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Refractory angina

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Number 72 - March 2017

Heart and Metabolism


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Mario Marzilli, MD, PhD, Italy

Luis Henrique W. Gowdak, MD, PhD, BrazilDerek J. Hausenloy, PhD, UKGary D. Lopaschuk, PhD, CanadaMichael Marber, MB (BS), PhD, UK

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Heart and Metabolism is a journal published three times a year, focusing on the management of cardiovascular diseases. Its aim is to inform cardiologists and other specialists about the newest findings on the role of metabolism in cardiac disease and to explore their potential clinical implications. Each issue includes an editorial, followed by articles on a key topic. Experts in the field explain the metabolic consequences of cardiac disease and the multiple potential targets for phar-macotherapy in ischemic and nonischemic heart disease.

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Contents

EDITORIALLiving with pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2L. H. W. Gowdak

ORIGINAL ARTICLESRefractory angina or inappropriate antianginal therapy? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4A. Huqi, M. Marzilli

Prevalence of refractory angina in clinical practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9L. H. W. Gowdak

Prognostic implications of refractory angina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13P. G. Steg

Nonpharmacological approaches to refractory angina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18R. Cheng, T. D. Henry

Clinical benefits of treating angina directly at the cardiac cell level with trimetazidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25I. Milinković, A. J. Coats, G. Rosano, Y. Lopatin, P. M. Seferović

CASE REPORT The role of optimal medical therapy in patients with refractory angina . . . . . . . . . . . . . . . . . . . . . . . . . . . 32L. H. W. Gowdak

REFRESHER CORNEREstimating ischemic burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37V. Agarwal, M. F. Di Carli

HOT TOPICSErrare humanum est, perseverare autem diabolicum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44A. Huqi

GLOSSARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47G. D. Lopaschuk

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Heart Metab. (2017) 72:2-3Editorial - luis Henrique Wolff GoWdak

In this issue of Heart & Metabolism, our attention is focused on the challenging clinical condition of refractory angina. William Heberden’s classic

description of angina pectoris was first presented to the Royal College of Physicians in 1768 and a few years later published in the Medical Transactions of the College. Although receiving praise for his detailed description of the symptoms accompany-ing the natural history of patients with exertional angina, Heberden humbly acknowledged that “with respect to the treatment of this complaint, I have little or nothing to advance.” Exactly two and a half centuries later, we are awed by the great develop-ments we have witnessed in the treatment of patients with stable angina, ranging from effective antianginal drugs to revascularization procedures (percutane-ous or surgical). But despite all the advances, we are occasionally faced with a patient with disabling symptoms related to myocardial ischemia and who becomes unresponsive after an initial course of medi-cal therapy. To make things worse, because of the anatomical complexity of the disease, including the diffuseness of the obstructive lesions, or because the patient is considered high risk, the Heart Team deems that revascularization is unsuitable, and the patient is said to have refractory angina. What happens then? The articles in this issue will give the reader a broader, updated, and (hopefully) uplifting perspective on the topic. We start our journey questioning the definition of refractory angina in light of what is known regarding the multiple pathophysiological mechanisms involved in angina or myocardial ischemia. After reading the article by Dr Huqi and Prof Marzilli, it becomes clear that one must first understand the underlying mecha-nism responsible for the clinical manifestations of any

disorder in order to propose an adequate therapeu-tic strategy. In the setting of stable angina, failing to adhere to this recommendation may lead not only to misuse of currently available pharmacological thera-pies, but also to overuse of myocardial revasculariza-tion procedures. In the end, many patients with ap-parent refractory angina may simply be undergoing inappropriate therapy. The difficulty in making a proper diagnosis of re-fractory angina may help explain the uncertainties regarding the true prevalence of refractory angina in daily clinical practice, which I discuss in a following article. Even so, the estimated incidence of patients fulfilling the criteria for refractory angina per year on both sides of the Atlantic make it clear we should be prepared for a growing population of patients with difficult-to-control symptoms. In addition to the evident impairment in quality of life that patients with refractory angina experience, persis-tent angina also has prognostic implications, as dis-cussed in the article by Prof Steg. Large, contempo-rary registries have shown that the presence of angina and/or myocardial ischemia identifies patients at higher risk for cardiovascular events, including cardiovascular death and/or myocardial infarction. Thus, our mission has been expanded, aiming to improve symptoms and to reduce the cardiovascular risk in patients with an-gina and/or ischemia. As a welcomed complement to the topic, the Refresher Corner article by Prof Di Carli and Prof Agarwal presents the many clinical tools at our disposal for estimating ischemic burden. Thanks to these tools, ischemia is no longer a dichotomous variable (present/absent), but rather a quantifiable one. The management of patients with refractory an-gina may seem, at first, to be a dead-end road, but it is not. There is, indeed, great opportunity for medical

Living with painLuis Henrique Wolff Gowdak, MD, PhD, FESCHeart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil

Correspondence: Luis Henrique Wolff Gowdak, MD, PhD, FESC, Heart Institute (InCor), University of São Paulo Medical School, Avenida Dr. Enéas de Carvalho Aguiar, 44, São Paulo, SP – 05403-000 BrazilE-mail: [email protected]

2

research to introduce new drugs and new nonphar-macological therapies for such patients. Prof Henry’s article goes through the surprisingly many options in different stages of development for clinical use in the management of patients with refractory angina. Many of these technologies are not available in all countries (eg, enhanced external counterpulsation [EECP]), and many are still in early phase clinical trials (such as cell-based therapies or the implantation of a coronary sinus reducer). Nevertheless, it is a comprehensive overview that serves as proof that patients with per-sistent angina have not been forgotten. No matter how fascinating it may be to look at so many different new technologies being devel-oped to manage a patient with persistent angina, we must bear in mind Prof Marzilli’s opening paper in this issue: how appropriate is antianginal therapy in a symptomatic patient? The paper by Prof Seferović and colleagues underscores the clinical benefit of treating angina directly at the level of the cardiac cell with trimetazidine. As an antianginal agent devoid of any significant hemodynamic effect, trimetazidine treats ischemia at the cellular level, regardless of the underlying mechanism of ischemia, rendering it an attractive option as add-on therapy. In line with Prof Marzilli’s advice, I share a clinical case in which the wise utilization of antianginal agents with different modes of action, according to their safety profile and tolerability, was of paramount importance in offering better symptom control in a patient initially referred to us as being refractory to medical therapy.

In the final article, with a provocative title written in Latin, Dr Huqi draws our attention to the long-stand-ing assumption that if there’s angina, one should find the obstruction and get rid of it. With few, but strong, arguments, she does show us that the relationship between a coronary stenosis and myocardial isch-emia is not always direct, meaning that we may have patients with angina and no obstructive coronary dis-ease, and that, conversely, we may find patients with obstructive coronary disease and no angina/isch-emia. It’s past time to rethink the “plumber theory” when treating a patient with stable angina. I run a clinical program at the Heart Institute in São Paulo, Brazil for patients with refractory angina. I lis-ten to them talking about what it is like to live with pain without any apparent perspective of relief. They live in fear and distress. They refrain from any physical effort; socialization is impaired. They have high rates of depression and anxiety. Editing this issue reminded me that just because something has never been done before, it does not mean it can’t be done. Clinical scientists are moved and touched by patients’ de-mands, and together with our colleagues from basic research, we all come together in search of a better understanding of the task at hand and, with that, so-lutions that at present are elusive. If I could reply to William Heberden on the treat-ment of patients with stable angina, I’d tell him, “With respect to the treatment of this complaint, I have so much to advance.” I hope you enjoy the reading as much as I have. L

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Heart Metab. (2017) 72:2-3 GoWdak

Living with pain

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Introduction

Cardiovascular disease remains the main de-terminant of global health and mortality. The incidence of ischemic syndromes, one of the

most relevant manifestations, increases with the oc-currence of traditional risk factors and with age. For instance, the prevalence of angina pectoris, which constitutes the most frequent clinical presentation, increases progressively among adults aged 40 years and older, ranging from 4% to more than 11%.1

Guideline-directed medical therapy (GDMT) and myocardial revascularization represent the corner-stone therapies for ischemic heart disease (IHD) pa-tients.2 Although significant advances have been reg-istered for both therapeutic strategies, large clinical trials consistently report that many patients complain with persistent symptoms and/or signs of myocardial ischemia.3-9 In some prospective studies, the propor-tion of patients with symptom persistence despite GDMT and revascularization may be as high as 25% to 35%.10,11 Given the burden of the disease and the

Refractory angina or inappropriate antianginal therapy?

Alda Huqi,1 MD, PhD and Mario Marzilli,2 MD, PhD1Cardiac Care Unit at the Santa Maria Maddalena Hospital, Volterra, Pisa, Italy2Cardiovascular Medicine Division, Pisa University Medical School, Pisa, Italy

Correspondence: Professor Mario Marzilli, Professor and Chairman, Cardiovascular Medicine Division, Pisa University Medical School, Via Paradisa, 2, 56100 Pisa, Italy

E-mail: [email protected]

AbstractIschemic heart disease (IHD) is a main determinant of global health and mortality. Despite significant advances in therapeutic options, many patients complain with persistent symptoms and/or signs of myocardial ischemia (ie, refractory angina). Main therapeutic strategies used in angina patients aim at either reducing the effects of coronary stenosis on coronary blood flow or at removing the coronary stenosis itself. However, obstructive coronary artery disease is not synonymous with IHD. Indeed, a number of other factors can precipitate myocardial ischemia, including microvascular dysfunction, focal or diffuse spasm, and altered mitochondrial metabolism. It is therefore not surprising that therapeutic strategies that target epicardial coronary stenosis are not effective in all IHD patients. When approach-ing a patient with angina, the multiple pathophysiology model should be adopted at all levels, includ-ing diagnostic and treatment strategies. Angina should be considered refractory once the underlying mechanism has been identified and the targeted treatment has failed to control symptoms. This attitude could help stratify risk and augment treatment strategies, in this way optimizing resource utilization and improving cardiovascular outcome in the individual patient. L Heart Metab. 2017;72:4-8

Keywords: CAD; guideline-directed medical therapy; persistent angina

Heart Metab. (2017) 72:4-8OriGinal Article

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Heart Metab. (2017) 72:4-8 Huqi and Marzilli


impact that angina has on quality of life and on prog-nosis,12 a better understanding of the “refractory an-gina/ischemia” phenomenon appears much needed.

Refractory angina

Refractory angina and/or ischemia can be defined as symptoms and/or signs of ischemia that are not adequately controlled with maximally tolerated GDMT and revascularization.13 GDMT includes lifestyle interventions (eg, smoking cessation), drugs for risk factor control (eg, antiplate-let therapy, cholesterol-lowering agents) and drugs aiming at controlling symptoms. In most guidelines, β-blockers (BBs) are the rec-ommended first-line treatment for symptom control. BBs inhibit the action of endogenous catecholamines (epinephrine and norepinephrine in particular) on ad-renergic receptors. Their antiangina effects are medi-ated through a reduction in ventricular inotropy, heart rate, and a decrease in the maximal velocity of myo-cardial fiber shortening, therefore keeping myocardial oxygen demand below the threshold at which angina occurs. Calcium-channel blockers (CCBs) can be used either as an alternative to or on top of BBs. CCBs are potent coronary and systemic arterial vasodila-tors that reduce blood pressure, as well as cardiac contractility. CCBs bind to and inhibit L-type calcium channels and thus reduce calcium influx into cells. In-tracellular calcium deprivation relaxes smooth muscle cells, causing vasodilation in the peripheral and coro-nary beds and increased coronary blood flow. Con-sequently, CCBs lower the frequency of angina and reduce the need for nitrates. Nitrates represent another important alternative, particularly for those patients in whom a complete

revascularization is not possible or whose symptoms are (at least in part) considered secondary to abnor-mal coronary vasomotion. Although the predominant effect of nitrates is to reduce preload—with a greater activity in venous than in arterial beds—at higher dos-es, a direct effect upon arteries also becomes evident and results in a reduction in blood pressure and after-load. These effects translate into reduced myocardial oxygen consumption and a higher threshold level be-fore angina is triggered. BBs, CCBs, and nitrates constitute the so-called traditional or hemodynamic antiangina agents. As mentioned, hemodynamic agents act by lowering rate-pressure product and/or producing systemic venodilation, thereby lowering left ventricular end-di-astolic pressure and volume and reducing myocardial wall tension. Therefore, their main action mechanism is a reduction in oxygen requirements. Drugs with alternative action mechanisms represent a second-line choice and, as such, have been given a lower class of recommendation.14 Trimetazidine acts at the mitochondrial level and exerts its action on myo-cardial ischemia independently from the precipitating mechanism. By preventing the deleterious effects of ischemia, trimetazidine maintains the contractile func-tion of the cardiac cell and reduces anginal symptoms. Ranolazine acts by blocking late sodium channels leading to the lowering of abnormally high cytosolic calcium levels. Ivabradine and nicorandil are two other agents that improve angina symptoms.15,16 Ivabradine reduces heart rate without affecting contractility and atrioventricular (AV) nodal conduction and without al-tering hemodynamics. Nicorandil increases potassium ion conductance and induces vasodilation through smooth muscle relaxation. If symptoms are not adequately controlled by GDMT with hemodynamic agents and with or without alternative agents (Table I), revascularization should be pursued in angina patients. However, none of the major international guidelines give clear indications on the time period for a drug therapy or combination to be considered “unsuccessful.” On the contrary, re-vascularization is often pursued without attempting

AbbreviationsBB: β-blocker; CAD: coronary artery disease; CCB: calcium-channel blocker; GDMT: guideline-directed medical therapy; IHD: ischemic heart disease

Hemodynamic agents Agents with alternative mode of action

β-Blockers (metoprolol, bisoprolol, carvedilol) Trimetazidine

Calcium-channel blockers (verapamil, diltiazem) Ranolazine

Nitrates (isosorbide mononitrate) Ivabradine

Nicorandil

Table I Drugs in ischemic heart disease.

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Huqi and Marzilli Heart Metab. (2017) 72:4-8Refractory angina or inappropriate antianginal therapy?

implementation and/or titration of adequate medical therapy, and less than half of patients directed to re-vascularization receive GDMT before percutaneous coronary intervention.17 Therefore, the rate of per-sistent angina despite maximally tolerated GDMT in clinical practice is not properly known.

IHD as a multifactorial disease

As mentioned, the two main therapeutic strategies used in angina patients aim at reducing the effects that a coronary stenosis produces on downstream flow (hemodynamic agents) or at removing the coro-nary stenosis itself (revascularization). This approach is based on the assumption that narrowing of the coronary artery limits resting and hyperemic coronary blood flow.18 However, several large-scale studies have shown that many patients with angina do not have obstructive coronary artery disease (CAD). On the other hand, most coronary atherosclerotic ob-structions are clinically silent.12,19,20 Indeed, the effect that a stenosis produces at the level of the down-stream coronary flow is not straightforward. Con-versely, factors other than atherosclerotic coronary obstructions, including focal or diffuse spasm of nor-mal or plaque-diseased arteries, and microvascular dysfunction due to activated platelets and/or release of constrictive, prothrombotic, and proinflammatory cytokines, can all precipitate myocardial ischemia.20,21 Moreover, likewise for a combustion engine with a perfect injection mechanism, a cardiomyocyte may still be unable to properly burn the fuel due to cellular dyshomeostasis with altered mitochondrial metabo-lism, dysfunction of extracellular matrix, barriers to oxygen transport, etc.21,22 The concept of IHD as a multifactorial disease has been endorsed by the latest edition of the European Society of Cardiology (ESC) guidelines.2 However, according to the same documents, the so-called “alternative mechanisms” are considered only after epicardial stenosis has been excluded, as if coronary atherosclerosis were to confer some sort of immu-nity versus other causes of myocardial ischemia. The frequent observation that symptoms and/or ischemia persist even after stenosis removal strongly chal-lenges this assumption. Indeed, patients with IHD are a heterogeneous group, including those in whom an epicardial stenosis is responsible for angina symp-toms, those with vasospastic angina, and those with

microvascular dysfunction, epicardial endothelial dys-function, slow coronary flow, etc.23 It is therefore not surprising that therapies that target obstructive CAD only cannot control symptoms in all IHD patients. The choice of the therapeutic strategy for control-ling angina symptoms should be based on these new concepts. Indeed, although from a pathophysiologi-cal standpoint, the role of alternative factors underly-ing angina has been fully acknowledged, little or no progress has been made in applying these new con-cepts to diagnostic and therapeutic protocols. BBs can be expected to be beneficial in patients with significant epicardial stenosis, whose symptoms are exacerbated by increased workload. Conversely, BBs can be counterproductive in patients with vaso-spastic angina; in such patients, nondihydropyridinic CCBs and nitrates have been shown to be particu-larly efficacious. Hemodynamic agents are probably neutral in oth-er patient subsets. Similarly, overrated use with im-proper selection of patients that would benefit from revascularization may have contributed to the lack of full-scale beneficial effects of angioplasty. Patients with angina and suspected IHD should undergo a thorough evaluation irrespective of the coronary angiographic results. In patients displaying obstructive CAD, the effect that the epicardial ste-nosis exerts on downstream coronary flow should be assessed. Indeed, inadequate microvascular re-modeling due to chronic low shear stress distal to the stenosis with decreased nitric oxide activity or a low perfusion pressure distally to a stenosis can negatively influence microvascular remodeling and the capacity of maximal vasodilation.24 Stenosis re-moval with coronary revascularization can reverse this effect, with angina patients obtaining symptom control. However, whether coronary microvascular dysfunction is a preexisting condition or is second-ary to chronic flow alterations and, as such, po-tentially reversible cannot be determined with the current state of knowledge. In fact, among revascu-larized patients with persistent angina, microvascu-lar dysfunction constitutes the most frequent under-lying cause. Although a number of drugs have been tested in this setting, none have produced convinc-ing results. Therefore, a patient with microvascular angina should not be labeled as a patient with re-fractory angina, but rather as a patient to whom we cannot offer appropriate therapy.

The overall unsatisfactory results of angina patients that are treated with the currently available therapeu-tic regimens have stimulated further research. Nev-ertheless, the lack of symptom control in all angina patients continues to be attributed to the inaccurate assessment of coronary plaques.25 As such, imaging modalities that assess anatomical and/or physiologi-cal relevance of epicardial coronary plaques are ab-sorbing major resources. This attitude is in line with the diagnostic and therapeutic protocols outlined in contemporary guidelines that aim at identifying and treating coronary obstructions. However, this ap-proach is in conflict with the multiple pathophysiology model for IHD and, again, explains the lack of benefit in all angina patients.

Conclusions

The inability of GDMT and revascularization to control symptoms in all patients with stable angina should not lead to an automatic labeling as “refractory an-gina.” When approaching a patient with angina, the multiple pathophysiology model should be adopted at all levels, including diagnostic and treatment strat-egies. Angina should be considered refractory once the underlying mechanism has been identified and the targeted treatment has failed to control symp-toms (eg, patients with diffuse CAD, not amenable to revascularization). On the contrary, patients with angina despite currently available therapies should be considered as “patients with angina and inappropri-ate treatment.” This attitude could help stratify risk and augment treatment strategies, in this way opti-mizing resource utilization and improving cardiovas-cular outcome in the individual patient. L

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Prevalence of refractory angina in clinical practice

Luis Henrique Wolff Gowdak, MD, PhD, FESCHeart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil

Correspondence: Luis Henrique Wolff Gowdak, MD, PhD, FESC, Heart Institute (InCor), University of São Paulo Medical School, Avenida Dr. Enéas de Carvalho Aguiar, 44, São Paulo, SP – 05403-000 Brazil


AbstractAccording to the American Heart Association, an estimated 15.5 million Americans aged 20 years and over have coronary artery disease, and 8.2 million are living with angina pectoris. Despite enormous advances in medical therapy and myocardial revascularization procedures, a growing number of patients will present with disabling symptoms due to myocardial ischemia, in whom a combination of classic anti-anginal drugs and angioplasty or bypass surgery is ineffective in providing symptom relief. Those patients are usually referred to as having refractory angina. They usually suffer from poor self-perceived health status, have significant impairments in quality of life with a high incidence of depression, and represent a burden to the health care system due to significant resource utilization, including rehospitalization. Because of the variability in defining unsuitability for revascularization and the use of different medical strategies for symptom control, and with only limited clinical data available from small, observational stud-ies, a precise estimate of the prevalence of refractory angina is not available. Nevertheless, its incidence has been estimated at between 5% and 15% of patients undergoing cardiac catheterization. Presently, the incidence of newly diagnosed patients with refractory angina in the United States is something between 50 000 to 100 000 per year. In Europe, the incidence is estimated to be at least 30 000 to 50 000 new cases per year. Because life expectancy is increasing worldwide, the number of patients who will fulfill the criteria for refractory angina is expected to increase as well. L Heart Metab. 2017;72:9-12

Keywords: optimal medical therapy; prevalence; refractory angina

According to the latest report from the American Heart Association1 based on data from the National Health and Nutrition Examination

Survey (NHANES), 2009 to 2012, an estimated 15.5 million Americans aged 20 years and over have coronary artery disease, translating to a prevalence of 7.6% for men and 5.0% for women. Based on the same document, in 2012, there were 8.2 million Americans living with angina pectoris with an esti-mated incidence of 565 000 newly diagnosed cases

each year. There is a strong association between aging and the prevalence of angina, as shown in Figure 1.1 The exact prevalence of angina in different coun-tries across the globe is challenging to determine be-cause of the lack of large-scale epidemiological stud-ies. In one of the few studies that examined this issue in 52 countries in all continents, comprising more than 210 000 participants, the prevalence of angina ranged from 2.44% in Tunisia to 23.89% in Chad.2

9

10

Despite enormous advances in medical therapy and myocardial revascularization procedures, a growing number of patients among those with stable angina pectoris struggle to cope with disabling symptoms caused by myocardial ischemia, in whom a combina-tion of classic antianginal drugs and angioplasty or bypass surgery is ineffective in providing symptom relief. Those patients are usually referred to as having refractory angina. For those patients to be labeled as “no-option” patients, a careful assessment of the relationship be-tween disabling symptoms, objective demonstrable myocardial ischemia, and unsuitability for revascular-ization must be performed (Figure 2).3 In a small study with 44 patients with refractory angina,4 the nursing diagnosis of activity intolerance was positively related to a higher Canadian Cardiovascular Society functional class and lower cardiac work during a treadmill test.

The latter element to be considered in the diag-nosis of refractory angina, the unsuitability for revas-cularization, is usually the most difficult one because it can reflect the extension of the disease, the risk profile of the patient, comorbidities, and the exper-tise of the health care providers in dealing with more complex, high-risk patients. For example, Atreya et al5 looked at predictors of medical management in patients undergoing elective coronary angiography for stable angina, and they found that the decision to proceed to percutaneous coronary intervention was largely dependent on patient and angiographic characteristics. Patients with advanced age and/or chronic kidney disease, or with distal and high-risk lesions, were more often referred for medical therapy. Another aspect concerning the refractoriness to medical therapy is how aggressive antianginal agents are being used. Usually, antianginal thera-pies include a combination of hemodynamic agents like β-blockers, calcium-channel antagonists, and long-acting nitrates, agents that are widely available. Agents with different mechanisms of action can be found in some, but not all, countries; examples in-clude trimetazidine, ivabradine, ranolazine, and nicor-andil. In 136 patients who initially received a diagno-sis of refractory angina, we have shown that intensive medical treatment with a combination of triple he-modynamic agents (β-blockers, calcium-channel an-tagonists, and long-acting nitrates) with trimetazidine and/or ivabradine was highly effective in providing an-gina relief: the number of angina attacks decreased from 7.8±9.4 to 3.8±5.1 and improvement in at least one Canadian Cardiovascular Society functional class occurred in half of those patients.6 So, a patient may be prematurely tagged as being refractory to medical therapy, even before all antianginal drugs have been used, leading to an overestimation of the number of patients with true refractory angina. One should keep in mind the concept that optimal medical therapy may be defined as the use of three or more antianginal drugs at maximally tolerated doses, including one heart rate–limiting agent and a coronary vasodilator. Patients with refractory angina usually suffer from poor self-perceived health status,7 have significant impairments in quality of life8 with a high incidence of depression,9 and represent a burden to the health care system due to significant resource utilization,10,11 including rehospitalization.12 They represent a very special subset in the spectrum of patients with angina

GoWdak Heart Metab. (2017) 72:9-12Prevalence of refractory angina in clinical practice

20-39 40-59 60-79 80+

0.2 0.30

2

4

8

6

10

12

Age (years)

WomenMen

Perc

ent o

f pop

ulat

ion

3.4

4.5

8.9

5.0

10.311.0

Cardiacpain

Myocardialischemia

Unsuitabilityfor

revascularization

Fig. 1 Prevalence of angina pectoris by age and sex (National Health and Nutrition Examination Survey, 2009-2012; National Center for Health Statistics and National Heart, Lung, and Blood Institute). Modified from reference 1: Mozaffarian et al; on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2016;133:e38-e360. © 2016, American Heart Association, Inc.

Fig. 2 Elements to be assessed in patients before they are diag-nosed with refractory angina.Modified from reference 3: Jolicoeur et al. Can J Cardiol. 2012; 28(2 suppl):S50-S59. © 2012, Elsevier.

11


Prevalence of refractory angina in clinical practice

pectoris and, although chronic myocardial ischemia could impair left ventricle contractility, the long-term left ventricular function is usually preserved in patients with refractory angina.13 Because of the variability in defining unsuitabil-ity for revascularization, the use of different medical strategies for symptom control, and the limited clini-cal data available from small, observational studies, a precise estimate of the prevalence of refractory an-gina is not available. Nevertheless, the incidence of refractory angina has been estimated at between 5% and 15% of pa-tients undergoing cardiac catheterization.14 In a study conducted more than 20 years ago, the incidence of “no-option” patients was determined to be 11.8% on the basis of coronary anatomy, myocardial perfusion defects, and symptoms.15 Presently, the incidence of newly diagnosed refractory angina in patients in the United States is something between 50 000 to 100 000 per year.15 In Europe, the incidence is estimated to be at least 30 000 to 50 000 new cases per year.14

Although the true prevalence of refractory angina, as previously discussed, is difficult to ascertain, in-vestigators agree that currently, up to 1.8 million in-dividuals from the United States and more than 500 000 Canadians are estimated to have refractory an-gina.15 In a recent study from Brazil,16 the prevalence of moderate-to-severe angina was determined from a nationwide registry of more than 60 000 individu-als. Participants were asked to answer the short ver-sion of the Rose/World Health Organization question-naire,17 translated into Portuguese and validated in another study.18 Investigators found that the overall frequency of moderate-to-severe angina was 4.2%, more common in women (5.2%) than in men (3.0%). Another difficult clinical scenario that may pres-ent itself as refractory angina relates to patients with angina in the absence of obstructive coronary artery disease at angiography and myocardial disease, now defined as type 1 coronary microvascular dysfunc-tion. There is no specific therapy for this condition, so treatment approaches often remain empiric.19 Because there is no obstructive disease, revascu-larization procedures are not indicated, and patients should be treated medically. However, despite sev-eral different combined strategies for optimization of medical therapy, a substantial number of patients may remain symptomatic. In a study by Lamendola et al,20 the resolution of symptoms was recorded dur-

ing a median follow-up of 11.5 years in 155 patients (mean age, 58.9±10 years; 40 men) with type 1 coro-nary microvascular dysfunction. Although obstructive coronary artery disease was excluded at baseline, 89 patients (57.8%) had to be readmitted to hospital because of recurrent angina, and coronary angiogra-phy had to be repeated at least once in 33 patients (21.3%). Symptom control was far from ideal; angina was considered to have improved over time in only 82 patients (52%), remained unchanged in 51 patients (33%), and got worse in 21 patients (14%), mean-ing that roughly half of patients with type 1 coronary microvascular dysfunction remained symptomatic despite treatment. Because life expectancy is increasing worldwide, cardiologists should prepare to deal with an even larger number of patients who will fulfill the criteria for refractory angina. This is only the beginning. L

REFERENCES

1. Mozaffarian D, Benjamin EJ, Go AS, et al; on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statis-tics—2016 update: a report from the American Heart Associa-tion. Circulation. 2016;133:e38-e360.

2. Liu L, Ma J, Yin X, Kelepouris E, Eisen HJ. Global variability in angina pectoris and its association with body mass index and poverty. Am J Cardiol. 2011;107(5):655-661.

3. Jolicoeur EM, Cartier R, Henry TD, et al. Patients with coronary artery disease unsuitable for revascularization: definition, gen-eral principles, and a classification. Can J Cardiol. 2012;28(2 suppl):S50-S59.

4. Rodrigues CG, de Moraes MA, Coutinho AO, Sauer JM, Kalil RA, Souza EN. Clinical comparison of patients with refractory angina with and without the nursing diagnosis of activity intol-erance. J Clin Nurs. 2012;21(23-24):3579-3582.

5. Atreya AR, Sivalingam SK, Arora S, et al. Predictors of medi-cal management in patients undergoing elective cardiac cath-eterization for chronic ischemic heart disease. Clin Cardiol. 2016;39(4):207-214.

6. Dourado LO, 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.

7. McGillion M, Arthur HM, Cook A, et al. Management of pa-tients with refractory angina: Canadian Cardiovascular So-ciety/Canadian Pain Society joint guidelines. Can J Cardiol. 2012;28(2 suppl):S20-S41.

8. Andréll P, Ekre O, Grip L, et al. Fatality, morbidity and quality of life in patients with refractory angina pectoris. Int J Cardiol. 2011;147(3):377-382.

9. Geovanini GR, Gowdak LH, Pereira AC, et al. OSA and de-pression are common and independently associated with re-fractory angina in patients with coronary artery disease. Chest. 2014;146(1):73-80.

10. Henry TD, Satran D, Hodges JS, et al. Long-term survival in patients with refractory angina. Eur Heart J. 2013;34(34):2683-2688.

11. Povsic TJ, Broderick S, Anstrom KJ, et al. Predictors of long-term clinical endpoints in patients with refractory angina. J Am

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GoWdak Heart Metab. (2017) 72:9-12Prevalence of refractory angina in clinical practice

Heart Assoc. 2015;4(2). doi:10.1161/JAHA.114.001287.12. Mentz RJ, Broderick S, Shaw LK, Chiswell K, Fiuzat M,

O’Connor CM. Persistent angina pectoris in ischaemic car-diomyopathy: increased rehospitalization and major adverse cardiac events. Eur J Heart Fail. 2014;16(8):854-860.

13. Slavich M, Maranta F, Fumero A, et al. Long-term preservation of left ventricular systolic function in patients with refractory angina pectoris and inducible myocardial ischemia on optimal medical therapy. Am J Cardiol. 2016;117(10):1558-1561.

14. Mannheimer C, Camici P, Chester MR, et al. The problem of chronic refractory angina; report from the ESC Joint Study Group on the Treatment of Refractory Angina. Eur Heart J. 2002;23(5):355-370.

15. Mukherjee D, Bhatt DL, Roe MT, Patel V, Ellis SG. Direct myo-cardial revascularization and angiogenesis – how many pa-tients might be eligible? Am J Cardiol. 1999;84(5):598-600, A8.

16. Lotufo PA, Malta DC, Szwarcwald CL, Stopa SR, Vieira ML, Bensenor IM. Prevalence of angina pectoris in the Brazilian population from the Rose questionnaire: analysis of the Na-tional Health Survey, 2013. Rev Bras Epidemiol. 2015;18(2 suppl):123-131.

17. Rose GA. The diagnosis of ischaemic heart pain and intermit-tent claudication in fields surveys. Bull World Health Organ. 1962;27:645-658.

18. Bastos MS, Lotufo PA, Whitaker AL, Bensenor IM. Validation of the short-version of Rose Angina Questionnaire in Brazil. Arq Bras Cardiol. 2012; 99(5):1056-1059.

19. Ong P, Athanasiadis A, Sechtem U. Treatment of angina pec-toris associated with coronary microvascular dysfunction. Car-diovasc Drugs Ther. 2016;30(4):351-356.

20. Lamendola P, Lanza GA, Spinelli A, et al. Long-term prog-nosis of patients with cardiac syndrome X. Int J Cardiol. 2010;140(2):197-199.

13

Angina pectoris is a common symptom of coronary artery disease (CAD) and, in the past, angina relief was the main goal of treatment,

as most antianginal agents did not affect long-term outcomes. However, over the past 40 years, the advent of myocardial revascularization dramatically changed the epidemiology of angina, both in terms of prevalence and prognostic implications; whereas angina was previously considered to be an “accept-able symptom” and treated with antianginal agents, in more recent years, the mere existence of angina despite medical therapy (and sometimes without a course of optimal antianginal therapy) has become a trigger for coronary angiography with a view to

revascularization. At the same time, due to accumu-lating evidence regarding the prognostic benefit of pharmacological therapy for stable CAD, the goals of therapy have moved toward prevention of cardiovas-cular death and acute myocardial infarction (MI).1 Given the expanding scope of percutaneous cor-onary intervention, today, the only patients who have persistent angina are typically those for whom revas-cularization is considered unsuitable either because they have undergone previous—often multiple—re-vascularization procedures or because they have severe comorbidities, left ventricular dysfunction, or very extensive and complex anatomical features of CAD.

Prognostic implications of refractory angina

Philippe Gabriel Steg, MD, FESC, FACCFrench Alliance for Cardiovascular Trials (FACT), a French Clinical Research Infrastructure (F-CRIN) Network,

University Hospital Department for Fibrosis, Inflammation, REmodeling in cardiovascular, respiratory and renal diseases (DHU FIRE), Paris, France; Paris-Diderot University, Paris, France; National Institute of Health and Medical

Research (Inserm) U1148, Paris, France; Cardiology, Bichat Hospital, Public Hospitals of Paris (AP-HP), Paris, France; Imperial College, National Heart and Lung Institute (NHLI), Royal Brompton Hospital, London, UK

Correspondence: Philippe Gabriel Steg, Département de Cardiologie, Hôpital Bichat, 46 rue Henri Huchard, 75018 Paris, France


AbstractIn the current era of widespread use of myocardial revascularization, angina has not disappeared. It is a common symptom among patients with stable coronary artery disease (affecting approximately 20% of patients) and has ominous prognostic implications in terms of subsequent risk of death and myocardial infarction. It is also associated with an increased risk of hospitalization for cardiovascular reasons and, as such, with increased costs. Refractory angina, (ie, chronic angina that cannot be controlled by a combina-tion of medical therapy, angioplasty, and bypass surgery, where the presence of reversible myocardial ischemia has been clinically established to be the cause of the symptoms) is a more limited subgroup, given the spontaneous tendency for anginal symptoms to improve over time and the existing pharmaco-logic armamentarium to treat symptoms. However, refractory angina remains associated with a sizeable long-term mortality, estimated at 20% over 5 years, and has an important impact on patients’ quality of life. L Heart Metab. 2017;72:13-17

Keywords: angina; ischemia; prognosis


14

Prognosis of patients with refractory angina

There is only limited contemporary data regarding the current prognosis of patients with stable angina and even less for those patients with refractory angina. Most studies are small or relatively old with a very large range (3% to 21%) of annual mortality reported for patients with refractory angina.2 In addition, there are several methodological issues that make it difficult to accurately and consistently assess the prognosis of patients with angina.3 First, there may be a dis-crepancy between outcomes assessed in population series (such as the Framingham study) versus those

obtained from clinical trials with highly selected par-ticipants. Furthermore, there are several definitions of angina, and though the expression “stable angina” is sometimes used to define a group of symptom-atic patients with angina, it is also sometimes used to refer to patients with established CAD, distancing it from an acute coronary syndrome, regardless of symptoms. Finally, given the marked predominance of men among patients with angina, the information regarding the prognosis of angina in women is limited. In historical series, mortality was very high; in the Framingham study, in the 1960s, 10-year mortal-ity rates in patients with angina were approximately 40% for men aged over 50 years and women aged over 60,4 quite like that of patients with a previous MI. In 1988, Swedish investigators from the Multifac-tor Primary Prevention Trial5 reported that men with angina but no previous MI had a 14.1% incidence of fatal and nonfatal coronary events during 7.3 years of follow-up; the incidence was 29.4% in men with angina and previous MI. More recently, in a series of 59 patients from the Cleveland Clinic, 1-year mor-tality was 17%.6 In a series of patients undergoing

AbbreviationsBARI-2D: Bypass Angioplasty Revascularization In-vestigation 2 Diabetes; CAD: coronary artery disease; CLARIFY: prospeCtive observational LongitudinAl RegIstry oF patients with stable coronarY artery dis-ease; MI: myocardial infarction; OPTIMIST: OPTions In Myocardial Ischemia Syndrome Therapy

Women

Coronary mortality compared withsex-speci�c general population

Lower Higher

Sex

WomenMen

WomenMen

WomenMen

WomenMen

WomenMen

Observed/expected deaths

18/3127/31

120/45356/158

587/418976/599

1630/13921064/841

775/678313/258

SMR(95% CI)

5.19 (3.08-8.20)4.14 (3.46-4.90)

2.65 (2.22-3.17)2.25 (2.03-2.50)

1.40 (1.29-1.52)1.64 (1.53-1.74)

1.17 (1.12-1.23)1.26 (1.19-1.34)

1.14 (1.07-1.23)1.21 (1.08-1.35)

P value forinteraction

0.45

0.14

0.005

0.05

0.40

Age group, y

45-54

55-64

65-74

75-84

85-89

Nitrate angina

Test-positive angina

Coronary SMR

Men

0.5 1.0 10

WomenMen

WomenMen

WomenMen

WomenMen

WomenMen

11/1120/21

55/12229/95

221/88452/242

322/187329/188

127/6474/39

12.10 (6.06-21.70) 5.63 (4.71-6.74)

4.69 (3.60-6.11)2.40 (2.11-2.73)

2.50 (2.20-2.86)1.87 (1.70-2.05)

1.72 (1.54-1.92)1.75 (1.57-1.95)

2.00 (1.68-2.37)1.93 (1.54-2.42)

0.02

<0.001

<0.001

0.83

0.87

45-54

55-64

65-74

75-84

85-89

Fig. 1 Prognosis of nitrate and test-positive angina: standardized mortality ratios for coronary heart disease, by sex, within age groups.Abbreviations: CI, confidence interval; SMR, standardized mortality ratios.After reference 9: Hemingway et al. JAMA. 2006;295:1404-1411. © 2006, American Medical Association.

steG Heart Metab. (2017) 72:13-17Prognosis of angina

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Heart Metab. (2017) 72:13-17 steG

Prognosis of angina

coronary angiography at the Duke University, mortal-ity was 38% at an average follow-up of 2.2 years in 487 patients who did not undergo revascularization.7 These figures suggest that mortality of this group may be very high and certainly higher than that of patients subjected to elective revascularization. Indeed, in an-other series from the Minneapolis Heart Institute, the mortality rate at 3 years for patients who underwent complete revascularization was lower than for those who underwent suboptimal revascularization or who were not amenable to revascularization (14.8% vs 6.6%, P=0.004, respectively).8

A large Finnish, prospective, population-based study examined coronary mortality in ambulatory patients with angina, defined either by the prescrip-tion of nitrates or by abnormal noninvasive or invasive test results.9 The age-standardized annual incidence per 100 population of all cases of angina was 2.03 in men and 1.89 in women, with a sex ratio of 1.07 (95% confidence interval, 1.06-1.09). Coronary mor-tality was highly correlated with age (Figure 1),9 but in each age group, the relative increase in mortality be-tween patients with versus those without angina was similar for men and women. In another study, angina

was present in approximately half of the patients after acute coronary syndrome, and it was associated with a marked increase in the risk of hospital admission.10

The prognostic importance of angina versus myo-cardial ischemia has been examined in several stud-ies.11,12 In the CLARIFY registry of stable CAD patients (prospeCtive observational LongitudinAl RegIstry oF patients with stable coronarY artery disease), among more than 20 000 patients who had undergone a noninvasive test for myocardial ischemia, 65% of the patients had neither angina nor evidence of myocar-dial ischemia, 15% had evidence of myocardial isch-emia but no angina, 9% had angina alone, and 11% had angina and ischemia. Angina, with or without ischemia, was clearly associated with higher rates of cardiovascular death or MI at follow-up, whereas silent ischemia was not (Figure 2).11 Interestingly, most outcome events occurred in patients with nei-ther.11 These findings are consistent with the litera-ture indicating that angina is associated with worse outcome.13,14 However, in the Heart and Soul study12 and in the BARI-2D trial (Bypass Angioplasty Revas-cularization Investigation 2 Diabetes),15 myocardial ischemia, rather than angina, appeared to be the key driver of prognosis.16

Finally, with respect to the outcome of patients with refractory angina, one of the most rigorous recent stud-ies was a single-center study (the OPTIMIST program [OPTions In Myocardial Ischemia Syndrome Therapy])

Lower risk Higher risk

CV death, nonfatal MI Ischemia only Angina only Both

CV death, MI-stroke Ischemia only Angina only Both

CV death Ischemia only Angina only Both

MI* Ischemia only Angina only Both

HR (95% CI)

0.90 (0.68-1.20)1.45 (1.08-1.95)1.75 (1.34-2.29)

0.90 (0.70-1.15)1.38 (1.06-1.80)1.57 (1.23-2.01)

0.86 (0.58-1.27)1.23 (0.80-1.89)1.89 (1.33-2.70)

0.93 (0.65-1.32)1.67 (1.18-2.35)1.66 (1.18-2.33)

P value

0.470.01<0.001

0.400.02<0.001

0.450.35<0.001

0.670.0040.004

HR (95% CI)0 2 3 41

Years since entered registry

Frac

tion

surv

ivin

g

0

1200

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

N at risk

1

1120

2

1035

3

918

4

773

5

618

6

452

7

334

8

267

9

177

10

44Fig. 2 Anginal symptoms during a noninvasive test are more prog-nostic than presence or absence of myocardial ischemia. Adjusted hazard ratios for the primary and various composite outcomes for patients with ischemia, angina, and both, relative to patients with neither angina nor ischemia. Outcomes are adjusted for age, sex, geographical region, smoking status, hypertension, dyslipidemia, and diabetes. *Indicates fatal and nonfatal.Abbreviations: CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction.After reference 11: Steg et al. JAMA Intern Med. 2014;174:1651-1659. © 2014, American Medical Association.

Fig. 3 Mortality estimation in patients with refractory angina. Kaplan-Meier survival curve in 1200 patients with refractory angina from the OPTIMIST study. The upper and lower lines represent 95% confidence intervals.Abbreviations: OPTIMIST, OPTions In Myocardial Ischemia Syndrome Therapy.After reference 2: Henry et al. Eur Heart J. 2013;34(34):2683-2688. © 2013, The Author. Published on behalf of the European Society of Cardiology.

conducted at the Minneapolis Heart Institute, which enrolled 1200 consecutive patients referred from 1996 to 2001 for refractory angina or myocardial ischemia. Most of these patients had undergone previous percu-taneous coronary intervention (74.4%), previous coro-nary artery bypass grafting (72.4%), and had had a pre-vious MI (72.6%). Overall, during a median follow-up of 5.1 years, 20.1% of the patients died, largely (71.8%) of cardiovascular causes. Kaplan-Meier analysis yielded a mortality of 3.9% at 1 year and 28.4% at 9 years (Fig-ure 3).2 The main independent predictors of all-cause mortality were age, diabetes, angina class, chronic kidney disease, left ventricular dysfunction, and con-gestive heart failure.2 These results suggest that, in the contemporary era, the actual outcome of patients with refractory angina may not be as severe as previously thought. The improvement in survival may reflect much broader use of secondary prevention and adherence to evidence-based medications (antiplatelet agents, β-blockers, statins, and renin-angiotensin antagonists), as well as aggressive risk factor modification.

Prognosis of patients with angina due to nonobstructive CAD

In most cases, angina stems from flow-limiting ste-noses in the coronary arteries. However, there may be other mechanisms for angina, with different out-comes. Patients with anginal symptoms and non-invasive evidence of myocardial ischemia in the ab-sence of obstructive epicardial CAD are referred to as having microvascular angina. Their prognosis was traditionally considered to be good,17 with long-term outcomes like those of the general population.18 However, recent studies, done largely in women, have highlighted that long-term outcomes may not be as favorable as previously thought.19-21 Another group of interest is the patient with vari-ant angina, typically corresponding to coronary artery spasm in angiographically normal coronary arteries. Whereas the acute episodes of spasm can be potential-ly lethal, the long-term outcome of these patients, once identified and treated with appropriate medical therapy, appears good, with a low long-term mortality.22

Conclusion

Despite today’s widespread use of myocardial revas-cularization, angina has not disappeared. It is a com-

mon symptom among patients with stable CAD and has ominous prognostic implications. Despite anginal symptoms’ tendency to spontaneously improve over time and the existence of a number of pharmacologic treatments for anginal symptoms, refractory angina, a more limited subgroup, is associated with sub-stantial long-term mortality—estimated at 20% over 5 years—and has an important impact on patients’ quality of life. L

REFERENCES

1. Task Force Members; 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.


3. Timmis AD, Feder G, Hemingway H. Prognosis of stable angi-na pectoris: why we need larger population studies with higher endpoint resolution. Heart. 2007;93:786-791.

4. Kannel WB, Feinleib M. Natural history of angina pectoris in the Framingham study. Am J Cardiol. 1972;29:154-163.

5. Hagman M, Whilhelmsen L, Pennert K, et al. Factors of impor-tance for prognosis in men with angina pectoris derived from a random population sample: the Multifactor Primary Prevention Trial, Gothenburg, Sweden. Am J Cardiol. 1988;61:530-535.

6. Mukherjee D, Comella K, Bhatt DL, Roe MT, Patel V, Ellis SG. Clinical outcomes of a cohort of patients eligible for therapeutic angiogenesis or transmyocardial revascularization. Am Heart J. 2001;142:72-74.

7. Kandzari DE, Lam LC, Eisenstein EL, et al. Advanced coronary artery disease: appropriate endpoints for trials of novel thera-pies. Am Heart J. 2001;142:843-851.

8. Williams B, Menon M, Satran D, et al. Patients with coronary artery disease not amenable to traditional revascularization: prevalence and 3-year mortality. Catheter Cardiovasc Interv. 2010;75:886-891.

9. Hemingway H, McCallum A, Shipley M, Manderbacka K, Mar-tikainen P, Keskimäki I. Incidence and prognostic implications of stable angina pectoris among women and men. JAMA. 2006;295:1404-1411.

10. Arnold SV, Morrow DA, Lei Y, Cohen DJ, Mahoney EM, Braunwald E, Chan PS. Economic impact of angina after an acute coronary syndrome: insights from the MERLIN-TIMI 36 trial. Circ Cardiovasc Qual Outcomes. 2009;2:344-353.

11. Steg PG, Greenlaw N, Tendera M, et al; Prospective Observa-tional Longitudinal Registry of Patients With Stable Coronary Artery Disease (CLARIFY) Investigators. Prevalence of anginal symptoms and myocardial ischemia and their effect on clinical outcomes in outpatients with stable coronary artery disease: data from the International Observational CLARIFY Registry. JAMA Intern Med. 2014;174:1651-1659.

12. Gehi AK, Ali S, Na B, Schiller NB, Whooley MA. Inducible isch-emia and the risk of recurrent cardiovascular events in outpa-tients with stable coronary heart disease: the heart and soul study. Arch Intern Med. 2008;168:1423-1428.

13. Cohn PF, Harris P, Barry WH, Rosati RA, Rosenbaum P, Wa-ternaux C. Prognostic importance of anginal symptoms in an-giographically defined coronary artery disease. Am J Cardiol. 1981;47:233-237.

14. Mozaffarian D, Bryson CL, Spertus JA, McDonell MB, Fihn

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Heart Metab. (2017) 72:13-17 steG

Prognosis of angina

SD. Anginal symptoms consistently predict total mortality among outpatients with coronary artery disease. Am Heart J. 2003;146:1015-1022.

15. Dagenais GR, Lu J, Faxon DP, et al; BARI 2D Study Group. Prognostic impact of the presence and absence of angina on mortality and cardiovascular outcomes in patients with type 2 diabetes and stable coronary artery disease: results from the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial. J Am Coll Cardiol. 2013;61:702-711.

16. Stone PH. Ischemia dictates outcome, not symptoms. J Am Coll Cardiol. 2013;61:712-713.

17. Lanza GA, Crea F. Primary coronary microvascular dysfunc-tion: clinical presentation, pathophysiology, and management. Circulation. 2010;121:2317-2325.

18. Kaski JC, Rosano GM, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA. Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study. J Am Coll Cardiol. 1995;25:807-814.

19. Jespersen L, Hvelplund A, Abildstrøm SZ, et al. Stable angina

pectoris with no obstructive coronary artery disease is asso-ciated with increased risks of major adverse cardiovascular events. Eur Heart J. 2012;33:734-744.

20. Gulati M, Cooper-DeHoff RM, McClure C, et al. Adverse car-diovascular outcomes in women with nonobstructive coronary artery disease: a report from the Women’s Ischemia Syndrome Evaluation Study and the St James Women Take Heart Proj-ect. Arch Intern Med. 2009;169:843-850.

21. Pepine CJ, Anderson RD, Sharaf BL, et al. Coronary micro-vascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia results from the National Heart, Lung and Blood Institute WISE (Women’s Ischemia Syndrome Evaluation) study. J Am Coll Cardiol. 2010;55:2825-2832.

22. Figueras J, Domingo E, Ferreira I, Lidón RM, Garcia-Dorado D. Persistent angina pectoris, cardiac mortality and myocardial infarction during a 12 year follow-up in 273 variant angina pa-tients without significant fixed coronary stenosis. Am J Cardiol. 2012;110:1249-1255.

18


Introduction

As the population ages and with improvements in outcomes for coronary artery disease (CAD), a growing number of patients experience

angina that is refractory to usual attempts at revas-cularization and medical therapy. The term refractory angina is defined as “a chronic condition caused by clinically established reversible myocardial ischemia in the presence of CAD, which cannot be adequately controlled by a combination of medical therapy,

angioplasty or coronary artery bypass graft,” and as a “debilitating disease characterized by severe, unremitting cardiac pain, resistant to all conventional treatments for [CAD]”.1,2

Epidemiology and natural history

Refractory angina is increasing in frequency, with an-giography revealing an estimated 10% to 15% of pa-tients with CAD that is not amenable to revasculariza-tion, resulting in an estimated prevalence of 1.8 million

Nonpharmacological approaches to refractory angina

Richard Cheng, MD; Timothy D. Henry, MDCedars-Sinai Heart Institute, Los Angeles, California, USA

Correspondence: Timothy D. Henry, MD, Cedars-Sinai Heart Institute, 127 S. San Vicente Boulevard, Suite A3100, Los Angeles, California 90048, USA


AbstractAn increasing number of patients have advanced coronary artery disease with ischemic symptoms that are refractory to medical therapy and revascularization. With the increasing adoption of percutaneous revascularization of chronic total occlusions, previously nonrevascularizable vessels may now be targets for revascularization, which may change the landscape of refractory angina. Several nonpharmacological approaches to refractory angina have emerged, including novel interventional, noninvasive, neuromodula-tory, and angiogenic approaches. Enhanced external counterpulsation remains the mainstay of noninva-sive therapy, increasing time to exercise-induced ischemia and reducing frequency of angina episodes. Cardiac shockwave therapy is a promising noninvasive therapy, but randomized data remain limited. Neuromodulatory approaches include spinal cord stimulation, which has demonstrated a reduction in frequency of angina episodes; however, randomized, double-blind clinical trials have yielded conflicting results. Cell-based therapies have shown a reduction in angina and an improvement in exercise tolerance, but advancement of such therapies awaits adequately powered phase 3 trials. Coronary sinus reduction is a novel interventional approach in which an hourglass-shaped device is implanted in the coronary sinus, creating a narrowing that increases upstream pressure, relieving angina. The recently reported COSIRA phase 2 randomized trial showed improvements in angina class and quality of life metrics, setting the stage for a larger definitive trial. In summary, novel nonpharmacological therapies are emerging as promis-ing options for the growing population of formerly “no-option” patients. L Heart Metab. 2017;72:18-24

Keywords: enhanced external counterpulsation; neuromodulation; PCI; refractory angina

19

Heart Metab. (2017) 72:18-24 cHenG and Henry


patients in the United States alone.2-4 Potential mech-anisms behind anginal pain are summarized in Figure 1.5 Historically, survival was reported to be poor.6 Out-comes from a contemporary cohort at a specialized refractory angina clinic in the United States are more optimistic, with 1-year and 9-year survival of 96.1% and 71.6%, respectively, highlighting the importance of aggressive risk factor modification, antiplatelet therapy, and the use of novel therapies.7

Revascularization

Stable ischemic heart disease guidelines recommend revascularization for obstructive CAD to improve symptoms that are persistent despite maximally tol-erated goal-directed medical therapy (GDMT) and also for select anatomical subsets in asymptomatic patients to improve prognosis.1,8 With the increasing adoption of percutaneous revascularization (ie, per-cutaneous coronary intervention [PCI]) of chronic total occlusions (CTO) leading to increasing success rates and safety, previously nonrevascularizable vessels are

now intervenable, which may change the landscape of refractory angina management. However, random-ized controlled trials (RCTs) are still needed.9,10

Guideline-directed medical therapy and pharmacological approaches

β-Blockers, calcium-channel blockers, and long-act-ing nitrates are mainstays of GDMT,1,8 although their ability to demonstrably reduce ischemic burden is limited. These agents improve symptoms by reducing heart rate, blood pressure, and myocardial contractil-ity, but are often limited by a patient’s ability to toler-ate them. Ranolazine has recently been approved in the United States and appears to decrease angina in refractory angina patients.10 The pathophysiology

AbbreviationsACC: American College of Cardiology; ACT-34: Autologous CD34+ cell Therapy; AHA: American Heart Association; CAD: coronary artery disease; CCS: Canadian Cardiovascular Society; COSIRA: COronary SInus Reducer for treatment of refractory Angina; CSWT: cardiac shockwave therapy; CTO: chronic total occlusion; DIRECT: DIrect myocardial laser revascu-larization (DMR) in Regeneration of Endomyocardial Channels Trial; EARL: European Angina Registry Link; EECP: enhanced external counterpulsation; ESC: European Society of Cardiology; MACE: major adverse cardiac events; MUST-EECP: MUlticenter STudy of Enhanced External Counterpulsation; PCI: percuta-neous coronary intervention; PMLR: percutaneous myocardial laser revascularization; QOL: quality of life; RASCAL: Effectiveness and Cost-Effectiveness of Spinal Cord Stimulation for Refractory Angina; RCT: random-ized controlled trial; RENEW: Efficacy and Safety of Intramyocardial Autologous CD34+ Cell Administration in Patients With Refractory Angina; SCS: spinal cord stimulation; STARTSTIM: Stimulation Therapy for Angina RefracTory to Standard Treatments, Interventions, and Medications; TMLR: transmyocardial laser revascularization

Fig. 1 Potential mechanisms for refractory angina extend beyond epicardial coronary artery disease (CAD)—the tip of the iceberg—to microvascular dysfunction and vasospastic angina. Neurogenic, psychogenic, and mitochondrial dysfunction may further drive angina and may be potential targets for intervention.Reproduced from reference 5: Jolicoeur EM and Henry TJ. Refractory angina. In: de Lemos J and Omland T, eds. Chronic Coronary Artery Disease: A Companion to Braunwald’s Heart Disease. Elsevier Health Sciences; 2017:412-432. © 2017 Elsevier.

and clinical efficacy of established and novel pharma-cological approaches to refractory angina have been previously summarized.5,10,11

Chronic total occlusions

CTO are occluded or near-occluded coronary block-ages lasting at least 3 months. Their corresponding myocardium may be supplied by collaterals, leading to jeopardized but viable myocardium, with resultant ischemic pain. However, the occlusion may be calci-fied and/or have anatomy not amenable to traditional antegrade approaches. Advances in CTO PCI, in-cluding CTO-specific equipment and retrograde ap-proaches have increased procedural success, and a recent meta-analysis of 25 nonrandomized stud-ies and 24 486 patients suggested successful CTO PCI to be associated with lower mortality, lower risk of stroke, less need for subsequent coronary artery bypass grafting, and lower risk for major adverse car-diac events (MACE) than unsuccessful CTO PCI.9 In nine studies reporting on angina, there was less re-sidual angina (odds ratio, 0.38; 95% confidence inter-val, 0.24-0.60).9 A smaller study at a single institution with propensity matching did not replicate the mortal-ity benefit seen in the unmatched pooled study,12 and randomized data is needed. Nonpharmacological ap-proaches to refractory angina, including CTO PCI, are summarized in Table I. European Society of Cardiology (ESC) guidelines recommend that PCI may be considered in patients with “expected ischemia reduction in a correspond-ing myocardial territory and/or angina relief.”1

Noninvasive approaches to refractory angina

Enhanced external counterpulsation

A mainstay of noninvasive therapy, enhanced exter-nal counterpulsation (EECP) utilizes pneumatic cuffs around the lower extremities; the cuffs inflate during diastole, augmenting coronary blood flow, and deflate during systole, decreasing afterload. The landmark trial MUST-EECP (MUlticenter STudy of Enhanced Exter-nal Counterpulsation) randomized 139 patients with refractory angina to 35 hours of active versus inac-tive counterpulsation. Time to exercise-induced ST-segment depression was increased, and angina was less frequent in the active counterpulsation group13; re-

sults supported by a meta-analysis of 18 nonrandom-ized studies including 1768 patients showed 85% of patients who underwent EECP had a reduction of at least one Canadian Cardiovascular Society (CCS) an-gina class.14 The anti-ischemic mechanistic benefits of EECP were further investigated in 42 patients random-ized to EECP versus sham treatment. EECP improved flow-mediated dilation of the brachial and femoral ar-teries and increased the endothelial-derived vasoactive agents nitric oxide and 6-keto-prostaglandin, whereas it decreased endothelin-1 and the inflammatory mark-ers tumor necrosis factor α and high-sensitivity C-re-active protein, among others.15 Moreover, in a perfu-sion stress test study of 175 patients, 83% of patients had improvement in perfusion images after a 35-hour course of EECP.16 EECP is approved and reimbursed for 35 hours over 7 weeks in the United States. American College of Cardiology (ACC) and Ameri-can Heart Association (AHA) joint guidelines rec-ommend that EECP may be considered for relief of refractory angina,8 whereas ESC guidelines recom-mend it should be considered.1,17

Cardiac shockwave therapy

Also known as extracorporeal shockwave therapy, car-diac shockwave therapy (CSWT) delivers low-energy shockwaves applied to the borders of ischemic zones under ultrasound guidance, creating mechanical stress, which may promote neovascularization. Although there have been several small RCTs, they have been limited by small sample size and lack of consistent use of sham control. In a recent meta-analysis of a mixture of ran-domized and nonrandomized trials, CSWT was asso-ciated with improvements in CCS angina class, quality of life (QOL) metrics, nitroglycerin dosage, New York Heart Association functional class, left ventricular ejec-tion fraction, 6-minute walk test (6MWT), left ventricular (LV) end diastolic dimensions, and myocardial viability.18 However, there was significant heterogeneity across tri-als highlighting the need for more randomized data.

Neuromodulatory approaches to refractory angina

Patients with a prominent neurogenic component to their cardiac pain may benefit from neuromodulation, which uses chemical, mechanical, or electrical means to interrupt pain signals, with therapies ranging from noninvasive to invasive approaches.5,10

20

cHenG and Henry Heart Metab. (2017) 72:18-24Nonpharmacological approaches to refractory angina



21

Transcutaneous electrical nerve stimulation

Low-voltage electrical currents are administered through electrodes placed on pain points and can be used to ameliorate angina before taking more de-finitive approaches. ESC guidelines recommend that transcutaneous electrical nerve stimulation may be

considered for refractory angina, though acknowl-edging the evidence is very limited.17

Spinal cord stimulation

In cardiac spinal cord stimulation (SCS), a multipolar electrode is implanted in the epidural space at the

Indication Reported benefits Guidelines Future directions

PCI of chronic total occlusions

CAD; evidence of ischemia in corresponding myocardial territory; angina

↑ Survival↓ Stroke↓ CABG↓ MACE↓ Angina

• ESC 2013: IIb, B • Randomized trials ongoing in DECISION-CTO, EURO-CTO

Enhanced external counterpulsation

CAD; refractory angina

↑ Time to exercise-induced ischemia*↓ Angina*↓ Nitroglycerin use*↑ Flow-mediated dilation*↑ Endothelial-derived

vasoactive agent profile*↓ Inflammatory markers*↓ Perfusion defect

• ACC/AHA 2012/2014: IIb, B

• ESC 2013: IIa, B• CCS 2012: may be

considered, weak, low-quality evidence

• Approved and reimbursed for 35 h over 7 weeks in the United States and parts of Europe

Cardiac shockwave therapy

CAD; ischemic heart disease; refractory angina

↓ Angina*↑ LVEF*↑ 6MWT*↓ Perfusion defect*

- • Further randomized data needed

Transcutaneous electrical nerve stimulation

Angina ↓ Angina • ESC 2013: IIb, C • Further randomized data needed

Spinal cord stimulation


↑ Exercise capacity*↑ QOL*↓ Angina↓ Nitroglycerin use

• ACC/AHA 2012: IIb, B

• ESC 2013: IIb, B• CCS 2012: may be

considered, weak, moderate-quality evidence

• STARTSTIM and RASCAL failed to fully enroll• Further randomized data needed

Transmyocardial laser revascularization


↓ Angina*↑ 30-d mortality*

• ACC/AHA 2012: IIb, B

• ESC 2013: III, A• CCS 2012: not

recommended, strong, high-quality evidence

• No further studies planned

Percutaneous myocardial laser revascularization


± Exercise duration*†± Angina*†± Perfusion imaging scores*†↑ 30-d myocardial infarction*†

• CCS 2012: may be considered, weak, moderate-quality evidence

• Negative DIRECT phase 2 study• No further studies planned

Coronary sinus reduction


↓ Angina*†↑ QOL*†↓ Perfusion defect

- • Successful COSIRA phase 2 study with sham control

Cell-based therapies CAD; refractory angina

↓ Angina*†↑ Exercise tolerance*†↓ MACE*†

- • CD34+: RENEW phase 3 trial terminated early for financial reasons,• Meta-analysis strongly positive

Table I Summary of nonpharmacological approaches to refractory angina. *Randomized data, †Sham intervention control arm includedAbbreviations: 6MWT, 6-minute walk test; ACC, American College of Cardiology; AHA, American Heart Association; CABG, coronary artery bypass grafting; CAD, coronary artery disease; CCS, Canadian Cardiovascular Society; COSIRA, COronary SInus Reducer for treatment of refractory Angina; DECISION-CTO, Drug-Eluting Stent Implantation versus Optimal Medical Treatment in Patients with Chronic Total Occlusion; ESC, European Society of Cardiology; DIRECT, DIrect myocardial laser revascularization (DMR) in Regeneration of Endomyocardial Channels Trial; EURO-CTO, European Study on the Utilization of Revascularization vs Optimal Medical Therapy for the Treatment of Chronic Total Coronary Occlusions; LVEDD, left ventricular end diastolic dimension; LVEF, left ventricular ejection fraction; MACE, major adverse cardiac events; PCI, percutaneous coronary intervention; QOL, quality of life; RASCAL, Effectiveness and Cost-Effectiveness of Spinal Cord Stimulation for Refractory Angina; RENEW, Efficacy and Safety of Intramyocardial Autologous CD34+ Cell Administration in Patients With Refractory Angina; STARTSTIM, Stimulation Therapy for Angina RefracTory to Standard Treatments, Interventions, and Medications.

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C7/T1 level near the afferent nerves. In a meta-anal-ysis of seven RCTs encompassing 270 patients with refractory angina, SCS was compared with coronary artery bypass grafting, percutaneous myocardial la-ser revascularization (PMLR), and SCS off control. As compared with SCS off control, cardiac SCS dem-onstrated improvements in exercise capacity and QOL.19 However, trial heterogeneity and lack of a usu-al care control limited their results. In a subsequently published EARL registry (European Angina Registry Link) of 235 patients, the 121 patients with implanted devices reported fewer angina episodes, reduced ni-trate use, and improved CCS angina class.20

STARTSTIM (Stimulation Therapy for Angina Re-fracTory to Standard Treatments, Interventions, and Medications), a contemporary RCT, randomized pa-tients to high-stimulation versus low-stimulation con-trol, but due to slow enrollment, the study was termi-nated early after 68 randomized patients. Although both groups saw decreases in angina episodes, the decreases were not different between groups, nor were improvements in total exercise time and time to angina onset.21 Similarly, RASCAL (Effectiveness and Cost-Effectiveness of Spinal Cord Stimulation for Refractory Angina) sought to randomize patients to SCS versus usual care but failed to meet enrollment targets. Of 29 randomized patients, there was a trend toward larger improvements in angina frequency and the 6-minute walk test in the SCS group.22

These two recent negative RCTs have dampened the enthusiasm for cardiac SCS. ACC/AHA and ESC guidelines published before such RCT results were available both recommend that SCS may be con-sidered for relief of refractory angina and, in the ESC guidelines, also for improving QOL.1,8,17

Transmyocardial laser revascularization

Although the exact mechanism behind its efficacy is unknown, transmyocardial laser revascularization (TMLR) employs high-powered carbon dioxide or xenon monochloride lasers by thoracotomy or ster-notomy to create multiple transmural channels in the LV myocardium. A recent Cochrane Review meta-analysis of seven nonblinded RCTs with 1137 pa-tients demonstrated superiority of TMLR in reducing angina by two angina classes (43.8% versus 14.8%). However, 30-day mortality by as-treated analysis was

alarmingly higher in the TMLR group (6.8%) than in the control group (0.8%).23 ACC/AHA guidelines rec-ommend that TMLR may be considered for relief of refractory angina,8 but CCS and ESC guidelines both recommend against its use, as the risks outweigh the potential benefit.1,2

An alternative delivery method using an endovas-cular catheter-based laser system showed promise in the early 2000s, and DIRECT (DIrect myocardial laser revascularization (DMR) in Regeneration of En-domyocardial Channels Trial), a phase 2 multicenter RCT, enrolled 298 patients to test the efficacy of PMLR against sham control. Exercise duration, angi-na class, and perfusion imaging scores were not dif-ferent between PMLR and sham control groups, and there was an increase in morbidity in PMLR-treated patients.24 It is not clear whether the lack of efficacy as compared with TMLR was due to differences in energy delivery, endocardial versus epicardial deliv-ery, or the removal of a placebo effect when a sham control arm was used.

Novel interventional technique

Coronary sinus reduction

The Reducer is an hourglass-shaped device that is implanted in the coronary sinus, creating a stenosis that modulates endocardial versus epicardial flow (Figure 2).5,25 At 3-year follow-up in first-in-human tri-als, the device was shown to have maintained pa-tency, and angina symptoms were reduced.26 The recently reported COSIRA (COronary SInus Reducer for treatment of refractory Angina) phase 2 trial was a double-blind, sham-controlled RCT randomizing 104 patients with CCS class III or IV refractory angina to treatment versus sham. At 6-month follow-up, im-provement of two CCS angina classes was achieved in 35% (treatment) versus 15% (sham), and improve-ment of one CCS angina class occurred in 71% ver-sus 42%.25 QOL metrics were also improved, along with improvements in perfusion imaging.25,26 A multi-center, randomized phase 3 trial (COSIRA) will begin in the United States in 2017.

Cell-based therapies

Cardiovascular cell therapy is a novel approach designed to promote neovascularization and en-


dothelial repair. A recent meta-analysis of six RCTs with 353 patients randomized in cell therapy trials showed improvements in angina episodes, use of antianginal medications, CCS angina score, exer-cise tolerance, myocardial perfusion, MACE, and arrhythmias in cell-treated patients.27 ACT-34 (Au-tologous CD34+ cell Therapy), the largest double-blind, placebo-controlled trial (N=167) included in that analysis, compared intramyocardial-delivered CD34+ cells versus placebo and demonstrated sig-nificant reduction in angina along with a significant improvement in exercise time.28,29 These results were maintained at 24 months, with a trend toward decreased MACE.29 The phase 3 RENEW trial (Ef-ficacy and Safety of Intramyocardial Autologous CD34+ Cell Administration in Patients With Refrac-tory Angina), which compared CD34+-cell injection, no intervention, or placebo injection was terminated

early, unfortunately, due to financial reasons; how-ever, it confirmed the improvements in exercise time and angina frequency seen in phase 1 and phase 2 trials.30 A definitive phase 3 trial is still needed.

Future directions and conclusions

Multiple nonpharmacological therapies are emerging as promising options for what have been previously considered “no-option” refractory angina patients. EECP remains a cornerstone noninvasive therapy; meanwhile, CTO revascularization, CSWT, and SCS require further randomized data. Moreover, novel ap-proaches in coronary sinus reduction and cell-based therapies have demonstrated promising results in rig-orously conducted double-blinded, sham-controlled randomized studies, and definitive trials are urgently needed. L

Fig. 2 Coronary sinus-reducer system (A), an hourglass-shaped metal mesh device mounted on a balloon catheter, expanded, and implanted in the coronary sinus. The vessel wall grows into the fenestrations in the metal mesh. The central orifice of the device remains patent, leading to a narrowed channel for blood flow, increased upstream pressure, and favorable coronary blood flow redistribution (B).Panel (A) reproduced from reference 25: Verheye S, Jolicoeur EM, Behan MW, et al. Efficacy of a device to narrow the coronary sinus in refractory angina. N Engl J Med. 2015;372:519-527. © 2015, Massachusetts Medical Society. Panel (B) reproduced from reference 5: Jolicoeur EM and Henry TJ. Refractory angina. In: de Lemos J and Omland T, eds. Chronic Coronary Artery Disease: A Companion to Braunwald’s Heart Disease. Elsevier Health Sciences; 2017:412-432. © 2017 Elsevier.



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2. McGillion M, Arthur HM, Cook A, et al. Management of pa-tients with refractory angina: Canadian Cardiovascular So-ciety/Canadian Pain Society joint guidelines. Can J Cardiol. 2012;28(2 suppl):S20-S41.

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8. Fihn SD, Blankenship JC, Alexander KP, et al. 2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Tho-racic Surgery, Preventive Cardiovascular Nurses Associa-tion, Society for Cardiovascular Angiography and Interven-tions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2014;64(18):1929-1949.

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12. Jaguszewski M, Ciecwierz D, Gilis-Malinowska N, et al. Suc-cessful versus unsuccessful antegrade recanalization of single chronic coronary occlusion: eight-year experience and out-comes by a propensity score ascertainment. Catheter Cardio-vasc Interv. 2015;86(2):E49-E57.

13. Arora RR, Chou TM, Jain D, et al. The MUlticenter STudy of Enhanced External CounterPulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ischemia and anginal episodes. J Am Coll Cardiol. 1999;33(7):1833-1840.

14. Zhang C, Liu X, Wang X, Wang Q, Zhang Y, Ge Z. Efficacy of enhanced external counterpulsation in patients with chron-ic refractory angina on Canadian Cardiovascular Society

(CCS) angina class: an updated meta-analysis. Medicine. 2015;94(47):e2002.

15. Braith RW, Conti CR, Nichols WW, et al. Enhanced external counterpulsation improves peripheral artery flow-mediated dilation in patients with chronic angina: a randomized sham-controlled study. Circulation. 2010;122(16):1612-1620.

16. Stys TP, Lawson WE, Hui JC, et al. Effects of enhanced exter-nal counterpulsation on stress radionuclide coronary perfusion and exercise capacity in chronic stable angina pectoris. Am J Cardiol. 2002;89(7):822-824.

17. Task Force Members; 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(38):2949-3003.

18. Wang J, Zhou C, Liu L, Pan X, Guo T. Clinical effect of car-diac shock wave therapy on patients with ischaemic heart dis-ease: a systematic review and meta-analysis. Eur J Clin Invest. 2015;45(12):1270-1285.

19. Taylor RS, De Vries J, Buchser E, Dejongste MJ. Spinal cord stimulation in the treatment of refractory angina: systematic re-view and meta-analysis of randomised controlled trials. BMC Cardiovasc Disord. 2009;9:13.

20. Andrell P, Yu W, Gersbach P, et al. Long-term effects of spi-nal cord stimulation on angina symptoms and quality of life in patients with refractory angina pectoris--results from the European Angina Registry Link Study (EARL). Heart. 2010;96(14):1132-1136.

21. Zipes DP, Svorkdal N, Berman D, et al. Spinal cord stimulation therapy for patients with refractory angina who are not candi-dates for revascularization. Neuromodulation. 2012;15(6):550-558; discussion 558-559.

22. Eldabe S, Thomson S, Duarte R, et al. The Effectiveness and Cost-Effectiveness of Spinal Cord Stimulation for Refractory Angina (RASCAL Study): a pilot randomized controlled trial. Neuromodulation. 2016;19(1):60-70.

23. Briones E, Lacalle JR, Marin-Leon I, Rueda JR. Transmyocar-dial laser revascularization versus medical therapy for refracto-ry angina. Cochrane Database Syst Rev. 2015(2):CD003712.

24. Leon MB, Kornowski R, Downey WE, et al. A blinded, random-ized, placebo-controlled trial of percutaneous laser myocardial revascularization to improve angina symptoms in patients with severe coronary disease. J Am Coll Cardiol. 2005;46(10):1812-1819.

25. Verheye S, Jolicoeur EM, Behan MW, et al. Efficacy of a de-vice to narrow the coronary sinus in refractory angina. N Engl J Med. 2015;372(6):519-527.

26. Konigstein M, Meyten N, Verheye S, Schwartz M, Banai S. Transcatheter treatment for refractory angina with the Coro-nary Sinus Reducer. EuroIntervention. 2014;9(10):1158-1164.

27. Khan AR, Farid TA, Pathan A, et al. Impact of cell therapy on myocardial perfusion and cardiovascular outcomes in patients with angina refractory to medical therapy: a systematic review and meta-analysis. Circ Res. 2016;118(6):984-993.

28. Losordo DW, Henry TD, Davidson C, et al. Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circ Res. 2011;109(4):428-436.

29. Henry TD, Schaer GL, Traverse JH, et al. Autologous CD34+ cell therapy for refractory angina: 2-year outcomes from the ACT34-CMI Study. Cell Transplant. 2016;25(9):1701-1711.

30. Povsic TJ, Henry TD, Traverse JH, et al. The RENEW trial: Ef-ficacy and Safety of Intramyocardial Autologous CD34+ Cell Administration in Patients With Refractory Angina. JACC Car-diovasc Interv. 2016;9(15):1576-1585.


24

25


Introduction

Patients presenting with symptoms of angina and/or signs of ischemia may have no visible coronary stenosis on angiography. In a large

registry of 398 978 patients undergoing elective invasive angiography, 37.6% of those without known

heart disease had no obstructive coronary artery disease (CAD).1 In addition, the analysis of 304 stable angina patients revealed normal or near normal coro-nary arteriograms in 47%.2 Acetylcholine testing trig-gered epicardial or microvascular coronary spasm, suggesting abnormal coronary vasomotion, in nearly two-thirds of these patients.3

Clinical benefits of treating angina directly at the cardiac cell level with trimetazidine

Ivan Milinković,1 MD; Andrew J. Coats,2 MD, PhD; Giuseppe Rosano,3,4 MD, PhD; Yuri Lopatin,5 MD, PhD; and Petar M. Seferović,1,6 MD, PhD

1Department of Cardiology, Clinical Center of Serbia, Belgrade, Serbia;2Monash and Warwick Universities, Coventry, UK;

3IRCCS San Raffaele, Rome, Italy; 4Cardiovascular and Cell Sciences Institute, St George’s University of London, London, UK;

5Volgograd Medical University, Cardiology Center, Volgograd, Russia; 6University of Belgrade School of Medicine, Belgrade, Serbia

Correspondence: Petar M. Seferović E-mail: [email protected]

AbstractPatients presenting with symptoms of angina and/or signs of ischemia may have no visible coronary stenosis on coronary angiography. Myocardial ischemia as a multifactorial process implies that anti-anginal management should not solely focus on large coronary vessels, but also on the microvessels and cardiac cells. Trimetazidine is an effective and well-tolerated anti-ischemic agent that provides symptom relief and functional improvement, and that offers cytoprotection during ischemia. It has anti-ischemic and antianginal effects directly on cardiac cells. The drug is suitable for use as a monotherapy and also as an adjunctive therapy when symptoms are inadequately controlled by nitrates, β-blockers, or calcium antagonists. Trimetazidine does not affect hemodynamic variables; it may improve left ventricular function in patients with chronic coronary artery disease or ischemic cardiomyopathy and in ischemia during percutaneous coronary intervention or coronary artery bypass grafting. According to the 2013 European Society of Cardiology (ESC) guidelines for the management of stable coronary artery disease, trimetazidine is indicated as a second-line treatment for angina/ischemia relief. In the 2016 ESC guidelines on diagnosis and treatment of heart failure, trimetazidine is considered for the treatment of stable angina pectoris with symptomatic heart failure with reduced ejection fraction. L Heart Metab. 2017;72:25-31

Keywords: antianginal; cardiomyocyte; trimetazidine

26

On the other hand, when coronary stenoses are documented, a wide variety in the severity of symp-toms, exercise intolerance, and stress echo test find-ings may be demonstrated.2 Long-term follow-up studies have shown that patients with coronary ste-nosis and evidence of ischemia have more adverse events, a poorer quality of life, and higher mortality than those without evidence of ischemia.4 Medical therapy is the mainstay of treatment of sta-ble angina. In the Euro Heart Survey, results from the analysis of 3779 patients with stable angina confirmed that the use of antianginal medications was similar or even greater in patients undergoing coronary revas-cularization. Only 3% of these patients received no antianginal medication, whereas 55% had two medi-cations, and an additional 20% had more than two.5 In addition, in the RITA-2 trial (second Randomized Intervention Treatment of Angina) comparing a medi-cal strategy with percutaneous coronary intervention (PCI) in patients with stable coronary disease, 5-year follow-up showed that 70% of patients with coronary angioplasty received more than one antianginal drug.6 These data indicate that in patients with stable CAD, antianginal medications are clinically justified, despite the use of myocardial revascularization procedures. Therefore, besides coronary obstruction, there are other mechanisms influencing myocardial oxygen supply and demand, resulting in ischemia. In addition to disturbances in cardiomyocyte metabolism (often deranged by comorbidities such as arterial hyperten-sion and diabetes), microparticle embolization, and micro- and macrovascular dysfunction could also be responsible for angina symptoms and ischemia. Also,

vessel stiffening, inflammation, thrombosis, and im-paired angiogenesis may play a role.3,7

Mitochondrial dysfunction and impaired energy production have been observed in various heart dis-eases. Increased amounts of fatty acid oxidized by the mitochondria in relation to carbohydrate oxidation can decrease cardiac efficiency and contribute to im-pairment of myocardial function in heart failure (HF), ischemic heart disease, and diabetic cardiomyopa-thies.8 Therefore, inhibition of mitochondrial fatty acid oxidation is a well-established target for treatment of these diseases. The recognition of myocardial ischemia as a mul-tifactorial process implies that antianginal manage-ment should not focus solely on large coronary ves-sels, but also on the microvessels and the cardiac cell. A more convenient approach would consist of a comprehensive therapeutic strategy that encompass-es all causes of ischemia. Trimetazidine, a reversible competitive inhibitor of 3-ketoacyl coenzyme A thio-lase, directly targets mitochondrial fatty acid oxidation enzymes, improves the function of failing hearts, and reduces rates of glycolysis and/or increases glucose oxidation, resulting in reduced proton levels.9

Effects of trimetazidine on clinical parameters and exercise tolerance in stable angina pectoris

According to the 2013 European Society of Cardi-ology (ESC) guidelines for the management of sta-ble CAD, the treatment of angina combines lifestyle changes and drug therapy with revascularization strategies. After initiation of optimal medical treat-ment, which includes at least one antianginal drug and drugs for event prevention, trimetazidine is indi-cated as a second-line treatment for angina/ischemia relief (class IIb, level of evidence B).10

The efficacy of oral trimetazidine, both as mono-therapy and adjunctive therapy, in patients with an-gina pectoris not sufficiently controlled by other anti-anginal agents has been evaluated in clinical trials. Trimetazidine has anti-ischemic efficacy that is similar to that of propranolol 20 mg thrice daily.11 When added to standard maintenance therapy (pro-pranolol, aspirin, and statin), trimetazidine improves angina class. This is due to a nonmechanical anti-ischemic mechanism of action, since heart rate and rate-pressure product remain unchanged in the trimetazidine group.12

AbbreviationsCABG: coronary artery bypass grafting; CAD: coro-nary artery disease; CLASSICA: the Most Effective Combination of Antianginal Drugs in the Treatment of Patients with Stable Angina; HF: heart failure; LV: left ventricular; LVEF: left ventricular ejection fraction; PCI: percutaneous coronary intervention; RITA-2: sec-ond Randomized Intervention Treatment of Angina; TACT: Trimetazidine in Angina Combination Therapy; TRIMPOL II: second TRIMetazidine in POLand study; TRIUMPH: TRImetazidine MR in patients with stable angina: Unique Metabolic PatH; VASCO: Efficacy of Trimetazidine on Functional Capacity in Symptom-atic Patients with Stable Exertional Angina

Milinković and otHers Heart Metab. (2017) 72:25-31Treating angina at the cardiac cell level: trimetazidine

27

Heart Metab. (2017) 72:25-31 Milinković and otHers Treating angina at the cardiac cell level: trimetazidine

In clinical practice, in the large prospective CLAS-SICA study (the Most Effective Combination of Anti-anginal Drugs in the Treatment of Patients with Stable Angina) cohort of 1213 angina patients, trimetazidine on top of other standard anti-ischemic therapy sig-nificantly reduced the number of angina attacks per week regardless of the baseline antianginal therapy.13

In the TRIUMPH trial (TRImetazidine MR in pa-tients with stable angina: Unique Metabolic PatH), in patients with stable angina, trimetazidine added to conventional therapy decreased the number of angi-na attacks and use of nitroglycerin tablets per week. It also lessened physical limitation and improved angina stability.14 Furthermore, in the TACT trial (Trimetazidine

Study No of pts Design Results

Vitale et al,15 2013.(VASCO trial)

645 Randomized double-blinded, placebo-controlled; symptomatic and asymptomatic patients with chronic ischemic heart disease.

Treatment with placebo or TMZ (70 mg/d and 140 mg/d) in addition to atenolol (50 mg/d); 12-week follow-up.

Total exercise duration (TMZ: 6% ± 23% vs placebo: 0.7% ± 5%; P=0.0074).

Time to 1-mm ST-segment depression (TMZ: 9.6% ± 33% vs placebo: 3% ± 16.8%; P=0.0239).

Makolkin et al,14 2004.(TRIUMPH trial)

846 Open-label, uncontrolled; stable angina patients.

Treatment with TMZ (70 mg/d) in addition to conventional therapy; 8-week follow-up.

Weekly number of angina attacks (11.2 ± 0.4 to 3.6 ± 0.2; P<0.0001).Weekly nitroglycerin use (11.9 ± 0.8 to 3.4 ± 0.2; P<0.0001).

QOL improvement (P<0.0001) for all five items: Physical limitation score (0.7 ± 0.7 to 61.0 ± 0.6).Angina stability score (57.6 ± 0.9 to 92.5 ± 0.7).Angina frequency score (33.3 ± 0.7 to 55.6 ± 0.8).Treatment satisfaction score (62.3 ± 0.7 to 77.4 ± 0.5).Disease perception score (36.7 ± 0.6 to 55.5 ± 0.7).

AE in 2.4% (22/906).

Chazov et al,16 2005.(TACT trial)

166 Randomized, placebo-controlled; stable angina patients resistant to nitrates or β-blockers.

Treatment with placebo or TMZ (60 mg/d) in addition to β-blockers or long-acting nitrates; 12-week follow-up.

Total exercise duration (417.7 ± 14.2 s to 506.8 ± 17.7 s in TMZ vs 435.3 ± 14.8 s to 458.9 ± 16.2 s in placebo; P<0.05).

Time to 1-mm ST-segment depression (389.0 ± 15.3 s to 479.6 ± 18.6 s in TMZ vs 411.8 ± 15.2 s to 428.5 ± 17.3 s in placebo; P<0.05).

Time to onset of angina (417.0 ± 16.9 s to 517.3 ± 21.0 s in TMZ vs 415.1 ± 16.5 s to 436.4 ± 18.5 s in placebo; P<0.005).

Weekly number of angina attacks (5.6 ± 0.6 to 2.7 ± 0.5 in TMZ vs 6.8 ± 0.7 to 5.1 ± 0.7 in placebo; P<0.05).

Weekly nitroglycerin use (5.2 ± 0.9 to 2.8 ± 0.8 in TMZ vs 5.5 ± 0.8 to 4.1 ± 0.9 in placebo; P=ns).

Szwed et al,17 2001.(TRIMPOL II trial)

347 Randomized, multicenter, double-blind, placebo-controlled; stable, effort-induced angina patients with documented coronary artery disease.

Treatment with placebo or TMZ (60 mg/d) in addition to metoprolol (100 mg/d), 12-week follow-up.

Time to 1-mm ST-segment depression (341 ± 114 s to 427 ± 134 s; P<0.01).

Total exercise duration (420 ± 108 s to 485 ± 122 s; P<0.05).Total work (8.43 ± 1.90 to 9.65 ± 2.22; P<0.05).Maximum ST depression (1.67 ± 0.46 mm to 1.42 ± 0.71 mm; P<0.01).Time to onset of angina (372 ± 116 s to 465 ± 124 s; P<0.01).Mean weekly number of angina attacks (4.0 ± 3.2 to 2.1 ± 2.4; P<0.01).Mean weekly nitrate consumption (2.8 ± 2.5 to 1.5 ± 1.9; P<0.05).

Angina pain intensity (Borg scale); P=ns.Rate-pressure product; P=ns.

Ruzyllo et al,18 2004.

94 Subgroup from TRIMPOL II; patients with history of revascularization for coronary artery disease and who are symptomatic after 6 months on metoprolol (100 mg/d).

Treatment with placebo or TMZ (60 mg/d) in addition to metoprolol (100 mg/d), 12-week follow-up.

Time to 1-mm ST-segment depression (385.1 s ± 144.6 s vs 465.0 s ± 143.8 s; P<0.01).

Exercise test duration (466.9 s ± 144.8 s vs 524.4 s ± 131.5 s; P=0.048).Total workload (9.0 m.e. ± 2.4 m.e vs 10.1 m.e. ± 2.4 m.e; P=0.035). Time to onset of angina (433.6 s ± 164 s vs 508.1 s ± 132.4 s; P=0.031).

Table I Trials on exercise tolerance and clinical effects of trimetazidine in stable angina pectoris. Abbreviations: AE, adverse events; ns, nonsignificant; pts, patients; QOL, quality of life; TACT, Trimetazidine in Angina Combination Therapy; TMZ, trimeta-zidine; TRIMPOL II, second TRIMetazidine in POLand study; TRIUMPH, TRImetazidine MR in patients with stable angina: Unique Metabolic PatH; VASCO, Efficacy of Trimetazidine on Functional Capacity in Symptomatic Patients with Stable Exertional Angina.

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in Angina Combination Therapy), trimetazidine com-bined with nitrates or β-blockers improved not only angina symptoms, but also stress echo parameters.16 Similar evidence comes from trials investigating the addition of trimetazidine to β-blocker monotherapy. The VASCO-angina trial (Efficacy of Trimetazidine on Functional Capacity in Symptomatic Patients with Stable Exertional Angina) gives evidence that stan-dard- and high-dose trimetazidine improves effort-induced myocardial ischemia and functional capacity in patients with chronic stable angina receiving ateno-lol.15 In the TRIMPOL II trial (second TRIMetazidine in POLand study), the combination of trimetazidine and metoprolol produced greater improvements in angina symptoms and parameters of exercise testing than metoprolol alone (Table I).17

A growing proportion of patients with stable angi-na require combined antianginal medications to con-trol symptoms. Indeed, in the subpopulation of pa-tients with a history of PCI or coronary artery bypass grafting (CABG) included in the TRIMPOL II study, trimetazidine provided antianginal efficacy in post-revascularized patients with recurrent angina despite monotherapy with metoprolol.18

A meta-analysis including 1628 patients with sta-ble angina pectoris confirmed the efficacy of trimeta-zidine as an addition to conventional antianginal agents, regardless of treatment duration.19 The ben-eficial effects were reflected in a decrease in the num-ber of angina attacks and a lower use of nitroglycerin, longer time to 1-mm ST-segment depression, higher total work, and longer exercise duration at peak ex-ercise. In the meta-analysis by Danchin et al on 19 028 patients with stable angina, trimetazidine mono-

therapy was comparable to non–heart-rate-lowering antianginal treatments, but was significantly better than placebo (Table II).20

Effects of trimetazidine on left ventricular function in stable angina pectoris and ischemic heart disease

A meta-analysis of 11 randomized clinical trials of 545 patients established the efficacy of trimetazidine as monotherapy in the treatment of stable angina pec-toris. Trimetazidine monotherapy improved left ven-tricular (LV) function compared with placebo, with an LV ejection fraction (LVEF) improvement of 6.88%, a reduction in LV end systolic volume by 11.58 mL, and a reduction in wall motion score index (WMSI) by 0.23.21

Effects of trimetazidine in patients with ischemic cardiomyopathy

In patients with ischemic cardiomyopathy, trimeta-zidine treatment has been associated not only with functional improvement and reduction in hospitaliza-tions and mortality, but also with a significant positive effect on LV remodeling.22 Trimetazidine improves LV remodeling processes, levels of natriuretic peptides and cardiac troponin, and arteriolar endothelium-de-pendent relaxation.23 Such results have been demon-strated only in ischemic, and not in nonischemic, HF patients.24,25

In the 2016 ESC guidelines on diagnosis and treatment of HF, trimetazidine is considered for the treatment of stable angina pectoris with symptomatic HF with reduced ejection fraction. It can be used to

Meta-analysis No of RCT/ No of pts

Design Results

Peng et al,19 2014.

13 / 1628 TMZ combination with antianginal drugs (β-blockers and calcium-channel blockers) vs antianginal drugs alone.

Weekly number of angina attacks (-0.95, 95% CI: -1.30 to -0.61; P<0.001).Weekly nitroglycerin use (-0.98, 95% CI: -1.44 to -0.52; P<0.001). Time to 1-mm ST-segment depression (+0.30 s, 95% CI: 0.17 to 0.43;

P<0.001).Total work (+0.82, 95% CI: 0.44 to 1.20; P<0.001). Exercise duration at peak exercise (+49.81 s, 95% CI: 15.04 to 84.57;

P<0.001).

Danchin et al,20 2011.

218 / 19 028 TMZ vs placebo.

TMZ vs non–heart-rate-lowering antianginal drugs.

Total exercise duration (+46 s, 95% CI: 28 to 66; P<0.001).Time to 1-mm ST-segment depression (+55 s, 95% CI: 35 to 77);

P<0.001).Time to onset of angina (+54 s, 95% CI: 24 to 84; P<0.001).

Weekly number of angina attacks (-0.28 s, 95% CI: -1.17 to 0.64; P=ns).Total exercise duration (+7 s, 95% CI: 12 to 28; P=ns).Time to 1-mm ST-segment depression (-1 s, 95% CI: -23 to 22; P=ns).Time to onset of angina (+8 s, 95% CI: -22 to 40; P=ns).

Table II Meta-analysis of randomized controlled trials on exercise tolerance and clinical effects of trimetazidine in stable angina pectoris. Abbreviations: CI, confidence interval; ns, nonsignificant; pts, patients; RCT, randomized controlled trials; TMZ, trimetazidine.

29


relieve angina in patients with persistent symptoms despite treatment with a β-blocker (or alternative) (class IIb, level of evidence A).26 This recommendation is based on drug effects to improve functional capac-ity, exercise duration, and LV function in patients with HF with reduced ejection fraction. Patients with diabetic cardiomyopathy have im-paired myocardial glucose handling and a more distal distribution of coronary atherosclerosis. Trimetazidine not only improves myocardial glucose utilization, but also the levels of glycated hemoglobin (HbA1c) and glycemia, and it increases forearm glucose uptake.27 In addition, in diabetic patients with ischemic heart disease, trimetazidine added to standard medical therapy has a beneficial effect on LV volumes and LVEF compared with placebo.28

Effects of trimetazidine in patients undergoing revascularization procedures

Elderly patients have an increased incidence of isch-emic dilated cardiomyopathy, often related to diffuse CAD. Adjunctive therapy with trimetazidine, added on to standard care, improves reverse remodeling and quality of life in these patients.29 The addition

of trimetazidine to standard care therapy in elderly patients with diabetes mellitus and multivessel CAD after drug-eluting stent implantation can have a ben-eficial effect on recurrent angina pectoris, as well as on LV function and structure.30

Furthermore, trimetazidine reduces the incidence of stent restenosis and major adverse cardiac and cerebrovascular events in patients undergoing PCI (Table III).31

There is some evidence of a positive effect of trimetazidine on myocardial preservation in CABG patients. In a meta-analysis of six trials including 505 patients, preoperative trimetazidine therapy appeared to reduce ischemia-reperfusion injury during and after CABG.32

Conclusions

Trimetazidine is an effective and well-tolerated anti-ischemic agent, which—in addition to providing symptom relief and functional improvement in pa-tients with angina pectoris—has a cytoprotective action during ischemia. It has anti-ischemic and an-tianginal effects directly at the cardiac cell level, by optimizing adenosine triphosphate (ATP) use and

Study No of pts Design Results

Xu et al,30 2014. 700 Single-center, prospective, randomized, double-blind; elderly (aged 68.94 ± 3.54 years) multivessel CHD patients with DM undergoing coronary angiography.

Treatment with placebo or TMZ (60 mg/d) in addition to conventional CHD treatment after DES implantation; 2-year follow-up.

LVEF (66.07% ± 4.04% vs 61.94% ± 3.05%; P<0.01).LVEDD (48.07 ± 4.43 mm vs 51.25 ± 3.57 mm; P<0.01).LVESD (30.81 ± 4.27 mm vs 33.48 ± 3.02 mm; P<0.01).

Recurrent angina pectoris, n (%): 102 (40.4) vs 130 (51.0); P=0.010.

Angina pectoris, n (%): 72 (28.2) vs 96 (37.6); P=0.024.Silent myocardial ischemia, n (%): 88 (34.5) vs 117 (45.9);

P=0.009.

Vitale et al,29 2004.

47 Randomized, controlled. Treatment with TMZ vs placebo, (mean

age 78 ± 3 years); 6-month follow-up.

LVEF (34.4% ± 2.3% vs 27% ± 2.8%; P<0.0001).LVEDD (58.6 ± 1.9 mm vs 64 ± 1.7 mm; P<0.0001).LVESD (44.5 ± 1.1 mm vs 50 ± 0.8 mm; P<0.0001).Smaller wall motion score index (1.24 ± 0.12 vs 1.45 ±

0.19; P<0.01).

Improvement in angina and NYHA class and QOL.

Rosano et al,28 2003.

32 Randomized, parallel control, (mean age 67 ± 6 years); DM patients with ischemic cardiomyopathy.

Treatment with TMZ (60 mg/d) vs placebo; 6-month follow-up.

LVEF improvement (5.4 ± 0.5% vs -2.4 ± 1.1%; P<0.01). LVEDD (63.2 ± 2.1 mm to 58 ± 1.6 mm vs 62.4 ± 1.7 mm

to 63 ± 2.1 mm; P<0.01). Improvement in wall motion score index and in the E/A

wave ratio.

Chen et al,31 2014.

635 Randomized, open; patients with DES (on TMZ for at least 30 days after stent implantation).

Treatment with TMZ vs control; 1-year follow-up.

Lower incidence of stent restenosis (4.2% vs 11.1%; P=0.001).

Higher LVEF (65.4 ± 10.7 vs 63.1 ± 10.4; P=0.006). Lower incidence of MACCEs (6.1% vs 10.8%; P=0.032). TMZ predictor for stent restenosis (OR: 0.376, 95% CI:

0.196 to 0.721; P=0.003).

Table III Trials on left ventricular function parameter effects of trimetazidine in stable angina pectoris and ischemic heart disease. Abbreviations: CHD, coronary heart disease; CI, confidence interval; DES, drug-eluting stent; DM, diabetes mellitus; LVEDD, left ventricular end-diastolic dimension; LVEF, left ventricular ejection fraction; LVESD, left ventricular end-systolic dimension; MACCEs, major adverse cardiac and cerebrovascular events; NYHA, New York Heart Association; OR, odds ratio; pts, patients; QOL, quality of life; TMZ, trimetazidine.

30


opposing deleterious effects of ischemia, maintain-ing the contractile myocardial function. The drug is suitable for use as monotherapy in patients with an-gina and as an adjunctive therapy where symptoms are not controlled by nitrates, β-blockers, or calcium antagonists. Trimetazidine does not affect hemody-namic variables, such as heart rate, systolic blood pressure, and the rate-pressure product. In addition, there is some evidence suggesting trimetazidine may improve LV function in patients with chronic CAD or ischemic cardiomyopathy and in patients experienc-ing ischemia during PCI or CABG. L

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Heart Metab. (2017) 72:32-36case report

The management of patients with refractory angina poses a major clinical challenge. Because of advanced coronary artery disease

(CAD), those patients are deemed to be unsuitable for myocardial revascularization procedures, which makes the role of optimal medical therapy (OMT) of paramount significance.1 The main goals when treat-ing such patients are directed toward an improvement in quality of life, which can be achieved by a reduction (as possible) in the number of angina attacks with a correspondent increase in exercise tolerance. Although no medical therapy has been specifi-cally conceived for patients with refractory angina, a judicious use of a combination of all agents currently approved in the management of patients with stable angina should be implemented.2 The more conven-

tional approach is to initially offer a combination of hemodynamic agents, such as β-blockers, calcium-channel blockers (CCB), and/or long-acting nitrates (LAN), at maximally tolerated doses. A limiting factor to a greater use for the above combination is that it can lead to a significant drop in arterial blood pressure (BP), with hypotension-related symptoms developing afterwards; additionally, other side effects, includ-ing headache, flushing (LAN and CCB), fatigue, de-pression, weakness, insomnia (β-blockers), swollen ankles, constipation, or flushing (CCB) may also oc-cur. In the COURAGE trial (Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation), for instance, at 3 years of follow-up, roughly 40% of patients were still complaining of angina, regardless of which arm of the trial they were assigned to (OMT

The role of optimal medical therapy in patients with refractory angina

Luis Henrique Wolff Gowdak, MD, PhD, FESCHeart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil

Correspondence: Luis Henrique Wolff Gowdak, MD, PhD, FESC, Heart Institute (InCor), University of São Paulo Medical School, Avenida Dr. Enéas de Carvalho Aguiar, 44, São Paulo, SP – 05403-000 Brazil


AbstractThe management of patients with refractory angina poses a major clinical challenge. Optimal medical therapy (OMT) is of paramount importance to improving quality of life by reducing (as much as possible) the number of angina attacks with a correspondent increase in exercise tolerance. For that, a judicious use of a combination of all agents currently approved in the management of patients with stable angina should be implemented. Guidelines usually recommend a combination of hemodynamic agents, such as β-blockers, calcium-channel blockers, and/or long-acting nitrates, at maximally tolerated doses, followed by the addition (as needed) of antianginal agents with different modes of action, such as trimetazidine, ivabradine, ranolazine, nicorandil, perhexiline, allopurinol, and/or fasudil (where available). Here, we describe the case of a patient who initially received a diagnosis of refractory angina and in whom OMT greatly helped to improve symptoms. L Heart Metab. 2017;72:32-36

Keywords: angina; coronary artery disease; treatment

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Optimal medical therapy in refractory angina

with or without percutaneous coronary intervention).3 At the same time point, in patients in the OMT-only group, 86% were taking β-blockers, 50% a CCB, and 61% a LAN.4 To answer the question of why investi-gators did not increase the use of those agents to a greater extent if patients were still symptomatic, one must look at the BP: at 123±0.78/70±0.52 mm Hg, BP most likely prevented any further attempt to adjust therapy.4 Moreover, for patients with stable CAD and hypertension, a systolic BP under 120 mm Hg and di-astolic BP under 70 mm Hg have each recently been shown to be associated with adverse cardiovascular

outcomes, including mortality.5 Therefore, if a patient is already being treated with a hemodynamic agent (alone or in combination) and remains symptomatic, one should consider OMT with antianginal agents devoid of a BP-lowering effect. Non–BP-lowering an-tianginal agents are trimetazidine, ivabradine, ranola-zine, nicorandil, perhexiline, allopurinol, and fasudil2 (Table I). However, availability and clinical indications of those agents vary from country to country. Another important aspect to take into consider-ation is whether left ventricular systolic dysfunction is present, as some antianginal agents are contra-indicated in patients with angina and left ventricular dysfunction—examples include diltiazem and vera-pamil—or their safety has not been properly assessed in this population. This article presents a clinical case that highlights the role of OMT in the management of a patient who initially received a diagnosis of refractory angina, and illustrates the rationale for a specific combination of antianginal agents in this scenario.

Clinical case

A 73-year-old man was referred to our outpatient clini-cal center for persistent angina due to advanced CAD. He had a long history of hypertension and type 2 dia-betes mellitus. Stable CAD was diagnosed at the age of 56, and he was managed medically until the age of 63, when he suffered an acute myocardial infarc-tion and, because of severe multivessel disease, he underwent a triple bypass surgery. He did quite well after the procedure and was asymptomatic without any functional limitation until 6 months ago, when an-gina relapsed and became progressively limiting. He was unable to perform any ordinary activity without pain, for which a short-acting nitrate was frequently taken. When first seen in another health facility, his heart rate (HR) was 80 beats per minute (bpm) and BP, 144/78 mm Hg. Findings on physical examination were unremarkable. He was on metoprolol succinate 50 mg/day, atorvastatin 80 mg/day, aspirin 100 mg/day, and perindopril 8 mg/day. Electrocardiography revealed abnormal Q waves in DII, DIII, and aVF. An echocardiogram showed a mildly enlarged left ventri-cle (left ventricular end diastolic diameter, 58 mm) with a moderately depressed left ventricular function (left ventricular ejection fraction, 40%). Metoprolol succi-nate was increased to 100 mg/day. On his next ap-

AbbreviationsBEAUTIFUL: morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction; BP: blood pressure; CAD: coronary artery disease; CCB: calcium-chan-nel blocker; COURAGE: Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation; HR: heart rate; LAN: long-acting nitrate; OMT: optimal medical therapy; SHIFT: Systolic Heart failure treatment with If inhibitor ivabradine Trial

Agent Mode of action

Trimetazidine

Inhibition of fatty-acid β-oxidation in mitochondria Increased ATP production in mitochondria Improved myocyte tolerance to ischemia

Ivabradine

Inhibition of sinus node If pacemaking current Pure heart rate reduction Prolongation of diastole Increased myocardial perfusion and collateral function

RanolazineInhibition of late inward Na+ current Reduction in Ca2+ in ischemic myocytes Improved left ventricular diastolic function

NicorandilRelease of nitric oxide free radicals Vasodilation of arterial and venous system Activation of ATP-sensitive K+ channels

Perhexiline

Inhibition of carnitine-palmitoyltransferase 1 and 2 Shifting myocardial metabolism from fatty acids to carbohydrates Enhancement of energy efficiency in ischemic myocytes

AllopurinolInhibition of xanthine oxidase Reduction in vascular oxidative stress

Fasudil

Inhibition of rho-kinase Reducing Ca2+ sensitization of vascular smooth muscle Maintenance of coronary vasodilation

Table I Nontraditional antianginal agents and their main mode of action. Abbreviations: ATP, adenosine triphosphate; Ca2+, calcium; K+, potassium; Na+, sodium.

pointment, he complained of experiencing ten angina attacks per week; he was feeling fatigued but with no shortness of breath. HR dropped to 72 bpm and BP to 136/72 mm Hg. Amlodipine 5 mg daily was added to his treatment regimen. One month later, he did not notice much improvement; angina was still bothering him with an average of eight attacks per week. HR remained unchanged at 74 bpm and BP further de-creased to 128/66 mm Hg. Isosorbide-5-mononitrate 20 mg twice daily was added to his treatment regimen. Two weeks later, he was brought to the emergency department after losing consciousness for about 3 minutes. Electrocardiography revealed his heart was in sinus rhythm with a HR of 80 bpm and no acute ischemic abnormalities; troponin levels were normal. BP was low at 96/50 mm Hg. Nitrates were discon-tinued, and because of persistent angina with a poor response to medical therapy, a coronary angiography was ordered (Figure 1). A heart team was consulted; because of the extension and diffuseness of the dis-ease, he was not considered a good candidate for another revascularization procedure and was referred to our center for further evaluation. At his first appointment in our facility, his disease was still considered to be Canadian Cardiovascular Society (CCS) class III-IV, he was on metoprolol suc-cinate 100 mg/day + amlodipine 5 mg/day, and he had a resting HR of 68 bpm and a BP of 124/60 mm Hg. Trimetazidine 35 mg twice daily was added to his treat-ment regimen. One month later, angina had improved from eight episodes per week to four, and he could walk briskly in the park without pain. His level of fatigue had improved as well. His vitals showed a HR of 72 bpm and a BP of 126/68 mm Hg. At that point, ivabradine

5 mg twice daily was added to his treatment regimen. At a follow-up visit, at which he had a HR of 68 bpm and no change in BP, ivabradine was uptitrated to 7.5 mg twice daily. When last seen, he could resume most of his daily activities without pain. Occasionally, angina recurred during more strenuous activities, but this was easily relieved by a short-acting nitrate. Another echo-cardiogram performed 6 months after OMT showed an increase in left ventricular ejection fraction from 40% to 46%. Figure 2 shows the process of optimization of medical therapy in this patient who initially received a diagnosis of refractory angina.

Discussion

This case illustrates that OMT can improve the quality of life, decrease the number of angina attacks, and increase exercise tolerance in patients who initially receive a diagnosis of refractory angina and have no perspectives for myocardial revascularization proce-dures, as our group has previously shown.6

The decision-making process in this patient fol-lowed the more common approach adopted in many international guidelines for the management of pa-tients with stable angina, which state that a combi-nation of β-blocker and CCB should be considered initially.7,8 If patients remain symptomatic, LAN should be considered along with other non–BP-lowering agents. In this symptomatic patient on metoprolol + amlodipine, severe hypotension developed after the introduction of LAN, and angina could not be ade-quately controlled. Ranolazine has not been recom-mended to be used in patients with angina and left ventricular systolic dysfunction because of the lack of

34

Fig. 1 Left panel shows the left coronary artery system with left anterior descending (LAD) artery occlusion after the first septal branch and multiple obstructive lesions in the left circumflex (LCX) artery territory. Center panel shows the occluded right coronary artery (RCA). No grafts were visible except for a left internal mammary artery (LIMA)-LAD seen in the right panel. Note the diffuse atherosclerosis from proximal to distal beds, leading to a thread-like appearance with small distal runoff in the LAD.Other abbreviation: OM, obtuse marginal branches.

GoWdak Heart Metab. (2017) 72:32-36Optimal medical therapy in refractory angina

35


Optimal medical therapy in refractory angina

safety data.9 Hypotension is an uncommon but po-tentially disturbing adverse effect associated with the use of nicorandil,10 available in some countries. Fa-sudil is a potent rho-kinase inhibitor and vasodilator11 that has not been approved by the US Food and Drug Administration or by the European Medicines Agen-cy. Perhexiline is an antianginal agent available in few countries; it has a narrow therapeutic index, and be-cause of high inter- and intraindividual pharmacoki-netic variability, it requires close monitoring to avoid the risk of hepatotoxicity or peripheral neuropathy.12 Trimetazidine, owing to its unique mode of action,13 devoid of any discernible hemodynamic effects and excellent tolerability, was a very good option for this patient, especially in the context of angina and left ventricular systolic dysfunction,14 in which trimetazi-dine was shown to increase left ventricle contractility and reduce the risk of death.15 Because of its syner-gistic antianginal effect when associated with conven-tional antianginal agents,16,17 the Brazilian guidelines on stable angina allowed for the addition of trimetazi-dine right after the use of β-blockers and before LAN in symptomatic patients.18 In adopting this strategy, a faster and better tolerated therapeutic strategy may be implemented for better angina control. After the

introduction of trimetazidine, the patient experienced a significant improvement in his clinical status, although mild angina was still present. Ivabradine was added be-cause of its proven efficacy in patients with stable CAD and moderate left ventricular dysfunction, not only in terms of symptom control but also for cardiovascular protec-tion, as demonstrated in the trials BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction)19 and SHIFT (Systolic Heart fail-ure treatment with If inhibitor ivabradine Trial).20 In fact, after 6 months on OMT, symptoms improved, as well as left ven-tricular systolic function.

In conclusion, in this nonrevascularizable patient with persistent angina, the combination of conven-tional antianginal agents (β-blockers and CCBs) with non–BP-lowering agents (trimetazidine and iv-abradine) provided an excellent control of angina and increase in exercise tolerance, with good tolerability and no side effects. L

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2. Giannopoulos AA, Giannoglou GD, Chatzizisis YS. Pharma-cological approaches of refractory angina. Pharmacol Ther. 2016;163:118-131.

3. Weintraub WS, Spertus JA, Kolm P, et al. Effect of PCI on qual-ity of life in patients with stable coronary disease. N Engl J Med. 2008;359(7):677-687.

4. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical ther-apy with or without PCI for stable coronary disease. N Engl J Med. 2007;356(15):1503-1516.

5. Vidal-Petiot E, Ford I, Greenlaw N, et al. Cardiovascular event rates and mortality according to achieved systolic and diastolic blood pressure in patients with stable coronary artery disease: an international cohort study. Lancet. 2016;388(10056):2142-2152.

6. Dourado LO, 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.

7. Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC

Angina CCS III-IV +LVEF 40%

HR: 80 bpmBP: 144/78 mm Hg

Stable CAD

Medicaltreatment

MI + 3-VD

Asymptomatic Asymptomatic

Age: 56 Age: 63 Age: 73

Coronaryangiography

Metoprolol increased Amlodipine added

CABG







Syncope

Trimetazidine added Ivabradine added


Angina CCS II-III +LVEF 40%


Angina CCS I-II +LVEF 46%


Isosorbide added Isosorbide withdrawn

Fig. 2 Optimal medical therapy in a patient with persistent angina unsuitable for revascularization.Abbreviations: BP, blood pressure; bpm, beats per minute; CABG, coronary artery bypass grafting; CAD, coro-nary artery disease; CCS, Canadian Cardiovascular Society classification; HR, heart rate; LVEF, left ventricular ejection fraction; MI + 3-VD, myocardial infarction + three-vessel disease.

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GoWdak Heart Metab. (2017) 72:32-36Optimal medical therapy in refractory angina

guidelines on the management of stable coronary artery dis-ease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013;34(38):2949-3003.

8. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the diagnosis and man-agement of patients with stable ischemic heart disease: a re-port of the American College of Cardiology Foundation/Ameri-can Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Asso-ciation, Society for Cardiovascular Angiography and Interven-tions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2012;60(24):e44-e164.

9. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guide-lines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18(8):891-975.

10. Arnold JM, Kowey PR, Wolf DL, Jungbluth GL, Hearron AE, Luderer JR. Dose-related haemodynamic effects and phar-macokinetics of oral nicorandil in patients evaluated for chest pain. Int J Cardiol. 1994;44(3):203-215.

11. Hirooka Y, Shimokawa H. Therapeutic potential of rho-kinase inhibitors in cardiovascular diseases. Am J Cardiovasc Drugs. 2005;5(1):31-39.

12. Phuong H, Choi BY, Chong CR, Raman B, Horowitz JD. Can

perhexiline be utilized without long-term toxicity? A clinical practice audit. Ther Drug Monit. 2016;38(1):73-78.

13. McCarthy CP, Mullins KV, Kerins DM. The role of trimetazidine in cardiovascular disease: beyond an anti-anginal agent. Eur Heart J Cardiovasc Pharmacother. 2016;2(4):266-272.

14. Lopatin YM, Rosano GM, Fragasso G, et al. Rationale and benefits of trimetazidine by acting on cardiac metabolism in heart failure. Int J Cardiol. 2016;203:909-915.

15. Grajek S, Michalak M. The effect of trimetazidine added to pharmacological treatment on all-cause mortality in patients with systolic heart failure. Cardiology. 2015;131(1):22-29.

16. Zhao Y, Peng L, Luo Y, et al. Trimetazidine improves exercise tolerance in patients with ischemic heart disease: a meta-anal-ysis. Herz. 2016;41(6):514-522.

17. Peng S, Zhao M, Wan J, Fang Q, Fang D, Li K. The efficacy of trimetazidine on stable angina pectoris: a meta-analysis of randomized clinical trials. Int J Cardiol. 2014;177(3):780-785.

18. Cesar LA, Ferreira JF, Armaganijan D, et al. Guideline for stable coronary artery disease. Arq Bras Cardiol. 2014;103(2 suppl 2):1-56.

19. Fox K, Ford I, Steg PG, et al. 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(19):2337-2345.

20. Borer JS, Swedberg K, Komajda M, et al. Efficacy profile of ivabradine in patients with heart failure plus angina pectoris. Cardiology. 2016;136(2):138-144.

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Heart Metab. (2017) 72:37-43RefresHer Corner

Ischemic heart disease (IHD) remains the leading cause of death in the world. Although the role of anatomically guided early revascularization is

firmly established in patients with acute coronary syndromes, its role in patients with stable IHD is more controversial. Indeed, in randomized controlled trials in patients with stable IHD, revascularization based on anatomic thresholds has not resulted in lower rates of adverse cardiovascular events than guideline-directed medical therapy1,2 or fractional flow reserve–guided percutaneous intervention.3 An alternative approach generated from observational4 and post hoc5 analyses proposes that there may be a threshold of inducible ischemia above which an early revascularization strategy could result in improved cardiovascular outcomes. This suggests that a binary approach based on the assessment

of the presence or absence of ischemia would be insufficient and that quantification of total ischemic burden is essential for selecting patients with stable IHD for revascularization.

Noninvasive quantification of ischemic myocardium

Radionuclide myocardial perfusion imaging

Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) are the two nuclear medicine–based approaches for evaluation of ischemia by myocardial perfusion imag-ing (MPI). The basic principle of radionuclide MPI for detecting obstructive coronary stenosis and quan-tification of ischemic myocardium is based on the

Estimating ischemic burdenVikram Agarwal, MD, MPH; Marcelo F. Di Carli, MD

Cardiovascular Imaging Program, Departments of Medicine and Radiology, The Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, and the Cardiovascular Division, Department of Medicine, Brigham and

Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

Correspondence: Marcelo F. Di Carli, MD. Brigham and Women’s Hospital, ASB-L1 037-C, 75 Francis St, Boston, Massachusetts 02115, USA


AbstractIschemic heart disease is the leading cause of death worldwide. Selection of patients that would be good candidates for management by revascularization is challenging, with accurate identification and quantification of ischemic burden playing a critical role. Current approaches for imaging and quantifica-tion of ischemia at rest and after stress are discussed here, including myocardial perfusion imaging (both single-photon emission computed tomography and positron emission tomography [PET]), stress echocardiography, cardiac magnetic resonance (CMR) imaging, and computed tomography, each with their advantages and limitations. Thus far, CMR perfusion and PET have been most accurate, with cardiac PET considered the gold standard for quantifying myocardial blood flow and coronary flow reserve (CFR); there is evidence that measures of CFR improves risk assessment beyond that previ-ously achieved and allows incorporation of measures of overall vascular health, including, for example, measures of effects of epicardial coronary stenoses, diffuse atherosclerosis and vessel remodeling, and microvascular dysfunction on myocardial perfusion. L Heart Metab. 2017;72:37-43

Keywords: coronary flow reserve (CFR); ischemic burden; multimodality cardiac imaging

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ability of a radiotracer to identify a transient regional perfusion deficit in a myocardial region subtended by a coronary artery with a flow-limiting stenosis. A reversible perfusion defect is indicative of ischemia, whereas a fixed perfusion defect generally reflects scarred myocardium from previous infarction (Fig-ure 1). Generally, myocardial perfusion defects during stress develop downstream from epicardial stenosis with greater than 50% luminal narrowing and become progressively more severe with increasing degree of stenosis. It is noteworthy that coronary stenoses of intermediate severity (eg, 50%-90%) associate with significant variability in the resulting maximal coronary blood flow, which in turns affects the presence and/or severity of regional perfusion defects.

Regional myocardial perfusion is usually as-sessed by semiquantitative visual analysis of the rest and stress images.6 The segmental scores are then summed into global scores that reflect the total bur-den of ischemia and scar in the left ventricle. Objective quantitative image analysis is a helpful tool for a more accurate and reproducible estimation of total defect size and severity, and it is generally used in combi-nation with semiquantitative visual analysis (Figure 2). The semiquantitative (visual) and quantitative scores of ischemia and scar are linearly related to the risk of adverse cardiovascular events and are useful in guid-ing patient management, especially in assessing the need for revascularization and the response to medi-cal therapy. The presence of transient left ventricular (LV) dilation during stress imaging (so-called transient ischemic dilation or TID) is an ancillary marker of risk that reflects extensive subendocardial ischemia and often accompanies radionuclide MPI studies with ex-tensive and severe perfusion abnormalities (Figure 1). It is often an important finding, particularly when it oc-curs in patients with no or only mild perfusion abnor-malities, suggesting the presence of more extensive balanced subendocardial ischemia. The presence of this abnormality has often been shown to be a har-binger of increased risk.7,8 Similarly, the presence of transient pulmonary radiotracer retention and right ventricular uptake during stress along with a drop in LV ejection fraction (LVEF) after stress (a sign of post-ischemic stunning) are also markers of multivessel LV ischemia (Figure 1).

Fig. 1 Rest-stress positron emission tomography in a 53-year-old woman with previous history of coronary artery bypass graft, showing large areas of severe stress-induced ischemia throughout the distribution of the left anterior descending artery and left circumflex artery (yellow arrows). In addition, on the stress images, there is transient ischemic dilation of the left ventricle and increased right ventricular uptake (red arrows).Abbreviations: ANT, anterior; HLA, horizontal long-axis view; INF, inferior; LAT, lateral; RstCTAC, rest computed tomography attenuation correction; SA, short-axis view; SEP, septum; StrCTAC, stress computed tomography attenuation correction; VLA, verticle long-axis view.

AbbreviationsCCTA: coronary computed tomography angiography; CMR: cardiac magnetic resonance; CT: computed tomography; DeFACTO: Determination of Fractional flow reserve by Anatomic Computed Tomographic angiOgraphy; DISCOVER-FLOW: Diagnosis of ISChemia-causing stenoses Obtained Via noninvasivE fRac-tional FLOW reserve; FFRCT: CT-based fractional flow reserve; IHD: ischemic heart disease; LV: left ventricu-lar; MPI: myocardial perfusion imaging; MRI: magnetic resonance imaging; NXT: Analysis of Coronary Blood Flow Using Coronary CT Angiography: NeXt sTeps; PET: positron emission tomography; SPECT: single-photon emission computed tomography

aGarWal and di carli Heart Metab. (2017) 72:37-43Estimating ischemic burden

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Heart Metab. (2017) 72:37-43 aGarWal and di carli Estimating ischemic burden

Echocardiography

The hallmark of myocardial ischemia during stress echocardiography is the development of new regional wall motion abnormalities and reduced systolic wall thickening. Stress echocardiography can be per-formed in conjunction with exercise or dobutamine stress. Stress echocardiography is best at identify-ing inducible wall motion abnormalities in previously normally contracting segments. In a patient with wall motion abnormalities at rest, the specificity of stress echocardiography is reduced, and worsening region-al function of a previously abnormal segment might reflect worsening contractile function in the setting of increased wall stress rather than new evidence of inducible ischemia. The advantages of stress echo-cardiography over other stress imaging techniques include its widespread availability, no use of ionizing radiation, and relatively low cost. However, there are a number of limitations for stress echocardiography, in-cluding the following: (i) there are technical challenges associated with image acquisition at peak exercise because of exertional hyperpnea and cardiac excur-

sion; (ii) sensitivity may be limited by rapid recovery of wall motion abnormalities, which can be seen with mild ischemia, especially with one-vessel disease; (iii) detection of residual ischemia within an infarcted ter-ritory may be difficult because of an abnormality in resting wall motion; (iv) the technique for acquisition of echocardiographic data and analysis of images is highly operator dependent; and (v) complete im-ages of good quality for viewing all myocardial seg-ments are obtained in only 85% of patients. Newer techniques, including second harmonic imaging and the use of intravenous contrast agents improve image quality, but their effect on diagnostic accuracy has not been well documented. The use of intravenous con-trast agents may also allow assessment of myocardial perfusion, although this is not approved or generally reimbursed, and data concerning the utility of con-trast perfusion echocardiography are limited. As with radionuclide MPI, stress echocardiography is often used for risk stratification in patients with suspected or known IHD. A negative stress echocardiogram re-sult is associated with an excellent prognosis, allow-ing identification of patients at low risk. Conversely,

Defect blackout mapPerfusionStrCTAC

LAD

LCX

117062.4 BQML

0.0 BQML

100.0 %RegionLADLCXRCATOT

Extent0 %

73 %42 %28 %

0.0 %RCA

Defect blackout mapPerfusionRstCTAC

LAD

LCX

86133.2 BQML

0.0 BQML


Extent0 %

48 %20 %17 %

0.0 %RCA

Defect blackout mapReversibility LAD

LCX

50.0 %

0.0 %


Fixed0 %9 %

11 %5 %

Nml100 %

27 %58 %72 %

Revers0 %

64 %31 %23 %

0.0 %RCA

Fig. 2 Polar map of a 72-year-old patient undergoing a rest-stress positron emission tomography, showing stress (top), rest (middle), and reversibility (bottom) plots. There is a medium-sized area of previous myocardial infarction, which involves 17% of the left ventricular mass in the distribution of the left circumflex territory, with a mild amount of residual stress-induced peri-infarct ischemia.Abbreviations: LAD, left anterior descending artery; LCX, left circumflex artery; Nml, normal; RCA, right coronary artery; Revers, reversibility; RstCTAC, rest computed tomography attenuation correction; StrCTAC, stress computed tomography attenuation correction; TOT, total.

40


the risk of adverse events increases with the extent and severity of wall motion abnormalities on stress echocardiography.

Cardiac magnetic resonance

The two approaches used with cardiac magnetic resonance (CMR) to evaluate patients with known or suspected IHD include the assessment of regional myocardial perfusion (the most common clinical ap-proach) or wall motion at rest and during stress, the latter being analogous to stress echocardiography. Whereas treadmill or bicycle exercise stress CMR is practiced in a small number of specialized centers,9 the logistics for stress magnetic resonance imaging (MRI) studies currently require the use of pharmaco-logic stress agents, including vasodilators or dobuta-mine. Myocardial perfusion is evaluated by injecting a bolus of a gadolinium-based contrast agent, followed by continuous data acquisition as the contrast pass-es through the cardiac chambers and into the myo-cardium. Qualitative or quantitative analysis of rapidly acquired, sequential images (a “cine loop”) obtained during the first pass of contrast into the myocardium can identify perfusion defects present at rest or un-der pharmacologically induced vasodilation. Relative perfusion deficits are recognized as regions of low signal intensity (black) within the myocardium (Figure 3). Stress CMR perfusion has better diagnostic accu-racy than stress echocardiography and SPECT, and comparable accuracy to that obtained by PET. Quan-

tification of ischemic burden with CMR perfusion is more challenging than radionuclide MPI because of the limited sampling of the left ventricle, which is re-stricted to three short-axis slices. The addition of the information from late gadolinium enhancement imag-ing allows differentiation between hypoperfused (po-tentially ischemic) and infarcted myocardium. As with other imaging modalities, there is evidence that isch-emia measurements derived from stress CMR stud-ies also have prognostic value. In line with the nuclear and echocardiography literature, a normal result on CMR study is associated with a good prognosis. Conversely, the presence of new wall motion abnor-malities, regional perfusion defects, the combination of wall motion abnormalities and perfusion defects, and the presence of late gadolinium enhancement are all predictors of adverse events.

Computed tomography

Preliminary studies indicate that contrast-enhanced computed tomography (CT) might be useful to visu-alize myocardial perfusion, thereby enabling quantifi-cation of ischemic burden. As with stress perfusion MRI, this technique is based on acquiring CT images during the first pass of iodinated contrast into the myocardium. When the myocardium is visualized ap-propriately, areas of hypoenhancement correspond with perfusion defects (Figure 4). When seen under resting conditions, such defects represent areas of previous myocardial infarction, particularly if they are also associated with wall thinning or intramyocardial calcification. When CT images are acquired during administration of vasodilators, such as adenosine,

Fig. 3 Vasodilator stress magnetic resonance (MR) myocardial perfusion study in a 69-year-old woman with exertional chest pain who was referred for ischemia assessment. Stress (top) and rest (bottom) first-pass perfusion images showing stress-induced first-pass perfusion defect in distribution of all three coronary vessels, including the left anterior descending coronary artery, the left cir-cumflex artery, and the right coronary artery territory (red arrows).

Fig. 4 Vasodilator stress computed tomography (CT) perfusion images in a magnetic resonance (MR) myocardial perfusion study in a 58-year-old male. There is a large area of stress-induced subendocardial perfusion defect extending from the base to the apex of the anterior and septal walls, which is consistent with ischemia in the distribution of the left anterior descending artery territory (yellow arrows). Images courtesy of Dr. Joao Lima, Johns Hopkins University.

41


areas of inducible ischemia can be visualized. Limi-tations of this technique include motion-related and beam-hardening artifacts that can mimic areas of myocardial hypoenhancement. Although this tech-nique remains experimental, the prospect of being able to perform a single scan that combines the ana-tomical information provided by coronary CT angiog-raphy (CCTA) with concomitant assessment of myo-cardial perfusion during pharmacologic stress is of potential clinical value. Recent relatively large clinical trials have shown that the technique is feasible and has reasonable diagnostic accuracy for identification of flow-limiting coronary stenoses.10

An alternative approach to the evaluation of flow-limiting stenosis is the use of CCTA data acquired at rest (without the use of adenosine-stimulated hyper-emic challenge as is performed in the catheterization laboratory) to solve numerous fluid dynamics equa-tions to noninvasively estimate lesion-specific frac-tional flow reserve (so-called FFRCT). Studies to date have shown only modest results with regard to the incremental value that the FFRCT information adds to CCTA data. First, the DISCOVER-FLOW study (Di-agnosis of ISChemia-causing stenoses Obtained Via

noninvasivE fRactional FLOW reserve) demonstrated that the addition of FFRCT to CCTA did not improve the sensitivity for detection of lesions with an inva-sive FFR value under 0.8 (91% for CCTA alone versus 88% for CCTA + FFRCT) but did improve the specificity of CCTA alone from 40% to 82%. Next, the DeFAC-TO study (Determination of Fractional flow reserve by Anatomic Computed Tomographic angiography) similarly demonstrated that sensitivity for detection of stenoses with an invasive FFR value under 0.8 re-mained comparable for CCTA alone versus CCTA + FFRCT (84% versus 90%), but specificity only margin-ally improved from 42% to 54%, and the study did not reach its prespecified primary end point for im-proving specificity. The most recent study, NXT (Anal-ysis of Coronary Blood Flow Using Coronary CT An-giography: NeXt sTeps), showed a sensitivity of 94% versus 86% for CCTA alone versus CCTA + FFRCT, and specificity of 34% versus 79%, respectively. The NXT study is an encouraging improvement to CCTA alone, but essentially demonstrates an accuracy of FFRCT now approaching SPECT or stress echocar-diography, although potentially inferior (without direct comparison) to stress MRI or PET.

Stress ECG Nuclear SPECT Nuclear PET Stress echocardiogram CCTA Cardiac MRI perfusion

Sensitivity ++ 86% 90% 80% 94% 84%

Specificity ++ 74% 89% 86% 82% 85%

Prognosis ++ ++++ ++++ +++ +++ +++

Radiation - +++ +++ - ++ -

Cost + +++ ++++ ++ ++++ ++++

Assessment of ischemic burden

Cannot be assessed

Semiquantitative assessment with SSS and SDS; automated quantification with TPD and TID ratio

Semiquantitative and automated quantification similar to SPECT; MBF and CFR quantification

Semiquantitative assessment with wall motion score index and number of ischemic segments

FFRCT, Stress CTP

Qualitative assessment of number of segments involved with first-pass perfusion, semiquantitative assessment of myocardial signal intensity with first-pass perfusion, fully quantitative method to assess absolute MBF

Future directions

Incorporation of Ca score

MBF and CFR assessment, CTAC, low radiation dose protocol, stress only protocol

New radiotracers – to facilitate exercise PET and wider use without need for on-site cyclotron, increasing application of CFR

Myocardial perfusion, strain, single-beat 3D acquisition

Further validation of data with Stress CTP; wider availability of FFRCT

Less laborious post processing involving quantitative and semiquantitative techniques; coronary plaque visualization

Table I Summary of different noninvasive imaging modalities to assess for underlying ischemia. Abbreviations: Ca, calcium; CCTA, coronary computed tomography angiography; CFR, coronary flow reserve; CTAC, computed tomography attenuation correction; ECG, electrocardiogram; FFRCT, computed tomography–based fractional flow reserve; MBF, myocardial blood flow; PET, positron emission tomog-raphy; SDS, sum different score; SPECT, single-photon emission computed tomography; SSS, sum stress score; Stress CTP, stress computed tomography perfusion; TID, transient ischemic dilation; TPD, total perfusion defect.

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Table I summarizes the different noninvasive imag-ing modalities to assess underlying ischemia. When interpreting this table, it is important to keep in mind that with any imaging modality, the diagnostic ac-curacy of the test is limited by posttest referral bias, which may increase the sensitivity and decrease the specificity of the test.

Coronary flow reserve

Myocardial blood flow (in mL/min/g of myocardium) and coronary flow reserve (CFR; defined as the ratio between peak stress and rest myocardial blood flow) are important physiologic parameters that can be measured by routine postprocessing of myocardial perfusion PET and CMR images. However, cardiac PET is considered the gold standard for quantifying myocardial blood flow and CFR and shows excellent accuracy and reproducibility. Pathophysiologically, CFR estimates provide a measure of the integrated effects of epicardial coronary stenoses, diffuse ath-erosclerosis and vessel remodeling, and microvascu-lar dysfunction on myocardial perfusion; as such, the value obtained is a more sensitive measure of myo-cardial ischemia. In the setting of increased oxygen demand, a reduced CFR can upset the supply-and-demand relationship and lead to myocardial ischemia, subclinical LV dysfunction (diastolic and systolic), symptoms, and death. These measurements of CFR have important diagnostic11-15 and prognostic16-22 im-plications in the evaluation and management20 of the patients with known or suspected IHD. Because quantitative measures of CFR integrate the fluid dynamic effects of atherosclerosis through-out the coronary arterial tree, including epicardial stenoses with early changes to endothelial and/or smooth muscle function, it may be a superior mea-sure of overall vascular health, providing unique infor-mation about clinical risk. Five studies have demon-strated that PET measures of CFR improve cardiac risk assessment. In the largest of these studies,23 CFR was prognostically important after adjusting for multiple factors, including LVEF at rest and conven-tional measures of ischemia. The lowest tertile of CFR had a hazard ratio of 5.6 and the middle tertile had a hazard ratio of 3.4. These results were confirmed by a similar study in a smaller cohort with a follow-up period of slightly more than a year.22 As discussed, the noninvasive PET measure of CFR can improve

risk classification, especially among high-risk cohorts (eg, diabetics, non–ST-segment elevation myocardial infarction, in patients with chronic renal impairment, and in those with high coronary calcium scores).24-26 Thus, assessment of CFR appears to permit a level of risk assessment beyond that achieved previously, with the potential for incorporation of vascular/endo-thelial status into routine patient investigations. Im-portantly, an abnormal CFR identified an increased risk of cardiac death even among those with normal scans by semiquantitative visual analysis. These find-ings suggest that coronary microvascular dysfunction is a widespread finding and that future work is need-ed to identify its putative role as a therapeutic target.

Summary

Identification and quantification of ischemic burden plays a pivotal role in guiding patient management. There are several noninvasive imaging approaches for the quantification of ischemic myocardium, each with their own strengths and weaknesses. Stress CMR perfusion and PET are the most accurate techniques. The added advantage of PET is the routine assess-ment of quantitative myocardial blood flow and CFR, which are integrated into clinical workflow. There is emerging evidence suggesting that in comparison with conventional ischemia assessment, CFR—a more sensitive marker of ischemia—provides incre-mental risk stratification and the potential for more accurate selection of revascularization candidates. L

REFERENCES

1. Boden WE, O’Rourke RA, Teo KK, et al; COURAGE Trial Re-search Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356(15):1503-1516.

2. Frye RL, August P, Brooks MM, et al; BARI 2D Study Group. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med. 2009;360(24):2503-2515.

3. Tonino PA, De Bruyne B, Pijls NH, et al; FAME Study In-vestigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009;360(3):213-224.

4. Hachamovitch R, Hayes SW, Friedman JD, Cohen I, Berman DS. Comparison of the short-term survival benefit associated with revascularization compared with medical therapy in pa-tients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed to-mography. Circulation. 2003;107(23):2900-2907.

5. Shaw LJ, Berman DS, Maron DJ, et al; COURAGE Investiga-tors. Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: results from the Clinical Outcomes Utilizing Revascularization and Aggres-

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sive Drug Evaluation (COURAGE) trial nuclear substudy. Circu-lation. 2008;117:1283-1291.

6. Tilkemeier PL, Cooke CD, Grossman GB, et al. Standardized reporting of radionuclide myocardial perfusion and function. J Nucl Cardiol. 2006;13(6):e157-e171.

7. Mandour Ali MA, Bourque JM, Allam AH, Beller GA, Watson DD. The prevalence and predictive accuracy of quantitatively defined transient ischemic dilation of the left ventricle on oth-erwise normal SPECT myocardial perfusion imaging studies. J Nucl Cardiol. 2011;18(6):1036-1043.

8. Petretta M, Acampa W, Daniele S, et al. Transient ischemic dilation in SPECT myocardial perfusion imaging for prediction of severe coronary artery disease in diabetic patients. J Nucl Cardiol. 2013;20(1):45-52.

9. Raman SV, Dickerson JA, Mazur W, et al. Diagnostic perfor-mance of treadmill exercise cardiac magnetic resonance: the prospective, multicenter Exercise CMR’s Accuracy for Cardio-vascular Stress Testing (EXACT) Trial. J Am Heart Assoc. 2016 19;5(8):e003811.

10. George RT, Mehra VC, Chen MY, et al. Myocardial CT per-fusion imaging and SPECT for the diagnosis of coronary ar-tery disease: a head-to-head comparison from the CORE320 multicenter diagnostic performance study. Radiology. 2014;272(2):407-416.

11. Danad I, Uusitalo V, Kero T, et al. Quantitative assessment of myocardial perfusion in the detection of significant coro-nary artery disease: cutoff values and diagnostic accuracy of quantitative [15O]H2O PET imaging. J Am Coll Cardiol. 2014;64(14):1464-1475.

12. Johnson NP, Gould KL. Physiological basis for angina and ST-segment change PET-verified thresholds of quantitative stress myocardial perfusion and coronary flow reserve. JACC Cardio-vasc Imaging. 2011;4(9):990-998.

13. Kajander SA, Joutsiniemi E, Saraste M, et al. Clinical value of absolute quantification of myocardial perfusion with 15O-water in coronary artery disease. Circ Cardiovasc Imaging. 2011;4(6):678-684.

14. Naya M, Murthy VL, Taqueti VR, et al. Preserved coronary flow reserve effectively excludes high-risk coronary artery disease on angiography. J Nucl Med. 2014;55(2):248-255.

15. Ziadi MC, Dekemp RA, Williams K, et al. Does quantification of myocardial flow reserve using rubidium-82 positron emission tomography facilitate detection of multivessel coronary artery disease? J Nucl Cardiol. 2012;19(4):670-680.

16. Fukushima K, Javadi MS, Higuchi T, et al. Prediction of short-term cardiovascular events using quantification of global myo-cardial flow reserve in patients referred for clinical 82Rb PET perfusion imaging. J Nucl Med. 2011;52:726-732.

17. Herzog BA, Husmann L, Valenta I, et al. Long-term prognostic value of 13N-ammonia myocardial perfusion positron emission tomography added value of coronary flow reserve. J Am Coll Cardiol. 2009;54:150-156.

18. Murthy VL, Naya M, Foster CR, et al. Association between coro-nary vascular dysfunction and cardiac mortality in patients with and without diabetes mellitus. Circulation. 2012;126:1858-1868.

19. Murthy VL, Naya M, Foster CR, et al. Improved cardiac risk as-sessment with noninvasive measures of coronary flow reserve. Circulation. 2011;124:2215-2224.

20. Taqueti VR, Hachamovitch R, Murthy VL, et al. Global coronary flow reserve is associated with adverse cardiovascular events independently of luminal angiographic severity and modifies the effect of early revascularization. Circulation. 2015;131(1):19-27.

21. Tio RA, Dabeshlim A, Siebelink HM, et al. Comparison be-tween the prognostic value of left ventricular function and myocardial perfusion reserve in patients with ischemic heart disease. J Nucl Med. 2009;50:214-219.

22. Ziadi MC, Dekemp RA, Williams KA, et al. Impaired myo-cardial flow reserve on rubidium-82 positron emission to-mography imaging predicts adverse outcomes in patients assessed for myocardial ischemia. J Am Coll Cardiol. 2011;58(7):740-748.

23. Dorbala S, Di Carli MF, Beanlands RS, et al. Prognostic value of stress myocardial perfusion positron emission tomography: results from a multicenter observational registry. J Am Coll Car-diol. 2013;61:176-184.

24. Murthy VL, Naya M, Foster CR, et al. Coronary vascular dys-function and prognosis in patients with chronic kidney disease. JACC Cardiovasc Imaging. 2012;5(10):1025-1034.

25. Naya M, Murthy VL, Foster CR, et al. Prognostic interplay of coronary artery calcification and underlying vascular dysfunc-tion in patients with suspected coronary artery disease. J Am Coll Cardiol. 2013;61(20):2098-2106.

26. Murthy VL, Naya M, Foster CR, et al. Association between coro-nary vascular dysfunction and cardiac mortality in patients with and without diabetes mellitus. Circulation. 2012;126:1858-1868.

Heart Metab. (2017) 72:44-46Hot Topics

The traditional understanding of stable coronary artery disease (CAD) is that this disease causes exercise- and/or stress-related chest symp-

toms that are caused by a 50% or greater narrowing of the left main coronary artery and/or a 70% or greater narrowing of one or several of the major coro-nary arteries.1 Therefore, identification and removal of obstructive CAD is a main therapeutic target. At initial presentation, the diagnosis of angina pectoris is supported by the use of noninvasive tests and risk stratification models.1,2 Thus, comparative ef-fectiveness trials that test the ability of a noninvasive strategy to improve the rate of diagnosis of obstruc-tive CAD at subsequent angiography have gained

increasing interest.3 The CE-MARC 2 study (Clinical Evaluation of Magnetic Resonance Imaging in Coro-nary Heart Disease 2), recently published in the Jour-nal of the American Medical Association, tested the hypothesis that cardiac magnetic resonance (CMR)-guided care is superior to UK national guidelines (Na-tional Institute for Health and Care Excellence [NICE]-guidelines)-directed care and myocardial perfusion scintigraphy (MPS)-guided care in reducing the oc-currence of unnecessary invasive angiography in pa-tients with suspected ischemic heart disease (IHD).4 Patients randomized to the NICE-guidelines–directed care were scheduled for cardiac computed tomogra-phy if the pretest likelihood for CAD was low (10%

Errare humanum est, perseverare autem diabolicum

Alda Huqi, MD, PhDCardiac Care Unit at the Santa Maria Maddalena Hospital, Volterra, Pisa, Italy

Correspondence: Dr. Alda Huqi, MD, PhD, Cardiac Care Unit at the Santa Maria Maddalena Hospital, Borgo San Lazzero n. 5, Volterra, Pisa, Italy


AbstractThe initial evaluation of patients with suspected chronic angina is supported by the use of noninvasive tests and risk stratification models, which aim to identify obstructive coronary artery disease (CAD). Therefore, comparative effectiveness trials, testing the ability of a noninvasive strategy to increase the diagnostic yield for obstructive CAD have drawn increasing interest. However, after an initial increase in the diagnostic yield, there remains a significant discrepancy in results from noninvasive tests and those from coronary angiography, the latter being considered the gold standard technique for diagnosing CAD. These findings are in line with the new paradigm for ischemic heart disease, with obstructive CAD considered only one among many other determinants. With that in mind and given also the low, but persistent, risk for adverse events and the increasing costs associated with invasive management, is it appropriate to continue investing major research efforts on the development of a strategy that identifies and removes obstructive CAD? L Heart Metab. 2017;72:44-46

Keywords: comparative effectiveness of noninvasive diagnostic strategies; coronary artery disease; ischemic heart disease; percutaneous coronary intervention

44

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Heart Metab. (2017) 72:44-46 Huqi Errare humanum est, perseverare autem diabolicum

to 29%), underwent MPS if the pretest likelihood for obstructed CAD was intermediate (30% to 60%), or were directly sent to coronary angiography if the like-lihood for obstructed CAD was high (61% to 90%). Patients randomized to the CMR-directed–care and MPS-directed–care groups underwent initial evalua-tion with CMR and MPS, respectively, and those with positive results were directed to coronary angiogra-phy. The primary end point was unnecessary coro-nary angiography, defined as a normal fractional flow reserve value (or computed angiographic assessment) for all vessels of 2.5 mm or more in diameter. At 12 months from inclusion, 42.5% of patients receiving NICE-guidelines–directed care underwent coronary angiography (34% because of a pretest likelihood of >61%, and the remaining because of a positive test result or physician judgment). The initial test result was deemed positive in 12.4% of patients in the CMR group and 18.2% of patients in the MPS group; re-spectively, 17.7% and 16.2% of them underwent cor-onary angiography. An unnecessary angiography was performed in 28.8% of patients included in the NICE-guidelines-directed–care group, 7.5% of patients in the CMR-directed–care group, and 7.1% of patients in the MPS-directed–care group. There was no signifi-cant difference in revascularization rates or major car-diovascular events between the three groups. Authors concluded that investigation by CMR and MPS result-ed in a lower probability of unnecessary angiography as compared with NICE-guidelines–directed care. The use of CMR and MPS significantly lowered the rate of negative coronary angiograms in the CE-MARC 2 study; however, when considering only the patients undergoing coronary angiography, the results are not that gratifying. Indeed, the rate of unneces-sary angiography was 67.6% (69 of the 102 patients undergoing coronary angiography) in the guidelines-directed group, 42.3% (36 of the 85 patients) in the CMR group, and 43.5% in the MPS group (34 of the 78 patients).

CE-MARC 2 is only the last of a long series of studies investigating the role of noninvasive strate-gies in diagnosing IHD.5 Noninvasive tests are used for detection and/or assessment of the functional sig-nificance of epicardial stenosis. Similarly, the clinical pretest probability cited in major guidelines uncondi-tionally refers to the probability of detecting CAD by coronary angiography.6,7 In line with previous studies,3 these findings confirm that, despite the adoption of progressively sophisticated tests and clinical pre-diction tools, there remains a significant divergence between the results from noninvasive strategies and those from invasive coronary angiography. Addition-ally, other studies have documented a high grade of variability among different noninvasive strategies.8,9 These findings are in line with the new paradigm for IHD, which considers obstructive CAD to be only one among many other determinants. Therefore, exclud-ing or confirming obstructive CAD should not be the sole focus when evaluating a patient with suspected heart disease. In line with these considerations, there are two main issues with this approach. Firstly, only a minority of patients with chest pain will have obstruc-tive CAD detected at coronary angiography,3,10-13 with as many as 55% to 75% of men and 75% to 90% of women with typical angina displaying no or mild CAD.14 Additionally, stable coronary plaques can be completely clinically silent.9,15,16 Secondly, contrary to expectations, revascularization by means of percuta-neous coronary intervention performed in chronic IHD patients has a limited, if any, impact on prognosis.17-19 Indeed, whereas the risk of major cardiovascular events is known to increase with increasing CAD bur-den, this risk does not appear to be reduced by per-cutaneous coronary intervention.15,20 Therefore, with the current attitude, we might be neglecting the patient subset with angina and no ob-structive CAD and are probably overtreating those with obstructive CAD. Given also the low, but persistent, risk for adverse events and the increasing costs as-sociated with invasive management, is it appropriate to continue investing major research efforts in develop-ing the best strategy to identify and remove obstructive CAD? Instead of repeatedly praising the modest re-sults of a single strategy, shouldn’t we take advantage of these tools and look carefully at the determinant fac-tors behind the discordant results. This could be a first step toward a better understanding and treatment of patients with suspected chronic IHD. L

AbbreviationsCAD: coronary artery disease; CE-MARC 2: Clinical Eval-uation of Magnetic Resonance Imaging in Coronary Heart Disease 2; CMR: cardiac magnetic resonance; IHD: ischemic heart disease; MPS: myocardial perfu-sion scintigraphy; NICE: National Institute for Health and Care Excellence

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Huqi Heart Metab. (2017) 72:44-46Errare humanum est, perseverare autem diabolicum

REFERENCES

1. Task Force Members; Montalescot G, Sechtem U, Achenback 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. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and man-agement of patients with stable ischemic heart disease: a re-port of the American College of Cardiology Foundation/Ameri-can Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses As-sociation, Society for Cardiovascular Angiography and In-terventions, and Society of Thoracic Surgeons. Circulation. 2012;126:e354-e471.

3. Patel MR, Peterson ED, Dai D, et al. Low diagnostic yield of elec-tive coronary angiography. N Engl J Med. 2010;362:886-895.

4. Greenwood JP, Ripley DP, Berry C, et al. Effect of care guided by cardiovascular magnetic resonance, myocardial perfusion scintigraphy, or NICE guidelines on subsequent unnecessary angiography rates: the CE-MARC 2 randomized clinical trial. JAMA. 2016;316:1051-1060.

5. Douglas PS, Hoffmann U, Patel MR, et al. Outcomes of ana-tomical versus functional testing for coronary artery disease. N Engl J Med. 2015;372:1291-1300.

6. Genders TS, Steyerberg EW, Alkadhi H, et al. A clinical predic-tion rule for the diagnosis of coronary artery disease: validation, updating, and extension. Eur Heart J. 2011;32:1316-1330.

7. Patel MR, Peterson ED, Dai D, et al. Low diagnostic yield of elective coronary angiography. N Engl J Med. 2010;362:886-895.

8. Alexander KP, Chen AY, Wang TY, et al. Transfusion practice and outcomes in non-ST-segment elevation acute coronary syndromes. Am Heart J. 2008;155:1047-1053.

9. Naya M, Murthy VL, Blankstein R, et al. Quantitative relation-ship between the extent and morphology of coronary athero-sclerotic plaque and downstream myocardial perfusion. J Am Coll Cardiol. 2011;58:1807-1816.

10. Hannan EL, Samadashvili Z, Cozzens K, et al. Appropriateness of diagnostic catheterization for suspected coronary artery dis-

ease in New York State. Circ Cardiovasc Interv. 2014;7:19-27.11. Patel MR, Dai D, Hernandez AF, et al. Prevalence and predic-

tors of nonobstructive coronary artery disease identified with coronary angiography in contemporary clinical practice. Am Heart J. 2014;167:846-852 e2.

12. Ong P, Athanasiadis A, Borgulya G, et al. Clinical usefulness, angiographic characteristics, and safety evaluation of intra-coronary acetylcholine provocation testing among 921 con-secutive white patients with unobstructed coronary arteries. Circulation. 2014;129:1723-1730.

13. Zheng X, Curtis JP, Hu S, et al. Coronary catheterization and percutaneous coronary intervention in China: 10-year results from the China PEACE-Retrospective CathPCI Study. JAMA Intern Med. 2016;176(4):512-521.

14. Cheng VY, Berman DS, Rozanski A, et al. Performance of the traditional age, sex, and angina typicality-based approach for estimating pretest probability of angiographically significant coronary artery disease in patients undergoing coronary com-puted tomographic angiography: results from the multinational coronary CT angiography evaluation for clinical outcomes: an international multicenter registry (CONFIRM). Circulation. 2011;124:2423-2432, 1-8.

15. Marzilli M, Merz CN, Boden WE, et al. Obstructive coronary atherosclerosis and ischemic heart disease: an elusive link! J Am Coll Cardiol. 2012;60:951-956.

16. Jespersen L, Hvelplund A, Abildstrom SZ, et al. Stable angina pectoris with no obstructive coronary artery disease is asso-ciated with increased risks of major adverse cardiovascular events. Eur Heart J. 2012;33:734-744.

17. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical ther-apy with or without PCI for stable coronary disease. N Engl J Med. 2007;356:1503-1516.

18. Trikalinos TA, Alsheikh-Ali AA, Tatsioni A, Nallamothu BK, Kent DM. Percutaneous coronary interventions for non-acute coro-nary artery disease: a quantitative 20-year synopsis and a net-work meta-analysis. Lancet. 2009;373:911-918.

19. Sedlis SP, Hartigan PM, Teo KK, et al. Effect of PCI on long-term survival in patients with stable ischemic heart disease. N Engl J Med. 2015;373:1937-1946.

20. Smilowitz NR, Sampson BA, Abrecht CR, Siegfried JS, Hoch-man JS, Reynolds HR. Women have less severe and extensive coronary atherosclerosis in fatal cases of ischemic heart dis-ease: an autopsy study. Am Heart J. 2011;161:681-688.

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Heart Metab. (2017) 72:47-48Glossary Gary d. lopascHuk

AngiogenesisAngiogenesis is the physiological process by which new blood vessels are formed from preexisting blood vessels. Angiogenesis is a critical process in normal growth and development, wound healing, and repair, as well as in the formation of granulation tissue.

CD34+ cellsCD34+ cells are hematopoietic stem cells that express the protein CD34, which is also known as hematopoi-etic progenitor cell antigen CD34. CD34 is a protein identified by the cluster of differentiation nomencla-ture used to identify cell surface molecules, and it is a cell surface glycoprotein that has been shown to par-ticipate in cell-cell adhesion. Identification of CD34+ cells is often used as a marker for activated hemato-poietic stem cells.

Framingham Heart StudyThe Framingham Heart Study was initiated in 1948 as a joint effort between the National Heart Institute (now the National Heart Lung and Blood Institute) and Boston College and is now the longest running prospective cohort study in the United States. The objective of the study was to identify risk factors for the development of cardiovascular disease over time in participants who had not yet developed car-diovascular disease or suffered myocardial infarction or stroke. The first generation of participants was enrolled in Framingham, Massachusetts in 1948; a second generation, in 1971; and a third generation, in 2002 and 2003. The Framingham Heart Study has contributed to the understanding of overall and cardiovascular mortality in the setting of various pa-thologies, including obesity, diabetes, and metabolic syndrome.

GlycolysisGlycolysis is the series of biochemical reactions oc-curring in the cytosolic compartment that converts a glucose molecule into two molecules of pyruvate. In the presence of oxygen (ie, the aerobic setting), pyruvate is transported into the mitochondria and undergoes oxidative decarboxylation, yielding acetyl coenzyme A. In the absence of oxygen (ie, the an-aerobic setting), pyruvate is reduced to lactate by the enzyme lactate dehydrogenase, which generates the nicotinamide adenine dinucleotide (NAD+) required to maintain flux through glycolysis.

HbA1c

Glycated hemoglobin (HbA1c) forms from the non-enzymatic coupling of glucose to the major compo-nent of adult hemoglobin (ie, HbA α2β2). Glucose, via a complex series of reactions, is coupled to specific valine residues of HbA β chains. HbA1c levels at a threshold of 6.5% can be used as a diagnostic test indicative of diabetes. HbA1c levels are reflective of av-erage glycemic control over a period of 2 to 3 months before testing/analysis.

If currentThe funny current (If), also referred to as a pacemaker current, is a hyperpolarization-activated inward cur-rent of mixed ionic nature (Na+, K+) that contributes to pacemaker activity in sinoatrial node cells (also atrioventricular node cells, and Purkinje fibers). The pore-forming subunits of the If channel are formed by members of the hyperpolarization-activated cy-clic nucleotide–gated gene family (HCN1-HCN4). As such, If is responsive to changes in intracellular cyclic adenosine monophosphate (cAMP) levels in response to, for example, the activation of β adreno-ceptors (increased cAMP) or M2 muscarinic recep-tors (decreased cAMP), and thus contributes to the basic physiological mechanisms mediating the ef-fects of the autonomic nervous system on heart rate.

Microvascular dysfunctionMicrovascular dysfunction (also known as small-vessel disease) occurs when damage arises in the walls and inner lining of the small coronary artery blood vessels that branch off from the larger coronary arteries (ie, left coronary artery). The damage in these smaller coronary artery blood vessels can produce spasms that decrease blood flow to the myocardium and thereby cause isch-emia, and is more likely to develop in women.

Silent ischemiaMyocardial ischemia describes the situation where the heart/myocardium does not receive enough blood through the coronary circulation. The reduced blood flow and subsequent lack of oxygen delivery to the myocardium produces the sensation of chest pain, which is known as angina. If an individual does not experience the sensation of pain, it is referred to as “silent ischemia.” Individuals who have experienced previous heart attacks or are diabetic are at increased risk for developing silent ischemia.

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Heart Metab. (2017) 72:47-48Glossary Gary d. lopascHuk

TNF-αTumor necrosis factor-α (TNF-α) is a proinflamma-tory cytokine produced primarily by macrophages (also by other cells of the immune system, cardiac myocytes, adipocytes, fibroblasts, neurons). TNF-α is produced as a 216-amino-acid transmembrane protein arranged as homotrimers. The metallopro-teinase, TNF-α converting enzyme (TACE/ADAM17) proteolytically cleaves transmembrane homotrimers, releasing soluble, 51-kDa TNF-α homotrimers. Both transmembrane and soluble TNF-α are biologically active, exerting effects via the activation of two re-ceptor subtypes, TNFR1 (transmembrane, soluble TNF-α homotrimers) and TNFR2 (transmembrane TNF-α homotrimers).

Variant anginaVariant angina (also known as vasospastic angina) is a form of angina (sensation of chest pain) that occurs at rest in cycles. It is typically caused by a vasospasm, which is an arterial spasm that induces vasoconstric-tion of smooth muscle cells within the blood vessel wall, leading to myocardial ischemia.

EDITORIALG. D. Lopaschuk

ORIGINAL ARTICLESDiabetes: the cost of globalization? P. M. Nilsson, L. Bennet

Better glycemic control and cardiovascular outcomes G. D. Lopaschuk

Treating myocardial ischemia in diabetics: drugs, surgery, and stents R. Belardinelli

Early detection of left ventricular dysfunction in diabetic patients D. Y. Leung, M. Leung

Clinical benefits of targeting cardiac cells directly with trimetazidine in patients with coronary disease and diabetes G. Fragasso, G. Anastasia, G. Monaca, G. Pinto

CASE REPORTManaging chest pain in a diabetic patientC. Scali

REFRESHER CORNERCardiac energy metabolism in diabetesK. L. Ho, J. Ussher

HOT TOPICSWhat cardiologists need to know about new drugs and new techniques to cure diabetesJ. E. Salles

GLOSSARYG. D. Lopaschuk

In the next issue:Cardiovascular diseases and diabetes: causes and cures

Cardiovascular diseases and diabetes: causes and cures

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