Clinical Briefs in Primary Care
Secondary Prevention of Lacunar Stroke
Source: SPS3 Investigators. N Engl J Med 2012;367:817-825.
Lacunar strokes L-CVA) are small subcortical brain infarctions that may comprise as many as 25% of ischemic strokes. Aspirin (ASA) monotherapy is already established as appropriate treatment for secondary prevention of ischemic stroke, as is clopidogrel (CLOP) monotherapy. In the CAPRIE trial, CLOP provided a marginal advantage over ASA for major adverse cardiovascular events (absolute risk reduction = 0.5%) in the overall study population, leading some to advocate clopidogrel routinely over ASA. It is often under-recognized that in the CAPRIE trial, study subjects who enrolled specifically because of previous stroke did not experience any statistically significant stroke reduction with CLOP compared to ASA; the outcomes were the same.
The Secondary Prevention of Small Subcortical Strokes (SPS3) trial is the first published trial to compare the efficacy of ASA monotherapy vs ASA + CLOP in reference to L-CVA. The study population included more than 30% Hispanics, concordant with the observation that L-CVA is more common in Hispanics.
At the conclusion of the trial (3.4 years mean), ASA + CLOP was not more effective than ASA alone in preventing L-CVA. Among the study population (n = 3020 adults with prior L-CVA), most new strokes were L-CVA (71%).
Unfortunately, as has been seen in other studies of combined ASA + CLOP, bleeding risk was significantly increased compared to ASA alone, as was all-cause mortality. Two prior trials in vasculopathic populations (MATCH, CHARISMA) have arrived at similar conclusions: For persons with stable non-acute vascular disease, ASA + CLOP is not more beneficial than ASA alone, but incurs greater bleeding risk.
Quality-of-life Effects of PSA Screening
Source: Heijnsdijk EA, et al. N Engl J Med 2012;367:595-605.
The European randomized study of Screening for Prostate Cancer (ERSPC) is a clinical trial in which adult men (n = 162,243) were randomized to prostate-specific antigen (PSA) screening or no screening. While this trial did find a statistically significant reduction in prostate cancer deaths, overall mortality was not affected, supporting the current recommendations by the United States Preventive Services Task Force (USPSTF) that PSA screening be abandoned. Although the USPSTF decision was based on the "hard" data about mortality, there is likely also substantial quality-of-life (QOL) burden engendered from PSA screening, since many — indeed, the vast majority of — men diagnosed with prostate cancer through PSA screening will die with, not from, their prostate cancer. Additionally, adverse effects of intervention for (the mostly) early prostate cancer detected through screening are not uncommon, and include erectile dysfunction and incontinence. Finally, even in men who elect not to have a surgical intervention in response to prostate cancer detected as a result of PSA screening, it would take little imagination to envision substantial ongoing concerns/anxieties referable to that diagnosis.
Heijnsdijk et al report that per 1000 men screened by PSA, nine fewer prostate-cancer related deaths would occur and 73 life-years would be gained. After adjustment for overdiagnosis and overtreatment of prostate cancer subsequent to PSA screening, these benefits were reduced by almost one-fourth. In an era when PSA screening is no longer supported because of an insufficiently favorable risk:benefit ratio, recognition of the negative QOL impact of PSA screening may help clinicians (and their patients) better come to terms with the now well-recognized limitations of PSA screening.
PSA Elevations After Prostate Cancer Radiotherapy
Source: Crook JM, et al. N Engl J Med 2012;367:895-903.
Since prostate cancer (PCA) is often an-drogen-dependent, PCA recurrences after radiotherapy are often treated with androgen deprivation by means of regimens consisting of continuous luteinizing hormone-releasing hormone agonists (LHRHa) combined with antiandrogens. Unfortunately, such treatment is associated with hot flashes, decreased libido, urinary symptoms, and fatigue. Might intermittent androgen deprivation be equally effective, but less problematic as far as adverse effects?
Crook et al randomized patients who had undergone radiation treatment for PCA but had a post-treatment PSA > 3.0 ng/dL to continuous or intermittent androgen deprivation.
For overall mortality, intermittent androgen deprivation was non-inferior to continuous treatment. The time to development of castration-resistant disease (the stage at which androgen deprivation no longer represses disease progression) was significantly longer for intermittent treatment. Similarly, the adverse effects of hot flashes, libido, and urinary symptoms were all significantly fewer in the intermittent treatment group. In addition to necessitating a substantially reduced amount of medication (and of course, expense), intermittent androgen deprivation regimens are non-inferior for overall mortality, and are associated with superior quality of life.
Attenuated CV Benefits of Clopidogrel in Diabetes
Source: Andersson C, et al. JAMA 2012; 308:882-889.
There is no controversy over whether antiplatelet therapy (e.g., aspirin, clopidogrel, prasugrel) reduces cardiovascular (CV) events when used for secondary prevention (i.e., post-acute coronary syndrome, post-myocardial infarction [MI], post-stroke). It is equally apparent that risk reduction through antiplatelet therapy is not equal among all risk groups. For instance, although aspirin (ASA) consistently shows CV risk reduction in mixed populations post-MI, two clinical trials of ASA comprised solely of diabetics failed to show benefit. Diabetics are known to have greater platelet reactivity, and their platelets are relatively resistant to antiplatelet effects as measured by medication-induced platelet aggregation inhibition testing.
Comparative benefits of clopidogrel in diabetics vs non-diabetics have not been described well enough. To assess whether diabetics fare as well with clopidogrel post-MI as non-diabetics, Andersson et al reviewed data from the Danish nationwide administrative registries of patients discharged from the hospital post-MI (n = 58,851), of which 12% had diabetes.
One-year follow-up compared outcomes among all persons treated with clopidogrel. Although all groups did have CV risk reduction from clopidogrel treatment, there was a significant difference between diabetics and non-diabetics, favoring non-diabetics. For instance, the hazard ratio (HR) for all-cause mortality was more than twice as favorable for non-diabetics (HR = 0.75, a 25% reduction) than diabetics (HR = 0.89, an 11% reduction).
The obstacle of clopidogrel-resistant platelets can be overcome by dose intensification (i.e., more clopidogrel), combination therapy (i.e., clopidogrel + ASA), or consideration of another P2y12 agent (i.e., prasugrel). Unfortunately, however, each of these methods has been associated with an increased risk for bleeding. Optimization of antiplatelet therapy in diabetics remains somewhat elusive.
Is A1c Always the Best Game in Town to Monitor Type 2 Diabetes?
Source: Wright LAC, Hirsch IB. Diabetes Spectrum 2012;25:141-148.
Even as time-honored a metric as A1c has limitations. There are, for instance, situations in which A1c can markedly mis-estimate actual sustained glucose concentrations. Since A1c measurement requires hemoglobin to be exposed to excess glucose for the entire life of a red cell (90-120 days), anything that shortens red cell life (e.g., thalassemia, Hgb C, HbS, hemolysis) will underestimate actual sustained glucose levels (since red cells don't live long enough to become fully glycosylated). Hemoglobin F, which is persistent in a small percentage of adults, glycosylates so rapidly that even very modest elevations of glucose can induce marked elevations of A1c (A1c 12%-17% or greater), grossly overestimating sustained glucose levels.
Fructosamine is a composite measure of relatively short-lived serum proteins that have become converted into irreversible ketoamines, of which glycated albumin is the primary component (approximately 90%). Since this process occurs over a few weeks, red cell life span — shortened or not — has no impact. Similarly, however, the measurement of fructosamine only provides an observation window of the sustained glucose levels in the preceding 2-3 weeks. Any condition that alters serum protein turnover (eg, thyroid dysfunction, hypopoproteinemia, nephrotic syndrome) can invalidate fructosamine measurement.
Glycated albumin, the primary protein constituent of fructosamine, has been compared with A1c and fructosamine in patients with advanced chronic kidney disease, and found to be the most accurate marker in this population, although it is subject to the same perturbations as fructosamine mentioned above.
One other serum marker not used commonly in the United States, but widely used in Japan, is 1,5 anhydroglucitol (1,5-AG), which reflects sustained glucose over a 2-14 day period. Normally, 1,5-AG is reabsorbed by renal tubules; when plasma and urine glucose are high, they compete with 1,5-AG for reabsorption, resulting in loss of 1,5-AG in the urine, with a corresponding diminution in plasma 1,5-AG. This metric has been found to be particularly useful in measurement of postprandial glucose excesses.
For the time being, A1c will remain the metric of choice for most patients. When A1c and individual glucose measurements are discordant, consideration of another metric is appropriate.Secondary Prevention of Lacunar Stroke; Quality-of-life Effects of PSA Screening; PSA Elevations After Prostate Cancer Radiotherapy; Attenuated CV Benefits of Clopidogrel in Diabetes; Is A1c Always the Best Game in Town to Monitor Type 2 Diabetes?
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