update on dual antiplatelet therapy cme/brochure… · dual antiplatelet therapy...

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Update on Dual Antiplatelet Therapy

Brian J. Corbett DO Assistant Professor of Medicine Cooper

Medical School of Rowan University

Disclosures

• None

Questions????????

• Which combination of DAPT?

• Optimal Duration of DAPT?

• Warfarin/NOAC Therapy?

Platelet inhibition represents the cornerstone of cardiovascular therapy…

CARDIOVASCULAR MEDICINE – KARDIOVASKULÄRE MEDIZIN – MÉDECINE CARDIOVASCULAIRE 2017;20(7–8):169–175

Presenter

Presentation Notes

Platelet inhibition represents the cornerstone of cardiovascular therapy, owing to the central role of platelets in the genesis of acute ischaemic events. Dual antiplatelet therapy (DAPT) addresses two main pathways of platelet activation: inhibition of cyclo-oxygenase-mediated thromboxane A2 formation by aspirin; and inhibition of the ADP-activated surface receptor P2Y12 by means of a family of drugs including cangrelor, clopidogrel, prasugrel, ticagrelor and ticlopidine

DAPT: Oral Agents Acetylsalicy

lic acid (ASA)

Ticlopidine hydrochloride

Clopidogrel bisulfate

Prasugrel hydrochloride

Ticagrelor

Trade Name Aspirin1-3 Ticlid®4 Plavix®5 Effient®6 Brilinta®7

Class Salicylate P2Y12 Receptor

Antagonist

P2Y12 Receptor

Antagonist

P2Y12 Receptor Antagonist

P2Y12 Receptor

Antagonist

Formulation Active Drug Active Drug Pro-Drug Pro-Drug Active Drug

Maintenance Dose

75-325 mg daily*

250 mg BID 75 mg daily 10 mg daily 90 mg BID

Reversible No No No No Yes

Eur Heart J Suppl. 2008;10(suppl_I):I8-I13. doi:10.1093/eurheartj/sun041

Clopidogrel

Presenter

Presentation Notes

The occurrence of death or myocardial infarction (MI) as a function of time in the PCI-Clopidogrel in Unstable angina to prevent Recurrent Events (PCI-CURE)16 study, and of death, MI, or stroke in the Clopidogrel for the Reduction of Events During Observation (CREDO) trial.17 Notice that in the PCI-CURE study, the PCI was performed after a median of 10 days from randomization, and only events occurring after PCI were taken into account. PCI, percutaneous coronary intervention.

Less Bleeding Less Cost

Ischemia

Why is DAPT so important ?

• Protect the stented vascular segment from the development of stent thrombosis while vascular healing and progressive strut endotheliazation – in-hospital mortality rate of 5% to 10% – 30-day mortality rate of 10% to 25%

JAMA. 2005;293:2126-2130

Stent Implantation

Endothelial Denudation Medial Dissection Exposure of sub-intimal components Thrombogenecity of metal

Activation of platelets

Thrombosis

Reaction to stent struts (Macrophages and Giant Cells)

Production of: Cytokines Mitogens Chemotaxic factors

Activation of vascular smooth muscle cells

Proliferation and migration of vascular smooth muscle cells

Restenosis

Stent thrombosis rates reduced with better technique and DAPT…

1. Schatz et al.Circulation. 1991;83:148;2. Fischman et al. N Engl J Med. 1994;331496; 3. Colombo et al. Circulation.1995;91:1676 4. Schomig et al. Circulation. 1994,90:2716; 5. Leon et al. N Engl J Med. 1998;339:1665; 6. Joner et al. J Am Coll Cardiol. 2006;48:193.

Independent Risk Factors for ST

J. Am. Coll. Cardiol. 2009;53;1399-1409

DAPT

Interindividual variability in platelet response to clopidogrel after stenting

Michelle O’Donoghue, and Stephen D. Wiviott Circulation. 2006;114:e600-e606

Source: Wiviott SD et al. NEJM 2007;357:2001-2015

Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON-TIMI 38)

0

5

9

60 90 180 270 360 450

HR 0.81, P=0.0004

Prasugrel

Clopidogrel

HR 0.80 P=.001

HR 0.77 P=.001

Days

CV

deat

h, M

I, or

str

oke

% 12.1

9.9 Bleeding Events

C (%) P (%) P-value TIMI major 1.8 2.4 .03 Life threatening 0.9 1.4 .01 Nonfatal 0.9 1.1 .23 Fatal 0.1 0.4 .002 ICH 0.3 0.3 .74

13,608 patients with high-risk ACS scheduled for PCI randomized to clopidogrel (300 mg LD and 75 mg MD) or prasugrel (60 mg LD and 10 mg

MD) for a median of 12 months

7

11

ACS=Acute coronary syndrome, ICH=Intracranial hemorrhage, LD=Loading dose, MD=Maintenance dose

0 30

Prasugrel reduces ischemic events with a higher rate of bleeding

Net Clinical Benefit Bleeding Risk Subgroups

0.5 1 2

Prior Stroke / TIA

Age > 75

Wgt < 60 kg

Rel Risk

+37%

-1%

+3%

Prasugrell Better Clopidogrell Better

HR

Pint = 0.006

Pint = 0.18

Pint = 0.36

PLATO: Primary Efficacy Endpoint

Days

9.8% 11.7%

0 60 120 180 240 300 360

12

10

8

6

4

2

0

%

No. at risk

Clopidogrel Ticagrelor

9,291 9,333

8,521 8,628

8,362 8,460

8,124 6,743 6,743

5,096 5,161

4,047 4,147 8,219

HR 0.84 (95% CI 0.77–0.92)

Clopidogrel

Ticagrelor

p=0.0003

Wallentin L: NEJM 2009; 361:1045-57

CV death, MI or stroke

N=18,624

Time to major bleeding – primary safety event

No. at risk

Clopidogrel Ticagrelor

9,186 9,235

7,305 7,246

6,930 6,826

6,670

Days from first IP dose

5,209 5,129

3,841 3,783

3,479 3,433

0 60 120 180 240 300 360

10

5

0

15

Clopidogrel

Ticagrelor 11.20 11.58

6,545

HR 1.04 (95% CI 0.95–1.13), p=0.434

K-M

est

imat

ed ra

te (%

per

yea

r)

Wallentin L: NEJM 2009; 361:1045-57

All patients Ticagrelor (n=6,732)

Clopidogrel (n=6,676) p value*

Dyspnea, %

Any dyspneaç event

Requiring discontinuation of study-

treatment

15.4 0.9

10.4 0.3

<0.0001 < 0.0001

Dyspnea

Specific P2Y12 Inhibitors: Recommendations

Clopidogrel Prasugrel Ticagrelor Cangrelor

Route Oral Oral Oral IV

Onest 120 – 360 min 60 min 30 min 2 min

Offset 5 days 7 days 5 days 60 min

Reversible No No Yes Yes

Platelet Inhibition

20 – 60% 60 – 80% 70 – 95% 95%

Dosing for PCI LD: 600 mg MD 75 mg

LD 60 mg MD 10 mg

LD 180 mg MD 90 mg BID

LD 3 mcg/kg MD 4 mcg/kg/min

Dosing for Bridging

LD none MD 0.75 mcg/kg/min

Duration of therapy still unclear?

Eliano Pio Navarese et al. BMJ 2015;350:bmj.h1618

No significant differences in all cause mortality between short term and 12 month dual antiplatelet therapy

Presenter

Presentation Notes

Fig 4 Individual and summary odds ratios for the endpoint of all cause mortality. Data stratified by duration of dual antiplatelet therapy: short term (<12 months) versus 12 months, and extended (>12 months) versus 12 months

Longer Duration: DAPT Trial

• 9961 patients • international, multicenter, randomized, placebo-

controlled trial

Mauri LM, et al. NEJM 2014;371:2155-66.

Myocardial infarction that was not related to stent thrombosis (P<0.001) accounted for 55% of the treatment benefit.

Long DAPT after drug-eluting stent reduced the risks of stent thrombosis and MACE and cerebrovascular events but…

Mauri LM et al NEJM 2014;371:2155-66

Development and Validation of a Prediction Rule for Benefit and Harm of Dual Antiplatelet Therapy Beyond 1 Year After Percutaneous Coronary

Intervention.

JAMA. 2016;315(16):1735-1749

Presenter

Presentation Notes

For patients randomized in the DAPT Study (derivation co- hort) with clinical predictive scores of 2 or higher (high score group; 50.8%), continued thienopyridine was associated with an absolute risk reduction in myocardial infarction or stent thrombosis that was 8.2 times greater than the absolute risk increase in moderate or severe bleeding. Conversely, among patients with scores lower than 2 (low score group; 49.2%), randomization to continued thienopyridine was associated with an absolute increase in bleeding that was 2.4 times the absolute reduction in myocardial infarction or stent thrombosis.

Q1 = Score -2 to 0 Q3 = Score Q2 = Score 1 Q4 = Score > 2

JAMA. 2016;315(16):1735-1749

Presenter

Presentation Notes

For patients randomized in the DAPT Study (derivation co- hort) with clinical predictive scores of 2 or higher (high score group; 50.8%), continued thienopyridine was associated with an absolute risk reduction in myocardial infarction or stent thrombosis that was 8.2 times greater than the absolute risk increase in moderate or severe bleeding. Conversely, among patients with scores lower than 2 (low score group; 49.2%), randomization to continued thienopyridine was associated with an absolute increase in bleeding that was 2.4 times the absolute reduction in myocardial infarction or stent thrombosis.

Optimal DAPT duration after PCI differs according to clinical presentation

GW Stone et al. European Heart Journal (2017) 0, 1–10

Presenter

Presentation Notes

Compared with ACS patients treated with 12-month . DAPT, those treated with 3-month DAPT (HR 2.08, 95%CI 1.10–3. . 93) but not 6-month DAPT (HR 1.28, 95%CI 0.73–2.27) had higher . composite MI or ST rates. Conversely, there was no significant difference in the risk of MI or ST in stable patients treated with 3-month, . 6-month, or 12-month DAPT. Finally, treatment with 3-month and 6- . month DAPT was associated with lower rates of major bleeding and . any bleeding compared with 12-month DAPT, independent of clinical presentation

So how do we decide?

Circulation. 2016;133:000–000

What has really changed?

European Heart Journal – Cardiovascular Pharmacotherapy (2015) 1, 191–197

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