Clinical Briefs in Primary Care
Dabigatran vs warfarin: Less bleeding?
Source: Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-1151.
Numerous prospective trials have confirmed that anticoagulant therapy with warfarin (WRF) provides substantial stroke risk reduction for patients with atrial fibrillation (AF). Overall, AF patients enjoy as much as a two-thirds reduction in risk of ischemic stroke when WRF has been compared with placebo in clinical trials. These benefits notwithstanding, utilization of WRF is complex and entails significant risk of bleeding. Direct thrombin inhibitors (DTIs) such as ximelagatran have previously demonstrated comparable stroke risk reduction in AF as WRF, with less risk of serious bleeding; additionally, direct thrombin inhibitors do not require ongoing monitoring to assure a therapeutic range, simplifying the level of involvement required of the patient. Unfortunately, clinical trials with earlier DTIs (e.g., ximelagatran) showed a significant risk of hepatotoxicity, precluding clinical use in the United States.
Dabigatran (DAB) is an oral DTI administered twice daily. Based upon favorable results from pilot trial data in AF and venous thromboembolism, a major clinical trial (n = 18,113) was undertaken to compare warfarin with DAB in AF.
After a median follow-up of 2 years, DAB fulfilled expectations that it provided risk reduction as great as or superior to WRF, with similar or fewer bleeding events. The orally administered DTI class shows great promise as an alternative to WRF.
Does SHBG increase risk of diabetes?
Source: Ding EL, et al. Sex hormone-binding globulin and risk of type 2 diabetes in women and men. N Engl J Med 2009;361:1152-1163.
Sex hormone-binding globulin (SHBG) is a protein that might seem to be most interesting to the endocrinologist, since its sole function — until very recently — has been thought to be regulation of the availability of gonadal steroids. For instance, in women with acne, the primary therapeutic effect of estrogen therapy (as in oral contraceptives) is that estrogen increases SHBG levels; the increased SHBG binds plasma testosterone, leaving less free (unbound) testosterone to drive acne.
It may be that SHBG has other pertinent functions. The Women's Health Study provided the data set from which the relationship between plasma SHBG and incidence of type 2 diabetes could be examined. Comparing the SHBG level in women with newly diagnosed diabetes to controls (total n = 718), a steep inverse linear relationship between SHBG and odds ratio for developing type 2 diabetes was demonstrated. Compared to women in the lowest quartile of SHBG, those in the highest quartile were more than 10 times less likely to have incident diabetes. Corroborating results were found in men looking at a similar population from the Physician's Health Study. The mechanism by which SHBG affects diabetes risk is speculated to be related to direct modulation of gonadal steroids on tissues, but is otherwise ill-defined.
There are identified genes associated with production of SHBG. Both SHBG levels and gene identification may become useful to predict risk of type 2 diabetes.
Effect of CYP2C19 variants on clopidogrel
Source: Shuldiner AR, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 2009;302:849-857.
Clopidogrel (cpg) and aspirin (ASA) are widely utilized as antiplatelet agents for both primary and secondary prevention of cardiovascular disease. Because platelet activation, adhesion, and aggregation are modulated by multiple redundant pathways, it should come as no surprise that any single pharmacologic intervention might be imperfect in its ability to curtail platelet activity. Additionally, even when an antiplatelet agent is mechanistically highly effective, intra-individual variations in metabolism and genetics exert great influence on pharmacokinetics.
CPG must be converted into an active metabolite by the P450 2C19 pathway to functionally impair platelet activity. The impact of genetic variations in 2C19 activity may be examined in vitro through platelet aggregometry. If the laboratory discerns meaningful differences in platelet activity related to genetic variations in 2C19, the next question would be whether such factors impact clinical endpoints.
Chromosomal analysis indicates a strong relationship between genetic variations in 2C19 activity and platelet aggregability in response to clopidogrel, consistently predicting incomplete CPG activity upon platelets.
After confirmation of the 2C19-clopidogrel relationship, a population of individuals undergoing PCI (after which clopidogrel treatment is standard) were followed for 1 year. During this year, those with genetic variants impairing the antiplatelet activity of CPG were more than twice as likely to incur a CV ischemic event or death. In the future, therapeutic choices may be directed by knowledge of such genetic variation.
Denosumab for osteoporosis
Source: Cummings SR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756-765.
It appears that osteoporosis (OSPS) is the end result of a war lost by the osteoblasts to the conquering osteoclasts, whether by frailty of the former, vociferousness of the latter, or some similar combination of factors. Indeed, our most popular tools for the prevention and treatment of OSPS — bisphosphonates — mediate improvements in bone mineral density through downregulation of osteoclasts.
Denosumab is an antibody against the activator of osteoclasts called RANKL. Once RANKL is antibody-blocked, osteoclast activity is reversibly inhibited. Denosumab has the desirable characteristic of only requiring a subcutaneous injection every 6 months.
The study by Cummings et al enrolled almost 8000 osteoporotic women who were randomized to denosumab or placebo twice yearly for 3 years. Over that interval, a 40%-60% decrease in hip fracture and vertebral fracture was seen (compared to placebo), with no incidence of the osteonecrosis that has been troublingly reported (albeit rarely) with bisphosphonates. The favorable tolerability of this agent (adverse effect profile similar to placebo) adds to the allure of this yet-to-be approved alternative for OSPS.
CRP and HTN treatment
Source: Fulop T, et al. C-reactive protein among community-dwelling hypertensives on a single-agent antihypertensive treatment. J Am Soc Hypertens 2009;3:260-266.
C-reactive protein (CRP) is a recognized marker of inflammation, and is linearly associated with acute cardiovascular endpoints (e.g., MI, stroke). Whether this association is causal, concomitant, or consequent remains a matter of great debate. Indeed, even for advocates of the "CRP-leads-to-CVD events" hypothesis, it remains to be determined whether interventions which specifically lower CRP reduce events, and if so, whether event reduction is secondary to CRP reduction, or another cotherapeutic effect (i.e., as in statin therapy, wherein CRP is reduced, but so is LDL).
Hypertension is recognized to be the most important modifiable risk factor for cardiovascular disease. Different classes of antihypertensive therapy might have different effects upon CRP. To address this, a subgroup of the Genetic Epidemiology Network of Arteriopathy study group was analyzed. In this population, 662 subjects who were on monotherapy for hypertension (HTN) had their CRP measured. After adjustment for a variety of other factors (e.g., age, gender, BMI, smoking, diabetes), there were distinct differences in mean CRP depending upon which class of HTN monotherapy was being used. Overall, CRP levels were lowest in persons on inhibitors of the renin-angiotensin-aldosterone group (e.g., ACE inhibitor, ARB) and highest in the group on diuretics.
Current expert opinion suggests that simple blood pressure reduction is the primary effector of CV risk reduction, regardless of therapeutic class. The debate about whether therapeutic side-stream characteristics (e.g., class of agent, activity upon the renin-angiotensin-aldosterone system, metabolic effects) are important in selection of treatment will likely gain further fuel by these observations that various classes of HTN treatment differ in their effect upon the inflammatory marker CRP.
Dabigatran vs warfarin: Less bleeding?; Does SHBG increase risk of diabetes?; Effect of CYP2C19 variants on clopidogrel; Denosumab for osteoporosis; CRP and HTN treatment;Subscribe Now for Access
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