Transcript The Evolution of Antiplatelet Therapy in ACS and PCI

Presenting Faculty:
Tomas Villanueva, DO, MBA, FACPE, SFHM
Clinical Assistant Professor of Medicine
College of Osteopathic Medicine
Nova Southeastern University
Medical Director, Hospital Medicine Program
Baptist Health System of Miami
Miami, FL
Dr. Villanueva has disclosed that he is a consulting editor for Hospital
Medicine Program Management and a reviewer for Hospital Medicine. He is
also on the speakers’ bureaus for American Regent, AstraZeneca, Forest,
Novo Nordisk, and Pfizer.
Pre-test
67 year old man with history of DM and GI bleed
six months ago is admitted with NSTE-ACS. Initial
ECG showed anterolateral ST depressions and
troponin levels rose to 1.3. He undergoes stenting
of the LAD with a drug-eluting stent (DES). He is
discharged to your care for further management.
%
%
%
%
What is the most appropriate daily dose of
aspirin to treat him with long-term?
A.
B.
C.
D.
81 mg QD
325 mg (enteric coated) QD
325 mg BID (to better prevent stent thrombosis)
It doesn’t matter
10
Countdown
How long should his P2Y12 inhibitor therapy
(clopidogrel, ticagrelor, or prasugrel) be continued?
A.
B.
C.
D.
One month
3-6 months
At least 12 months
It depends on which P2Y12 inhibitor he was
placed on
10
Countdown
Should the patient be placed on a PPI?
25%
25%
25%
25%
A.
B.
C.
D.
It depends
Yes
No
Maybe
10
Countdown
Pathophysiology of Plaque Rupture
and Acute Coronary Syndromes
Coronary Atherosclerotic Plaque
• Coronary artery
smooth muscle
thickening
• Foam cells
accumulate in
smooth muscle
• Core of extracellular
lipid accumulates
Ruptured Vulnerable Plaque
with Thrombus Formation
Ruptured
Vulnerable
Fibrous
Cap
Thrombus
Plaque Core
Plaque Rupture with Coronary Thrombus
Platelet Aggregation
Platelet Cascade in ACS
1 Adhesion
2 Activation
Thrombin
Platelets
von Willebrand
Factor/GP lb Bind
ADP
5 HT
Collagen
GP la/lla Bind
Lipid
Core
TXA2
3 Aggregation
4 Platelet Plug
Activated
GP llb/llla
Fibrinogen
Schafer AI. Am J Med. 1996.
Mortality in the Global Registry of Acute
Coronary Events (GRACE)
% Mortality
16
STEMI
12
Mortality from
D/C to six months
STEMI – 4.8%
NSTEMI – 6.2%
Unstable – 3.6%
8
NSTEMI
UA
4
0
0
30
60
90
120
Days
150 180
N=43,810
Fox KA, et al. BMJ. 2006;
Goldberg RJ, et al. Am J Cardiol. 2004.
Aspirin for ACS and Secondary Prevention
Aspirin in Acute Coronary Syndromes (ACS)
Acute MI
Unstable Angina
P<.0001
Death or MI
Patients (%)
20
P=.001
Reocclusion
30
17.1
P=.012
MI
4
25.0
15
3.3
15
11.8
3
20
11.0*
6.5*
1.9*
2
10
5
5
Placebo
N= 397
9.4*
10
10
0
P<.001
Vascular Death
1
ASA
399
0
Placebo
513
ASA
419
0
Placebo
8,587
ASA
8,600
0
Placebo
8,587
ASA
8,600
MI=myocardial infarction
ASA=acetylsalicylic acid
RISC=Research on Instability in Coronary Artery Disease
RISC Group. Lancet. 1990;
Roux S, et al. J Am Coll Cardiol. 1992; ISIS-2. Lancet. 1988.
Chronic ASA Doses and Vascular Events
in High Risk Patients
Antithrombotic Trialists Collaboration. Br Med J. 2002.
Relationship Between Major Bleeding
and ASA Dose in ACS Patients
Post-hoc Analysis from CURE
ASA + Clopidogrel
ASA + Placebo
Incidence of Major
Bleeding (%)
4.9%
5.0
3.7%
4.0
3.4%
3.0%
3.0
2.0
2.8%
1.9%
1.0
0
≤100 mg
(N=5,320)
101–199 mg
≥200 mg
(N=3,109)
(N=4,110)
ASA dose (range 75-325 mg)
Peters RJ, et al. Circulation. 2003.
Aspirin Dosing After ACS/PCI:
Current ACCF/AHA Recommendations
• UA/NSTEMI (2011 Focused Update):1
• 75-162 mg indefinitely
• STEMI (2004 Guideline):2
• 75-162 mg indefinitely
• Secondary Prevention (2011 Update):3
• 75-162 mg indefinitely
• PCI (2011 Guideline):4
• Aspirin indefinitely (class I; LOE A)
• Reasonable to use 81 mg/day in preference to higher
maintenance doses (class IIa; LOE B)
1Wright
RS, et al. Circulation. 2011;
2Antman EM, et al. J Am Coll Cardiol. 2004;
3Smith S, et al. J Am Coll Cardiol. 2011;
4Levine GN. J Am Coll Cardiol. 2011.
Clopidogrel After NSTE-ACS
CURE Trial:
Primary Composite Endpoint (MI/CVA/CV Death)
at 12 Months in Patients with NSTE-ACS
11.4%
12
% With Event
20% RRR
P=.00009
Placebo
+ Aspirin
14
9.3%
10
Clopidogrel
+ Aspirin
8
6
4
2
0
3
6
9
12
Follow-up (Months)
Yusuf S, et al. N Engl J Med. 2001.
Clopidogrel For Primary and
Secondary Prevention
CHARISMA Trial Design
(Clopidogrel in Addition to Aspirin in Patients Without Recent ACS)
Patients age ≥45
years at high risk of
atherothrombotic
events*
(N=15,603)
Low dose ASA 75-162 mg/day
R
Clopidogrel
75 mg/day
(N=7,802)
Double-blind treatment up to 1040 primary efficacy
events (CV death, MI or CVA)
Low dose ASA 75-162 mg/day
*Documented CAD,
CVD, symptomatic
PAD or >=2 CRF
Placebo
1 tablet/day
(N=7,801)
1-month
visit
3-month
visit
Visits every 6 months
Final visit
(Fixed study
end date)
Bhatt DL, et al. Am Heart J. 2004.
Cumulative event rate (%)
CHARISMA: Overall Population: Primary Efficacy Outcome
(MI, Stroke, or CV Death)†
8
Placebo + ASA*
7.3%
6
Clopidogrel + ASA*
6.8%
4
RRR: 7.1% [95% CI: -4.5%, 17.5%]
P=.22
2
0
0
6
12
18
24
30
Months since randomization§
† First
Occurrence of MI (fatal or non-fatal), stroke (fatal or non-fatal), or cardiovascular death
*All patients received ASA 75-162 mg/day
§The number of patients followed beyond 30 months decreases rapidly to zero and there are
only 21 primary efficacy events that occurred beyond this time (13 clopidogrel and 8 placebo)
Bhatt DL, et al. N Engl J Med. 2006.
CHARISMA Primary Efficacy Results (MI/Stroke/CV Death)
by Pre-Specified Entry Category
Population
RR (95% CI)
Qualifying CAD, CVD or PAD
P value
0.88 (0.77, 0.998)
.046
1.20 (0.91, 1.59)
.20
0.93 (0.83, 1.05)
.22
(N=12,153)
Multiple Risk Factors
(N=3,284)
Overall Population*
(N=15,603)
0.4 0.6 0.8
Clopidogrel Better
1.2 1.4 1.6
Placebo Better
*A statistical test for interaction showed marginally significant heterogeneity
(P=.045) in treatment response for these pre-specified subgroups of patients
Bhatt DL, et al. N Engl J Med. 2006.
Primary Outcome Event Rate (%)
CHARISMA – Prior MI
10
N=3,846
8.3%
8
Placebo + ASA
Clopidogrel + ASA
6.6%
6
4
2
HR=0.774 (95% CI [0.613–0.978])
P=.031
0
0
6
12
18
24
Months Since Randomization
Bhatt DL, et al. J Am Coll Cardiol. 2007.
30
Clopidogrel should be considered in a non-diabetic
patient with high risk for atherosclerosis but has not
had an episode of ACS.
A. True
B. False
10
Countdown
P2Y12 Inhibitor Therapy After Stenting
Coronary Stenting
Lesion crossed
with guidewire
Lesion dilated
with balloon
Stent aligned
in lesion
Deployed stent
In artery
Coronary Stenting
Pre-PTCA
Post-Balloon
Post-Stent
CREDO: One Year Primary Outcome
Stable CAD and ACS Patients Rx with Bare Metal Stents (BMS)
27% RRR
P=.02
Death, MI, or Stroke
15
Placebo
N=1063
11.5%
10
8.5%
Clopidogrel
N=1,053
5
0
0
3
6
9
12
Months
Steinhubl SR, et al. JAMA. 2002.
Continued Risk of Drug Eluting Stent (DES)
Thrombosis
Stent Thrombosis (%)
DES Stent Thrombosis In The Bern/Rotterdam Two Center Experience
14
Paclitaxel DES
3
2
Sirolimus DES
1
0
0
365
730
1,095
Days After Stenting
P. Wenaweser and P.W. Serruys, ESC 2006.
(Slide courtesy of Roxana Mehran, Columbia University)
Newer P2Y12 Inhibitors
∙ Prasugrel
∙ Ticagrelor
Prasugrel
• Thienopyridine
• “Irreversible” platelet
inhibition
• Rapidly metabolized
prodrug
• Rapid onset of action
• Greater and more
reliable platelet
inhibition than
clopidogrel
Bhatt DL. N Engl J Med. 2009;
van Giezen JJ. Eur Heart J Suppl. 2008.
PRINCIPLE-TIMI 44
Prasugrel vs. Clopidogrel
Loading Dose
Maintenance Doses
Inhibition of
Platelet Aggregation (%)
100
80
*
†
**
†
†
Pras 10 mg
* *
* * *
* *
§
Clop 75 mg
!
*
40
*
Clop 600 mg
Pras 60 mg
60
*
Clop 75 mg
!
20
Clop 300 mg
*P<.001 vs. Clop 300 mg
mean ± SEM
20 μM ADP
0
0 0.25 0.5
Time
1
2
Hours
4 6 24 3 4
5
6
7
8
9
or 600 mg LD
P<.001 vs. Clop 300
!
P<.05 vs. Clop 300
§P<.05 vs. Clop 300/75
†
Days
Wiviott SD, et al. Circulation. 2007.
TRITON-TIMI 38:
Study Design
ACS (STEMI or UA/NSTEMI) and Planned PCI
ASA
N=13,600
Double-blind
CLOPIDOGREL
300 mg LD/75 mg MD
PRASUGREL
60 mg LD/10 mg MD
Median duration of therapy: 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehospitalization for Recurrent Ischemia
CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies:
Pharmacokinetic, Genomic
LD=loading dose; MD=maintenance dose
Wiviott SD, et al. N Engl J Med. 2007.
TRITON-TIMI 38
Timing of Benefit: Landmark Analysis
8
Primary Endpoint (%)
(CV death, MI, CVA)
Clopidogrel
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=.01
2
6.9
HR 0.80
P=.003
1
0
0
1
2
Loading Dose
3
0
30 60 90
Days
180
270
360
450
Maintenance Dose
Wiviott SD, et al. N Engl J Med. 2007.
TRITON-TIMI 38:
Definite and Probable Stent Thrombosis
Definite & Probable Stent
Thrombosis (%)
2.5
Clopidogrel
Any Stent at Index PCI
N=12,844
2.4
(142)
2
1.1
(68)
1
Prasugrel
0
0 30 60 90
180
270
360
HR 0.48
P<.0001
NNT=77
450
Days
Wiviott SD, et al. N Engl J Med. 2007.
TRITON-TIMI 38:
Bleeding Events
4
Prasugrel
Clopidogrel
ICH in Pts with
Prior Stroke/TIA
(N=518)
% Events
P=.03
Clopidogrel 0 (0%)
Prasugrel 6 (2.3%)
P=.02
2.4
2
1.8
P=.01
P=NS
1.4
0.9
0.9
1.1
P=.002
0.4
0.1
P=NS
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
ARD=absolute risk difference
Life Threatening
ARD 0.5%
HR 1.52
Nonfatal
ARD 0.2%
Fatal
ARD 0.3%
ICH
ARD 0%
Wiviott SD, et al. N Engl J Med. 2007.
TRILOGY ACS Study Design
Medically Managed
UA/NSTEMI Patients
Randomization Stratified by:
Age, Country, Prior Clopidogrel Treatment
(Primary analysis cohort — Age <75 years)
Medical Management Decision ≤72 hrs
(No prior clopidogrel given) – 4% of total
Clopidogrel*
300 mg LD
+
75 mg MD
Prasugrel*
30 mg LD
+
5 or 10 mg MD
Median Time to
Enrollment=4.5 Days
Medical Management Decision ≤ 10 days
(Clopidogrel started ≤72 hrs in-hospital OR
on chronic clopidogrel) – 96% of total
Clopidogrel*
Prasugrel*
75 mg MD
5 or 10 mg MD
Minimum Rx Duration: 6 months; Maximum Rx Duration: 30 months
Primary Efficacy Endpoint: CV Death, MI, Stroke
*All patients were on aspirin and low-dose aspirin (<100 mg) was strongly recommended. For patients
<60 kg or ≥75 years, 5 mg MD of prasugrel was given
Adapted from Chin CT, et al. Am Heart J. 2010.
TRILOGY ACS:
Primary Efficacy Endpoint*
Primary Efficacy Endpoint (%)**
20
HR ≤1Year: 0.99 HR >1 Year: 0.72
(0.84, 1.16) (0.54, 0.97)
16.0%
13.9%
15
10
Clopidogrel
Prasugrel
HR: 0.91
P=.21 (NS)
5
Interaction P=.07
0
0
No. at risk
Prasugrel: 3,620
Clopidogrel: 3,623
180
360
540
Time, days
3,248
3,244
2,359
2,390
*Primary endpoint=CV death, nonfatal MI, nonfatal stroke
**Primary analysis excludes age >75 yrs
1,611
1,596
720
900
953
946
389
399
Roe MT, et al. N Engl J Med. 2012.
Ticagrelor
•Non-thienopyridine
•“Reversible” binding
of P2Y12 receptor
•Active drug
•Quick onset of action
•Greater degree of
and more reliable
platelet inhibition
than clopidogrel
Bhatt DL. Nature Reviews Cardiology. 2009;
van Giezen JJ. Eur Heart J Suppl. 2008.
DISPERSE 2
Comparative Effects on Platelet Aggregation of Ticagrelor vs. Clopidogrel
Inhibition of Platelet Aggregation (IPA)
IPA, % (mean ± SEM)
100
75
Ticagrelor 90 mg
Ticagrelor 180 mg
50
Ticagrelor 270 mg
Clopidogrel 300 mg
25
0
0
2
4
6
8
10
12
Time Post Dose (Hours)
Keeley EC, et al. Lancet. 2006.
PLATO Study Design
NSTEMI-ACS (moderate-to-high risk), STEMI (if primary PCI)
Clopidogrel-treated or -naive;
randomized within 24 hours of index event
(N=18,624)
Clopidogrel
If pretreated, no additional loading dose;
if naive, standard 300 mg loading dose,
then 75 mg QD maintenance;
(additional 300 mg allowed pre-PCI)
Ticagrelor
180 mg loading dose, then
90 mg BID maintenance;
(additional 90 mg pre-PCI)
6-12-month exposure
Primary endpoint: CV death + MI + Stroke
Primary safety endpoint: Total major bleeding
Wallentin L, et al. N Engl J Med. 2009.
PLATO:
Cumulative incidence (%)
Time to Primary Efficacy Endpoint*
13
12
11
10
9
8
7
6
5
4
3
2
1
0
11.7%
Clopidogrel
9.8%
Ticagrelor
HR 0.84 (95% CI 0.77-0.92)
P=.0003
0
60
120
180
240
300
360
Days after Randomisation
No. at risk
Ticagrelor
9,333
8,628
8,460
8,219
6,743
5,161
4,147
Clopidogrel
9,291
8,521
8,362
8,124
6,650
5,096
4,047
*Composite of CV death, MI, or stroke
Wallentin L, et al. N Engl J Med. 2009.
PLATO:
Secondary Efficacy Endpoints
Myocardial infarction
Clopidogrel
6
5.8
5
Ticagrelor
4
3
HR 0.84 (95% CI 0.75-0.95)
P=.005
2
7
6.9
1
Cumulative incidence (%)
Cumulative incidence (%)
7
Cardiovascular death
6
Clopidogrel
5
5.1
4.0
Ticagrelor
4
3
2
HR 0.79 (95% CI 0.69-0.91)
P=.001
1
0
0
0
60
120 180 240 300 360
Days after randomisation
0
60
120 180 240 300 360
Days after randomisation
Wallentin L, et al. N Engl J Med. 2009.
PLATO: Overall, Non-CABG and
CABG-related Major Bleeding
P=.43 (NS)
Ticagrelor
13
Estimated Rate (% per year)
12
11.6
Clopidogrel
11.2
11
10
P=.57 (NS)
9
8
7.9
P=.32 (NS)
9
8
7.7
7
7
6
6
5
5
4
4
3
3
2
2
1
1
0
0
PLATO
TIMI criteria
criteria major
major
bleeding
bleeding
7.4
7.9
P=.32 (NS)
P=.026
5.3
5.8
4.5
3.8
P=.025
2.8
2.2
Non-CABG
PLATO
major
bleeding
Non-CABG
TIMI major
bleeding
CABG
PLATO
major
bleeding
CABG
TIMI major
bleeding
Wallentin L, et al. N Engl J Med. 2009.
PLATO:
Stent Thrombosis*
Stent
Thrombosis, %
Ticagrelor
(N=5,640)
Clopidogrel
(N=5,649)
HR (95% CI)
P Value
Definite
71 (1.3%)
106 (1.9%)
0.67 (0.52-0.91)
.009
Probable of
definite
118 (2.1%)
158 (2.8%)
0.75 (0.59-0.95)
.02
Possible,
probable, or
definite
155 (2.8%)
202 (3.6%)
0.77 (0.62-0.95)
.01
*Evaluated in patients with any stent during the study
Wallentin L, et al. N Engl J Med. 2009.
Cardiovascular death, MI, or Stroke (%)
PLATO:
Initial Non-Invasive Strategy Subgroup
•N=5,216 (1/4 total study population, 1/3 NSTE-ACS population)
•In-hospital procedures: cath 41.9%; PCI 20.4%; CABG 4.0%
•By final follow-up: revascularization 40% (PCI only 72.6%; CABG
only 25.8%; both 1.6%)
14.3% HR 0.85
20
16
12.0%
Clopidogrel
12
P=.04
Ticagrelor
8
4
0
0
60
120
180
240
300
360
Days after Randomization
James SK, et al. BMJ. 2011.
PLATO:
Initial Non-Invasive Strategy Subgroup
All-cause Mortality (%)
10
•N=5,216
•In-hospital procedures: cath 41.9%; PCI 20.4%; CABG 4.0%
•By final follow-up: revascularization 40% (PCI only 72.6%;
CABG only 25.8%; both 1.6%)
8
8.2%
HR 0.75
P=.01
Clopidogrel
6
6.1%
Ticagrelor
4
2
0
0
60
120
180
240
300
360
Days after Randomization
James SK, et al. BMJ. 2011.
Summary of P2Y12 Inhibitor Properties and Use
Class
“Reversibility”
Activation
Onset of effect
Duration of effect
Withdrawal before
major elective surgery
Contraindications/
Caveats
Clopidogrel
Prasugrel
Ticagrelor
Thienopyridine
Thienopyridine
Triazolopyrimidine
Irreversible
Irreversible
Reversible
Prodrug, limited by
metabolism
Prodrug, not limited by
metabolism
Active drug
2-4 hr
30 min
30 min
3-10 days
5-10 days
3-4 days
5 days
7 days
5 days
•Contraindicated in
patients with hx CVA/TIA
•Generally not
recommended in patients
age >75 years (bleeding
risk)
•Increased bleeding risk if
body weight <60 kg
•Concomitant ASA dose
should be <100 mg
•Contraindicated if severe
hepatic impairment
•Avoid use with strong
CYP3A inhibitors* or CYP3A
inducers**
•600 mg loading dose (not
FDA approved) provides
faster, greater, and more
reliable platelet inhibition
•CYP2C19 *2 or *3 alleles
are poor metabolizers and
have reduced antiplatelet
effects
*clarithromycin, ketoconazole, indinavir, itraconazole, etc.
**rifampin, carbamazepine, dexamethasone, phenytoin, phenobarbital
Based in part from Hamm CW, et al. Eur Heart J.
2011, as well as drug PIs and study protocols.
Which of the following features do prasugrel
and ticagrelor NOT share?
A.
B.
C.
D.
Platelet receptor target
Superiority over clopidogrel in preventing stent thrombosis
Once-daily dosing
No generic formulation available
10
Countdown
Patients on ticagrelor should be on a dose of
aspirin under 100 mg per day.
A. True
B. False
10
Countdown
2012 ACCF/AHA Selected Recommendations for
Antiplatelet Therapy in UA/NSTEMI
Recommendation
COR
LOE
I
A
I
B
I
C
•Aspirin indefinitely
I
A
•P2Y12 inhibitor therapy (clopidogrel or ticagrelor) for up to 12
months
I
B
Early Invasive Strategy, Medium to High Risk Patients:
•Aspirin indefinitely
•P2Y12 inhibitor therapy (clopidogrel, ticagrelor, or prasugrel) in postPCI patients at least 12 months
•If the risk of morbidity because of bleeding outweights the
anticipated benefits afforded by P2Y12 receptor inhibitor therapy,
earlier discontinuation should be considered
Initial Conservative (noninvasive) Strategy
COR=class of recommendation; LOE=level of evidence;
ACCF=American College of Cardiology Foundation; AHA=American
Heart Association; GPI =glycoprotein IIb/IIIa Inhibitor
Jneid H, et al. J Am Coll Cardiol. 2012.
2011 ACCF/AHA/SCAI PCI Recommendations:
P2Y12 Inhibitor Therapy with Coronary Stents
Recommendation
COR LOE
P2Y12 inhibitor therapy (clopidogrel, prasugrel, or ticagrelor for at least 12
months in patients receiving a stent (BMS or DES) during PCI for ACS
I
B
Clopidogrel for at least 12 months in patients treated with a DES for a nonACS indication, if patients are not at high risk of bleeding
I
B
Clopidogrel for a minimum of 1 month and ideally up to 12 months in
patients receiving a BMS for a non-ACS indication (unless the patient is at
increased risk of bleeding; then it should be given for a minimum of two
weeks)
I
B
Earlier discontinuation (e.g., <12 months) of P2Y12 inhibitor therapy after
stent implantation if the risk of morbidity from bleeding outweighs the
anticipated benefit afforded by a recommended duration of P2Y12 inhibitor
therapy
IIa
C
Continuation of DAPT beyond 12 months in patients undergoing DES
implantation
IIb
C
Levine GN, et al. J Am Coll Cardiol. 2011.
ESC Recommendations for P2Y12 Inhibitors in
Patients with CKD
Clopidogrel
Experience is limited in patients with
severe renal impairment; use with
caution
Prasugrel
No dosage adjustment is necessary for
patients with renal impairment; limited
experience in ESRD
Ticagrelor
No dose reduction is necessary for
patient with renal impairment; limited
experience in dialysis
Hamm CW, et al. Eur Heart J. 2011.
Prasugrel is NOT indicated for ACS
patients that will undergo a PCI.
A. True
B. False
10
Countdown
PPI Treatment With Dual Oral Antiplatelet
Therapy (DAPT)
COGENT Trial – Effect of PPI
on Composite GI Events
Omeprazole
Probability of Freedom
from Primary GI Endpoint
1.00
Placebo
0.90
HR 0.34, 95% CI 0.18-0.63
P<.001 by the log-rank test
0.00
0
50
100
150
180
200
523
553
260
250
231
215
Time (Days)
No. at Risk
Placebo
Omeprazole
1,885
1,876
1,455
1,500
951
987
Bhatt DL, et al. N Engl J Med. 2010.
COGENT Trial – Effect of PPI on
Composite Cardiovascular Events
Probability of Freedom from
Primary CV Endpoint
1.00
Omeprazole
Placebo
0.90
HR 0.99, 95% CI 0.68-1.44
P=.98 by the log-rank test
0.00
0
50
100
150
180
200
515
537
250
242
218
205
Time (Days)
No. at Risk
Placebo
Omeprazole
1,885
1,876
1,449
1,488
945
966
Bhatt DL, et al. N Engl J Med. 2010.
PPI Therapy and DAPT Recommendations Based on
Risk of GI Bleeding
Recommendation
COR
LOE
PPI use for patients with history of prior GI bleeding
who require DAPT
I
C
PPI use for patients with increased risk of GI
bleeding (advanced age, concomitant use of
warfarin, steroids, NSAIDs, H. pylori infection, etc.)
who require DAPT
IIa
C
Routine use of a PPI for patients at low risk of GI
bleeding, who have much less potential to benefit
from prophylactic therapy
III: No
Benefit
C
How Much of the Patient
Are We Treating?
1,000 m2
0.0002 m2
=1/5,000,000
Courtesy of Steven Steinhubl.
Patients Not Receiving Therapy
(% of subpopulation)
Established Therapies Are Consistently
Underused in All Patient Types
60
Antiplatelets
50
39
40
Statin
46
44
36
30
30
20
Lipid-lowering
14
19
24
18
18
28
19
10
0
CAD (N=40,258)
Cerebrovasc Dis
(N=18,843)
PAD (N=8,273)
≥3 Risk Factors
(N=12,389)
Bhatt DL, et al. JAMA. 2006.
% Reduction in Primary Endpoint
Placebo-Controlled Mega-Trials of Statin Therapy in
Primary and Secondary Prevention
50
45
40
35
30
25
20
15
10
5
0
43%
36%
31%
30%
28%
24%
WOSCOPS
(CAD death
or no NFMI)
4S (total
mortality)
37%
CARE (CAD
death Or
NFMI)
23%
LIPID (total HPS (total
mortality) mortality or
Vasc Event)
GREACE ASCOTS-LLP
CARDS
(total
(NFMI + Fatal (MACCE)
mortality)
CHD)
NCEP ATP III
Latest Recommendations for Primary and Secondary Screening,
Prevention, and Therapy: Secondary Prevention
• All patients hospitalized for CAD should have
lipid profile obtained within 24 hours of
admission
• All patients with CAD should be screened
• Drug Rx can be started simultaneously with
life-style changes
• CAD-equivalents include:
• PVD, AAA, carotid disease
• Diabetes
• Multiple CRF conferring high risk of
developing CAD
• Goal: LDL <100 mg/dL
Grundy SM, et al. J Am Coll Cardiol. 2004.
NCEP ATP III Update
• Emphasized LDL <100 mg/dL is a “minimal
goal of therapy” for secondary prevention
• Consider goal of <70 mg/dL in very high risk
patients
• These patients are those with established
CVD plus:
• Multiple major risk factors (especially DM)
• Severe and poorly controlled risk factors
(especially continued smoking)
• Multiple risk factors of metabolic syndrome (TG
>200, etc.)
• Patients with ACS
Grundy SM, et al. J Am Coll Cardiol. 2004.
Which of the following medical therapies is MOST
effective at preventing stent thrombosis?
A.
B.
C.
D.
E.
F.
Statins
Beta blockers
ACEI-ARB
Good glycemic control in diabetic patients
Dual antiplatelet therapy
Good blood pressure control in hypertensive
patients
10
Countdown
Medication Adherence
Medication Adherence
• One in three patients fail to fill their prescriptions
• Approximately three of four Americans report they do not
consistently take their medications as directed
• Sixty percent of patients cannot correctly name their medications and
up to 20% of patients take other people’s medications
• Between 33 and 69 percent of medication-related hospital admissions
in the U.S. are due to poor adherence
• Approximately one-fourth of all nursing home admissions are related
to improper self-administration of medications
• In common chronic conditions such as diabetes and hypertension,
adherence rates average between 50-65 percent
National Transitions of Care Coalition. Available at: http://www.ntocc.org.
Medication Adherence Decreases Over One Year
Discharge
1 Year
*P=.03
**P<.001
% Patients
Study Design
• Canadian
Survey
• 1956 NSTEMI
patients
prospectively
followed
• Hospital and
discharge data
collected by
chart review
• One-year
adherence
data collected
by patient
telephone
interview
OA=oral
anticoagulant
OMT=optimal
medical therapy
Bagnall AJ, et al. Circ Cardiovasc Qual Outcomes. 2010.
Reasons Medications Were Not Used
Canadian Survey
Conclusions
• Physicians underestimated risk or were misinformed about guidelines
• One third of EBT nonadherent patients had stopped their own treatment
• Antiplatelet, β-blocker, and ACEI use declined during the year after discharge
Suggested solutions
• Discharge contract signed by patient
• Cardiac rehab and education
Bagnall AJ, et al. Circ Cardiovasc Qual Outcomes. 2010.
Predictors of Antiplatelet Discontinuation
One-Year Follow-Up After DES Implantation
OR, odds ratio of
discontinuation
of antiplatelet
therapy
Ferreira-González I, et al. Circulation. 2010.
Rehospitalizations:
Medicare Fee-for-Service
• Analysis of Medicare Claims data from 2003-2004
• Includes the 11,855,702 Medicare beneficiaries discharged from the hospital
Summary Analysis
19.6%
34.0%
≤30 days
≤90 days
• 19.6% (nearly 1/5) were rehospitalized
within 30 days
• 34% were rehospitalized
within 90 days
• 50.2% of those rehospitalized within
30 days after a medical discharge there
was no bill for a visit to a physician
office
Jencks FS, et al. N Engl J Med. 2009.
Case Study
• Jose is a 66-year-old gentlemen with a h/o HTN and
dyslipidemia, transferred to the tele floor from the ICU with
the Dx of a STEMI and implantation of a drug-eluting stent
(DES).
• The patient and his family were poor historians on admission
and it is unclear whether his medical and medication history
are accurate.
• Jose is anxious to “get out of here” and thinks this is “no big
deal”.
Continuity of Care:
Key Information Exchange Between the
Inpatient Team and the Primary Care Team
Pre-hospitalization and Hospitalization
• Medication reconciliation during pre-hospitalization may be
complicated by the lack of a reliable source of medication
history and should be re-evaluated 24 hours after the patient
is admitted
• Contact with the PCP is appropriate during the hospital stay,
and may offer valuable insight about issues related to
discharge planning
• A particular challenge of ACS care is the extensive amount of
complex information which must be shared quickly and
accurately with all stakeholders
• The risk of miscommunication is real
Case Study, Continued…
• Jose’s PCP provided more information about his medical and
medication history
• His father died of a heart attack at age 62
• Smoked on/off for several years and has been poorly
compliant with diet, exercise, and taking statins
• He may not comprehend the seriousness of his heart disease
and how secondary preventive measures may reduce his risk
of further events
• His history of poor adherence raises concern that he will not
persist with recommended ACS medications after discharge
Discharge and Post-Discharge
• Discharge is one of the most crucial transitions in
care, with potential impact on patient outcomes
post-discharge, including readmission
• The discharge summary is an obvious target for
quality improvement, as it is the most common
vehicle for sharing patient information with the
PCP and other healthcare providers
Overcoming Barriers to Communication
•
•
•
•
Poor literacy
Poor English proficiency
Poor understanding of medical jargon
Inadequate time with the clinician for questions
and answers
• Poor cognition
• Lack of communication between healthcare
professionals, specifically among physicians
• Financial barriers to medication use
Case Study, The Finale…
• After verbally describing his discharge medications to
Jose and his family, and providing written patient
materials, you ask Jose to explain why his prescribed
dual antiplatelet therapy is important
• A consult is requested from pharmacy for additional
counseling
• Because you have been in direct contact with the PCP,
you call now to express your concerns, in addition to
noting Jose’s poor comprehension in the discharge
summary
Transitioning the Patient With ACS From
Inpatient to Primary Care
• Timely and accurate communication between the inpatient team and the
PCP/PCHM is a vital component of a safe transition from inpatient to
primary care.
• Communication directly impacts the continuity of care, patient outcomes,
patient and caregiver satisfaction, and use of health care resources.
• The inpatient team should be cognizant of gaps in care related to how
information is generated, recorded, and shared between the inpatient
setting and primary care.
• The inpatient team responsibility for the patient does not end at the time
of discharge. All reasonable effort should be done to assure that our
patients, their caregivers and their outpatient providers are given all the
tools necessary to complete and maintain the patient’s therapy.
Post-test
67 year old man with history of DM and GI bleed
six months ago is admitted with NSTE-ACS. Initial
ECG showed anterolateral ST depressions and
troponin levels rose to 1.3. He undergoes stenting
of the LAD with a drug-eluting stent (DES). He is
discharged to your care for further management.
What is the most appropriate daily dose of
aspirin to treat him with long-term?
0%
0%
0%
0%
A.
B.
C.
D.
81 mg QD
325 mg (enteric coated) QD
325 mg BID (to better prevent stent thrombosis)
It doesn’t matter
10
Countdown
How long should his P2Y12 inhibitor therapy
(clopidogrel, ticagrelor, or prasugrel) be continued?
A.
B.
C.
D.
One month
3-6 months
At least 12 months
It depends on which P2Y12 inhibitor he was
placed on
10
Countdown
Should the patient be placed on a PPI?
A.
B.
C.
D.
It depends
Yes
No
Maybe