Download Myocardial Ischemia Redefined

Clinical Trial Update
Issues in chronic myocardial ischemia treatment
Implications for clinical trials
Pathophysiology of angina is complex; relationship of angina to ACS
is unclear
Despite existing treatments, ischemic episodes frequently occur
PCI is one approach to reduce angina frequency
Trials of all proven noninterventional therapies alone and
in combination are needed
Bhatt AB, Stone PH. Curr Opin Cardiol. 2006;21:492-502.
Boden WE et al. Am Heart J. 2006;151:1173-9.
Stable CAD: Multiple treatment options
Lifestyle
intervention
Reduce
symptoms
Treat
underlying
disease
PCI
Medical
therapy
CABG
SAFE-LIFE: Evaluation of intensive lifestyle
intervention
N = 101 with CAD
Advice on
Mediterranean
diet
Stress
management
≥30 min daily
Encouraged
to physical
activity
3-day nonresidential retreat
Weekly 3-hr meetings x 10 weeks
Biweekly 2-hr meetings x 9 months
Control group received printed lifestyle advice only
Michalsen A et al. Am Heart J. 2006;151:870-7.
SAFE-LIFE: Reduction in angina at 1 year with
intensive lifestyle intervention
Angina frequency
Angina score
20
0
10
-5
0
-10
-10
Percent -15
change -20
-20
-30
P = 0.015
-25
-40
-30
-50
-35
Control
Lifestyle
P = 0.01
-60
Michalsen A et al. Am Heart J. 2006;151:870-7.
Chronic ischemic heart disease: Treatment gaps
• Most patients have relative intolerances to maximum doses of
traditional antianginal agents (-blockers, CCBs, and nitrates)
• Patients continue to experience myocardial ischemia
• -blockers and many CCBs have similar depressive hemodynamic and
electrophysiologic effects
• Antianginal drugs without these limitations are needed
Pepine CJ et al. Am J Cardiol. 1994;74:226-31.
Gibbons RJ et al. www.acc.org.
Novel anti-ischemic strategy
O2 demand
Ca2+ overload
Heart rate
Blood pressure
Preload
Contractility
Electrical instability
Myocardial dysfunction
Ischemia
O2 supply
Development of ischemia
Nitrates, β-blockers, CCBs
Consequences of ischemia
Ranolazine (late Na+ current inhibition)
Courtesy of PH Stone, MD and BR Chaitman, MD. 2006.
Ranolazine clinical trial program
Silent
CAD
Stable
angina
Unstable
angina
Myocardial
infarction
NSTEMI
MARISA
CARISA
ERICA
Heart
failure
Death
STEMI
MERLIN-TIMI 36
Courtesy of BR Chaitman, MD.
Ranolazine clinical trial program in chronic
stable angina
Ranolazine dosing
(mg bid)
Background
antianginal therapy
Study
N
MARISA
191
500
1000
1500
No
CARISA
823
750
1000
Amlodipine 5 mg
Atenolol 50 mg
Diltiazem 180 mg
ERICA
565
1000
Amlodipine 10 mg
Monotherapy Assessment of Ranolazine In Stable Angina
Combination Assessment of Ranolazine In Stable Angina
Efficacy of Ranolazine In Chronic Angina
Chaitman BR et al. J Am Coll Cardiol. 2004.
Chaitman BR et al. JAMA. 2004.
Stone PH et al. J Am Coll Cardiol. 2006.
MARISA, CARISA, ERICA main findings
• As monotherapy, ranolazine improves exercise
performance in the absence of clinically meaningful
pathophysiologic effects
• These studies provide evidence of additional
antianginal and anti-ischemic efficacy in patients who
remain symptomatic on standard therapies or maximal
amlodipine therapy
Chaitman BR et al. J Am Coll Cardiol. 2004.
Chaitman BR et al. JAMA. 2004.
Stone PH et al. J Am Coll Cardiol. 2006.
Challenges in selected populations:
Experience with ranolazine
Women
Ischemic
heart
disease
Elderly
Diabetes
Antianginal efficacy by gender
Improved exercise duration
MARISA
CARISA
†
60
150
NS
Exercise
duration, sec
(Δ from
placebo)
40
‡
‡
NS
†
NS
Exercise
duration, sec
(Δ from
baseline)
*
20
0
NS
100
NS
50
0
500 mg
1000 mg 1500 mg
Ranolazine
Women
Placebo
750 mg
1000 mg
Ranolazine
Men
*P = 0.014, †P < 0.001, ‡P ≤ 0.037 vs placebo
Wenger NK et al. Am J Cardiol. 2007;99:11-8.
Antianginal efficacy by gender
Improved angina score
NS
30
P = 0.016
SAQ angina
frequency score
(Δ from
baseline)
20
10
0
Placebo + amlodipine
Women
ERICA study
SAQ = Seattle Angina Questionnaire
Ranolazine + amlodipine
Men
Wenger NK et al. Am J Cardiol. 2007;99:11-8.
Antianginal efficacy by age
P = 0.074
3.5
3.0
Angina
attacks per
week
(trimmed
mean)
3.30
P = 0.15
3.25
2.91
2.83
2.5
2.0
1.5
1.0
0.5
0.0
Age <65 years
Placebo + amlodipine
ERICA study
Age ≥65 years
Ranolazine + amlodipine
Stone PH et al. J Am Coll Cardiol. 2006;48:566-75.
Antianginal efficacy by diabetes status
4
3.4
3.0
3
Angina
episodes
per week
(mean)
2.6
2.5
2.1
2
1.0
1
0
Diabetes (n = 189)
Placebo
CARISA study
P = 0.81 (interaction between diabetes
status and treatment effect)
Ranolazine
750 mg bid
No diabetes (n = 634)
Ranolazine
1000 mg bid
Timmis AD et al. Eur Heart J. 2006;27:42-8.
CARISA: Reductions in A1C (diabetes substudy)
n = 131 with diabetes (n = 31 on insulin)
AIC change from baseline
0
-0.02
-0.2
Least
squares
mean
(%)
Possible mechanisms:
Insulin sensitivity
Physical activity
-0.4
-0.5
-0.6
*
-0.72
-0.8
*
Placebo
*P ≤ 0.008 vs placebo
Ranolazine
750 mg bid
Ranolazine
1000 mg bid
Cooper-DeHoff R, Pepine CJ. Eur Heart J. 2006;27:5-6.
Timmis AD et al. Eur Heart J. 2006;27:42-8.
Summary: Ranolazine in challenging populations
• Antianginal efficacy independent of:
– Gender
– Age
– Diabetes status
• Also associated with ↓A1C in patients with diabetes
Wenger NK et al. Am J Cardiol. 2007.
Stone PH et al. J Am Coll Cardiol. 2006.
Timmis AD et al. Eur Heart J. 2006.
ROLE: Long-term safety and tolerability in stable
CAD patients
N = 746 ranolazine patients who completed MARISA or CARISA
2.8-year mean follow-up; >80% entered open-label extension
• Adverse events:
– Most common: dizziness (11.8%) and constipation (10.9%)
– Discontinuation: dizziness (0.9%), constipation (0.6%)
– Total of 72 patients (9.7%) discontinued due to adverse events
• ECG findings:
– Mean QTc prolongation 2.4 ms (P < 0.001 vs baseline)
– QTc >500 ms in 10 patients (1.2%)
– No cases of Torsades de Pointes
Ranolazine Open-Label Experience
Koren MJ et al. J Am Coll Cardiol. 2007;49:1027-34.
MERLIN-TIMI 36: Study design
Patients with non-ST-elevation ACS
treated with standard medical/interventional therapies
N = 6560
IV/oral ranolazine
Randomized
Double-blind
Placebo
Primary efficacy endpoint:
CV death, MI, recurrent ischemia
Safety endpoints:
All-cause death, CV hospitalization, symptomatic documented arrhythmia,
clinically significant arrhythmia on Holter during first 7 days
Metabolic Efficiency with Ranolazine for Less Ischemia
in Non-St-Elevation Acute Coronary Syndromes
Morrow DA et al. JAMA. 2007;297:1775-83.
MERLIN-TIMI 36: Effect on primary endpoint
Ranolazine vs placebo within 48 hrs of ischemic symptom onset
30
CV death,
MI, or
recurrent
ischemia
(%)
20
HR 0.92
(95% CI 0.83-1.02)
Log-rank P = 0.11
10
0
0
180
360
540
Days
No. at risk
Placebo
Ranolazine
Placebo
3281
3279
2454
2450
Ranolazine
1223
1223
268
269
Morrow DA et al. JAMA. 2007;297:1775-83.
MERLIN-TIMI 36: Components of primary endpoint
n = 3279 ranolazine group, n = 3281 placebo group
CV death or MI
Recurrent ischemia
HR 0.99
(95% CI 0.85-1.15)
Log-rank P = 0.87
20
20
Placebo 10.5%*
15
HR 0.87
(95% CI 0.76-0.99)
Log-rank P = 0.03
Cumulative
percentage 10
15
10
Ranolazine 10.4%*
5
0
Placebo
16.1%*
Ranolazine 13.9%*
5
0
0
180
360
540
0
180
360
540
Days
*Event rates at 12 months
Morrow DA et al. JAMA. 2007;297:1775-83.
MERLIN-TIMI 36: Efficacy results in major
subgroups
Subgroup
n
Primary endpoint
Favors ranolazine
Favors placebo
Pinteraction
Gender
Men
Women
4269
2291
0.12
Age
<75 years
≥75 years
5406
1154
0.80
Diabetes
No DM
DM
4340
2220
0.39
TIMI Risk
0-3
4-7
3601
2959
0.16
Index event
UA
NSTEMI
3067
3342
0.85
STD ≥1 mm
No
Yes
4255
2304
0.23
Overall
6560
0.6
0.8
1.2
1.4
1.6
HR (95% CI)
STD = ST-segment depression
Morrow DA et al. JAMA. 2007;297:1775-83.
MERLIN-TIMI 36: Primary arrhythmia endpoints
Rate (%)
Ranolazine
Placebo
P
52.1
60.6
<0.001
SVT ≥4 beats
44.7
55.0
<0.001
New-onset AF
1.7
2.4
0.08
Bradycardia, heart block, pause ≥2.5 sec
39.8
46.6
<0.001
Bradycardia
35.6
43.0
<0.001
Pause ≥3 sec
3.1
4.3
0.01
Ventricular events
VT ≥3 beats
Supraventricular events
Bradycardiac events
SVT = supraventricular tachycardia
Scirica BM et al. Circulation. 2007;116.
MERLIN-TIMI 36: Reduction in VT lasting ≥8 beats
10
8.3%
RR 0.65
P < 0.001
8
Placebo
5.3%
RR 0.67
P = 0.008
6
Incidence
(%)
4
Ranolazine
2
RR 0.63 (0.52-0.76)
P < 0.001
0
0
24
48
72
96
120
144
168
Hours from randomization
Scirica BM et al. Circulation. 2007;116.
MERLIN-TIMI 36: Incidence of VT ≥8 beats
in high-risk subgroups
Ranolazine
(%)
Placebo
(%)
EF ≥40%
5.3
7.3
0.011
EF <40%
8.8
16.6
0.005
QTc ≤450 msec
5.2
7.8
<0.001
QTc >450 msec
5.6
10.5
0.002
TRS 0-4
5.5
8.2
<0.001
TRS 5-7
4.4
8.9
0.001
No prior HF
5.2
8.1
<0.001
Prior HF
5.4
9.3
0.013
No ischemia on cECG
5.0
8.3
<0.001
Ischemia on cECG
6.3
8.3
0.12
0.1
TRS = TIMI risk score
cECG = continuous ECG
1
RR (95% CI)
P
10
Scirica BM et al. Circulation. 2007;116.
MERLIN-TIMI 36: Ventricular tachycardia events
Ranolazine
(%)
Placebo
(%)
P
Polymorphic VT ≥8 beats
1.2
1.4
0.40
Sustained VT (≥30 sec)
0.44
0.44
0.98
Monomorphic VT
0.13
0.22
0.37
Polymorphic VT
0.32
0.22
0.46
Scirica BM et al. Circulation. 2007;116.
MERLIN-TIMI 36: Major safety outcomes
Event rate (%)
Ranolazine
(n = 3268)
Placebo
(n = 3273)
P
All-cause death
5.3
5.4
0.91
Sudden cardiac death
1.7
1.8
0.43
All-cause death or CV hospitalization
33.2
33.4
0.53
Symptomatic documented arrhythmia
3.0
3.1
0.84
Clinically significant arrhythmia on Holter*
73.7
83.1
<0.001
*VT ≥3 beats, SVT ≥120 bpm, new AF,
bradycardia <45 bpm, CHB, or pulse >2.5 sec
Morrow DA et al. JAMA. 2007;297:1775-83.
MERLIN-TIMI 36: Sudden cardiac death
by subgroup
Ranolazine (%)
Placebo (%)
P
1.7
1.8
NS
EF ≥40%
1.5
1.5
0.48
EF <40%
2.7
4.9
0.07
QTc ≤450 msec
1.4
1.6
0.86
QTc >450 msec
3.0
3.0
0.27
TRS 0-4
1.2
1.3
0.47
TRS 5-7
3.5
3.9
0.73
No prior HF
1.2
1.3
0.63
Prior HF
4.1
4.3
0.58
Overall
Scirica BM et al. Circulation. 2007;116.
MERLIN-TIMI 36: Summary and implications
• In patients with ACS, ranolazine added to standard
therapy was associated with
– No difference in:
• Composite efficacy endpoint of CV death, MI, recurrent ischemia
• Safety endpoints of all-cause death, all-cause death or CV
hospitalization, symptomatic documented arrhythmia
– Significant reduction in arrhythmias detected by Holter
monitoring during first 7 days
Findings do not support use of ranolazine in ACS but add to previous
safety data and provide additional support for ranolazine as antianginal
therapy in stable CAD
Morrow DA et al. JAMA. 2007;297:1775-83.
Stable CAD: Multiple treatment options
Lifestyle
intervention
Reduce
symptoms
Treat
underlying
disease
PCI
Medical
therapy
CABG
ACIP: Study design
Angiographic CAD (≥50% stenosis in ≥1 major vessel or branch) suitable
for revascularization + ischemia during exercise or pharmacologic stress
testing and ≥1 asymptomatic episode during 48-hr AECG
Angina-guided
strategy
(n = 183)
Ischemia-guided
strategy
(n = 183)
Revascularization
strategy
(n = 192)
Primary outcome: Absence of ischemia at 12 weeks
Secondary outcomes: Death, MI, recurrent hospitalization for cardiac
disease, nonprotocol revascularization at 1 and 2 years
Asymptomatic Cardiac Ischemia Pilot
Pepine CJ et al. J Am Coll Cardiol. 1994:24:1-10.
Davies RF et al. Circulation. 1997;95:2037-43.
ACIP: Baseline characteristics
Angina-guided
Ischemia-guided
Revascularization
Age (years)
61
62
61
Women (%)
10
15
17
Diabetes (%)
11
19
18
Heart failure (%)
3
2
4
Hypertension (%)
32
41
39
Family history (%)
45
36
43
Smoking (%)
19
17
13
Prior MI (%)
38
40
43
Davies RF et al. Circulation. 1997;95:2037-43.
ACIP: Two-year cumulative all-cause mortality
rates for the treatment strategies
8
6.6% Angina guided
6
4.4% Ischemia guided
Percent
P = 0.34
P < 0.005
4
P < 0.05
2
1.1% Revascularization
0
0
4
8
12
15
20
24
Follow-up (months)
Davies RF et al. Circulation. 1997;95:2037-43.
SWISSI II: Study design
Recent first MI with asymptomatic myocardial ischemia on exercise testing and
1- or 2-vessel coronary disease suitable for PCI
PCI (n = 96)
Randomized,
unblinded
Anti-ischemic therapy*
(n = 105)
Primary outcomes: Cardiac death, nonfatal MI, symptom-driven
revascularization
Follow-up: 10.2 years (mean)
*Nitrates, β-blockers, CCBs
All patients also received aspirin and statin
Swiss Interventional Study on Silent Ischemia Type II
Erne P et al. JAMA. 2007;297:1985-91.
SWISSI II: Baseline characteristics
PCI
Anti-ischemic therapy
Age (years)
54.4
56.2
Female (%)
11.5
13.3
Diabetes (%)
9.4
13.3
Hypertension (%)
44.8
44.8
Dyslipidemia (%)
75.0
58.1
Family history of CAD (%)
44.8
40.0
Smoking (%)
72.9
74.3
Erne P et al. JAMA. 2007;297:1985-91.
SWISSI II: Treatment effect on primary outcome
Cardiac death, nonfatal MI, symptom-driven revascularization
1.00
PCI
0.75
Event-free
survival
0.50
Drug therapy
0.25
0
No. at risk
PCI
Anti-ischemic
drug therapy
*Log-rank
P < 0.001*
0
96
105
5
10
Time from randomization (years)
77
64
15
54
37
Erne P et al. JAMA. 2007;297:1985-91.
ACIP, SWISSI II: Summary and implications
• ACIP: In patients with documented CAD + symptomatic
and asymptomatic ischemia, PCI compared with antiischemic or antianginal therapy reduced 2-year risk of
major CV events
• SWISSI II extended these finding to post-MI patients
with asymptomatic ischemia and a longer 10-year
follow-up
• Data reported after ACIP and SWISSI II began suggest
that risk factor management in these trials was not
optimal
Davies RF et al. Circulation. 1997;95:2037-43.
Erne P et al. JAMA. 2007;297:1985-91.
COURAGE: Defining optimal care
Clinical Outcomes Utilizing Revascularization and Aggressive Drug
Evaluation
Intensive
lifestyle
intervention
Intensive
medical
therapy
Reduce
symptoms
Treat
underlying
disease
Revascularization?
What is the definitive role of PCI in chronic
angina and stable CAD?
• PCI improves angina and short-term exercise capacity
• However, compared to optimal medical therapy,
does PCI
–
–
–
–
–
Prolong survival?
Reduce risk of subsequent MI?
Reduce hospitalization for unstable angina?
Decrease need for subsequent CABG?
Improve quality of life?
Courtesy of WE Boden, MD.
Patient expectations about elective PCI for stable
CAD
N = 52 consecutive patients scheduled for first elective PCI;
semi-structured questionnaire completed prospectively
Do you think the angioplasty will prevent a heart attack?
Yes
75%
Do you think the angioplasty will help you live longer?
Yes
71%
Holmboe ES et al. J Gen Intern Med. 2000;15:632-7.
COURAGE: Study design
AHA/ACC Class I/II indications for PCI, suitable coronary artery anatomy +
≥70% stenosis in ≥1 proximal epicardial vessel + objective evidence of ischemia
(or ≥80% stenosis + CCS class III angina without provocation testing)
Optimal medical therapy* + PCI
(n = 1149)
Randomized
Optimal medical therapy*
(n = 1138)
Primary outcomes: All-cause mortality, nonfatal MI
Secondary outcomes: Death, MI, stroke; ACS hospitalization
Follow-up: Median 4.6 years
*Intensive pharmacologic therapy + lifestyle intervention
CCS = Canadian Cardiovascular Society
Boden WE et al. Am Heart J. 2006;151:1173-9.
Boden WE et al. N Engl J Med. 2007;356:1503-16.
COURAGE: Lifestyle intervention
and risk factor goals
• Smoking cessation
• LDL-C (mg/dL)
60-85
• Exercise program
– ≥30 min moderately intensive exercise
5x/week
• Nutrition counseling
– Total dietary fat
– Saturated fat
– Dietary cholesterol
• HDL-C (mg/dL)
≥40
• Triglycerides (mg/dL)
<30% of calories
<7% of calories
<200 mg/day
• Weight control
– BMI <25 kg/m2 (if baseline BMI 25.0-27.5)
– 10% relative weight loss
(if baseline BMI >27.5)
<150
• BP (mm Hg)
<130/85
<130/80 if diabetes or
renal disease present
• A1C (%)
<7.0
Boden WE et al. Am Heart J. 2006;151:1173-9.
COURAGE: Pharmacologic therapy
• Antiplatelet
– Aspirin
– Clopidogrel in accordance with
established practice standards
• Dyslipidemia
– Simvastatin ± ezetimibe,
ER niacin, or fibrates
• -blocker
– ER metoprolol
• Calcium channel blocker
– Amlodipine
• Nitrate
– Isosorbide 5-mononitrate
• ACEI, ARB, or diuretic
– Lisinopril or losartan
Boden WE et al. Am Heart J. 2006;151:1173-9.
Boden WE et al. N Engl J Med. 2007;356:1503-16.
COURAGE: Baseline angiographic data
PCI + medical therapy
(n = 1149)
Medical therapy
(n = 1138)
Vessels with disease (%)
1
2
3
31
39
30
30
39
31
Disease in graft vessel* (%)
62
69
Proximal LAD disease (%)
31
37†
60.8
60.9
Ejection fraction (%)
*Patients who underwent previous CABG
†P = 0.01
Boden WE et al. N Engl J Med. 2007;356:1503-16.
COURAGE: Baseline angina
PCI + medical therapy
(n = 1149)
Medical therapy
(n = 1138)
12
30
36
23
13
30
37
19
Median duration (mo)
Interquartile range
5
1-15
5
1-15
Median episodes/week
Interquartile range
3
1-6
3
1-6
CCS class (%)
0
I
II
III
Boden WE et al. N Engl J Med. 2007;356:1503-16.
COURAGE: Inducible ischemia at baseline
PCI + medical therapy
(n = 1149)
Medical therapy
(n = 1138)
Nuclear imaging, % (n)
70 (685)
72 (708)
Single reversible defect, % (n)
22 (154)
23 (161)
Multiple reversible defects, % (n)
65 (444)
68 (483)
Boden WE et al. N Engl J Med. 2007;356:1503-16.
COURAGE: Treatment effect on primary outcome
All-cause death, MI
1.0
0.9
Survival
free of
primary
outcome
0.8
HR 1.05
(0.87-1.27)
P = 0.62*
0.7
0.6
0.5
0
0
1
2
3
4
Years
Medical therapy
No. at risk
Medical therapy
PCI
*Unadjusted, log-rank
1138
1149
1017
1013
959
952
834
833
5
6
7
PCI + medical therapy
638
637
408
417
192
200
30
35
Boden WE et al. N Engl J Med. 2007;356:1503-16.
COURAGE: Treatment effect on angina
80
P = 0.02
NS
3
Years
5
P < 0.001
70
60
Angina-free
(%)
50
40
30
20
NS
10
0
Baseline
PCI + medical therapy
1
Medical therapy
Boden WE et al. N Engl J Med. 2007;356:1503-16.
COURAGE: Treatment effect in CV
and diabetes subgroups
Baseline characteristics
PCI better
Myocardial infarction
Yes
No
Extent of CAD
Multivessel disease
Single-vessel disease
Diabetes
Yes
No
Angina
CCS 0-I
CCS II-III
Ejection fraction
≤50%
>50%
Previous CABG
No
Yes
0.25
0.50
Medical therapy better
1.00
1.50
Hazard ratio (95% CI)
1.75
2.00
Boden WE et al. N Engl J Med. 2007;356:1503-16.
COURAGE: Change in quality-of-life scores
After 1 year, both strategies associated with comparable improvement
90
85
80
SAQ
QOL
score
75
70
65
60
55
50
Baseline
6
24
48
Time (months)
PCI + medical therapy
Medical therapy
WS Weintraub, MD. Presented at ACC. 2007.
COURAGE: Summary and implications
• PCI added to optimal medical therapy did not reduce
risk of death, MI, or other major CV events compared
with optimal medical therapy alone
• Findings reinforce existing clinical practice guidelines
– Optimal medical therapy and aggressive management of
multiple treatment targets without initial PCI can be
implemented safely in the majority of patients with chronic
stable angina, even those with objective evidence of ischemia
and significant multivessel CAD
Boden WE et al. N Engl J Med. 2007;356:1503-16.