Cardiology News

9 ACC 2016

Vol. 13 • No. 1 • 2016 • C ardiology N ews

Novel drug fails to prevent contrast-induced nephropathy

BY BRUCE JANCIN C MX-2043, a novel agent intend- ed for prevention of contrast- induced nephropathy, failed in the phase II, double-blind, placebo- controlled CARIN clinical trial pre- sented at the annual meeting of the American College of Cardiology. The drug had also shown promise in small preliminary studies for the prevention of periprocedural myo- cardial infarction in patients under- going coronary stenting. There again, however, CMX-2043 – a derivative of alpha lipoic acid with antioxi- dant and cell membrane-stabilising properties – proved ineffective in

losmapimod, a drug developed to improve outcomes in patients with an acute coronary syndrome. “It’s a bit distressing” to witness back to back presentations of clini- cal trials that proved resoundingly negative despite very strong-looking preliminary data, commented dis- cussant Dr Anthony N. DeMaria, professor of medicine at the Univer- sity of California, San Diego. What’s going on here? he asked. “I think it’s a fundamental truth that a lot of things that look good in preclinical work, even when backed up by a lot of solid science, don’t pan out in human studies,” Dr Bhatt

was present in terms of the primary study endpoint: the incidence of acute kidney injury as defined by at least a 0.3 mg/dL rise in serum creatinine from baseline on day 4. No dose response to CMX-2043 was evident, nor did the investigational agent have any impact on the risk of major adverse cardiovascular events. Immediately prior to Dr Bhatt’s presentation, Dr Michelle L. O’Donoghue of Brigham and Women’s Hospital presented the equally negative results of the LAT- ITUDE-TIMI 60 trial, a phase III trial of the investigational mitogen- activated protein kinase inhibitor

the 361-patient, 31-centre phase II trial, reported Dr Deepak L. Bhatt, professor of medicine at Harvard Medical School and executive direc- tor of interventional cardiovascular programs at Brigham and Women’s Hospital, both in Boston. All participants in CARIN had baseline severe impairment of kidney function or mild to moderate renal impairment plus another risk factor, such as diabetes or age greater than 75 years. One hour prior to coronary angiography, they received various doses of CMX-2043 or placebo. Unfortunately, no difference between the four treatment arms

replied. “That’s a challenge, and probably in no other arena more so than in tackling inflammation and antioxidant therapy.

I think it’s a fundamental truth that a lot of things that look good in

“There’s a graveyard of compounds that have not worked, and now we’ve perhaps added another one,” Dr Bhatt continued. “But it doesn’t mean that scientific inquiry isn’t im- portant, because I think eventually we’ll have drugs for these problems, whether it’s reperfusion injury or contrast-induced nephropathy. It’ll probably just take a lot more time and effort.” The one solace regarding the CARIN trial, in Dr Bhatt’s view, is that it highlighted the advantages of what is known as an adaptive trial design. Instead of jumping from positive early-phase results straight to a definitive 10,000-patient phase III clinical trial, investigators were able to obtain answers regarding the drug’s ability to prevent two major problems in patients undergoing coronary angiography – contrast- induced nephropathy and major adverse cardiac events – by means of a single 361-patient trial that was comparatively inexpensive. Acute kidney injury secondary to exposure to contrast agents re- mains a significant problem, with an incidence of 20–25% in high- risk patients. Numerous proposed prophylactic agents have ultimately proved not useful, including sodium bicarbonate, N-acetylcysteine, and intravenous fenoldopam. Indeed, the only preventive meas- ures of proven effectiveness are hydration with saline for 12 hours preangioplasty, and limiting the vol- ume of contrast agent used. In real- world clinical practice, however, it’s often impractical to administer the optimal 12 hours of saline because of hospital pressure to get patients out quickly, Dr Bhatt observed. “There remains an important un- met clinical need to find agents that reduce the occurrence of contrast nephropathy,” he stressed. Ischemix funded the CARIN trial. Dr Bhatt reported receiving a re- search grant from the company that was directed to Brigham and Women’s Hospital. preclinical work, even when backed up by a lot of solid science, don’t pan out in human studies.

NEW

Resolute Onyx ™ ZOTAROLIMUS-ELUTING CORONARY STENT SYSTEM MOSTDELIVERABLEDES 1 FEATURINGCOREWIRE TECHNOLOGY BROADSIZEMATRIX OPTIMISINGTREATMENTOF COMPLEXCASES PROVEN LONG-TERMSAFETYANDEFFICACY 2,3 THEGLOBAL RESOLUTE PROGRAM

Bayer Xarelto ®

1 Based on bench test data vs. Promus Premier™ DES, Synergy™ II DES, Xience Xpedition™ DES and Resolute Integrity™ DES. 2 Silber S et al. Eur Heart J. 2014;35(29):1949-1956 3 Kandzari D et al. JACC. 2013; Vol.6, No. 5: 504-512

5

Medtronic Resolute Onyx™

8–9

Novartis Entresto

13