dual anti-platelet therapy after bypass · dual anti-platelet therapy after bypass ......

Dual Anti-Platelet Therapy After Bypass Surgery

APACVS 37th Annual Meeting –

Miami, Florida, April 2018

Mohammed Waseem Akhter, MD, FACCAssistant Professor of Medicine

University of Massachusetts Medical School

▪ No conflicts of interest.

DISCLOSURES

▪ Overview of ACS and antiplatelet agents.

▪ Describe the role of dual antiplatelet therapy (DAPT)

in acute coronary syndromes.

▪ Review ACC/AHA guidelines for DAPT in patients

who undergo CABG.

▪ Briefly discuss the different clinical outcomes after

CABG while on DAPT.

OBJECTIVES

▪ Acute coronary syndromes (ACS) are a spectrum of conditions

Acute Coronary Syndromes

Unstable

AnginaNSTEMI STEMI


Vulnerable Plaque

- Thin fibrous cap- Lipid Rich pool- Local inflammatory

environment(T cells, foam cells)

Adapted from: Yeghiazarians Y et al. N Engl J Med 2000; 342:101-114



Plaque Rupture

Thrombus

formation

- Platelet

activation, and

aggregation

- Thrombin

formation

- Fibrinogen to

fibrin conversion


Complete

coronary

occlusion

Spontaneous lysis,

repair and wall

remodeling

Incomplete

coronary

occlusion

STEMI Unstable angina or NSTEMI

▪ Salicin, derived from Willow Bark,

has been used since the time of

the ancient Greek philosopher,

Hippocrates, to relieve dull aches

and pains.

▪ Acetylsalicylic acid (Aspirin) is now

synthesized from salicin derived

from meadowsweet.

Aspirin (Acetylsalicylic Acid)

Aspirin inactivates Cyclooxygenase-2


• Aspirin inhibits the production of prostoglandins and thromboxanes by inactivating cyclooxygenase enzymes by acetylation of their serine residues.

• Aspirin’s inactivation of cyclooxygenase is irreversible.

• Prostoglandins are responsible for delivering pain responses, causing fever, and causing inflamation.

• Thromboxanes are primarily responsible for causing blood to coagulate. Inhibition of thromboxanes by low doses of aspirin reduces the risk of heart attack or stroke.


Antiplatelet Drugs

COX Inhibitors

ADP antagonists

Aspirin

TiclopidineClopidogrelPrasugrelTicagrelor

P2Y12 inhibitors

CLOPIDOGREL PRASUGREL TICAGRELOR

OH

OH

O

OH

N

S

NH

NN

NN

F

F

Data in CABG patients are limited:

▪ Mostly ACS patient randomized and then undergoing CABG (CURE, CHARISMA, CREDO, PLATO)

▪ Observational analyses

▪ Small randomized trials (graft patency endpoints)

P2Y12 Inhibitors Post-CABG

• Efficacy of clopidogrel is hampered by slow and variable transformation to the active metabolite

• There is modest and variable platelet inhibition

• In Genetically pre-disposed poor-responders there is an increased risk of stent thrombosis and MIs.

• Postulated but unproven interaction with PPIs.

Clopidogrel

Clopidogrel

Adenosine Diphosphate-Receptor Antagonists

Newer Oral Antiplatelet Drugs

Prasugrel• Thienopyridine

• More rapid onset of action than clopidogrel

• Irreversible inhibitor of the P2Y12 receptor

Ticagrelor • Cyclo-pentyl-triazo-

pyrimidine (CPTP)

• More rapid onset of action than clopidogrel

• Reversible inhibitor of the P2Y12 receptor

Acute coronary syndromes

Stable Ischemic Heart Disease

PCI

Aspirin

ClopidogrelPrasugrelTicagrelor

2016 ACC/AHA Guideline Focused

Update on Duration of Dual Antiplatelet

Therapy in Patients With Coronary

Artery DiseaseDeveloped in Collaboration with American Association for Thoracic Surgery,

American Society of Anesthesiologists, Society for Cardiovascular Angiography and

Interventions, Society of Cardiovascular Anesthesiologists,

and Society of Thoracic Surgeons

Endorsed by Preventive Cardiovascular Nurses Association and

Society for Vascular Surgery

© American College of Cardiology Foundation and American Heart

Association

Release of the ACC/AHA Focused Update on the Duration of Dual Antiplatelet Therapy (DAPT) represents an important event, in that its findings impact sixalready released ACC/AHA Clinical Practice Guidelines:• ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention

• ACCF/AHA Guideline for Coronary Artery Bypass Graft (CABG) Surgery

• ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease (SIHD)

• ACC/AHA Guideline for the Management of ST-Elevation Myocardial Infarction (STEMI)

• ACC/AHA Guideline for Non–ST-Elevation Acute Coronary Syndromes (NSTEMI)

• ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery

Recommendations on Dual Antiplatelet Therapy

http://content.onlinejacc.org/article.aspx?articleid=1147816&_ga=1.106797891.1916235904.1455651606

http://content.onlinejacc.org/article.aspx?articleid=1147818&_ga=1.106797891.1916235904.1455651606

http://content.onlinejacc.org/article.aspx?doi=10.1016/j.jacc.2012.07.013&_ga=1.174447202.1916235904.1455651606




Table 1. Applying

Class of Recommendation

and

Level of Evidence

Recommendations are classified in guidelines according to the evidence supporting the usefulness and efficacy of the procedure/treatment:

• Class I - Conditions for which there is evidence and/or general agreement that a given procedure or treatment is useful and effective.

• Class II - Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness or efficacy of a procedure or treatment.

– Class IIa - Weight of evidence or opinion is in favor of usefulness or efficacy

– Class IIb - Usefulness or efficacy is less well established by evidence or opinion.

Recommendations

Recommendations are classified in guidelines according to the evidence supporting the usefulness and efficacy of the procedure/treatment:

• Class III - Conditions for which there is evidence and/or general agreement that the procedure/treatment is not useful or effective, and in some cases may be harmful.

Recommendations

2016 ACC/AHA Duration of DAPT Guideline Focused Update

Concepts and Recommendations for DAPT and

Duration of Therapy

– Aspirin Dosing in Patients Treated With DAPT

– Specific P2Y12 Inhibitors

Aspirin Dosing in Patients Treated With DAPT

COR LOE Recommendation

IIn patients treated with DAPT, a daily aspirin dose of 81 mg (range, 75 mg to 100 mg) is recommended.

Specific P2Y12 Inhibitors

COR LOE Recommendations

IIa B-R

In patients with ACS (NSTE-ACS or STEMI) treated with DAPT after

coronary stent implantation and in patients with NSTE-ACS treated

with medical therapy alone (without revascularization), it is

reasonable to use ticagrelor in preference to clopidogrel for

maintenance P2Y12 inhibitor therapy.

IIa B-R


coronary stent implantation who are not at high risk for bleeding

complications and who do not have a history of stroke or TIA, it is

reasonable to choose prasugrel over clopidogrel for maintenance

P2Y12 inhibitor therapy.

III:

HarmB-R

Prasugrel should not be administered to patients with a prior

history of stroke or TIA.

Specific P2Y12 Inhibitors

COR LOE Recommendations

IIa B-R


coronary stent implantation and in patients with NSTE-ACS treated

with medical therapy alone (without revascularization), it is

reasonable to use ticagrelor in preference to clopidogrel for

maintenance P2Y12 inhibitor therapy.

IIa B-R


coronary stent implantation who are not at high risk for bleeding

complications and who do not have a history of stroke or TIA, it is

reasonable to choose prasugrel over clopidogrel for maintenance

P2Y12 inhibitor therapy.

III:

HarmB-R

Prasugrel should not be administered to patients with a prior

history of stroke or TIA.

More potent Thienopyridines demonstrate slightly better outcomes compared to Clopidogrel

Ticagrelor > ClopidogrelPrasugrel > Clopidogrel

Except if there is a prior history of bleeding complications, stroke or TIA………… then avoid Prasugrel

2016 ACC/AHA Duration of DAPT Guideline Focused Update

Coronary Artery Bypass Graft

Recommendations for Duration of DAPT in

Patients Undergoing CABG

COR Recommendations

I

I

I

IIb



COR Recommendations

I

In patients treated with DAPT after coronary stent implantation who subsequently undergo CABG, P2Y12 inhibitor therapyshould be resumed postoperatively so that DAPT continues until the recommended duration of therapy is completed.

I

I

IIb



COR Recommendations

I


I

In patients with ACS (NSTE-ACS or STEMI) being treated with DAPT who undergo CABG, P2Y12 inhibitor therapy should be resumed after CABG to complete 12 months of DAPT therapy after ACS.

I

IIb



COR Recommendations

I


I



IIb



COR Recommendations

I


I



IIb

In patients with SIHD, DAPT (with clopidogrel initiated early postoperatively) for 12 months after CABG may be reasonable to improve vein graft patency.

Figure 3. Treatment Algorithm for Management and Duration of

P2Y12 Inhibitor Therapy in Patients Undergoing CABG

On-pump CABG

Use of cardiopulmonary bypass can result in platelet dysfunction and clotting disorders, which can prevent early graft thrombosis.

On-pump versus off-pump CABG

Off-pump CABG

Off-pump bypass might act as a hypercoagulable state, because of higher level of platelet activity & relative aspirin resistance.

Early graft loss is related to post surgical factors such as inflammation and conduit trauma, which can result in a prothrombotic state and occlusion of the graft.

Am J Cardiol 2018;121:32–40

The authors:

▪ Reviewed 943 publications after searching key words in the following databases: PubMED, Cochrane and Web of Science.

▪ After excluding non-relevant studies they analyzed data from 8 RCT ,5 post hoc analyses of RCT, and 4 observational studies (a total of 11,135 patients with a mean follow-up of 23 months).

▪ Primary outcome of interest was a composite of MI, stroke or death (>30 days).

Meta-Analysis

▪ Secondary outcomes included major bleeding, all-cause mortality, MI, stroke, and graft occlusion.

▪ Sub-group data analysis was based on:

oStudy Type - RCT versus observational trials

oCABG technique – On-pump versus Off-pump CABG

oClinical presentation – ACS versus non-ACS

Meta-Analysis

▪ At a mean follow-up of 23 months, DAPT was associated with a lower incidence of the composite of MI, stroke, or death.

▪ No evidence of interaction by study type (RCT vs observational).

▪ CABG technique and clinical presentation did not effect the outcome.

▪ Graft occlusion was less with DAPT than with aspirin monotherapy.

Meta-Analysis – Key results

RESULTS FROM THE EXCEL TRIAL

Impact of Post-Discharge Dual Antiplatelet Therapy vs. Aspirin Alone After CABG in Patients with Left Main Disease

• Post Hoc analysis (therefore non-randomized data).

• Unmeasured confounders could not be accounted for but the results were hypothesis-generating.

DAPT vs ASA alone after CABG

Patients with left main disease and low or

intermediate SYNTAX scores (n=1,905)

CABG (n=957)PCI (n=948)

Discharged on

DAPT

(n=292)

Discharged on Aspirin

Alone

(n=604)

Did not undergo CABG (n=34)

Died before discharge (n=12)

Not prescribed ASA (n=10)

Missing data (n=5)

STUDY POPULATION

randomization

DAPT 292

Number at risk:

289 286 284 282

604 592 581 574ASA 568

1.7%

4.5%

Death

, M

I o

r str

oke (

%)

0

5

10

15

20

Time in Months

0 3 6 9 12

DAPT at discharge

Aspirin at discharge

P value = 0.04

HR: 0.58 [95% CI: 0.15, 0.98]

1- Year Post-Discharge Outcomes

Primary EndpointDeathMIStroke

3- Year Post-Discharge Outcomes

TIMI Major or Minor Bleeding

P value = 0.73

HR: 1.36 [95% CI: 0.23, 8.16]

0.5%

0.7%

0

5

10

15

20

Time in Months

0 6 12 18 24 30 36

DAPT at discharge

Aspirin at discharge

DAPT 292

Number at risk:

288 278 276 252

604 589 565 561Aspirin 495

284

578

265

552

Ble

ed

ing

(%

)

• One-third of patients undergoing CABG were discharged on DAPT (almost always aspirin plus clopidogrel)

• Patients were more likely to be discharged on DAPT if they were treated in North America; had recent tobacco use, prior stroke, or NSTEMI at presentation; or had off-pump surgery

• Patients were less likely to be discharged on DAPT if they had post-operative bleeding

• Recent MI did not predict post-discharge DAPT

Interesting Findings

A patient recently received a DES for unstable angina, then needed an emergent CABG. How long after the CABG should she continue DAPT?

- Limited randomized data (there are subgroup analyses)

- Trend that Prasugrel & Ticagrelor are associated with lower

mortality in ACS patients treated with CABG

- A recent survey of Canadian surgeons revealed limited use

of DAPT in all ACS patients post DES and then CABG

Practical consideration

A patient recently received a DES for unstable angina, then needed an emergent CABG. How long after the CABG should she continue DAPT?

- Greater use of DAPT:

▪ When the previously stented vessel was large and not

bypassed OR

▪ The target vessel was not of great quality OR

▪ The conduit for bypass was suboptimal

Practical consideration

• These findings highlight the need for a large, randomized trial of DAPT vs. aspirin alone after CABG

More studies are needed…..

Off vs on-pump

CABG

Choice of P2Y12i

with ASA

Bleeding risk vs

graft patency

Key Take Away Points

AspirinLow dose

Class IPresent as SIHD, ACS, PCI

Indefinitely

“Reduces graft occlusion and adverse cardiac events (MI, Stroke

& Death)”

Post-CABG Treatment

Key Take Away Points

DAPTASA + P2Y12i Post CABG Tx

Class IPCI

▪ 1m, 6m, 12m▪ Benefit shown

for ↓ CV events

ACS Class I

▪ 12m▪ Benefit shown

for ↓ CV events

SIHD Class II▪ 12m▪ Graft patency

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