Download Objectives Patient Case: KS Match the Following Match the

4/9/2013
Objectives
Lindsey Clark, PharmD, BCPS
UC Health: University of Cincinnati Medical Center
Cardiology-Medicine Clinical Pharmacy Specialist
May 3, 2013
Patient Case: KS
41 F admitted for biopsy of
renal mass
Home Medications
PMH:
CAD with multiple stents to
RCA, L circumflex, and LAD
○
Most recent DES placed to
LAD 23 days ago
Rabdomyosarcoma of right
eye s/p head and neck
radiation
Left renal mass (shown to be
enlarging on CT abdomen
after stent placed)
HTN, HLD, GERD,
Depression
Review pharmacology of antiplatelet therapy
Identify recommended indications for dual
antiplatelet therapy (DAPT)
Assess cardiac and bleeding risk of patients on
DAPT who must undergo surgery
Develop an appropriate bridging strategy for
patients on DAPT undergoing surgery
Match the Following
Aspirin 325 mg daily
Clopidogrel 75 mg daily
Isosorbide mononitrate 30 mg QHS
Metoprolol XL 50 mg daily
Rosuvastatin 20 mg QHS
Furosemide 20 mg Q48H
Fentanyl 75 mcg TD Q48H
Fluoxetine 10 mg daily
Pantoprazole 40 mg daily
Senna 1 tab BID
Zolpidem 5 mg QHS
Nitroglycerin SL PRN
Tizanidine PRN
Vicodin PRN
Promethazine PRN
Match the Following
According to package inserts, how long should each
agent be held prior to surgery?
Aspirin
Ticlopidine
3. Clopidogrel
4. Prasugrel
5. Ticagrelor
Continue
5 days
C. 7 days
D. 10-14 days
E. None of the above
1.
A.
2.
B.
Platelets
According to package inserts, how long should each
agent be held prior to surgery?
Aspirin
Ticlopidine
3. Clopidogrel
4. Prasugrel
5. Ticagrelor
Continue
5 days
C. 7 days
D. 10-14 days
E. None of the above
1.
A.
2.
B.
Gurbel PA and Udaya ST. Circulation 2010;121:569-583.
Patrono C et al. Chest 2008;133:199-233.
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Adenosine Diphosphate (ADP)
Clopidogrel
Prasugrel
Ticagrelor
Abciximab
Eptifibatide
Tirofiban
P2Y12
GP IIb/IIIa
PI3K
Thrombin
PAR-1
Rap1b/Akt
Phospholipid Release
Intracellular Signaling
Arachadonic Acid
Aspirin
COX-1
Thromboxane A2 (TxA2)
TxA2
Gurbel PA and Udaya ST. Circulation 2010;121:569-583.
Indications for DAPT
Indication
Recommended
Duration
Study
Coronary Artery Disease
Primary Prevention
N
Secondary Prevention
N
NSTEMI/UA without PCI
Y
CHARISMA
CHARISMA
1 year (min 1 month)
CURE
STEMI without PCI
Y
Minimum14 days
COMMIT, CLARITYTIMI 28
PCI
Y
BMS: Min 1 month
DES: Min 1 year
PCI-CURE, CREDO
BASKET-LATE
Drug Eluting
Stent (DES)
vs. Bare Metal
Stent (BMS)
Timing
Stroke
Atherosclerotic ischemic
(1°and 2°prevention)
N (Y)
MATCH
SAMMPRIS
Cardioembolic (AF)
N (Y)
CLAAF, ACTIVE-A,
ACTIVE-W
N
CAMPER, CASPAR
Peripheral Arterial Disease
AF = Atrial fibrillation; min = minimum; NSTEMI = Non-ST elevation myocardial infarction; PCI = Percutaneous coronary intervention; STEMI
= ST elevation myocardial infarction; UA = Unstable angina
Reaume KT, et al. Ann Pharmacother. 2008;42:550-7.
Antman EM, et al. Circulation. 2008;117:296-329.
Anderson JL, et al. Circulation. 2011;123:e426-e579.
American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 Supplements.
Delayed Arterial Healing in
Drug-Eluting Stents
Early Stent Thrombosis
• Acute
• Subacute
DES
BMS
< 24 hours
24 hours to 1 month
Late Stent Thrombosis
1 month to 1 year
Very Late Stent Thrombosis
> 1 year
Restenosis
Shuchman M. N Engl J Med. 2006; 355:1949-1952.
Incidence of Surgery within
One Year after Stenting
Bare metal stent
Mean % endothelialization
100
Neointima
90
80
Strut
70
60
15-mo. following stent
placement in the LAD
50
40
Drug-eluting stent
30
Bare metal stent
20
Drug-eluting stent
10
0
1
2
4
5
6
9
19
20
24
50
Months after implantation
Joner M, et al. J Am Coll Cardiol. 2006;48:193-202.
Savonitto S, et al. J Thromb Haemost 2011; 9: 2133–42.
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Cardiac Risk Scoring Systems
NSQIP Risk Model
Revised Cardiac Risk Index
(RCRI)
Cardiac and non-cardiac surgery
Non-emergent, non-cardiac surgery
Predicts
Myocardial Infarction
Cardiac arrest
Myocardial infarction
Primary cardiac arrest
Ventricular fibrillation
Pulmonary edema
Complete heart block
Includes
Age
Serum creatinine > 1.5 mg/dL
ASA Physical Status Class
Preoperative functional status
Type of surgery
High-risk type of surgery
History of ischemic heart disease
History of heart failure
Historiy of cerebrovascular disease
Diabetes requiring insulin
Serum creatinine > 2 mg/dL
surgicalriskcalculator.com/miorcardiacarrest
0 points: 0.4%
1 point: 0.9%
2 points: 6.6%
3 or more: 11%
Use
Scoring
C-statistic
2007 = 0.884
2008 = 0.874
C-statistic = 0.747
NSQIP = National Surgical Quality Improvement; ASA = American Society of Anesthesiologists
MICA = intraoperative or postoperative myocardial infarction or cardiac arrest
Gupta PK, et al. Circulation. 2011 Jul 26;124(4):381-7.
Lee TH, et al. Circulation. 1999; 100:1043-1049.
Cardiac Risk for Surgery
Gupta PK, et al. Circulation. 2011 Jul 26;124(4):381-7.
Major Events vs.
Days from Stent Placement
P = 0.003
Barash P, Akhtar S. Br. J. Anaesth. 2010;105:i3-i15
Surgical Related Bleeding Risk
Risk of Bleeding
Type of Surgery (non-cardiac)
Low
Endoscopy; biopsies
Eye anterior chamber (cataract surgery)
Dental extraction and dental surgery
Otolaryngology surgery
Minor orthopaedic surgery
Cutaneous surgery; plastic surgery
Intermediate
Visceral surgery
Major orthopaedic surgery
Urologic surgery
High
Intracranial neurosurgery
Spinal canal surgery
Eye posterior chamber surgery
Transurethral prostatectomy
Motovska Z. Drugs 2011;71(14):1797-1806
Major Events vs. Surgical Risk
P = 0.136
Motovska Z. Drugs 2011;71(14):1797-1806
P = 0.046
P < 0.001
P <0.001
Motovska Z. Drugs 2011;71(14):1797-1806
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Major Events vs.
Need for Emergent Surgery
Now with a better understanding of risks of bleeding and
stent thrombosis what would you like to do with KS’s
DAPT prior to biopsy?
A. Continue both aspirin and clopidogrel
B. Continue aspirin alone and stop clopidogrel 5 days before
biopsy
C. Stop both aspirin 7 days before and clopidogrel 5 days
before biopsy,
D. Continue aspirin, stop clopidogrel 5 days before biopsy,
and start eptifibatide
E. Postpone the biopsy
P = 0.003
P = 0.006
P = 0.016
Motovska Z. Drugs 2011;71(14):1797-1806
Patient Case: KS
Clopidogrel discontinued 23 days after DES placed and aspirin
discontinued 26 days after DES placed
Eptifibatide 180 mcg/kg bolus then 2 mcg/kg/min
Preoperative Management
Surgical vs. Cardiac Risk Level
KS undergoes biopsy 5 days after clopidogrel discontinued
Cardiac Risk
More than 3 months after PCI, BMS, or
CABG
More than 6 months after ACS or MI
More than 12 months after regular DES
Peripheral and wall surgery
Minor ENT and orthopedics
Endoscopy without biopsy or resection
Eye anterior chamber or dentistry
Intermediate
Six to 12 weeks after PCI, BMS, or CABG
Six to 24 weeks after ACS or MI
More than 12 months after high-risk DES
Visceral and vascular surgery
Major ENT and orthopedics
Urology
Endoscopy with biopsy or resection
High
< 6 weeks after PCI, BMS, CABG, ACS,
or MI
< 12 months after DES
Cardiac surgery
Surgery with massive bleeding
Surgery in closed space (intracranial,
intramedullary canal, posterior eye
chamber)
Aspirin 325 mg daily reinitiated day of biopsy
Eptifibatide continued until pathology results reported
Proliferation of malignant spindle cells
Surgical Risk
Low
Heme/onc and urology determine that surgery will be
necessary for removal of the left renal mass
Chassot PG, et al. Br J Anaesth. 2007;99(3):322.
Preoperative Management
Surgical vs. Cardiac Risk Level
Chassot PG, et al. Br J Anaesth. 2007;99(3):322.
Preoperative Management
Surgical vs. Cardiac Risk Level
Chassot PG, et al. Br J Anaesth. 2007;99(3):322.
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Recommendations
What if surgery is unavoidable?
If surgical need known prior to PCI, recommend placement of BMS
or balloon angioplasty
Stress the importance of minimum duration of DAPT
Tirofiban
BMS: 1 month
Eptifibatide
Postpone surgery until minimum duration met
If surgery cannot be postponed,
Cangrelor
Consider continuing aspirin during the peri-operative period
Restart P2Y12 inhibitor as soon as possible post-operatively
P2Y12 Inhibitors
Ticagrelor
DES: 12 months
Platelet function assessment
GP IIB/IIIA Inhibitors
High risk surgeries should be performed at hospitals with 24
hour cath lab facilities
Reversal of antiplatelet medications
Continue DAPT
Grines CL, et al. Circulation. 2007;115:813-818.
Assessment of Platelet Function
Type
Test
Advantages
Platelet-Platelet Aggregation
Platelet aggregometry
• Turbidometric
Gold standard
• Impedance
Whole blood assay
Sample preparation
Reproducibility
Expensive
Large sample needed
Time consuming
Activation
Dependent
VerifyNow
Simple, rapid POC
Small sample volume
No instrument adjustment
Plateletworks
Little sample preparation
Not well studied
Flow Cytometry
Low sample volume
Sample preparation
Expensive
Requires flow cytometer
Experienced staff
Clot Shear
Resistance
Shear
Induced
Platelet
Adhesion
Thromboelastogram
POC; Platelet clot formation
and clot lysis data
Limited studies
Impact Cone and
Plate(let) Analyzer
Simple, rapid POC
Small sample volume
High shear
Not widely available
Patni R, et al. Heart Lung Circ. 2012 Aug;21(8):455-62.
Braunwald E, et al. Clin. Cardiol. (Suppl. 1) 31, 3, I-10–I-16 (2008)
DES placed within 6
months of surgery
Admit 2 – 3 days
prior to surgery
for tirofiban
infusion
Abciximab
Tirofiban
Eptifibatide
Antibody Fab
fragment
Nonpeptide
Cyclic
heptapeptide
Molecular Weight
48 kDa
< 1 kDa
< 1 kDa
Onset
Rapid
Rapid
Rapid
Drug half-life
10-30 min
2h
2.5 h
Excretion
Unknown
40-70% renal
50% renal
24-48 hours
50% to normal
within 4 hours
4-6 hours
Structure
Return of platelet
function
Eikelboom JW, et al. Chest 2012;141;e89S-e119S.
Bridge with Tirofiban
Bridge with Tirofiban
Discontinue
Clopidogrel +/Aspirin 5 days
prior to surgery
GP IIB/IIIA Inhibitors
Disadvantage
Discontinue
tirofiban 4 hours
prior to surgery
Resume DAPT
as soon as
possible
Retrospective, observational study of 36 patients
15 CABG
No MACE noted
6 bleeding episodes noted
21 non-cardiac interventions
○ 9 Minor
○ 12 Major
Outcomes followed for 30 days post bridge
Major adverse cardiac events (MACE)
○ Death, repeat MI, target vessel or target lesion revascularization, or stent thrombosis
Bleeding
○ Hematuria, GI bleed, transfusion w/o bleeding, decrease Hgb, post-op
bleeding requiring intervention
TUR = Transurethral resection; CABG = Coronary artery bypass grafting
Exclusion: thrombocytopenia, anemia, decreased renal function,
serious liver disease, and recent CVA or any operation < 6 weeks
Marcos EG, et al. Neth Heart J. 2011;19:412–417.
Marcos EG, et al. Neth Heart J. 2011;19:412–417.
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Bridge with Eptifibatide
Study
Patients
Morrison, et al
19 patients with
median DES
placement 102 days
prior to surgery
• 6 non-cardiac
• 13 cardiac
Start eptifibatide median 2
days after last dose of
clopidogrel
100 consecutive
patients with stent
needing surgery
• 22 non-cardiac
• 71 cardiac
• 7 did not undergo
surgery
• 89% of patients
had a DES
• Median time from
stent placement was
156 days
Start eptifibatide bridge to
surgery (median duration of
infusion 5 days)
Retrospective
chart review
Rassi, et al
Retrospective
chart review
Bridge with Eptifibatide
Intervention
Outcomes
Stopped eptifibatide median
10 hours prior to surgery
Propensity matched control
comparison of 68 of 71
cardiovascular surgery
patients
7 (53.9%) major bleeds in
cardiac surgery
2 minor bleeds
– 1 CTS & 1 non-cardiac surg
Blood transfusions:
65% bridged vs. 66% control
Mean # of units transfused:
4.84 ± 6.93 bridged
3.65 ±7.46 control
Return to the OR for bleeding
or tamponade (p 0.085):
10% bridged vs. 2.9% control
Morrison TB, et al. Cath and Card Intervent 2012;79:575–582.
Rassi AN, et al. Am J Cardiol 2012 Aug 15;110(4):485-90.
Rassi AN, et al. Am J Cardiol 2012 Aug 15;110(4):485-90.
P2Y12 Inhibitors
Pharmacokinetic Variability
The ONSET/OFFSET Study
Clopidogrel
Prasugrel
Ticagrelor
Cangrelor
Thienopyridine
Thienopyridine
ATP analog
ATP analog
Oral daily
Oral daily
Oral BID
Continuous
Intravenous Infusion
No
No
Yes
Yes
Peak Platelet
Inhibition
4-6 hours
2 hours
2 hours
30 minutes
CYP450
Metabolism
CYP2C19
CYP3A4
CYP2B6
CYP3A4
CYP3A5
None
Half Life
6-8 hours
2-15 hours
6-12 hours
3 minutes
5 days
7 days
5 days
TBD
Structure
Dosing
Reversible
Hold prior to
surgery
ATP = Adenosine triphosphate; TBD = To be determined
Packard KA, et al. Pharmacotherapy 2012;32(3):244–273.
The ONSET/OFFSET Study
Gurbel PA, et al. Circulation. 2009;120:2577-2585.
The ONSET/OFFSET Study:
Subgroup Analysis
(n = 14)
(n = 46)
Gurbel PA, et al. Circulation. 2009;120:2577-2585.
Storey RF, et al. J Thromb Haemost 2011; 9:1730–7.
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Bridge Trial:
Cangrelor vs. Placebo
210 patients
randomized
Administered for at least 48 hours prior to surgery
Stopped 1-6 hours before CABG
Primary Endpoint
Platelet reactivity assessed using VerifyNow®
○ Measured in P2Y12 reaction units (PRUs)
○ Goal PRU < 240
106
cangrelor
104
placebo
Secondary Endpoints
400
300
200
100
0
Baseline 1
Efficacy: 90
Safety: 101
Efficacy: 93
Safety: 106
Cangrelor
Platelet Reactivity (PRU)
Continuous infusion of cangrelor 0.75 mcg/kg/min
Placebo
Patients undergoing non-emergent cardiac surgery
Platelet Reactivity (PRU)
Bridge Trial: Efficacy
2
3
4
5
6
7
400
300
200
100
Last sample
on infusion
Day
Excessive CABG surgery-related bleeding
0
Pre-CABG
sample
Placebo
86
76
73
57
34
24
14
2
Placebo
84
75
Cangrelor
85
80
70
55
33
7
6
1
Cangrelor
84
78
Composite: death, MI, stroke, or urgent revascularization
Angiolillo DJ, et al. JAMA. 2012;307(3):265-274
Angiolillo DJ, et al. JAMA. 2012;307(3):265-274
Reversal of Antiplatelet Therapy:
Platelet Protocol
Bridge Trial: Safety
Cangrelor
(n = 102)
Placebo
(n = 96)
p-value
Protocol defined
bleeding
12 (11.8)
10 (10.4)
0.76
BARC Bleeding
10 (9.8)
10 (10.4)
0.89
Ischemic
3 (2.8)
4 (4)
NR
Endpoint
BARC = Bleeding Academic Research Consortium
Protocol defined
Surgical reexploration
2-4 hour chest tube output of > 1.5 L
PRBC transfusion > 4 units
BARC Bleeding
Reoperation following closure of sternotomy
Chest tube output of > 2 L in 24 hours
PRBC or whole blood transfusion of > 5 units
Fatal bleeding
Perioperative intracranial bleeding
Angiolillo DJ, et al. JAMA. 2012;307(3):265-274
Thiele T, et al. J Thromb Haemost 2012; 10: 968–71.
Reversal of Antiplatelet Therapy:
Platelet Protocol
14 patients enrolled
Indications for dual
antiplatelet therapy:
Surgical interventions
Reversal of Antiplatelet Therapy:
Platelet Protocol
Spine surgery (n = 5)
Orbita bottom surgery (n = 1)
months (n = 9)
BMS < 4 weeks, ACS <
12 months, severe
coronary artery
stenosis, insertion of a
renal artery BMS< 9
days, transaortic valve
implantation < 3 months
(n = 1 each).
Orthopedic hip/knee joint
Results
Clopidogrel reinitiation median 48 hours
Intracranial surgery (n = 2)
Insertion of a DES < 12
Thiele T, et al. J Thromb Haemost 2012; 10: 968–71.
PCs = Platelet Concentrates; ASA = Aspirin
Nephrectomy patient developed prolonged
bleeding but no PRBCs transfused
1 ACS reported after hemicolectomy
○ No stent thrombosis seen on catheterization
replacement surgery (n = 4)
Nephrectomy (n = 1)
Hemicolectomy (n = 1)
Limitations:
May not be applicable for other P2Y12 inhibitors
Platelet transfusion reactions or adverse effects
Thiele T, et al. J Thromb Haemost 2012; 10: 968–71.
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Non-cardiac Surgeries on DAPT
Non-cardiac Surgeries on DAPT
PAVR = Percutaneous aortic valve replacement
CEA = Carotid endarterectomy; EVAR = Endovascular abdominal aortic aneurysm repair;
oAAA = Open abdominal aortic aneurysm repair
Stone DH, et all. J Vasc Surg 2011;54:779-84.
Quante M, et al. Arch Surg. November 2011;146(11):1334-1335.
Patient Case: KS
Cost and Other Considerations
Discussion between attending surgeon and interventional
cardiologist (and pharmacists)
Aspirin 81 mg daily
Eptifibatide continued until 4-6 hours prior to surgery
Resection of retroperitoneal mass 40 days after DES placed
Eptifibatide reinitiated when immediate surgical bleeding risk
stable
Agent
Cost per unit
Ticagrelor
$3.48
Eptifibatide
$328.32
Platelets
Approx $500
Cangrelor
TBD
Approximately 6 hours after surgery
Clopidogrel 300 mg once day after surgery then 75 mg daily
Admission to the hospital?
Days off work for patient?
Waiting for OR scheduling?
Duration of therapy?
Platelet function testing?
Cost of a bleeding episode?
Cost of a cath lab visit?
Conclusions
Recommended Actions
Indication for dual
antiplatelet therapy?
Data regarding bridging strategies for patients requiring DAPT is
limited
Small study sizes
Case reports or retrospective
Urgency for surgery?
Variability in definitions and practices with transfusions
Cardiac vs. surgical
bleeding risk?
A multidisciplinary care team should have open communication
and come to a consensus for, and with, each patient
Future directions?
Cangrelor FDA approval
Discussion among
providers
Shorter duration of DAPT after DES placement?
○ RESET Trial (J Am Coll Cardiol 2012;60:1340–8)
○ MATRIX Registry (Catheter Cardiovasc Interv. 2012 Sep 1;80(3):408-16.)
○ CREDO-Kyoto PCI/CABG Registry Cohort-2 (Circ Cardiovasc Interv. 2012
Jun;5(3):381-91.)
Plan development
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Lindsey Clark, PharmD, BCPS
UC Health: University of Cincinnati Medical Center
Cardiology-Medicine Clinical Pharmacy Specialist
May 3, 2013
9