Symptomatic patients treated with b-blockers: what is your strategy for further optimizing therapy in these stable CAD patients?

Symptomatic patients treated with b-blockers: what is your strategy for further optimizing therapy
in these stable CAD patients?

1. M. Grabowski, Poland
2. S. M. S. Hiremath, India
3. E. López de Sá, Spain
4. L. A. Machado César, Brazil
5. Q. N. Nguyen, Vietnam
6. D. Pop, Romania
7. Z. Raissouni, Morocco
8. E. J. F. Ramos, Philippines
9. I. Simova, Bulgaria
10. E. Tagliamonte, , Italy
11. K. Toth,, Hungary

1. M. Grabowski, Poland

Eugenio Jose F. RAMOS, MD, MBA
Clinical Cardiologist
Senior Vice President of Medical Services
The Medical City

1 It is important to note that randomized clinical trials have showed that ivabradine has an anti-ischemic effect not only when used as monotherapy, but also when used in combination with a β-blocker.2

A recent pooled analysis of three studies (ADDITIONS, REDUCTION, and RESPONSIVE), which included a total of 8555 patients, showed that treatment with ivabradine was associated with a reduction in the mean number of angina attacks and the use of short-acting nitrates, and an improvement in clinical status and QoL. After 4 months of treatment with ivabradine, 85% of patients achieved a heart rate of less than 70 bpm or a reduction in heart rate of at least 10 bpm. In patients with an elevated heart rate despite the use of a β-blocker, ivabradine significantly reduced the number of angina attacks and the use of short-acting nitrates.

A post hoc analysis from the ADDITIONS trial focused only on patients taking metoprolol (mean dose, 109 mg/day).3 At the end of the study, of the patients treated with metoprolol plus ivabradine for 4 months, 80% were receiving a daily dose of metoprolol of at least 95 mg, and 55% were treated with the maximum dose of ivabradine (15 mg/day). Another post hoc analysis from the ADDITIONS database, which investigated the effectiveness and tolerability of ivabradine in combination with a β-blocker,4 confirmed that this treatment is an effective and well-tolerated antianginal treatment in patients with stable angina after a percutaneous coronary intervention. This treatment reduces the frequency of weekly angina attacks (84% reduction) and nitrate consumption, leading to an improvement in the Canadian Cardiovascular Society (CCS) class and a substantial improvement in QoL.

Recently, a form of angina occurring in the absence of obstructive disease has been described. It is known as “microvascular angina” and is thought to be caused by structural alterations in the coronary microvasculature. New anti-ischemic drugs, including ivabradine, have been shown to be effective in some patients with microvascular angina.

Treatment strategies have a fundamental role in improving angina. To reduce the heart rate and control angina, ivabradine may be considered in all eligible patients with a heart rate ≥70 bpm, including those with a concomitant β-blocker treatment.5 The possible clinical outcomes include symptom relief, increased exercise capacity, and improved QoL, and thus it may actually provide complete management of stable angina pectoris. Treatment with ivabradine is usually well tolerated with a low risk of side effects, contraindications, drug-drug interactions, and precautions.

1. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R; BEAUTIFUL Investigators. 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. Eur Heart J. 2009;30:2337-2345.
2. Werdan K, Perings S, Köster R, et al. Effectiveness of ivabradine treatment in different subpopulations with stable angina in clinical practice: a pooled analysis of observational studies. Cardiology. 2016;135:141-150.
3. Werdan K, Ebelt H, Nuding S, Höpfner F, Stöckl G, Müller-Werdan U; ADDITIONS Study Investigators. Ivabradine in combination with metoprolol improves symptoms and quality of life in patients with stable angina pectoris: a post hoc analysis from the ADDITIONS Trial. Cardiology
. 2016;133:83-90.
4. Werdan K, Ebelt H, Nuding S, Höpfner F, Stöckl G, Müller-Werdan U. Ivabradine in combination with beta-blockers in patients with chronic stable angina after percutaneous coronary intervention. Adv Ther. 2015;32:120-137.
5. Montalescot G, Sechtem U, Achenbach S, et al. 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. Eur Heart J. 2013;34:2949-3003.

2. S. Hiremath, India

President – Cardiological Society of India
Director, Cath Lab, Ruby Hall

Among people 60 to 79 years old, approximately 25% of men and 16% of women have coronary heart disease, and these figures rise to 37% and 23% among men and women >80 years old, respectively. The principal goals of management in patients with stable coronary artery disease (CAD) are to decrease mortality and myocardial infarction, to ensure symptom-free long-term survival, and to improve overall quality of life. Compared with medical therapy, coronary revascularization reduces mortality or myocardial infarction rates in patients with ST-segment elevation myocardial infarction and in high-risk patients with acute coronary syndromes. However, in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation) and BARI 2D (Bypass Angioplasty Revascularization Investigation 2–Diabetes) trials, an initial management strategy of revascularization plus optimal medical therapy for patients with stable CAD did not reduce the long-term rates of death, myocardial infarction, or other cardiovascular events compared with the optimal medical therapy alone.1,2 About 30% of the patients enrolled in the BARI trial never returned to work after a coronary revascularization, and 15% to 20% of patients rated their own health as “fair” or “poor” despite revascularization.2

An estimated 50% of the reduction in cardiovascular mortality in the past few decades is attributed to aggressive lifestyle and risk-factor modification, together with the use of recommended dosages of antiplatelet agents and statins.3 β-Blockers reduce myocardial oxygen consumption by reducing heart rate, myocardial contractility, and afterload, and attenuate cardiovascular remodeling with long-term use by decreasing left ventricular wall tension. Long-term β-blocker treatment is well tolerated, has proven benefits in stable ischemic heart disease— as it reduces the ischemic burden and increases the ischemic threshold—and improves survival in patients with left ventricular dysfunction or a history of myocardial infarction. However, optimization of the β-blocker dose is limited by the occurrence of adverse effects, such as hypotension, bronchospasm, fatigue, lethargy, sexual dysfunction, and sleep disturbances, and it has the potential to worsen symptoms in patients with significant depressive illness or peripheral artery disease. Calcium channel blockers or long-acting nitrates should be prescribed in combination with a β-blocker to provide symptom relief when the initial β-blocker monotherapy is unsuccessful in patients with stable ischemic heart disease.

Ivabradine is a specific inhibitor of the If current of pacemaker cells in the sinoatrial node. This action results in a reduction in heart rate, prolonging diastole and thereby improving myocardial oxygen balance. Ivabradine has no effect on blood pressure, myocardial contractility, or intracardiac conduction parameters. It improves exercise capacity and reduces angina frequency by effectively controlling heart rate. In the BEAUTIFUL trial (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventric- ULar dysfunction), ivabradine reduced the composite primary end point (ie, cardiovascular death, hospitalization for an acute myocardial infarction, and hospitalization for new-onset or worsening heart failure) and the hospitalizations for myocardial infarction.4 The effect was predominant in patients with a heart rate ≥70 bpm. Ivabradine is thus an effective antianginal agent, alone or in combination with β-blockers. Due to its focused action on the sinoatrial node, it is safer in terms of adverse effects and drug interactions.

1. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007; 356:1503-1516.
2. Bypass Angioplasty Revascularization Investigation (BARI) Investigators. Five year clinical and functional outcome comparing bypass surgery and angioplasty in patients with multivessel coronary disease: a multicentre randomized trial. JAMA. 1997;277:715-721.
3. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980–2000. N Engl J Med. 2007;356:2388-2398.
4. Fox K, Ford I, Steg PG, et al. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:807-816.

3. E. López de Sá, Spain

Esteban LÓPEZ de SÁ, MD, FESC
Professor of Cardiology
Hospital Universitario La Paz,
Madrid, SPAIN

Β-Blockers are the first drugs with demonstrated efficacy in relieving the symptoms of stable angina. The β-blocker dose is generally uptitrated to reduce the patient’s heart rate at rest and, during exercise, to a frequency below the level that triggers angina or leads to harmful side effects. Checking whether these objectives have been met is probably the most reasonable initial strategy for optimizing antianginal therapy in those patients who remain symptomatic despite therapy with β-blockers. Unfortunately, this approach fails to alleviate symptoms in a significant number of patients. Since the main objective of the management of stable angina is to control symptoms, it makes no sense to continue increasing the β-blocker dose, especially if the β-blocker produces uncomfortable symptoms due to side effects. In this case, a combination with another antianginal drug would be recommended.

However, for stable angina, the hypothesis that low doses of multiple drugs could offer better control of symptoms with fewer adverse effects, as is the case when treating hypertension, remains controversial. The TIBET trial (Total Ischaemic Burden European Trial),1 which was designed to determine the impact of a moderate dose of atenolol vs nifedipine or an atenolol/nifedipine combination in patients with mild chronic stable angina, demonstrated that, when compared with placebo, each medication alone, and in combination, significantly reduced symptoms. However, the trial did not reveal any significant advantage of the combination over the single-drug treatments, although combination therapy led to a larger reduction in baseline blood pressure than either treatment alone. In contrast, a small trial that evaluated the antianginal efficacy of combining ivabradine (7.5 mg twice a day) with bisoprolol (5 mg/day) vs uptitrating bisoprolol to a target dose of 10 mg/ day in patients with stable angina and left ventricular dysfunction suggested that the addition of ivabradine might be superior to increasing the β-blocker dose for symptom control.2

In order to assess potential new treatments for stable angina patients, a distinction should be made between those treatments that improve the prognosis and those that only improve symptoms. With regard to improving the prognosis, only β-blockers and ivabradine have been shown to improve outcomes in patients with heart failure or left ventricular dysfunction over other antianginal drugs. Therefore, the most reasonable second step is to assess whether the patient is a good candidate for this therapy based on the ejection fraction, presence of sinus rhythm, and heart rate. Outside of this setting, the choice of one antianginal drug over another should be based on the clinical profile of the patient because there is no study that demonstrates that one has an advantage over another. However, since antianginal drugs differ in their mechanisms of action, the treatment can be tailored to suit the patient’s needs. For example, the most appropriate strategy for a patient with high blood pressure and a slow heart rate is a dihydropyridine calcium channel blocker or nitrates, and for a patient with a slow heart rate and low blood pressure, the choice must be ranolazine or trimetazidine. Ivabradine should be used in those with sinus rhythm and a resting heart rate >70 bpm because the ESC guidelines state that combining β-blockers with non-dihydropyridine calcium channel blockers should be avoided due to the risk of bradycardia or atrioventricular block.3 Therefore, I usually increase the dose of β-blockers in combination with the addition of another antianginal agent.

1. Fox KM, Mulcahy D, Findlay I, Ford I, Dargie HJ; TIBET Study Group. The Total Ischaemic Burden European Trial (TIBET). Effects of atenolol, nifedipine SR and their combination on the exercise test and the total ischaemic burden in 608 patients with stable angina. Eur Heart J. 1996,17:96-103.
2. Amosova E, Andrejev E, Zaderey I, Rudenko U, Ceconi C, Ferrari R. Efficacy of ivabradine in combination with beta-blocker versus uptitration of beta-blocker in patients with stable angina. Cardiovasc Drugs Ther. 2011,25:531-537.
3. Task Force M, Montalescot G, Sechtem U, et al. 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. Eur Heart J. 2013,34:2949-3003.

4. L. A. Machado César, Brazil

Associate Professor of Cardiology
University of São Paulo
Medical School
São Paulo, BRAZIL

When treating patients with coronary artery disease (CAD), persistence of angina symptoms despite βblocker therapy is a frequent scenario. This situation happens because, until now, we have considered β-blockers as the best first-line antianginal drugs, even in the absence of studies showing a reduction in events in patients with stable CAD. The only exceptions are for patients after an acute coronary syndrome when β-blocker treatment confers protection over a period of months. In fact, there has only been one study with a long follow-up—the Norwegian Multicentre Study.1 In this study, patients were followed-up after an acute coronary event for a mean of 2.5 years. This trial took place in the 1980s when other therapies such as primary angioplasty, thrombolytic therapy, anti-platelets, anti-coagulants, and statins were not available or routinely used. Other post– myocardial infarction trials followed-up patients for no more than 3 months, but β-blockers are now the first-line treatment of choice for angina based on these post–myocardial infarction studies.

Until recently, we uptitrated the β-blocker dose and added a long-acting nitrate to treat angina. However, this will usually eliminate angina in only a few patients, especially if the heart rate is already below 70 bpm. At least 20% of patients cannot take nitrates due to headaches, and, even with nitrates, many continue to have angina. Another strategy is to add a dihydropyridine calcium channel blocker to the β-blocker, but this strategy results in angina control in only a few more patients. Some studies have showed that adding nifedipine2 or amlodipine3 to a β-blocker does not reduce angina episodes substantially, and the same is observed when a long-acting nitrate is added to β-blockers.3 For a while there was a lack of new strategies to treat angina other than interventions such as coronary artery bypass grafting (CABG) and angioplasty. However, many patients treated with CABG and angioplasty continue to have angina symptoms.

New agents were developed in order to achieve a better control of angina symptoms in most patients. Some studies show that trimetazidine has a substantial antianginal effect when added to any previous antianginal therapy, such as β-blocker monotherapy, β-blockers combined with nitrates, or β-blockers combined with calcium channel blockers.

The effect is similar regarding the percent reduction in angina, regardless of the previous treatment. Ivabradine, a drug that reduces heart rate, is another drug that can be used to control angina episodes. It was tested against atenolol, amlodipine, and combined with a β-blocker as a baseline therapy. All studies confirmed the benefits of ivabradine as an effective antianginal drug.4,5 There are also others drugs, such as nicorandil and ranolazine, but I have no experience with them.

At the moment, my strategy for treating angina is as follows: (i) if the patient is on an average dose of a β-blocker, exceptionally I consider uptitration; (ii) I add ivabradine first if the heart rate is above 70 bpm; (iii) if angina persists, I uptitrate ivabradine to 7.5 mg twice a day; and (iv) if necessary, I add trimetazidine next. The heart rate of patients taking β-blockers and ivabradine together usually goes down to almost 60 bpm. With a heart rate of <70 bpm at the beginning, I add trimetazidine first, and, if the ejection fraction is <40%, I use both ivabradine (for heart rates >70 bpm) and trimetazidine. Long-acting nitrates remain the third option. This is what the stable coronary disease guidelines from the Brazilian Society of Cardiology suggest,6 and reflects my current practice.

1. Norwegian Multicenter Study Group. Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med. 1981;304:801-807.
2.Fox KM, Mulcahy D, Findlay I, Ford I, Dargie HJ; TIBET Study Group. The Total Ischaemic Burden European Trial (TIBET). Effects of atenolol, nifedipine SR and their combination on the exercise test and the total ischaemic burden in 608 patients with stable angina. Eur Heart J. 1996;17(1):96-103.
3. Dourado LC, Poppi NT, Adam EL, et al. The effectiveness of intensive medical treatment in patients initially diagnosed with refractory angina. Int J Cardiol. 2015;186:29-31.
4. Köster R, Kaehler J, Meinertz T; REDUCTION Study Group. Treatment of stable angina pectoris by ivabradine in every day practice: the REDUCTION study. Am Heart J. 2009;158(4):e51-e57.
5. Werdan K, Ebelt H, Nuding S, Höpfner F, Stöckl G, Müller-Werdan U. Ivabradine in combination with beta-blockers in patients with chronic stable angina after percutaneous coronary intervention. Adv Ther. 2015;32(2):120-137.
6. Cesar LA, Ferreira JF, Armaganijan D, et al; Sociedade Brasileira de Cardiologia. Guideline for stable coronary disease. Arq Bras Cardiol. 2014;103(supp2):1-56.

5. Q. N. Nguyen, Vietnam

Quang Ngoc NGUYEN, MD, PhD,
Department of Cardiology, Hanoi Medical
University, Coronary Care Unit
Vietnam National Heart Institute

Stable coronary artery disease (CAD) can easily progress into an acute coronary syndrome, which might lead to fatal outcomes, especially in patients with a heavy atherosclerotic burden. Both the severity of lumen stenosis and the atheroma burden are predictors of plaque rupture and future major adverse cardiac events.1 For CAD patients, symptoms (typical angina or limitation in exercise capacity) are warning signs to reconsider the stability state of the entire coronary artery tree.

Initially, I determine: (i) if there is any existing lesion that needs to be revascularized; (ii) if there is any new relevant plaque rupture to fix; and (iii) if there is any significant emerging stenosis to treat. While the second point should be ruled out by serial testing of cardiac troponin, the first and third points usually take time and resources and involve the use of noninvasive or invasive cardiac imaging procedures and anatomical or functional approaches. Aggressive approaches should be reserved only for high-risk groups, such as patients with a previous stent or bypass, suggestive ischemic changes on a resting electrocardiography, and new abnormal wall motion or mitral valve dysfunction evidenced by echocardiography.

Second, for newly symptomatic stable patients, I determine if there are comorbidities that may result in similar signs/symptoms. The most common causes are uncontrolled hypertension, atrial fibrillation with rapid ventricular response, frequent ventricular premature beats (especially in patients with scars from a previous myocardial infarction), and the less common cause is uncompensated heart failure. Ambulatory blood pressure and heart rate monitoring could easily exclude these issues, and reflect the patient’s blood pressure and heart rate variability, which recently emerged as a new risk factor for future cardiovascular adverse events and as a marker of efficacy or treatment adherence.

Finally, for newly symptomatic stable patients, I determine whether patients are adherent to their treatment or if their treatment regimen is suboptimal. In daily practice, patients receiving long-term treatment usually tend to cut their treatment short due to financial cost, medication side effects, or psychological reasons. It is critical to reeducate this kind of patient on the importance of secondary prevention against the progression of atherosclerosis and the occurrence of unpredictable major adverse cardiac events, and to discuss the balance between potential side effects and future benefits.

For patients receiving a suboptimal treatment regimen, I would add another kind of anti-ischemic drug rather than uptitrate the β-blocker, to minimize the adverse effects and maximize the antianginal effect, an approach that is similar to that of the evidence-based blood pressure–lowering or cholesterol-lowering strategies. Adding one more drug to either lower heart rate continuously (such as ivabradine or a calcium channel blocker) or optimize cellular energy metabolism (such as trimetazidine or ranolazine) is a matter of choice. Ivabradine appears to affect coronary collateral function positively in chronic stable CAD patients,2 which could benefit patients who are not amenable to further coronary revascularization. In addition to the standard existing β-blocker treatment in stable CAD patients, adding ivabradine significantly improves the symptoms and quality of life,3 which further supports using a multiple anti-ischemic drug combination strategy.

In heart failure patients ivabradine should also be a first-line treatment due to its additional prognostic benefit. Ivabradine also has a demonstrated efficacy in particular subpopulations where β-blocker use is limited, such as patients with asthma, chronic obstructive pulmonary disease, peripheral vascular disease, diabetes, or elderly patients (older than 80).4 However, in stable CAD patients without left ventricular dysfunction, β-blockers and ivabradine have symptomatic benefits but lack prognostic benefits.5 A recent analysis has raised some concerns about increased central systolic pressure, which can abolish the potential benefits of heart rate–lowering therapy with β-blockers or ivabradine, especially in patients with hypertension and CAD.6 In such patients, a vasodilating β-blocker, calcium channel blocker, or metabolic anti-ischemic agent should be the first-line treatment.

1. Mancini GB, Hartigan PM, Shaw LJ, et al. Predicting outcome in the COURAGE trial (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation): coronary anatomy versus ischemia. JACC Cardiovasc Interv. 2014;7(2): 195-201.
2. Lupi A, Rognoni A, Cavallino C, Secco GG, Rosso R, Bongo AS. Ivabradine for treatment of coronary artery disease: from last chance resort to mainstem of a reasoned therapy. Cardiovasc Hematol Agents Med Chem. 2015;13:4-9.
3. Werdan K, Ebelt H, Nuding S, Höpfner F, Hack G, Müller-Werdan U. Ivabradine in combination with beta-blocker improves symptoms and quality of life in patients with stable angina pectoris: results from the ADDITIONS study. Clin Res Cardiol. 2012;101:365-373.
4. Tendera M, Borer JS, Tardif JC. Efficacy of If inhibition with ivabradine in different subpopulations with stable angina pectoris. Cardiology. 2009;114(2):116-125.
5. Ferrari R, Fox K. Heart rate reduction in coronary artery disease and heart failure. Nat Rev Cardiol. 2016;13(8):493-501.
6. Messerli FH, Rimoldi SF, Bangalore S, Bavishi C, Laurent S. When an Increase in central systolic pressure overrides the benefits of heart rate lowering. J Am Coll Cardiol. 2016;68(7):754-762.

6. D. Pop, Romania

Dana POP, MD, PhD
Professor, Cardiology Department
University of Medicine and Pharmacy
“Iuliu Haţieganu” Cluj-Napoca

Mortality due to ischemic heart disease (including stable angina) continues to be very high in Europe: 40% in men and 49% in women, despite the complex methods of treatment currently available.1 The ESC guidelines on the management of stable coronary artery disease recommend β-blockers and/or calcium channel blockers as first-line antianginal medications, along with short-acting nitrates.2 If symptoms persist, ivabradine, long-acting nitrates, nicorandil, ranolazine, or trimetazidine should be added. Obviously, we must not forget cardioprotective medications (statins, antiplatelet agents, angiotensin-converting enzyme inhibitors).2 The guidelines also recommend using optimal drug therapy in all patients, even those with an indication for revascularization.2 However, there are many patients who continue to have effort angina and/or decreased exercise capacity despite an appropriate first-line treatment including maximal tolerated doses of β-blockers. On the other hand, while β-blockers are the most frequently prescribed drug class in patients with stable coronary artery disease, data from registries and studies show that they are used at low doses. This low dosing could be explained by limitations for β-blocker uptitration due to tolerability issues. These limitations raise questions about how we can optimize medical therapy in these patients.

In this context, we must remember that in a healthy person adaptation to exercise involves both peripheral (eg, arteriolar vasodilation in striated muscle, vasoconstriction in other territories, such as venous territories, and increased O2 factor extraction) and central mechanisms (eg, increased preload, heart rate, ejection fraction, and contractility). All of these changes lead to an increase in O2 intake in the muscles during exercise. In effort angina, there is an imbalance between oxygen requirements and intake due to the presence of coronary stenoses. Myocardial ischemia (clinically manifested by angina attacks) is significantly influenced by a number of other factors that need to be treated. Collateral circulation plays an important role in preserving coronary flow reserve. Bradycardia also favors the development of collateral circulation, facilitating angiogenesis and arteriogenesis. Ivabradine 7.5 mg twice daily stimulates collateral blood vessel growth in the ischemic myocardium, and the induced reduction in heart rate is accompanied by a significant increase in myocardial perfusion through collateral vessels.3 Coronary reserve has a primary role in adaptation to exercise, and heart rate reduction is associated with improved myocardial coronary perfusion. Recent experimental studies have demonstrated that ivabradine may increase coronary reserve up to 26%, helping to ensure an optimal supply of oxygen under myocardial ischemia conditions.4 Increasing diastolic perfusion time is another important mechanism (myocardial perfusion occurs predominantly in diastole). Ivabradine has proven its effectiveness in this respect, as it has been shown to trigger an increase of 41% in diastolic perfusion time.4 Finally, ensuring that coronary flow is optimal may help to relieve ischemia in stable angina. Although atenolol and ivabradine cause a similar improvement in coronary flow at rest, during physical effort the improvement in coronary flow is significantly higher in patients treated with ivabradine.5 The mechanisms described above, which improve myocardial perfusion, may explain the well-known effects of ivabradine (reduced number of angina attacks, increased exercise capacity, improved quality of life).6 Ivabradine represents a viable therapeutic alternative for patients with stable angina who remain symptomatic despite being treated with a β-blocker at the maximum tolerated dose.■

1. Townsend N, Nichols M, Scarborough P, Rayner M. Cardiovascular disease in Europe—epidemiological update 2015. Eur Heart J. 2015;36(40):2696-2705.
2. Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease. Eur Heart J. 2013;34(38):2949-3003.
3. Gloekler S, Traupe T, Stoller M, et al. The effect of heart rate reduction by ivabradine on collateral function in patients with chronic stable coronary artery disease. Heart. 2014;100(2):160-166.
4. Colin P, Ghaleh B, Monnet X, et al. Contributions of heart rate and contractility to myocardial oxygen balance during exercise. Am J Physiol Heart Circ Physiol. 2003;284(2):H676-H682.
5. Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K; INITIATIVE Investigators. Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26:2529-2536.
6. Vardas EP, Skalidis EI. The role of ivabradine in improving myocardial perfusion, adding to the antianginal benefits. Eur Heart J Suppl. 2015;17(suppl G):G19-G23.

7. Z. Raissouni, Morocco

Chief of Cardiac Imaging
Service de Chirurgie Cardiovasculaire Hôpital
Militaire d’Instruction, Mohammed V- Université
Mohamed V Souissi, Rabat

Coronary artery disease is the most frequent type of heart disease, and stable angina pectoris (SAP) is one of its more common presentations. SAP is the clinical expression of myocardial ischemia secondary to an imbalance in myocardial oxygen supply and demand. The goals of treatment include relief of symptoms and inhibition of disease progression. Here we focus on the role of medical therapy in the management of SAP. Two major classes of drugs are essential for SAP therapy and are prescribed as first-line treatment: anti-ischemic drugs and drugs that prevent myocardial infarction (MI) and death.1

Anti-ischemic drugs include β-blockers, calcium channel inhibitors, and nitrates (short- and long-acting). The mechanisms of action of most of these drugs involve a reduction in systemic vascular resistance, coronary vasodilatation, or negative inotropism, which improves the imbalance between myocardial oxygen supply and requirement.

Numerous drugs are available to improve prognosis by preventing MI and death. Aspirin at a dose of 75 mg per day reduces cardiovascular morbidity and mortality by 33% in patients with coronary artery disease.1 Clopidogrel combined with aspirin is not significantly more effective than aspirin alone in reducing the rate of MI, stroke, or death. Statins lower the rate of coronary events and mortality by 35% in patients with coronary artery disease.2 Two large clinical trials (EUROPA [EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease] and HOPE [Heart Outcomes Prevention Evaluation]) found angiotensin-converting enzyme (ACE) inhibitors effective in reducing morbidity and mortality in high-risk patients with cardiovascular disease, The European Society of Cardiology (ESC) guidelines recommend ACE inhibitors for patients with a history of heart failure, hypertension, or diabetes.1

To further optimize therapy in these patients, new anti-ischemic drugs with novel mechanisms of action have been developed.3 These drugs are prescribed as second-line treatments after β-blockers, aspirin, statins, and ACE inhibitors and their mechanisms of action include:
• Sinus node inhibition (ivabradine)
• Metabolic and/or ion modulation (trimetazidine, ranolazine,)
• ATP-gated K+ channels activation—preconditioning (nicorandil)
• Xanthine oxidase inhibition (allopurinol)

Of the drugs listed above, trimetazidine and ivabradine are the most widely used in second line when symptoms persist.

Ivabradine is a heart rate–lowering agent that selectively blocks the sinus node If current, decreasing the myocardial oxygen demand without any negative inotropic effects. The European Medicines Agency (EMA) approved it for the treatment of SAP in patients intolerant to—or inadequately controlled by— β-blockers and with a heart rate >60 bpm.1,4 Ivabradine is also recommended by the ESC guidelines with a IIa level of evidence, as it offers clear therapeutic benefits for a whole range of patients with SAP in sinus rhythm.

Trimetazidine is a metabolic agent that acts at the cellular level to improve myocardial metabolism during ischemia. By increasing glucose utilization it increases the production of adenosine triphosphate (ATP) per unit of oxygen consumed. Added to β-blockers, trimetazidine (35 mg twice daily) improves effort-induced myocardial ischemia, as reviewed by the EMA in June 2012.5 These data indicate that trimetazidine is safe and effective for the treatment of SAP symptoms, either as monotherapy or adjunctive treatment, and that it can be considered as a second-line treatment (IIb).1

SAP symptoms can usually be managed using optimum doses of one of the available antianginal drugs, along with lifestyle modifications, and drugs such as aspirin, statins, and ACE inhibitors. Several new drugs with a different mechanism of action provide new treatment options, and have precise indications in the new European guidelines. Finally, patients who remain symptomatic despite medical treatment should be considered for revascularization.

1. Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease. Eur Heart J. 2013;34(38):2949- 3003.
2. Opie LH, Commerford PJ, Gersh BJ. Controversies in stable coronary artery disease. Lancet. 2006;367:69-78.
3. Chaitman BR. Pharmacological approaches to the symptomatic treatment of chronic stable angina: a historical perspective and future directions. Can J Cardiol. 2005;21:1031-1034.
4. Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K. Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26:2529-2536.
5. European Medicines Agency. Questions and answers on the review of medicines containing trimetazidine (20 mg tablets, 35 mg modified release tablet and 20 mg/ml oral solution). Available at: document_library/Referrals_document/Trimetazidine_31/WC500129195.pdf (9 March 2012).

8. E. J. F. Ramos, Philippines

Chief of Cardiac Imaging
Service de Chirurgie Cardiovasculaire Hôpital
Militaire d’Instruction, Mohammed V- Université
Mohamed V Souissi, Rabat

Β-Blockers have been used for decades in the management of ischemic heart disease, mainly to decrease oxygen demand through heart rate reduction. In patients with stable coronary artery disease (CAD), angina pectoris occurs at certain thresholds of physical activity, triggered by an increase in heart rate and relieved by rest and the corresponding heart rate normalization. Patients oftentimes learn to anticipate the onset of angina pectoris at specific physical exertion levels. Other than the avoidance of physical exertion, optimal use of β-blockers and anticipatory use of nitrates— orally or sublingually—minimize the occurrence of angina. When angina occurs in spite of such measures, or at lower physical exertion levels, coronary angiography is warranted. In the COURAGE trial (Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation), however, a significant percentage of post–percutaneous coronary intervention (PCI) patients continued to have angina at 1 year post-intervention,1 implying that mechanisms other than stenosis of the epicardial arteries are involved.

In places where access to a cardiac catheterization laboratory is limited, or when coronary intervention is not feasible, optimizing medical therapy on top of β-blockers, antiplatelets, nitrates, and statins requires more aggressive reduction of cardiovascular risks and the use of newer drugs. The challenge increases when the patient is hypertensive or diabetic, or both, with evidence of ventricular hypertrophy and diastolic dysfunction and peripheral and microvascular circulatory disorder. It gets worse when the patient has contraindications to the use of β-blockers, or when increasing the dose of the β-blocker is not medically feasible.

At the cellular level, optimal therapy in stable CAD requires efficient production of mitochondrial ATP to meet the metabolic demands of the cardiac myocytes in times of stress.2 Oxidative stress and the production of oxygen free radicals contribute significantly to angina pectoris.3 Coronary flow occurs during diastole; therefore, increasing diastolic duration by decreasing the heart rate improves coronary flow in addition to decreasing the demand for oxygen. β-Blockers decrease heart rate but negatively affect myocardial contractility at high doses. Their α-agonist effect also promotes vasoconstriction. The non-dihydropyridine calcium channel blockers diltiazem and verapamil reduce heart rate and cause coronary vasodilation, but have negative inotropic effects at higher doses.

Ivabradine, with its neutral impact on myocardial contractility or blood pressure, has made optimal therapy in stable CAD patients with concomitant disorders much easier to achieve. These patients are likely to be already on many other drugs like aspirin, β-blockers, nitrates, statins, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, all of which have unique properties in restoring or preserving myocardial function. Drug-drug interaction is a real risk in this situation, however, but interactions between these drugs and ivabradine have been shown to be safe. A study has shown that ivabradine prolongs diastolic duration more than β-blockers even at a similar level of heart rate reduction.4 Ivabradine alleviates myocardial ischemia and reduces angina pectoris not only by reducing oxygen demand but also by improving oxygen supply through coronary vasodilation at the microvasculature level. Moreover, a study showing a favorable effect of ivabradine in endothelial function points to an improvement in the efficiency of energy production at the intracellular level.5

Optimal therapy of stable CAD patients treated with β-blockers who are still symptomatic requires a combination of drugs that promote myocardial perfusion, maintain coronary reserve, and improve cellular function, given at dosages that do not cause side effects or increase the risk of drug-drug interactions. Ivabradine has been shown not only to decrease oxygen demand through heart rate reduction, but also to increase coronary flow and improve cellular function.

1. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356:1503-1516.
2. Pepine CJ, Nichols WW. The pathophysiology of chronic ischemic heart disease. Clin Cardiol 2007;30:I4-I9.
3. Stanley WC, Lopaschuk GD, Hall JL, McCormack JG. Regulation of myocardial carbohydrate metabolism under normal and ischemic conditions. Potential for pharmacological interventions. Cardiovasc Res. 1997;33:243-257.
4. Colin P, Ghalel B, Monnet X, et al. Contributions of heart rate and contractility to myocardial oxygen balance during exercise. Am J Physiol Heart Circ Physiol. 2003;284:H676-H682.
5. Mangiacapra F, Colaiori E, Ricottini E, et al. Heart rate reduction by Ivabradine for improvement of endothelial function in patients with coronary artery disease: the randomized open-label RIVENDEL study. Eur Heart J. 2015;36(suppl 1):1105.

9. I. Simova, Bulgaria

Associate Professor
Head of Cardiology Department
Acibadem City Clinic
Cardiovascular Center
University Hospital

Β-Blokers are the most frequently prescribed drug class in patients with stable coronary artery disease (SCAD). Dosing regimens, however, are often suboptimal due to problems of tolerability. This is probably the reason why many patients with SCAD still continue to experience angina symptoms and/or limitation in exercise capacity, despite β-blocker therapy. Presented here is a personal perspective and a stepby- step management strategy for patients who remain symptomatic despite therapy with β-blockers.

Step 1: control risk factors
Risk factors—which include hypertension, hypercholesterolemia, diabetes, a sedentary lifestyle, obesity, and smoking— should be addressed and properly controlled. The patient’s blood pressure should be measured at every visit, while lipid status, serum glucose, and glycated hemoglobin should be assessed periodically.

In addition, the importance of maintaining a healthy lifestyle should be promoted and counseling on smoking cessation, diet, regular physical activity, and weight loss—if necessary— should be provided. Depression, anxiety, and distress should also be addressed.

Risk factors should be taken into account when prescribing concomitant medications. For example, if a patient has diabetes and should take a diuretic for blood pressure control, then a metabolically neutral diuretic, like indapamide, should be prescribed, instead of hydrochlorothiazide.

Step 2: address precipitating factors
Patients whose symptoms have worsened while on -blocker therapy should be evaluated for the presence of precipitating factors, like hyperthyroidism, anemia, tachyarrhythmias, aortic stenosis, hypertrophic cardiomyopathy, fever, malignant hypertension, hypotension, etc…. If present, these conditions should be treated.

Step 3: assess -blocker treatment
Β-Blockers are clearly effective in controlling exercise-induced angina, improving exercise capacity, and limiting ischemic episodes. There is no unequivocal evidence, however, that β-blocker therapy improves prognosis in SCAD patients without myocardial infarction or heart failure. If a patient is symptomatic while on β-blocker therapy, the first thing to do is to assess treatment compliance. If poor compliance is due to forgetfulness, then the patient should be instructed on the importance of persisting with the treatment. Poor compliance, however, is often due to the adverse effects of β-blockers, which include hypotension, fatigue, depression, bradycardia, heart block, bronchospasm, peripheral vasoconstriction, hypoglycemia, or masked hypoglycemia. If these adverse effects are present, then the patient is intolerant to β-blockers. Depending on the findings, there are several possible scenarios:

• If the patient can tolerate β-blockers but compliance is suboptimal, then compliance should be reinforced.
• If the β-blocker dose is suboptimal, and the treatment is tolerated, then the dose should be uptitrated.
• If the patient is intolerant to β-blockers, then the dose should be down titrated in order to find the maximal tolerated dose. There are patients, however, that do not tolerate any β-blocker dose and the therapy should be discontinued. In case of β-blocker intolerance, then a second anti-ischemic agent should be added.

Step 4: choose a second anti-ischemic agent
• If the resting heart rate (HR) is ≥70 beats per minute (bpm), then ivabradine should be added and uptitrated in order to achieve a resting HR of 50-60 bpm.
• If the resting HR is <60 bpm, then we should consider adding a dihydropyridine calcium channel blocker, and/or long-acting nitrate, and/or trimetazidine for symptomatic relief.

Step 5: consider coronary revascularization
If all of the above-mentioned measures have been addressed and the patient is still symptomatic, then the physician should consider referring the patient for coronary angiography with a view to revascularization.

Montalescot G, Sechtem U, Achenbach S, et al. 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. Eur Heart J. 2013;34:2949-3003.

10. E. Tagliamonte, Italy

Cardiology Division
“Umberto I” Hospital
Nocera Inferiore

Stable angina pectoris is the most common manifestation of coronary artery disease (CAD). Although the annual mortality rate is relatively low, anginal symptoms are often disabling. The aims of treatment are to relieve anginal symptoms and improve the quality of life. In patients who remain symptomatic despite optimal medical treatment, there is evidence that coronary revascularization improves anginal symptoms. However, in a substantial proportion of these patients, the prevalence of angina at follow-up remains high despite successful revascularization. These findings suggest that, although revascularization is effective in removing coronary stenosis, other mechanisms, including coronary microvascular dysfunction, contribute to the pathogenesis of ischemia and angina in these patients.

Resting heart rate (HR) is an important and independent risk factor and a predictor of cardiovascular mortality and morbidity. HR-lowering agents have been shown to improve clinical outcomes, although whether HR reduction is the only mechanism of benefit is hard to demonstrate and is perhaps too simplistic. Β-Blockers are used as first-line therapy to control symptoms in patients with chronic stable angina and they can significantly reduce cardiovascular events. More recently, the sinus node If channel inhibitor ivabradine, which reduces HR both at rest and during exercise, has been proven to have antianginal efficacy.

Because of their HR-lowering effects, ivabradine and β-blockers are often considered to be “similar” drugs. Large clinical trials have investigated the use of ivabradine as an alternative to β-blockers, when β-blockers cannot be tolerated or are contraindicated, or in addition to them, when HR is not adequately controlled. But we should ask ourselves whether their effect is really that similar. Recent experimental and clinical investigations have demonstrated that ivabradine may reduce myocardial ischemia and its consequences not only through HR lowering, but also through additional pleiotropic mechanisms that contribute to improve coronary vascular and myocardial structure and function.1 It is clear that diastolic perfusion time mainly affects subendocardial blood flow, since coronary blood flow is greatest during diastole. In experimental studies, ivabradine increased diastolic time both at rest and during treadmill exercise to a greater extent than atenolol, though both drugs had a similar effect on HR. These data were also confirmed in humans, as recently demonstrated in clinical studies on patients with stable CAD.

Moreover, contrary to β-blockers, ivabradine does not increase or unmask α-adrenergic coronary vasoconstriction in the epicardial coronary arteries and, more importantly, in the coronary microcirculation. This effect of ivabradine is especially important in human atherosclerotic coronary vessels, since α-adrenergic vasoconstriction is enhanced in the presence of endothelial dysfunction.

Reduced coronary flow reserve (CFR) may reflect narrowing of the epicardial coronary arteries or dysfunction of the coronary microcirculation. Ivabradine and β-blockers were found to have a different effect on CFR, with two studies showing that ivabradine has a stronger effect on CFR than β-blockers, despite both drugs achieving a similar HR reduction.2,3

Finally, the development of collateral circulation is a natural mechanism that can compensate for the limitation of coronary flow resulting from coronary stenosis progression, and it is advantageous in protecting tissues from ischemia. In patients with stable CAD ivabradine has been shown to improve coronary collateral function.4

Clinical and experimental studies show that the effect of ivabradine on the pathophysiology of the coronary circulation is different from that of β-blockers, as it has both antianginal and anti-ischemic effects. Since β-blockers and ivabradine produce a similar reduction in HR, the effect of ivabradine treatment actually appears to go beyond its HR-lowering effect. Thus, ivabradine should not be considered as an alternative to β-blockers, it should be a first-choice treatment in symptomatic patients with stable CAD, even in those already treated with β-blockers. Further studies may even suggest that ivabradine is preferable to β-blockers in these patients.

1. Camici PG, Gloekler S, Levy BI, et al. Ivabradine in chronic stable angina: Effects by and beyond heart rate reduction. Int J Cardiol. 2016;215:1-6.
2. Skalidis EI, Hamilos MI, Chlouverakis G, Zacharis EA, Vardas PE. Ivabradine improves coronary flow reserve in patients with stable coronary artery disease. Atherosclerosis. 2011;215:160-165.
3. Tagliamonte E, Cirillo T, Rigo F, et al. Ivabradine and bisoprolol on doppler-derived coronary flow velocity reserve in patients with stable coronary artery disease: beyond the heart rate. Adv Ther. 2015;32:757-767.
4. Gloekler S, Traupe T, Stoller M, et al. The effect of heart rate reduction by ivabradine on collateral function in patients with chronic stable coronary artery disease. Heart. 2014;100:160-166.

11. K. Toth, Hungary

Kalman TOTH, MD
1st Department of Medicine
Medical School
University of Pecs

Β-Blockers are the most frequently prescribed drug class in patients with stable coronary artery disease (CAD), although they are often used at low doses as β-blocker uptitration can be limited by problems of tolerability. Moreover, many patients with stable CAD continue to experience angina symptoms and/or limitation in exercise capacity despite the use of β-blockers. Clinical trials and meta-analyses have shown that almost half of stable CAD patients experience typical angina symptoms that impact their daily activities and lifestyle. The main purpose of treatment, besides improving the prognosis, is to reduce the frequency and severity of angina so that quality of life improves.

It is well known that a high resting heart rate worsens cardiovascular outcomes.1 It increases the myocardial oxygen demand and decreases diastolic time, and as a result myocardial perfusion is altered, leading to ischemia and anginal symptoms.2 In CAD the recommended target resting heart rate is 55-60 bpm, although in refractory angina it can even be lowered to <50 bpm in case of asymptomatic bradycardia. Β-Blockers, which are the first-line treatment, should be uptitrated and when symptoms are not relieved, they can be combined with dihydropyridine calcium antagonists. Although the efficacy of β-blockers is proven, difficulties often arise regarding initiation, uptitration, and maintenance of β-blocker treatment because of adverse effects or because of an inadequate response due to a α-receptor polymorphism. If firstline medications are not sufficient in combination, a second line treatment (long-acting nitrates, ivabradine, ranolazine, trimetazidine, or nicorandil) can be given. Ivabradine is a specific sinus node inhibiting agent that can be used in patients with sinus rhythm whose heart rate is ≥70 bpm. It inhibits the If current in the sinus node and—in contrast to β-blockers—does not have negative inotropic effects. It decreases heart rate but has no effect on cardiac output and blood pressure. Several clinical trials have demonstrated the benefit of combining a β-blocker with ivabradine. This combination improves chronotropic reserve and exercise tolerance due to an additive antianginal effect, decreases angina episodes and nitroglycerin consumption, and enhances quality of life.3,4 This therapeutic strategy can be applied in patients with sinus rhythm when uptitrated β-blockers do not achieve the desired heart rate reduction and the patient remains symptomatic. Furthermore it can also facilitate the uptitration of β-blocker therapy.

Trimetazidine is another second-line option. It improves myocardial glucose utilization—thereby increasing coronary flow reserve, decreasing the frequency of anginal episodes and nitrate consumption, and improving exercise tolerability— but has no effect on heart rate and has no negative inotropic and vasodilatory effects.5 In clinical practice trimetazidine is a safe and effective agent that can be used as an add-on treatment in patients who are symptomatic or intolerant to first-line antianginal therapies, and also in patients with bradycardia and atrial fibrillation.

Although a number of clinical studies have demonstrated that combining ranolazine with traditional medical therapy provides sufficient angina relief,6 we have limited clinical experience with this drug since it is not currently available in several European countries. Long-acting nitrates can also be added sequentially if symptoms persist. Unfortunately, nitrate tolerance can develop with continuous exposure. Moreover, headache and hypotension can also limit its use. Nicorandil is another vasodilator, which acts both as a nitric oxide donor and an arterial K+ ATP channel opener. It is recommended as a second line agent after β-blockers and calcium channel antagonists, although there is limited clinical experience with this drug since it is not available in several European countries.

In conclusion, ivabradine is an option for symptomatic patients in sinus rhythm after β-blockers and calcium channel blockers have been uptitrated. In case of bradycardia and atrial fibrillation other therapeutic options like trimetazidine, ranolazine, and vasodilatory drugs can provide alternative treatments, even though the last two drugs can often produce adverse effects owing to their hemodynamic action.

1. Fox K, Borer JS, Camm AJ, et al; Heart Rate Working Group. Resting heart rate in cardiovascular disease. J Am Coll Cardiole. 2007;50:823-830.
2. Diaz A, Bourassa MG, Guertin MC, Tardif JC. Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J. 2005;26:967-974.
3. Amosova E, Andrejev E, Zaderey I, Rudenko U, Ceconi C, Ferrari R. Efficacy of ivabradine in combination with β-blocker versus uptitration of β-blocker in patients with stable angina. Cardiovasc Drugs Ther. 2011;25:531-537.
4. Zarifis J, Grammatikou V, Kallistratos M, Katsivas A. Antianginal efficacy of ivabradine in patients with history of coronary revascularization. Angiology. 2017;68: 10-18.
5. Chazov EI, Lepakchin VK, Zharova EA, et al. Trimetazidine in angina combination therapy – the TACT study: trimetazidine versus conventional treatment in patients with stable angina pectoris in a randomized, placebo-controlled, multicenter study. Am J Ther. 2005;12:35-42.
6. Morrow DA, Scirica BM, Chaitman BR, et al; MERLIN-TIMI 36 Investigators. Evaluation of the glycometabolic effects of ranolazine in patients with and without diabetes mellitus in the MERLIN-TIMI 36 randomized controlled trial. Circulation. 2009;119:2032-2039.