Clinical Briefs in Primary Care
NSAIDs and the Risk of Upper Gastrointestinal Bleeding
Source: Lanas A, et al. N Engl J Med 2000;343:834-839.
The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is commonly acknowledged as one of the most important contributors to risk for upper gastrointestinal (GI) bleeding, attributed to inhibition of COX-1. Among the tools used to try to reduce such risk, animal studies have shown that substances that stimulate nitric oxide (NO) in the GI tract may reduce NSAID-induced gastric damage. Since agents like nitroglycerin, a prototypic NO source, are inexpensive, readily available, well tolerated, and thoroughly studied, if similar effects were seen in humans, perhaps GI toxicity of NSAIDs could be reduced. Of concern, however, is the knowledge that NO inhibits platelet aggregation, which in the face of GI bleeding, might retard coagulation and, hence, worsen the problem.
To examine the relationship between NSAIDs and nitrosovasodilators (e.g., nitroglycerin) in respect to GI bleeding, Lanas and colleagues performed a case-control study (n = 3353) comparing persons admitted for GI bleeding with patients admitted for other diagnoses and other local outpatients.
Almost half of persons with GI bleeding had been taking a NSAID in the week before admission. Increased risk of GI bleeding associated with NSAID use ranged from an odds ratio of 7.4 (mostly traditional dose non-COX-1-sparing NSAIDs) to 2.4 (low-dose aspirin), which came as little surprise. On the other hand, use of nitrovasodilators was associated with a statistically significant 0.6 odds ratio of GI bleeding, and even in persons taking a NSAID, nitrovasodilator therapy was associated with a decreased odds ratio of GI bleed. It is hoped that new NO-releasing NSAIDs, which are currently under investigation, will demonstrate favorable effects on GI toxicities.
Comparative Efficiency of PSA Screening Strategies for Prostate Cancer Detection
Source: Ross KS, et al. JAMA 2000;284:1399-1405.
Despite the fact that prostate-specific antigen (PSA) screening has not been proven to reduce mortality from prostate cancer, millions of U.S. men undergo this testing annually in hopes that such screening will have a favorable effect. Sufficient numbers of clinicians have embraced the intuitive positive effect of PSA testing that despite unproven efficacy, using PSA screening has become perceived more as the norm than the exception. In an effort to evaluate, by means of a statistical marker, which modifications of PSA screening might enhance its efficacy, Ross and colleagues compared several PSA screening strategies in this trial.
Considerations focused upon the PSA threshold for prostate biopsy (i.e., the PSA level at which biopsy would be recommended), the frequency of PSA testing (testing interval), and age of PSA testing initiation.
According to Ross et al’s statistical model, if PSA testing were to begin at age 40-45 (instead of the more traditional 50 years of age), followed by testing every two years at age 50, mortality would be favorably affected, with fewer PSA tests and biopsies. On the other hand, if the threshold for biopsy of the prostate were to be reduced below a PSA level of 4.0 ng/mL, no measurable net benefit would be anticipated.
White Coat Effect of Alcohol
Source: Ryan WM, Howes LG. Am J Hypertens 2000;13:1135-1138.
The lifestyle habit of imbibing alcohol in moderation has been associated with a reduced risk of ischemic heart disease, attributed to such benefits as an improved HDL cholesterol. On the other hand, the relationship between alcohol consumption and elevated blood pressure has also been consistently noted. Since one reason that the alcohol-blood pressure relationship has not led to anticipated negative heart disease impact might be that alcohol induces spurious, or transient, BP elevations, Ryan and Howes studied the relationship between alcohol intake and clinic, as well as ambulatory monitored blood pressure.
The study group included 121 adult men with either controlled hypertension (77%) or who were normotensive. Persons with established liver disease were excluded. More than half of participants consumed alcohol daily. Alcohol consumption was not related to the systolic blood pressure as measured by ambulatory monitoring, but was associated with clinic systolic blood pressure. Ryan and Howes suggest that much of the relationship between alcohol consumption and blood pressure is attributable to the white coat effect, as ambulatory pressure is not related. Additionally, for persons in whom clinic and ambulatory blood pressure show marked discrepancy, a case can be made for investigation of alcohol intake as an explanation.
Polymorphisms in the Factor VII Gene and the Risk of MI
Source: Girelli D, et al. N Engl J Med 2000;343:774-780.
Myocardial infarction (mi) often results from the collusion of atherosclerotic coronary vascular disease and abnormal coagulation factors, including factor VII (F7). Elevated F7 levels have been reported in some (but not all) studies to be a predictor of mortality due to coronary heart disease, and are influenced by both environmental and genetic factors. Genetic polymorphisms result in variable levels of F7, and since some data suggest that F7 levels may either favorably, or unfavorably, affect the course of severe atherosclerosis, Girelli and colleagues selected a population (n = 444) of persons with angiographically proven severe multivessel coronary artery disease for evaluation of the relationship between F7 and vascular outcome.
Several different genetic polymorphisms were associated with statistically significantly different levels of F7. Similarly, some genotypes were found to be cardioprotective, in that they were associated with lesser frequency of MI than others. As anticipated, genotypes with the lowest mean activated F7 were also associated with reduced odds ratio for MI.
Girelli et al conclude that some of the difference in frequency of MI among persons with equally severe coronary artery stenosis may be secondary to differences in F7 levels, reflecting different underlying genetic polymorphisms.
Arthritis Drugs and GI Toxicity
Source: Silverstein FE, et al. JAMA 2000;284:1247-1255.
The commonly quoted risk of significant gastrointestinal (GI) ulcer complications of NSAID treatment is 2-4% per year from the older, nonspecific NSAIDs. Newer COX-2 specific agents have been developed intending safer GI toxicity profiles, with equal therapeutic efficacy. The current trial compared patients with osteoarthritis or rheumatoid arthritis treated with six months therapy of celecoxib (Celebrex), ibuprofen (Motrin, and others), or diclofenac (Voltaren, and others).
Approximately 8000 patients were randomized. The dose of celecoxib used was substantially higher than typically used in practice in the United States: 400 mg twice daily. Doses of ibuprofen (800 t.i.d.) and diclofenac (75 mg b.i.d.) were more typical of standard use.
The annualized rate of GI ulcer complications in the celecoxib group was approximately half that of persons taking nonspecific NSAIDs (0.76% vs 1.45%). For GI adverse events of sufficient effect to cause drug withdrawal, celecoxib was associated with equal or lower rates than nonspecific NSAIDs, with the exception of rash, which was about twice as common on celecoxib, and pruritus, which was about 1.5 times more frequent with celecoxib. On the other hand, overall GI symptoms were significantly less frequent on celecoxib than comparators.
Silverstein and associates conclude that celecoxib, even in doses 2-4 times greater than typically used, provides a greater safety profile than traditional NSAIDs.
Effect of Niacin in Patients with Diabetes and Peripheral Arterial Disease
Source: Elam MB, et al. JAMA 2000;284:1263-1270
Arteriosclerotic vascular disease remains the primary cause of death in diabetics, attributable to some degree to lipid aberrations often seen in this population. Although niacin treatment in nondiabetic populations demonstrates favorable effect on LDL, HDL, and triglycerides, concern about potential worsening of diabetic control as a result of niacin therapy has widely restricted its use. Conclusions that niacin is "relatively contraindicated" in diabetes stem from limited clinical data. Since lipid control and subsequent cardiovascular disease end points are of crucial importance, and expanding the therapeutic choices might enhance success in achieving normolipidemia, a trial in high-risk individuals with peripheral vascular disease (n = 468), of whom about 30% were diabetic, was performed to ascertain the potential role of niacin therapy. Patients received nicotinic acid at doses up to 3000 mg/d (or less, if not tolerated) for up to 60 weeks.
Niacin increased HDL (29%), and reduced LDL (8-9%) and triglycerides (23-28%) in diabetic and nondiabetic persons. There was no effect of niacin treatment from baseline on hemoglobin A1c, despite a small increase in glucose levels. Elam and colleagues conclude that niacin therapy may be safely and effectively prescribed in diabetics, and may serve as rational alternatives to patients who fail or do not tolerate statins or fibrates.
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