Management of Symptomatic Patients with Chronic Coronary Syndromes: A Case-based Review on the Role of Ranolazine

Coronary artery disease (CAD) affects 200 million individuals worldwide and is the leading cause of premature death globally.¹ In patients with CAD, the pathological conditions produced by the chronic mismatch between myocardial oxygen supply and consumption (i.e. chronic coronary syndrome [CCS]) may result in angina on exertion, which is one of the most common symptoms of CCS. As global life expectancy increases and cardiovascular (CV) risk factors are not yet adequately controlled, especially in Asia, the burden of angina is expected to increase.

The management of angina has traditionally been dominated by first-line drugs: β-blockers, calcium channel blockers (CCBs) and nitrates. However, newer, second-line drugs, such as ivabradine, ranolazine and trimetazidine, have more recent clinical evidence. Given that patients with angina have diverse comorbidities and underlying pathophysiology, experts are advocating for a rational approach that considers comorbidities and underlying mechanisms of angina, rather than a rigid stepwise approach.^2–4

Ranolazine is an antianginal drug used for the symptomatic treatment of angina and is the first in a new class of antianginal medications to be approved in nearly two decades.⁵ Ranolazine acts by inhibiting ion channels responsible for the late sodium current. The late sodium current is activated by myocardial ischaemia and increases myocardial ischaemia, the risk of arrhythmias and impairs ventricular function.⁶ Ranolazine’s anti-ischaemic and antianginal actions do not reduce blood pressure (BP), heart rate (HR), and rate-pressure product (RPP).⁷ This review uses a case-based approach to demonstrate the clinical utility of ranolazine in the management of patients with CCS.

Methods

Eight real-world cases of angina managed with ranolazine in Malaysia, Indonesia, the Philippines and Thailand are described. The authors, who are cardiologists from these countries, as well as from Spain and the UK, presented and discussed these cases at an expert meeting held in a hybrid format (virtually and face-to-face) in April 2024. Patient details were anonymised.

The authors highlighted key learning points from the cases presented. The discussion of each case and key learning points were supported by a review of the literature identified using the search terms “chronic coronary syndrome”, “stable ischaemic heart disease”, “angina”, “antianginal” and “ranolazine”. Relevant articles were included in the discussion of cases.

Persistent Angina after First-line Pharmacotherapy

Case 1. Persistent Angina after CCB Treatment in a Patient with Dyslipidaemia and Prediabetes

A 58-year-old man presented with exertional chest pain (visual analogue score [VAS] 5/10) over a 2-month period. His medical history included dyslipidaemia (managed with simvastatin 10 mg daily) and prediabetes (HbA_1c 6.2%). His HR was 70 BPM and BP 120/70 mmHg. His 12-lead ECG and echocardiogram showed no abnormalities. During a treadmill stress test (TST), he achieved 10.1 metabolic equivalents (METs), with ST-segment upslope depression of 2 mm at 7 METs, but experienced no angina (these findings suggest a generally favourable prognosis). His CT coronary angiography revealed a calcium score of 305 and spotty calcification in the proximal to mid-left anterior descending (LAD) artery with significant stenosis (80%) of the mid-LAD (Figure 1).

These findings as well as treatment options (revascularisation versus pharmacotherapy) were discussed with the patient. Due to the favourable benefits of medication over revascularisation based on the ISCHEMIA trial, and the recommendations of the latest European Society of Cardiology (ESC) CCS guidelines, the initial shared treatment decision was medical therapy consisting of aspirin 81 mg once daily and the initiation of sustained-release verapamil 120 mg once daily for angina control.^3,8

Six months later, chest tightness during exertion persisted (VAS 3/10). His HR was 62 BPM and his BP was 110/60 mmHg. Ranolazine 500 mg twice daily was added to the treatment, which effectively relieved the angina symptoms. His HbA_1c was 6%. The patient has been followed up for 5 years and no further chest pain has been reported.

Case 2. Persistent Angina after CCB Treatment in a Patient with Chronic Obstructive Pulmonary Disease

A 76-year-old man presented to hospital due to recurrent chest pain occurring over the previous 2 months, described as heaviness and pressure in the chest upon exertion. The pain episodes lasted a few minutes and were relieved by rest and sublingual nitroglycerin. Three years prior, he had experienced a non-ST-elevation MI, which was treated with acute percutaneous coronary intervention (PCI) to the LAD. His comorbidities included chronic obstructive pulmonary disease (COPD) treated with inhaled triple combination therapy, hypertension and dyslipidaemia. His medications included perindopril 5 mg once daily, diltiazem 100 mg once daily and atorvastatin 40 mg once daily. Physical examination on admission revealed a few extrasystoles and occasional rhonchi in both lungs with no wheezing. His HR was 100 BPM and his BP was 110/80 mmHg. His ECG showed sinus tachycardia, confirmed premature atrial complexes and poor R wave progression. Chest X-ray showed hyper-inflated lungs with no congestion. Creatinine was 1.4 mg/dl, serum potassium was 4.6 mmol/l, and troponin T was 14 ng/dl. Echocardiogram showed normal ejection fraction (EF) (58%), hypokinesia of the anterior wall and borderline left ventricular hypertrophy. There was no pulmonary hypertension and no significant valvular lesions. Coronary arteriography revealed a severe stenosis of the LAD and left circumflex artery (LCx).

He was initially treated with low-dose metoprolol 25–50 mg, but this was later discontinued due to exacerbation of his COPD. Diltiazem was titrated to 200 mg once daily and oral isosorbide mononitrate (ISMN) to 10–20 mg. However, he experienced orthostatic hypotension, which led to the withdrawal of ISMN and a decrease in the diltiazem dose to 100 mg once daily. Ranolazine 375 mg twice daily was started. The patient then reported markedly improved symptoms, and his walking distance increased. Ranolazine was increased to 375 mg three times daily, which resulted in further symptomatic improvement. Subsequent ECGs revealed sinus rhythm with rare premature atrial contractions. Ranolazine was continued indefinitely as maintenance therapy.

Case 3. Persistent Angina after an Episode of Acute Coronary Syndrome Treated with β-blockers in a Patient with Multiple Comorbidities

A 53-year-old female with hypertension, type 2 diabetes (T2D) and hyperthyroidism presented to the clinic with a chief complaint of chest heaviness. She complained of chest pain 1 year prior and was given a long-acting nitrate 60 mg once daily. However, she did not experience relief and discontinued her treatment. Chest pain recurred 6 hours before admission, characterised as on-and-off chest heaviness (VAS 7/10) that radiated to her back, with each episode lasting for 15–20 minutes. Her BP on admission was 100/60 mmHg and her HR was 55–65 BPM. Her ECG showed normal sinus rhythm and nonspecific ST-T wave changes. Troponin I was negative, renal and liver function were normal. Fasting blood sugar was 106.4 mg/dl and HbA_1c was 7%. Her 2D echocardiography showed an EF of 69% with normal wall motion.

She was admitted for suspected acute coronary syndrome (ACS) and was treated with dual antiplatelet therapy and a high-dose statin plus ezetimibe. Nebivolol 2.5 mg once daily was started but was eventually discontinued due to episodes of asymptomatic bradycardia. Sublingual isosorbide dinitrate (ISDN) 5 mg and oral ISMN 30 mg were given due to the persistence of chest pain but were later discontinued due to severe headache.

Ranolazine 375 mg twice daily was prescribed, and the angina decreased in frequency and severity. A coronary angiogram showed mild myocardial bridging of the mid-LAD, an uncommon cause of angina. Persistence of angina prompted an increase in the ranolazine dose to 500 mg twice daily, which rendered the patient symptom-free, allowing her to walk long distances. The patient has been taking ranolazine for the past 6 months, with no reported adverse events.

Discussion: Persistent Angina after First-line Pharmacotherapy

In patients with CCS, initial therapy with medication alone can satisfactorily control symptoms and reduce the risk of CV events.^2,9 In keeping with optimal treatment guidelines, one or two antianginal drugs and the addition of drugs for the secondary prevention of CV disease typically comprise initial pharmacotherapy. While there is no singular definition of optimal treatment in CCS, the patient’s profile, characteristics, and preferences should all be considered.¹⁰

Conventional treatment should first be maximised before considering revascularisation. This is especially relevant to Asia, where access to revascularisation may be limited by the lack of healthcare infrastructure, geographic distances and transportation and the ability to pay.¹¹ In case 1, the patient was a suitable candidate for medical therapy – there was no compelling indication for revascularisation and the patient responded to initial therapy with medication alone.

While the patient reported a decrease in pain severity after 6 months of CCB treatment, he was still experiencing chest tightness upon exertion. Persistent angina after β-blockers or CCB treatment indicates the need for add-on ranolazine. The benefit of ranolazine as an add-on therapy in patients with CCS was demonstrated in the CARISA trial, a randomised controlled trial that showed ranolazine reduced angina frequency and improved exercise tolerance when taken together with amlodipine, atenolol or diltiazem (Table 1).¹² As a non-haemodynamic antianginal agent, ranolazine has no effect on BP, HR, and RPP and can be chosen in preference to haemodynamic agents to avoid potential adverse events.

A clinician’s primary approach to the treatment of CCS should also be based on the patient’s comorbidities. Cases 2 and 3 demonstrate the challenges in the management of angina in patients with concomitant diseases, such as COPD or metabolic disorders, respectively.

Regarding Case 2, most clinicians avoid the use of a β-blocker in patients with COPD due to the risk of exacerbation. Some studies suggest that the adverse effect of β-blocker therapy on the forced expiratory volume in 1 second is minimal, and that the use of highly cardioselective agents such as nebivolol may minimise this risk.^13,14 However, the use of other drug classes with no impact on the bronchial tree may further minimise this risk. The patient in case 2 was treated with a CCB; however, the presence of hypokinesia on echocardiography favours the use of ranolazine over CCB treatment in this patient.

In case 3, the presence of T2D as a comorbidity is noteworthy as there is strong evidence supporting the role of ranolazine in patients with T2D with persistent angina. The MARISA and the CARISA trials (Table 1) have demonstrated improvements in exercise capacity in ranolazine-treated patients, including those in the T2D subgroup.^12,15 Importantly, TERISA, a randomised, double-blind trial that included 949 patients with T2D and chronic stable angina, showed that ranolazine (target dose 1,000 mg twice daily) for 8 weeks was superior to placebo in achieving angina relief (Table 1).¹⁶ Additionally, in TERISA, patients on ranolazine achieved lower glycated haemoglobin (HbA_1c) levels versus placebo recipients, suggesting that ranolazine may be the preferred antianginal agent in individuals with T2D, as recommended by the American Heart Association.¹⁷

Atrial arrhythmia and sinus tachycardia are typically encountered in COPD patients experiencing acute respiratory failure (in part due to the use of β-adrenergic therapy for reversible airway obstruction) and those with hyperthyroidism. In cases 2 and 3, ranolazine can be a preferable option due to the possible ameliorating action on AF.¹⁸

Both patients in cases 2 and 3 also received nitrates, which were discontinued due to adverse events. There is also evidence that nitrates are associated with non-response, tolerance or tachyphylaxis, and risks of inducing microvascular dysfunction and oxidative stress with prolonged continual administration.¹⁹ A meta-analysis also revealed a deleterious effect of long-acting nitrates in certain patients, referred to as the 0-hour effect, which is characterised by increased angina symptoms and significantly shorter exercise duration at 24 hours post-dose in the intermittent administration group versus the placebo group.²⁰

The use of nitrates is high in Asia, despite several factors among Asian patients limiting its benefit, including a higher prevalence of nitrate tolerance, a higher prevalence of an ALDH2 gene mutation that may reduce nitrate effect, and a higher risk of hypotension and headaches compared with western patients.²¹ In placebo-controlled trials, 82% of patients complained of headaches and nearly 10% were unable to tolerate nitrates due to disabling dizziness.²² Other adverse events such as rebound angina and orthostatic hypotension have been reported.

Hypotension is also common in patients on nitrates; therefore, BP monitoring is important. While headache frequency decreases over time due to tolerance, this also renders long-term nitrate therapy ineffective. A nitrate-free interval is necessary to maintain optimal therapeutic response and ranolazine is a suitable option during nitrate-free intervals. Aside from being a potential substitute for nitrate therapy, as demonstrated by cases 2 and 3, replacing nitrates with ranolazine may relieve symptoms and is a practical and effective alternative to nitrates because of its haemodynamic and tolerability profile.¹⁹

The ranolazine dosage can be escalated safely and can result in an improvement in angina symptoms. The three-fold dose range of ranolazine was tested in the MARISA trial (Table 1) and demonstrated that a progressive increase in plasma concentrations correlated with an increase in exercise durations. The tolerability of ranolazine at doses of 500–1,500 mg twice daily appears tolerable with no or minimal effects on BP and HR.¹⁵

The increasing burden of angina in Asia suggests that treatment costs also need to be considered. Pharmacoeconomic studies have demonstrated the cost-effectiveness of ranolazine in patients with CCS and the incremental cost–utility ratio is particularly effective in non-hospitalised patients with mild or moderate angina frequency.²³

It is also important to note that the prescribing information of ranolazine recommends uptitrating the starting dose (375 mg twice daily) to 500 mg twice daily instead of 375 mg three times daily (i.e. the uptitration dose of case 2).

Lastly, while cases 1–3 all demonstrate symptom improvement after ranolazine use, a subset of patients may still complain of angina. In such patients with persistent angina after therapy such as β-blockers and or CCB plus ranolazine, clinical data on the efficacy and safety of the addition of other antianginal agents (such as ivabradine, nicorandil or trimetazidine) are scarce. The use of such a strategy should consider several factors, such as the patient’s haemodynamic profile, comorbidities and the pathophysiological basis of myocardial ischaemia in each patient, as well as concomitant medications with potential drug interactions, patient preferences, and the possibility of revascularisation. Notably, the 2024 ESC guidelines recommend myocardial revascularisation of functionally significant obstructive CAD to improve symptoms (Level IA recommendation).³

Key learning points

• Initial therapy with medication alone is highly effective in patients with chronic, stable coronary artery disease.
• Ranolazine is highly effective for the control of angina in patients already receiving β-blocker or CCB treatment.
• The presence of comorbidities should be considered in patients with angina. The absence of effect of ranolazine on haemodynamics and the bronchial tree, in addition to its pleiotropic effects and a favourable effect on metabolic profile, suggests it can be a preferable option for patients with comorbidities such as COPD, hyperthyroidism or T2D.^12,15–17
• Ranolazine has been demonstrated to improve angina symptoms and to reduce HbA_1c in patients with T2D.^12,15,16
• Ranolazine dosage may be escalated to achieve freedom from angina and improve quality of life. When uptitrating ranolazine, the initial dose of 375 mg twice daily should be switched to 500 mg twice daily, as per its label.
• The use of nitrates has been associated with adverse events, non-response, tolerance or tachyphylaxis, and microvascular dysfunction.^19,20

Persistent Angina after Revascularisation

Case 4. Persistent Angina Post-PCI with No Signs of Heart Failure

A 56-year-old man was admitted to the emergency room with sudden chest pain accompanied by mild shortness of breath. The patient had stable BP and no signs of pulmonary congestion or acute heart failure on admission. ECG revealed ST elevation on V1-V6 (Figure 2), confirming an acute anterior MI and an old inferior MI. A coronary angiogram revealed total occlusion in the mid-LAD and up to 30% stenosis in the proximal LAD with a normal right coronary artery. Primary PCI with a sirolimus drug-eluting stent (DES) was successfully deployed in the culprit lesion. He was discharged with aspirin, ticagrelor, candesartan, atorvastatin, bisoprolol and ISDN. Ten days after discharge, the patient still complained of chest discomfort; hence, bisoprolol was increased to 5 mg once daily. One month later, the patient complained of dizziness. He was switched from ISDN to nitroglycerin; however, the patient complained of worsened dizziness. Ranolazine 500 mg twice daily was initiated, which resulted in the relief of chest discomfort and dizziness.

Case 5. Angina in a Heart Failure Patient with Angina after Coronary Artery Bypass Grafting

A 63-year-old male smoker with T2D and dyslipidaemia was referred to the emergency room for non-ST-elevation MI. He underwent coronary angiography which revealed three-vessel disease and HF with reduced EF (HFrEF) (EF 28%). He was given sacubitril/valsartan 49/51 mg and bisoprolol 5 mg and then underwent coronary artery bypass grafting (CABG) 6 weeks later. He also received spironolactone 25 mg once daily and sacubitril/valsartan was uptitrated to 97/103 mg. Two weeks after discharge, the patient suffered a syncopal attack and was noted to be bradycardic; hence, bisoprolol was withheld. He was suspected of having sick sinus syndrome and an implantable loop recorder was implanted. He was then prescribed amlodipine, which was later discontinued due to leg oedema and labile BP. He eventually received an ICD.

Ten months later, the patient presented with acute decompensated HF and unstable angina. Repeat coronary arteriography revealed a patent left internal mammary artery-to-LAD graft, a patent saphenous vein graft (SVG)-right posterior descending artery and SVG-obtuse marginal branch (OM) graft stump with chronic total occlusion of the left main stem and LCx. Intravascular ultrasound-guided angioplasty with DES placement to the chronic total occlusion was performed (Figure 3). Despite angioplasty, on follow-up the patient continued to complain of angina (CCS-1 to 2). Ivabradine 2.5 mg OD and slow-release trimetazidine 35 mg twice daily were added with no relief of angina. Subsequently, ranolazine 375 mg twice daily was added to the treatment, which improved his symptoms and quality of life. To date, the patient is well and has a good functional class with an EF of 38% and has remained on the lower dose of ranolazine.

Case 6. Persistent Angina in a Patient with Diastolic Dysfunction Treated with PCI

A 40-year-old man with obesity (BMI 33.2 kg/m²), hypertension and dyslipidaemia, and a 1-month history of fatigue following mild exercise was admitted for dyspnoea on exertion. Physical examination revealed a BP of 142/90 mmHg, HR of 92 BPM and bibasal rales. Laboratory findings showed normal kidney function and increased HbA_1c (7.4%). Resting ECG showed sinus rhythm with no signs of ischaemia. An echocardiogram revealed an LVEF of 68%, concentric left ventricular hypertrophy and diastolic dysfunction. He was diagnosed with acute decompensated HF, hypertensive heart disease and newly diagnosed T2D. He was treated with sacubitril/valsartan, a mineralocorticoid receptor antagonist, a sodium–glucose cotransporter 2 inhibitor, other oral diabetes medications, a diuretic and nebivolol 2.5 mg once daily prior to discharge. He was stable without significant complaint until 3 months post-discharge when he started to experience typical anginal symptoms. TST revealed ischaemia and coronary angiography showed a 60–70% stenosis at the mid LCx-OM1. The nebivolol dose was increased to 5 mg once daily and a long-acting nitrate was initiated. Additionally, he actively tried to lose weight, started routine exercise and made dietary changes.

After 2 months, he was admitted with an ACS and PCI with DES implantation to the LCx-OM1 was performed. However, he continued to experience angina requiring sublingual glycerin trinitrate (GTN) 4 to 5 times a week. Ranolazine 375 mg twice daily was initiated, resulting in significant improvement of his angina with a concomitant decrease in GTN use. The patient is being followed up at least every 6 months; there has been no need to increase the ranolazine dose.

Discussion: Persistent Angina after Revascularisation

Cases 4 to 6 demonstrate the persistence of symptoms after revascularisation, which is a common occurrence. Studies have shown that the recurrence of angina after successful PCI has an incidence rate of 32.3% during the first year after the procedure.²⁴ Furthermore, the persistence of angina is more likely among Asians due to several factors, including a higher incidence of microvascular dysfunction, vasospasm and stent restenosis, with one study showing that South Asians were 81% and 64% less likely to report angina resolution after PCI or CABG, respectively, compared with western counterparts.²⁵ The 2019 ESC guidelines suggest the addition of a second-line antianginal drug to control the symptoms of residual angina.¹⁹

The efficacy of ranolazine 375 mg twice daily in addition to standard anti-ischaemic treatment in patients with recurrent angina post-complete revascularisation by PCI was evaluated in a single-centre, open-label, prospective registry.²⁶ The study showed that, with the addition of ranolazine 375 mg twice daily to first-line therapy, there were significant improvements in exercise ECG test results after 1 month of treatment.

Case 5 depicts the evolution of HF in CCS, starting with angina and progressing to HF. In a review of the aetiology of HF, CAD was found to be the leading cause of HF globally.²⁷ In another report from major registries, not only was there a marked increase in the prevalence of HF, but also 7–28% of patients with CCS were diagnosed with HF.²⁸

The use of CCB treatment was inappropriate in case 5, given the presence of HF. While there are vasoselective CCBs that do not adversely affect survival, the negative inotropic action of CCBs can lead to an increased risk of CV events, worsening HF or deterioration in cardiac function. The American Heart Association/American College of Cardiology guidelines on HF state that most CCBs should not be used in patients with HFrEF.²⁹ In the 2019 ESC guidelines, the use of non-dihydropyridine CCBs in patients with LV dysfunction is not advised.¹⁹ Instead of CCBs, ranolazine should be considered as the drug has documented therapeutic action in myocardial ion channels and energy usage.³⁰

The use of ranolazine in HF is supported by various investigational studies. In a canine model of induced HFrEF through intracoronary microembolisation, ranolazine notably increased LVEF (27% versus 36%, p=0.0001) and stroke volume (20 ml versus 26 ml) without changing systemic BP or HR. The same study also demonstrated the prevention of progressive LV dysfunction and remodelling with chronic treatment of ranolazine alone or when combined with enalapril or metoprolol.³¹ The MERLIN-TIMI 36 trial (Table 1) also showed that in patients with BNP >80 pg/ml, ranolazine reduced the primary composite endpoint of CV death, MI and recurrent ischaemia (HR 0.79; 95% CI [0.66–0.94]; p=0.009).¹⁸

While the authors note that there are countries where trimetazidine and ranolazine are used in combination, as in case 5, to date, no studies have been performed to support this strategy. However, in a recent review of angina treatment, it was suggested that patients with reduced HR or BP should receive ranolazine or trimetazidine.⁴

Case 6 also highlights the importance of lifestyle modification, which can have a profound impact on the improvement of CCS symptoms, cardiac functional capacity and quality of life. Patients with CCS should be advised on dietary therapy and adopt healthy eating habits, smoking cessation, increased physical activity, exercise-based cardiac rehabilitation, and weight management goal of 5–10% reduction in body weight.

Key learning points

• Successful PCI still requires accurate surveillance of the patient’s symptoms; angina may occur in more than 30% of patients after successful primary PCI.
• Adequate use of antianginal therapy is mandatory to achieve symptom relief and improve exercise tolerance in patients with persistent angina after successful revascularisation.
• CCBs are contraindicated in patients with HFrEF and agents with minimal impact on haemodynamics, such as ranolazine, are more appropriate for improving angina and reducing the use of nitrates.^18,19,29
• The concomitant use of trimetazidine and ranolazine in patients with HF is not well supported by evidence.
• Patients with CCS should be advised on lifestyle modification, exercise-based cardiac rehabilitation, and weight management.

Ischaemia with Non-obstructive Coronary Arteries

Case 7. Angina in a Patient with INOCA Treated with Third-line Ranolazine

The patient was a 56-year-old woman who presented with breathlessness and chest discomfort, prompting a consultation. TST showed significant ECG ST-segment depression at low output and she experienced angina requiring sublingual GTN at the end of the TST. Multislice CT coronary angiography revealed normal coronary arteries with a normal calcium score. Her gastroduodenoscopy was unremarkable. She was counselled for the diagnosis of possible ischaemia with no obstructive coronary arteries (INOCA). The patient was initiated on bisoprolol 1.25 mg once daily and subsequently uptitrated to 2.5 mg once daily. However, she complained of lethargy with the β-blocker and her angina symptoms did not improve (CCS-2). Bisoprolol was switched to diltiazem 60 mg three times daily but she remained at CCS-2 after 4 weeks. She was switched to ranolazine 375 mg twice daily, which resulted in significant improvement (CCS-0) after 6 weeks of therapy. No adverse events attributed to ranolazine have been reported during her 12 months of follow-up.

Case 8. Angina in a Patient with INOCA and Comorbidities

A 60-year-old woman had a history of hypertension and T2D treated with losartan, amlodipine, metformin and empagliflozin. She had an 8-year history of chest pain described as heaviness, induced by exertion and relieved by rest. She had a stroke 5 years previously and was initiated on statins. TST had equivocal results, but chest pain persisted. The patient had also developed a cervical spine problem that affected her upper extremities but not ambulation. Subsequent follow-up showed signs and symptoms of HF, including bipedal oedema and CCS-2 angina. ECG showed chronic changes in the inferior wall leads. N-terminal pro-B-type natriuretic peptide was elevated at 424 pg/ml (normal range of <125 pg/ml). Resting 2D echocardiography showed a normal EF (64%). Dobutamine stress echocardiography showed inducible ischaemia in the inferior wall segment, but coronary angiogram showed angiographically normal coronary arteries. Thus, the patient was diagnosed with HF with preserved EF due to INOCA, T2D and hypertension. The patient was treated with ranolazine 375 mg twice daily, which relieved the angina. Lifestyle modification including diet was reinforced, along with physical activity of moderate intensity. The patient was still on ranolazine at the last follow-up (9 months since treatment initiation), with no need for any dose increase.

Discussion: Angina in INOCA

Case 7 is a classic case of cardiac syndrome X or INOCA, which is more commonly seen in women.³² It presents with typical angina but does not present with significant obstructive coronary artery stenoses (>50% obstruction).^32,33 Several studies have shown that INOCA is more common among Asian populations than in white, most likely due to a higher prevalence of diabetes, microvascular disease and vasospasm.^34,35

Diagnosis can be implicated by conventional coronary angiography, but the two main pathophysiologies (microvascular angina [MVA] and/or vasospastic angina [VSA]) may not be immediately apparent from standard coronary arteriography, hence require a physiological coronary arteriogram with flow measurement and challenge with intracoronary adenosine and acetylcholine.³³

In cases 7 and 8, both patients presented with ischaemia; however, in patients without evidence of ischaemia, the most common causes of chest pain are non-ischaemic, highlighting the need to document the presence of ischaemia to guide therapy. Confirming the presence of ischaemia through invasive or non-invasive testing, such as TST and cardiac MRI (CMR), is an important step in diagnosing and assessing the efficacy of treatments for MVA.³⁶

A CMR perfusion test is expensive, but can identify subendocardial hypoperfusion.³⁷ Invasive tests with acetylcholine/adenosine may be conducted only if the catheterisation lab is already set up during the initial coronary angiography and only if needed to determine the patient’s exact phenotype.

Half of the patients enrolled in the CorMicA trial, the first randomised controlled trial linked to stratified medical therapy in angina, were overweight or obese, based on BMI.³³ Most patients presenting with the symptoms of INOCA were obese and had poorly treated hypertension, hyperlipidaemia and T2D. Therefore, management of risk factors is crucial.

Apart from control of CV risk factors and lifestyle changes, treatment for INOCA traditionally involves medications such as statins, CCBs and β-blockers.³² However, traditional antianginals such as β-blockers are less likely to be prescribed among Asians with VSA.³⁸ Furthermore, MVA is generally unresponsive to traditional antianginal treatments and necessitates the use of alternative therapies such as ranolazine.^36,39 Several studies have investigated the effectiveness of ranolazine in treating different types of angina, including MVA.^7,36,39 Ranolazine has been shown to improve the coronary reserve flow in MVA, thereby increasing the myocardial perfusion index.^32,40 In one study, ranolazine was associated with improved TST duration and improved quality of life scores in patients with MVA.³⁹ Similarly, a randomised, double-blind, placebo-controlled, crossover trial found that in women with no obstructive CAD and ≥10% ischaemic myocardium on adenosine stress CMR imaging, the use of ranolazine was associated with significantly better physical functioning, angina stability and quality of life.⁴¹ Two systematic reviews confirmed that ranolazine improved coronary microvascular function and was associated with increased CFR and global myocardial perfusion reserve index, as well as improved physical functioning and quality of life.^40,42 Lastly, in a recent meta-analysis that included placebo-controlled trials, ranolazine improved outcomes, including angina and quality of life scores.⁴²

INOCA is associated with HF through microvascular dysfunction, especially in patients with preserved EF. In patients with INOCA, HF is associated with adverse clinical events, such as recurrent ischaemia, frequent hospitalisations, decreased quality of life, and cardiac death.^43,44 Therefore, the early and accurate diagnosis of HF in INOCA is critical for providing the most suitable treatment plan and best possible outcome for each patient.

Ranolazine may be added to this patient’s treatment regimen because of its favourable haemodynamic and pleiotropic effects, and the presence of contraindications for CCB treatment in HF, as described previously. Even though this patient was being treated with HF medication, the patient’s pro-BNP level was around 400 pg/ml, whereas patients in HF trials had much higher BNP levels. Furthermore, BNP levels are around 95% higher in women than in men. Given these uncertain features, the diagnosis of HF should be confirmed because the presence of HF would contraindicate the use of CCBs.

Key learning points

• INOCA is a diagnostic challenge, and microvascular examination is expensive and not widely available in many countries in Asia. Hence, the diagnosis of INOCA requires a high index of suspicion.
• A large proportion of patients with INOCA may have persistent symptoms and impaired quality of life despite treatment with traditional antianginal drugs, including β-blockers, CCBs, or long-acting nitrates. Ranozaline has shown benefit in these patients and may be preferred in patients with INOCA.
• Patients with INOCA are at increased risk of HF and adverse outcomes; however, the diagnosis of HF should be confirmed as this impacts treatment decisions.
• Ranolazine may also be preferred in patients with INOCA and HF due to its favourable haemodynamic effects.

Limitations

The cases presented here were not randomly selected. As the cases demonstrated the utility of ranolazine across various patient profiles, selection bias is present. The authors also acknowledge that some patients may not respond to or receive a net clinical benefit from ranolazine therapy.

Conclusion

Angina caused by ACS and CCS may share similar characteristics, but their management differs. Angina in CCS can be managed by optimising oral antianginal drugs and often requires a combination of drugs with differing mechanisms of action. Effective angina control, crucial for improving the quality of life of CCS patients, usually necessitates a combination of medications.

The latest ESC guidelines on CCS recommend the selection of antianginal therapy according to the pathophysiology of angina and comorbidities rather than using a pre-established first- and second-line therapy.³

Supported by robust clinical trial data, ranolazine is an effective antianginal medication with a unique mechanism of action that is unlike that of other anti-ischaemic drugs. For the past several decades, ranolazine has played a common yet central role as an anti-ischaemia and antianginal drug, including treatment in those with INOCA or fixed, significant CAD. Ranolazine’s haemodynamic, pleiotropic and metabolic profile provides a rational approach for each patient’s individualised treatment regimen. Ranolazine may also be beneficial for patients with insufficient control of angina or those experiencing side effects from previous treatments. Ranolazine is well tolerated with few reported adverse events and has few contraindications.

Ranolazine may be used in patients with CCS with comorbidities; however, excluding severe renal failure, liver cirrhosis and moderate to severe liver impairment. Patients with severe renal impairment (i.e. glomerular filtration rate <30 ml/min/1.73 m²) may be at risk of renal failure while on ranolazine. Liver cirrhosis is a contraindication to ranolazine use; the maximum concentration of ranolazine increased by 80% in cirrhotic patients with at least moderate hepatic impairment versus those without hepatic impairment. Also, ranolazine is a substrate of CYP3A; hence, ranolazine should not be combined with strong inhibitors of CYP3A (e.g. ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir and saquinavir) and inducers of CYP3A (e.g. rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine and St John’s wort).