Optimal Adjunctive Medical Therapy With PCI A Primervnha.org.vn/upload/hoinghi/mayo/5. Dieu tri...
Transcript of Optimal Adjunctive Medical Therapy With PCI A Primervnha.org.vn/upload/hoinghi/mayo/5. Dieu tri...
Optimal Adjunctive Medical
Therapy With PCI A Primer
Gregory W. Barsness, MD, FACC, FAHA, FSCAI
Consultant, Internal Medicine & Cardiology and Radiology Director, Mayo Clinic EECP Laboratory
Director, Cardiac Care Unit
Mayo Clinic College of Medicine
No Relationships to Disclose
2011 Mayo Clinic Symposium Bach Mai Hospital, Hanoi
The
Challenge
The Balance
Bleeding
Clotting
The Balance
Bleeding Clotting
The Balance
Age
Renal Failure
Bleeding Risk
Stable Angina (Elective PCI)
ACS (Urgent PCI)
The Balance
The Tools
Antiplatelet Agents
Aspirin
Thienopyridines: Clopidogrel, Ticlopidine
Glycoprotein IIb/IIIa Inhibitors
Others: Prasugrel, Ticagrelor, Cangrelor
Antithrombins
Unfractionated Heparin
Low Molecular Weight Heparins
Direct Antithrombins: Bivalirudin
Nat Rev 2003
Antiplatelet
agents
sites of action
Aspirin
Pharmacology
Prodrug, metabolized to salicylate
Absorption affected by food, antacid
buffer, enteric coating, chewing
Irreversible COX-1, COX-2 inhibition
Effect within minutes, peak in 1-2 hours
Aspirin
Beneficial in PTCA
77% reduction in ischemic complications Schwartz et al NEJM 1988
Dosing for PCI
On aspirin, then 75 to 325 mg before PCI
No aspirin, then 325 mg ≥2 hrs before PCI
Maintenance dose 162 mg
Low dose has similar efficacy but decreased bleeding then with higher doses
Clopidogrel Pharmacology
Absorption – not affected by food or antacids
Prodrug - converted by liver to active metabolite
Elimination half-life = 8 hours
Irreversible binding: biologic effects = platelet life
CREDO 28-Day Outcome Time to Effect of 300 mg Loading Dose
0
2
4
6
8
10
<6 Hours 6-24 Hours Overall
Death
/MI/
Urg
en
t R
evasc
Pretreatment
No Pretreatment
Steinhubl, TCT 2002
P=0.23
P=0.05
300 mg has insignificant effect
if < 6 hours before PCI
Clopidogrel Early Effect with 600 mg Oral Load
Circulation 2005;24:2560-4
20
30
40
50
60
<1 hr 2 to 4 hrs 4 to 6 hrs >6 hrs
5 mmol
ADP
platelet
aggreg
ation
(%)
Time from load
Clopidogrel load prior to PCI
2-12 hours 600 mg
>12 hours 300 mg
Newer P2Y12 Antagonists Pharmacology
Route Onset of action Platelet binding Biologic half-
life
Prasugrel PO Prodrug
peak = 2 hrs
irreversible 7-10 days
Cangrelor IV immediate reversible 3-6 min
Ticagrelor PO Not a prodrug
peak = 2 hrs
reversible 6 hrs
TRITON-TIMI 38 CV Death, MI, Stroke
0
5
10
15
0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450
Pri
mary
en
dp
oin
t (%
)
Days
Prasugrel
Clopidogrel
ITT = 13,608
Wiviott et al: NEJM 357:2001, 2007
HR 0.77 P=0.0001
HR 0.80 P=0.0003
12.1 (781)
HR 0.81 (0.73-0.90) P=0.0004 NNT=46
9.9 (643)
Less MI, but more bleeding!
Prasugrel is more potent than clopidogrel
Single 60 mg dose more effective than
single 300 mg dose clopidogrel
10 mg repeated dosing more effective
than 75 mg clopidogrel
Prasugrel
Alternative to clopidogrel at time of PCI
Caution in age >75 or weight <60 kg
Due to rapid onset and higher potency,
reasonable to wait until coronary anatomy
defined before loading
Discontinue 7 days prior to CABG
FDA Black Box Warning
Avoid use in patients with
prior stroke or TIA Absolute Contraindication
PLATO Trial CV Death, MI or Stroke
Days after randomisation
0 60 120 180 240 300 360
11 10
9 8 7 6 5 4 3 2 1 0
Cu
mu
lati
ve i
ncid
en
ce (
%)
9.8
11.7
HR 0.84 (95% CI 0.77–0.92), p=0.0003
Clopidogrel
Ticagrelor
Reduction in All Cause Mortality,
CV Mortality, MI, Stent Thrombosis
No Increase in Bleeding
12
Ticagrelor
Ventricular pauses ≥3 seconds in first week
Dyspnea
Creatinine (reversible)
FDA boxed warning
“…aspirin doses above 100 milligrams
per day decrease the effectiveness of
the medication.”
CP1279938-1
Medical therapy without stent
or PTCA alone
Bare-metal stent group
Drug-eluting stent group
ASA 75-162 mg/d indefinitely
+
Clopidogrel 75 mg/d for at least 1 mo
(class IA) and ideally up to
12 months
ASA 162-325 mg/d for at least 1 mo, then
75-162 mg/d indefinitely
+ Clopidogrel 75 mg/d or
Prasugrel 10 mg/d for 12 months.
Shorter duration if bleeding risk>benefit
ASA 162-325 mg/d for at least 3 mo for SES,
6 mo for PES, then 75-162 mg/d indefinitely
+ Clopidogrel 75 mg/d or
Prasugrel 10 mg/d for at least 12 months
Shorter duration if bleeding risk>benefit
Long-term Antiplatelet Therapy Acute and Stable Coronary Syndromes
Glycoprotein IIb/IIIa Inhibitors Pharmacology
Platelet
binding
Drug:
receptor
ratio
Dose
adjust
Plasma
half-life
Biologic
half-life
Abciximab Irreversible 1.5:1 Wt only 10-15
min
12-24 hrs
Epifibatide Reversible >>100:1 Wt + Crcl 2-2.5
hrs
=plasma
Tirofiban Reversible >>100:1 Wt + Crcl 2-2.5
hrs
=plasma
Drug Placebo RRR Trial IIb/IIIa (%) (%) (%)
EPIC Abciximab 8.3 12.8 35
EPILOG Abciximab 5.3 11.7 55
CAPTURE Abciximab 11.3 15.9 29
IMPACT-II Eptifibatide 9.5 11.4 17
RESTORE Tirofiban 8.0 10.5 24
EPISTENT Abciximab 5.3 10.8 51
ESPRIT Eptifibatide 6.8 10.5 35
Pooled 7.8 11.6 33
Composite endpoint
0.25 4 1
Odds ratio and 95% CIs
GP IIb/IIIa
better
Placebo
better
GP IIb/IIIa Inhibitors for PCI
Sabatine. Am J Med 2000;109:224-237
Studies done prior to routine clopidogrel
loading
Minimal benefit in low risk patients with
clopidogrel preload especially 600 mg > 2 hrs prior to PCI
Consider early GP IIb/IIIa inhibitor if no
clopidogrel preload
In ACS, no benefit to “upstream use”
unless no clopidogrel or prasugrel load
No need for prolonged infusion once
oral thienopyridine initiated
TF
Thrombin (IIa)
Prothrombin Endothelial cell
VIIa X Xa
UFH + AT
Fondaparinux + AT LMWH + AT
UFH + AT LMWH + AT
Bivalirudin
Hirudin
Thrombotic Cascade
The Tools
Antithrombin
Thrombin
Factor
Xa
Low-molecular
weight heparin
Pentasaccharide
sequence Factor
Xa
Antithrombin
Weitz: NEJM, 1997
Unfractioned
heparin
Pentasaccharide
sequence 13 unit
sequence
CM969878-26
Fondaparinux sodium (Synthetic pentasaccharide )
5 13 5
AT AT II X
UFH LMWH
5
Fondaparinux
X AT
Unfractionated Heparin Pharmacology
Discovered in cat brain tissue
Family of structurally-related
glycosaminoglycan compounds
MW 5-30,000 daltons (average 15k)
About 1/3 of molecules are active
Unfractionated Heparin Pharmacology
Narrow therapeutic window
Unpredictable dose-response curve
Heterogeneous mixture of active + inactive
Nonspecific binding to cells, plasma proteins
Inactivated by platelet factor 4
Requires and dependent on a cofactor (AT)
Rebound increase in thrombin generation
Intravenous administration required
Expensive monitoring required (aPTT)
UFH in PTCA Reducing Abrupt Closure
Narins, et al, Circulation 1996
UFH in PCI (and Stenting) Reducing Early Events
Chew, et al, Circulation 2001
Ischemic Events
Bleeding
Low Molecular Weight Heparins Pharmacology
Produced by depolymerization of UFH
Better bioavailability
Predictable dose-response curve
Ease of administration
Possibly improved safety profile
Coagulation monitoring unnecessary
Issues for PCI
Not readily reversible
Difficult to monitor
Direct Antithrombins Pharmacology
Direct reduction of thrombin activity
Inhibits clot-bound thrombin
Independent of AT
Examples
Hirudin, bivalirudin, lepirudin, argatroban,
efegatran, inogatran, melagatran
Bivalirudin Key Findings in ACUITY PCI
Bivalirudin Hep + GP IIb/IIIa
Composite ischemic 9% 8%
NNH = 100
Major bleeding 4% 8%
NNT = 25
Patients with no
clopidogrel preload
Composite ischemic 10% 7%
NNH = 33
Anticoagulant Choice Elective PCI
Class I recommendations
UFH (70-100 IU/kg IV bolus) or
Enoxaparin (0.75 mg/kg IV bolus) or
Bivalirudin if HIT
Class IIa recommendation
Bivalirudin in low-risk patients as alternative to UFH and GP IIb/IIIa inhibitor (0.5 mg/kg bolus with 1.75 mg/kg/hr drip)
Preload with clopidogrel
Anticoagulant Choice NSTEMI PCI
Very High Ischemic Risk
UFH + GP IIb/IIIa inhibitor (ACT 200-250s)
Bivalirudin (with clopidogrel load)
High Ischemic Risk
UFH (ACT 250-300s) ± GP IIb/IIIa inhibitor
Bivalirudin (including clopidogrel)
Enoxaparin
if <8 hours since last SC→no extra
if 8-12 hours, then 0.3 mg/kg IV
if >12 hours, then 0.75 mg/kg IV
Anticoagulant Choice Principles
Pretreatment with dual antiplatelet
therapy essential, regardless of
anticoagulant regiment
Avoid switching anticoagulants
(crossover) at the time of PCI,
especially between LMWH and UFH
If pre-PCI fondaparinux,
use UFH at time of PCI to
avoid catheter thrombosis