# Presentation: 816077

## Ranolazine Benefit/Risk

**Jeremy N. Ruskin, MD, FACC**

## Current Management of Patients With Angina Pectoris 

**Many patients face recurrent episodes of angina pectoris that limit physical activity and impair quality of life**
**Epidemiologic data suggest that a significant minority of patients with angina are inadequately treated with available therapies and would benefit from additional pharmacological alternatives**
**1 year after angioplasty or surgery for relief of ischemia 10 to 20% of patients still have angina and 60 to 80% are still taking antianginal medications**

**†****Serruys PW, et al. Arterial Revascularization Therapies Study Group. *****N Engl J Med.***** 2001; 344:1117-1124.**

## Limitations to Uptitration of Currently Available Antianginal Drugs 

**Beta blockers**
**Bradycardia**
**Hypotension**
**Fatigue and/or depression**
**Calcium channel blockers **
**Bradycardia**
**Hypotension**
**LV dysfunction**
**Long-acting nitrates**
**Headache**
**Hypotension**
**Need for drug free interval**

## Advantages of Ranolazine

**Novel agent**
**Pharmacodynamically distinct from other antianginals**
**Hemodynamically neutral at therapeutic doses**
**Safe and effective alone or combination with other antianginal drugs**

## Consistent Benefit of Ranolazine in Patients With Comorbidities and in Combination With Other Drugs 

**CHF**
**Diabetes**
**COPD**
**Prior myocardial infarction **
**Previous revascularization**
**Patients with low heart rates or ****blood pressures**
**Other antianginal medications**

## Ranolazine Increases Total Exercise Duration: Quantitative Effect Comparable to Other Antianginals

|  | Mean increase in placebo-corrected exercise time, sec | Study populationtest procedures |
| --- | --- | --- |
| Ranolazine(monotherapy)	500 bid	1000 bid(combined Rx)	1000 bid | 243324 | 
	Severely impaired patients
	Stringent test criteria |
| Atenolol	100 mg qd	100 mg qd | 
3929 | 	(NDA 18-240, vol 1.2)
Mod impaired patients
Test at peak drug levels |
| Diltiazem (SR form)(Cardizem CD)	360 mg qd (Tiazac) 	360 mg qd |  22
27 | 	
	Mod impaired patients |
| Transdermal TNG	0.8 mg/hr | 28 | 	 (Circ. 91:1368, 1995)
	Mod Impaired patients |

## Ranolazine: Overall Safety Outcomes

**AEs mild to moderate**
**No serious organ toxicity**
**Discontinuations infrequent**
**Drug-drug interactions well characterized**
**Effect on the QTc interval (dose-dependent)**

## Mean Change in QTc

**   ****Ranolazine****	****Terfenadine**
**       ****QTci****	**** ****QTcB**

## Similar QTc Effects in High-Risk Patient Subgroups Compared to Overall Population

**Similar QTc Effects in High-Risk Patient Subgroups Compared to Overall Population**

## Electrophysiological Events Associated With Drug Induced Torsade de Pointes

**Prolongation of ventricular action potential (QTc)**
**Increase in dispersion of refractoriness (********APD)**
**Induction of early afterdepolarizations (EADs)**

## Ranolazine Preclinical Profile

| Ranolazine does not . . . | Ranolazine does . . . |
| --- | --- |
| Induce EADs | Suppress EADs |
| Increase dispersion | Reverse dispersion caused by known QT prolonging drugs |
| Cause arrhythmias in any experimental model | Reverse arrhythmias caused by known QT prolonging drugs |

## QT Effects of RanolazineSummary

**Well-characterized and linearly related to plasma concentration**
**Side effects limit exposure to concentrations ****< 8,000 ng/mL **
**Syncope occurs but with no evidence of arrhythmic mechanism**
**No case of TdP observed (> 1700 patient-yr)**
**Ventricular arrhythmias not more frequent than placebo**
**Extensive nonclinical studies demonstrate a unique EP profile and no evidence for proarrhythmia**

## Ranolazine Benefit/Risk Summary

**Effective and well tolerated antianginal**
**Unique clinical profile (hemodynamically neutral) **
**Unique preclinical profile (no proarrhythmia)**
**Theoretical risk associated with QTc prolongation**
**Risk management strategies**
**Dose titration**
**Labeling**
**Physician and patient education**
**Post marketing studies**