Ethnic and Racial Differences in the Smoking-Related Risk of Lung Cancer

Source: Haiman CA, et al. N Engl J Med. 2006;354:333-342.

Although cigarette smoking is the primary risk factor for lung cancer (LCA), with similar amounts of smoking exposure some groups demonstrate greater incidence of LCA than others. To gain insight into LCA susceptibility, an analysis of data from the Multiethnic Cohort Study stratified smokers (n = 183,813) by number of cigarettes smoked, gender, and ethnicity (African American, Japanese-American, Latino, Native Hawaiian, and Caucasian). Three tiers of smoking intensity were selected: 10 or less, 11-20, and 30 or greater cigarettes per day.

For the lowest tertile of smoking intensity, African Americans and Native Hawaiians had a three-fold greater risk of LCA than Japanese Americans or Latinos, and more than double the risk of Caucasians. At intermediate levels of smoking intensity, the African American/Hawaiian population risk was still more than double that of Latino/Japanese Americans. At the highest levels of smoking, risks were similar between all ethnicities, and were only modestly influenced by gender. Although the explanation for differences between LCA risk amongst different ethnicities is not fully clear, it is recognized that, for instance, Blacks have higher levels of cotinine (a primary nicotine metabolite) than others who smoke the same number of cigarettes, suggesting a difference in metabolism, greater environmental exposure, different smoking technique, or some combination of similar factors.

Neuropathy Among the Diabetes Control and Complications Trial Cohort

Source: Martin CL, et al. Diabetes Care. 2006;29:340-344.

Neuropathy is one of the 3 cardinal microvascular complications of diabetes that have been show to be favorably impacted by tight glucose control. At the conclusion of the Diabetes Control and Complications Trial (DCCT), neuropathy was reduced by approximately one-third in the tight control group vs conventional treatment. Study subjects from both treatment arms were encouraged to participate in tight control from that point onward, since better control was associated with numerous favorable outcomes.

Eight years after DCCT completion 1,257 of the original 1,441 participants were re-examined for neuropathy. Neuropathy was assessed by symptoms alone or by the Michigan Neuropathy Screening Instrument (MNSI). Even though the overall level of glycemic control amongst the 2 groups was quite similar over the 8 year hiatus since DCCT conclusion, there remained a statistically significant lesser prevalence of neuropathy in the group originally assigned to tight control. Overall, the prevalence of neuropathy according to the MNSI was 64% less in the prior tight control group. Lower extremity amputations were similar in both groups.

These data support the concept that early intensive treatment of diabetes may have long-lasting impact. Eight years after participation in a 6.5 year (mean) intensive treatment trial, subjects achieving lower levels of A1c continue to enjoy lesser prevalence of neuropathy.

Saw Palmetto for BPH

Source: Bent S, et al. N Engl J Med. 2006;354:557-566.

Benign Prostatic Hyperplasia (BPH) is the most common neoplastic condition in aging men. Alpha blockers (ABL) such as alfuzosin, doxazosin, tamsulosin, and terazosin provide substantial symptomatic relief, but are not disease-modifying (ie, they do not alter outcomes such as need for surgical intervention or acute urinary retention). Alpha reductase inhibitors such as dutasteride and finasteride are disease modifying, but do not provide prompt symptomatic relief. Many men and their clinicians look to alternative therapies such as saw palmetto (SAW) for treatment, rather than rely upon the above traditional methods. Small studies, some with design flaws, have suggested beneficial effects for men with BPH using SAW. The study by Bent follows rigorous methodology to clarify the effectiveness of SAW for both subjective (eg, quality of life) and objective (eg, prostate size, urinary flow rate, PSA) parameters.

Men older than age 49 (n = 225) with moderate-to-severe BPH were randomly assigned to SAW (160 mg b.i.d.) or placebo and followed for 1 year. To cut to the chase,’ SAW was not superior to placebo for any measured end point. The evidence-based role of SAW for treatment of BPH is tenuous.

Quality of Reporting of Noninferiority and Equivalence Randomized Trials

Source: Henanff AL, et al. JAMA. 2006;295:1147-1151.

When one reviews the literature it is likely expected that the statistical analyses performed, the complexity of which is often beyond the ken of the practicing clinician, have been appropriately conducted and accurately reflect both the content and intent of the results. Unfortunately, sometimes this is not the case.

Noninferiority trials are usually designed to show that product B, which entered the therapeutic arena after product A, does not fall below a prespecified margin of efficacy compared to product A, in which case product B may be fairly described as "not inferior to product A." This is not the same as saying that product A and B are equivalent.’ To make that statement, an equivalency trial must be performed, which demonstrates that the efficacy of product B is within prespecified boundaries above and below when compared to product A.

The authors reviewed 116 noninferiority trials and 36 equivalence trials from literature published between 2003-2004. Discouragingly, all but 33 trials had deficits in sample size or its calculation, utilization of confidence intervals, or P value calculation. When subjected to the authors’ prespecified criteria for adequacy of study design that further included a requirement that authors justify the margins chosen to determine noninferiority, only 7 trials (4.3%) ultimately were fully satisfactory. Twelve percent of the 33 trials which satisfied overall quality concerns were considered highly misleading:’ ie, equivalence or non-inferiority was claimed when results were insufficiently robust to do so. The authors suggest that their observations call for greater rigor and uniformity both in design and reporting of noninferiority or equivalence trials.

Thyroid Status, Cardiovascular Risk, and Mortality

Source: Cappola AR, et al. JAMA. 2006;295:1033-1041.

Concern has been raised that subtle perturbations of thyroid function might lead to adverse cardiovascular outcomes. Specifically, subclinical hyperthyroidism has had a reputation of being etiologically involved with a greater incidence of atrial fibrillation. To study the relationship between thyroid dysfunctions and cardiovascular outcomes, investigators from the Cardiovascular Health Study followed subjects (n = 3,233) for new onset atrial fibrillation, coronary heart disease, stroke, cardiovascular mortality, and all-cause mortality, looking for a relationship between thyroid status and outcomes.

Only 1.5% of individuals had subclinical hyperthyroidism (ie, TSH subnormal, with normal T3 and T4). However, the risk of developing atrial fibrillation over the study period was twice as great in persons with subclinical hyperthyroidism as in those without thyroid dysfunction. There was no association of subclinical hyperthyroidism with other adverse outcomes. Similarly, the other thyroid dysfunctions (subclinical and overt hypothyroidism) were not associated with adverse CV outcomes.

Mid-life adults with subclinical hyperthyroidism are at increased risk of atrial fibrillation.

Glucosamine, Chondroitin Sulfate, and the Two in Combination for Osteoarthritis

Source: Clegg DO, et al. N Engl J Med. 2006;354:795-808.

Osteoarthritis (OA) is the most common chronic disabling condition in America. Because there are no disease-modifying drugs to treat OA, intervention relies upon symptomatic relief and improvement of function, which are usually concordant. NSAIDs and Coxibs (eg, celecoxib) have been a mainstay of therapy, but heightened awareness of the GI toxicity of traditional NSAIDs, coupled with publicity about cardiovascular risks of coxibs (ie, rofecoxib, valdecoxib) have tempered enthusiasm for their routine use.

Popular opinion, and a modest number of favorable clinical trials, have encouraged utilization of glucosamine and chondroitin for OA. Their apparent lack of toxicity, in the face of recent reappraisal of NSAID/coxib safety profiles, is additionally reassuring. Indeed, metaanalysis of existing trials has also been supportive. A single, large, randomized controlled trial was devised to help clarify uncertainties remaining after the metaanalysis indicated remaining methodologic uncertainties.

Subjects with knee OA (n = 1583) were randomized to glucosamine, chondroitin (or both), celecoxib, or placebo and followed for 6 months. Concomitant acetaminophen up to 4000 mg/d was allowed as back-up medication.

Neither glucosamine nor chondroitin, nor the combination was statistically superior to placebo in the overall analysis. In the subgroup with moderate-to-severe pain at baseline (22% of the total population), the combination of glucosamine and chondroitin was superior to placebo. That the overall population did not benefit from chondroitin or glucosamine, coupled with the fact that amongst responders, response time was quicker with celecoxib, suggests a secondary role, if any, for the glucosamine and chondroitin.