Strategies to minimize bleeding in ACS Sunil V. Rao MD FACC FSCAI The Duke Clinical Research Institute Duke University Medical Center

Off-label uses of drugs/devices may be discussed Disclosures Consultant, Honoraria The Medicines Company, Terumo Medical, ZOLL Research funding Bellerophon Off-label uses of drugs/devices may be discussed

Bleeding in ACS Bleeding is acute and chronic risk in ACS patients Bleeding is associated with medication discontinuation, adverse short and long-term clinical outcomes, and increased costs Strategies exist to reduce short- and long-term bleeding risk

In-hospital outcomes - ACS N=20,515 STEMI pts and 31,664 NSTEMI pts from AR-G Roe MT, et. al. JACC 2010

Bleeding in Stable angina, NSTEMI, & STEMI NCDR CathPCI Rates Overall rate = 2.1% NSTEMI Overall rate = 4.8% STEMI Overall rate = 12.7% Access site bleeds are 29.8% of all bleeds Rao SV, et. al., JACC 2010

Excessive Dosing of Anticoagulants by Age Alexander KP, et. al. JAMA 2005

Excess Dosing More Likely to Bleed Excess dosing of Gp IIb/IIIa and bleeding in women N=32,601 patients from CRUSADE Overall Women Men 1.46 (1.22, 1.73) 1.72 (1.30, 2.28) 1.27 (0.97, 1.66) 0.5 1.0 1.5 2.0 2.5 Excess Dosing More Likely to Bleed The attributable risk for bleeding due to excess dosing was 25% in women vs. 4.4% in men Alexander KP, et. al. Circulation 2006

Effect of EHR on medication errors

HORIZONS-AMI: Primary outcomes N=3602 pts HORIZONS-AMI: Primary outcomes N=3602 pts. with STEMI undergoing Primary PCI Stone GW, et. al. NEJM 2008

Minor Bleed P=0.25 Major or Minor P=0.54 HEAT PPCI - Safety Outcomes Major Bleed BARC grade 3-5 Minor Bleed BARC grade 2 Bivalirudin Heparin n % Minor Bleed 83 9.2 % v 10.8 % 98 Major or Minor 113 12.5 % 13.5 % 122 Minor Bleed P=0.25 Major or Minor P=0.54 Rates of minor bleeding – and rate of combined major or minor bleeding were also similar Shahzad A. ACC 2014

Radial mega-analysis N=76 studies (15 rand; 61 obs); 761,919 patients Bertrand OF, et. al. AHJ 2012

Combining radial approach and bivalirudin N=501,017 pts from NCDR CathPCI Baklanov D, et. al. Circ Intv. 2013

CHARISMA Trial: 3-Year Moderate or Severe Bleeding Among Patients with Prior MI, Stroke or Symptomatic PVD Instant Hazard of Bleeding Bhatt, JACC 2007

CHARISMA – Long-term moderate or severe bleeding N=15,603 pts with stable vascular disease or risk factors CHARISMA – Long-term moderate or severe bleeding – 12 month landmark N=15,603 pts with stable vascular disease or risk factors Berger PB, et. al. Circulation 2010

“Nuisance” Bleeding and Drug Discontinuation N=2360 unselected pts. receiving DES Prospective data collection Major events adjudicated Serebruany bleeding classification* % discontinued Even “nuisance’ bleeding can impact adherence. In this study, 11% of patients with nuisance bleeding discontinued their clopidogrel despite having a DES *Alarming bleeding = ICH, life-threatening, + transfusion Internal bleeding = hematoma, epistaxis, mouth or vaginal, Melena, IO, hematuria or hematemesis Nuisance bleeding = bruising, petechiae, ecchymosis Overall rate of bleeding=32.4% Roy P, et. al. AJC 2008

PREMIER Registry: Mortality Among Patients Continuing vs Discontinuing Thienopyridine Therapy 15 P<0.001 Continued Discontinued 10 Mortality (%) 5 The Kaplan-Meier mortality plots show the rate of death for those who continued thienopyridine therapy (solid line) and those who did not (dashed line). The origin is at the time of the patient’s MI, but the lines begin at the 1-month assessment point. 1 2 3 4 5 6 7 8 9 10 11 12 Months N at Risk Continued 431 430 429 420 Discontinued 68 67 66 65 62 Spertus JA, et al. Circulation. 2006;113:2803-2809.

Minimizing bleeding risk with ACS chronic therapy Majority of risk is GI bleeding Use PPIs Reduce aspirin dose Avoid newer P2Y12 in high risk groups Prior Stroke/TIA

COGENT Randomized Controlled Trial 1.00 Combo: clopidogrel 75mg + omeprazole 20 mg ACS or PCI patients requiring > 1yr clopidogrel N= 3627 (4000 anticipated) 0.98 0.96 Survival Probability 69 v. 67 CV events HR = 1.02 95% CI = 0.70; 1.51 0.94 Placebo Despite numerous findings to the contrary from observational studies, a randomized controlled trial has shown no clinically relevant adverse cardiovascular interactions between clopidogrel and omeprazole in patients with acute coronary syndromes undergoing PCI and receiving subsequent dual antiplatelet therapy. In addition, results of the COGENT trial show the positive effects of prophylactic PPI use in preventing GI events in these patients. In a late-breaker session yesterday, Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital, Boston, Mass., presented data from the multicenter, prospective COGENT trial that randomized 3,627 ACS patients receiving PCI and subsequent dual antiplatelet therapy (clopidogrel and aspirin) to either the PPI omeprazole or placebo. Patients were followed out to 133 days (maximum of 362). Bhatt said there were 136 adjudicated CV events and 105 adjudicated GI events. There were no differences in clinical cardiovascular endpoints of CV death and MI between the two groups (see Figure). Bhatt said the incidence of composite GI events, which included GI bleeding, symptomatic ulcer disease, obstruction or perforation, was significantly lower in the omeprazole group: 38 events in the treatment arm vs. 67 in the placebo arm (HR=0.55; 95% CI, 0.36-0.85, P=.007). The results of COGENT are preliminary, Bhatt said, because researchers were still evaluating some patients. He did not expect the outstanding patients to significantly change the conclusions, though. Bhatt said the trial was halted early because the sponsor, Cogentus Pharmaceuticals, declared bankruptcy. Patients were older than 21 and well-matched for baseline inclusion criteria. Observational trials Two previously-published observational trials had diametrically opposed results concerning concomitant use of clopidogrel and PPIs. Ho et al published results earlier this year showing concomitant use of clopidogrel and a PPI after hospital discharge for acute coronary syndromes was associated with an increased risk of adverse outcomes compared with use of clopidogrel without PPI. In the TRITON-TIMI 38 trial, however, O’Donaghue and colleagues group concluded that patients receiving clopidogrel and a PPI had similar rates of adverse events. Robert A. Harrington, MD, of Duke University Medical Center, Durham, N.C., who was on a panel that discussed the COGENT findings yesterday, said the message from the COGENT trial is to “be cautious if you are trying to interpret treatment effects from observational data.” 0.92 Treated In contrast, 38 v. 67 GI events, HR 0.55, 95% CI =0.36; 0.85 0.90 30 60 90 120 150 180 210 240 270 300 330 360 390 Days Bhatt, TCT 2009

Platelet Inhibition for CVD: Aspirin

What is the right dose of ASA? Suggested Loading dose: 160-325 mg Daily dose: 75-81 mg Campbell, JAMA 2007

CURE: Major Bleeding by Aspirin Dose Through Follow-Up Placebo + Aspirin* Clopidogrel + Aspirin* 75-100 mg 1.9% 3.0% 101-199 mg 2.8% 3.4% 200-325 mg 3.7% 4.9% The incidence of major bleeding increased with increasing aspirin dose in both treatment groups, with the highest incidence among patients receiving more than 200 mg of aspirin. *Other standard therapies were used as appropriate. Peters RJ, et al. Circulation. 2003;108:1682-1687. Peters RJ, Mehta SR, Fox KA, et al, for the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) Trial Investigators. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation. 2003;108:1682-1687.

Landmark Analyses Region and ASA Dose Mahaffey KW, et. al. Circulation 2011 ASA: <300 mg is low-dose; ≥300 mg is high-dose.

Net Clinical Benefit: Bleeding Risk Subgroups Post hoc analysis Risk (%) Yes +37 Prior Stroke/TIA No Pint = 0.006 -16 ≥75 -1 Age <75 Pint = 0.18 -16 <60 kg +3 Weight ≥60 kg Pint = 0.36 -14 -13 0.5 1 2 Prasugrel Better Clopidogrel Better HR Wiviott et al. N Engl J Med. 2007;357:2001.

Bleeding in ACS Bleeding is acute and chronic risk in ACS patients Bleeding is associated with medication discontinuation, adverse short and long-term clinical outcomes, and increased costs Strategies exist to reduce short- and long-term bleeding risk In-hospital: Dosing nomograms, radial access Chronic Rx: PPIs, Reduce ASA dose, avoid potent P2Y12 in prior TIA/Stroke

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