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Novel agents in the treatment of stable angina

An article from the e-journal of the ESC Council for Cardiology Practice

In stable angina, added to lifestyle changes and risk factor control, pharmacological treatment aims to reduce the associated risk and symptoms. The novel anti-ischemic drugs ivabradine, nicorandil, ranolazine and trimetazidine have been introduced for more effective symptom control. Review here their mechanisms of action and side effects.

Acute Coronary Syndromes


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). 


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).

Drugs  Mechanism of action Dose   Contraindications Major adverse effects
Ivabradine Reduction of pacemaker activity in
sinus node
Oral dose of 5 to 7,5 mg twice daily  Severe liver disease, low heart rate or heart
rhythm disorder, allergy
Visual disturbances 
Nicorandil opening the mitochondrial adenosine triphosphate-sensitive potassium channels   20 mg twice daily Low blood pressure, heart failure Oral, intestinal and perianal
Ranolazine Inhibition of the late inward sodium channel 500-2000 mg daily Liver cirrhosis Nausea, dizziness, asthenia, prolongation of the QT interval
Trimetazidine Inhibition of the reduction of adenosine triphosphate, stimulation of glucose consumption by the myocardium  20 mg  thrice daily or 35 mg twice daily Pregnancy, breastfeeding, history of
allergy, Parkinson disease, tremors and movement
disorders,  severe renal impairment
Gastric discomfort, headache , movement disorders


1. Heart Disease and Stroke Statistics - 2014 Update: A Report From the American Heart Association. 
Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, et al; on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2013 Dec 18. [Epub ahead of print].
2. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Task Force Members, Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, Budaj A, et al. Eur Heart J 2013; 34(38):2949-3003. 
3. European Cardiovascular Disease Statistics 2012. Nichols M, Townsend N, Luengo-Fernandez R, Leal J, Gray A, Scarborough P, Rayner M (2012). European Heart Network, Brussels, European Society of Cardiology, Sophia Antipolis.
4. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.   Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP, et al. Circulation 2012; 126(25):3097-137.
5. Management of stable coronary artery disease. Pfisterer ME, Zellweger MJ, Gersh BJ. Lancet 2010; 375(9716 ):763-72.
6. Stable angina pectoris: the medical management of symptomatic myocardial ischemia. Parker JD, Parker JO. Can J Cardiol 2012; 28(2 Suppl):S70-80.
7. Medical management of stable coronary atherosclerosis. Pellicori P, Costanzo P, Joseph AC, Hoye A, Atkin SL, Cleland JG. Curr Atheroscler Rep 2013; 15(4):313.
8. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Fox K, Ford I, Steg PG, Tendera M, Ferrari R. Lancet 2008; 372 (9641):807–816. 
9. Relationship between ivabradine treatment and cardiovascular outcomes in patients with stable coronary artery disease and left ventricular systolic dysfunction with limiting angina: A subgroup analysis of the randomized, controlled BEAUTIFUL trial. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R; BEAUTIFUL Investigators. Eur Heart J 2009; 30(19):2337-45.
10. Effects of ivabradine in patients with stable angina receiving beta-blockers according to baseline heart rate: an analysis of the ASSOCIATE study. Tardif JC, Ponikowski P, Kahan T; ASSOCIATE Investigators. Int J Cardiol 2013; 168(2);789-94.
11. Rationale, design, and baseline characteristics of the Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease (SIGNIFY trial): a randomized, double-blind, placebo-controlled trial of ivabradine in patients with stable coronary artery disease without clinical heart failure. Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R. Am Heart J 2013; 166(4);654-661.
12. Effect of nicorandil on coronary events in patients with stable angina: the Impact Of Nicorandil in Angina (IONA) randomised trial. IONA Study Group. Lancet 2002; 359(9314):1269–1275.
13. Ranolazine for chronic stable angina. Nash DT, Nash SD. Lancet 2008; 372(9646):1335–1341.
14. Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina: results from the TERISA randomized clinical trial (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina). Kosiborod M, Arnold SV, Spertus JA, McGuire DK, Li Y, Yue P, et al. J Am Col Cardiol 2013; 61(20);2038-45. 
15. Trimetazadine for stable angina. Ciapponi A, Pizarro R, Harrison J.  Cochrane Database Syst Rev 2005:CD003614.


Notes to editor

Rose Mary Ferreira Lisboa da Silva
MD, PhD, Associate Professor, Faculty of Medicine, Federal University of Minas Gerais, Brazil.
Author disclosures: None declared.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.