous immune globulin (IVIG), known to have neutralizing antibodies against several bacterial toxins, has improved symptoms in some patients.
Diagnostic Criteria of Kawasaki Disease Diagnosis is established when fever has been present for five or more days; four of the following five symptoms are present; and other diagnoses have been excluded. If coronary aneurysms are documented, only three of the five symptoms are required for diagnosis.
- Erythema, edema or desquamation of the hands and feet.
- Polymorphous rash.
- Conjunctival injection (bilateral, nonexudative).
- Lesions of the mouth; red or cracked lips, strawberry tongue or injected mucosa.
- Cervical lymphadenopathy.
Reprinted with permission from Bradley DJ, Glodé MP. Kawasaki disease. The mystery continues. West J Med 1998;168:24.The criteria for diagnosis are noted in the accompanying table. Fever, a blotchy exanthem, desquamation of the palms of the hands and the soles of the feet, ocular involvement and erythema of the oral mucosa are usually present. Adenitis occurs in two thirds of patients, along with a wide variety of systemic complaints and signs. Sinus tachycardia at rest occurs in most children. The three phases in the course of Kawasaki disease include: (1) the acute phase, consisting of approximately 10 days of fever, oral changes and lymphadenitis; (2) the subacute phase, during which fever and skin manifestations have resolved but irritability and conjunctival injection may continue; and (3) the convalescent phase, beginning at the end of clinical signs and concluding with the resolution of all serum abnormalities.
Characteristic laboratory findings include an elevated leukocyte count with a leftward shift, elevated platelet counts and greatly elevated erythrocyte sedimentation rate and C-reactive protein levels. Sterile pyuria and albuminuria may be noted early in the disease. Subtle electrocardiographic abnormalities may occur, including mild prolonged PR interval, T-wave flattening or inversion, and nonspecific ST segment changes.
Patients are generally admitted to the hospital for management. High-dose aspirin therapy reduces the fever and clinical symptoms and is continued, in reduced dosages, until all laboratory evidence of disease has resolved. IVIG is very helpful in reducing disease symptoms but has side effects, including fever, chills, hypotension and rare episodes of hemolytic anemia. All other treatments are considered investigational at present.
The best known complication of Kawasaki disease is formation of coronary artery aneurysm. Treatment with IVIG reduces the incidence of this complication. Myocardial infarction occurs in less than 0.5 percent of affected children. Other reported cardiac lesions include insufficiency of the aortic and mitral valves, myocardial dysfunction, conduction system inflammation and myocardial fibrosis.
The authors conclude that a definitive diagnostic test and a treatment for cases that are refractory to aspirin and IVIG are needed for Kawasaki disease.
RICHARD SADOVSKY, M.D.
Bradley DJ, Glodé MP. Kawasaki disease. The mystery continues. West J Med January 1998;168:23-9.
Level of Alcohol Intake and Risk of Breast Cancer
Many studies have sought to determine the association between alcohol consumption and the risk of breast cancer in women. Smith-Warner and colleagues analyzed seven prospective studies to assess the relationship between alcohol intake and breast cancer.
The Pooling Project identified studies that had enrolled at least 200 women with breast cancer, assessed dietary intake and contained a validation study of the dietary assessment. Daily intake of alcohol (in grams) was calculated, and the type of alcoholic beverage consumed was recorded.
Alcohol intake ranged from 3.22 to 12.58 g per day among the women who drank alcohol. Nondrinkers accounted for 22.5 to 55.3 percent of the control subjects. Women who drank 30 to 59 g of alcohol per day, on average, were significantly more likely to develop invasive breast cancer (relative risk: 1.41). The relative risk was slightly lower (1.31) for women whose average intake was more than 60 g per day, although this group accounted for less than 1 percent of the women. For an increase in alcohol intake of 10 g per day, the risk of breast cancer increased from 3 to 16 percent (9 percent in the pooled analysis).
The authors conclude that there is a positive association between invasive breast cancer in women and alcohol consumption. The higher risk occurred when the women drank, on average, 2.3 to 4.5 bottles of beer, 2.8 to 5.6 glasses of wine or two to four shots of liquor daily.
GRACE BROOKE HUFFMAN, M.D.
Smith-Warner SA, et al. Alcohol and breast cancer in women. A pooled analysis of cohort studies. JAMA February 18, 1998;279:535-40.
EDITOR'S NOTE: Alcohol consumption is known to have a beneficial effect on cardiovascular disease and overall rates of mortality in women, yet this analysis points out the benefits of moderation and the risk of excess. Finding a modifiable risk factor for breast cancer in women is quite encouraging and provides one more reason to screen patients for excessive alcohol intake.
--G.B.H.
Inherited Bleeding Disorders in Women with Menorrhagia
Menorrhagia is a common complaint that may have several causes, but a specific etiology can be identified in fewer than one half of cases. Kadir and colleagues investigated the role of inherited bleeding disorders in women with menorrhagia.
Women who were referred to a London teaching hospital for treatment of heavy regular menstrual periods were screened for inclusion in the study. Exclusion criteria included diagnosed endocrine or bleeding conditions, use of intrauterine devices and use of certain medications, including anticoagulants, nonsteroidal anti-inflammatory agents (NSAIDs) and oral contraceptives. Before screening, patients underwent physical examination and pelvic ultrasonography. Patients with physical conditions such as fibroid tumors, polyps and ovarian tumors that could contribute to menorrhagia were also excluded from the study. Menorrhagia was confirmed by use of standardized charting of blood loss. In 150 women, activated partial thromboplastin time, factor VIII activity, von Willebrand-factor antigen and activity, and factor XI were measured.
Inherited bleeding disorders were identified in 26 of the study subjects (17 percent). The most common condition was von Willebrand's disease (15 women with mild disease and three with disease of moderate severity). Factor XI deficiency occurred in four patients, and two women had both von Willebrand's disease and factor XI deficiency. Two women had another bleeding disorder.
Women with bleeding disorders were significantly more likely than other patients with menorrhagia to report heavy periods since menarche but had no greater incidence of previous anemia, blood transfusions or family history of bleeding disorders. Women with bleeding disorders also reported a greater incidence of symptoms such as easy bruising, bleeding after tooth extraction, and postpartum and postoperative bleeding (but not of symptoms such as bleeding from the nose or gums) when compared with the patients who did not have bleeding disorders.
The authors conclude that bleeding disorders, especially von Willebrand's disease, may occur in a greater proportion of women with menorrhagia than was previously believed. The diagnosis should be suspected in women with a normal pelvic examination who have experienced menorrhagia since menarche, particularly if additional reports of excessive bleeding are given. The authors encourage screening for bleeding disorders, especially von Willebrand's disease, before invasive investigations or treatments for menorrhagia are performed.
ANNE D. WALLING, M.D.
Kadir RA, et al. Frequency of inherited bleeding disorders in women with menorrhagia. Lancet February 14, 1998;351:485-9.
EDITOR'S NOTE: This study emphasizes the importance of considering the "whole patient" in managing a symptom like menorrhagia. The finding of a bleeding disorder in 17 percent of patients in this study may be high as a result of selection of more severe cases for referral to the teaching hospital and the high proportion of Jewish women (known to have a high prevalence of factor XI deficiency) in the referral population. Nevertheless, correct identification of these cases may prevent treatment failures and unnecessary surgery in women with menorrhagia. Apart from menorrhagia, other symptoms of the disorder(s) may be subtle or nonexistent. Von Willebrand's disease actually refers to a group of conditions that usually have mild symptoms. However, since up to 1.3 percent of the population are affected, most practices undoubtedly include several undiagnosed cases.
--A.D.W.
Comparison of 'Statin' Drugs for Hypercholesterolemia
Treatment goals established by the Adult Treatment Panel of the National Cholesterol Education Program based on an individual's risk factors for coronary artery disease and low density lipoprotein (LDL) levels are as follows: (1) LDL cholesterol level of 100 mg per dL (2.59 mmol per L) or less for patients with coronary artery disease; (2) LDL cholesterol level less than 130 mg per dL (3.37 mmol per L) in patients with two or more risk factors for coronary artery disease; and (3) LDL cholesterol level less than 160 mg per dL (4.14 mmol per L) in patients with less than two risk factors for coronary artery disease. The Adult Treatment Panel of the National Cholesterol Education Program recommends bile acid resins, nicotinic acid and the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors as first-line drug treatments for hypercholesterolemia. Jones and associates compared the efficacy of atorvastatin with other "statin" drugs in patients with hypercholesterolemia.
This study was a multicenter, open-label, randomized, parallel group, eight-week comparative trial of the HMG-CoA reductase inhibitor atorvastatin with equivalent dose strengths of simvastatin, pravastatin, lovastatin and fluvastatin. The full approved range of drug dosages was tested. Patients with severe comorbidities or hypersensitivity to this class of drugs were eliminated from the study. Medications known to affect lipid levels were not permitted during the study. After dietary stabilization, 534 patients were randomly assigned to one of 15 treatment groups representing the full range of accepted dosing for these drugs. Sixteen patients withdrew from the study. Adverse events, serum transaminase levels and creatinine kinase concentrations were recorded.
Atorvastatin, in 10-, 20- and 40-mg doses given once daily produced significantly greater reductions in LDL cholesterol and total cholesterol levels than simvastatin, pravastatin, lovastatin and fluvastatin. The difference was not significant when atorvastatin, in a dosage of 80 mg given once daily, was compared with lovastatin at 40 mg given twice daily. The effects on triglyceride levels were only different at the 40-mg dosage level, when atorvastatin produced a greater reduction. Increases in high density lipoprotein cholesterol levels, ranging from 3.0 to 9.9 percent, were not different among reductase inhibitors except at the 40-mg dosage level, when simvastatin produced significantly greater elevations than atorvastatin. The overall frequency of adverse events was similar among treatment groups, most commonly consisting of myalgia, abdominal pain, diarrhea, flatulence and nausea. There were no instances of serum transaminase or creatine phosphokinase levels elevated persistently more than three times the upper limit of normal.
The authors conclude that atorvastatin, administered in dosages of 10 to 80 mg to patients with primary hypercholesterolemia, lowers LDL cholesterol levels by 35 to 61 percent, establishing it as the most efficacious HMG-CoA reductase inhibitor for lowering LDL cholesterol levels. Clinically significant adverse effects are rare.
RICHARD SADOVSKY, M.D.
Jones P, et al. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholestermia (the CURVES study). Am J Cardiol March 1, 1998;81:582-7.
Vagal Stimulation to Halt Supraventricular Tachycardia
The use of vagal stimulation to halt supraventricular tachycardia is a standard medical therapy. Two methods of vagal stimulation, the Valsalva maneuver and carotid sinus massage, have been used in urgent situations. Lim and associates compared the success rates of these two methods of vagal stimulation in terminating spontaneous supraventricular tachycardia in an emergency department setting.
All patients with supraventricular tachycardia whose rhythm did not reveal obvious atrial flutter, atrial fibrillation or sinus tachycardia and who were hemodynamically stable were randomly assigned to undergo either the Valsalva maneuver or carotid sinus massage. Those who had carotid sinus massage were further randomized to undergo either right or left carotid sinus massage first. If the tachycardia was not terminated by the first method of vagal stimulation, the alternative maneuver was attempted. The Valsalva maneuver was performed by blowing into a mouthpiece with sustained resistance for 30 seconds or more. Carotid sinus massage was performed in the standard manner for 10 seconds with the head tilted to the opposite side. If both methods of vagal stimulation failed, patients were managed with pharmacotherapy or cardioversion. All patients in whom rhythm conversion occurred were monitored by continuous electrocardiography for an additional two hours. If there was no recurrence during the observation period, the patient was discharged with an outpatient appointment.
A total of 148 episodes of supraventricular tachycardia occurred among 126 patients. The success rate as the initial vagal technique was 19.4 percent (12 of 62 patients) for the Valsalva maneuver and 10.5 percent (nine of 86 patients) for carotid sinus massage. The difference was not statistically significant. The success rate with right carotid sinus massage was the same as that for left carotid sinus massage. In some cases, the alternative maneuver was successful when the initial attempt failed. There was no significant difference in success rates between the two techniques as alternative maneuvers.
Three patients whose rhythm converted with the Valsalva maneuver had recurrence during observation. One of the patients whose rhythm converted with carotid sinus massage had recurrence during observation. Reported complications of carotid sinus massage include ventricular fibrillation, monoplegia, hemiplegia and cervicomediastinal hematoma. The only reported complication of the Valsalva maneuver is hypotension from straining.
The authors conclude that vagal maneuvers are safe and efficacious in ending about 25 percent of spontaneous supraventricular tachycardias if performed properly. Some evidence indicates that the Valsalva maneuver is more efficacious in men and that carotid sinus massage is more efficacious in older patients.
RICHARD SADOVSKY, M.D.
Lim SH, et al. Comparison of treatment of supraventricular tachycardia by Valsalva maneuver and carotid sinus massage. Ann Emerg Med January 1998;31:30-5.
Raloxifene for Treatment of Postmenopausal Osteoporosis
Raloxifene, recently labeled by the U.S. Food and Drug Administration for prevention of postmenopausal osteoporosis, is a benzothiophene that acts on estrogen receptors. Previously, only estrogen and alendronate were labeled for this. Consultants for The Medical Letter on Drugs and Therapeutics reviewed the data on raloxifene, a selective estrogen receptor modulator that is similar to tamoxifen.
Tamoxifen acts as an estrogen agonist in bone and as an estrogen antagonist in the breast, but because of its partial estrogen agonist function in the uterus, its use increases the risk of endometrial cancer. Raloxifene, by comparison, has an estrogen agonist effect on bone and antagonist effect on the breast and the uterus. A double-blind study of 601 postmenopausal women compared the effect of 30, 60 or 150 mg of raloxifene with that of placebo. All of the women in the study also took elemental calcium daily.
Bone density in the lumbar spine, hip and femoral neck decreased in the women who took placebo and increased with all doses of raloxifene. Endometrial thickness measured by sonography remained the same for all study groups. Levels of low-density lipoprotein cholesterol decreased more in women taking raloxifene.
Previous comparisons have shown that raloxifene is slightly less effective in reducing bone loss in the hip than estrogen plus a progestin, or alendronate, and its effect on the lumbar spine is about one half that of older drugs. No direct comparisons with other drugs are available. Raloxifene is excreted almost entirely in the feces, and about 60 percent of the drug is absorbed when taken orally. Cholestyramine decreases the absorption of raloxifene by 60 percent, thus the manufacturer recommends that the two drugs be taken two hours apart. Raloxifene decreases the effect of warfarin. Hot flashes and leg cramps may occur. Like estrogen, raloxifene increases the risk of venous thromboembolism. Because it is a known teratogen, pregnant women should not take raloxifene.
In short-term studies, raloxifene has not been shown to increase the incidence of cancer. Raloxifene is available in 60-mg tablets and is taken once daily without regard to meals. A 30-tablet bottle costs the pharmacist $59.40.
The Medical Letter consultants advise, based on data from one short-term study, that raloxifene may be effective in preventing postmenopausal bone loss without increasing the risk of breast or uterine cancer. Long-term studies are needed to determine the safety and effectiveness of raloxifene.
BARBARA APGAR, M.D., M.S.
Medical Letter consultants. Raloxifene for postmenopausal osteoporosis. Med Lett Drugs Ther March 13, 1998;40:29-30.
EDITOR'S NOTE: The beneficial effect of estrogen in reducing bone loss and decreasing the incidence of spine and hip fractures is well documented. Based on currently available data, it is not clear if raloxifene will have the same effect. With the intense interest in this drug, long-term studies are needed to determine if breast stimulation and subsequent breast cancer are decreased.
--B.A.
Increase in Drug Abuse Among U.S. Adolescents
Substance abuse in U.S. adolescents is known to be associated with increased morbidity and mortality. In addition, illicit drug use has been linked to an increase in school dropout rates and the incidence of sexually transmitted diseases, including human immunodeficiency virus (HIV) infection. After a decline in the late 1980s and 1990s, adolescent drug use has apparently increased over the past few years. Brasseux and associates at the Children's National Medical Center in Washington, D.C. performed a 12-month study to determine the prevalence of drug use in adolescents attending their urban health clinic.
Adolescents from 12 to 21 years of age who presented for routine health care were included in the study. Urine specimens obtained from the patients were anonymously screened for the presence of five drugs: cannabinoids, cocaine, amphetamines, opiates and phencyclidine (PCP). All specimens that tested positive by immunoassay were sent to a reference lab for gas chromatography/mass spectrometry confirmation testing.
From April 1995 to March 1996, 1,313 patients (428 males, 885 females) were seen at the clinic. The mean age was 16 years. A total of 179 patients (14 percent) tested positive for one or more drugs. Of these, 166 tested positive for cannabinoids. Males were more likely to test positive for at least one drug (18 percent) than females (11 percent). Grouped by age, the highest overall use was among 18- to 21-year-olds, followed by 15- to 17-year-olds and then 12- to 14-year-olds. In a similar study of 1,312 adolescents tested from 1989 to 1990 for the presence of four drugs, only 5 percent had positive urine drug tests. There was a consistent increase in drug use, and cannabinoids in particular, in the more recent cohort. There was a decrease in cocaine use.
The authors conclude from their study that there has been a definite increase in drug use among adolescents seen at their clinic. The upward trend in marijuana use is consistent with drug-use trends reported by other national surveys. The results of this study are more significant in that most other data are from self-reported use, which may underestimate the prevalence of drug use. A particularly rapid rise in drug use among younger adolescents (from 12 to 17 years of age) was noted, with a greater than fourfold increase in drugs identified in the urine. The authors point out that physicians need to be aware that drug-use patterns may shift rather abruptly among adolescents, and counseling should focus on specific trends. Moreover, they believe that early interventions to discourage drug use and other risk behaviors must begin in elementary school.
JEFFREY T. KIRCHNER, D.O.
Brasseux C, et al. The changing pattern of substance abuse in urban adolescents. Arch Pediatr Adolesc Med March 1998;152:234-7.
Amlodipine or Diltiazem with Atenolol for Angina
Angina symptoms that are not resolved with beta-blocker therapy may be relieved with the addition of amlodipine or diltiazem. Diltiazem has a negative chronotropic effect that adds to its antianginal efficacy but may also result in symptomatic bradycardia and fatigue. Amlodipine has greater selectivity for vascular smooth muscle over nodal and contractile cardiac tissue, causing no change in the cardiac rate. Knight and associates compared the efficacy of amlodipine with that of diltiazem to supplement atenolol therapy in patients with stable angina pectoris.
A total of 97 patients participated in the randomized, double-blind parallel group study. Patients with positive stress tests on screening received atenolol, 50 mg per day, with sublingual glyceryl trinitrate as required. If a further exercise test performed after two to three weeks of therapy demonstrated results consistent with the initial test, the patient was included in the study and randomized to receive either amlodipine (5 mg once daily) with diltiazem placebo or diltiazem (90 mg twice daily) with amlodipine placebo. If angina was still present after four weeks, the dosage was doubled for an additional four weeks. Patients recorded onset and duration of angina attacks and glyceryl trinitrate use. Ambulatory STsegment monitoring and exercise testing were completed after the double-blind treatment.
Both amlodipine and diltiazem significantly reduced the frequency of angina attacks and glyceryl trinitrate consumption. Both drugs reduced systolic blood pressure slightly, and neither affected the heart rate significantly. In both treatment groups, more than 60 percent of the patients progressed to the higher dosage of study medication. The incidence of adverse effects was higher in the group taking diltiazem, with severe adverse events including syncope, atrial fibrillation and bradycardia. The most serious adverse effect with amlodipine therapy was severe edema.
The authors conclude that both amlodipine and diltiazem provide an improvement in exercise parameters when added to a beta blocker in the treatment of patients with angina. Both drugs are well tolerated, although adverse events were more likely in the diltiazem group. The pattern of adverse events was also different, with an increased incidence of bradycardia in the diltiazem group.
RICHARD SADOVSKY, M.D.
Knight CJ, et al. Amlodipine versus diltiazem as additional antianginal treatment to atenolol. Am J Cardiol January 15, 1998;81:133-6.
Treatment of Recurrent Genital Herpes Infections
Acyclovir has been widely used as an effective and well-tolerated drug for the treatment of recurrent genital herpes simplex virus infection. Early initiation of treatment has been shown to reduce duration of viral shedding, time until healing and time until clearance of lesions. Since acyclovir is administered five times a day for five days, valacyclovir has been proposed as an alternative therapeutic agent. Tyring and associates compared the effectiveness of the two drugs in the treatment of recurrent genital herpes infections.
The double-blind, randomized study included 1,200 immunocompetent patients with recurrent genital herpes. Study subjects underwent therapy with oral valacyclovir, 1,000 mg twice daily; oral acyclovir, 200 mg five times daily, or placebo.
Both valacyclovir and acyclovir significantly decreased the length of the genital herpes episode compared with placebo. The episode resolved in approximately 75 percent of patients within six days of active drug therapy compared with eight days for placebo. Patients who initiated treatment within six hours after the prodrome experienced resolution 11 percent more quickly than those who started therapy after 24 hours. Both active drugs significantly reduced the time until lesion healing compared with placebo. Median healing times were 4.8 days for both active drugs, compared with 6.0 days for placebo. Healing time was faster in younger patients. At least one culture for herpes simplex virus was obtained from approximately 90 percent of the patients in each treatment group. Culture results were negative in 49 percent of the active drug groups, compared with 29 percent in the placebo group. The duration of viral shedding was significantly longer in the placebo group. Both active drugs significantly decreased the duration of pain compared with placebo. On the third day of treatment, only 12 to 15 percent of patients in the active drug groups reported moderate or severe pain, compared with 25 percent of patients receiving placebo. Adverse events were similar in all study groups, with headache, nausea and diarrhea occurring most frequently.
The authors conclude that treatment of recurrent herpes infections with a twice-daily regimen of valacyclovir or a five-timesdaily regimen of acyclovir is significantly more effective than placebo in decreasing pain, and shortening the overall length of an episode and the period of viral shedding, with no significant differences between the two regimens. Because of the more convenient dosing schedule and the potential for improvement in compliance, valacyclovir is a useful alternative to acyclovir.
BARBARA APGAR, M.D., M.S.
Tyring SK, et al. A randomized, placebo-controlled comparison of oral valacyclovir and acyclovir in immunocompetent patients with recurrent genital herpes infections. Arch Dermatol February 1998;134:185-91.
Transient Post-Transfusion Blood Abnormalities
Laboratory evaluation is often necessary in the first 24 hours after a transfusion to monitor the patient's condition. Wiesen and colleagues evaluated the changes that occur in blood chemistry after transfusion.
Thirty-nine adult patients who were scheduled to receive two units of packed red blood cells were included in the study. Patients were excluded from participation if they had hemolytic anemia or recent active bleeding. The following serum levels were checked before the transfusion and at 15 minutes, one hour, two hours and 24 hours after the transfusion: potassium, blood urea nitrogen, total bilirubin and lactate dehydrogenase.
Before the transfusion, the median bilirubin level was 0.7 mg per dL (11.97 µmol per L), and it increased to 1.4 mg per dL (23.95 µmol per L) at 15 minutes, one hour and two hours after the transfusion. By 24 hours after the transfusion, the bilirubin level had returned to pretransfusion levels. In nearly one half of patients, this represented a change from a normal value before the transfusion to an abnormal value in the hour following the transfusion. Similarly, lactate dehydrogenase levels started within the normal range, increased to abnormal levels in the two hours after transfusion, but returned to normal within 24 hours. The only other value that changed, but in a clinically nonsignificant way, was the blood urea nitrogen level.
The authors conclude that elevations in bilirubin or lactate dehydrogenase are not a cause for alarm, and abnormalities should not be aggressively evaluated unless the changes are not transient or are associated with new symptoms. Other blood chemistry abnormalities should not be attributed to receipt of packed red blood cells.
GRACE BROOKE HUFFMAN, M.D.
Wiesen AR, et al. Transient abnormalities in serum bilirubin and lactate dehydrogenase levels following red blood cell transfusions in adults. Am J Med February 1998;104:144-7.
Transrectal Ultrasound in Evaluation of Male Infertility
Although only a fraction of men with infertility have a demonstrable distal ductal abnormality, it is crucial to identify these patients to determine if the defect is correctable and to avoid unnecessary testing in men with noncorrectable abnormalities who should proceed to assisted reproduction. In the absence of retrograde ejaculation, neurologic disorders and diabetes, men with azoospermia and low ejaculate volumes (1.5 mL or less) should be examined for congenital anomalies or obstructive defects of the distal genital tract. Kuligowska and Fenlon evaluated the effectiveness of transrectal ultrasound in infertile men to evaluate its role in patient care.
Male patients with infertility, low ejaculatory volumes and azoospermia were evaluated. On the basis of the location and nature of the transrectal ultrasound findings, the men were selected for either surgery or radiologic intervention. Of the 276 men who underwent transrectal ultrasound examination, 70 (25.4 percent) had no anatomic abnormalities of the distal genital system. In the remaining patients, the most common abnormality was congenital bilateral absence or hypoplasia of the vas deferens (94 patients, or 34.1 percent), which was associated with nonvisualization of both ejaculatory ducts at transrectal ultrasound. Other abnormalities included occlusion of the vas deferens, seminal vesicles and ejaculatory ducts by calcification or fibrosis (43 patients, or 15.6 percent); unilateral absence or hypoplasia of the vas deferens (31 patients, or 11.2 percent); obstructing cysts (26 patients, or 9.4 percent); and distal ductal obstruction secondary to calculi (12 patients, or 4.4 percent).
Patients were selected for further intervention on the basis of the ultrasound findings. Congenital and acquired ductal anomalies may be amenable to radiologic or surgical intervention, depending on the nature and location of each abnormality. Cysts above the level of the prostate can be effectively treated with transrectal ultrasound-guided needle aspiration. Cyst aspiration can be therapeutic by relieving obstruction and providing sperm for in vitro fertilization. Congenital bilateral vas agenesis and diffuse ductal occlusion are nonsurgically correctable defects. By correctly identifying this particular cause of infertility with transrectal ultrasound, such patients can be spared further unnecessary investigation and inappropriate treatments.
The authors conclude that transrectal ultrasound is the ideal method for evaluation of potentially correctable genitourinary defects in infertile men. Normal distal ductal anatomy is easily depicted with this technique. Transrectal ultrasound offers an innovative diagnostic approach in infertile men with low-volume azoospermia.
BARBARA APGAR, M.D., M.S.
Kuligowska E, Fenlon HM. Transrectal US in male infertility: spectrum of findings and role in patient care. Radiology April 1998;207:173-81.
Schizophrenia as a Long-term Outcome of Pregnancy
There is little consensus as to which, if any, specific pregnancy and perinatal factors may be related to the development of adult schizophrenia, although accumulating evidence supports links with exposure to perinatal infection, poor nutrition and hypoxia. The evidence for a perinatal schizophrenia link is less secure than that for a childhood neurologic handicap. Jones and associates conducted an investigation to determine the effect of pregnancy and neonatal factors associated with adult-onset schizophrenia in the delivered infant.
For each of the mothers of 11,017 infants in the 1966 North Finland birth cohort, standardized assessments made during pregnancy, delivery and the neonatal period were linked to the national psychiatric case register. Patients were followed until age 28. Seventy-six individuals who met the DSM-III-R criteria for schizophrenia were identified, as were links between perinatal events and subsequent development of schizophrenia.
Body mass indexes of the mothers were studied. The mothers with a body mass index of 29 or greater were more likely to have affected offspring, but this difference was not statistically significant. Smoking status was not predictive of schizophrenia. Women who described themselves as having been depressed during the sixth or seventh month of pregnancy were more likely to deliver an affected offspring. Factors such as maternal fever and abnormal delivery did not predict schizophrenia. The children with schizophrenia were more likely to have been born small and early, and evidence indicated that a small placenta was more common in this group. A short gestation period but an appropriate growth rate was associated with the development of schizophrenia in a subgroup of children. Subsequent schizophrenia was approximately seven times more likely in infants who had perinatal brain damage. Of the 125 survivors of severe perinatal brain damage, six (4.8 percent) eventually developed schizophrenia. Infants who spent a prolonged period of newborn life in the intensive care unit were also significantly more likely to develop schizophrenia.
The authors conclude that specific aspects of pregnancy and the perinatal period are associated with later development of schizophrenia and that these effects appear to be largely related to the child and not to the delivery per se. There was no association with conventional obstetric risk factors in the mothers. The possibility that schizophrenia may be more common in the large number of babies who survive significantly preterm birth remains a concern. The significance of timing is not completely clear, but the evidence indicates that very early birth may be a risk factor.
BARBARA APGAR, M.D., M.S.
Jones PB, et al. Schizophrenia as a long-term outcome of pregnancy, delivery, and perinatal complications: a 28-year follow-up of the 1966 North Finland General Population Birth Cohort. Am J Psychiatry March 1998; 155:355-64.
Choice of Management for the Third Stage of Labor
A major concern in managing the third stage of labor (delivery of the placenta and membranes) is to minimize the risk of postpartum hemorrhage. Maternal blood loss of 500 mL (15 oz) or more within 24 hours of delivery is defined as postpartum hemorrhage, and the condition is associated with significant rates of short- and long-term morbidity. The controversy has been complicated by the role of maternal position, which is believed to significantly influence maternal blood loss. Rogers and colleagues compared two approaches to management of the third stage of labor in a large population of women at low risk for postpartum hemorrhage.
The two principal management strategies for the third stage of labor are expectant management (sometimes called conservative management) and active management. Active management protocols include routine administration of a uterotonic drug, early clamping and cutting of the cord, and controlled cord traction. Expectant management depends on expulsion of the placenta through maternal effort and may incorporate early suckling to stimulate natural uterine contractions.
Women with uncomplicated pregnancies and no risk factors for postpartum hemorrhage were invited to join the study between 24 and 32 weeks of gestation. Random allocation of 1,512 participants was achieved by use of sealed envelopes opened only after labor had begun and the likelihood of normal delivery with low risk of postpartum hemorrhage was confirmed. Patients were assigned to one of four strategies: expectant management with upright posture, expectant management with supine posture, active management with upright posture or active management with supine posture. Over 90 percent of women received the form of management assigned. Data were collected about blood loss, postdelivery hemoglobin concentration, use of blood transfusion and iron therapy, and indicators of infant health.
The groups were comparable in all significant variables, and the overall rate of postpartum hemorrhage was 11.7 percent. The 764 mothers in the expectant management group had significantly higher rates of postpartum hemorrhage (126 patients, or 16.5 percent) than the 748 mothers who underwent active management (51 patients, or 6.8 percent). The rate of blood loss in excess of 1,000 mL (30 oz) was also higher in the expectant group, but the difference was not statistically significant.
Mothers in the expectant management group experienced significantly higher rates of other measures of blood loss, such as levels of postnatal hemoglobin less than 10 g per dL (100 g per L), need for blood transfusions and iron medication. This group also was more likely to have a prolonged third stage of labor (greater than 30 minutes) and need for uterotonic medication. The two groups did not differ in the rate of hypertension, but mothers in the expectant group reported less nausea and vomiting. No significant differences in health at six weeks postpartum or in outcomes for the infants were recorded. Analyses of the study data did not find differences in postpartum hemorrhage according to maternal posture.
The authors conclude that active management significantly reduced the risk of postpartum hemorrhage. They calculate the relative risk of postpartum hemorrhage with expectant management to be 2.4, thus active management of 10 mothers would be necessary to prevent one case of postpartum hemorrhage. Furthermore, maternal posture did not contribute significantly to the outcome of third-stage management. They report that many mothers expressed a preference for expectant management and emphasize the importance of individualized decisions based on balancing the risks and advantages of each management strategy.
ANNE D. WALLING, M.D.
Rogers J, et al. Active versus expectant management of third stage of labour: the Hinchingbrooke randomised controlled trial. Lancet March 7, 1998;351:693-9.
Incidence of Concussion in Elite Soccer Players
Soccer is one of the fastest growing sports in the United States and one of the most popular sports in the world. In soccer, the head is used to advance or control the ball. Previous studies have shown head and neck injuries account for 4 to 22 percent of soccer injuries. Another study indicated that players have a 50 percent chance of sustaining a concussion if they participate in soccer for 10 years. Boden and associates conducted a study to evaluate the incidence and mechanisms of concussion in elite college soccer players.
A prospective study was performed on seven men's and eight women's varsity soccer teams in the Atlantic Coast Conference. For each incidence of concussion during the 1995 or 1996 seasons, a detailed questionnaire was completed by the team trainer. The authors also calculated athlete exposures to possible injury by considering the number of players, practices and games for each season. There were 162 players on men's teams in 1995 and 163 in 1996. The women's teams fielded 188 players for both seasons. There were 29 concussions in 26 players during the two seasons. Seventeen concussions (59 percent) occurred in men, while 12 (41 percent) occurred in women. Twenty concussions occurred during games and nine during practice. The overall incidence of concussion was 0.96 per team per season and 0.49 per 1,000 athlete exposures. The types of activity causing the concussions included collisions with another player, being hit in the head by a soccer ball from a close kick and striking the ground in a fall. No concussions resulted from a player heading the ball. Concussions were classified by trainers as grade 1 in 24 athletes (83 percent) and grade 2 in five patients (17 percent); however, three concussions should have been diagnosed as grade 2 based on the symptoms reported.
The authors conclude that risk for concussions in elite athletes was high, with more risks for male athletes than for female athletes. The most common cause of injury was a collision with another player. The authors did note that the study was performed on elite athletes, who may be more competitive than average soccer players; they also recognized that these athletes had better control of their bodies during practices and games. The final conclusion is that concussions in soccer are more common than was originally thought.
KARL MILLER, M.D.
Boden BP, et al. Concussion incidence in elite college soccer players. Am J Sports Med March/April 1998;26:238-41.
Teratogenic Risk of SSRIs Used During Pregnancy
Previous studies have hinted at an increased risk of perinatal complications in pregnant women who take fluoxetine. Kulin and colleagues evaluated pregnancy outcomes in women who received selective serotonin reuptake inhibitors (SSRIs) during pregnancy.
Women who contacted the Teratology Information Service about exposure to fluvoxamine, paroxetine or sertraline during pregnancy were included in this prospective, controlled cohort study. These patients were matched with randomly selected women who received counseling but were determined to have been exposed only to nonteratogenic substances. The SSRI dosage and the length of treatment were determined, and the women were contacted about nine months after their delivery to determine the outcome of the pregnancy. Rates of major malformations (anomalies having significant medical or social consequences) were determined.
Of the 267 women included in the study, 147 used sertraline, 97 used paroxetine and 26 took fluvoxamine. The SSRI was used throughout the pregnancy by 49 women. The rates of spontaneous and elective abortion, stillbirth and major malformations were not significantly different between the SSRI and the control groups. Neonates exposed to SSRIs had a relative risk of major malformations of 1.06. Pregnancy outcomes did not differ between women who took the SSRI for only the first trimester and those who took it for the entire pregnancy.
The authors conclude that SSRIs used during pregnancy do not increase teratogenic risk when used in recommended dosages.
GRACE BROOKE HUFFMAN, M.D.
Kulin NA, et al. Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors. A prospective controlled multicenter study. JAMA February 25, 1998;279:609-10.
Long-Acting Calcium Channel Blockers in Hypertension
Published reports have suggested that the use of calcium channel blockers is associated with an increased risk of myocardial infarction compared with diuretic and beta-blocker therapy. These reports were retrospective studies of patients using short-acting formulations. The newer, longer-acting calcium channel blockers differ markedly from the earlier preparations in terms of pharmacokinetics, pharmacodynamics and tolerability profiles. Kloner and associates reviewed the hypertension clinical trial databases compiled by Pfizer Inc. to evaluate the incidence of adverse cardiovascular events and rates of mortality in patients taking amlodipine or nifedipine in the gastrointestinal therapeutic system (GITS) formulation.
Data from all worldwide Pfizer-sponsored studies for the treatment of hypertension were included. Adverse cardiovascular events that were recorded included new or worsened angina, myocardial infarction, serious arrhythmia, stroke, congestive heart failure and bleeding. Deaths were categorized as cardiovascular or noncardiovascular.
In the amlodipine hypertension trials, most patients were exposed to treatment for five to 16 weeks, with 2,576 patients (8 percent of the total) using amlodipine for 17 weeks to more than two years. The incidence of adverse events in this group was equal to or lower than that in the aggregate comparative trial and placebo groups. In the nifedipine GITS hypertension trials, in which large numbers of patients (30 percent) took the drug for over six months, the incidence of adverse events also was not significantly different from that of the comparative trial groups and placebo groups. Although exposure to the trial drug may have been short in many of the study patients, the mechanisms hypothesized by some investigators to cause an increase in cardiac events with calcium channel blockers, such as proarrhythmia, negative inotropic effects, worsening ischemia and bleeding, do not necessarily require long-term exposure for an event to occur. The adverse events that were described with use of short-acting calcium channel blockers after acute myocardial infarction were most common within the first few weeks of drug therapy.
The authors conclude that patients taking amlodipine or nifedipine GITS do not have an increased risk of death or cardiovascular adverse events.
RICHARD SADOVSKY, M.D.
Kloner RA, et al. Safety of long-acting dihydropyridine calcium channel blockers in hypertensive patients. Am J Cardiol January 15, 1998;81:163-9.
Optimization of Medication Use in the Elderly Population
Geriatric medicine differs from conventional medicine in a number of ways. Complete knowledge of the medication regimen and compliance issues may pose a particular challenge. Monane and associates review common problems associated with medication use in the elderly, including noncompliance, polypharmacy, undermedication or omission, use of over-the-counter medications and alcohol consumption, and offer some suggestions for improvement.
Noncompliance may be detected subjectively by patient interviews, pill counts and refill records, or more objectively by monitoring serum levels and urine assays to measure drug metabolites or marker compounds. Compliance rates in patients taking long-term therapy can range from 40 to 60 percent. Poor compliance can have serious clinical consequences; if unrecognized, noncompliance can increase both the patient's risk and cost, since physicians may increase the dosage or prescribe additional medications. Strategies to improve compliance include patient education, promoting compliance and simplifying the medical regimen. Encouraging the family or caregiver to monitor compliance is also essential.
Polypharmacy, which the authors define as the use of five or more prescription and/or over-the-counter medications, is the principal drug safety problem in the United States. Forty percent of patients who live in long-term care facilities and up to 6 million older Americans living in the community are affected. The definition of polypharmacy is helpful as a quick screening tool to identify patients whose medication records may need additional physician review. The use of several prescribing physicians or several pharmacies, and inadequate communication among the physicians and pharmacies is often implicated as the principal cause of inappropriate polypharmacy. Strategies for preventing the problem focus on improving communication between physicians and patients with regard to the exact number and type of medications used, the use of a single pharmacy or pharmacy network and regular, comprehensive medication reviews.
Inadequate dosage or omission of an appropriate prescription is another common problem. Inadequate dosage has been reported with calcium supplements, transdermal nitroglycerin and bronchodilators. Frequent omissions include iron supplements in patients following surgery, cholesterol-lowering agents, oral hypoglycemic agents and bronchodilators.
Nonprescription drugs represent an important therapeutic tool but can also include risks. Many prescription drugs have been reclassified for over-the-counter use. These agents are used more often by patients with higher education levels, less time for physician visits, or less access to medical care.
Consumption of alcohol while taking certain medications can cause dangerous drug interactions, such as drowsiness and impaired physical and cognitive function. Alcohol may affect the way drugs work and may worsen or accelerate symptoms of chronic diseases common in older adults.
The authors conclude that medication use in older adults is associated with an increased risk for adverse events. Noncompliance and polypharmacy are the principal problems. However, omission or underdosage may result in an incomplete therapeutic response or progression of a disease state. Patients and their caretakers must be encouraged to monitor medication regimens and to communicate effectively with physicians and pharmacies. Physicians must individualize medication regimens, balancing the risk-benefit ratio to the specific patient circumstances.
RICHARD SADOVSKY, M.D.
Monane M, et al. Optimal medication use in elders: key to successful aging. West J Med October 1997;167:4;233-7.
Treatment Of Anogenital Warts With 0.5 Percent Podofilox Gel
Anogenital warts (condylomata acuminata) are difficult to treat successfully. The 0.5 percent podofilox solution is approved for self-use and, when used in three-day treatment cycles over a four-week period, appears to be less toxic than podophyllum resin. Previous studies have demonstrated a patient preference for self-treatment of genital warts. The gel was formulated as an easier-to-apply alternative. Tyring and associates performed a double-blind, randomized, vehicle-controlled study of podofilox gel in patients with anogenital warts.
A total of 292 immunocompetent patients were included in the study. The majority of the warts were located on the penile shaft in men and on the labia in women. Approximately 20 percent of the subjects had received previous treatment for warts. During the study period, participants were randomized to receive podofilox gel or vehicle gel. The topical medication was applied twice a day for three consecutive days, followed by four days without treatment (one cycle). Patients used the medication for two to eight treatment cycles.
The 0.5 percent podofilox gel was significantly more effective than vehicle gel for clearing anogenital and external genital warts after four weeks and eight weeks of treatment. Treatment success increased 31 percent (from 62 to 81 patients) with an additional four to eight weeks of podofilox gel therapy. No significant differences in clearance rates in men or women were apparent. Significantly fewer warts remained after active drug therapy. Physician assessment of response to treatment demonstrated that 73.8 percent of the patients treated with 0.5 percent podofilox gel had either moderate or marked improvement or complete clearing of warts after four weeks. At eight weeks, 81.1 percent of the patients treated with podofilox gel had either moderate or complete clearance of warts, compared with 17.2 percent of the patients treated with the vehicle gel. Significantly more patients discontinued treatment with the vehicle gel because of ineffective clearance of warts.
Adverse effects were significantly greater in the active drug group. The most common adverse events were burning, inflammation, itching, erosion, pain and bleeding. Burning was the most frequently reported side effect in the active drug group during the first six weeks. Almost all local adverse effects resolved within four weeks of cessation of treatment. The incidence of inflammation and erosion was significantly greater in men than in women. In women with external warts, the most common adverse event was burning (75.3 percent). For those with perianal warts, the most common local adverse events were burning in women (91.7 percent) and inflammation and pain in men (71.4 percent).
The authors conclude that 0.5 percent podofilox gel was significantly more effective than the vehicle gel in reducing numbers of genital warts (external and perianal) in both men and women. The gel form is easier to apply than the solution and does not have a higher adverse event profile.
BARBARA APGAR, M.D., M.S.
Tyring S, et al. Safety and efficacy of 0.5% podofilox gel in the treatment of anogenital warts. Arch Dermatol January 1998;134:33-8.
Weight Change and Risk of Hypertension in Women
The association between obesity and hypertension has been clearly demonstrated. Short-term weight loss appears to reduce blood pressure in patients with hypertension. The degree to which long-term weight reduction prevents or delays the onset of hypertension is less clear. Huang and associates investigated the effect of long-term and medium-term weight changes in a cohort of women without diagnosed hypertension at baseline.
The Nurses' Health Study is a long-term follow-up study of nurses who were 30 to 55 years of age at the time of study entry in 1976. Questionnaires were sent every two years to identify diagnoses of hypertension and other medical events and to measure risk factors. Body mass index (BMI) was used as a measure of obesity. Women were divided into nine groups based on amount of weight gain or loss. The stable weight group was used as the baseline. Incidence of hypertension was determined by self-report of high blood pressure as diagnosed by a physician. A total of 16,395 cases of hypertension were diagnosed in the cohort of 82,473 women.
Higher current BMI was strongly associated with an increasing risk for hypertension. Women with a BMI of 31 kg (68.2 lb) per m2 had a relative risk of 6.31 of being diagnosed with hypertension. An increase in BMI of 1 kg (2.2 lb) per m2 was associated with a 12 percent increase in risk for hypertension. Higher BMI at 18 years of age was associated with an increased risk for hypertension later in life. Risk of hypertension was reduced by 15 percent with a weight loss of 5 to 9.9 kg (11 to 21.78 lb) and by 26 percent for a weight loss of 10 kg (22 lb) or more. Both attained BMI and history of weight changes appeared to be independent predictors of risk for hypertension.
The authors conclude that higher BMI at age 18 appears to be associated with later development of hypertension, while higher BMI at midlife appears to be even more strongly associated. Long-term and medium-term weight loss were associated with a substantially reduced risk for subsequent hypertension. Sustained weight loss appears to have a stronger protective effect. This association is strongest in women with a higher baseline BMI. Weight loss in women who are already overweight appears to be an effective strategy for reducing the risk of hypertension.
RICHARD SADOVSKY, M.D.
Huang Z, et al. Body weight, weight change, and risk for hypertension in women. Ann Intern Med January 15, 1998;128:81-8.
EDITOR'S NOTE: We have known for a long time that overweight persons with hypertension may lower their blood pressure by losing weight. The current study now defines weight reduction as a primary prevention method against the development of hypertension. This appears to be true in persons with or without a family history of hypertension. In our discussions with overweight patients about the potential complications of their weight, talking about hypertension allows a powerful "teachable moment" to emphasize the value of weight reduction.--r.s.
Linoleic Acid and Calcium for Prevention of Preeclampsia
Although the physiopathogenesis of preeclampsia remains uncertain, a decrease in prostaglandin (PGE2) level has been implicated, possibly because of prostaglandin's role in regulating intracellular ionic calcium levels. Supplementation of prostaglandin precursors and calcium could, therefore, prevent preeclampsia by sustaining PGE2 levels. Herrera and colleagues studied women at high risk of preeclampsia to investigate the effect of linoleic acid and calcium supplementation.
Over 1,600 healthy Colombian primigravid patients between 28 and 32 weeks of gestation were screened to identify those who were at increased risk of preeclampsia. Inclusion criteria for high risk included a biopsychosocial profile score of three or greater, a positive roll-over test and a mean arterial pressure of 85 mm Hg or greater. Exclusion criteria were previous elevations of diastolic blood pressure, drug use or history of cardiovascular or renal disease. After collection of baseline data, 89 patients who met the criteria provided blood samples for laboratory analysis and completed nutritional inventories. The patients were randomly assigned to receive either 450 mg of linoleic acid plus 600 mg of calcium or identical placebo tablets. Patients were instructed to take the medications in the morning, to rest in the left lateral position for at least 30 minutes daily and to avoid taking acetylsalicylic acid and nonsteroidal anti-inflammatory drugs. The patients were monitored every four weeks until 36 weeks of gestation and then twice per week until delivery. Preeclampsia was defined as pregnancy-induced hypertension (repeated measures of 140/90 mm Hg or greater), with proteinuria greater than .003 g per dL (0.3 g per L).
The treated women did not differ from the women in the placebo group in any demographic or obstetric variable. The groups were also comparable in nutritional profiles and in measures of compliance during the study. The incidence of preeclampsia in the treated women was 9.3 percent, significantly lower than the 37.2 percent in the control group. Two patients (4.7 percent) in the treated group and six patients (14 percent) in the control group developed severe preeclamptic toxemia. Treated women had lower mean diastolic blood pressures, longer gestation periods, higher birth weights, fewer low birth weight infants, fewer infants small for gestational age, and a lower rate of cesarean delivery. No side effects attributable to the treatment or placebo were reported.
The authors conclude that daily dietary supplementation with linoleic acid and calcium during the third trimester reduces the incidence of preeclampsia in high-risk patients and contributes to improved pregnancy outcomes.
ANNE D. WALLING, M.D.
Herrera JA, et al. Prevention of preeclampsia by linoleic acid and calcium supplementation: a randomized controlled trial. Obstet Gynecol April 1998;91:585-90
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