AJCM Update

We present a review of recent articles relevant to today’s practicing physicians. Publication does not suggest an endorsement of content or a validation of conclusions. It is recommended that prior to incorporating any of this information into your practice, you carefully review the citations here, as well as related articles.

Alternative Medicine
The SU. VI. Max Study: A Randomized, Placebo-Controlled Trial of the Health Effects of Antioxidant Vitamins and Minerals

The Supplementation en Vitamines et Mineraux Antioxidants (SU.VI.MAX) study is a randomized, doubleblinded, placebo controlled, primary prevention trial. It is designed to test the efficacy of nutritional doses of supplementation with a combination of antioxidant vitamins and minerals in reducing the incidence of cancer and ischemic cardiovascular disease in the general population.

After a media campaign 79,976 French adults volunteered to participate; of these 14,412 were eligible to participate and were invited to enroll. A total of 13,017 French adults were enrolled and randomized. Of those, 7,876 were women aged 35-60 and 5,141 were men aged 45-60. There were 270 patients that withdrew within three days because they could not accept the constraints of the study participation, and six were subsequently found to be outside the age range and declared ineligible. The remaining 12,741 subjects were then randomized, 6,364 to the intervention group and 6,377 to the placebo group. All participants took a single daily capsule of 120mg ascorbic acid, 30mg vitamin E, 6mg of beta carotene, 100ug of selenium, and 20mg zinc or a matching placebo. Capsules were prepared in 52 weekly packages of seven capsules and delivered to the patients annually. Patients were followed for 7.5 years.

At years two, five and seven blood samples were taken to determine the levels of the supplements being studied. At years one, three and seven a physical examination was performed which included anthropometric measurements, blood pressure assessment, electrocardiogram, fecal occult blood for patients over 45 years of age and a papanicolaou test for women. Women older then 50 years also had a screening mammography if they had not had one in the previous two years. Among the participants, 739 withdrew consent during the study and 736 were lost to follow-up. At the end of follow-up, 74% of the patients reported having taken at least two-thirds of the capsules. There was no significant difference in capsule consumption between the treatment and placebo groups.

There were 271 patients who developed ischemic cardiovascular disease (CVD) during the study, 134 in the intervention group and 137 in the placebo group. There were no differences in incidence of CVD between the groups, and no differences in incidence of CVD for gender.

There were 562 cancers that occurred, 504 were invasive and 58 were in situ, of which 267 were in the intervention group and 295 in the placebo group. When these were broken down by gender, women in the intervention group developed 179 (4.7%) cancers, versus 171 (4.4%) in the placebo group, which was not a significant difference. However for men, there were 88 (3.5%) in the intervention group who developed cancer, versus 124 (4.9%) in the placebo group. This was statistically significant.

For overall mortality, there were a total of 174 deaths, 103 men and 71 women. The women had 36 (0.9%) deaths in the intervention group and 35 (0.9%) in the placebo group. The men had 40 (1.6%) deaths in the intervention group and 63 (2.5%) deaths in the placebo group. Again, there was a significant difference in the mortality for the men, but not for the women.

The authors conclude that after 7.5 years, low-dose antioxidant supplementation lowered total cancer incidence and all cause mortality in men but not in women. Supplementation may be effective in men only because of their lower baseline status of certain oxidants, especially of beta carotene.

Hercberg et al, Arch Intern Med, November 22, 2004 164:2335-2342

Editor’s note: This was a well designed study. There need to be more studies of claims of nutritional supplements, most of which are anecdotal. These results look promising for at least a segment of the population (men). The results deserve repeat studies and longer term follow-up. - MSB.

Neurology
Methylprednisolone, Valacyclovir or the Combination for Vestibular Neuronitis

Vestibular Neuronitis has an incidence of about 3.5 per 100,000 patient population. It accounts for 7% of patients who present to outpatient clinics specializing in dizziness, and is the second most common cause of peripheral vestibular vertigo (benign positional vertigo is the first). Recent autopsy studies have shown herpes simplex type 1 (HSV1) in the vestibular ganglia, suggesting a reactivation of HSV1 as a cause for the symptoms.

This was a prospective, randomized, double-blind study which looked at treating vestibular neuronitis with methylprednisolone, valacyclovir, methylprednisolone plus valacyclovir, or placebo. The authors recruited patients between 18 and 80 years of age. All patients underwent complete neurologic, neuro-ophthalmologic and neurootologic examination, as well as electronystagmography, neuro-orthoptic examination (detailed measurement of eye movements), cranial MRI, laboratory testing and measurement of heart rate and blood pressure. There were 157 patients who underwent screening, of which 141 met the inclusion criteria and were willing to participate. There were 38 patients assigned to the placebo group, 33 to the valacyclovir group, 35 to the methylprednisolone group, and 35 assigned to the combination of valacyclovir and methylprednisolone.

Methylprednisolone or matching placebo was administered as a single morning dose of 100mg on days one through three, 80mg on days four through six, 60mg on days seven through nine, 40mg on days 10-12, 20mg on days 13-15, 10mg on days 16-18, 20 and 22. Valacyclovir or matching placebo was given as two 500mg capsules three times daily for seven days. The study drugs were first administered to all patients on the day of admission, which was within three days of the onset of symptoms. Patients were also given 150mg pirenzepine once a day to reduce secretion of gastric acid, and if necessary between 50mg and 150mg of dimenhydrinate for a maximum of three days as an antiemetic.

The number of patients that had a complete recovery was eight of 30 ( 26.7%) in the placebo group, 22 of 29 ( 75.9%) in the methylprednisolone group, 10 of 27 (37.0%) in the valacyclovir group, and 22 of 28 ( 78.6 %) in the methylprednisolone plus valacyclovir group.

The authors conclude that methylprednisolone significantly improves the recovery of peripheral vestibular function in patients with vestibular neuronitis, whereas valacyclovir does not.

Strupp et al, NEJM July 22, 2440 351(4);354-61

Pediatrics
Efficacy and Safety of Statin Therapy in Children with Familial Hypercholesterolemia

This was a randomized, double-blinded, controlled study that looked at the efficacy and development of the precursors to artherosclerotic disease in children with familial hypercholesterolemia.

Between December 1997 and October 1999, 274 consecutive children between the ages of 8 and 18 were screened for the study. The children had one parent with a diagnosis of clinical or molecular hypercholesterolemia, two fasting LDL-C levels of >155 and triglyceride levels below 350. Of the patients screened, 44 declined participation. The remaining 230 children completed three months of a fat-restricted diet, following which the lipid studies were repeated. Of these, 214 children met inclusion criteria and were randomized to receive pravastatin (106 patients) or placebo (108 patients).

The primary efficacy outcome measured was the intima- media thickness (IMT) of the carotid arteries. An experienced, blinded ultrasonographer measured the IMT on entry, one and two years follow-up. Lipids were measured after at least 12 hours fasting at three month intervals for the first year, and six month intervals for the second year. To measure primary safety outcomes, one and two year levels of sex steroids, gonadotropins, liver function tests (LFT’s) and variables of the pituitary-adrenal axis were obtained. Also recorded at these times were height, weight, body surface area, body-mass index, tanner stage, menarche or testicular volume. School records were reviewed for yearly progress.

As expected, the pravastatin group had significantly reduced LDL-C and triglyceride levels. Compared with baseline, the pravastatin group showed regression of IMT (mean –0.01mm), versus placebo which showed progression (mean +0.005mm). There was no significant difference in any of the growth parameters, hormone levels or LFT’s.

The authors conclude that two years of pravastatin therapy induced a significant regression of carotid atherosclerosis in children with familial hypercholesterolemia, with no adverse effects on growth, sexual maturation , hormone levels or muscle tissue.

Weigman et al, JAMA, July 21, 2004, 292(3);331-337

Editor’s note: A well designed study. The results at two years are impressive, however the long term effect on morbidity and mortality will require further study and will not be known for a generation. - MSB

A Randomized Trial of a Single Dose of Oral Dexamethasone for Mild Croup

This was a random, double-blinded, multicenter trial designed to see if children with mild croup derive benefit from dexamethasone, as do children with severe croup.

Children who presented at one of four Canadian pediatric emergency departments and had mild croup were eligible for the study. Mild croup was defined as onset within the previous 72 hours of a seal-like barking cough and a score of two or less out of 17 on the validated croup scoring system of Westley, et al. Typically, at least 60% of children who present for emergency care for croup have mild croup, and are discharged without observation or treatment.

During the enrollment period, 2,901 children with croup were seen at the four medical centers. Of these, 720 children, 359 children were randomly assigned to receive one oral dose of dexamethasone (0.6mg per kg) and 361 were randomized to receive placebo. Baseline characteristics were the same in both groups. After receiving treatment, children were observed for 30 minutes. If vomiting occurred, one additional dose was given. Additional treatments, provided at the discretion of the attending physician could include mist, antibiotics, and nebulized epinephrine or beta-agonists. Because none of these treatments alter croup symptoms for more than two hours, they were not expected to interfere with the assessment of the effectiveness of dexamethasone.

The primary outcome was whether there was a return visit to the health care provider for croup within seven days after the day of treatment. The secondary outcome was the presence of symptoms on days one, two and three after treatment randomization. Of the patients who received placebo, 54 (15.3%) returned for care within seven days, as opposed to 26 (7.3%) in the dexamethasone group. The authors found that in order to prevent one return visit it was necessary to treat 13 patients with dexamethasone. Among the 720 patients, there were no cases of gastrointestinal bleeding, complicated varicella or bacterial tracheitis.

The authors conclude that for children with mild croup, dexamethasone is an effective treatment that results in consistent and small but important clinical and economic benefits. Although the long term effects of this treatment are not known, our data supports the use of dexamethasone in most, if not all children with croup. - MSB

Bjornson et al, NEJM September 23, 2004, 351:13;1306-1313

Preventative Medicine
A Randomized Trial of Nortriptyline Combined with Transdermal Nicotine for Smoking Cessation

This was a randomized, double-blinded, controlled study to determine if the addition of nortriptyline to transdermal nicotine would improve the rate of smoking cessation. Patients were between the ages of 18 and 65 and smoked at least ten cigarettes a day.

Out of 402 patients screened for the study, 158 patients met the inclusion criteria and were randomized to receive transdermal nicotine with nortriptyline (79 patients), or transdermal nicotine with placebo (79 patients). Beginning 14 days before the quit date, the patients took one capsule of either 25mg nortriptyline or matching placebo before bedtime. After four days the dose was increased to two capsules, and after four more days the dose was increased to three capsules if tolerated.

Patients who smoked more than 15 cigarettes per day were started on transdermal nicotine at a dose of 21mg/24hr on quit day and continued on this for four weeks, then reduced to 14mg/24hr for two weeks and then reduced again to 7mg/hr for two weeks. Patients that smoked 10-15 cigarettes per day were treated with a lower dose of transdermal nicotine, 14mg/24hr for six weeks, then reduced to 7mg/24hr for two weeks. All patients received transdermal nicotine for a total of eight weeks beginning on quit day.

At six months the cessation rate was 23% (18/79) for the nortriptyline group, and 10% (8/79) for placebo. Adverse side effect rate was significantly higher in the nortryptyline group, with dry mouth (38%) and sedation (20%) being the most common side effects. There was no difference in withdrawal symptoms.

The authors conclude that nortriptyline combined with transdermal nicotine resulted in an increased rate of cessation with little effect on withdrawal symptoms. This combination may represent an option for smokers in whom standard therapy has failed.

Prochazka et al, Arch Intern Med. November 8, 2004, 164;2229-2233

Editors note – The authors correctly point out that this may be an option in patients that fail standard therapy, as opposed to a first line therapy. - MSB

Psychiatry
Antidepressants and the Risk of Suicidal Behavior

This was a matched, case-controlled study that looked at the risk of suicidal ideation and behavior in patients on selected antidepressant medications. The impetus for the study was publicity in the mainstream media of suicidal behavior among patients on antidepressants, most notably teenagers. The authors compared amitryptiline, fluoxetine and paroxetine to dothiepin. These were chosen because they are the most commonly prescribed antidepressants in the United Kingdom (UK).

The population base was all patients who filled at least one prescription for amitryptiline, fluoxetine and paroxetine or dothiepin between the years 1993 and 1999. Data was taken from the UK General Practice Research Database (GPRD). More than three million United Kingdom residents have been enrolled with selected general practitioners who have agreed to provide data for the GPRD. The GPRD is a highly accurate, detailed and complete medical database encompassing more than three million people over a 10 year period.

There were 159,810 people that filled prescriptions for one of the antidepressant medications. Of these, 36,165 (22.6%) patients received amitriptyline; 46,587 (29.2%) received dothiepin; 49,587 (31.1%) received fluoxetine; and 35,465 (22.2%) received paroxetine. Patients may have used more than one antidepressant medication.

Cases were those patients that had a first time recorded diagnosis of non-fatal suicide ideation or attempted suicide. For each case, up to four controls were matched by age, sex and duration of recorded history in the GPRD. Cases and controls had at least one prescription for one of the four study drugs within 90 days before their index date. The same exclusions were applied to cases and controls. The study included 555 cases with first time, non-fatal suicide behavior or ideation, and 2,062 controls.

The authors compared patients that were first prescribed an antidepressant medication 90 days or longer before their index date to patients that were first prescribed an antidepressant between one and nine days before their index date. The authors found that for patients first prescribed an antidepressant medication between one and nine days before their index date, their relative risk of suicidal behavior was 4.07, and their relative risk of fatal suicide was 38.0. There were no significant associations between the use of a particular study antidepressant and the risk of suicide.

The authors conclude that the risk of suicidal behavior after starting antidepressant treatment is similar among users of amitryptiline, fluoxetine, and paroxetane compared with the risk among users of dothiepin. The risk of suicidal behavior is increased in the first month after starting antidepressants, especially during the first one and nine days. A possible small increase in risk (borderline significance) among those starting the newest antidepressant, paroxetine, is of a magnitude that could readily be due to uncontrolled confounding by severity of depression. Based on the limited information, the authors also conclude that there is no substantial difference in effect of the four drugs on people aged 10 to 19 years.

Jick et al, JAMA, July 21, 2004, 292(3):338-343

Editor’s note: While not a randomized, controlled study, the information intuitively makes sense and is probably valid. This is one of many situations where the mainstream media gets into a feeding frenzy on a subject, prompting recalls and lawsuits. When these events are reported in the mainstream media, the emphasis is on suicide risk increasing with the use of antidepressants. There is little if any mention of the fact that the patients were emotionally troubled, which is why they were put on antidepressants to begin with!! - MSB

Radiology
Magnetic Imaging of the Breast Prior to Biopsy

This was a prospective, multicenter investigation of the International Breast MR Consortium, which was conducted at 14 centers in North America and Europe between June 1998 and October 2001. The study looked at the accuracy of breast MRI as an adjunct to mammography in the detection of breast cancer.

There were 1,004 women that met entry requirements. Of these 1,004 women, 821 had a complete MRI examinations and histopathology studies. Of these 821 patients, 695 (84.7%) had abnormal mammograms, 491 (59.8%) classified as category 4 (suspicious abnormality) and 204 (24.8%) classified as category 5 (highly suggestive of malignancy). The remaining women had clinically suspicious lesions (palpable mass, nipple discharge, etc.), 42 (5.1%) with benign mammographic findings, 59 (7.2%) with no mammographic findings and 25 (3.1%) with no reported mammographic results.

There were 404 patients with malignant index lesions, of which 63 had ductal carcinoma in situ (DCIS), and 341 had invasive carcinoma. There were 417 patients with nonmalignant index lesions, of which 366 were benign, 47 showed atypical histology, and 4 were lobar carcinoma in situ.

Of the 404 patients with malignant lesions, MRI identified 356 as malignant, resulting in sensitivity of 88.1%. Sensitivity for Invasive carcinoma was 90.9% and for DCIS 73.0%. MRI was negative for malignancy in 281 of the 417 patients without malignant lesions, resulting in a specificity of 67.4%. There was no difference in specificity for DCIS or invasive carcinoma.

The authors conclude that breast MRI has high sensitivity but only moderate specificity independent of breast density, tumor type, and menopausal status. Although the positive predictive value of MRI is greater than mammography, MRI does not obviate the need for subsequent tissue sampling in this setting.

Bluemke et al, JAMA, December 8, 2004, 292(22):2735- 2742

Editor’s note: The conclusions are not completely supported by the author’s own data. The MRI has a high sensitivity for invasive carcinoma (90.9%), but not for DCIS (73.0%). The authors combined the data from both tissue types into their conclusion, stating a sensitivity of 88.1%, but this is misleading for DCIS. The author’s correctly state that MRI does not obviate the need for tissue sampling in this setting. One would therefore ask if MRI is warranted at all in this setting if tissue sampling and mammography are performed and still considered the standard of care. This may change in the future as MRI technology improves, however, at this time MRI does not appear to add anything to the patient’s evaluation. - MSB

Sports Medicine
Sildenafil Increased Exercise Capacity during Hypoxia at Low Altitudes and at Mount Everest Base Camp

Alveolar hypoxia causes pulmonary hypertension and enhanced right ventricular afterload, which may impair exercise tolerance. The phosphodiesterase-5 inhibitor sildenafil has been reported to cause pulmonary vasodilation. This study was designed to investigate the effects of sildenafil on exercise capacity under conditions of hypoxic pulmonary hypertension.

This was a randomized, double-blinded, placebo controlled crossover study. Fourteen healthy volunteers (12 men, 2 women) were enrolled in the study. Eight participants were experienced mountaineers who had repeatedly performed alpine-style climbing to altitudes higher than 6,000 meters. The other six participants were healthy, well trained, experienced trekkers who had repeatedly performed alpine-style climbing to altitudes above 3,500 meters.

The participants were 33 to 44 years of age, median age 36.5 years. All patients underwent ECG, pulmonary function testing, and measurement of peripheral arterial oxygen saturation. Systemic pulmonary artery pressure was measured by doppler echocardiography, and cardiac output was assessed non-invasively by using a gasrebreathing technique. Exercise capacity was quantified on a cycle ergometer.

The first phase of the study took place at low altitude (171 meters above sea level). Participants were examined while breathing room air, both at rest and during exercise. After a six hour rest period, they were exposed to a hypoxic gas mixture, with 10% fraction of inspired oxygen via a tight fitting mask. After the first hour the patients were given 50 mg sildenafil or matching placebo tablet. After two hours, echocardiography was performed at rest. Cross-over was done, and there was a washout period of at least 24 hours.

During the second phase all participants ascended from Kathmandu, Nepal to the base camp at Mount Everest in eight days (5,245 meters above sea level). After six days of acclimatization, baseline high altitude measurements were obtained. Subjects received either sildenafil or placebo during two consecutive days in a cross-over design. This allowed intra-individual comparison of the effects of sildenafil.

At low altitude, 50mg of sildenafil significantly increased arterial oxygen saturation during exercise, reduced systolic pulmonary arterial pressure at rest and during exercise, and increased maximum workload and cardiac output compared with placebo. At high altitude sildenafil had no effect on oxygen saturation at rest and during exercise, but reduced systolic pulmonary arterial pressure at rest and during exercise. At high altitude, sildenafil increased maximum workload and cardiac output compared to placebo. Of note, at high altitude sildenafil exacerbated existing headache in two participants.

The authors conclude that sildenafil reduces pulmonary hypertension at rest and during exercise while maintaining gas exchange and systemic blood pressure. To the authors knowledge, sildenafil is the first drug shown to increase exercise capacity during severe hypoxia both at sea level and at high altitude. - MSB

Ghofrani et al, Ann Intern Med, August 3, 2004 141(3):169- 177

Women’s Health
Screening for Chlamydia Trachomatis in Women 15 to 29 years of Age: A Cost-Effective Analysis

This was a case-based analysis to assess the cost effectiveness of annual chlamydia trachomatis screening on women aged 15 to 29 years of age. Among the consequences of asymptomatic chlamydia infections are pelvic inflammatory disease, ectopic pregnancy and infertility.

Using published literature, the authors used a cohort of 100,000 sexually active, non-pregnant women beginning at 15 years of age and used age-specific probability of developing an acute c. trachomatis infection. The outcome measures were clinical events associated with c. trachomatis, lifetime costs, quality-adjusted life expectancy and incremental cost-effectiveness ratios.

The authors found that screening all women between 15 and 29 years of age annually for c. trachomatis and semi annual screening of all women with a positive history was beneficial. There was a reduction in the rates of ectopic pregnancy, tubal infertility, PID and chronic pelvic pain, as well as improvement in quality-adjusted life-years.

The authors conclude that annual c. trachomatis screening for all women aged 15 to 29 years and selective targeting of those with a history of infection for semi-annual screening is very cost effective compared with other well accepted clinical interventions.

Hu et al, Ann Intern Med, October 5, 2004 - 141;7:501-513
Editor’s note: While not a prospective-blinded study, these guidelines are reasonable, improve quality of life and are cost effective. - MSB

AJCM Update Section Editor: Matthew S. Berry, MD. FACP, FAAEP

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