Recurrent angina after percutaneous coronary interventions

by F. Mangiacapra, A. Creta,
and G. Di Sciascio, Italy

Antonio CRETA, MD
Unit of Cardiovascular
Science, Department of
Medicine, Università Campus
Bio-Medico di Roma

Despite the technical progress in coronary angioplasty leading to the treatment of more complex and extensive atherosclerotic lesions, the prevalence of anginal pain after successful percutaneous coronary revascularization (PCI) remains high. Recurrent angina, defined as the persistence of chest pain due to myocardial ischemia after revascularization, may be triggered by several causes not necessarily related to revascularization failure. Chest pain of coronary origin may recur after PCI due to both structural and functional causes, many of which have a common pathophysiological background, such as endothelial dysfunction. Appropriate diagnostic tools, including intracoronary physiological assessment, should be used for the correct identification of the conditions provoking recurrent angina. In light of the complex pathogenesis of this disorder, treatment strategies should be tailored to the clinical characteristics of each patient. In addition to mechanical therapies for the treatment of structural disorders, pharmacological therapy should be optimized with the use antianginal drugs and other compounds that may help treat the pathological conditions behind recurrent angina to maximize the benefit for patients. This article will analyze the most common causes of recurrent angina after PCI and focus on possible diagnostic and therapeutic approaches.

Percutaneous coronary intervention (PCI) is a cornerstone in the treatment of coronary artery disease (CAD). Through the restoration of epicardial coronary flow, PCI procedures aim to abolish myocardial ischemia. Timely revascularization is a life-saving procedure in acute coronary syndromes, whereas in the context of stable CAD, the main goal of PCI is to improve the quality of life by relieving the principal clinical manifestation of myocardial ischemia, ie, angina pectoris.1 However, despite technical progress, the prevalence of anginal pain after successful revascularization remains high. Recurrent angina, defined as the persistence of chest pain due to myocardial ischemia after revascularization, represents a clinical challenge for cardiologists for both diagnosis and treatment.

Several causes may be responsible for recurrent angina after PCI, and recurrent angina does not necessarily derive from revascularization failure. It is important to highlight that recurrent angina is distinct from refractory angina, which is defined as a chronic condition caused by clinically established reversible myocardial ischemia in the presence of CAD that cannot be controlled adequately with a combination of medical therapy, angioplasty, or coronary artery bypass grafting.2 The aim of this article is to analyze the most common causes of recurrent angina after PCI and to focus on possible diagnostic and therapeutic approaches.

Magnitude of the problem

Recurrent angina remains a highly prevalent condition, occurring in 20% to 60% of patients within 1-year post-PCI.3 In a recent study that analyzed 9081 patients treated with PCI in two hospitals, 9.8% were readmitted within 30 days after the procedure.4 The main cause for early readmission was chest pain or other symptoms concerning for angina (38.1% of cases).4 In the large randomized RITA-2 trial (second Randomized Intervention Treatment of Angina), which compared medical therapy alone with PCI in patients with chronic stable angina, the percentage of symptomatic subjects (Canadian Cardiovascular Society score >2) was reduced from 60% to 20% within 1 year post-PCI, while the percentage remained unchanged in the medical arm.5 However, after a long-term follow- up, no difference was found in the incidence of angina between the interventional and medical groups.6

In the more recent COURAGE trial (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation), 2287 patients with stable CAD were randomized to PCI plus medical therapy or medical therapy alone.7 At baseline, 22% of patients were angina-free. PCI was superior to medical therapy in reducing anginal symptoms at both the 12- and 24- month follow-up, whereas no significant difference was found at the 36-month follow-up. Moreover, in the PCI group, the percentage of angina-free patients was 57% at 12 months and 59% at 24 and 36 months, which means that nearly 40% of patients still experienced chest pain after coronary revascularization.8

Of note, most of the patients enrolled in the studies mentioned above received bare-metal stents (BMS) and, in some cases, the recurrence of angina may be related to in-stent restenosis, a complication that has drastically decreased with the advent of drug-eluting stents (DES). However, in a prospective study of 200 patients treated with DES, at 4 weeks post–PCI, 21% still experienced angina.9 More recently, in the SYNTAX trial (Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery), the reported rate of freedom from angina in patients undergoing PCI for left-main or three-vessel disease was just 71.6% at 12 months.10

Potential causes of recurrent angina

Recurrent angina may be due to structural or functional causes.
Structural causes of recurrent angina
Stretch pain
Stretch pain is a precordial pain that develops in the immediate phase after stent implantation, and it is not associated with myocardial ischemia. Stretch pain may occur after PCI due to overexpansion of the treated vessel segment, which is “stretched” by the stent, with a resulting stimulation of the sensory nerves located in the adventitia. Stretch pain is a common condition after PCI (36% to 41% of the cases) with a generally benign prognosis, although it may be associated with a higher risk of stent restenosis.11,12

In-stent restenosis
In-stent restenosis (ISR) is a condition characterized by a reduction in lumen diameter following stent implantation due to arterial damage resulting in neointimal proliferation. Binary angiographic restenosis is defined as a ≥50% luminal narrowing at the follow-up angiography. Clinically relevant ISR is defined as a binary angiographic restenosis with symptoms or signs of myocardial ischemia or as a ≥70% luminal narrowing. Neointimal proliferation occurs gradually, usually 5 to 12 months after PCI (earlier for BMS than for DES), and unstable angina represents the most common clinical presentation, followed by myocardial infarction.13 BMS are associated with a 20% to 30% rate of ISR 6 to 9 months after implantation. The incidence of ISR has dramatically dropped after the advent of DES, although it is still encountered in 5% to 10% of patients with second-generation DES.14 A study with angiographic follow-up, which was conducted in 10 004 patients 6 to 8 months after PCI, reported an ISR incidence of 30.1% with BMS, 14.6% with first-generation DES, and 12.2% with second-generation DES.15 Moreover, in the recent RESOLUTE All-comers trial (a randomized comparison of a zotarolimus-eluting stent with an everolimus-eluting stent for percutaneous coronary intervention), which compared zotarolimus-eluting stents with everolimus-eluting stents, the rates of target lesion failure and clinically indicated target lesion revascularization were 15% and 7%, respectively.16 In conclusion, despite technical innovation, ISR remains one of the leading cause of recurrent angina.

Stent thrombosis
Stent thrombosis is the most detrimental manifestation of stent failure and often presents as an acute myocardial infarction or sudden cardiac death. The global incidence of stent thromticle bosis is roughly 1% per year, and it is more frequent after a PCI that is performed in the context of acute coronary syndrome. A recent network meta-analysis has shown that all contemporary DES (with the exception of paclitaxel-eluting stents and bioresorbable vascular scaffolds) were superior to BMS in terms of stent thrombosis occurrence.16

Incomplete revascularization
When coronary revascularization is not able to remove myocardial ischemia completely, chest pain recurs early after PCI,17 which has important prognostic implications. In the SYNTAX trial, the residual atherosclerotic burden was strongly associated with the 5-year mortality rate.18 Moreover, in a meta-analysis including 89 883 patients with multivessel CAD, revascularization was incomplete in 56% of those treated with PCI, which was associated with a significant increase in total mortality, myocardial infarction, and repeat revascularization as compared with complete revascularization.19 Similar results were recently obtained in a subanalysis of the SCAAR registry (Swedish Coronary Angiography and Angioplasty Registry).20

In addition to the technical aspects of PCI that prevent the treatment of all coronary lesions—which are related to anatomy complexity and atherosclerotic burden—diagnostic issues may also be responsible for incomplete revascularization. In fact, angiography alone is not always able to identify functionally significant coronary stenoses, and a significant proportion of angiographically intermediate lesions are not correctly classified and, consequently, not appropriately treated.21 In other words, even when angiographically complete revascularization is achieved, other lesions are considered insignificant, and therefore, left untreated. These untreated lesions may induce ischemia and thus recurrent angina. Therefore, regular physiological assessment of coronary stenoses using fractional flow reserve (FFR) and FFR-guided PCI may help optimize treatment strategies and achieve functionally complete coronary revascularization.22,23

CAD progression
The development of significant disease in previously untreated coronary segments is common, especially in high-risk patients, such as those with diabetes mellitus. Symptomatic progression of coronary disease after PCI accounts for up to 50% of repeat revascularizations in diabetic patients, which has a significant impact on clinical outcomes.24 In a prospective study that evaluated 428 patients treated with PCI, after 5 years, 110 patients (25.7%) had a new clinical event (ie, myocardial infarction or repeat revascularization), and 37.1% of the repeat revascularization cases were due to disease progression in previously untreated coronary segments.25

Myocardial bridging
Myocardial bridging is a coronary anomaly that may be associated with exertional angina, acute coronary syndromes, cardiac arrhythmias, syncope, or even sudden cardiac death.26

In a recent study of 139 patients with angina in the absence of obstructive CAD, the prevalence of myocardial bridging identified using intravascular ultrasound (IVUS) was as high as 57.9%, and this condition was often associated with endothelial dysfunction.27

Functional causes of recurrent angina
Up to one-third of patients with recurrent chest pain after PCI do not have evidence of obstructive CAD.28,29 In this setting, functional causes of recurrent angina, which include epicardial coronary spasm (often at the stent edge) and microvascular dysfunction, should be considered. Both of these conditions may occur in the presence of endothelial dysfunction. The vascular endothelium is a multifunctional organ whose integrity is essential to normal vascular physiology, and whose dysfunction may be crucial in the pathogenesis of vascular disease. In fact, endothelial dysfunction is considered the primum movens of atherosclerosis; therefore, it may predispose patients treated with PCI to ISR30 and CAD progression.31

Epicardial coronary spasm
The acetylcholine provocation test (ACH test) may be used to assess coronary endothelial function because, when the endothelium is functioning normally, ACH causes vasodilation by stimulating the release of endothelium-derived relaxing factor; whereas, when the endothelium is removed or damaged, ACH causes vasoconstriction. In a series of 104 patients with a previous PCI, recurrent angina, and angiographic evidence of a nonsignificant ISR, the intracoronary ACH test was normal in only 34% of patients, while it elicited enhanced epicardial vasoconstriction (evidence of a ≥75% reduction in vessel diameter and symptoms) or microvascular vasoconstriction (only symptoms and ECG changes) in the others.32 Of note, in patients previously treated with PCI, epicardial vasoconstriction was most often localized to distal segments,32 and stent length seemed to be linked to a positive ACH test at angiographic follow-up after DES implantation (vasoconstriction is more common with increasing stent length).33 Versaci et al also reported a high percentage of ergonovine- induced coronary spasm in patients with recurrent angina.29

Microvascular dysfunction
Microvascular dysfunction due to endothelial impairment is another potential cause of recurrent angina despite angiographically unobstructed epicardial coronary arteries. In a recent study, Li et al have shown for the first time that PCI patients experiencing recurrent angina in the absence of structural causes had a significantly higher index of microvascular resistance (IMR) and lower coronary flow reserve (CFR) than a control group.34 Exercise-induced ischemia late after successful PCI also seems to be related to distal coronary endothelial dysfunction,35 and peripheral endothelial dysfunction can predict recurrent angina after PCI30 and worse outcomes in patients with CAD.36,37

Diagnostic approach

The first step in the diagnostic approach to recurrent angina should be an accurate evaluation of symptoms to assess the probability of facing true angina versus chest pain deriving from other causes not related to myocardial ischemia. It is important to ascertain whether the chest pain characteristics are similar to those reported before the revascularization procedure and to quantify the time between the procedure and the new onset of symptoms. The longer this interval is, the higher the probability that symptoms are due to CAD progression, rather than other causes. Physicians should also interrogate the patients carefully regarding compliance to dual antiplatelet therapy because premature discontinuation is one of the most common causes of stent thrombosis.

In symptomatic patients after PCI, an imaging stress test (stress echocardiography, magnetic resonance imaging, or myocardial perfusion scintigraphy [MPI]) is recommended by the European Society of Cardiology (ESC) guidelines.1 For patients with low-risk findings (ie, ischemia <5% of the myocardium), the suggested strategy is to reinforce medical therapy and promote lifestyle changes. A coronary angiogram is recommended for patients with intermediate- to high-risk findings (ischemia at low workload, early onset ischemia, multiple zones of high-grade wall motion abnormality, or reversible perfusion defect). However, for patients with typical symptoms suggesting an ischemic origin and/or in the presence of high-risk features for PCI failure (eg, diabetes mellitus, diffuse CAD, poor compliance to treatment), physicians may decide to perform a cardiac catheterization directly, without prior noninvasive tests.1 In the absence of angiographic evidence of stent failure or CAD progression, functional causes of recurrent angina could be investigated in the catheterization laboratory through a comprehensive invasive assessment, including an ACH test for endothelial dysfunction,27 IMR and CFR measurement for coronary microvascular dysfunction,38-40 and FFR measurement for occult or diffuse epicardial coronary disease.41-46 Intracoronary imaging with IVUS or optical coherence tomography may also be used to search for anatomical abnormalities (eg, myocardial bridging) that are not apparent on coronary angiography, but may be responsible for inducible ischemia.26

Treatment strategies

In patients with evidence of stent failure or functionally significant atherosclerotic lesions (residual or novel), repeat PCI is the treatment of choice. However, optimizing medical therapy is crucial for these patients and those with functional causes of recurrent angina.

According to the most recent ESC guidelines, the first-line therapy for angina relief should include short-acting nitrates plus β-blockers or non-dihydropyridine calcium channel blockers (CCBs).2 Dihydropyridine-CCBs may be an alternative for patients with low heart rate or intolerance/contraindications to β-blockers and non-dihydropyridine CCBs. Furthermore, dihydropyridine- CCBs can be used in association with β-blockers for patients with persistent angina and a Canadian Cardiovascular Society (CCS) score >2. As a second-line therapy, it is recommended to add either a long-acting nitrate or one of three options—ivabradine, nicorandil, or ranolazine; trimetazidine may also be considered. A second-line treatment may be used as first-line treatment in selected patients. However, in all cases, medical therapy should be tailored to each patient according to the underlying cause of recurrent angina, heart rate, blood pressure, tolerance, comorbidities, etc. As an example, in the case of angina with a microvascular origin, β-blockers remain the first-line treatment, while chronic preventive treatment of vasospastic angina is mainly based on the use of CCBs.

Ivabradine, a direct inhibitor of the sinus node If current, reduces heart rate, which results in the prolongation of diastole and a reduction in myocardial oxygen demand, without affecting inotropism or blood pressure. It is approved in Europe (at a dose of up to 7.5 mg twice daily) for the treatment of chronic stable angina in patients who have a heart rate ≥70 bpm (in sinus rhythm) and who are intolerant to or inadequately controlled by β-blockers. Ivabradine was as effective as atenolol in terms of antianginal and anti-ischemic events in a double blinded trial that enrolled 939 patients with stable angina.47 Moreover, in patients with chronic stable angina pectoris treated with atenolol and with a heart rate >60 bpm, the addition of ivabradine improved exercise tolerance, without affecting safety or tolerability.48

The SIGNIFY trial (Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease)49 failed to demonstrate a reduction in the composite end point of death from cardiovascular causes or nonfatal myocardial infarction in patients with stable CAD, but no clinical heart failure, who were treated with ivabradine at a dose of up to 10 mg twice daily, in addition to standard medical therapy. However, in the SIGNIFY trial, ivabradine produced consistent improvements in self-reported quality of life parameters related to angina pectoris, particularly in terms of angina frequency and disease perception.50

In the recent RIVENDEL study (heart Rate reduction by IVabradine for improvement of ENDothELial function in patients with coronary artery disease),51 the hypothesis tested was that, through a reduction in heart rate and consequent reductions in oxidative stress, vasoconstriction, smooth muscle cell migration and proliferation, inflammation, and extracellular matrix degradation at the level of the arterial wall, ivabradine could exert a beneficial effect on vascular endothelial function. Patients with CAD who underwent complete revascularization by PCI were randomized to receive ivabradine or to continue with standard medical therapy, and endothelial function was assessed by flow-mediated dilatation (FMD) of the brachial artery up to 8 weeks after enrollment. The addition of ivabradine to standard medical therapy significantly improved endothelial function proportionally to the reduction in heart rate. Ivabradine treatment also resulted in a significant reduction in the proportion of patients with endothelial dysfunction, defined as FMD <7%. Based on these results and in light of the potential effects of endothelial dysfunction on the genesis of recurrent angina, ivabradine may play a central role in the pharmacological armamentarium for the treatment of patients with CAD undergoing PCI.

Ranolazine acts as a late sodium current blocker that reduces intracellular calcium overload during ischemia, without negative inotropic, chronotropic, or dromotropic effects.52 Its efficacy in patients with chronic stable angina has been assessed in several randomized trials. Ranolazine reduces the frequency of angina, increases pain-free exercise duration and time to ST-segment depression, improves exercise performance, and reduces the use of sublingual nitroglycerin.53-55

The antianginal efficacy of ranolazine has also been proven in diabetic patients with CAD.56 In the MERLIN-TIMI 36 trial (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 36), which evaluated patients with a history of acute coronary syndrome, ranolazine did not reduce the incidence of myocardial infarction or death,57 but, in the subgroup of patients with prior chronic angina, it significantly reduced recurrent ischemia,58 and it also modestly improved angina and quality of life compared with placebo.59 The recent RIVER-PCI trial (Ranolazine for Incomplete Vessel Revascularization) failed to demonstrate any benefit of ranolazine in terms of a reduction in ischemia-driven revascularization or hospitalization without revascularization in patients with a history of chronic angina who had incomplete revascularization after a PCI.60 In this population, ranolazine also had a neutral effect on angina frequency and quality of life at the 1-year follow-up.3

Nicorandil is a nitrate derivative of nicotinamide. It activates adenosine triphosphate–sensitive potassium channels and promotes systemic venous and coronary vasodilation through a nitrate effect. This drug was evaluated in the IONA trial (Impact Of Nicorandil in Angina), which enrolled 5126 patients with chronic stable angina.61 The addition of nicorandil to standard therapy reduced the composite primary end point (coronary death, nonfatal myocardial infarction, or unplanned hospitalization for angina). However, symptom relief was not reported in this trial.61 Older studies have shown that the antianginal properties of nicorandil are similar to those of oral nitrates, β-blockers, and calcium channel blockers.62

Trimetazidine inhibits fatty acid oxidation, resulting in a shift to glucose metabolism, which is more efficient, and a reduction in myocardial oxygen demand. In the TRIMPOL II trial (TRIMetazidine in POLand), the addition of trimetazidine to standard therapy reduced angina episodes and improved exercise tolerance.63 A recent meta-analysis confirmed the efficacy of trimetazidine in the treatment of stable angina pectoris versus conventional antianginal agents.64 However, large outcome trials evaluating the role of trimetazidine in stable CAD patients are still needed.

Other compounds
In addition to pure antianginal drugs, other compounds may be useful in the treatment of patients with recurrent angina. Allopurinol, an inhibitor of xanthine oxidase used in the prevention of gout, seems to have an antianginal effect, probably by improving endothelium-dependent vasodilation and abolishing oxidative stress.65 In a randomized crossover study of 65 patients with CAD, allopurinol 600 mg/day increased the time to both ST-segment depression and chest pain, compared with placebo.66 Larger trials are necessary to confirm these interesting results. High-dose statin therapy is well known to improve endothelial function and clinical outcomes in patients with CAD, and there is also evidence for a reduction in angina and ischemic episodes.67,68


Recurrent angina is a common event after PCI that may have several causes which often share a common pathophysiological background. The diagnosis and treatment of recurrent angina represent a clinical challenge, and an accurate identification of the underlying causes is crucial to select the right treatment strategy.■

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Keywords antianginal drug; coronary atherosclerosis; myocardial ischemia; percutaneous coronary intervention; recurrent angina