Antagonist molecules in the treatment of angina

Abstract

Introduction

Management of chronic angina has evolved dramatically in the last few decades with several options for pharmacotherapy outlined in various evidence-based guidelines.

Areas covered

There is a growing list of drugs that are currently being investigated for treatment of chronic angina. These also include several herbal medications, which are now being scientifically evaluated as potential alternative or even adjunctive therapy for angina. Gene- and cell-based therapies have opened yet another avenue for management of chronic refractory angina in ‘no-option’ patients who are not candidates for either percutaneous or surgical revascularization and are on optimal medical therapy. An extensive review of literature using PUBMED, Cochrane database, clinical trial databases of USA and European Union was done and summarized in this review. This review will attempt to discuss the traditional as well as novel therapeutic agents for angina.

Expert opinion

Several pharmacological and non-pharmacological therapeutic options are now available for treatment and management of chronic refractory angina. Renewed interest in traditional therapies and cell- and gene-based modalities with targeted drug delivery systems will open the doors for personalized therapy for patients with chronic refractory angina.

1. ANGINA, A HISTORICAL PROSPECTIVE

Although often thought to be a modern disease, the history of angina could have started with an atypical presentation 330 years ago. A historical perspective of angina is outlined in an excellent treatise by Opie [1]. Heberden first described angina, in 1772, as a disorder of the breast in a lecture given to Royal College of Physicians. He was the first to describe the association of exertion to symptom exacerbation, and distribution of pain to left arm and left sub-sternal area. John Hunter described precipitation of angina by emotional crisis in 1793, and performed an autopsy on a patient who suffered from ‘a violent transport of anger’ who ‘fell down and expired immediately’. The two coronary arteries had become one piece of bone. Parry localized the syndrome to heart in 1799, where he linked it to poor blood flow. Alan Burns described the supply and demand hypothesis in 1809, and Virchow described ischemia in 1858. Osler described the coronary lesions as cause of angina ‘obliterative endarteritis’. Sir Thomas Lewis, in 1933, described the concept of absolute and relative ischemia and postulated ‘substance P’ as the origin of the muscular pain in claudication. Lauder Brunton first used amyl nitrate to treat angina in 1867. It was not until the mid-20^th century when beta-blockers (BB) and calcium channel blockers (CCB) were first discovered and used to treat angina.

2. ANGINA – A GLOBAL ISSUE

Over the past century, the global burden of cardiovascular disease (CVD) has increased dramatically. The proportion of deaths attributable to ischemic heart disease was <10% at the turn of 20^th century, increasing to approximately 30% of deaths worldwide and nearly 50% of deaths in the industrial world. Coronary artery disease (CAD) is the leading cause of death and disability worldwide, resulting in 7.2 million deaths per year [2]. CVD is the leading cause of death worldwide, accounting for around 16.7 million deaths each year, mainly from heart attacks and strokes [3]. This number is predicted to increase to approximately 25 million deaths by 2020, if the current trends continue [4]. Current estimates show that the global burden of CVD far exceeds that of its death toll, affecting an estimated 128 million people, or nearly eight times the number for cardiovascular mortality.

3. PATHOPHYSIOLOGY OF ANGINA

Understanding the basic pathophysiology of angina is paramount to appropriately treat the patients. By definition, myocardial ischemia results from an imbalance between myocardial energy supply, from insufficient sources of oxygen and substrate (glucose, free fatty acids (FFAs)), and myocardial oxygen demand. Mismatch of myocardial oxygen supply and demand is the common pathway which results in angina, however the mechanisms behind this mismatch are complex, involving substrate supply and utilization, enzymatic activities, and other variables involved in intermediary metabolism and mitochondrial function. These play important roles in the pathogenesis of myocardial ischemia in angina, acute coronary syndromes (ACS), and during reperfusion ischemic injury (Figure 1). Major determinants of myocardial oxygen demand are heart rate, blood pressure, and myocardial wall tension, in turn influenced by preload, afterload, and contractility. Physiological increases in myocardial oxygen needs are normally provided by rises in coronary blood flow. Ability of coronary arteries to increase flow to meet myocardial metabolic demand during exercise, called coronary flow reserve, is about four to six times the resting value at maximum dilatation of the coronary arteries [5, 6]. Coronary auto regulation is a complex phenomenon with many regulating variables, and detailed discussion is beyond the scope of this review [7]. Clinically, angina may be further subdivided according to common usage [8], as follows:

Figure 1.

Pathophysiology of chronic stable angina.

3.1 Chronic, stable

Chronic stable angina is generally due to one or more significant obstructive lesions in coronary arteries, defined as stenosis of ≥50% of the diameter of the left main coronary artery or stenosis of ≥70% of the diameter of a major epicardial vessel, and as stenoses are fixed, the angina is due to demand ischemia.

3.2 Decubitus

Attacks of decubitus angina occur upon recumbency, which raises end-diastolic volume, myocardial wall tension, and hence oxygen demand.

3.3 Nocturnal

Anginal discomfort awakens the patient, generally due to respiratory pattern changes, episodic tachycardia, hypoxia due to respiratory changes, or recumbency.

3.4 Refractory

Stable chronic angina is termed refractory when it is not controllable by a combination of maximal anti-anginal medication, angioplasty or coronary artery bypass surgery, or when the risks are unjustified.

3.5 Unstable (also called crescendo or rest)

Symptoms are recent onset, severe, and occur at rest or with minimal exertion, last >10 minutes, and follow a crescendo pattern. Unstable angina is an ACS, and when myocardial necrosis becomes evident from elevations in biomarkers, such as troponin I and troponin T, the applicable clinical term becomes non-ST-elevation myocardial infarction, or NSTEMI, in the absence of ST-segment changes. The European Society of Cardiology defines ACS as acute chest pain (ie, chest pain at rest >20 min within the prior 48 hours) together with electrocardiographic (ECG) changes suggesting myocardial ischemia and/or elevation of cardiac markers.

3.6 Microvascular (also called Syndrome X)

More common in women, angina-like pain, ‘normal’ or non-obstructive CAD by coronary angiograms, and positive exercise tests, sometimes with perfusion defects by stress imaging, are a basic diagnostic triad in microvascular angina [9]. Response to nitrates and other anti-ischemic agents is less reliable, and hormonal abnormalities, changes in pain perception with exaggerated sensitivity, insulin resistance, and psychological overlays may be modifying factors, just as in angina associated with obstructive CAD. Also as with obstructive CAD, most of these patients have varying degrees of endothelial dysfunction proportional to their atherosclerosis risk factor burden. Many have vascular smooth muscle dysfunction and/or even microvascular spasm. Again, similar to obstructive CAD patients, release of vasoactive substances, autonomic dysfunction, and loss of estrogen may all contribute. Chest pain may occur at rest, and/or under conditions of cardiac stress without evidence of ischemia. Gastroesophageal reflux disease (GERD) and esophageal motility and airway disorders are common comorbidities. In part, treatment is difficult because therapeutic responses may not be sustained and because the field lacks an evidence base of large, longer-term randomized controlled trials. Consequently, no guidelines exist to inform practitioners on the management of these patients.

3.7 Coronary artery spasm

Some forms (e.g., rest angina with ST segment elevation) are also called Prinzmetal’s or variant angina, or angina inversa. This variant form of angina occurs at rest, often at night or early morning hours, or with exertion. It is caused by focal or diffuse spasm of an epicardial coronary artery. Most often it is associated with a non-obstructive atherosclerotic lesion. Coronary spasm is a more common cause of chest pain and ACS than formerly believed, and may contribute to pathology with or without coexisting obstructive plaques, more frequently found in men. Over the years, coronary spasm has been linked to hypertension, Asian origin, low intracellular magnesium levels, hyperinsulinemia, defective focal nitric oxide production, and use of tobacco or cocaine as well as oral decongestants containing sympathetic amines.

3.8 Atypical angina

Patients with nonclassical symptoms and signs, such as absence of substernal location and character, exertional trigger, or typical relief with rest or nitroglycerin, are grouped under the term atypical angina. Atypical presentations are more frequent in women and diabetics, displaying variable pain intensity or thresholds, timing, and characteristics. Palpitations, sharp lancinating or back pain are confounding complaints.

3.9 Silent ischemia and anginal equivalents

In some patients, particularly diabetics and the elderly, myocardial ischemia may cause symptoms other than precordial discomfort. These may include dyspnea, diaphoresis, nausea and emesis, fatigue, weakness, altered sensorium, light headedness, and fainting. In the absence of chest pressure, heaviness, pain or sensorial cognition, ischemia is also called silent ischemia.

4. MANAGEMENT OF ANGINA – BASIC PRINCIPLES AND TRADITIONAL THERAPIES

Guidelines for the management of stable angina have been published by the American Heart Association (AHA), American College of Cardiology (ACC), and the European Society of Cardiology (ESC) [10–12]. The key to chronic management of patients with stable angina is treatment of underlying atherosclerotic disease and reduction of other established cardiovascular risks. This is critical to prevent future cardiac events and progression of CAD, which can worsen angina, even if there is complete revascularization [12–13]. One of the most effective treatments for reducing symptoms of angina is revascularization [14]. Several randomized trials, however, have demonstrated that revascularization does not improve the mortality in patients with stable chronic angina [15–19]. In a recently published meta-analysis of 10 prospective randomized controlled trials with a total of 6752 patients, no differences between percutaneous coronary intervention (PCI) versus medical therapy for all-cause mortality, cardiovascular mortality, angina relief at the end of follow-up were noted. PCI was not associated with reductions in all-cause or cardiovascular mortality, myocardial infarction (MI), or angina relief [20]. Surgical revascularization was in fact superior to percutaneous revascularization (BARI2D and FREEDOM) in reducing the death and MI in patients with diabetes [17–19, 21] and those with severe left main, proximal LAD disease or high syntax score (SYNTAX) [22]. These findings continue to support existing clinical practice guidelines that medical therapy be considered the most appropriate initial clinical management for patients with stable angina. Other non-pharmacological interventions include cardiac rehabilitation, the alleviation of angina symptoms through training, and mechanical therapies, such as external enhanced counterpulsation, extracorporeal shockwave myocardial revascularization, spinal-cord stimulators, stellate-ganglion block, and coronary-sinus occluders and are beyond the scope of this review.

4.1 Optimal medical therapy

as defined by COURAGE trial [15] includes: anti-platelet therapy with aspirin (81–325mg daily), or 75mg Clopidogrel if intolerant to aspirin; long acting beta-blocker (BB), calcium channel blocker (CCB) and a long acting nitrate alone or in combination; angiotensin-converting enzyme inhibitor (ACEi) or aldosterone receptor blocker (ARB) as tolerated; aggressive reduction of low density lipoprotein (LDL) to target of 65–85mg/dl using a statin alone or in combination with ezetamibe. Once LDL is at goal, target high-density lipoprotein (HDL) is above 40mg/dL and triglycerides below 150mg/dL. Lifestyle interventions include regular physical activity, complete cessation of tobacco use and exposure to tobacco smoke, and diet modifications to improve blood pressure, blood glucose levels, and serum lipid levels, along with control of diabetes and weight management [11, 23]. In pooled data including 5034 patients obtained from the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) diabetes subgroup (n = 766 of 2287), the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial (n = 2368), and the FREEDOM (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes) trial (n = 1900), the percentages of patients achieving the 1-year low-density lipoprotein cholesterol targets compared with baseline increased from 55% to 77% in COURAGE, from 59% to 75% in BARI 2D, and from 34% to 42% in FREEDOM. Although similar improved trends were seen for systolic blood pressure, glycemic control, and smoking cessation, only 18% of the COURAGE diabetes subgroup, 23% of BARI 2D patients, and 8% of FREEDOM patients met all four pre-specified treatment targets at 1 year of follow-up. These disappointing results suggest that a significant proportion of diabetic (and non-diabetic) CAD patients fail to achieve pre-specified targets for four major modifiable cardiovascular risk factors even in clinical trials with well-planned, guideline-based secondary prevention algorithms [24].

4.2 Traditional therapies

include BBs, nitrates, and CCBs. These agents work by reducing myocardial oxygen demand (by attenuation of the increase in heart rate, blood pressure, and contractility that occur during work activity), lowering ventricular preload, or improving blood supply by augmenting coronary vasodilatory capacity [25, 26].

4.2.1 Nitrates

produce direct, endothelium-independent vasodilatation and reduce myocardial ischemia by relaxation of venous smooth muscle, which lowers ventricular preload and oxygen demand [8]. Short-acting nitrates provide effective symptomatic relief and can be used as prophylaxis before physical exertion that might induce angina [27]. Long-acting nitrates available in multiple formulations are often used to prevent or reduce the frequency of angina in patients with CAD either as monotherapy or in combination with BB or CCB.

4.2.2 Beta-adrenergic receptor blockers

BBs are usually indicated as first-line therapy for patients with stable angina [11, 12]. These drugs reduce death and recurrent infarction in patients with previous myocardial infarction and in those with depressed left ventricular function, and also lower heart rate and systolic blood pressure by inhibition of β1 and β2 adrenergic receptors, which are activated by circulating endogenous norepinephrine and epinephrine in response to exercise or stress. The risk of suffering cardiovascular death or myocardial infarction was reduced by some 30% in post-MI trials with beta blockers [28] however, large BB studies in stable angina, the angina pectoris study in Stockholm ‘APSIS’ [29] and total ischemic burden European trial ‘TIBET ‘ [30] studies, did not show a significant difference in outcome between patients treated with BB or CCB.

4.2.3 Calcium channel blockers

Several clinical studies have demonstrated anti-anginal efficacy of CCBs [31–35]. The CCBs are all effective antihypertensive agents, a feature that is particularly helpful in the management of patients with both angina and hypertension. While CCBs have been used extensively in treatment of angina, their impact on cardiovascular outcomes in coronary artery disease and stable angina has not been systematically evaluated in randomized controlled trials. In the INVEST trial [36], no difference were noted in prevention of the outcome of all-cause mortality, nonfatal MI, or nonfatal stroke in patient with hypertension and CAD treated either with Verapamil or Atenolol based therapies. Furthermore, similar results were observed comparing the treatment strategies for all-cause mortality, cardiovascular death, cardiovascular hospitalization, and blood pressure control.

Information concerning the effect of the specific classes of anti-anginal therapy on long-term clinical outcome is limited. As such, there is little rationale, in many patients, to choose one class of anti-anginal over another based on a different effect of therapy on clinical outcome or events. ACC/AHA and ESC guidelines for management of chronic stable angina, recommend using BBs as initial therapy for relief of symptoms in patients with chronic stable angina. While BBs have been shown to reduce mortality after MI [28] and may be a valid treatment for patients with stable angina, recently published data from the REACH registry have questioned these benefits [37]. Among patients enrolled in the international REACH registry, BB use was not associated with a lower event rate of cardiovascular events at 44-month follow-up, even among patients with prior history of MI. CCBs or long-acting nitrates as stand alone agent(s) or as an adjunctive therapeutic agent are recommended for relief of symptoms when BBs are contraindicated or cause unacceptable side effects or when initial treatment with BBs is unsuccessful in patients with chronic angina.

5. SECOND-GENERATION ANTI-ANGINAL DRUGS

Over the past decade, several newer agents have been described and are being used increasingly in daily clinical practice.

5.1 Ranolazine

is an active piperazine derivative, which has been studied, in several placebo-controlled, randomized trials of stable angina, either as monotherapy [38] or when added to background therapy with β-adrenergic-receptor blockers, calcium-channel blockers, or nitrates [39,40]. Ranolazine reduced angina-attack frequency and nitroglycerin consumption, and increased exercise treadmill duration, time to onset of angina, and ischemic ST-segment depression on treadmill testing without a clinically significant change in heart rate or blood pressure [38]. Ranolazine is now approved for first-line therapy of angina in the United States. Ranolazine has additional clinical implications with emerging role in arrhythmias, heart failure and reduction of hemoglobin glycosylation [41].

5.2 Nicorandil

Nicorandil, a nicotinamide-nitrate ester [N-(2-hydroxyethyl)-nicotinamide nitrate], is the only clinically available potassium channel opener with antianginal effects, and with comparable efficacy and tolerability to existing antianginal therapy. The IONA (impact of nicorandil in angina) trial was carried out in the UK in which 5126 high-risk angina patients were randomly assigned to receive either placebo or nicorandil [42, 43]. Nicorandil reduced the risk of the primary composite end point (CHD death, nonfatal myocardial infarction [MI], or unplanned hospitalization with cardiac chest pain) by 17% (p = 0.014) over a mean follow-up of 1.6 years. Likelihood of deaths from all causes and fatal myocardial infarction was reduced by 35% in patients treated with nicorandil in a prospective observational study of a large cohort of patients who had angiographic evidence of CAD (Japanese Coronary Artery Disease Study) [44]. Nicorandil is not currently Food and Drug Administration (FDA) approved in the USA but is used in Europe and Japan. The ESC lists a class I indication for nicorandil (level of evidence C) for patients with intolerance or contraindications to BB or CCB, and a class IIa indication (level of evidence C) for patients in whom dual antianginal therapy with other classes of drugs is unsuccessful [12].

5.3 Bepridil

It was first approved by the FDA in 1990. It is a CCB, but it is often placed in a category of its own. Bepridil acts as a direct negative chronotrope, ionotrope and vasodilator and is thus able to provide angina relief. Another difference from commonly used CCBs is that bepridil inhibits receptor-operated, voltage-gated calcium channels as well as potassium currents and intracellular calcium/calmodulin complexes. This action results in decreased myocardial oxygen consumption, coronary vasodilation, and increased coronary blood flow. Bepridil helps to decrease the frequency of angina attacks, as measured by the use of nitrates. However, concerns regarding prolongation of the corrected QT interval and torsade de pointes have limited its use in North America [45].

5.4 Ivabradine

Heart rate reduction is a well-accepted and effective approach for the prevention of angina pectoris. Ivabradine decreases heart rate through selective inhibition of I_f, an inward potassium current that is activated by hyperpolarization over the diastolic range of voltages of myocytes in the sinoatrial node [46–49]. Ivabradine reduces the firing rate of the pacemaker cells in the sinoatrial node without affecting the duration of the action potential [47] and is most effective during tachycardia. Ivabradine is effective in the treatment of stable angina both as monotherapy and when given in combination with a BB [50–52].

5.5 Trimetazidine

During hypoxia, glucose oxidation is preferable to the oxidation of free fatty acids (FFA) for the generation of the ATP necessary for myocyte function. Modulation of cardiac metabolism by partial inhibition of the oxidation of FFA has been tested as a strategy to alleviate stable angina [53–55]. Of the numerous inhibitors of fatty-acid oxidation that have been developed, trimetazidine is the most widely used throughout Europe and Asia, but is not available in North America. Trimetazidine exerts no significant negative inotropic or vasodilatory properties at rest or during exercise [56–59]. The actual mechanism of antianginal effect is debatable with some research demonstrating a reduction in the rate of FFA oxidation accompanied by an increase in glucose oxidation rate during low-flow ischemia thought to be due to the inhibition of a key enzyme in the β-oxidation pathway [56]. Trimetazidine has been shown in several randomized, controlled trials to reduce symptoms of angina and to improve exercise capacity [53–55]. The Task Force on the Management of Stable Angina Pectoris of the ESC lists trimetazidine as a class IIb indication (level of evidence B) as adjunct or substitution therapy when conventional drugs are not tolerated [12].

5.6 L-Arginine

L-Arginine is the substrate for nitric oxide synthase. It has been shown that l-arginine administration improves endothelium dependent vasodilation in patients with risk factors for atherosclerosis, such as hypercholesterolemia, smoking, aging, and hypertension and in patients with coronary artery disease, microvascular angina pectoris, and peripheral arterial disease [60–65]. The clinical studies on oral l-arginine therapy as an antianginal are somewhat contradictory. No improvement in exercise tolerance in a group of 40 men with stable angina receiving l-arginine 5 mg was seen as compared to placebo [66]. However, a single-center, double-blind, placebo-controlled trial involving 22 patients with stable angina showed that treatment with l-arginine resulted in an increase in exercise duration and maximum workload during stress testing as well as an increase in the time to onset of ST-segment depression [67]. The FDA currently licenses l-arginine for use in the USA.

5.7 Perhexiline

Perhexiline was first introduced in the 1970s as an anti-anginal agent effective at relieving symptoms of angina, improving exercise tolerance, and increasing workload needed to induce ischemia. The drug works in part by modifying myocardial substrate utilization from fatty acids to carbohydrates [68]. The use of perhexiline fell out of practice in mid 1980s due to reports of hepatotoxicity and peripheral neuropathy [69, 70]. These effects were later shown to occur in patients who were ‘slow hydroxylators’ secondary to a polymorphic variant of the cytochrome P-450 enzyme (CYP2D6) which metabolizes the drug [71]. Adverse effects of the drug are completely avoided by maintaining drug plasma concentration between 0.15 and 0.60 mg/L. In a large multicenter experience on the use of perhexiline in chronic heart failure and refractory angina using 151 patients in UK, perhexiline therapy was shown to provide symptomatic relief in the majority of patients with minimal side effects or toxicity [72]. Careful therapeutic level monitoring for dose titration is important to prevent acute and chronic toxicity. Patients with refractory angina were more likely to be responders. In the UK, perhexiline is available off license, on a named patient and named consultant cardiologist basis. In some parts of the world, particularly Australia, perhexiline is quite widely used in the treatment of refractory angina and unstable angina, with excellent results [73].

6. NOVEL THERAPIES FOR ANGINA

6.1 Etoximir

It is similar to perhexiline, and is a potent carnitine phosphate transferase-1 inhibitor [74]. Etomoxir was initially introduced into the clinical market as a potential diabetic agent [75] and has shown potential as an antianginal agent in ex vivo research but is yet to be investigated in a randomized controlled trial [76]. An initial small, non-randomized study showed improvement in symptoms in heart failure [77]. Following this, the drug was withdrawn from the market because of side effects on the liver, which was detected in a larger, randomized study [78].

6.2 Omapatrilat

During myocardial ischemia, atrial and brain natriuretic peptides and bradykinin are released, all of which have anti-ischemic properties. These vasoactive peptides are inactivated by neprilysin, and bradykinin is also degraded by angiotensin-converting enzyme [79]. In a proof-of-concept study, omapatrilat, a potent vasopeptidase inhibitor with selective and competitive inhibitory activity of angiotensin-converting enzyme and neprilysin, was tested in 348 patients with stable angina [80]. Treatment with omapatrilat significantly increased total exercise capacity, time to onset of angina, and time to onset of ischemic ST-segment depression at peak plasma concentrations, with fewer patient reports of exercise-induced angina, compared with placebo. The beneficial effects were less evident 24 h after dosing. Omapatrilat is not commercially available, primarily due to concerns over angioedema.

6.3 Fasudil

The Rho-related GTP-binding proteins mediate intracellular signaling induced by activation of heterotrimeric G-protein-coupled receptors and growth receptors and regulate the sensitivity of vascular smooth muscle in the cardiovascular system to calcium, and have been shown in animal models of ischemic heart disease to reduce hypercontraction of vascular smooth muscle and ischemic ST-segment depression [53, 81]. Fasudil is a Rho kinase inhibitor. In a small double blind, placebo-controlled, randomized clinical trial using 84 patients with stable angina, fasudil was compared with placebo [82]. In this proof-of-concept trial, fasudil and placebo both tended to increase treadmill exercise time compared with baseline (by 118 s and 86 s, respectively), although the differences were not statistically significant. Fasudil did, however, significantly prolong the time to exercise-induced ischemic ST-segment depression compared with placebo.

6.4 DW1865

DW1865, a novel Rho kinase inhibitor, exhibited significant antihypertensive properties both in in vitro and in vivo, presumably via inhibition of intracellular Rho kinase activation [83]. In the rat heart-derived H9c2 cell line, DW1865 blocked angiotensin II-induced stress fiber formation and cellular hypertrophy. These cellular effects of DW1865 suggest that the beneficial effects of Rho kinase inhibition exceed blood pressure lowering to include potential reduction of hypertrophy in cardiomyocytes. DW1865 may be useful as an effective Rho kinase inhibitor in pharmaceutical or clinical applications in treatment of ischemic heart disease.

6.5 Allopurinol

Allopurinol inhibits xanthine dehydrogenase/oxidase, an enzyme required in the oxidation of hypoxanthine and xanthine, which produces uric acid. This agent has long been commercially available and, at therapeutic doses, results in a direct decrease in uric acid and an indirect decrease in purine synthesis by feedback inhibition of amidophosphoribosyltransferase, a rate-limiting enzyme. Recently, interest has grown in the possible antianginal effects of allopurinol. In a small, placebo-controlled, randomized trial of 65 patients with stable angina, high-dose allopurinol (300 mg twice daily) significantly increased total exercise duration, time to onset of angina, and ischemic ST-segment depression [84]. The exact mechanism of action is unknown, but inhibition of xanthine dehydrogenase/oxidase might reduce oxidative stress in ischemic myocardium. Additional randomized, placebo-controlled trials are required in larger series of patients to confirm these findings before allopurinol can be recommended as an effective antianginal therapy.

6.6 Testosterone

Testosterone has been shown to result in coronary artery dilation and increased blood flow in humans. The mechanism appears to be endothelium independent and may involve the ion channels on vascular smooth muscle cells [85]. Numerous cross-sectional case control studies report hypotestosteronaemia in patients with CAD [86, 87]. Several small studies have reported beneficial anti-ischemic effect of testosterone delivered via transdermal [88], intra-muscular [89] and chronic administration via oral therapy [90]. Acute administration of testosterone also provides rapid improvements in myocardial ischemia [91, 92] prompting the suggestion that testosterone may beneficially influence coronary vascular tone. This was confirmed in a subsequent study by Webb et al [93] in which intra-coronary infusion of physiological concentrations of testosterone increased coronary artery diameter and coronary blood flow in male patients with CAD, consistent with a direct coronary vasodilatory action. Although none of the patients experienced adverse prostatic or hematological effects, concern exists regarding possible health effects of long-term therapy with testosterone in the general male population.

6.7 Estrogen

Estrogen has also been investigated as an antianginal agent and has been shown to dilate coronary arteries and improve endothelial function [94]. A randomized, double blind, placebo-controlled trial involving 74 female patients with stable angina showed that estradiol and norethindrone therapy improved exercise duration and the time to onset of ST-segment depression [95]. There was also a reduction in the number of ischemic events in the treatment group. However, concern was raised in the Women’s Health Initiative study, which showed that overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women [96]. These benefits, however, must be weighed against the potential for an initial increase in cardiac events caused by estrogen therapy in females with coronary artery disease. Given concerns about potential side effects, neither testosterone nor estrogen is recommended for treatment of refractory angina.

6.8 Molsidomine

Molsidomine or N-ethoxycarbonyl-3-morpholinosydnonimine (SIN10) is a nitric oxide donating vasodilator [97] and has been used to treat angina. When compared with placebo, it reduced the incidence of anginal attacks, the use of sublingual nitrates, and increased exercise capacity in patients with stable angina [98]. Higher doses provided better protection from angina, although hypotension was a side effect [99]. This new drug is not yet in routine clinical use; however, it may serve as useful alternative or adjunct to conventional antianginal treatment. Further studies and longer follow-up will determine its place in patients with coronary artery disease.

6.9 Mildronate

Mildronate is a structural aza-analogue of the carnitine precursor gamma-butyrobetaine (GBB). It inhibits carnitine biosynthesis reversibly. The efficacy of mildronate has been shown to improve systolic function, improve arterial vascular tone, increase stress tolerance and reduce anginal symptoms [100, 101]. Dose dependent improvement in exercise tolerance in patients with stable angina treated with standard therapy was noted in a Phase II, placebo-controlled, double-blind randomized trial [102]. Mildronate is approved for clinical use in Latvia, Lithuania, Russia and Ukraine.

6.10 Phosphodiestrase inhibitors

The efficacy of phosphodiesterase type 5 inhibitors (PDE5I) in cardiovascular diseases appears to be related primarily to beneficial effects on endothelial function [103]. In fact, the PDE5I sildenafil was originally investigated for its potential in treating angina, however, the data from phase I trial for anti-anginal use was not encouraging. Recent studies suggest that the drug has powerful cardioprotective effect against ischemia/reperfusion injury, doxorubicin-induced cardiomyopathy and anti-hypertensive effect induced by chronic inhibition of nitric oxide synthase in animals [103].

6.11 Amiodarone

Combination therapy of amiodarone with conventional antianginal therapy is well tolerated and results in a significant improvement in exercise capacity and a mild reduction of symptoms in patients who have continued, limiting angina pectoris with conventional triple therapy [104].

6.12 Omecamtiv mecarbil

The cardiac myosin activator omecamtiv mecarbil has been studied in healthy volunteers in whom it produced dose-dependent and concentration-dependent increases in systolic ejection time, fractional shortening, and ejection fraction without increasing oxygen consumption, thereby increasing myocardial efficiency [105, 106]. In a double-blind, placebo-controlled, crossover, dose-ranging, Phase II trial investigating the effects of omecamtiv mecarbil (formerly CK-1827452), given intravenously for 2, 24, or 72 h to patients with stable heart failure and left ventricular systolic dysfunction receiving guideline-indicated treatment, concentration-dependent increases in left ventricular ejection time (up to an 80 ms increase from baseline) and stroke volume (up to 9.7 mL) were recorded, associated with a small reduction in heart rate [107]. Angina was not noted in the study population despite increased chronotropy, and this may potentially be exploited as a novel agent for patients with angina and depressed LV function.

7. THERAPEUTIC ANGIOGENESIS AND ANGINA

Despite several options for medical management of angina, there are substantial numbers of patients who continue to have refractory symptoms lacking further treatment options. Therapeutic angiogenesis has become an important focus of cardiovascular research. The goal is to enhance neovascularization and arterial blood flow to myocardium, which in turn may relieve myocardial ischemia and improve regional and global ventricular function [108]. The natural process of angiogenesis is complex, with a large number of angiogenic growth factors, as well as inhibitors of angiogenesis, having been identified [109]. Clinical experience with protein growth factors and genes encoding for these growth factors to enhance myocardial angiogenesis primarily involves vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). Protein alone, plasmid, and adenoviral vectors using a variety of delivery methods (intravenous, intracoronary, and intramyocardial) have been used in clinical trials of angiogenesis. Initial pre-clinical phase I trials were promising [110–113] and led to several phase II trials which had disappointing results. These data have been reviewed extensively in various publications [114, 115]. The clinical benefit of angiogenic therapy for refractory angina has been difficult to prove, in part because of heterogeneous patient populations, suboptimal patient selection, and placebo effects. The primary efficacy endpoint was also different in various trials and has included the assessment of anginal functional class, exercise tolerance time, improvement in myocardial perfusion, or freedom from cardiovascular events.

8. CELL-BASED THERAPIES

Several experimental and small to intermediate pre-clinical data suggest feasibility and safety of cell-based therapies in patients with ischemic cardiomyopathy [116–119]. To date, different autologous adult stem and progenitor cells, in particular several subtypes of bone marrow-derived cells, isolated adipose tissue-derived or cardiac derived stem/progenitor cells are under preclinical and clinical evaluation. Additionally, embryonic stem cells and induced pluripotent stem cells provide regenerative capacity and improve cardiac function after ischemia in animal models. Overview of cell types for cardiac repair in acute myocardial infarction and chronic ischemic cardiomyopathy is elegantly discussed in an extensive review by Templin et al [120] and Sequeira et al [121]. The best method for delivery of the stem cells is contentious. Several modalities with varying success and pitfalls have been described. These include peripheral infusion, intramyocardial injection during bypass grafting, endocardial using various catheters as well as intracoronary infusion [120–124].

Few of the landmark studies on cell based therapy for chronic myocardial ischemia and angina are outlined in this section. In the randomized-controlled, double-blind trial conducted by van Ramshorst et al [125], intramyocardial application of BMCs resulted in a modest but significant improvement of myocardial perfusion as assessed by SPECT, angina severity, and quality of life during a 3-month follow-up in patients with severe angina (classes III–IV), despite optimal medical therapy, ineligible for myocardial revascularization, and evidence of myocardial ischemia at baseline. Similarly, 6 months after direct injection of autologous BMCs in patients with severe refractory angina, a significant improvement of exercise time, LV function, and NYHA functional class was observed in the PROTECT-CAD trial [126]. Significant improvements in angina frequency and exercise tolerance in patients with refractory angina who received intramyocardial injections of autologous CD34+ cells (10⁵ cells/kg) was the high light of ACT34-CMI trial [127]. The G-CSF in Angina patients with Ischemic heart disease to stimulate Neovascularization (GAIN 1) trial sought to assess the safety and efficacy of an intracoronary infusion of CD133⁺ stem cells following pretreatment with G-CSF in patients with refractory angina. The rate of serious adverse events was significant, with numerous episodes of myocardial ischemia. While there was an improvement in a range of subjective angina parameters, there was no change in myocardial perfusion or ischemia detected by SPECT imaging or dobutamine echo. Furthermore, the addition of intracoronary CD133⁺ did not improve either subjective or objective parameters of myocardial ischemia [128].

The mechanism of therapy is not clearly understood. Improvements are mostly attributed to paracrine factors. These appear to contribute to cardiac repair possibly through neo-vascularization, angiogenesis, less inflammation, smaller infarct size, and decreased fibrosis. Paracrine secretions contribute to enhanced cardiomyocyte survival by decreasing apoptosis, while increasing cell proliferation and mobilizing other stem cells to the infarct zone [129, 130].

9. HERBAL MEDICINES IN TREATMENT OF CHRONIC ANGINA

Botanicals have been used widely in traditional Chinese and Indian medicine. These include hawthorn leaf and flower extract for heart failure and coronary insufficiency; garlic for atherosclerosis; Ginkgo biloba extracts for peripheral arterial occlusive disease; and horse chestnut extract for chronic venous insufficiency. Herbs such as Salviae miltiorrhizae Radix (‘dan shen’ in Chinese), Notoginseng Radix (‘san qi’), Chuanxiong Rhizoma (‘chuan xiong’), and Crataegi fructus (‘shan zha’) are common Chinese herbs used in the treatment of a wide range of cardiovascular conditions, including angina pectoris. Key botanicals used to treat stable angina pectoris, including their main active constituents and pharmacological actions are elegantly reviewed by O’Brien and Vitetta [131].

10. EXPERT OPINION

Chronic and refractory angina remains a global problem despite the availability of several options for management including revascularization, non-pharmacological tools like enhanced external counterpulsation, coronary sinus reducer stents, acupuncture, transcutaneous electrical nerve stimulation, spinal cord stimulation, transmyocardial revascularization as well as numerous drugs. As with the entire spectrum of coronary disease, optimal medical therapy and risk factor modification provides important prognostic and symptomatic benefit in these patients. A wide array of pharmacological armamentarium is now available to manage the patients with chronic stable angina as outlined in Table 1 [27, 31–36, 38–40, 42, 43, 45, 50, 51, 53, 54, 67, 72, 78, 80, 82–84, 87–92, 95, 97, 102, 107, 132–144].

Table 1.

Pharmacological agents for management of chronic stable angina.

Drugs/Class	Mechanism of Action	ACC/AHA class/ level of evidence	ESC class/level of evidence	Key references, trials
Aspirin	Irreversible cyclooxygenase inhibitor, reduces thrombotic events	Class 1A	Class 1A	APTC meta-analysis [132].
Clopidogrel	Adenosine diphosphate P2Y12 inhibitor. No additional benefit, increase risk of bleeding	Class IB indicated in patients with ASA intolerance.	Class IIB	CHARISMA trial [133].
Statins	HMG Co~A reductase inhibitors	Class 1A	Class 1A	Baigent et al [134].
ACE inhibitors		Class 1A	Class 1A	HOPE [135].
Beta-adrenergic blockers Cardiolselective Non Cardioselective	Competitive catecholamione inhibition via β1 and β2 receptor blockade. Increased diastolic filling. Reduces oxygen demand via negative inotropic effect, decrease HR and BP.	Class 1B started and continued for 3 years in all patients with normal LV function after MI or ACS. Class IIb for all other patients.	Class 1A post MI or with CHF	GEMINI [136], CAS [137–141]
Nebivolol	Selective β1 antagonist, vasodilator via nitric oxide generation	FDA approved for hypertension	Approved for HTN	[142]
Calcium channel blockers Dihydropyridine: Nifedipine, Amlodipine, Felodipine, Nicardipine Nondihydropyridine: Verapamil and Diltiazem.	Inhibition of L-type calcium channel. Increased vasodilation Decreased inotropy. Dihydropyridines contraindicated in heart failure.	Class IIB, for relief of symptoms when BB are contraindicated or cause unacceptable side effects	No evidence to support the for prognostic reasons in uncomplicated stable angina, rate lowering CCB may be used as an alternative to BB post MI in patients without heart failure who do not tolerate BB.	[31–36]
Nitrates	Indirect nitric oxide donor Block calcium entry in smooth muscle cells and promote their relaxation through production of cyclic guanosine monophosphate (cGMP). Reduce preload Redistribution of coronary blood flow from healthy to ischaemic areas	Class 1B for symptom relief.	No prognostic benefit, used for symptom relief only	[27, 143]
Ranolazine	Late Na current inhibitor Prevents Ca overload Improves myocardial perfusion.	Class IIB	Not licensed to use	MARISA, CARISA and ERICA [38–40]
Nicorandil	Potassium channel opener	Not approved in USA	Class I C for patients with intolerance or contraindications to BB or CCB, and a class IIC for patients in whom dual antianginal therapy with other classes of drugs is unsuccessful	IONA study group [42, 43]
Bepridil	Negative chronotrope, ionotrope and vasodilator. Inhibits receptor-operated, voltage-gated calcium channels as well as potassium currents and intracellular calcium/calmodulin complexes. Causes decreased myocardial oxygen consumption, coronary vasodilation, and increased coronary blood flow.	Approved by FDA for chronic angina in 1990, however not used in routine practice due to increased incidence of torsades des pointes and agranulocytosis		[45]
Ivabradine	Blocks sinoatrial node If entry currents. Decrease HR.	Not approved in the USA	Class IIB, BB intolerant patients	INITIATIVE [50], ASSOCIATE [51].
Trimetazidine	Metabolic modulator, partially inhibit β-oxidation and increase glucose oxidation	Not approved in the USA	Class IIB	[53, 54], TACT [144]
L-Arginine	Substrate for nitric oxide synthase. Improves endothelium-dependent vasodilation.			[67]
Perhexiline	Modifies myocardial substrate utilization from fatty acids to carbohydrates	Not approved	Available off license in the UK	[72]
Etoximir	Fatty acid metabolism modulator	Not approved	Not approved	ERGO [78]
Omapatrilat	Vasopeptidase inhibitor with selective and competitive inhibitory activity of ACE	Not approved	Not approved	[80]
Fasudil	Rho kinase inhibitor	Not approved	Not approved	[82]
DW1865	Rho kinase inhibitor	Not approved	Not approved	[83]
Allopurinol	Xanthine oxidase inhibitor	Not approved	Not approved	[84]
Testosterone	Endothelium-independent vasodilation	Not approved	Not approved	[87–92]
Esgtrogen	Vasodilation and endothelial function improvement	Class III	Not approved	[95]
Molsidomine	Nitric oxide donor			[97]
Mildronate	Inhibits carnitine biosynthesis. Improves systolic function, arterial vascular tone, stress tolerance and reduces anginal symptoms		Approved for clinical use in Latvia, Lithuania, Russia and Ukraine.	[102]
Omecamtiv mecarbil	Cardiac myosin activator			[107]

ACE: Angiotensin-converting enzyme; ASA: Aspirin; BB: Beta-blockers; BP: Blood pressure; CCB: Calcium channel blockers; cGMP: Cyclic guanosine monophosphate; CHF: Congestive heart failure; FDA: Food and Drug Administration; HR: Heart rate; MI: Myocardial infarction.

Despite the fact that BBs have disease-modifying properties and exert favorable effects on arrhythmias, heart failure and prevention of sudden death, their use as first-line therapy of stable angina will likely be revisited given the data from REACH registry. There is a lack of evidence that CCBs are disease-modifying, and their therapeutic role will be probably reduced in the near future. Long-acting nitrates are used on an empirical basis as randomized controlled trials are lacking, and are therefore expected to be replaced by the newer anti-anginal treatments, particularly ranolazine, which will likely have more robust use in clinical practice for management of angina given several positive pleotropic effects on arrhythmia suppression, heart failure as well as glycemic control besides anti-anginal properties.

Ivabradine and nicorandil are already indicated as second line options in patients inadequately controlled by first-line treatments or in whom such treatments are contraindicated or not tolerated. With more evidence coming in favor of these two molecules, there use is likely to become more global with acceptance in US markets. Several old drugs are being re-evaluated for their anti-anginal properties, in particular, amiodarone and sildenafil. Allopurinol is also getting attention and these agents offer exciting adjunct therapies for angina treatment. More recently, an increase in exercise capacity was described in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension, who were treated with a novel solouble guanylate cyclase stimulator, riociguat [144, 145]. It will be interesting to see if there will be a role for this drug in patients with chronic angina. Several new drugs are being studied and offer additional therapeutic potentials (Table 2).

TABLE 2.

Current open trials for various pharmacological therapeutic modalities for management of angina.

Trial	Condition	Objective	Outcomes	Principal Investigator
Cell Therapy in Severe Chronic Ischemic Heart Disease (MiHeart) NCT01727063	Chronic ischemic heart disease Coronary artery disease Angina pectoris	Phase II/III, multicenter, randomized, double-blind, placebo-controlled study of the efficacy of intramyocardial injection of autologous bone-marrow cells in patients with severe, chronic ischemic heart disease undergoing coronary bypass surgery	Increase in myocardial perfusion, improvement in LV function and in angina class	Luis Henrique W Gowdak, Heart Institute, Sao Paulo, Brazil
Intracardiac CD133+ cells in patients with no-option resistant angina (Regent Vsel Study) NCT01660581	Stable angina	A randomized, prospective, double-blind study to evaluate intracardiac injections of bone marrow, autologous CD133+ cells (electromechanical mapping based) in patients with resistant angina and no effective revascularization option	Improvement of myocardial perfusion and function, and on decrease of occurrence of symptomatic angina	Wojciech Wojakowski, Katowice-Ochojec, Silesian, Poland
Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina (RENEW), NCT01508910	Chronic myocardial ischemia Refractory angina pectoris (advanced) coronary heart disease	Phase III, prospective, randomized, double-blinded, active-control and unblinded SOC controlled study to determine the efficacy and safety of targeted intramyocardial delivery of autologous CD34+ cells (auto-CD34+ cells) for increasing exercise capacity during standardized exercise testing in subjects with refractory angina pectoris and chronic myocardial ischemia	Change from baseline in total exercise time on exercise tolerance test, angina frequency and MACE	Adel Nada, Baxter Healthcare Corp.
Efficacy and Safety of Ad5FGF-4 for Myocardial Ischemia in Patients With Stable Angina Due to Coronary Artery Disease – ASPIRE. NCT01550614	Stable angina	Randomized, controlled, parallel group, multicenter Phase III study to evaluate the efficacy and safety of Ad5FGF-4 using SPECT myocardial perfusion imaging in patients with stable angina	Change in reversible perfusion defect size, angina frequency, quality of life and functional class using CCS angina classification	Ivan Gordeev, Municipal Hospital #15, Moscow, Russia
Endocardial VEGF-D Gene Therapy for the Treatment of Severe Coronary Heart Disease - A Phase I Single-blinded Placebo-controlled Phase I Clinical Trial, NCT01002430	Angina pectoris myocardial infarction	Phase I single-blinded placebo-controlled trial	Assessments for safety and tolerability as measured as the acute and late adverse effects, laboratory parameters, biodistribution of the vector, anti-adenovirus antibodies and VEGF-levels before and in several time points after the gene transfer	Juha Hartikainen, Kuopio, Finland.
VM202 in Subjects With Chronic Refractory Myocardial Ischemia, NCT01002495	Myocardial ischemia	A Phase I/II open-label, dose-escalation study to assess the safety and tolerability of VM202 in subjects with chronic refractory myocardial ischemia	Evaluate safety and tolerability of a catheter-based, endocardial injection of different doses of VM202, assessment of angiogenic potential. Efficacy measures include exercise treadmill test, SPECT, cardiac MRI and change in use of anti-anginal medications	ViroMed Co., Ltd. and VM Biopharma
NIRVANA – Nebivolol for the Relief of Microvascular Angina in Women, NCT01665508	Microvascular angina	Phase IV, open-label study	Seattle angina questionnaire score, peak VO2 measurement	Nandita S Scott and Malissa J Wood, MGH, Boston, MA, USA
Research on Nicorandil Treatment of Patients Diagnosed as Coronary Heart Disease With Stable Angina, NCT01396395	Stable angina Coronary disease	A Phase IV randomized, placebo-controlled, double-blind, cross-over study	Number of ischemic attacks measured by 24-hour Holter monitoring	Yong Huo, Peking University, Beijing, China
Comparative Study to Assess the Efficacy of Nicorandil+Atenolol vs Atenolol in Treatment naïve Patients of Chronic Stable Angina, NCT01397994	Chronic stable angina	Phase IV, open-label, randomized, parallel arrangement, safety/efficacy study	Changes in perfusion will be evaluated in each arm at week 4 and comparison between the two study arms will be made to document the anti-ischemic effects of nicorandil using Ex-SPECT MPI	Tariq Ashraf, National Institute of Cardiovascular disease, Karachi, Pakistan
The Influence of Febuxostat on Coronary Artery Endothelial Dysfunction in Participants With Chronic Stable Angina, NCT01763996	CAD	Randomized, double blind, crossover assignment, phase IV efficacy study	Change in coronary artery flow from rest to isometric handgrip using MR	Takeda Global Research and Development Center, Inc
Effect of Molsidomine on the Endothelial Dysfunction in Patients With Stable Angina Pectoris Undergoing a Percutaneous Coronary Intervention, MEDCOR, NCT01363661	Stable angina pectoris Atherosclerosis	Phase IV, randomized, double-blind, placebo-controlled, parallel assignment efficacy study	Change versus baseline in the score of endothelial function by reactive hyperemia in the two groups after one year of treatment	Emanuele Barbato, Onze Lieve Vrouw Ziekenhuis, Aalst, Belgium
Phase III Trial of Dantonic® (T89) Capsule to Prevent and Treat Stable Angina (CAESA) - NCT01659580	Angina pectoris	Phase III, randomized, double-blind, confirmatory safety/efficacy study of Dantonic® (T89), a botanical drug consists of extracts of Danshen (Radix Salviae Miltiorrhizae) and Sanqi (Radix Notoginseng) with borneol in a capsule form	Change in symptom limited total exercise duration	Henry He Sun, Tasly Pharmaceuticals
Testosterone Therapy on Angina Threshold and Atheroma in Patients With Chronic Stable Angina, NCT00131183	Angina	Phase IV, randomized, double-blind, safety/efficacy study	Change in time to ST- segment depression of > 1mm during exercise testing.	Kevin S Channer, Sheffield, South Yorkshire, UK
YM758 in subjects with stable angina, EUCTR2005-002456-18-SK	Angina	A randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability and preliminary efficacy of a 4-week treatment with YM758, a novel hyperpolarization-activated inward current inhibitor which has been shown to prolong the AH intervals when given during atrial burst pacing [130]	Safety and tolerability of different oral doses of YM758 in subjects with stable angina.	Astellas Pharma Europe
Clinical efficacy of Pentalong® in stable Angina patients after 12 Weeks of routine administration: a randomised, double-blind, placebo-controlled trial. – CLEOPATRA, EUCTR2008-007093-37-DE	Stable, effort-induced angina pectoris	A randomized, double-blind, placebo-controlled multi-center study designed to demonstrate the anti-anginal efficacy of PETN 80 mg b.i.d. (morning and midday) as compared with placebo on top of anti-anginal background treatment. Pentaerithrityltetranitrate (PETN), brand name Pentalong® is a long acting NO donor and has recently been described as an organic nitrate ester that (in contrast to other nitrate acid esters) does not induce oxidative stress	Change in Total Exercise duration from baseline after 12 weeks of treatment with PETN 80 mg b.i.d.	Actavis Deutschland GmbH
Effects of Sildenafil on Signs and SYmptoms of Ischemia, Myocardial BlooD Flow, and Markers of ANgiogenesis in Patients with REfractory CoronarY Artery Disease – SYDNEY, EUCTR2010-023375-26-AT	Refractory angina	Randomized, double-blind, placebo-controlled study designed to prospectively investigate if intermittent phosphodiesterase 5 inhibition for 15 weeks improves myocardial perfusion by angiogenesis in patients with therapy refractory myocardial ischemia due to CAD	Total exercise duration	Rudolf Berger, Waehringer Guertl 18–20, 1090 Vienna, Austria
Effects of Inorganic Nitrite on cardiac and skeletal muscle: Physiology, pharmacology and therapeutic potential in patients suffering from Angina (UKCRN ID 13271).	Angina	Single center randomized, double-blind, placebo-controlled study on patients with chronic stable angina (>2 months duration) who are on no background antianginal therapy other than short- acting nitrates	Increase in the time to onset of angina using a modified Bruce exercise test	M P Frenneaux, University of Aberdeen, UK
Danhong injection in treatment of angina, NCT01681316	Chronic stable angina	Phase IV, randomized, multi-center, double-blind, placebo-controlled trial designed to evaluate the effect of Danhong Injection on the relief of angina	Change in angina-frequency score on the Seattle Angina Questionnaire	Zhong Wang, Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences

Cell and gene therapy continues to be a challenge. Although important progress is occurring in the use of stem cells for cardiac repair, the most optimal stem cell(s) for treatment of patients with infarcted myocardium has not yet been determined and requires identification. This will require comparison studies of human embryonic stem cells, bone marrow stem cells, allogeneic mesenchymal stem cells, circulating stem cells and umbilical cord blood cells in research animals and in patients. The ideal stem cell for cardiac repair should be non-toxic; not require immune suppression of the patient; create or stimulate healthy and functional cardiac muscle and blood vessels; improve heart function; and limit left ventricular remodeling. In addition, the optimal stem cell(s) should be easily harvested, readily propagated ex vivo in large numbers without neoplastic differentiation, and be available as a standardized ‘off the shelf’ treatment for prompt cardiac repair in patients. Several trials using various cell types as well as delivery vehicles are currently being carried out, and outcomes from these studies will have the potential to completely revolutionize anti-anginal management (Table 2).

Trends of future medical care that may require advanced drug delivery systems include individualized therapy and the capability to automate drug delivery. Implantable drug delivery devices that promise to address these anticipated needs have been constructed in a variety of ways using micro- and nano-electromechanical systems (MEMS or NEMS)-based technology. These devices expand treatment options for addressing unmet medical needs related to dosing. Within the last few years, advances in several technologies (MEMS or NEMS fabrication, materials science, polymer chemistry, and data management) have converged to enable the construction of miniaturized implantable devices for controlled delivery of therapeutic agents from one or more reservoirs. Suboptimal performance of conventional dosing methods in terms of safety, efficacy, pain, or convenience can be improved with advanced delivery devices. In addition, innovative drug-medical device combinations may protect labile active ingredients within hermetically sealed reservoirs [146].