clinical trial update

Clinical Trial Update

Issues in chronic myocardial ischemia treatment

Bhatt AB, Stone PH. Curr Opin Cardiol. 2006;21:492-502.Boden WE et al. Am Heart J. 2006;151:1173-9.

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

Pathophysiology of angina is complex; relationship of angina to ACS is unclear

Implications for clinical trials

Stable CAD: Multiple treatment options

Reduce symptoms

Treat underlying

diseasePCI

Lifestyle intervention

CABG

Medicaltherapy

SAFE-LIFE: Evaluation of intensive lifestyle intervention

Michalsen A et al. Am Heart J. 2006;151:870-7.

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

N = 101 with CAD

SAFE-LIFE: Reduction in angina at 1 year with intensive lifestyle intervention

Angina score

-35

-30

-25

-20

-15

-10

-5

0

Percent change

Control Lifestyle

Angina frequency

-60

-50

-40

-30

-20

-10

0

10

20

Michalsen A et al. Am Heart J. 2006;151:870-7.

P = 0.015 P = 0.01

Chronic ischemic heart disease: Treatment gaps

• Most patients have relative intolerances to maximum doses of traditional antianginal agents (-blockers, CCBs, and nitrates)

Pepine CJ et al. Am J Cardiol. 1994;74:226-31.

Gibbons RJ et al. www.acc.org.

• Antianginal drugs without these limitations are needed

• Patients continue to experience myocardial ischemia -blockers and many CCBs have similar depressive hemodynamic and

electrophysiologic effects

Novel anti-ischemic strategy

Consequences of ischemia

Electrical instabilityMyocardial dysfunctionIschemia

Heart rateBlood pressurePreloadContractility

Development of ischemia

Courtesy of PH Stone, MD and BR Chaitman, MD. 2006.

Ranolazine (late Na+ current inhibition)Nitrates, β-blockers, CCBs

O2 demand

O2 supply

Ca2+ overload

StableStableanginaangina

UnstableUnstableanginaangina

Myocardial Myocardial infarctioninfarction

Heart Heart failurefailure

Silent Silent CADCAD DeathDeath

NSTEMINSTEMI STEMISTEMI

MARISACARISAERICA

MERLIN-TIMI 36

Courtesy of BR Chaitman, MD.

Ranolazine clinical trial program

Ranolazine clinical trial program in chronic stable angina

Study NRanolazine dosing

(mg bid)Background antianginal therapy

MARISA 191 50010001500

No

CARISA 823 7501000

Amlodipine 5 mgAtenolol 50 mgDiltiazem 180 mg

ERICA 565 1000 Amlodipine 10 mg

Chaitman BR et al. J Am Coll Cardiol. 2004.Chaitman BR et al. JAMA. 2004.

Stone PH et al. J Am Coll Cardiol. 2006.

Monotherapy Assessment of Ranolazine In Stable AnginaCombination Assessment of Ranolazine In Stable AnginaEfficacy of Ranolazine In Chronic Angina

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

Elderly Diabetes

Ischemic heart

disease

Antianginal efficacy by gender

Wenger NK et al. Am J Cardiol. 2007;99:11-8.

MARISA CARISA

Ranolazine

*P = 0.014, †P < 0.001, ‡P ≤ 0.037 vs placebo

Exercise duration, sec

(Δ from placebo)

60

40

20

0500 mg 1000 mg 1500 mg

Exercise duration, sec

(Δ from baseline)

150

100

50

0Placebo 750 mg 1000 mg

Women Men

NS

*

NS†

NS

†

NS

‡

NS

‡

Ranolazine

Improved exercise duration

SAQ angina frequency score

(Δ from baseline)

0

10

20

30

Placebo + amlodipine Ranolazine + amlodipine

Antianginal efficacy by gender

Wenger NK et al. Am J Cardiol. 2007;99:11-8.

ERICA studySAQ = Seattle Angina Questionnaire

Women Men

NS

P = 0.016

Improved angina score

Antianginal efficacy by age

3.30 3.25

2.83 2.91

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Anginaattacks per

week(trimmed

mean)

Age <65 years Age ≥65 years

Stone PH et al. J Am Coll Cardiol. 2006;48:566-75.

Placebo + amlodipine Ranolazine + amlodipine

P = 0.074 P = 0.15

ERICA study

Antianginal efficacy by diabetes status

3.03.4

2.1

2.6

1.0

2.5

0

1

2

3

4

Diabetes (n = 189) No diabetes (n = 634)

Anginaepisodes per week (mean)

Timmis AD et al. Eur Heart J. 2006;27:42-8.

Placebo Ranolazine 750 mg bid

Ranolazine 1000 mg bid

CARISA studyP = 0.81 (interaction between diabetes status and treatment effect)

CARISA: Reductions in A1C (diabetes substudy)

Possible mechanisms: Insulin sensitivityPhysical activity

-0.02

-0.5

-0.72-0.8

-0.6

-0.4

-0.2

0

Cooper-DeHoff R, Pepine CJ. Eur Heart J. 2006;27:5-6.Timmis AD et al. Eur Heart J. 2006;27:42-8.*P ≤ 0.008 vs placebo

n = 131 with diabetes (n = 31 on insulin)

Least squares

mean(%)

*

*

AIC change from baseline

Placebo Ranolazine 750 mg bid

Ranolazine 1000 mg bid

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

• 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.

2.8-year mean follow-up; >80% entered open-label extension

N = 746 ranolazine patients who completed MARISA or CARISA

MERLIN-TIMI 36: Study design

IV/oral ranolazine Placebo

Patients with non-ST-elevation ACStreated with standard medical/interventional therapies

N = 6560

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

RandomizedDouble-blind

Morrow DA et al. JAMA. 2007;297:1775-83.

Metabolic Efficiency with Ranolazine for Less Ischemia in Non-St-Elevation Acute Coronary Syndromes

MERLIN-TIMI 36: Effect on primary endpoint


Ranolazine vs placebo within 48 hrs of ischemic symptom onset

No. at riskPlaceboRanolazine

32813279

24542450

12231223

268269

HR 0.92(95% CI 0.83-1.02)Log-rank P = 0.11

30

20

10

00 180 360 540

Days

Placebo Ranolazine

CV death, MI, or

recurrent ischemia

(%)

MERLIN-TIMI 36: Components of primary endpointMERLIN-TIMI 36: Components of primary endpoint

Morrow DA et al. JAMA. 2007;297:1775-83.*Event rates at 12 months

n = 3279 ranolazine group, n = 3281 placebo group

CV death or MI Recurrent ischemia

Ranolazine 13.9%*

Placebo 16.1%*

0 180 360 5400

5

10

15

20

0

5

10

15

0 180 360 540

Ranolazine 10.4%*

20

Days

Cumulativepercentage

HR 0.99(95% CI 0.85-1.15)Log-rank P = 0.87

HR 0.87(95% CI 0.76-0.99)Log-rank P = 0.03

Placebo 10.5%*

MERLIN-TIMI 36: Efficacy results in major subgroups


0.6 0.8 1.41.2 1.6

Favors ranolazine Favors placebo

Gender MenWomen

Age <75 years≥75 years

Diabetes No DMDM

SubgroupPrimary endpoint

n

TIMI Risk 0-34-7

STD ≥1 mm NoYes

Overall 6560

42692291

54061154

43402220

36012959

42552304

Pinteraction

0.12

0.80

0.39

0.16

0.23

Index event UANSTEMI

30673342

0.85

HR (95% CI)

STD = ST-segment depression

MERLIN-TIMI 36: Primary arrhythmia endpoints

Rate (%)

Ranolazine Placebo P

Ventricular events

VT ≥3 beats 52.1 60.6 <0.001

Supraventricular events

SVT ≥4 beats 44.7 55.0 <0.001

New-onset AF 1.7 2.4 0.08

Bradycardiac events

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

Scirica BM et al. Circulation. 2007;116.

SVT = supraventricular tachycardia

MERLIN-TIMI 36: Reduction in VT lasting ≥8 beats


0

2

4

6

8

10

0 24 48 72 96 120 144 168

Hours from randomization

Incidence

(%) Ranolazine

Placebo

RR 0.63 (0.52-0.76)P < 0.001

RR 0.67P = 0.008

RR 0.65P < 0.001

8.3%

5.3%

Ranolazine(%)

Placebo(%) P

RR (95% CI)

Ischemia on cECG 6.3 8.3 0.12

No ischemia on cECG 5.0 8.3 <0.001

Prior HF 5.4 9.3 0.013

No prior HF 5.2 8.1 <0.001

TRS 5-7 4.4 8.9 0.001

TRS 0-4 5.5 8.2 <0.001

0.1 1 10

QTc >450 msec 5.6 10.5 0.002

QTc ≤450 msec 5.2 7.8 <0.001

EF <40% 8.8 16.6 0.005

EF ≥40% 5.3 7.3 0.011

MERLIN-TIMI 36: Incidence of VT MERLIN-TIMI 36: Incidence of VT ≥≥8 beats 8 beats in high-risk subgroupsin high-risk subgroups

TRS = TIMI risk scorecECG = continuous ECG Scirica BM et al. Circulation. 2007;116.

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


MERLIN-TIMI 36: Ventricular tachycardia eventsMERLIN-TIMI 36: Ventricular tachycardia events

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

Ranolazine (%) Placebo (%) P

Overall 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


MERLIN-TIMI 36: Sudden cardiac death MERLIN-TIMI 36: Sudden cardiac death by subgroupby subgroup

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

Stable CAD: Multiple treatment options

Reduce symptoms

Treat underlying

diseasePCI

Lifestyle intervention

CABG

Medicaltherapy

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 weeksSecondary outcomes: Death, MI, recurrent hospitalization for cardiac

disease, nonprotocol revascularization at 1 and 2 years

Pepine CJ et al. J Am Coll Cardiol. 1994:24:1-10.Davies RF et al. Circulation. 1997;95:2037-43. Asymptomatic Cardiac Ischemia Pilot

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

P < 0.05

P = 0.34

P < 0.005

0

2

4

6

8

Percent

24201512840

Follow-up (months)

1.1% Revascularization

4.4% Ischemia guided

6.6% Angina guided

Davies RF et al. Circulation. 1997;95:2037-43.

SWISSI II: Study design

Erne P et al. JAMA. 2007;297:1985-91.

PCI (n = 96)Anti-ischemic therapy*

(n = 105)

Recent first MI with asymptomatic myocardial ischemia on exercise testing and 1- or 2-vessel coronary disease suitable for PCI

Primary outcomes: Cardiac death, nonfatal MI, symptom-driven revascularization

Follow-up: 10.2 years (mean)

Randomized, unblinded

*Nitrates, β-blockers, CCBsAll patients also received aspirin and statinSwiss Interventional Study on Silent Ischemia Type II

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

Erne P et al. JAMA. 2007;297:1985-91.

Cardiac death, nonfatal MI, symptom-driven revascularization

No. at riskPCIAnti-ischemic

drug therapy

*Log-rank

1.00

0.25

0.50

0.75

0

PCI

Drug therapy

P < 0.001*

0

96105

5 10 15

77 5464 37

Time from randomization (years)

Event-free survival

ACIP, SWISSI II: Summary and implications

• ACIP: In patients with documented CAD + symptomatic and asymptomatic ischemia, PCI compared with anti-ischemic 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

Reduce symptoms

Treat underlying

disease

Revascularization?

Intensive lifestyle

intervention

Intensive medicaltherapy

Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation

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

Holmboe ES et al. J Gen Intern Med. 2000;15:632-7.

Do you think the angioplasty will prevent a heart attack?

Yes 75%

Do you think the angioplasty will help you live longer?

Yes 71%

N = 52 consecutive patients scheduled for first elective PCI; semi-structured questionnaire completed prospectively

COURAGE: Study design

Boden WE et al. Am Heart J. 2006;151:1173-9. Boden WE et al. N Engl J Med. 2007;356:1503-16.

Optimal medical therapy* + PCI (n = 1149)

Optimal medical therapy*(n = 1138)

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)

Primary outcomes: All-cause mortality, nonfatal MI

Follow-up: Median 4.6 years

Randomized

*Intensive pharmacologic therapy + lifestyle interventionCCS = Canadian Cardiovascular Society

Secondary outcomes: Death, MI, stroke; ACS hospitalization

COURAGE: Lifestyle intervention and risk factor goals

• Smoking cessation

• Exercise program– ≥30 min moderately intensive exercise

5x/week

• Nutrition counseling– Total dietary fat <30% of calories– Saturated fat <7% of calories– Dietary cholesterol <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)

• LDL-C (mg/dL)60-85

• HDL-C (mg/dL)≥40

• Triglycerides (mg/dL) <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

• ACEI, ARB, or diuretic– Lisinopril or losartan

-blocker– ER metoprolol

• Calcium channel blocker– Amlodipine

• Nitrate– Isosorbide 5-mononitrate

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

313930

303931

Disease in graft vessel* (%) 62 69

Proximal LAD disease (%) 31 37†

Ejection fraction (%) 60.8 60.9

Boden WE et al. N Engl J Med. 2007;356:1503-16.

*Patients who underwent previous CABG†P = 0.01

COURAGE: Baseline angina



CCS class (%) 0 I II III

12303623

13303719

Median duration (mo) Interquartile range

51-15

51-15

Median episodes/week Interquartile range

31-6

31-6


COURAGE: Inducible ischemia at baseline



Nuclear imaging, % (n) 70 (685) 72 (708)

Single reversible defect, % (n) 22 (154) 23 (161)

Multiple reversible defects, % (n) 65 (444) 68 (483)


COURAGE: Treatment effect on primary outcome

HR 1.05(0.87-1.27)P = 0.62*


All-cause death, MI

*Unadjusted, log-rank

No. at riskMedical therapy 1138 1017 959 834 638 408 192 30PCI 1149 1013 952 833 637 417 200 35

Medical therapy PCI + medical therapy

Survival free of primaryoutcome

0 2 4 70

0.5

0.6

0.7

0.8

1.0

0.9

Years6531

COURAGE: Treatment effect on angina

0

10

20

30

40

50

60

70

80

Baseline 1 3 5

PCI + medical therapy Medical therapy


P < 0.001P = 0.02 NS

Angina-free(%)

NS

Years


COURAGE: Treatment effect in CV and diabetes subgroups

0.25 0.50 1.00 2.001.751.50

Medical therapy betterPCI betterMyocardial infarctionYesNo

Extent of CADMultivessel diseaseSingle-vessel disease

DiabetesYesNo

AnginaCCS 0-ICCS II-III

Ejection fraction

>50%Previous CABG

NoYes

≤50%

Baseline characteristics

Hazard ratio (95% CI)

COURAGE: Change in quality-of-life scores

WS Weintraub, MD. Presented at ACC. 2007.

50

55

60

65

70

75

80

85

90

Baseline 6 24 48

PCI + medical therapy Medical therapy

Time (months)

SAQ QOL score

After 1 year, both strategies associated with comparable improvement

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


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