scranton heart institute, p.c. anti-platelet medications for elective percutaneous coronary...

Scranton Heart Institute, P.C.

Anti-Platelet Medications For Elective Percutaneous Coronary Interventional Procedures - 2011

Stafford M. Smith, M.D., FACP, FACC


Blood Platelets – High Power Magnification

Dense (delta) granules contain ADP, Ca++, and serotonin.

Lambda granules contain hydrolytic enzymes.

Alpha granules contain PF4, transforming GFβ1, platelet-derived growth factor, fibronectin, B-thromboglobulin, vWF, fibrinogen,

and Factors V and XII.


Thienopyridine Agents

Ticlopidine: ~ 30-35% platelet inhibition *2% incidence of serious neutropenia.

Clopidogrel: ~ 30-50% platelet inhibition. Prasugrel: ~ 60% platelet inhibition

TRITON-TIMI 38 – 50% reduction in stent thrombosis (ST) was offset by increased bleeding (particularly in high risk groups).

Ticagrelor: ~ 70% platelet inhibition (short-acting, reversible agent) PLATO – Significant reduction in ischemic events without an

increase in bleeding.


CLOPIDOGREL IS INDICATED FOR:

1. A reduction of rate of CV death, MI, stroke, or refractory ischemia in patients with ACS (unstable angina or non-ST-elevation MI), including those who are managed medically and those with coronary revascularization.

2. To reduce the rate of death from any cause, re-infarction, or stroke in patients with STEMI.

3. To reduce the rate of new ischemic stroke or MI, and other vascular deaths in patients with history of recent MI, STROKE, or PAD.


Clopidogrel – “Boxed Warning”

Effectiveness is dependent on activation to an active metabolite via CYP2C19. Poor metabolizers of CYP2C19 treated with clopidogrel at recommended doses exhibit higher cardiovascular (CV) event rates following acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention than patients with normal CYP2C19 function. Tests are available to identify a patient's CYP2C19 genotype and to determine therapeutic strategy. Consider alternative treatment in poor metabolizers.


PRASUGREL INDICATIONS

A reduction of thrombotic CV events [stent thrombosis (ST)] in patients with acute coronary syndrome (ACS) [unstable angina, non-ST-elevation MI] and STEMI, who are to be managed with percutaneous coronary intervention (PCI).


Prasugel’s “boxed warning”1. Prasugrel may cause significant, sometimes fatal, bleeding. Risk

factors include: <60kg body weight, propensity to bleed, and concomitant use of medications that may increase bleeding.

2. Do not use in patients with active pathological bleeding or history of transient ischemic attacks (TIA) or stroke.

3. Prasugrel is not recommended in patients ≥75 yrs., due to increased risk of fatal intracranial bleeding.

4. Do not start prasugrel in patients likely to undergo urgent coronary artery bypass graft surgery (CABG).

5. Discontinue prasugrel at least 7 days prior to surgery.6. Suspect bleeding in any patient who is hypotensive that has

recently undergone coronary angiography, PCI, CABG, or other surgical procedures.

7. If possible, manage bleeding without discontinuation.8. Discontinuation of prasugrel within the first few weeks after an ACS

increases the risk of subsequent cardiovascular events.


Coronary Heart Disease Syndromes And Interventional Procedures

1.6 million hospital discharges for ACS in the U.S. in 2003. Roughly 30% of ACS patients have STEMI. ~ 2.7 million heart catheterizations are done in the US annually. ~ 1/3 of these require coronary intervention (~900,000/year). The majority of interventional procedures involve the use of

endovascular stents. Approximately 1 million coronary stents are implanted in the US

annually (~ 1.3 stents per patient)


Dual Anti-Platelet Therapy (DAPT)

CURE: 22% reduction in adverse clinical events with DAPT (31% reduction in patients that underwent PCI with stents) Only BMS were used in this study.

The Bern-Rotterdam Experience: 65% of stent thromboses (ST) occurred within the first 6 months after PCI and DES. The annual rate of ST according to this registry was 0.6% out to 4 years.

Duke Database: Increased incidence of death or MI in DES patients if DAPT was discontinued within 6 months.

The Tycoon Registry: 4 late ST when DAPT was discontinued after 1 year (with DES). None ST if DAPT continued out to 2 years.

1 Randomized Trial And Several Registries Suggesting A Benefit With Prolonged Use Of DAPT


Dual Anti-Platelet Therapy (DAPT)

The Guthrie Registry: No increase in CV events for DES patients if DAPT discontinued after 1 year.

The Milan Database: No difference in events for DES patients if DAPT was discontinued after 6 months.

The large DAPT trial will definitively address the optimal length of DAPT Rx. Results will be available in 2015.

Conflicting Data Regarding The Use Of Prolonged DAPT


MECHANISMS OF PLATELET ACTIVATION AND AGGREGATION.

Chhatriwalla A K , Bhatt D L Circ Cardiovasc Interv 2008;1:217-225

Copyright © American Heart Association


PLATELET AGGREGATION

Platelets aggregate by using fibrinogen and vWF as a connecting bridge. The glycoprotein IIbIIIa receptor

binds fibrinogen, fibronectin, vitronectin, thrombospondin, and vWF.


AHA/ACC/SCAI/ACS/ADA SCIENCE ADVISORY

Prevention of Premature Discontinuation of Dual Antiplatelet Therapy in Patients With Coronary Artery StentsA Science Advisory From the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, With Representation From the American College of Physicians

This advisory stresses the importance of 12 months of dual antiplatelet therapy after placement of a drug-eluting stent, and educating the patient and healthcare providers about hazards of

premature discontinuation. It also recommends postponing elective surgery for 1 year, and if surgery cannot be deferred, considering the continuation of aspirin during the perioperative period in high-

risk patients with drug-eluting stents.

J Am Coll Cardiol, 2007; 49:734-739, doi:10.1016/j.jacc.2007.01.003 (Published online 17 January 2007).© 2007 by the American College of Cardiology Foundation


ACC/AHA Guidelines

A loading dose of thienopyridine is recommended for patients in whom PCI is planned…(as early as possible) before or at the time of PCI. [Class 1]

In patients receiving a stent: The duration of thienopyridine therapy should be at least 12 months. [Class 1]

If the risk of morbidity due to bleeding outweighs the benefit, earlier discontinuation should be considered. [Class 1]

Continuation of clopidogrel or prasugrel beyond 15 months may be considered in patients undergoing DES placement. [Class 2B]

J Am Coll Cardiol, 2009; 54:2205-2241, doi:10.1016/j.jacc.2009.10.015 (Published online 18 November 2009).© 2009 by the American College of Cardiology Foundation

2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (Updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (Updating the 2005 Guideline and 2007 Focused Update)A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines


Prevalence, Predictors, and Long-Term Prognosis of Premature Discontinuation of Oral Antiplatelet Therapy After Drug Eluting Stent Implantation

1,358 Consecutive Patients Followed For 3 Years Early Discontinuation (< 12 Months vs. Late

Discontinuation (> 12 Months) 52% Increase In Cardiac Events (p < 0.001) 55% Increase in ST (p = 0.038) 65% Increase in All-Cause Mortality (p < 0.001) 76% Increase in Cardiovascular Death (p = 0.007)

Rossini, Capodanno, Lettieri, Musumeci, et al., Am J Cardiol Vol. 107, 2, P186-19415, Jan 2011


Duration of Dual Anti-Platelet Therapy After Implantation of Drug-Eluting Stents

Cumulative risk of a cardiac death or MI at 2 years: 1.8% on DAPT, 1.2% on aspirin alone (p = 0.17).

No difference in the risk of MI, stroke, stent thrombosis, need for repeat revascularization, major bleeding, or death from any cause.

This study had inadequate statistical power to provide a definitive conclusion regarding the safety of clopidogrel discontinuation after 12 months.

Additional studies addressing the use of dual antiplatelet therapy after implantation of DES are ongoing.

Park SJ, Park DW, Kim YH, et al. N Engl J Med 2010; Mar 15


CONCERNS REGARDING PROLONGED DAPT

Bleeding: 1% risk of a major bleeding event per year.

Cost: (Should improve when generic clopidogrel becomes available ~ 2011?)

Perioperative Management: Multiple issues, Hypercoagulability


STENT THROMBOSIS


Blood Clotting Red Blood Cell

Platelet

Fibrin Mesh


Coronary Stent Thrombosis and Noncardiac Surgery

Authors Year Type Time Period Patients, n DES, %

Time From PCI to

Surgery

Mortality Rate,* % (95%

CI)Kaluza et al 2000 Retr, NR 1996–1998 40 0 <42 d 21.4 (10.2–

35.0)Wilson et al 2003 Retr, NR 1990–2000 207 0 <60 d 3.4 (1.2–6.3)

Sharma et al 2004 Retr, NR 1995–2000 47 0 <90 d 18.4 (8.6–30.4)

Reddy et al 2005 Retr, NR 1999–2004 56 0 ... 8.6 (2.3–17.5)

Leibowitz et al 2006 Retr, NR 1995–2002 94 0 <90 d 14.6 (8.1–22.4)

Vicenzi et al 2006 Prosp, NR 2001–2004 103 ... <1 y 5.7 (1.8–11.1)

Compton et al 2006 Retr, NR 2003–2006 38 100 ... 2.5 (0.0–7.9)

Schouten et al 2007 Retr, NR 1999–2005 192 52 <2 y 3.1 (1.0–6.1)

PCI indicates percutaneous coronary intervention; Retr, retrospective; Prosp, prospective; and NR, nonrandomized.

*Mortality rates were calculated using the adjusted Wald interval.


Predictors of DES Thrombosis: Considerations for Prolonged Dual

Antiplatelet Therapy (DAPT)

Clinical Angiographic

Advanced age Long stentsAcute coronary syndrome Multiple lesionsDiabetes Overlapping stentsLow ejection fraction Ostial or bifurcation lesionsPrior brachytherapy Small vesselsRenal failure Suboptimal stent results


CLINICAL ALERT

ACCF/AHA Clopidogrel Clinical Alert: Approaches to the FDA "Boxed Warning“; A Report of the American College of Cardiology

Foundation Task Force on Clinical Expert Consensus Documents and the American Heart

Association Endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of

Thoracic Surgeons J Am Coll Cardiol, 2010; 56:321-341, doi:10.1016/j.jacc.2010.05.013 (Published online 28 June 2010).© 2010 by the American College of Cardiology Foundation

CYP2C19 polymorphism accounts for only 12% of variability in clopidogrel platelet response.

The positive predictive value of CYP2C19 polymorphisms is estimated to be between 12% and 20% in patients with ACS undergoing PCI.


Platelet Testing

Genetic Testing: CYP2C19 – “Poor Metabolizers” Platelet Function Testing: (“Verify Now”, TEG,

others) – “Hyporesponders” [< 20% platelet inhibition] *A positive association with an increased risk of death, MI, and ST

Both? Neither?


Clinical Events as a Function of Proton Pump Inhibitor Use, Clopidogrel Use, and Cytochrome P450 2C19 Genotype in a Large Nationwide Cohort of Acute Myocardial Infarction

PPI use was not associated with an increased risk for in-hospital events (survival, reinfarction, stroke, bleeding, and transfusion).

PPI treatment was not an independent predictor of 1-year survival (hazard ratio, 0.97; 95% confidence interval 0.87 to 1.08; P=0.57) or 1-year MI.

PPI use was not associated with an increased risk of cardiovascular events or mortality in patients administered clopidogrel for recent MI, whatever the CYP2C19 genotype.

Results From the French Registry of Acute ST-Elevation and Non–ST-Elevation Myocardial Infarction (FAST-MI) Registry

Circulation. 2011;123:474-482 January 24, 2011, doi: 10.1161/CIRCULATIONAHA.110.965640


ADDITIONAL CLINICAL TRIALS SUPPORTING THE SAFETY OF CLOPIDOGREL USE WITH PPIs

1. COGENT: 2009 (> 3,600 patients)2. Sub-analysis from TRITON-TIMI 38:

2009 (> 13,000 patients)3. Sub-analysis from PRINCIPLE-TIMI

44; 2007 (201 patients)


GASTRO-ESOPHAGEAL REFLUX DISEASE (GERD) & ESOPHAGEAL

CARCINOMA

o GERD occurs in 30-40% of adults.o Barrett’s esophagitis affects 1.6% of the general

population.o The incidence of esophageal cancer has

quadrupled in the past several years (There were >16,000 new cases annually in the US, and > 14,000 deaths recorded annually in the US; as of 2009).

o H2 antagonists are less effective than PPIs to control reflux symptoms.

A consideration to support the more liberal use of proton pump inhibitors in the general population…


Atrial Fibrillation AF: The most common sustained cardiac arrhythmia. The incidence and prevalence of AF increases

progressively with age. New cases range from < 0.5% at age 55 to 3.5% at age

> 85 years. AF occurs at a frequency of 5% in patients with new

ischemic stroke. AF occurs at a frequency of 10% in patients after

acute MI. The prevalence of AF in the general population is 0.5

– 1%. Rotterdam Study: The lifetime risk of developing AF

at age 55 is ~ 24% in men and 22% in women.


Anticoagulation (Anti-Thombin Therapy) in Atrial Fibrillation

Requirement Indicated By CHADS2 Score.

“Age-Adjusted” Risk Of Stroke Is 4 X – 5 X Increased Without Treatment.

Anticoagulation Reduces The Risk To Close To That Of The General Population.

Warfarin: Antagonizes Vitamin K-Dependent Clotting Factors (II, VII, IX, X), long T1/2; requires monitoring and dose adjustments.

Dabigatran: Reversible Direct Thrombin Inhibitor. Factor X Inhibitors


Combination therapy with aspirin, clopidogrel, and warfarin following coronary stenting is associated

with a significant risk of bleeding

• Patients on chronic warfarin therapy who receive a coronary stent need to be treated with “triple therapy” (aspirin, clopidogrel & warfarin).

• Single center study (107 consecutive patients). “Triple therapy” patients were younger and more likely to have hypertension.

• “Triple therapy” patients had more major bleeding (6.6% vs. 0%; p = 0.03) and minor bleeding (14.9% vs. 3.8%; p = 0.01), compared with the DAPT group.

• In the “triple therapy” group, the INR or aspirin dosage did not influence the bleeding risk.

• For patients on warfarin, the addition of DAPT is associated with approximately a 7% major bleeding risk.

Khurram Z, Chou E, Minutello R, Bergman G, Parikh M, Naidu S, Wong SC, Hong MK. Lenox Hill Hospital, New York, New York, USA.


OPTICALCOHERENCE

TOMOGRAPHY(OCT)

OCT Image IVUS Image


Conclusions DAPT remains the standard of

care after coronary stenting (to reduce the incidence of adverse cardiac events (particularly ST).

Early discontinuation of DAPT is associated with an increased incidence of serious adverse outcomes.

The current recommended minimum duration of DAPT is 12 months after DES.

There is concern regarding the previously reported incidence of VLST. Additional studies are ongoing.

Clinicians need to weigh the specific risks of surgery vs. the risks of DAPT discontinuation. The incidence of ST associated with specific non-cardiac procedures has not been established.

Certain clinical and angiographic features may help identify individuals who may be at an augmented risk of ST.

The “boxed warning” identified differences in clopidogrel metabolism, but this phenomenon does not fully explain the differences in clinical events, and the incidence of low anti-platelet activity.


Conclusions The role of platelet testing has not

been defined. Current testing methods have not correlated well with the liklihood of clinical events.

Data regarding the interaction between PPIs and clopidogrel has been mixed. The preponderance of information from randomized trials suggest that there is no significant increase in the incidence of clinical events with this combination.

GERD is a common clinical problem, with symptoms similar to IHD, and with serious consequences (left untreated).

There is significant overlap in the patient population that require both DAPT and antithrombin Rx. The combination of these agents places the patient at an increased risk of a bleeding event.

New antiplatelet and antithrombin agents may prove safer in combination for these indications. Clinical trials are ongoing to address the optimal regimens and durations to be used.

New technological devices for interventional cardiologists appear promising to assess and improve the safety of terminating DAPT early.

scranton heart institute, p.c. anti-platelet medications for elective percutaneous coronary...

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