CVD Critical Pathways Group 2005 Teleconferences

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CVD Critical Pathways Group 2005 Teleconferences
December 7, 2005
This activity is supported by an educational
grant from the Bristol-Myers Squibb/Sanofi
Pharmaceuticals Partnership.
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Faculty
Gregg C. Fonarow, MDEliot Corday Professor of
Medicine and Cardiovascular ScienceDirector,
Ahmanson-UCLA Cardiomyopathy CenterUCLA Division
of CardiologyUCLA Medical CenterLos Angeles,
California
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Disclosure Statement

• The Network for Continuing Medical Education
  requires that CME faculty disclose, during the
  planning of an activity, the existence of any
  personal financial or other relationships they or
  their spouses/partners have with the commercial
  supporter of the activity or with the
  manufacturer of any commercial product or service
  discussed in the activity.

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Faculty Disclosure Statement

• Gregg C. Fonarow, MD, has served as a consultant
  to and has received research support from
  GlaxoSmithKline, Pfizer Inc., and Scios Inc. He
  has also received honoraria from Merck Co.,
  Inc.
• Charles V. Pollack, Jr., MA, MD, FACEP,
  representing the team from Pennsylvania Hospital
  has served as a consultant to Millennium
  Pharmaceuticals Inc. and Schering-Plough
  Corporation, has received honoraria from Aventis
  Pharmaceuticals Inc., Bristol-Myers Squibb
  Company, Millennium Pharmaceuticals Inc.,
  Sanofi-Synthelabo Inc., and Schering-Plough
  Corporation, and research support from Aventis
  Pharmaceuticals Inc.

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Polling Question 1

• Did you attend the 2005 American Heart
  Association Scientific Sessions?
• Yes, I attended the entire duration of the
  conference
• Yes, I attended part of the conference
• No, I did not attend

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Update on the 2005 AHA Scientific Sessions
Gregg C. Fonarow, MD
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Update on the 2005 AHA Scientific Sessions

• FIELD (Fenofibrate Intervention and Event
  Lowering in Diabetes)
• IDEAL (Incremental Decrease in Endpoints Through
  Aggressive Lipid Lowering)
• SURVIVE (Survival of Patients with Acute Heart
  Failure in Need of Intravenous Inotropic Support)
• REVIVE-2 (Randomized Evaluations of Levosimendan)
• More Lessons from CRUSADE (Can Rapid Risk
  Stratification of Unstable Angina Patients
  Suppress Adverse Outcomes with Early
  Implementation of the ACC/AHA Guidelines)
• New PCI Guidelines (Excerpts from New PCI
  Guidelines (review of oral antiplatelet
  recommendations)

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FIELD Design
9795 patients, Age 50-75 years, type 2 diabetes
diagnosed after age 35 years, no clear indication
for cholesterol-lowering therapy at baseline
(total cholesterol 116-251 mg/dL, plus either
total cholesterol to HDL ratio 4.0 or
triglyceride gt88.6 mg/dL)
Placebo N4900
Fenofibrate (200 mg daily) n4895

• Endpoints
• Primary Composite of CHD death or nonfatal MI
  at 5-year follow-up
• Secondary Composite of total CV events, CV
  mortality, total mortality, stroke, coronary
  revascularization and all revascularization at
  5-year follow-up

Keech A, et al. Lancet. 2005.3661849-1861.
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FIELD Primary Endpoint
Composite CHD death or nonfatal MI at 5 years
( of treatment arm)

• The primary composite endpoint of CHD death or
  nonfatal MI was not significantly lower in the
  fenofibrate group compared to the placebo group.

5.9
6
5.2
4
2
0
P0.16
Keech A, et al. Lancet. 2005.3661849-1861.
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FIELD Primary Endpoint
CHD death or nonfatal MI at 5-year follow-up (
of treatment arm)

• CHD death was not significantly different between
  treatment groups
• Nonfatal MI was significantly lower in the
  fenofibrate group compared with the placebo group

4.2
4
3.2
2.2
1.9
2
0
CHD Death
Nonfatal MI
P0.01
P0.22
Keech A, et al. Lancet. 2005.3661849-1861.
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FIELD Secondary Endpoint
Secondary Composite Endpoint of Total CV Events
at 5-Year Follow-up

• The secondary composite endpoint of total CV
  events was significantly lower in the
  fenofibrate group compared to the placebo group
  ( of treatment arm)

13.9
15
12.5
10
5
0
P0.035
Keech A, et al. Lancet. 2005.3661849-1861.
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FIELD Secondary Endpoint
Individual Components of Secondary Endpoint

• CV Mortality, Total Mortality, and Stroke were
  not significantly different between the
  fenofibrate and placebo groups

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7.3
6.6
6
3.6
4
3.2
2.9
2.6
2
0
CV Mortality
Total Mortality
Stroke
P0.41
P0.18
P0.36
Keech A, et al. Lancet. 2005.3661849-1861.
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FIELD Secondary Endpoint
Individual Components of Secondary Endpoint

• Percentage of coronary revascularization and all
  revascularization were significantly lower in the
  fenofibrate group compared to placebo

9.6
10
7.8
7.4
5.9
5
0
Coronary revascularization
All Revascularization
P0.003
P0.001
Keech A, et al. Lancet. 2005.3661849-1861.
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IDEAL Trial Study Design
8,888 patients 80 years with definite history of
myocardial infarction and qualified for statin
therapy at time of recruitment Pts. on statin
therapy at baseline simvastatin (50),
atorvastatin (11), pravastatin (10) baseline
LDL 121.5 mg/dL total cholesterol 196 mg/dL
median time from last MI 21 mos in atorvastatin
group, 22 mos in simvastatin group 19 female,
mean age 62 yrs, fasting blood samples were
obtained at baseline, 12 weeks, 24 weeks, 1 year
and each year thereafter, mean follow-up median
of 4.8 years. Randomized to
High-dose atorvastatin 80 mg/day If LDL was lt40
mg/dL at 24 wks dose could be reduced to 40
mg/day n4,439
Standard-dose simvastatin 20 mg/day If
cholesterol gt190 mg/dL at 24 wks dose could be
increased to 40 mg/day n4,449
Primary Endpoint Composite of major coronary
event, defined as coronary death, hospitalization
for nonfatal acute MI or resuscitated cardiac
arrest. Secondary Endpoint Major cardiovascular
events, any CHD event, hospitalization with a
primary diagnosis of congestive heart failure,
peripheral artery disease, any cardiovascular
events and all-cause mortality.
Pedersen TR, et al. JAMA. 20052942437-2445.
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IDEAL Trial Primary Endpoint
Primary composite of major coronary event ()

• The primary composite endpoint of major coronary
  event occurred in 9.3 of the atorvastatin group
  and 10.4 of the simvastatin group.

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10.4
9.3
9
Percent
6
3
0
Atorvastatin
Simvastatin
P0.07
Major coronary event defined as coronary death,
hospitalization for non-fatal acute MI or
resuscitated cardiac arrest. Pedersen TR, et al.
JAMA. 20052942437-2445.
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IDEAL Trial Primary Endpoint (cont)

• Among the components of the primary endpoint,
  there was no difference in CHD death or cardiac
  arrest with resuscitation, but nonfatal MI
  occurred less frequently in the atorvastatin
  group.

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7.2
6.0
6
4.0
3.9
Percent
4
2
0.2
0.2
0
CHD death
Cardiac arrest with resuscitation
Nonfatal MI
PNS
P0.02
P0.90
Pedersen TR, et al. JAMA. 20052942437-2445.
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IDEAL Trial Secondary Endpoints
Major cardiovascular events and any
cardiovascular event ()

• Major cardiovascular events, defined as any
  primary event plus stroke, occurred less often in
  the atorvastatin group.
• Any cardiovascular event, defined as major CV
  event plus hospitalization for CHF and peripheral
  artery disease, also occurred less often in the
  atorvastatin group.

30.8
32
26.5
24
Percent
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13.7
12.0
8
0
Major CV events
Any CV event
P0.02
Plt0.001
Pedersen TR, et al. JAMA. 20052942437-2445.
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IDEAL Trial Serious Adverse Events
Serious adverse events and adverse event
resulting in permanent study drug discontinuation
()

• There was no difference in the frequency of
  serious adverse events, but adverse events
  resulting in permanent drug discontinuation was
  more frequent in the atorvastatin group.

47.4
46.5
48
40
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24
16
9.6

4.2
8
0
SAE
SAE drug discontinuation
Plt0.001
P0.42
Pedersen TR, et al. JAMA. 20052942437-2445.
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IDEAL Trial Serious Adverse Events (cont)
Liver enzyme elevation and myalgia ()
Atorvastatin
Simvastatin

• Liver enzyme elevation occurred more frequently
  in the atorvastatin group, as did myalgia.

2.2
2

1.1
0.97
1
0.11
0
Liver Enzyme Elevation
Myalgia
Plt0.001 ALT gt3x upper limit of normal
Plt0.001
Pedersen TR, et al. JAMA. 20052942437-2445.
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REVIVE 2 Design
600 patients with acute decompensated heart
failure, left ventricular ejection fraction
35, and dyspnea at rest despite IV diuretics
Levosimendan (12 µg/kg bolus plus 0.1-0.2
µg/kg/min infusion for 24 hours)
Placebo

• Endpoints
• Primary The primary end point consisted of
  changes in symptoms, death, or worsening HF over
  five days.
•  Secondary All-cause mortality at 90 days, BNP,
  days alive out of hospital, change in patient
  dyspnea assessment

Packer M, et al. Presented at American Heart
Association Scientific Sessions 2005. November
1316, 2005. Dallas, TX.
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REVIVE-2 Approximate Time-dependent Rates of
Moderate or Marked" Improvement in Patient
Global Assessment
Packer M, et al. Presented at American Heart
Association Scientific Sessions 2005. November
1316, 2005. Dallas, TX.
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Adverse Events in REVIVE-2
Packer M, et al. Presented at American Heart
Association Scientific Sessions 2005. November
1316, 2005. Dallas, TX.
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REVIVE-2 Secondary Endpoint
All-cause mortality at 90 days ( of treatment
arm)
There was a trend for an increase in all-cause
mortality between treatment groups at 90 days
15. 1
15
11.6
10
5
0
Levosimendan
Placebo
Packer M, et al. Presented at American Heart
Association Scientific Sessions 2005. November
14, 2005. Dallas, Tx
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SURVIVE-W Design
1327 patients with acute decompensated heart
failure, left ventricular ejection fraction
30, clinical need for inotropic therapy after
intravenous diuretics and/or vasodilators
Levosimendan (12 µg/kg bolus plus 0.1-0.2
µg/kg/min infusion for 24 hours) n663
Dobutamine ( 5 µg/kg/min infusion for 24
hours) n664

• Endpoints
• Primary All cause mortality at 6 months
• Secondary All-cause mortality at 31 days, BNP
  at 24 hours, days alive out of hospital, change
  in patient dyspnea assessment, change in patient
  global assessment

Mebazaa A. Presented at American Heart
Association Scientific Sessions 2005. November
14, 2005. Dallas, TX.
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SURVIVE-W Primary Endpoint
All-Cause Mortality at 6 months ( of treatment
arm)

• There was no significant difference in the
  primary endpoint of all-cause mortality between
  the levosimendan and dobutamine groups

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27.9
30
26.1
25
20
15
10
5
0
P0.401
Mebazaa A. Presented at American Heart
Association Scientific Sessions 2005. November
14, 2005. Dallas, TX.
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SURVIVE-W Secondary Endpoint
All-cause mortality at 31 days ( of treatment
arm)

• There was no difference in all-cause mortality
  between treatment groups at 31 days

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13.7
11.9
10
5
0
HR 0.85 PNS
Mebazaa A. Presented at American Heart
Association Scientific Sessions 2005. November
14, 2005. Dallas, TX.
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SURVIVE-W Post-hoc Analysis
All-cause mortality at 5 days ( of treatment
arm)

• In a post-hoc analysis, all-cause mortality at 5
  days was not significantly different between
  treatment groups

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6.0
6
4.4
4
2
0
PNS
Mebazaa A. Presented at American Heart
Association Scientific Sessions 2005. November
14, 2005. Dallas, TX.
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Patterns and Impact of Aspirin Dosing in NSTEMI
Results from the CRUSADE Initiative

• 22,618 patients with NSTEMI
• Patients were from 369 hospitals in the CRUSADE
  program
• Evaluated between 5/03 and 9/04
• Analysis included acute (lt24 hours) and discharge
  aspirin doses in relation to concomitant
  clopidogrel use and other clinical predictors

Tickoo S, et al. Presented at American Heart
Association Scientific Sessions 2005. November
14, 2005. Dallas, TX. Abstract 2090.
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Patterns and Impact of Aspirin Dosing in NSTEMI
Results from the CRUSADE Initiative

• ASA at discharge with concomitant clopidogrel
  (n12,635)
• 37.6 (n4745) received 81 mg ASA
• 58.5 (n7397) received 325 mg of ASA
• Patients who were discharged from a cardiology
  inpatient service (n11,587)
• 37.5 (n4350) received 81 mg ASA
• 58.5 (n6780) received 325 mg ASA

Tickoo S, et al. American Heart Association
Scientific Sessions 2005. November 14, 2005.
Dallas, TX. Abstract 2090.
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Patterns and Impact of Aspirin Dosing in NSTEMI
Results from the CRUSADE Initiative

• ASA at discharge without concomitant clopidogrel
  (n4772)
• 44.0 (n2101) received 81 mg ASA
• 51.2 (n2445) received 325 mg of ASA
• CONCLUSION The majority of patients with NSTEMI
  are still being treated with 325 mg ASA at
  discharge, both with and without concomitant
  clopidogrel despite recent studies that have
  demonstrated a better safety profile with
  low-dose ASA.
• Further quality improvement interventions are
  needed

Tickoo S, et al. American Heart Association
Scientific Sessions 2005. November 14, 2005.
Dallas, TX. Abstract 2090.
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ACC/AHA/SCAI 2005 Guideline Update for PCIOral
Antiplatelet Adjunctive Therapies

• Patients already taking daily chronic ASA therapy
  should take 75 mg to 325 mg ASA before the PCI
  procedure is performed

A
Patients not already taking daily chronic ASA
therapy should be given 300 to 325 mg of aspirin
at least 2 hours and preferably 24 hours before
the PCI procedure is performed
C
Adapted from Smith SC Jr, et al. Available at
www.acc.org/clinical/guidelines/percutaneous/updat
e/index_rev.pdf
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ACC/AHA/SCAI 2005 Guideline Update for PCIOral
Antiplatelet Adjunctive Therapies

• After the PCI procedure, in patients with neither
  ASA resistance, allergy, nor increased risk of
  bleeding, ASA 325 mg daily should be given for at
  least 1 month after bare-metal stent
  implantation, 3 months after sirolimus-eluting
  stent implantation, and 6 months after
  paclitaxel-eluting stent implantation, after
  which daily chronic ASA use should be continued
  indefinitely at a dose of 75 to 162 mg.

B
Adapted from Smith SC Jr, et al. Available at
www.acc.org/clinical/guidelines/percutaneous/updat
e/index_rev.pdf
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ACC/AHA/SCAI 2005 Guideline Update for PCIOral
Antiplatelet Adjunctive Therapies

• A loading dose of clopidogrel should be
  administered before PCI is performed

A
An oral loading dose of 300 mg, administered at
least 6 hours before the procedure, has the best
established evidence of efficacy.
B
Adapted from Smith SC Jr, et al. Available at
www.acc.org/clinical/guidelines/percutaneous/updat
e/index_rev.pdf
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ACC/AHA/SCAI 2005 Guideline Update for PCIOral
Antiplatelet Adjunctive Therapies

• In patients who have undergone PCI, clopidogrel
  75 mg daily should be given for at least 1 month
  after bare-metal stent implantation (unless the
  patient is at increased risk of bleeding then it
  should be given for a minimum of 2 weeks), 3
  months after sirolimus stent implantation, and 6
  months after paclitaxel stent implantation, and
  ideally up to 12 months in patients who are not
  at high risk of bleeding.

B
Adapted from Smith SC Jr, et al. Available at
www.acc.org/clinical/guidelines/percutaneous/updat
e/index_rev.pdf
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ACC/AHA/SCAI 2005 Guideline Update for PCIOral
Antiplatelet Adjunctive Therapies

• If clopidogrel is given at the time of procedure,
  supplementation with GP IIb/IIIa receptor
  antagonists can be beneficial to facilitate
  earlier platelet inhibition than with clopidogrel
  alone.

B
For patients with an absolute contraindication to
ASA, it is reasonable to give a 300-mg loading
dose of clopidogrel, administered at least 6
hours before PCI, and/or GP IIb/IIIa antagonists,
administered at the time of PCI.
C
Adapted from Smith SC Jr, et al. Available at
www.acc.org/clinical/guidelines/percutaneous/updat
e/index_rev.pdf
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ACC/AHA/SCAI 2005 Guideline Update for PCIOral
Antiplatelet Adjunctive Therapies

• When a loading dose of clopidogrel is
  administered, a regimen of greater than 300 mg is
  reasonable to achieve higher levels of
  antiplatelet activity more rapidly, but the
  efficacy and safety compared with a 300-mg
  loading dose are less established.

C
It is reasonable that patients undergoing
brachytherapy be given daily clopidogrel 75 mg
indefinitely and daily aspirin 75 to 325 mg
indefinitely unless there is significant risk for
bleeding.
C
Adapted from Smith SC Jr, et al. Available at
www.acc.org/clinical/guidelines/percutaneous/updat
e/index_rev.pdf
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Featured Institution

• Pennsylvania Hospital
• Philadelphia, Pennsylvania

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Polling Question 2
If you participated in a previous teleconference,
how much progress have you made since
then? (Please refer to the checklists on the
next 3 slides.)

• 1) We are currently on the same item
• 2) We have since moved to the next checkbox on
  the checklist
• 3) We have progressed by more than one item on
  the checklist
• ACS pathways are up-to-date and regularly
  followed

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Progress ChecklistImmediate Goals
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Progress ChecklistShort-term Goals/Activities
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Progress ChecklistLong-term Goals/Activities
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Question-and-Answer Session
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Concluding Remarks
Gregg C. Fonarow, MDNext program Wednesday,
January 18, 2006at 1200 Noon Eastern Time (900
AM Pacific Time)Topic Public Reporting of
Quality-of-Care Measures and Pay for
Performance How Do They Impact Your
Institution?Faculty Christopher P. Cannon, MD