The role of optimal medical therapy in patients with stable coronary artery disease

JPS Sawhney; Dhiman Kahali; Bhupen Desai; Suresh KP Kumar; M Vishvanathan; Vishal Rastogi

doi:10.4103/JCPC.JCPC_43_17

REVIEW ARTICLE

Year : 2018 | Volume : 7 | Issue : 2 | Page : 60-71

The role of optimal medical therapy in patients with stable coronary artery disease

JPS Sawhney MD, DM ¹, Dhiman Kahali MD, DM ², Bhupen Desai MD, DM ³, Suresh KP Kumar MD, DM ⁴, M Vishvanathan MD, DM ⁵, Vishal Rastogi MD, DM ⁶
¹ Sawhney Heart Centre, New Delhi, India
² Department of Cardiology, BM Birla Heart Research Centre, Kolkata, West Bengal, India
³ Department of Cardiology, Desai Heart Care Clinic, Borivali West, Mumbai, Maharashtra, India
⁴ Department of Cardiology, Kauvery Hospital, Chennai, Tamil Nadu, India
⁵ Department of Cardiology, Jaslok Hospital, Mumbai, Maharashtra, India
⁶ Department of Cardiology, Fortis Escorts, New Delhi, India

Date of Web Publication

23-Mar-2018

Correspondence Address:
Dr. JPS Sawhney
Sawhney Heart Centre, West Punjabi Bagh, New Delhi
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/JCPC.JCPC_43_17

Abstract

Coronary artery disease (CAD) is a leading cause of mortality and morbidity around the globe. The fact that prevalence and mortality due to CAD are declining in developed countries cannot be held true in developing countries. Almost fourfold increase in CAD prevalence has been reported in India in the past 40 years. This incidence is likely to increase further in the coming years. The heterogeneity of the disease presentation is an important challenge in the management of these patients, and the current therapies are not universally effective in controlling these symptoms. Even with the advancements in medical therapies over the last two decades, it is unclear whether percutaneous coronary intervention (PCI) provides a prognostic advantage over optimal medical therapy (OMT) in the management of stable angina patients. The current review primarily focuses on the use of OMT for stable CAD patients and also discusses the role of coronary revascularization, especially PCI, in the management of these patients. This is based on evidence-based recommendations and guidelines.

Keywords: Angina, coronary artery disease, optimal medical therapy, percutaneous coronary intervention

How to cite this article:
Sawhney J, Kahali D, Desai B, Kumar SK, Vishvanathan M, Rastogi V. The role of optimal medical therapy in patients with stable coronary artery disease. J Clin Prev Cardiol 2018;7:60-71

How to cite this URL:
Sawhney J, Kahali D, Desai B, Kumar SK, Vishvanathan M, Rastogi V. The role of optimal medical therapy in patients with stable coronary artery disease. J Clin Prev Cardiol [serial online] 2018 [cited 2023 Mar 29];7:60-71. Available from: https://www.jcpconline.org/text.asp?2018/7/2/60/228341

Introduction

Coronary artery disease (CAD) is a leading cause of mortality and morbidity around the globe.^[1] It results from the development of obstructive coronary artery plaques, reducing the oxygen supply to the myocardium.^[2] Stable CAD (SCAD) is for the most part characterized by episodes of reversible myocardial demand/supply incongruity, leading to myocardial ischemia or hypoxia, which are usually inducible by exercise, emotion, or other stress and are reproducible, which may also be occurring spontaneously.^[3]

Despite the fact that the prevalence and mortality due to CAD are declining in the developed countries, the same cannot be held true for developing countries.^[1],[4] About fourfold increase in CAD prevalence has been reported in India during the past 40 years.^[1],[5] Faulty lifestyle with early development of various cardiovascular (CV) risk factors remains the primary cause of this rapid raise in the CAD prevalence in India. While the INTERHEART study suggested that almost 90% of all the myocardial infarctions (MIs) could be explained by the nine conventional CV risk factors,^[6] even in India, the role of several new nonconventional risk factors remains putative. Comparative studies on newer risk factors demonstrate that Indians have higher C-reactive protein, plasminogen activator inhibitor 1, homocysteine levels, and lipoprotein (a).^[4] The most striking feature of the management of patients with CV disease in India is its heterogeneity, ranging from patients treated at tertiary and teaching hospitals to those who have limited access to the quality healthcare and are therefore poorly treated.^[7]

There are two major aims of the management of SCAD patients – to obtain relief of symptoms and to prevent future CV events.^[3] There are multiple medical and revascularization modalities, including percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG), available for the treatment of SCAD.^[8] All patients with SCAD first require optimal medical therapy (OMT) to alleviate symptoms, to avert disease progression, to prevent CV events, and to decrease mortality.^[2] Revascularization is indicated in patients who remain symptomatic despite OMT. In such patients, when coronary anatomy is suitable, PCI is a feasible, safe, and effective treatment option to relieve ischemic symptoms.^[9] However, the symptomatic benefit provided by PCI is known to diminish with time, with many patients requiring to re-initiate antianginal drugs or undergo repeat revascularization after a few years. In addition, because of the concurrent advancements in medical therapies over the last two decades, it is unclear whether PCI provides a prognostic advantage over OMT in the management of stable angina patients.^[10],[11] Therefore, in the current clinical practice, several practical issues confront the physicians responsible for the care of SCAD patients whose symptoms are adequately controlled with OMT. These include – Should all patients with significant coronary lesions (i.e. those capable of producing ischemia) undergo PCI? Or does evidence-based data indicate that the best therapeutic approach to such patients is ensuring they are on OMT? Or should PCI be performed, but only in certain subsets of patients?

The current review primarily focuses on the use of OMT for SCAD patients and also discusses the role of coronary revascularization, especially PCI, in the management of these patients. This is based on the evidence-based recommendations and guidelines.

Available Treatment Options

The goals and objectives of the treatment for SCAD as per the 2012 guideline from the American College of Cardiology/American Heart Association ^[12] are as follows:

To decrease the premature CV death
To prevent complications of SCAD that brings about impairment in the functionality of the patients' well-being, including nonfatal acute MI and congestive heart failure (CHF)
To maintain or restore a level of activity, functional capacity, and quality of life of the patient to their satisfactory limits
To completely, or nearly completely, eliminate ischemic symptoms
To minimize costs of healthcare, in particular by eliminating avoidable adverse effects.

Keeping the above in consideration, the available therapeutic options for the treatment of SCAD can be broadly classified as follows:

OMT
Myocardial revascularization, including PCI and CABG.

Enhanced-external counterpulsation is another option in patients who continue to have significant angina despite OMT and are not candidates for revascularization for some reasons.

Optimal Medical Therapy

All the standard guidelines (2012 ACC/AHA guideline ^[12] and 2013 European Society of Cardiology [ESC] guideline ^[3]) emphasize on the use of OMT as the primary treatment modality for patients with SCAD, which has also been found to delay the progression of atherosclerosis and interception of coronary thrombosis.^[13] Initial medical therapy has been considered to be safe and effective over PCI.^[14]

Among the available pharmacotherapies, antiplatelets (primarily aspirin and clopidogrel when aspirin is contraindicated) and statins universally reduced the risk of adverse CV events, including CV mortality, and are indicated in all patients with SCAD. Beta-blockers reduced CV mortality in those who have suffered an acute coronary event during the past 3 years at least and in those who have left ventricular (LV) systolic dysfunction.^[3],[12] Angiotensin-converting enzyme inhibitors (ACE-Is) provide prognostic benefit in SCAD patients who also have hypertension, diabetes, LV systolic dysfunction, or chronic kidney dysfunction (CKD).^[3],[12] All other medical therapies are aimed primarily at relieving anginal symptoms [Table 1].

Table 1: Currently available antianginal drugs for optimal medical therapy (based on their indications and level of evidence

Click here to view

Nitroglycerin/glyceryl trinitrate

Standard therapy for immediate relief of angina is short-acting, sublingual nitroglycerin.^[3],[15] Long-acting nitrates are used as part of OMT to reduce CV morbidity and enhance the quality of life by preventing recurrent angina attacks and improving exercise capacity.

Mechanism of action

Glyceryl trinitrate (GTN) reduces the anginal symptoms by decreasing myocardial oxygen consumption as a function of:

Reducing preload, systolic wall stress, and afterload
Restoring flow imbalances, dilating coronary arteries (prestenotic, stenotic, and poststenotic segments)
Increasing subendocardial myocardial perfusion by lowering LV diastolic pressure
Preventing coronary artery vasospasm
Acting as a physiologic substitute for endothelium-derived relaxing factor in the presence of endothelial dysfunction.^[15]

GTN has the following beneficial effects on the CV system:

Epicardial coronary vasodilation
Decreased coronary vascular resistance
Enhanced coronary collateral flow
Decreased likelihood of coronary steal
Increased venous capacitance and decreased preload
Reduced myocardial oxygen consumption and increased exercise capacity.^[16]

Uses in patients with stable coronary artery disease

Short-acting nitrates are used for the following purposes:

To provide relief from acute anginal pain
Used prophylactically to improve exercise tolerance and prevent exercise-induced ischemia
Used as a supplement to long-acting nitrates in case of acute attacks
The long-acting nitrates are used either as monotherapy or in combination with beta-blockers or calcium channel blockers (CCBs) to prevent or reduce the frequency of angina in patients with SCAD.^[16] However, routine use of long-acting nitrates in patients with SCAD should preferably be avoided in view of the risk of worsening endothelial dysfunction.^[3],[12] Unlike the short-acting nitrate therapy, the long-term usage of nitrates worsens endothelial dysfunction through the accumulation of oxygen-free radicals.

Adverse effects

They include hypotension, syncope, headache, and tolerance.

Precautions/contraindications

They include LV outflow tract obstruction and erectile dysfunction (concomitant use of phosphodiesterase 5 inhibitors).

Evidence base

In a multicenter, double-blind, crossover trial in patients of stable angina, nitroglycerin prophylaxis had shown its effectiveness by decreasing the number of angina episodes (4.9 ± 1.7, P < 0.005) and improving exercise capacity when compared to placebo (6.4 ± 1.5 episodes/week).^[17] Another randomized, double-blind, placebo-controlled study reported the efficaciousness of controlled-release isosorbide-5-mononitrate in the improvement of exercise tolerance in stable effort angina pectoris.^[18]

A postmarketing study was conducted to assess the safety and efficacy of nitroglycerin controlled-release tablets in patients with chronic stable angina. The nitroglycerin controlled-release tablet was found to be significantly effective in reducing the frequency of angina attacks and also in reducing the pill burden per week compared to baseline.^[19]

Nitrates, when prescribed continuously or at frequent intervals, are associated with blunting of their therapeutic effects, which is known as “nitrate tolerance.”^[20] This can be resolved or decreased by providing a nitrate-free interval or declining nitrate levels at night.^[21] Therefore, a nitrate-free period of 10–12 h per day or a low nitrate level at night is generally recommended.

Beta-blockers

Beta-blockers are the first-line antianginal medications used for most patients with SCAD,^[3],[12] particularly if there is concomitant hypertension, LV systolic dysfunction, or previous history of an acute coronary event. Beta-blockers contribute to achieve the resting heart rate goal of 50–60 beats/min, and compared to CCBs, they effectively alleviate symptoms of angina and improve exercise tolerance.^[2]

Mechanism of action

Beta-blockers act by blocking β1 and β2 adrenergic receptors, thereby leading to decrease in heart rate, increase in diastolic filling time, and decrease in cardiac contractility. This negative inotropic and chronotropic effect decreases myocardial oxygen demand.^[2]

Those beta-blockers which act on β1 receptors (cardio-selective agents) minimize adverse effects, especially the bronchoconstriction that can be caused by beta 2 antagonism.^[2]

Following are the therapeutic benefits of beta-blockers in patients with SCAD:

They relieve angina symptoms and improve myocardial ischemia (because they decrease cardiac oxygen demand)^[2],[22]
When used in patients with a history of MI, acute coronary syndrome, or LV dysfunction, they reduced the risk of major adverse CV events and improved CV mortality.^[23]

Adverse effects

They include hypotension, syncope, sexual dysfunction, fatigue, exercise intolerance, insomnia, and life-threatening bradyarrhythmias.^[23]

Precautions/contraindications

They include bradycardia, atrioventricular (AV) conduction problems, sick sinus syndrome, peripheral vascular disease, and chronic obstructive pulmonary disease.

Evidence base

A meta-analysis showed that long-term use of beta-blockers resulted in a 23% reduction in the risk of death, driven mostly by a 32% reduction in the risk of sudden death.^[24] Another recent meta-analysis with 464,000 patients confirmed that beta-blockers should be the first-line therapy in patients with CAD.^[25] In the first 2 years after MI, beta-blockers double the reduction in CV events compared with all other antihypertensive agents.^[2]

Andersson et al. conducted a study to assess the benefit of beta-blockers in newly diagnosed coronary heart disease and to determine whether there was a differential effect in patients with and without incident acute MI.^[26] Of 26,793 total patients, 74% were initiated on beta-blocker treatment on discharge, 14% started beta-blockers during the 1^st year of follow-up, and 12% did not use beta-blockers during the average of 3.7-year follow-up. The unadjusted mortality rate and rate of death or acute MI were lower in patients taking beta-blockers than among those not taking beta-blockers.

Calcium channel blockers

CCB can be used as an alternative when beta-blocker cannot be used or when symptoms are not relieved with it. They result in coronary vasodilation, decrease myocardial oxygen demand, and thus, help in relieving angina symptoms. When the primary goals of treatment are quality of life, normal sexual function, and preserved exercise capacity, CCBs are preferred over beta-blockers.^[2] In addition, owing to their effect on vascular smooth muscles, CCBs are considered drugs of choice, along with nitrates, for the management of Prinzmetal's angina.

Mechanism of action

CCBs inhibit the movement of calcium through L-type slow calcium channels of cell membranes in the myocardium, cardiac conduction tissues, and vascular smooth muscle. CCBs dilate peripheral and coronary arteries and to a varying degree depress myocardial contractility and intracardiac conduction.^[2]

CCBs include dihydropyridines (DHP, e.g. nifedipine, amlodipine), benzothiazepines (e.g. diltiazem), and phenylalkylamines (e.g. verapamil).^[2] All three classes of agents have been shown to have similar antianginal effect, but the latter two classes of agents have more marked negative inotropic and chronotropic effects.

CCBs have the following therapeutic benefits in patients with SCAD:

Control heart rate and the angina symptoms (by producing coronary vasodilatation)
Decrease the peripheral vascular resistance
Reduce the risk of heart failure.^[2]

Adverse effects

They include hypotension, fatigue, edema, and dizziness.

DHP may cause reflex tachycardia, flushing, headache, and ankle swelling. Diltiazem and verapamil depress cardiac conduction and cause bradycardia. Verapamil may cause constipation.

Precautions/contraindications

All CCBs, especially non-DHP CCBs, should be used very carefully in patients with heart failure or significant LV systolic dysfunction. Non-DHP CCBs should not be prescribed to patients with AV block or those treated with a beta-blocker. DHP-CCBs, mainly the short-acting ones, should be used with caution in patients with severe aortic valve stenosis.

Evidence base

Non-DHP CCBs are indicated as the first-line agents for the treatment of SCAD, when beta-blockers are contraindicated or not tolerated (provided the CCBs themselves are also not contraindicated for the same reasons).^[3],[12] In addition, studies have shown that long-acting DHP CCBs such as nifedipine (extended-release preparations) and amlodipine have good therapeutic efficacy in relieving ischemic symptoms in patients with SCAD.^[27],[28] Amlodipine has also been shown to reduce exercise-induced symptoms more effectively than atenolol.^[29] In another study, it significantly reduced the risk of heart failure also.^[30]

A Coronary Disease Trial Investigating Outcome with Nifedipine (ACTION) trial was a study conducted on symptomatic stable chronic angina patients (n = 3825) who were ambulatory, aged >35 years with symptoms for ≥1 month.^[28] The study compared nifedipine 60 mg with the placebo. It showed that nifedipine was effective and safe for the treatment of angina, with no increase in MI or CHF. There was also a decrease in the need for coronary angiography and PCI in the individuals treated with nifedipine.^[28]

Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT) trial was conducted on symptomatic patients (n = 1997) with angiographically documented CAD and diastolic blood pressure <100 mmHg.^[31] The study group compared amlodipine 10 mg versus enalapril 20 mg versus placebo. A sub-study of 274 patients measured atherosclerosis progression by intravascular ultrasound. The study results showed decreased CV events and reduced progression of atherosclerosis with amlodipine.

Antiplatelet agents

Antiplatelet therapy is an important component of CAD management because platelet aggregation at atherothrombotic plaque sites is responsible for the development of clinically significant thrombosis and resultant MI. The most common antiplatelet agents used are aspirin and clopidogrel.

Mechanism of action

Aspirin inhibits cyclooxygenase 1 and 2, thereby reducing prostaglandin and thromboxane-A production and preventing platelet aggregation
Clopidogrel inhibits adenosine diphosphate receptors, thereby preventing platelet aggregation.^[2]

Use in SCAD

These agents are used for the following indications in patients with CAD.^[3],[12]

Aspirin

Indicated in all patients with obstructive CAD, it decreases nonfatal MI, strokes, and vascular deaths.

Clopidogrel

As a replacement for aspirin in all patients with obstructive CAD, when aspirin is contraindicated, it is used in combination with aspirin in patients with acute vascular event (coronary or cerebrovascular) during the preceding 1 year, peripheral arterial disease, or after coronary stent placement.

Adverse effects

Both aspirin and clopidogrel are associated with an increased risk of hemorrhagic events;^[2] aspirin causes more gastrointestinal bleeding than clopidogrel.

Evidence base

Various studies and guidelines have explicated the benefits of aspirin in secondary prevention of CAD.^[2] In the Antithrombotic Trialists Collaboration Study, patients with a history of MI who were treated with aspirin for a mean of 27 months had fewer nonfatal MIs, strokes, and vascular deaths.^[32] In addition to this, a meta-analysis has further demonstrated that the benefits of aspirin are similar across a dose range of 50–300 mg/day.^[33] When the patients are treated at this dose for a mean of 33.3 months, the numbers need to be treated to prevent one event are 33 for vascular death, 25 for stroke, 14 for any cause of CV death, and 12 for nonfatal MI. However, given the safety concerns with aspirin, the current guidelines recommend 75–150 mg/day dose of aspirin, because at this dose, the risk–benefit ratio appears to be the most favorable.^[3],[12]

Bhatt et al. reported that a combination of clopidogrel with aspirin was not significantly more effective than monotherapy with aspirin in reducing the rate of CV events among patients with stable CV disease or those with multiple CV risk factors; rather, it was seen that there was an increased risk of bleeding in the group taking clopidogrel.^[34] Hence, routine addition of clopidogrel to aspirin is not recommended in SCAD patients.

Statins

A large number of studies have shown that statin significantly reduces the risk of CV events in all patient populations and the overall benefit is in proportion to the baseline risk.^{[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46]} Hence, all the guidelines uniformly recommend statins for patients with SCAD.^[3],[12]

Mechanism of action

Statins inhibit 3-hydroxymethyl glutaryl coenzyme A reductase, which is responsible for the reduction in the serum low-density lipoprotein (LDL)-cholesterol level. This significantly blunts every step of atherogenesis, from plaque formation to plaque rupture, and thus reduces the risk of CV events. The statins also have anti-inflammatory, antithrombotic, and several other nonlipid effects. However, it is not clear whether these effects are also mediated through lowering of LDL-cholesterol only, with consequent suppression of inflammatory cascade. Evidence, however, seems to indicate that reduction in LDL-cholesterol is the most important and the most relevant mechanism of benefit with statins. All the major studies have consistently shown that in any patient cohort, the benefit with statins is directly proportional to the magnitude of reduction in LDL-cholesterol. For every 1 mmol/dl reduction in LDL-cholesterol, the risk of CV events is reduced by approximately 22% (relative risk reduction).^[46] A similar benefit has been observed with other nonstatin therapies also, which further supports the evolving understanding that the so-called pleiotropic effects of statins have little, if any, independent role in preventing the CV events.^[46]

Adverse effects

They include myalgia, rise in creatine kinase levels, rhabdomyolysis, derangement of liver function tests, and disturbances of glucose homeostatic with development of new-onset diabetes (estimated at 3 per 1000 patient-years with high-intensity statin therapy and 1 per 1000 patient-years with moderate-intensity statin therapy).

Clinical usage

All the current guidelines consider the patients with documented atherosclerotic CV disease (which includes patients with SCAD also) at a very high risk of adverse CV events.^{[47],[48],[49],[50]} Statin therapy is recommended in such patients to lower LDL-cholesterol to <70 mg/dl or by at least 50% from the baseline (which leads to a lower LDL-cholesterol level). High-intensity therapy (rosuvastatin 20–40 mg/d and atorvastatin 40–80 mg/d) is recommended to achieve these objectives unless contraindicated.

The Lipid Association of India has recommended a target of LDL-cholesterol <50 mg/dl in such patients.^[50],[51] This seems to be more appropriate in light of the new evidence showing further event reduction when LDL-cholesterol is lowered to such low levels.^[52]

In patients who present with an acute coronary event, immediate initiation of high-intensity therapy has been shown to produce incremental CV benefit. The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study ^[53] reported that 80 mg atorvastatin within 24–96 h after hospital admission reduced the risk of composite primary endpoint of death, MI, cardiac arrest, and recurrent ischemia by 16% compared to placebo.^[28] Once the high-intensity statin therapy is initiated, it is preferable to continue it for as long as possible unless there are any compelling reasons to reduce the dose. Aggressive lipid lowering with atorvastatin 80 mg has also been shown to be both safe and effective in reducing the excess of CV events in a high-risk population with CKD and CAD.^[54]

Newer Agents Ranolazine

Mechanism of action

Ranolazine is a cell membrane inhibitor of the late sodium current, which has a potential to prolong corrected QT (QTc) interval. Because of this unique mechanism of action, further studies with ranolazine are warranted in patients with heart failure and arrhythmias.^[55]

Ranolazine has following therapeutic benefits in patients with SCAD:^[56],[57]

Reduces the angina incidence and sublingual nitroglycerin consumption
Improves exercise tolerance in patients with SCAD
Improves endothelial function, asymmetric dimethylarginine, and C-reactive protein levels in patients with SCAD.

Adverse effects

They include dizziness, headache, constipation, and nausea.

Precautions/contraindications

Caution needs to be exercised when using with QT-prolonging agents or in the presence of significant liver disease; contraindicated with strong CYP3A4 inhibitors (ketoconazole, clarithromycin, or nelfinavir) and CYP3A inducers (rifampin and phenobarbital).^[3],[12]

Evidence base

Studies such as the Monotherapy Assessment of Ranolazine in Stable Angina (MARISA),^[58] Combination Assessment of Ranolazine in Stable Angina (CARISA),^[59] and the Efficacy of Ranolazine in Chronic Angina (ERICA)^[60] have demonstrated that ranolazine significantly reduces angina frequency and improves exercise performance in CAD patients.

Babalis et al. conducted a study on the effect of ranolazine on LV systolic and diastolic function in patients suffering from chronic stable angina.^[61] The study results showed that patients treated had better diastolic function parameters than those in the control group. Yet, another study showed that ranolazine was more effective in those with higher levels of glycosylated hemoglobin.^[62]

The ACC/AHA guideline recommends ranolazine as a substitute for beta-blockers if the latter is contraindicated or not tolerated and in combination with beta-blockers when the patients continue to remain symptomatic despite optimum dose of beta-blockers.^[12]

Ivabradine

Mechanism of action

Ivabradine inhibits the I_f (pacemaker) current in the sinoatrial node and reduces the heart rate without affecting blood pressure or LV systolic function.^[63] It increases diastolic perfusion time, improving energetics in the ischemic myocardium.^[64] Through these mechanisms, ivabradine reduces the symptoms and reduces ischemia in patients with stable angina pectoris.

Small-scale studies have also demonstrated a beneficial effect of ivabradine on coronary collateral function in patients with chronic SCAD [Table 2].^[65]

Table 2: Ivabradine versus placebo in stable coronary artery disease

Click here to view

It should be remembered that ivabradine is effective only in patients with normal sinus rhythm.

Adverse effects

They include bradycardia, blurred vision, headache, atrial fibrillation, and supraventricular tachyarrhythmias.

Its use is contraindicated in patients with severe hepatic disease. It should be used carefully in individuals >75 years of age, those with severe renal dysfunction, and those taking drugs that can prolong QTc.^[3]

Evidence base and uses

The morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left-ventricULar dysfunction (BEAUTIFUL) study ^[66] was a large-scale randomized study to assess the morbidity and mortality benefits of ivabradine in patients with SCAD. Nearly 11,000 individuals with SCAD with LV ejection fraction <40% were randomized to receive either ivabradine 5 mg twice daily (with dose titration to 7.5 mg twice daily) or a matching placebo. Ivabradine did not reduce the incidence of primary outcome (a composite of CV death, admission to hospital for acute MI, and admission to hospital for new onset or worsening heart failure), either in the whole group or in those with baseline heart rate >70 bpm. However, it reduced the risk of admission to hospital for fatal and nonfatal MI and of coronary revascularization in patients with baseline heart rate >70 bpm. Subsequently, another large study – Study Assessing the Morbidity–Mortality Benefits of the I_f Inhibitor Ivabradine in Patients with Coronary Artery Disease (CAD)^[63] – evaluated the role of ivabradine in SCAD patients without clinical heart failure. A total of 19,102 patients who had both SCAD without clinical heart failure and a heart rate of >70 bpm were randomly assigned to placebo or ivabradine, at a dose of up to 10 mg twice daily, with the dose adjusted to achieve a target heart rate of 55–60 bpm. No benefit was observed with ivabradine.

Based on these observations, ivabradine is currently recommended as a second-line agent for the management of angina in patients with SCAD with LV systolic dysfunction with resting heart rate >70 bpm. Its use may be justified even in patients with preserved LV systolic function when beta-blockers are contraindicated or not tolerated.^[3]

Trimetazidine

Mechanism of action

Trimetazidine is an anti-ischemic metabolic modulator which acts by inhibition of β-oxidation of free fatty acid and increases pyruvate dehydrogenase activity. Because of such an action, it improves the ability of the myocardium to withstand ischemia. As a result, there are reduction in angina frequency and improvement in myocardial function in patients with SCAD.^[67]

Trimetazidine is also known to compensate decreased glucose uptake and metabolism in cardiac cells which might be because of altered insulin levels or sensitivity of the cells to insulin. With the available evidence, it is postulated that trimetazidine likely has cardioprotective benefits in patients with a history of diabetes and cardiomyopathy.^[68]

Furthermore, once daily regimen was associated with higher adherence compared to multiple doses.^[67]

Contraindications

Trimetazidine should be avoided in CKD patients and the patients with movement disorders such as Parkinsonism ^{More Details}. Further, it has to be cautiously used in elderly patients.^[3]

Evidence base and uses

Trimetazidine has not been evaluated in large outcome studies in SCAD patients. However, several small studies have shown its benefit.^{[69],[70],[71]} In a placebo-controlled study, 166 stable angina patients resistant to nitrates or beta-blockers were randomized to receive either a placebo (n = 80) or trimetazidine (n = 86).^[69] After a 12-week therapy, the patients in trimetazidine group showed an increase in exercise test duration, time to 1-mm ST depression, and time to onset of anginal pain, and there was a decrease in a mean number of angina attacks per week when compared to placebo.

Another study which aimed at clinical benefits of trimetazidine in patients with recurrent angina reported excellent tolerability of the drug and recommended the same for elderly and coronary diabetic patients, especially those with impaired LV function.^[72] It was observed that trimetazidine use was associated with longer time to onset of angina (508.1 ± 132.4 vs. 433.6 ± 164 s, P = 0.031); total duration of exercise was significantly greater than that recorded for patients with placebo plus metoprolol (524.4 ± 131.5 vs. 466.9 ± 144.8, P = 0.048); and also the mean angina attacks per week were significantly reduced (1.7 ± 2.3 for patients in the trimetazidine group vs. 3.1 ± 2.9 in the placebo group).

Coronary Revascularization

Coronary artery revascularization is performed to relieve symptoms, improve quality of life, and prevent CV death. In patients with unstable CAD, the benefits from coronary revascularization are well established. However, in patients with SCAD, the benefits of revascularization, particularly survival benefit, are less well established.

Currently, the ACC/AHA guideline recommends CABG for achieving survival benefit in the following subsets of SCAD patients:^[12]

Class 1 indication:

Unprotected left main CAD (LMCAD)
Three-vessel disease with or without proximal left anterior descending (LAD) artery disease
Two-vessel disease with proximal LAD artery disease
Survivors of sudden cardiac death with presumed ischemia-mediated ventricular tachycardia.

Class IIa indication:

Two-vessel disease without proximal LAD artery disease
One-vessel proximal LAD artery disease (provide left internal mammary artery is used as the conduit).

In comparison, PCI has only Class IIb indication with uncertain benefit for most of these conditions, except the following:

Survivors of sudden cardiac death with presumed ischemia-mediated ventricular tachycardia (provided coronary anatomy is suitable for PCI) – Class I indication
Unprotected LMCAD if all the following conditions are met-low SYNTAX score of <22, ostial or trunk LMCAD, Society of Thoracic Surgeons-predicted risk of operative mortality >5% – Class IIa indication.

However, for symptomatic relief of angina, both CABG and PCI are valid options, depending on the coronary anatomy, comorbidities, and surgical versus PCI risks. The following are the indications for coronary revascularization for relief of angina:

Class I indication:

>1 significant stenoses amenable to revascularization and unacceptable angina despite OMT.

Class IIa indication:

>1 significant stenoses amenable to revascularization and unacceptable angina in whom OMT cannot be implemented because of medication contraindications, adverse effects, or patient preferences.

Among patients with previous CABG with >1 significant stenoses associated with ischemia and unacceptable angina despite OMT, PCI is preferred (Class IIa) over CABG (Class IIb).

In comparison, the ESC guideline does not specify the mode of revascularization when mentioning the indications for coronary revascularization in SCAD. As per the ESC guideline, revascularization is indicated in the following settings:^[3],[73] [Table 3]

Table 3: Indications for revascularization of stable coronary artery disease patients on optimal medical treatment

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For improving prognosis:

LMCAD with stenosis >50%
Any proximal LAD stenosis >50%
Two-vessel or three-vessel disease with stenosis >50% with impaired LV function (LV ejection fraction <40%)
Large area of ischemia (>10% of the LV myocardium)
Single remaining patent coronary artery with stenosis >50%.

All the above are Class I indications.

For relief of angina:

Any coronary stenosis >50% in the presence of limiting angina or angina equivalent, unresponsive to OMT – Class I indication.

The choice between PCI and CABG is dictated by the coronary anatomy, comorbidities, and the surgical risk.

Diabetes mellitus warrants specific mention, in view of the results of some recent landmark trials, particularly the Future REvascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multi-vessel Disease (FREEDOM) trial.^[74] The current evidence suggests that among patients with diabetes mellitus with multivessel CAD who needs coronary revascularization, CABG is associated with better long-term outcomes as compared to PCI. The difference is driven mainly by the greater need of repeat revascularization among patients undergoing PCI initially.

Role of Percutaneous Coronary Intervention in the Management of Stable Coronary Artery Disease

It is evident from the above discussion that routine PCI in all patients with SCAD is not indicated. However, in clinical practice, given the relatively low procedural risks associated with PCI, PCI is often recommended to a large majority of the patients with SCAD, many of whom may not require any form of coronary revascularization. Hence, the subsequent section aims to put the role of PCI in SCAD in perspective.

Based on the current evidence, following are the circumstances in which PCI is indicated in patients with SCAD:

Persistent lifestyle-disabling anginal symptoms despite maximal medical therapy
Substantial ischemia on cardiac stress testing, such as significant ST-segment changes and hypotensive response during early stages
Presence of >10% reversible ischemic myocardium on nuclear stress perfusion imaging or a corresponding area of jeopardized myocardium on other forms of cardiac stress testing (e.g., stress echocardiography)
Refractory anginal symptoms despite medical therapy and hemodynamically significant coronary stenosis with positive fractional flow reserve (FFR) testing (≤0.80) during cardiac catheterization.^[75]

There are several reasons why PCI is not universally superior to OMT in patients with SCAD [Figure 1] and [Figure 2]. These include (1) a large proportion of acute coronary events are caused by nonstenotic lesions, not addressed by PCI, (2) PCI does not prevent progression of other coronary lesions or development of new lesions, (3) unlike CABG, PCI provides protection only against the lesion treated and not against the vessel treated, and (4) PCI associated with the risk of procedural complications as well as that of subacute thrombosis and restenosis.

Figure 1: Primary and secondary outcomes in the PCI and medical therapy groups in the COURAGE trial. COURAGE- Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation; PCI- percutaneous coronary intervention. Based on data from- 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(15):1503–1516.

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Figure 2: Kaplan–Meier Curves for the primary endpoint, according to the intention-to-treat analysis. PCI- percutaneous coronary intervention Modified from- Blumenthal RS, Cohn G and Schulman SP. Medical therapy versus coronary angioplasty in stable coronary artery disease: a critical review of the literature. J Am Coll Cardiol. 2000;36(3):668–673.

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Studies Comparing Optimal Medical Therapy Versus Percutaneous Coronary Intervention in Stable Coronary Artery Disease

A number of studies have compared PCI with OMT alone in patients with SCAD.

Boden et al. conducted the famous Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial.^[76] It was a randomized trial involving 2287 patients who had objective evidence of myocardial ischemia and significant CAD. The study found that as an initial management strategy in patients with SCAD, PCI did not reduce the risk of death, MI, or other major CV events when added to OMT [Figure 1]. Although compared to OMT, PCI provided greater relief from angina, the incremental benefit diminished over time. The authors concluded that as an initial treatment strategy, OMT without routine PCI could be implemented safely in vast majority of patients with SCAD.

In the Atorvastatin Versus Revascularization Treatment (AVERT) trial,^[77] an 18-month, open-label, multicenter trial, the SCAD patients with one- or two-vessel CAD were arbitrarily divided to receive aggressive lipid-lowering therapy with atorvastatin 80 mg/day or PCI. Atorvastatin group when compared to PCI group had significantly lower total cholesterol, LDL-cholesterol (77 vs. 119 mg/dL), and triglycerides. Aggressive lipid lowering with a statin was found to be at least as effective as PCI in minimizing the number of ischemic events in the study participants.^[47]

The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) study was a randomized trial which was conducted in 2368 patients with both type 2 diabetes and CAD.^[78] Participants were randomized to revascularization with intensive medical therapy or intensive medical therapy alone and to undergo either insulin-sensitization or insulin-provision therapy. The survival rate was 88.3% among patients in the revascularization group and 87.8% among patients in the medical therapy group for a 5-year period (P = 0.97). Furthermore, in the PCI stratum, there was no significant difference between revascularization and the medical therapy with respect to the composite primary endpoint of death rate from any cause, MI, or stroke. In comparison, CABG reduced the risk of major CV events, when compared to medical therapy alone.

Angioplasty Compared To Medicine - 2 (ACME 2) trial was conducted in 101 patients where PCI versus medical therapy was assessed in double-vessel CAD patients.^[79] PCI and medically treated groups showed comparable results with respect to improvement in exercise duration, time to onset of angina, frequency of angina, thallium perfusion scores, quality-of-life scores, number of deaths, and MIs. When added to medical therapy, PCI did not reduce the rate of death or major CV events.^[47]

The FFR versus Angiography for Multivessel Evaluation - 2 (FAME 2) trial evaluated whether revascularization guided by functional significance of the coronary lesions could lead to better outcomes as compared to OMT alone. The trial recruited 1220 patients, out of whom 888 patients with at least one functionally significant (FFR <0.8) coronary stenosis (>50% anatomic severity) were randomized to receive either OMT alone or OMT plus FFR-guided PCI with drug-eluting stents. The primary endpoint was a composite of death, MI, or urgent revascularization. The recruitment was halted prematurely after enrollment of 1220 patients because of a significant difference in the incidence of primary endpoint in the two groups – 4.3% in the PCI group and 12.7% in the medical therapy group (hazard ratio with PCI – 0.32; 95% [confidence interval (CI) 0.19–0.53; P<.001). However, the difference was primarily because of the greater need for urgent revascularization in the OMT alone group, without any significant difference in death or MI. In patients without ischemia, the outcome appeared to be favorable with OMT alone.

More recently, a unique trial – The Objective Randomised Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina (ORBITA) – was published.^[80] The trial was based on the premise that in the previous studies comparing PCI versus OMT, some of the symptomatic benefits observed with PCI could have resulted from the placebo effect of the procedure. Hence, this trial was conducted to eliminate this placebo effect by comparing PCI with a sham procedure. A total of 230 patients with symptomatic severe single-vessel CAD were enrolled into the study. After the initial 6-week phase of medical optimization, 200 patients underwent randomization to undergo either PCI or a sham procedure. Most of the lesions (69%) were in the LAD artery and the mean area of stenosis was 84.4 ± 10.2% with a mean FFR of 0.69 ± 0.16. In the PCI arm, all patients received drug-eluting stents. It was found that at 6 weeks after the procedure, there was no significant difference in the primary endpoint of exercise time increment between the two groups. Most of the secondary endpoints, including time to 1-mm ST depression, peak oxygen uptake, Duke treadmill score, functional class, and angina frequency also did not show any differential change between the two groups. Only advantage with PCI was a greater improvement in dobutamine-induced wall motion score index (from 1.11 before randomization to 1.03 at 6-week follow-up) as compared to the sham procedure arm (from 1.11 to 1.13).

In yet another recent cohort study,^[81] Furtado et al. evaluated clinical outcomes in 560 patients with SCAD who were either treated initially with OMT alone (n = 288) or were subjected to revascularization (PCI, n = 159 and CABG, n = 113) procedures. Primary endpoints were overall mortality and combined events of death, acute coronary syndrome, and stroke. Mortality rate were 11.1% with OMT, 11.9% in PCI, and 15.9% in CABG patients, with no statistical difference. The combined outcomes occurred more often among patients initially submitted to PCI compared to OMT (hazard ratio 1.50, 95% CI 1.05–2.14) and did not differ between OMT and CABG patients (hazard ratio 1.24, 95% CI 0.84–1.83). Among patients with diabetes (n = 198), PCI was the only therapeutic strategy predictive of combined outcomes as it was associated with greater risk of adverse events (hazard ratio 2.14; 95% CI 1.25–3.63).

Pursnani et al. carried out a systematic review and meta-analysis of 12 randomized clinical trials which aimed to establish whether PCI lessened the CV outcomes in comparison to OMT in patients with SCAD.^[10] Only those studies were included in the analysis that had defined SCAD by either coronary angiography or a positive stress test, compared PCI versus OMT, and had described at least one of the following outcomes – all-cause mortality, CV death, nonfatal MI, revascularization, or freedom from angina. Studies involving patients with acute coronary syndrome during the 1 week before the onset of trial and those which included CABG as revascularization were excluded.^[9] The results showed that PCI had no significant improvement in mortality (relative risk 0.85; 95% CI 0.71–1.01), cardiac death (relative risk 0.71; 95% CI 0.47–1.06), nonfatal MI (relative risk 0.93; 95% CI 0.70–1.24), or repeat revascularization (relative risk 0.93; 95% CI 0.76–1.14). PCI, however, provided a greater angina relief compared with OMT alone.

Stergiopoulos and Brown performed a systematic review and meta-analysis of eight randomized clinical trials with an objective to compare initial coronary stent implantation with medical therapy and to determine the effect on death, nonfatal MI, unplanned revascularization, and persistent angina.^[82] The study included were those which were prospective, randomized trials of PCI + OMT versus OMT (aspirin, beta-blockers, ACE-I, and statins) alone in patients with SCAD (who were followed up for a minimum period of 1 year) and stent implantation had to exceed 50% of PCI procedures. The following were the main conclusions:

No significant differences in both the groups in the point estimates for death, unplanned revascularization, and freedom from angina between the studies of stable post-MI patients and the studies that randomized patients with angina or ischemia
The odds ratio for nonfatal MI for stent placement compared with medical therapy was 1.49 (95% CI, 1.00–2.21) (P = 0.05) in the post-MI studies compared with 1.04 (95% CI, 0.84–1.28) (P = 0.73) in stable angina/ischemia trials
OMT could be recommended as the initial therapy in SCAD patients than PCI.

Thus, it is apparent that from the above randomized and meta-analytical studies, routine PCI has no incremental benefit over OMT as the initial treatment strategy in patients with SCAD. With OMT, the symptoms of SCAD can be improved substantially. OMT should be prescribed to all patients with SCAD unless it is not tolerated or contraindicated. Monitoring and optimization along with individualization of drug treatment should be considered. PCI is recommended in patients who have hemodynamically significant lesion and who remain symptomatic despite OMT.

Financial support and sponsorship

This publication was funded by Abbott Healthcare Pvt Ltd.

Conflicts of interest

There are no conflicts of interest.

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