Novel agents in the treatment of stable angina

Background

A 2014 survey carried out in the American population showed that prevalence of angina pectoris increases with age, from 2.9% to 11.9% with a mean of 3.2%. The age-adjusted prevalence is higher among women than among men and the annual rate of new episodes of angina pectoris per 1,000 is between 14.1 and 39.3, according to age, gender and ethnicity (1). European data from 2013 showed a 0.6 to 1.4% annual incidence of cardiac death rates in the context of coronary artery disease (CAD) - the most common cause of death in Europe. Cardiac death accounts for 22% of deaths in women and 20% of those in men and is generally higher in Central and Eastern Europe. Discharge rates -the measure of the number of patients who leave the hospital after receiving care - are around 600 per 100,000 on average (2,3). 
The clinical presentation of typical stable angina is a substernal chest discomfort (pressure, heaviness, constricting or burning) related to exercise or emotional stress, which disappears in a few minutes after stopping of the precipitating factors and/or is responsive to nitrates. This discomfort is due the narrowing of ≥70% of one or several of the major coronary arteries and ≥50% of the left main coronary artery. Microvascular dysfunction and coronary vasospasm may aggravate the impairment of coronary flow. 

Pharmalogical treatment

Management aims to improve prognosis and reduce symptoms. Besides lifestyle modifications and control of risk factors, drugs include therapy to prevent myocardial infarction (MI) and death: these are 1) antiplatelet agents, beta-blockers, rennin-angiotensin aldosterone blockers and 2) anti-ischemic drugs, which are beta-blockers, nitrates, non-dihydropyridine and calcium channel blockers.
The decision to carry out non-pharmacological treatment such as percutaneous or surgical revascularisation should be based on risk stratification by clinical history, physical examination, as well as noninvasive and invasive complementary tests (4,5,6). 
Secondary prevention varies considerably across Europe. Statistics from 2012 showed that antiplatelet agents are used by between 88% and 99% of patients; statins, by 38-96%, and angiotensin converting enzyme inhibitors by 46-90% of patients. 
The 2013 European guidelines on stable coronary artery disease recommend adding long-acting nitrates, ivabradine, nicorandil, ranolazine (class IIa), or trimetazidine (class IIb) for second-line treatment. These new anti-anginal agents have been used to better control the symptoms (Table 1). 

Ivabradine was approved by the European Medicines Agency in 2005. It is a specific sinus node inhibiting agent whose effect is highest in patients with a heart rate ≥ 70 bpm, alone or in combination with a beta-blocker. Ivabradine inhibits the If current, an important current involved in generating the early phase of spontaneous diastolic depolarisation in pacemaker cells, reducing the frequency of action potential initiation and lowering heart rate. It decreases the body's demand of myocardial oxygen, without any effect on blood pressure or myocardial contractility or conduction times, and results in reduction in angina symptoms and sublingual nitrate consumption (8). The use of ivabradine resulted in a reduction in major adverse cardiovascular events (cardiovascular mortality or hospitalisation for fatal and nonfatal MI or heart failure) and in coronary revascularisation for those with stable CAD, limiting angina, and left ventricular systolic dysfunction (9). There is also evidence of significant improvement in exercise capacity at a dose of 5 to 7.5 mg twice daily in addition to atenolol (10). Its benefits in reducing cardiovascular events are being tested in the SIGNIFY study in patients over 55 years of age with stable CAD (n=19,102). Results are expected to be published in 2014 (11). The most frequent adverse effect (in up to 25% of patients) is a generally transient, unusually increased sensitivity to bright light.   

Nicorandil's anti-anginal properties have been known for over 30 years and was approved over a decade ago. It has a dual mechanism of action: it increases cyclic guanosine monophosphate and facilitates the opening of mitochondrial potassium adenosine triphosphate channels. This results in the systemic veins and the coronary arteries, and protects ischemic myocytes by opening the mitochondrial adenosine triphosphate-sensitive potassium channels. In a 2002 Lancet article publishing the results of a placebo-controlled trial in over 5,000 patients, a twice daily regimen of 20 mg of nicorandil reduced the combined cardiovascular events and the rate of acute coronary syndromes, but it did not significantly improve mortality (12). 

Ranolazine was approved in 2009 for patients unresponsive or intolerant to first choice drugs for the treatment of stable angina (see here indicated and off-label use of ranolazine). It selectively inhibits the late sodium influx in the myocardium, attenuating the ischaemic abnormalities of ventricular repolarisation and the resulting reduced contractility and improves exercise tolerance while reducing the frequency of angina episodes. Ranolazine can improve myocardial ischemia without affecting heart rate or blood pressure (13). In a recent study, ranolazine was well tolerated and was effective in reducing episodes of angina in patients with CAD and diabetes, despite treatment with up to two agents, especially those with higher HbA1C levels (14).

Trimetazidine is another novel anti-anginal agent. Although documented clinical experience is limited, it has been approved in Europe in 2012. It inhibits reduction of intracellular adenosine triphosphate levels via conservation of cellular metabolism in ischemic regions and stimulates myocardial glucose consumption through inhibition of fatty acid metabolism. Trimetazidine is effective in the treatment of stable angina compared with placebo, alone or combined with conventional anti-anginal agents, but data from the literature review are unclear regard to mortality, cardiovascular events and quality of life (15). 

Conclusions

The novel anti-ischemic agents ivabradine, nicorandil, ranolazine and trimetazidine are effective for the control of episodes of stable angina, as monotherapy or in combination with beta-blockers. Reduction of cardiovascular events, including mortality, has been demonstrated with the use of ivabradine.
Ranolazine is mainly useful in those patients who cannot tolerate upward titration of conventional anti-anginal agents due to depressive effects on heart rate and blood pressure.
Overall, randomised controlled studies are needed. The choice of treatment should be individual and based on the severity of symptoms, tolerance of therapy, comorbidities and risk stratification. 

Table 1 - Mechanism of action, dose, contraindications, adverse effects of the novel anti-anginal agents (2, 6, 7, 12, 13).