Medical and Interventional Treatment of Refractory Angina

Review Article

J Cardiovasc Disord. 2021; 7(2): 1048.

Medical and Interventional Treatment of Refractory Angina

Valchanov K¹*, Tan Z¹ and Valchanova A²

1Department of Anaesthesia, Royal Columbian Hospital, 330 E Columbia St, New Westminster, Canada

2Student at University College London, London, UK

*Corresponding author: Kamen Valchanov, Department of Anaesthesia, Royal Columbian Hospital, 330 E Columbia St, New Westminster, BC V3L 3W7, Canada

Received: September 08, 2021; Accepted:October 08, 2021; Published: October 15, 2021


Refractory Angina Pectoris is a chronic pain condition relating to myocardial ischaemia in the presence of coronary artery disease despite optimal medical therapy. It affects a cohort of patients with a subset of the coronary perfusion deficiencies. While there is no cure for these patients, an array of medical and interventional treatment is available in 2021. In this article we discuss the options available with an explanation of the mechanisms of action and evidence for their use.

Keywords: Refractory Angina Pectoris; Chronic Coronary Disease; Spinal Cord Stimulation



Refractory Angina Pectoris (RAP) is defined as “a chronic condition caused by clinically established reversible myocardial ischaemia in the presence of coronary artery disease, which cannot be adequately controlled by a combination of medical therapy, angioplasty, or coronary artery bypass grafting” [1]. RAP encompasses conditions where the ischaemic pain is due to a deficiency in distal myocardial perfusion such as microvascular obstruction and where patients have already undergone often extensive coronary revascularization both surgically and percutaneously. In many of these patients, further revascularization is not technically possible, or such procedures carry a prohibitive risk.

However, the routine assessment of microvascular obstruction is both technically challenging and infrequently performed. With recent advances in coronary revascularization, the paradigm of what is not possible or too risky is constantly evolving. This improvement has been arguably most marked in the field of percutaneous coronary intervention for chronic total occlusions. This advance alone has led to a reduction in patients who have ‘no option’ for further coronary revascularization in 2021. However, a small subset of patients with stable coronary atherosclerosis who have a significant morbidity and reduction in quality of life due to ongoing chest pain still exists.


Over the last 20 years, significant progress has been made in reducing the mortality in patients suffering with coronary atherosclerosis, whilst the morbidity of patients living with daily stable angina remains a significant burden on the health economy. The prevalence of RAP is around 10% in patients with chronic stable coronary disease [2].

Although RAP may not, in isolation, result in a substantial reduction in life expectancy, it does frequently impair the quality of life [3]. In a large case series from Duke Database Cardiovascular Disease, patients with RAP have a small increase in mortality rates at 3 years, but a high incidence of resource utilization and hospital admissions [4]. This was costed in 2012 at 10,185 USD per patient. This implication is significant when one considers that 77.6% of patients are still alive at 9 years [5]. Even 21 years ago the cost of hospitalization of RAP in the UK in 2000 was estimated as £208 million per year [6].

Many publications have addressed the predictive test for death and further myocardial infarction, and the most useful test associated with these two events is the plasma concentration of hs-cTnT over 5ng/l [7]. Interestingly, a study in the New England Journal of Medicine [8] randomly assigned 5179 patients with moderate to severe coronary ischemia to either conservative management or aggressive revascularisation strategy. As expected, 90% of the patients had also symptoms of angina. The authors’ findings were that at 3.2 years both groups had similar results in terms of mortality. The health status of the same group of patients in the ISCHEMIA trial [8] showed also similar results in both groups, but better anginal control in the invasive strategy group. These results support the hypothesis that invasive treatment of coronary obstructive lesions is mandated only in symptomatic patients with angina.

Assessment of RAP

Clinical history

A key concept of the management of patients with refractory angina is that the chest pain they are experiencing is, indeed, caused by an insufficiency in myocardial oxygen delivery. We, as clinicians, are often surprised by the enormous variation in perceived pain by patients suffering with myocardial ischaemia, most notably in those patients with end organ signs of neuropathy. The diagnosis of anginal pain is in the history. Description of the type of pain (heaviness, gripping, suffocating), location and radiation, provoking and relieving factors, duration and frequency form the basis underlying a definitive diagnosis. However, typical angina is considered to be an uncommon presentation [9]. The perceived pain of refractory angina is worse in patients suffering from anxiety and depression [10]. With time and treatment, the pain is associated with lower emotional arousal. However, as a chronic pain of more than 3 months duration, there is undoubtedly a superimposed emotional and psychosocial component. Therefore, in the management of refractory angina, it is equally important to consider a holistic approach to pain, rather than solely concentrate on myocardial oxygen delivery.

The ESC 2019 Guidelines [11] place some emphasis on the holistic approach to the assessment of angina with a screen for noncardiac vascular disease, arrythmias, valvular or hypertrophic cardiac disease and significant other co-morbidities such as thyroid disease, anaemia and renal dysfunction.


The route which the physician may choose for investigation of RAP would very much depend on the pre-test probability calculated on an individual basis for each patient. The use of computed tomography coronary angiography has a prominent role in the new ESC guidelines [11], alongside functional assessments of myocardial ischaemia such as stress echocardiography, cardiac magnetic resonance imaging and radioisotope based myocardial perfusion scanning. If a patient has a high pre-test probability of obstructive coronary disease, then the first line investigation may well be invasive coronary angiography, especially in the presence of reduced left ventricular function. Invasive angiography may also be more useful in patients with arrhythmias which can result in poor gating of the CTCA, or in cases where the likelihood of a high coronary calcium score making accurate luminal assessment difficult. The ESC guidelines also give due prominence to the Fractional Flow Reserve (FFR) assessment of indeterminate lesions and encourage pressure wire assessment in all patients with multi-vessel disease prior to referral for surgical revascularisation

Diagnosis and syndromes

RAP pain as a condition is caused by the deficiency of oxygen delivery to the cardiomyocytes. RAP, therefore, requires viable myocardium. Areas where cardiomyocytes are replaced by fibrosis are unlikely to produce ischaemic pain. In other cases, a typical anginal pain is present but no epicardial structural cause for the ischaemia can be found. As discussed, these patients may be suffering with undetected microvascular obstruction, or indeed the presence of vasospastic coronary reactivity which can be refractory to optimal vasodilatation with calcium channel blockers and longacting nitrates. A further subset of this population are those patients labelled with cardiac syndrome X, who have unobstructed epicardial coronaries but objective evidence of ischaemia on exercise testing [12]. The hypothesised mechanisms underlying this condition include undiagnosed microvascular obstruction and an abnormal pain perception from the myocardium. Up to 20% of patients complain from angina but have no angiographic stenosis [13]. How can pain be explained in these patients? It is stipulated that angina can be explained by very high or low coronary flow reserve; diffuse atherosclerosis; heterogeneous endothelial dysfunction; or diffuse epicardial atherosclerosis. The important phenomenon of subendocardial ischaemia [14] which occurs due to increased coronary pressure gradient in periods of increased demand has been widely recognised. These patients may not have angiographically diagnosed flow obstruction.

The recently published European Society of Cardiology guidelines (2019) [11] on Chronic Coronary syndromes, outline a six-step approach for those patients with angina and suspected Coronary Artery Disease (CAD). Thereafter, lifestyle interventions, drug therapy and revascularisation options are considered. Emphasis is placed on individual risk/benefit analysis and a multi-disciplinary approach to revascularisation recommendations.

Management of RAP (Figure 1)

Citation: Valchanov K, Tan Z and Valchanova A. Medical and Interventional Treatment of Refractory Angina. J Cardiovasc Disord. 2021; 7(2): 1048.