Major steps have been made in the treatment of ischemic heart disease from the 
discovery of nitrates as antianginal medication to the techniques of 
percutaneous angioplasty. This incredible therapeutic progress has resulted in a 
reduced incidence of ischemic heart disease and related mortality and morbidity. 
However, statistical and epidemiological data indicate that in ischemic heart 
disease, despite the achievement of great success, there is a necessity for a 
further step toward treatment, considering the fact that the characteristics of 
this population are changing (increased prevalence of subendocardial infarction 
compared with classic transmural infarction, especially in the elderly 
population). Furthermore, the need for alternative therapeutic approaches to 
traditional ones is recognized. Ranolazine is a selective inhibitor of Na 
channels that prevents pathological extension of late Na current developing in 
the ischemic myocardial cell. This current is responsible for calcium overload, 
with consequent impairment of diastolic relaxation. Ranolazine reduces Na 
overload induced by calcium and improves diastolic relaxation and coronary 
subendocardial flow, without affecting hemodynamic parameters such as blood 
pressure, heart rate, or inotropic state of the heart, avoiding undesirable side 
effects. Efficacy of ranolazine has been evaluated in several trials, using 
clinical and instrumental endpoints (MARISA and CARISA) or, more recently, using 
endpoints such as mortality and reinfarction (ERICA and MERLIN-TIMI 36). 
Ivabradine acts through the inhibition of late Na current (also known as If), 
which controls the spontaneous diastolic depolarization of sinus node cells. The 
partial inhibition of these channels reduces the frequency of sinus node action 
potential initiation, resulting in decreased heart rate without effects on 
contractility, atrio-ventricular conduction, or repolarization. The BEAUTIFUL 
trial has tested whether the effect of ivabradine in lowering heart rate is able 
to reduce mortality and cardiovascular morbidity in patients with coronary 
artery disease and left ventricular systolic dysfunction. The most significant 
results were obtained in the subgroup of patients with life-limiting exertional 
angina. In this group, ivabradine significantly reduced the primary endpoint, a 
composite of cardiovascular death, hospitalization for fatal and nonfatal acute 
myocardial infarction (AMI) or heart failure, by 24%, and hospitalizations for 
AMI by 42%. In the subgroup of patients with baseline heart rate >70 bpm, 
hospitalizations for AMI and revascularization were reduced by 73% and 59%, 
respectively.