PracticeUpdate: Cardiology

AHA 2016

9

EXPERT OPINION Dr Joerg Herrmann on the FUTURE, EUCLID, ART and PRECISION trials

Written by Joerg Herrmann MD

The FUTURE trial The FUTURE trial set out to randomise over 1,700 patients with multivessel CAD that had to include the LAD to either FFR or angiography alone in order to test if FFR helps guide treatment strategy and thereby improves outcome. The study was powered to detect a 30% relative reduction in the risk of MACE. However, at just over 900 patients, the data safety monitoring and steering committee advised to stop the trial in view of an >2-fold increase in overall mortality in the FFR group. One-year outcome data available for nearly 800 patients does not show a significant difference in overall MACE and only a trend towards higher overall and CV mortality in the FFR group. In summary, this trial may cast some uncertainty on the future of the use of FFR in clinical practice. Further data are needed on the impact on decision making and how this could be linked to adverse outcomes. By itself the FFR procedure does not increase the risk and nothing else is evident and intuitive. However, the trial is a good reminder that one of the greatest benefit in all previous FFR trials was the reduction of stent implantations when haemodynamically not required, and thereby a reduction of costs and related risks. The EUCLID trial Encouraged by the results of the PLATO trial of superior outcomes of ticagrelor compared with clopidogrel in ACS patients and the PEGASUS trial on the benefits of ticagrelor over aspirin in patients with PAD,

In the post-hoc analyses of any CV, GI, or renal event, celecoxib had the lowest risk, naproxen had intermediate risk and ibuprofen the highest risk. These findings are striking as they grant absolution to a drug condemned in the cardiovascular community.

analyses it was associated with a lower risk of cardiovascular events and mortality compared with ibuprofen. Celecoxib was associated with a lower risk of major GI events compared with both naproxen and ibuprofen and a lower risk of serious renal events than ibuprofen and even naproxen in the on-treatment analyses. In the post-hoc analyses of any CV, GI, or renal event, celecoxib had the lowest risk, naproxen had intermediate risk and ibuprofen the highest risk. These findings are striking as they grant absolution to a drug condemned in the cardiovascular community. These charges date back to COX-2 inhibitor story, which made headlines just over a decade ago, pointing out the increased risk of cardiovascular events with these drugs. Vioxx was the prime contender and eventually left the market in 2004; Bextra followed in 2005. This has left Celebrex as the sole COX-2 inhibitor on the US market with stern black box warnings. Other NSAIDs have also been confronted with heightened levels of concern eg, ibuprofen, whereas Naproxen has prevailed in current opinion as one of the safer representatives in his class. PRECISION would attest that it is safer than ibuprofen, but even so, the winner is, this time: celecoxib, but against NSAIDS that also carry a risk.

5 years of follow-up. However, the incidence of sternal wound complication and reconstruction was 2 and 3-fold higher, respectively, with bilateral IMA bypass grafting, and all of these events occurred in the first year and mainly in diabetics and those with high BMI. Of further note, 14% of patients assigned to bilateral IMA underwent single IMA only versus 2.4% of patients assigned to single IMA undergoing bilateral IMA bypass surgery. In summary, adding one more IMA graft to patients undergoing CABG with LIMA grafting does not add further clinical benefit but may increase the risk of sternal wound complication especially in at risk populations. The PRECISION trial This mega trial involved nearly 1,000 centres worldwide that enrolled 24,000 osteoathritis or RA patients with CV disease or risk requiring NSAID therapy for at least 6 months. Patients were randomly assigned to celecoxib 100 mg bid, ibuprofen 600 mg tid, or naproxen 375 mg bid in conjunction with esomeprazole. Celecoxib was not inferior to naproxen and ibuprofen with regards to major adverse cardiovascular events in the intention- to-treat analyses. In fact, in the on treatment

the EUCLID trial was pursued. This was a trial assessing the incidence of cardiovascular death, MI, and stroke in nearly 14,000 patients with symptomatic PAD randomised to ticagrelor or clopidogrel. No difference in the primary composite endpoint was found, even though there was a significant, 20% lower rate of ischaemic stroke in the ticagrelor group. There was no difference in bleeding events. Even though contrary to the study hypothesis, one important point is that poor metabolisers of clopidogrel were excluded from this trial. Thus, in essence this trial then shows that clopidogrel is as effective as ticagrelor in this population when effectively metabolised. The observation of the difference of a lower rate of strokes with ticagrelor needs further exploration. These findings are opposite to the PLATO trial results. The ART trial The ART trial randomised >3000 patients scheduled for coronary artery bypass grafting (CABG) to either left or bilateral internal mammary (IMA) bypass grafting (of note, over three quarters of patients had two or three additional grafts). No significant differences in major cardiovascular outcomes were found over

Dr Herrmann is Associate Professor of Medicine at Mayo Graduate School of Medicine, Rochester, Minnesota.

Extended-duration betrixaban reduces stroke risk vs standard-dose enoxaparin in hospitalised medically ill patients

T his outcome of a substudy of the Acute Medically Ill Venous Thromboembolism Prevention with Extended Duration Betrixaban (APEX) trial was reported at the AHA Scientific Sessions 2016. Michael Gibson, MS, MD, of Beth Israel Deaconess Medical Center, Boston, Massachusetts,

Among hospitalised medically ill patients, extended-duration betrixaban has been shown to significantly reduce all-cause and ischaemic stroke versus standard-of-care enoxaparin through 77 days.

to treat 233) and ischaemic strokes (0.48% vs 0.91%, relative risk 0.53 [0.30–0.94], P = 0.026; absolute risk reduction 0.43%, number needed to treat 233) were observed among patients treated with betrixabanthan with enoxaparin through 77 days offollow-up. Among high-risk subjects (those with congestive heart failure or ischemic stroke as their index event) betrixaban reduced the risk of all-cause stroke (0.72% vs 1.48%, relative risk 0.49 [0.26–0.90], P = 0.019; absolute risk reduction 0.76%, number needed to treat 132); and ischaemic stroke (0.63% vs 1.38%, relative risk 0.45 [0.24– 0.87], P = 0.014, absolute risk reduction 0.75%, number needed to treat 134) vs enoxaparin. Dr Gibson concluded that among hospitalised medically ill patients, extended-duration betrixaban significantly reduced all-cause stroke and ischaemic stroke through 77 days of follow-up. Extended-duration thrombo- prophylaxis with an experimental oral factor Xa inhibitor may reduce the risk of stroke among hospital- ised medically ill patients.

Little is known, however, about the effectiveness of novel oral anticoag- ulants for stroke prevention in this context. APEX evaluated extended- duration thromboprophylaxis with the oral anticoagulation betrixa- ban in the prevention of venous thromboembolism. In this retrospective substudy, Dr Gibson and colleagues compared extended-duration betrixaban versus standard thromboprophylactic enoxaparin in the reduction of stroke among hospitalised medically ill patients. Hospitalised acutely medically ill subjects (n=7513) were randomised in a double- dummy, double-blind fashion to either extended-duration oral betrixaban (80 mg once daily for 35 to 42 days) or standard-dose subcutaneous enoxaparin (40 mg once daily for 10 ± 4 days) for venous thromboprophylaxis. Mean participant age was 76 years, 45% were male, 13% had a stroke, and 45% had congestive heart failure. Fewer all-cause strokes (0.54% vs 0.97%; relative risk 0.56 [0.32– 0.96], P = 0.032, absolute risk reduction 0.43%; number needed

explained that stroke is a leading cause of morbidity and mortality worldwide. In-hospital stroke complicates 0.04% to 0.06% of all hospitalisations and constitutes 2.2% to 15.2% of all strokes. Stroke among patients hospi- talised for acute medical illness portends a less favourable outcome than community-onset stroke.

© 2016 AHA

VOL. 1 • No. 3 • 2016