Clinical Briefs in Primary Care
Clopidogrel + aspirin in atrial fibrillation
Source: The ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009;360:2066-2078.
Essentially all patients with Atrial Fibrillation (FIB) merit consideration of antithrombotic therapy. For persons with low-risk FIB, aspirin (ASA) is generally preferred; for others, coumadin provides greater risk reduction.
Traditionally, in FIB patients who cannot receive coumadin, ASA alone is used, with recognition that risk reduction with ASA is less than with coumadin. Adding clopidogrel (CPG) to ASA might provide additional antithrombotic efficacy, and was the subject of this trial.
FIB patients (n = 7554) with indications for, but contraindications to, coumadin were randomized to ASA alone (75-100 mg/d) or ASA 75 mg/d + CPG 75 mg/d. At a median follow-up of 3.6 years, there was a statistically significant 11% relative risk reduction (0.8% absolute risk reduction, NNT = 125) in vascular events (primarily stroke) favoring ASA + CPG.
That's the good news. The bad news is that major bleeding (consistently seen in secondary prevention trials of an ASA + CPG combo) was increased by a statistically significant 57% (absolute risk increase 0.7%, NNH = 143).
The modest risk reduction seen with the addition of CPG to ASA is essentially offset by the risk of major bleed. An accompanying editorial suggests that "… clopidogrel plus aspirin will most likely provide a net clinical benefit." I respectfully submit that the equipoise of risk reduction with excess bleeding in this trial, when coupled with the increased expense and complexity of dual therapy, leaves little to celebrate.
Preserving beta-cell function in DM2
Source: Bunck MC, et al. One-year treatment with exenatide improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients. Diabetes Care 2009;32:762-768.
A cardinal manifestation of type 2 diabetes (DM2) is progressive loss of beta-cell function (β-CF). Indeed, at the time of diagnosis, as much as 50% of β-CF has already been lost.
In addition to monitoring glucose control, this trial also measured β-CF after 1 year of treatment with either exenatide or insulin added to metformin in DM2 patients (n = 69).
At 1 year, the reduction in A1c was essentially equivalent: 0.8 (exenatide) vs 0.7 (insulin glargine). As has been previously seen, the effects on body weight differed: At 1 year, body weight increased by 1 kg on insulin vs a 3.6 kg decrease on exenatide.
At the conclusion of the trial, β-CF was measurably improved on exenatide, including first-phase insulin secretion, but was unchanged in the insulin group. Once insulin and exenatide were stopped, β-CF fell back to its pre-treatment levels in both groups.
The clinical implications of these results remain indeterminate, since cessation of exenatide was associated with prompt (< 4 weeks) resumption of pretreatment β-CF levels. Nonetheless, these results hold promise that sustained incretin-mimetic therapy might provide sustained improvements in β-CF.
Enhancing macrovascular outcomes in DM2
Source: BARI 2D Study Group. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009;360:2503-2515.
Macrovascular disease — primarily MI and stroke — is the most common cause of death and disproportionately common in persons with type 2 diabetes mellitus (DM2). BP control and reduction in LDL have both shown risk reduction of major CV events (MACE) in DM2.
Because of their high-risk status, diabetics with established coronary artery disease (CAD) are considered potential candidates for revascularization, based upon the premise of benefits seen in other high-risk populations. The recognized association of increased insulin levels with adverse MACE outcomes also suggests that insulin-sparing treatments (e.g., insulin sensitizers such as metformin, thiazolidinediones) might be beneficial. To study this, a large group of DM2 subjects (n = 2368) with established CAD was randomized to revascularization or medical therapy, and also randomized to insulin sensitizers (metformin, thiazolidinediones) or non-sensitizers (sulfonylurea and/or insulin).
At the end of 5 years, the groups did not differ in outcomes. Looking specifically at the group that underwent revascularization with CABG (vs PCI), there were significantly fewer new CV events with intervention than with medical therapy; however, the CABG group was at substantially higher risk for events at baseline. Recall that a similar study, the COURAGE trial, found no advantage to revascularization vs medical therapy in non-diabetics with chronic stable CAD. Over a 5-year interval, for most DM2 subjects, medical therapy provides equally good outcomes as surgery, and choice of therapy based upon insulin-sensitization has no effect. Persons who would qualify because of baseline high risk for CABG instead of PCI might achieve better outcomes with revascularization than medical therapy.
Recent insights into lactose intolerance
Source: Gaskin DJ, Ilich JZ. Lactose maldigestion revisited: Diagnosis, prevalence in ethnic minorities, and dietary recommendations to overcome it. Am J Lifestyle Med 2009;3:212-218.
Nelson Textbook of Pediatrics reports that lactase deficiency (LAC) occurs in 15% of whites, 40% of Asians, and 85% of blacks. Activity of lactase decreases with age. Additionally, LAC may be inherited or acquired.
Although there is some support for diagnosing LAC by response to a dairy-free diet, specific testing — hydrogen breath tests (believed to be the test of choice), lactose tolerance test, stool acidity test — can confirm the diagnosis.
Symptoms of LAC are usually dependent upon the dose of lactose: In 1 report, 20-30% of LAC subjects developed symptoms after drinking 1 glass of milk, increasing to 50% after 2 glasses. At a threshold of 50 g lactose (about four 8-ounce glasses of milk), all subjects were symptomatic.
Not everyone who perceives themselves to be lactase-deficient is: Of 40 teenage girls reporting symptomatic LAC, only 18 were confirmed by hydrogen breath testing. Perhaps not surprisingly, the BMD of self-diagnosed LAC was lower than that of the control group, corroborating the potential skeletal health consequences of dairy avoidance.
Probiotic treatment has been shown to favorably affect symptoms. In a study of Chinese subjects with LAC, Bifidobacterium animalis improved symptoms. Lactase supplements, taken 30 minutes prior to lactose ingestion, reduce — but may not totally resolve — symptoms. Osteoporosis remains a prominent global problem. Better management of LAC may reduce risk for osteoporosis.
Tamsulosin and ophthalmic surgery
Source: Bell CM, et al. Association between tamsulosin and serious ophthalmic adverse events in older men following cataract surgery. JAMA 2009;301:1991-1996.
By age 70, most men have BPH, for which α-blockers (e.g., tamsulosin, alfuzosin, terazosin, doxazosin) commonly provide symptomatic relief. Alpha receptors, the site through which prostate and bladder symptoms are believed to be ameliorated, are also present in the iris. At ophthalmic surgery, mydriasis is dependent on activation of the iris smooth muscle dilator muscle, which can be blocked by tamsulosin, resulting in intraoperative floppy iris syndrome (IFIS).
Drawing upon a database of senior men who had undergone cataract surgery between 2002 and 2007 (n = 96,128), adverse ophthalmic outcomes (retinal detachment, lens fragmentation or displacement, or endophthalmitis) within 14 days of surgery were compiled. Comparisons were made between men who did and did not receive α-blockers, with further comparison of tamsulosin vs other α-blockers.
Overall, postoperative adverse events were rare (0.3%). Nonetheless, the odds ratio for an adverse event was more than 2-fold higher in subjects treated with tamsulosin, and was not seen with other α-blockers. The increased risk for postoperative adverse events was limited to subjects receiving tamsulosin within 14 days of surgery; past users (> 14 days) of any a-blocker, including tamsulosin, had no greater risk.
Aspirin for primary prevention of CV events
Source: Antithrombotic Trialists Collaboration. Aspirin in the primary and secondary prevention of vascular disease. Lancet 2009;373:1849-1860.
Because studies of secondary prevention of CV disease contain a preselected, very high-risk group, risk reduction is more readily demonstrated than in a primary prevention population. The relative merits (or lack of same) of aspirin for primary prevention could readily confuse even the most stalwart clinician-scientist, since august consensus groups have offered widely divergent opinions based upon the same data.
The Antithrombotic Trialists Collaboration is perhaps the most widely recognized group to provide advice about aspirin treatment. In their most recent publication addressing aspirin for prevention of vascular disease, they analyzed data from 95,000 individuals in clinical trials for primary prevention.
For primary prevention, there was a reduction of CV events from 0.57%/year to 0.51%/year (a 12% relative risk reduction; P < 0.05); reduction in stroke was not significant. This 0.06%/year absolute risk reduction in CV events was offset by an absolute increase in risk of 0.03%/year in major bleeding. Perhaps most important is that although vascular events were reduced, vascular death was not significantly affected. The authors conclude: "In primary prevention … aspirin is of uncertain net value as the reduction in occlusive events needs to be weighed against any increase in major bleeds."
Clopidogrel + aspirin in atrial fibrillation; Enhancing macrovascular outcomes in DM2; Recent insights into lactose intolerance; Tamsulosin and ophthalmic surgery; Aspirin for primary prevention of CV eventsSubscribe Now for Access
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