Transcript Document

Anti-Platelet Medications For
Elective Percutaneous Coronary
Interventional Procedures - 2011
Stafford M. Smith, M.D., FACP, FACC
Scranton Heart Institute, P.C.
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.
Scranton Heart Institute, P.C.
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 (shortacting, reversible agent)

PLATO – Significant reduction in ischemic events without an
increase in bleeding.
Scranton Heart Institute, P.C.
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, reinfarction, 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.
Scranton Heart Institute, P.C.
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.
Scranton Heart Institute, P.C.
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).
Scranton Heart Institute, P.C.
Prasugel’s “boxed warning”
1.
2.
3.
4.
5.
6.
7.
8.
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.
Do not use in patients with active pathological bleeding or history
of transient ischemic attacks (TIA) or stroke.
Prasugrel is not recommended in patients ≥75 yrs., due to
increased risk of fatal intracranial bleeding.
Do not start prasugrel in patients likely to undergo urgent coronary
artery bypass graft surgery (CABG).
Discontinue prasugrel at least 7 days prior to surgery.
Suspect bleeding in any patient who is hypotensive that has
recently undergone coronary angiography, PCI, CABG, or other
surgical procedures.
If possible, manage bleeding without discontinuation.
Discontinuation of prasugrel within the first few weeks after an
ACS increases the risk of subsequent cardiovascular events.
Scranton Heart Institute, P.C.
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)
Scranton Heart Institute, P.C.
Dual Anti-Platelet Therapy (DAPT)
1 Randomized Trial And Several Registries Suggesting A
Benefit With Prolonged Use Of 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.
Scranton Heart Institute, P.C.
Dual Anti-Platelet Therapy (DAPT)
Conflicting Data Regarding The Use Of
Prolonged 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.
Scranton Heart Institute, P.C.
MECHANISMS OF PLATELET ACTIVATION AND AGGREGATION.
Chhatriwalla A K , Bhatt D L Circ Cardiovasc Interv 2008;1:217-225
Copyright © American Heart Association
Scranton Heart Institute, P.C.
PLATELET AGGREGATION
Platelets aggregate by using fibrinogen and vWF as a
connecting bridge. The glycoprotein IIbIIIa receptor
binds fibrinogen, fibronectin, vitronectin,
thrombospondin, and vWF.
Scranton Heart Institute, P.C.
AHA/ACC/SCAI/ACS/ADA SCIENCE ADVISORY
Prevention of Premature Discontinuation of Dual
Antiplatelet Therapy in Patients With Coronary Artery
Stents
A 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
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
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 highrisk patients with drug-eluting stents.
Scranton Heart Institute, P.C.
ACC/AHA Guidelines
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
 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]
Scranton Heart Institute, P.C.
Prevalence, Predictors, and Long-Term Prognosis of
Premature Discontinuation of Oral Antiplatelet
Therapy After Drug Eluting Stent Implantation
Rossini, Capodanno, Lettieri, Musumeci, et al., Am J Cardiol Vol. 107, 2, P186-19415, Jan 2011
 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)
Scranton Heart Institute, P.C.
Duration of Dual Anti-Platelet Therapy
After Implantation of Drug-Eluting Stents
Park SJ, Park DW, Kim YH, et al. N Engl J Med 2010; Mar 15
 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.
Scranton Heart Institute, P.C.
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
Scranton Heart Institute, P.C.
STENT THROMBOSIS
Scranton Heart Institute, P.C.
Blood Clotting
Red Blood Cell
Platelet
Fibrin Mesh
Scranton Heart Institute, P.C.
Coronary Stent Thrombosis
and Noncardiac Surgery
Time Period Patients, n
1996–1998
40
DES, %
0
Time From
Mortality
PCI to
Rate,* % (95%
Surgery
CI)
<42 d
21.4 (10.2–
35.0)
<60 d
3.4 (1.2–6.3)
Authors
Kaluza et al
Year
2000
Type
Retr, NR
Wilson et al
2003
Retr, NR
1990–2000
207
0
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.
Scranton Heart Institute, P.C.
Predictors of DES Thrombosis:
Considerations for Prolonged Dual
Antiplatelet Therapy (DAPT)
Clinical
Angiographic
Advanced age
Acute coronary syndrome
Diabetes
Low ejection fraction
Prior brachytherapy
Renal failure
Long stents
Multiple lesions
Overlapping stents
Ostial or bifurcation lesions
Small vessels
Suboptimal stent results
Scranton Heart Institute, P.C.
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.
Scranton Heart Institute, P.C.
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?
Scranton Heart Institute, P.C.
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
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
 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.
Scranton Heart Institute, P.C.
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)
Scranton Heart Institute, P.C.
GASTRO-ESOPHAGEAL REFLUX
DISEASE (GERD) & ESOPHAGEAL
CARCINOMA
A consideration to support the more liberal use of proton pump inhibitors in the
general population…
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.
Scranton Heart Institute, P.C.
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.
Scranton Heart Institute, P.C.
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
Scranton Heart Institute, P.C.
Combination therapy with aspirin, clopidogrel, and
warfarin following coronary stenting is associated
with a significant risk of bleeding
Khurram Z, Chou E, Minutello R, Bergman G, Parikh M, Naidu S, Wong SC, Hong MK. Lenox Hill Hospital,
New York, New York, USA.
• 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.
Scranton Heart Institute, P.C.
OCT Image
IVUS Image
OPTICAL
COHERENCE
TOMOGRAPHY
(OCT)
Scranton Heart Institute, P.C.
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.
Scranton Heart Institute, P.C.
 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).
Scranton Heart Institute, P.C.
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.