Prognosis of angina pectoris

Introduction

Stable angina pectoris (SAP) affects up to 5% of the adult population over the age 40 in most developed countries [1]. Patients with SAP often complain about poor quality of life and are considered frequent users of healthcare services. In many ways, prognostic assessment for SAP is crucial. On the one hand, it helps clinicians in either performing best diagnostic testing or identifying the most appropriate therapeutic approach and, on the other hand, it serves as a powerful motivational tool. Whether angina pectoris should be acknowledged as an independent predictor of future cardiovascular (CV) events or rather as a marker of disease severity has long been debated.

Currently, the physicians’ decision-making process is predominantly based on the ever more refined diagnostic imaging and laboratory tests rather than on an isolated incidence of angina pectoris, an inevitably subjective symptom of SAP. The Duke treadmill score is the only tool used for patient mortality risk evaluation which takes into account a clinical parameter such as angina pectoris (Table 1) [2].

Table 1. Duke Treadmill Score.

CV: cardiovascular

SAP is the most frequent coronary artery disease (CAD) manifestation, and very often may be a harbinger of its severest clinical presentation, acute coronary syndrome (ACS). It is indeed an insidious disease. Nevertheless, over time its type may change from one to another, and alter the final prognosis significantly. An individual’s prognosis varies up to tenfold with regard to baseline characteristics, functional and anatomical factors. Some patients are stable over the years and others experience rapid progression and abrupt fluctuations over days or weeks. In contrast, atherosclerosis may evolve over decades and patients may remain asymptomatic.

REACH, COURAGE …       

Data from the Framingham Heart Study demonstrated that the two-year incidence rates of non-fatal myocardial infarction (MI) and CAD death were 14.3% and 5.5% in men and 6.2% and 3.8% in women, respectively [3]. Cohn et al proved that annual mortality in the asymptomatic group of patients was 2.7% compared with 5.4% among patients with angina [4]. Murphy et al conducted a 20-year follow-up of the Renfrew-Paisley study to examine the long-term CV consequences of angina. It showed that 67.7% of men with angina and 45.4% of men without angina died. The results for women were 43.3% and 30.4%, respectively. Angina and ischaemic changes on electrocardiogram (ECG) both indicated an elevated risk; however, the abnormality on ECG appeared to be a significantly stronger risk predictor than angina alone. Compared to 32.7% of patients who remained asymptomatic, 43.5% of patients with angina experience a CV hospitalisation. In all, almost two thirds of men and half of women who are middle-aged patients with angina will die or require hospitalisation for a CV reason over the next 20 years [5].

The Reduction of Atherothrombosis for Continued Health (REACH) four-year follow-up study highlighted that patients with SAP and angina prior to baseline were more likely to be older, female and diagnosed with heart failure (HF) or polyvascular disease. Furthermore, they were less prone to experience ischaemic events and coronary revascularisation procedures before enrolment. Finally, this study revealed that patients with angina had higher rates of future CV death, MI and stroke, and were more susceptible to HF, CV hospitalisation and coronary revascularisation. Interestingly, lower-risk patients with angina tend to have recurrent CV events more often than higher-risk patients. Polyvascular disease was found to be the strongest predictor of future ischaemic events. In addition, the authors drew our attention to diabetes mellitus (DM) which thus far has been considered an atherosclerosis risk equivalent. However, myocardial ischaemia rather than angina by itself among diabetic patients appeared to be a significantly stronger predictor of future CV events [6].

These days, patients with SAP frequently receive percutaneous coronary intervention (PCI) as an initial management strategy instead of intensive medical therapy (e.g., nitrates, beta-blockers, statins), lifestyle intervention and risk factor reduction. The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial was designed to assess the impact of adding PCI to optimal medical therapy (OMT). It did not demonstrate superiority of PCI added to OMT over OMT alone with regard to long-term prognosis being affected by death, MI, or other major CV events. We have to remember that PCI is widely acknowledged as beneficial for patients with ACS on account of rapid enhancement of short-term prognosis but should not be used as a first-line therapy for patients with SAP. At the beginning of the follow-up period, PCI was proved to decrease both angina and subsequent revascularisation in comparison to OMT alone; however, in time, a considerable decrease was noted in the medical therapy group as well. Therefore, PCI may be safely deferred among patients with SAP - unlike OMT, which is associated with better prognosis and angina-free status over the long term [7].

SAP risk stratification is very often based on either coronary angiography, which determines anatomic burden, or stress single-photon emission computed tomography (SPECT), which is used for ischaemic burden evaluation. The COURAGE substudy revealed that both anatomic burden and left ventricular (LV) ejection fraction should be considered independent predictors of death, MI or non-ST-segment elevation acute coronary syndrome rather than ischaemic burden. However, unfortunately none of these factors identified patients who would particularly benefit from an initial invasive treatment [8].

Cardiovascular risk scoring

Nowadays, the classic risk factors serve to elucidate most CV events. According to the INTERHEART study, there are nine potentially modifiable risk predictors such as smoking, raised apolipoprotein B/apolipoprotein A1 ratio, hypertension, DM, abdominal obesity, psychosocial factors, lack of daily fruit and vegetable consumption, regular alcohol use and physical inactivity that collectively account for over 90% of initial acute MI events [9]. Therefore, integrating the taking of a precise medical history and total risk evaluation for individual patients into a therapeutic decision-making process seems fundamental and may considerably improve prognosis.

Umberto Barbero et al performed a meta-analysis of 42 studies among patients with SAP to determine multivariate predictors of major adverse cardiovascular events (MACE) [1]. Despite the great variety of patients with SAP, they compiled a list of a few easily noticeable and low-cost clinical features that may assist physicians in rapid identification of patients who require extended diagnostics, and more intensive treatment or follow-up. The most potent predictors of MACE appeared to be male sex, reduced ejection fraction, DM, prior acute MI and high C-reactive protein. According to this study, patients with an increased risk should have their personal risk factors aggressively modified and medical therapy should be instituted immediately. In case of symptoms of angina, fractional flow reserve (FFR) for guidance of PCI is highly recommended [2].

The ESC initiated the Systematic Coronary Risk Evaluation (SCORE) project to estimate better the total CV death risk over a 10-year period, and identify low- and high-risk groups of patients. Furthermore, the SCORE risk scale can be adapted easily to various countries and cultures which makes it more accurate and flexible to manage. The Framingham Risk Score (FRS) is another risk scoring system recommended by the ESC. It predicts not only the development of CAD but also the death risk due to cardiovascular disease (CVD) [1]. Tolunay et al assessed the relation between the SYNTAX score and, among others, SCORE and FRS. They revealed that the most reliable risk assessment tool for establishing prognosis among patients with SAP in terms of CAD severity and its extensiveness is SCORE [10].

Epicardial adipose tissue

Obesity has become a serious global issue. An excessive adipose tissue accumulation may put individuals at risk for numerous chronic health conditions, for example, heart disease, stroke, hypertension, DM, osteoarthritis, and various cancers.

Epicardial adipose tissue (EAT) is regarded as an independent and more reliable marker for visceral adipose tissue (VAT) compared to the widely used body mass index or waist circumference [11]. EAT was found to be associated with higher levels of chemokine and inflammatory cytokines than subcutaneous fat which might eventually result in destructive changes of coronary arteries and myocardium [12]. There are multiple publications demonstrating the epicardial fat thickness predictive value of CAD presence and severity, including CV death [13]. Nevertheless, epicardial fat thickness or volume may easily be measured with standard echocardiography or computed tomographic scans but may also be a novel, modifiable therapeutic target. Perhaps in the near future EAT measurement might become a part of routine echocardiography. In his study, Iacobellis summarised the results of various trials and showed a satisfactory reduction of epicardial fat due to thiazolidinediones, glucagon-like peptide 1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and statins [14].

Doomed to worse prognosis

The vast majority of patients with SAP are adults or elderly people who are very often a challenging group in terms of treatment. Regardless of the physiologic impact of ageing, they generally suffer from numerous comorbidities which undoubtedly lead to a less favourable final outcome and they deserve a special approach.

DM has already been acknowledged as a worldwide pandemic. The dramatic prevalence, especially in DM type 2, is predominantly associated with widespread obesity, and it concerns all age groups of both men and women. Even paediatricians call for action to prevent and decrease overweight and obesity among children. However, in the late 1990s multiple trials demonstrated that DM is an independent risk factor for CVD [15]. Furthermore, patients with DM who developed CVD were reported to have a worse prognosis for survival compared to non-diabetic patients. Apart from that, DM is closely related to the atypical or even asymptomatic manifestation of CAD.

Chronic obstructive pulmonary disease (COPD) is an umbrella term defining a progressive lung disease. Many people think that quitting smoking is tantamount to a decrease in the COPD incidence rate; however, they forget that ageing plays a role at least as significant as smoking in COPD pathogenesis. Multivariate publications suggest the frequent coexistence of CVD and COPD. Chen et al performed one of the largest meta-analyses which showed that patients suffering from COPD had a two to five times higher risk of major CVD types such as CAD, cardiac dysrhythmia, heart failure, diseases of pulmonary circulation, and arterial diseases [16]. The above results show a pressing need for new therapeutic strategies to be developed to enhance prognosis among patients suffering from CVD and COPD.

Unsolved issues

According to recent studies, 10% to 30% of optimally treated patients with CAD still tend to experience symptoms [17]. This results in low quality of life and increased CV risk and, finally, imposes a great economic healthcare burden. Effective treatment is one of the most vital conditions for the success of satisfactory control of SAP.

When standard treatment fails, we may think of a new percutaneous device, the coronary sinus reducer. Its implantation offers a prognostic benefit and relief of symptoms, but we may also anticipate MI alleviation possibly due to blood redistribution in the myocardium. Angina pectoris resistant to treatment is associated with high hospitalisation rates and decreased exercise capacity. Verheye et al reported that patients in Canadian Cardiovascular Society class III or IV, who had the coronary sinus reducer implanted, already noted improvement in the quality of life after six months [18]. This publication certainly offers food for thought to us physicians, because favourable prognosis means a lot to our patients but the quality of their life is no less important.

Huang et al conducted a systematic review comparing the prognosis of patients with non-obstructive CAD (vessel diameter narrowed to <50%) versus normal arteries. It indicates that, despite having multiple therapeutic options, patients with non-obstructive CAD very often remain undertreated in current clinical practice. They are more likely to be discharged without further evaluation if their coronary arteries are normal or near normal on angiography and less likely to be treated with aspirin and statins. According to this study, patients with non-obstructive CAD in particular require more attention and must not be neglected because of a higher risk of MACE [19].

Conclusions

Multiple risk factors, comorbidities, treatment non-compliance, but also new therapeutic options and many other circumstances all independently affect the final outcome of patients with SAP. Most studies indicate a positive correlation between SAP and increased CV risk (death and non-fatal MI); however, an explicit prognosis assessment is almost impossible to establish. We believe that there are no dominant risk factors, and that a comprehensive approach to the patients is the only one that is recommended. Perhaps implementation of wide-ranging educational programmes even for children would greatly assist physicians’ and future patients’ primary prevention efforts. Finally, early identification and treatment of patients may very often be the guarantee of an enhanced prognosis and quality of life and also the reduction of further complications.