Renal Patients Facing Contrast Exposure -- How Should You ACT? Day 3 Highlights From AHA 2010

Melissa Walton-Shirley, MD


November 17, 2010

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Hello. It's day 3 of the 2010 American Heart Association meeting. Today's information might just change the way you prepare your patients with renal insufficiency for contrast exposure as we discuss the ACT [Acetylcysteine for the Prevention of Contrast-Induced Nephropathy Trial.][1] We'll also look at BASKET PROVE [Basel Stent Cost Effectiveness Trial - Prospective Validation Examination] trial[2] and platelet inhibition strategies, as well as the GRAVITAS [Gauging Responsiveness With A VerifyNow Assay-Impact On Thrombosis And Safety] study,[3] which addressed the theory of utilizing the VerifyNow assay to guide clopidogrel dosing. Finally, we'll hear what doesn't work in peripheral vascular disease in the TAMARIS [NV1FGF Gene Therapy on Amputation- Free Survival in Critical Limb Ischemia - Phase 3 Randomized Double-Blind Placebo-Controlled] trial.[4]

First, let's look at the ACT trial.[1] This very important study addressed the common practice of premedication of renal patients who are facing contrast exposure. It's generally common in practice to hydrate the patient with normal saline, with or without bicarbonate. It's also usual to administer N-acetyl-L-cysteine, marketed under the name Mucomyst®, before and after the procedure. In this trial, the practice was replicated and compared with a placebo group who received intravenous hydration; the greatest majority of placebo patients also received bicarbonate.

At the 30-day endpoint, this trial (the largest randomized trial of N-acetyl-L-cysteine in history) did not demonstrate any benefit of this strategy over that of placebo. It was the hope of the presenter that this information would not only assist in clinical practice strategies but would also provide information to drive change in current guidelines.

The BASKET PROVE trial[2] looked at the signal noted in the original BASKET trial, suggesting that patients with large epicardial vessels might have a higher event rate with drug-eluting stents, as compared with bare metal stents (BMS). A total of 2314 patients were randomly assigned, in a 1:1:1 fashion, to receive a Cypher (Johnson & Johnson; Miami Lakes, Florida), Vision (Abbott Vascular; Abbott Laboratories, Illinois), or Xience V stent. (Abbott Vascular). Dedicated questionnaires were administered at 12 and 24 months. The primary endpoints were cardiac death and myocardial infarction (MI) up to 24 months. Comparisons were also made between sirolimus and bare metal, and everolimus and bare metal. One of the main secondary endpoints, of course, was target vessel revascularization (TVR).

The conclusion was that a drug-eluting stent may be used without evidence of increased late cardiac events in large vessels, and a BMS may still be used, but with an expected higher TVR rate. Finally, the performance of both drug-eluting stents, the Cypher and the Xience, was similar.

The GRAVITAS study[3] was the largest dedicated randomized trial to test patients with a baseline high platelet reactivity. The VerifyNow assay for platelet activity was employed in order to predict whether patients might benefit from a dose of 150 mg of clopidogrel, more than the standard 75-mg dose. A total of 5429 patients (60% of whom had stable angina; the remainder had mostly unstable angina) were screened with the VerifyNow P2Y12 screen at 12 and 24 hours post-MI. Less than half (2214 patients) were found to have high residual platelet reactivity ≥ 230 platelet reactivity units; of those, 1109 were given a high-dose clopidogrel load at 600 mg, followed by 150 mg per day for 6 months; 1105 patients were given the standard 75-mg dose daily.

This experiment was deemed a neutral trial, failing to affect the primary endpoint of cardiovascular death, nonfatal MI, or stent thrombosis at 6 months. There was much discussion as to how the other platelet inhibitors that are coming down the pike might have influenced this outcome in patients with high residual platelet reactivity.

The presenter of the TAMARIS study[4] began by reminding the audience of the grave cardiovascular risks and poor outcome predicted by the presence of peripheral vascular disease. In the first year after diagnosis, 20% of those patients will be deceased and 35% will require an amputation. This study was born of an overwhelmingly positive, small phase 2 trial of 125 patients that suggested a decrease in limb loss when NV1FGF, a nonviral recombinant DNA plasmid, was used. The initial gene-transfer trial suggested a lower combined major amputation and death rate at 25 weeks. Based on the hope that these results could be replicated, TAMARIS (the largest trial to date in chronic lower extremity ischemia patients, with ischemic skin lesions unsuitable for revascularization) was postulated. Unfortunately, 4 doses of 4 mg of NV1FGF delivered intramuscularly did not improve amputation-free survival, underscoring the importance of conducting large phase 3 trials before coming to any conclusions. Unfortunately, we are left to still search for answers for those with no options for lower-extremity revascularization.

It's been a fascinating 3 days here at the 2010 American Heart Association meeting. We're glad to have you join us for the day in review. Join us next time at the American College of Cardiology meeting in 2011, where we'll continue to look at the day's most interesting clinical trials. I'm Melissa Walton-Shirley, hoping that you have a most productive and pleasant practice week.


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