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

2. 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

3. 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

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

5. 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

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

7. 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

8. Effect of EHR on medication errors

10. 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

11. Minor Bleed P=0.25 Major or Minor P=0.54
HEAT PPCI - Safety Outcomes
Major Bleed BARC grade 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= 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

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

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

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

15. 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

16. “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

17. PREMIER Registry: Mortality Among Patients Continuing vs Discontinuing Thienopyridine Therapy15
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:

18. 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

19. 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 = % 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, , 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

20. Platelet Inhibition for CVD: Aspirin

21. What is the right dose of ASA?
Suggested
Loading dose: mg
Daily dose: mg
Campbell, JAMA 2007

22. CURE: Major Bleeding by Aspirin Dose Through Follow-Up
Placebo
+ Aspirin*
Clopidogrel + Aspirin*
mg % 3.0%
mg 2.8% 3.4%
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:
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:

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

24. 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.

25. 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

26. Duke Univ. Medical Center Duke Clinical Research Institute