Clinical Briefs
By Louis Kuritzky, MD, Clinical Assistant Professor, University of Florida, Gainesville. Dr. Kuritzky is a consultant for Sucampo Pharmaceuticals, Takeda, Boehringer Ingelheim; and is a consultant and on the speaker's bureau for Novo Nordisk, Lilly, Daiichi Sankyo, Forest Pharmaceuticals, Cephalon, Novartis, and Sanofi Aventis.
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 low-risk FIB patients, 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.
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 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.
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 (b-CF). Indeed, at the time of diagnosis, as much as 50% of b-CF has already been lost.
In addition to monitoring glucose control, this trial also measured b-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, b-CF was measurably improved on exenatide, including first-phase insulin secretion, but was unchanged in the insulin group. Once insulin and exenatide were stopped, b-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 b-CF levels. Nonetheless, these results hold promise that sustained incretin-mimetic therapy might provide sustained improvements in b-CF.
The ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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