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Prostate Cancer Among Men with a Prostate- Specific Antigen Level < 4.0 ng/mL
Source: Thompson IM, et al. N Engl J Med. 2004;350:2239-2246.
The Prostate Cancer Prevention Trial enrolled 18,882 men to evaluate whether an alpha-reductase inhibitor, finasteride, could prevent incident prostate cancer in men with normal PSA levels(< 3.0 ng/mL). Half of the men in this trial received placebo, but nonetheless subsequently underwent prostate biopsy at the end of the 7-year study. A PSA level of < 4.0 in asymptomatic men is commonly observed as the boundary for consideration of prostate cancer, although it has been recently suggested that the threshold be reduced to 2.5 ng/mL.
The end-of-study prostate biopsy identified prostate cancer in 15.2% of the 2950 men in the placebo group. Eighty percent of tumors identified had low Gleason scores (6 or less). There was a significant difference in PSA levels between the men who were determined to have prostate cancer and those with normal biopsies (PSA mean, 1.78 vs 1.34). Additionally, rate of rise of PSA was associated with risk of prostate cancer.
At first glance, such data might stimulate clinicians to consider lowering the threshold for prostate biopsy. However, since the currently available trial data have not provided convincing evidence that intervention based upon PSA-screening has had a favorable effect upon all-cause mortality, whether more vigorous attention to lesser PSA levels will ultimately benefit men remains unknown.
Mirtazapine for Reducing Nocturnal Itch in Patients with Chronic Pruritus
Source: Hundley JI, Yosipovitch G. J Am Acad Dermatol. 2004;50:889-891.
Pruritus is a commonplace com plaint of persons with dermatological disorders like psoriasis, atopic dermatitis, and chronic urticaria. Nocturnal itch interrupts sleep and compromises quality of life. Traditional antihistamines offer some relief, but may be limited by daytime somnolence. The concept that antidepressants might be beneficial for pruritus is bolstered by the observation that doxepin, a tricyclic antidepressant, has been found to be a dramatically more potent histamine receptor blocker than even the most potent traditional antihistamines (eg, cetirizine, loratadine). Mirtazapine, an antidepressant, has been reported to effectively treat pruritus of cholestasis, lymphoma, and uremia.
Three patients with intractable pruritus (failed treatment with high dose antihistamines, and some other agents) responded promptly to mirtazapine 15 mg/d, including one patient who had not responded to doxepin. Mirtazapine has potent H1-antihistamine activity, but it is theorized that its adrenergic antagonism may also be involved in pruritus relief. This small pilot trial provides hope that larger trials will confirm the efficacy of mirtazapine for this and other pruritus disorders.
Interventions for the Prevention of Postoperative Nausea and Vomiting
Source: Apfel CC, et al. N Engl J Med. 2004;350:2441-2451.
As many as 1 out of 3 post-surgical patients suffer nausea and vomiting (N&V), unless prophylaxed with antiemetic pharmacotherapy. Worldwide, 75 million persons per year undergo a surgical procedure requiring anesthesia, hence optimizing N&V outcomes is a epidemiologically compelling. Not only are the symptoms troublesome, but N&V leads to serious postsurgical consequences such as aspiration, wound dehiscence, and esophageal rupture.
Six different treatments, alone and in combination, were evaluated in 5199 patients: ondansetron, dexamethasone, droperidol, substituting propofol for other anesthetics, nitrous oxide omission from the multi-drug anesthetic regimen, and remifentanil substitution for fentanyl.
The antiemetics (ondansetron, dexamethasone, droperidol) reduced N&V by about 26%, propofol by 19%, and nitrous oxide omission by 12%. Fentanyl substitution by remifentanil was not effective to reduce N&V. Combined interventions were additive to reduce N&V. Since all interventions except fentanyl substitution were beneficial, it is recommended that initial choice be based upon safety and cost. Patients at low-risk might uncommonly require prophylaxis, whereas high-risk patients could benefit from a combination of treatments.
Multivitamin Supplements and HIV Disease Progression and Mortality
Source: Fawzi WW, et al. N Engl J Med. 2004;351:23-32.
The greatest burden of the HIV epidemic resides outside the United States. Especially in economically lesser-privileged nations, not all individuals who might benefit from antiretroviral (ARV) treatment can obtain it. Observational studies have suggested that micronutrient supplementation (MNS) might be a favorable immunomodulator in HIV, perhaps delaying disease progression. If this were confirmed with interventional studies, a delay in onset of advanced disease would reduce the number of individuals needing ARV. Of course, MNS is also markedly less costly than ARV.
HIV-infected pregnant women (n = 1078) were enrolled beginning in 1995. Women were assigned to vitamin A (30 mg beta carotene + 5000 IU preformed vitamin A), multivitamins excluding vitamin A (20 mg B1, 20 mg B2, 25 mg B6, 100 mg niacin, 50 mg B12, 500 mg vitamin C, 30 mg vitamin E, 0.8 mg folic acid), the combination of both, or placebo.
Investigators measured CD4, CD8, and CD3 counts, and viral load; typical symptoms and signs of HIV disease such as diarrhea, wasting, thrush, and angular cheilitis were also followed.
The primary outcome (death or stage 4 HIV disease) was statistically reduced by multivitamins (relative risk = 0.71), as were many of the individual HIV-related complications (eg, thrush, cheilitis). Vitamin A alone produced no measurable benefit, and the addition of extra vitamin A to the multivitamin regimen actually appeared to reduce some of the benefits of multivitamins alone.
The Long-term Outcomes of Sibutramine Effectiveness on Weight (LOSE Weight) Study
Source: Porter JA, et al. Am J Manag Care. 2004;10:369-376.
Clinical trials in research settings may not reflect accurately what clinicians in a non-academic milieu may anticipate, despite using the same fundamental pharmacologic tools. Drug efficacy is sometimes distinguished from drug effectiveness by defining the former as data from randomized trials, and the latter as results in the typical practitioner’s settings.
The United States Preventive Services Task Force has encouraged diet, behavioral interventions, and pharmacologic treatment as reasonable evidence-based management choices for obesity. Sibutramine (SIB) is an FDA approved tool for adjunctive pharmacotherapy of obesity, and clinical trials confirm its durable efficacy (2 years duration). Porter and colleagues studied the effectiveness of SIB in a group-model HMO.
All of the participants (total n = 588) participated in an educational program for weight management, including seminars and visits with prevention specialists. Half of the group also received SIB, beginning with 10 mg daily, increased to 15 mg daily if the patient had not lost at least 4 pounds at the and of the first month of treatment. Sibutramine dose was decreased to 5 mg if adverse effects on pulse or BP occurred.
At 6 months, weight loss in the SIB group was substantially greater than the comparator group (6.87 kg vs 3.1 kg); this disparate success was evidenced at 1 year, with maintenance of weight loss still superior in recipients of SIB. These results closely reflect data generated by academic clinical trials. The efficacy and effectiveness of SIB appear comparable.
Trial of Atorvastatin in Rheumatoid Arthritis (TARA)
Source: McCarey DW, et al. Lancet. 2004;363:2015-2021.
Modulation of lipid levels appears to be the primary mechanism for beneficial effects of statins upon cardiovascular disease. At the same time, statins have been demonstrated in-vitro to impact on numerous aspects of inflammatory pathways, such as adhesion molecule expression and leukocyte cytokine release; similarly, vascular effects including smooth muscle apoptosis and endothelial cell function have been shown.
It has been suggested that the exaggerated cardiovascular risk associated with rheumatoid arthritis (RA) might be mediated to some degree by inflammatory pathways common to both rheumatoid arthritis and the vasculopathy. Based upon promising animal data, a study in human RA (n = 116) was undertaken to specifically examine the effects of atorvastatin (vs placebo) upon 1) a rheumatoid disease activity score (primary outcome), and 2) various secondary outcomes, including laboratory data (CRP and ESR), swollen joint count, and others. Atorvastatin was administered in a dose of 40 mg daily, in addition to traditional RA disease-modifying therapy.
After 6-months treatment there was a statistically significant improvement in the RA disease activity score, CRP, ESR and swollen joint count. There was no adverse event signal amongst atorvastatin subjects greater than placebo. Statins may have a role in attenuating cardiovascular risks in RA through both modulation of inflammatory processes and dyslipidemia.