Treatment of Chronic Treatment of Chronic AnginaAngina

How to control difficult angina

Anthony Haney MD, FACC

DisclosureDisclosure

• Speaker’s bureau - Gilead Sciences (ranolazine/Ranexa)

• Discussing non-FDA approved therapies

Stable AnginaStable Angina

• Classic angina is substernal chest discomfort that occurs predictably and is relieved by rest or nitroglycerin

• Stable pattern for >2 weeks

• Patients with angina may curtail activity to avoid anginal episodes

• Patients under report symptoms

Chestnut LG, et al. Med Decis Making. 1996;16:65-77.Williams SV, et al. Ann Intern Med. 2001;135:530-547.

ClassificationClassification

Class I Angina with strenuous exertion

(shoveling snow)

Class II Mild limitation of normal activity

(walking up hill quickly)

Class III Marked limitation of nl activity

(walking 1-2 blocks)

Class IV Unable to do physical activity

(may occur even at rest)

Chronic Angina Is Chronic Angina Is Prevalent in the United States Prevalent in the United States

• ~10 million Americans have angina pectoris

– 500,000 new cases are reported annually

• Median angina frequency is ~2 episodes per patient per week

– > 18 million episodes each week or ~30 episodes each second

American Heart Association. Heart Disease and Stroke Statistics, 2009 Update. Pepine CJ, et al. Am J Card. 1994;74:226-231.

New Cases of Stable Angina Per Year (Among Americans ≥ 45 Years of Age)

Men Total

Inci

den

ce

(Nu

mb

er o

f N

ew C

ases

)

320,000

180,000

500,000

Women

Symptoms Other Than Classic Chest Symptoms Other Than Classic Chest Pain Are Common in Chronic AnginaPain Are Common in Chronic Angina

GenderGenderTypical Angina Typical Angina

SymptomsSymptomsAtypical Angina Atypical Angina

SymptomsSymptoms

Male (n = 2249) 55%* 34%*

Female (n = 976) 28% 53%

– Shortness of breath– Fatigue– Weakness

– Lightheadedness– Diaphoresis

– Nausea– Indigestion

• Anginal equivalents are common

• In 3225 patients referred to Duke University for cardiac catheterization, atypical angina symptoms were reported in both men and women

*p < 0.05 for comparison across genderAlexander KP, et al. J Am Coll Cardiol. 1998;32:1657-1664. Ellis K, et al. Manual of Cardiovascular Medicine. 2nd ed. 2004. McSweeney JC, et al. Circulation. 2003;108:2619-2623.

Differential Diagnosis of noncardiac Differential Diagnosis of noncardiac chest painchest pain

Pain Symptoms Occur at the End Pain Symptoms Occur at the End of the Ischemic Cascadeof the Ischemic CascadeM

agn

itu

de

of

Isch

emia

Stress Duration

↓ Relaxation

Systolic Dysfunction

↓Diastolic Filling

ECG

PAIN

BiochemicalAlterations

Adapted from Kern MJ. In: Braunwald’s Heart Disease. 7th ed. 2005.

ST alterations

Diastolic Dysfunction

↓ Contraction

Myocardial Ischemia: Unbalanced Oxygen Supply and Demand

Ischemia

Oxygen Demand

Systolic Pressure

Volume Overload

Contractility

Heart Rate

LV Wall Tension

OxygenSupply

CoronaryBlood Flow

Coronary Perfusion Pressure

Coronary Vascular

Resistance

LV = left ventricular.Kern MJ. In: Braunwald’s Heart Disease. 7th ed. 2005. Naik H, et al. In: Lilly L, ed. Pathophysiology of Heart Disease. 4th ed. Baltimore, MD: Lippincott, Williams & Wilkins; 2007:141-167.

External Compression

Intrinsic Regulation

Impaired microvascular perfusion in the anginal syndrome

0

0.1

0.2

Endocardium Epicardium Endocardium Epicardium

Myocardial perfusion

index*

Rest Adenosine infusion

P = 0.02 P = 0.002P < 0.001

Panting JR et al. N Engl J Med. 2002;346:1948-53.

Control (n = 10) Chest pain with normal coronary angiogram (n = 20)

P = NS

*Assessed via magnetic resonance imaging

Diminished microvascular perfusion

Angina treatment: Objectives

Reduce ischemia and relieve anginal symptoms

Improve quality of life

Prevent MI and death

Improve quantity of life

Gibbons RJ et al. ACC/AHA 2002 guidelines. www.acc.org/clinical/guidelines/stable/stable.pdf

Symptom management

Aggressive risk factor reduction

Lifestyle modification

Antiplatelet therapy

Comprehensive management of myocardial ischemia

Symptoms of Angina Persist Despite Symptoms of Angina Persist Despite OMT ± PCIOMT ± PCI

88

3428 26

87

42

3328

0

20

40

60

80

100

Baseline 1 Year 3 Years 5 Years

PCI + OMTOMT

Co

nti

nu

ing

An

gin

a (%

)

p < 0.001

p = 0.02

p = NS

p = NS

The COURAGE Study (N = 2287)

Ranexa was approved after the COURAGE trial was initiated, and therefore was not part of the trial.PCI = percutaneous coronary intervention; OMT = optimal medical therapy; CAD = coronary artery disease.Boden WE, et al. N Engl J Med. 2007;356:1503-1516.

One-quarter to one-third of One-quarter to one-third of patients had persistent patients had persistent angina/ischemia despite angina/ischemia despite OMT ± PCIOMT ± PCI

Physiologic Effects of Physiologic Effects of Antianginal TreatmentsAntianginal Treatments

1Less reflex tachycardia with amlodipine. 2Specific data not available. CCB = calcium channel blocker; DHP = dihydropyridineBagger JP, et al. Cardiovasc Drugs Ther. 1997;11(3):479-484. Gibbons RJ, et al. ACC/AHA 2002 Chronic Angina Guidelines. 2003;41:159-168. Kerins DM, et al. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: The McGraw-Hill Companies; 2001:843-870. Lilly L, ed. Pathophysiology of Heart Disease. 4th ed. Baltimore, MD: Lippincott, Williams & Wilkins; 2007:141-167. Ranexa® (ranolazine extended-release tablets) PI. 3/2009.

/

Beta-blockers

DHP CCBs

Non-DHP CCBs

Long-acting nitrates

Ranolazine

Revascularization

Therapy

Coronaryblood flow

Arterialpressure

Venousreturn

Myocardialcontractility

Heartrate

O2 DemandO2 Supply

/

1

222

2

Beta BlockersBeta Blockers

• Decreases oxygen demand by lowering heart rate, myocardial contractility and wall stress

• Titrate resting HR to 50-60’s

• Typically use cardioselective (metoprolol or atenolol)

• Improves mortality in post MI and LV dysfunction patients

• Dose related effect

Beta Blocker IssuesBeta Blocker Issues

• Rebound angina with withdrawal

• Adverse effects

– Fatigue/Exercise intolerance

– Bronchoconstriction

– Erectile dysfunction

– Central side effects (nightmares/insomnia/depression)

Calcium Channel BlockersCalcium Channel Blockers

• Dihydropyridines (nifedipine, amlodipine)– Relax vascular smooth muscle/vasodilators

– Reduce coronary resistance/increase coronary blood flow

• Verapamil– Negative inotrope/lowers HR

– Lowers blood pressure (less potent vasodilation)

• Diltiazem– Potent coronary, mild systemic vasodilator

– Lowers HR (less than verapamil)

When to use When to use Calcium Channel BlockersCalcium Channel Blockers

• Contraindication or intolerance to beta blockers

• Add if BP above goal

• Ongoing symptoms in spite of BB/NTG

• Combination therapy with BB or NTG is more effective than either agent alone

• Strongly consider if vasospasm is suspected

CCB issuesCCB issues

• Do not use short acting nifedipine due to reflex tachycardia/?mortality increase

• Adverse effects

– Edema

– Constipation

– Dizziness

– GERD

NitratesNitrates

• Systemic vasodilation >> coronary vasodilation

• Venodilation reduces preload reducing wall stress and decreasing oxygen demand

• Arteries with flow-limiting disease are maximally dilated at rest

• Reduces/reverses coronary vasospasm

• Reduce resistance to coronary blood flow from epi to endocardium

Nitrate IssuesNitrate Issues

• Nitrate Tolerance

• Rebound angina

• Headache, flushing, lightheadednesss (elderly)

• Cannot be used with ED drugs

• Less effective in Asians

• Response to NTG is not predictive of CAD

Nitrate UseNitrate Use

• Sublingual/Spray – Acute angina– May be used as prophylaxis– Spray lasts 2-3 years

• Isosorbide Dinitrate– Dose 8AM, 1PM, 6PM – Start 10mg and titrate to 40mg

• Isosorbide Mononitrate– Dose in AM– Start at 30mg and titrate to 120mg

• Nitroglycerin Patch– Apply at 8AM and remove 8PM

Ranolazine/RanexaRanolazine/Ranexa

• First new antianginal class approved since 1960’s

• Late Na+ current inhibitor

• Safe & well tolerated

– Nausea

– Dizziness

Ischemic MyocytePeak Sodium Current

Pike MM, et al. Am J Physiol. 1990;259:H1767-H1773. Ju YK, et al. J Physiol. 1996;497:337-347.Canty JM Jr. In: Heart Disease: A Textbook of Cardiovascular Medicine. 8th ed. Philadelphia, PA: WB Saunders Co; 2008:1167-1168.Lazdunski M, et al. J Mol Cell Cardiol. 1985;17:1029-1042.

‡

Ischemic MyocyteLate Sodium Current

Pike MM, et al. Am J Physiol. 1990;259:H1767-H1773. Ju YK, et al. J Physiol. 1996;497:337-347.Canty JM Jr. In: Heart Disease: A Textbook of Cardiovascular Medicine. 8th ed. Philadelphia, PA: WB Saunders Co; 2008:1167-1168.Lazdunski M, et al. J Mol Cell Cardiol. 1985;17:1029-1042.

0

Sodium Current (mV)

Cardiac SodiumChannel Current

Increased Late Sodium Current

Peak Sodium Current (systole)

‡

Pike MM, et al. Am J Physiol. 1990;259:H1767-H1773. Ju YK, et al. J Physiol. 1996;497:337-347. Lazdunski M, et al. J Mol Cell Cardiol. 1985;17:1029-1042. Meyer M, et al. J Mol Cell Cardiol. 1998;3:1459-1470. Canty JM Jr. In: Heart Disease: A Textbook of Cardiovascular Medicine. 8th ed. Philadelphia, PA: WB Saunders Co; 2008:1167-1168. Bing OHL, et al. J Clin Invest. 1971;50:660-666. Bache RJ, et al. Circ Res. 1981;49:742-750.

Ischemic MyocyteLate Sodium Current

Sodium-Calcium ExchangerSodium-Calcium Exchanger

‡

Na+/Ca2+ overload and ischemia

Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13.

Late Na+ current

Diastolic wall tension (stiffness)

Intramural small vessel compression( O2 supply)

O2 demand

Na+ overload

Ca2+ overload

Myocardial ischemia

The Anti-ischemic Effects of Ranexa Are The Anti-ischemic Effects of Ranexa Are Independent of Hemodynamic ChangesIndependent of Hemodynamic Changes

The rate pressure product (RPP) data are based on a post hoc analysis of patients in the CARISA trial.All patients were maintained on either amlodipine, diltiazem, or atenolol.

Please see Important Safety Information on slides 46-50 within this presentation. bpm = beats per minute; SBP = systolic blood pressure.Stone PH, et al. Circulation. 2006;114:II-715. Abstract 3362.Ranexa® (ranolazine extended-release tablets) PI. 3/2009.

Minimal changes in mean heart rate (< 2 bpm) and SBP (< 3 mm Hg) were observed in patients treated with Ranexa in controlled clinical studies

8,000

12,000

16,000

20,000

24,000

Rest0 min

Stage 03 min

Stage 0.56 min

Stage 19 min

Stage 212 min

Stage 315 min

Stage 418 min

RP

P (

mm

Hg

× b

pm

)

Exercise

Placebo (n = 244)1000 mg bid Ranexa (n = 238)

CARISACARISACARISACARISA

Ranexa: ContraindicationsRanexa: Contraindications

Ranexa is contraindicated in patients:

• Taking strong inhibitors of CYP3A, such as ketoconazole, clarithromycin, or nelfinavir

• Taking inducers of CYP3A, such as rifampin or phenobarbital

• With clinically significant hepatic impairment

Please see full prescribing information.Ranexa® (ranolazine extended-release tablets) PI. 3/2009.

Myocardial ischemia: Sites of action of anti-ischemic medication

Consequences of ischemia

Ca2+ overloadElectrical instabilityMyocardial dysfunction(↓systolic function/ ↑diastolic stiffness)

Ischemia

↑ O2 DemandHeart rateBlood pressurePreloadContractility↓ O2 Supply

Development of ischemia

Traditionalanti-ischemicmedications:β-blockersNitratesCa2+ blockers

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

Ranolazine

Exercise vs PCI in low-risk CAD

N = 101 men with CCS class I–III angina*

20 min bicycle ergometry daily PCI

Assessed at 12 months

Lower resting HR (P < 0.01)

Greater improvement in maximal O2 uptake (P < 0.001)

Hambrecht R et al. Circulation. 2004;109:1371-8.

Fewer rehospitalizations

Lower cost

Exercise vs PCI

*>80% had 1- or 2-vessel disease

Enhanced External CounterpulsationEnhanced External Counterpulsation

• Increases BP and diastolic augmentation

• Improve coronary collateral flow

• Well tolerated

• Daily treatments for 7 weeks

• Approved only for patients with class III or IV angina who are not candidates for revascularization

• Benefits are inconclusive

EECP improves angina class

73.4

39.5

22.0

0

10

20

30

40

50

60

70

80

≥1 class ≥2 classes ≥3 classes

Improvement in CCS angina class

Patients(%)

Lawson WE et al. Cardiology. 2000;94:31-5.

N = 2289 consecutive EECP Clinical Consortium patients

EECP = enhanced external counterpulsation

Transmyocardial Laser Transmyocardial Laser RevascularizationRevascularization

• Transmural channels created by a laser

• Potential mechanisms

– Angiongenesis

– Denervation

– Remodeling

• Periop complications limit usefulness

• May be combined with CABG

• Initial studies showed promise in reducing symptoms but likely a large placebo effect

Surgical laser TMR improves angina class

8376

13

32

8778

0

20

40

60

80

100

3 12Time (months)

Improvement*(% of patients)

TMR Medical Crossover from medical

Allen KB et al. N Engl J Med. 1999;341:1029-36.

N = 275 with CCS class IV angina

*Reduction of ≥2 CCS classes†Due to treatment failureTMR = transmyocardial revascularization

P < 0.001 TMR vs medical

(both time points)

†

Transmyocardial Laser Transmyocardial Laser Revascularization – DIRECT trialRevascularization – DIRECT trial

Spinal cord stimulationSpinal cord stimulation

• Suppresses intrinsic cardiac neurons

• Reduces sympathetic activity

• No clinical rebound effect

• Primarily analgesic effect

• SPiRiT trial compared spinal cord stimulation to TMLR in 60 patients- no significant difference between the groups in terms of the primary end point of total exercise time or in other parameters such as CCS functional class

Medical therapy versus Medical therapy versus revascularizationrevascularization

Major benefit of PCI: Angina symptom relief

51

17 1912 13

72

0

10

20

30

40

50

60

70

80

No change Moderate improvement Large improvement

Change in QOL scoreAngina absent Angina present

Spertus JA et al. Circulation. 2004;110:3789-94.

N = 1020 undergoing elective PCI; 1 year follow-up

Patients(%)

Seattle Angina Questionnaire

Meta-analysis of 11 randomized trials; N = 2950

Stable CAD: PCI vs conservative medical management

PCI

CABG

Nonfatal MI

Cardiac death or MI

Death

Katritsis DG et al. Circulation. 2005;111:2906-12.

0 1 2

0.34

0.82

0.12

0.28

0.68

P

Risk ratio(95% Cl)

Favors PCIFavors medical

management

Survival Free of Death from Any Survival Free of Death from Any Cause and Myocardial InfarctionCause and Myocardial Infarction

Number at RiskMedical Therapy 1138 1017 959 834 638 408 192 30PCI 1149 1013 952 833 637 417 200 35

Years0 1 2 3 4 5 6

0.0

0.5

0.6

0.7

0.8

0.9

1.0

PCI + OMT

Optimal Medical Therapy (OMT)

Hazard ratio: 1.0595% CI (0.87-1.27)P = 0.62

7

Courage Trial ConclusionsCourage Trial Conclusions

• As an initial management strategy in patients with stable coronary artery disease, PCI did not reduce the risk of death, MI, or other major cardiovascular events when added to optimal medical therapy

• As expected, PCI resulted in better angina relief during most of the follow-up period, but medical therapy was also remarkably effective, with no between–group difference in angina-free status at 5 years

COURAGE: Lifestyle modification goals

<25 (if baseline 25.0–27.5)

10% relative weight loss (if baseline BMI >27.5)

BMI (kg/m2)

≥30 min moderately intensive exercise 5 times per week

Physical activity

<200 mg/dayDietary cholesterol

<7% of caloriesSaturated fat

<30% of caloriesTotal dietary fat

CessationSmoking

Boden WE et al. Am Heart J. 2006.

Lifestyle characteristics Goal

COURAGE: Medical therapy goals

<7.0A1C (%)

<130/85<130/80 if diabetes or renal disease present

BP (mm Hg)

<150Triglycerides (mg/dL)

≥40HDL-C (mg/dL)

60–85LDL-C (mg/dL)

Boden WE et al. Am Heart J. 2006.

Medical therapy versus Medical therapy versus revascularizationrevascularization

How to choose the best How to choose the best strategystrategy

Stress TestingStress Testing

• Prognostic/Risk stratification

• Evaluate efficacy of medical therapy

• Identify high risk patients (>3% annual mortality)

– EF <35%

– High risk treadmill score (ekg changes in stage I or II)

– Large reversible perfusion defects (particularly anterior)

– Moderate reversible defects with LV dilatation/dysfunction

– Multiple vascular territories involved

– Transient chamber dilatation during stress testing

Refer for Cath & RevascularizationRefer for Cath & Revascularization

• Angina that interferes with patient’s lifestyle despite maximal tolerable medical therapy (class III or IV)

• Patients with high-risk findings on noninvasive testing

• Survivors of SCD

• Symptoms/signs of CHF

• Equivocal noninvasive testing

• EF <45% with class I or II angina

Factors which may prevent Factors which may prevent RevascularizationRevascularization

• Diffuse CAD/unsuitable anatomy/poor targets

• Prior CABG(s)

• Lack of vascular conduits

• Severely impaired LV function/CHF

• Concurrent disease (chronic kidney disease, advanced DM, prior CVA, infections, obesity)

• Advanced age especially with comorbidities

Risk of PCIRisk of PCI

• Risk of complication increases as patients age

80’s 60’s

Risk of death 3.8% 1%

Risk of renal failure 3.2% 1%

Risk of vascular comp 6.7% 3.3%

Follow up visitsFollow up visits

• Change in physical activity

• Change in frequency, severity or pattern of angina

• Tolerance/compliance with medical regimen

• Risk factor modification

• New or worsened comorbid conditions

Novel therapiesNovel therapies

• Inhibition of fatty acid oxidation

– Utilize glucose instead of fatty acids as energy source

– Increases cardiac metabolic efficiency

• Potassium channel activator (Nicorandil)

– Vasodilator

– Mimics ischemic preconditioning

– Approved in multiple countries

Novel therapiesNovel therapies

• Allopurinol (treatment for gout)

– Increased exercise time and time to onset of ST depression in small study when added to OMT

– Improves endothelium-dependent vasodilation and reduces oxidative stress

• Endothelin receptor blockers (typically used for primary pulmonary HTN)

– Vasodilator (coronary)

– No clinical trials yet

Novel therapiesNovel therapies

• Ivabradine

– Inhibits sinus node

– Approved in Europe

• Rho kinase inhibitor

– Relaxes vascular smooth muscle

• Testosterone (side effects)

• Stem cell therapy

• Therapeutic Angiogenesis

SummarySummary

• Angina is not always chest pain

• Angina is caused by a problem with oxygen demand and/or supply

• Treatment of angina includes aggressive risk factor modification to prevent progression of disease

• Choice of antianginals should consider comorbidities and side effects

• Antianginal med benefits are additive

SummarySummary

• Antianginal meds/dosages are often not optimized for maximal effect

• Several nonRx options are available and effective

• Revascularization is effective at relieving angina quickly

• Revascularization does not reduce risk of MI/death in low risk patients

• All patients with angina need risk stratification • Goal = elimination of angina and return to

normal activity