Secondary Prevention of Coronary Artery Disease

Abstract

Cardiovascular atherosclerotic disease (CvAD) and its consequences, coronary artery disease (CAD) and cerebrovascular disease (CvD), remain the major cause of morbidity and mortality in all countries. Addressing the predisposing factors related to lifestyle, such as smoking, lipid-rich diet, excessive stress, and lack of exercise, is important for primary and secondary prevention. In addition, the systematic use of cardioprotective medications, such as antiplatelets, statins, beta-blockers, and angiotensin-converting enzyme inhibitors, as well as new generation antidiabetics, for appropriate control, based on recent guidelines, of blood pressure, plasma glucose and lipid levels, lead to a further decrease in the risk for secondary cardiovascular events including cardiovascular death.

1. Introduction

The incidence and mortality of cardiovascular atherosclerotic disease (CvAD) and its clinical consequences, coronary artery disease (CAD) and cerebrovascular disease (CvD), although declining in some countries, due to better understanding of the predisposing risks and to the introduction of newer and more effective cardioprotective therapies, they are still considered a major cause of morbidity and mortality, influencing negatively the health systems of most countries [1].

Primary and secondary prevention of cardiovascular atherosclerotic disease, through adaptation of a healthy lifestyle, is an important part of the overall management. This includes avoidance of smoking, by preventing initiation or by cessation, of salt and of saturated lipids. In addition, engagement in regular physical activity and exercise programs, either in organized group rehabilitation settings, or as a lone approach, maintenance of a normal body weight, blood pressure, plasma glucose, and lipid levels, are important primary and secondary prevention measures [2].

Prevention of cardiovascular events in persons with established coronary artery disease is the topic of this chapter.

2. The risk factors

The main cardiovascular risk factors are: cigarette smoking, hypertension, diabetes, obesity, and elevated total and LDL cholesterol.

2.1 Smoking

Chronic smokers carry a higher risk for cardiovascular disease, lung disease, and cancer than nonsmokers [3]. Moreover, it has been observed in large-scale surveys that approximately 18-30% of patients continue smoking after their first cardiovascular event. The percentage of active smokers at the time of consultation, in EUROASPIRE III, was 18.2%, nearly one in every five patients [4]. In EUROASPIRE IV, the prevalence of persistent smoking among patients who were smoking prior to the coronary event was 49.3%, despite the fact that most patients reported an intention to quit smoking [5]. Smoking cessation recommendations are shown in Table 1.

Recommendation	Class	Level
All smoking of tobacco should be stopped.	I	A
Smoking cessation is recommended regardless of weight gain.	I	A

Table 1.

Recommendations on smoking (ESC guidelines 2021).

Quitting smoking after a cardiovascular event is important to reduce new events and mortality [6]. It is perhaps the most effective prevention measure reducing both the occurrence of myocardial infarction and death [7]. A chronic smoker who quits may gain some weight, up to 5 kg. However, the benefits overweigh the small risk of gaining weight [8]. Patients restarting smoking are usually those who suffer from some degree of depression related to their cardiovascular event. The approach of these patients must be different since they may need psychological support in addition to medical counseling and therapies [9].

2.2 Lipids

It is known that key role in atherogenesis plays the entry of oxidized LDL into the arterial wall [10]. Clinical trials have evidenced that reduction of LDL levels, with lipid-lowering drugs, reduces the risk of cardiovascular atherosclerotic disease [11]. There is no lower limit for LDL, presently, and no J-curve phenomenon has been observed so far, therefore the principle “the lower the better,” seems to apply to explain the relation between LDL levels and the risk for cardiovascular atherosclerotic disease.

LDL can be measured directly, or it can be calculated using the Friedewald formula [12]. The calculation is valid when triglycerides are less than 400 mg (4.5 mmol/L). If more, then direct measurement is advised.

In mmol/L: LDL = total cholesterol – HDL – (0.45 × triglycerides).

In mg/dL: LDL = total cholesterol – HDL – (0.2 × triglycerides).

The Martin-Hopkins equation can be used instead to improve Friedewald estimation, especially in lower LDL groups [13].

The non-HDL level is another useful index to explain the cardiovascular risk [14]. It is calculated by subtracting HDL from total cholesterol, and it is not influenced by the LDL levels and can also be measured in the non-fasting state.

Treating LDL is not an easy task. There are many drugs available with varying degree of tolerability and with some variations in the therapeutic effects [15]. The decision for initiation of therapy should be taken together with the patient since this will be life-long. Possible side effects should be explained carefully weighing the benefits for reducing the risk for events to the possible side effects.

Patients with established cardiovascular atherosclerotic disease should have their LDL levels below 55 mg/dL (1.4 mmol/L), whereas patients at high risk with multiple risks but without established cardiovascular disease should have their LDL lower than 70 mg/dL (1.8 mmol/L). Benefit has also been shown in patients who had their LDL lowered to less than 40 mg/dL (1.0 mmol/L). This is irrespective of gender or history of diabetes [16].

Regarding triglycerides, it is advised that their concentration should not exceed 150 mg/dL (1.7 mmol/L) as higher values may indicate an increased risk for events [17].

Achieving high levels of HDL is desired, and it is advised that this is done mainly with lifestyle measures, such as physical activity, rather than with drugs.

Secondary causes for dyslipidemias should always be addressed and if present, treated, although in patients with established CvAD administration of lipid-lowering drugs is recommended despite presence or not of secondary causes. Conditions, which may influence the lipid metabolism, include thyroid disease, hepatic disorders, renal disease, and Cushing syndrome [18].

It is known from epidemiological studies that high consumption of fish, vegetables, fruits, nuts, and whole grains, and lower consumption of red meat, processed food, saturated fat, carbohydrates, and salt are related to lower cardiovascular events [19].

Lipid-lowering medications include 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, bile acid sequestrants, cholesterol gastrointestinal absorption inhibitors (ezetimibe), and PCSK9 inhibitors [20].

Statins are effective lipid-lowering drugs in reducing the levels of LDL, reducing hence the risk for a new event including cardiovascular mortality. They may also reduce triglycerides and increase HDL. Statins are considered first-line treatment in patients with chronic CvAD. Among the most frequent side effects of statin administration is myopathy in varying degree. Rhabdomyolysis is a rare side effect and needs immediate interruption of statin. Temporary rise in the hepatic enzymes has been observed in some patients. This is reversible in most cases. A few patients complain of weight gain. In general, statins are quite safe drugs with significant cardioprotective effects [21].

In patients not achieving the goals, ezetimibe, a cholesterol-absorption inhibitor, may be added. This causes further reduction in LDL [22]. Ezetimibe is considered as a second-line lipid-lowering drug, either in combination with a statin or alone if statins are not tolerated [22].

A newer group of lipid-lowering drugs are proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9 inhibitors). These monoclonal antibodies are considered very effective in reducing LDL. They are prescribed in addition to the maximum tolerated dose of statins plus ezetimibe, or when statins are not tolerated. There are currently two PCSK9 inhibitors approved by the FDA: Repatha (Evolocumab) and Praluent (Alirocumab). Administered subcutaneously every 2–4 weeks, the PCSK9 antibodies evolocumab and alirocumab reduce LDL by up to 60% in a broad range of populations. Two large cardiovascular outcome trials involving a total of 46,000 cardiovascular high-risk patients on guideline-recommended lipid-lowering therapy showed that treatment with evolocumab and alirocumab led to a relative reduction of cardiovascular risk by 15% after 2.2 and 2.8 years of treatment, respectively [23]. It seems that they also have an effect of triglycerides, on Lp(a), and on HDL.

Inclisiran is a long-acting hepatic PCSK9 synthesis inhibitor, known as siRNA (small interfering RNA interference). It works differently from the PCSK9 inhibitors by interrupting the “printing” of PCSK9 protein from the messenger RNA. It is also given twice yearly, whereas the others are given every two weeks. Inclisiran, given twice yearly, is associated with a reduction in LDL levels by 47.5% and 44.2%, after 210 days and 4 years, respectively [24]. The recommendations for lipid-lowering therapy are shown in Table 2.

Recommendation	Class	Level
It is recommended that a high-intensity statin is prescribed up to the highest tolerated dose to reach the LDL goals set for the specific risk group.	I	A
In patients with established cardiovascular atherosclerotic disease lipid-lowering treatment with an ultimate LDL goal of <55 mg/dL (1.4 mmol/L) and a > 50% reduction in LDL vs. baseline is recommended.	I	A
For secondary prevention patients not achieving their goals on a maximum tolerated dose of a statin plus ezetimibe, combination therapy including a PCSK9 inhibitor is recommended.	I	A

Table 2.

Recommendations in lipid therapy (ESC guidelines 2021).

2.3 Hypertension

A number of studies have correlated hypertension with a new event and with increased mortality in patients with CvAD [25, 26, 27]. Hypertension is defined as elevated blood pressure, systolic, diastolic, or both [28]. Although the upper acceptable limits of systolic and diastolic blood pressure are 140 and 90 mmHg, respectively, these may differ in relation to the way the measurement is done. For example, in the ambulatory BP measurement, the upper mean limits of normal are 130 and 80 mmHg, and home measurements are up to 135 and 85 mmHg, respectively [29]. These are shown in Table 3. Table 4 shows the recommended values of BP in different clinical conditions in patients with diabetes, chronic kidney disease, coronary disease, and stroke.

Category	SBP (mmHg)		DBP (mmHg)
Office BP	≥140	and/or	≥90
Ambulatory BP
Daytime (or awake) mean	≥135	and/or	≥85
Night-time (or asleep) mean	≥120	and/or	≥70
24-h mean	≥130	and/or	≥80

Table 3.

Definitions of hypertension (ESC guidelines 2021).

Age group	Office SBP treatment target ranges (mmHg)
	Hypertension	+ DM	+ CKD	+ CAD	+ Stroke/TIA
18 − 69 years	120–130	120–130	<140–130	120–130	120–130
	Lower SBP acceptable if tolerated
≥70 years	<140 mmHg, down to 130 mmHg if tolerated
DBP treatment	<80 for all treated patients

Table 4.

Blood pressure target values in various clinical conditions (ESC guidelines 2021).

2.4 Diabetes

In the EUROASPIRE IV survey [30], conducted in 24 European countries, among patients with coronary artery disease and less than 80 years old, 26.8% of the participants reported having diabetes and 37.6% had a BMI above 30. This high prevalence of diabetes and obesity indicates the need for intensive secondary approach including both lifestyle and adherence to cardioprotective medications, including the newer SGLT2i, in an attempt to reduce morbidity and mortality. Table 5 summarizes the recommendation for the treatment of patients with diabetes.

Recommendation	Class	Level
It is recommended that in persons with type 2 diabetes and cardiovascular atherosclerotic disease, the use of GLP-1RA or SGLT2 inhibitor with proven outcome benefits is recommended to reduce cardiovascular and/or cardiorenal outcomes.	I	A

Table 5.

Recommendations for the treatment of patients with diabetes (ESC guidelines 2021).

3. Cardiac rehabilitation

Every patient having an acute cardiovascular event should undergo short- and long-term cardiac rehabilitation. This is an intervention, which needs the participation of many professionals, including cardiologists, nurses, exercise physiologists, psychologists, and dieticians. Participation in rehabilitation programs is associated with an improvement in the quality of life, a reduction in hospitalizations, and in mortality [31].

Cardiac rehabilitation is not applied uniformly across Europe. In some countries, participation reaches the high 90%, whereas in other countries participation is negligible or absent.

Some general rules should apply for an effective rehabilitation program. Firstly, it must start the day after the acute cardiovascular event, for example, an acute myocardial infarction. It must be supervised by cardiologist and carried out by trained health professionals. The sessions and the time for each session should be individualized, but some general rules regarding a minimum time should be taken into consideration. All recognized cardiovascular risks should be addressed during rehabilitation. The European Association of Preventive Cardiology has set minimal and optimal standards for effective secondary prevention through cardiac rehabilitation [32]. The recommendations for cardiac rehabilitation are shown in Table 6.

Recommendation	Class	Level
Participation in a medically supervised, structured, cardiac rehabilitation program for patients after an atherosclerotic cardiovascular event and/or revascularization, and for patients with heart failure (mainly HFrEF) is recommended to improve patient outcomes.	I	A

Table 6.

Recommendations for cardiac rehabilitation (ESC guidelines 2021).

4. The EUROASPIRE surveys

Since cardiovascular atherosclerotic disease (CvAD) remains the leading cause of disability and death across the globe, the main objectives of prevention is to reduce morbidity and mortality. Observational studies and randomized controlled trials, with lifestyle modification and pharmaceutical interventions, have evidenced a favorable influence of the known cardiovascular risk factors, on morbidity and mortality, and on preservation of the quality of life, in patients at high risk or with established CvAD.

The Joint European Societies (JES) guidelines on cardiovascular disease prevention published from 1994 to 2016 defined the lifestyle and risk factor goals for patients with coronary disease: give up smoking, choose healthy food, be physically active, have a body mass index (BMI) of less than 25 kg/m², and blood pressure of <140/90 mmHg (<130/80 mmHg if diabetes is present, a LDL cholesterol of <70 mg/dL (<1.8 mmol/L) or at least 50% reduction from baseline, glycated hemoglobin (HbA1c) <7.0% in the presence of diabetes, and appropriate use of cardioprotective medications which include: aspirin and other antiplatelets, β-blockers, angiotensin-converting enzyme inhibitors (ACEi)/angiotensin II receptor blockers (ARBs), and statins.

The EUROASPIRE (European Action on Secondary and Primary Prevention by Intervention to Reduce Events) surveys are audits designed to assess the clinical outcome and the degree to which the guidelines on cardiovascular disease prevention are met in the European populations. The surveys started in 1995-1996 and until 2014, four surveys have been completed among nine countries (1995-6), fifteen countries (1999-0), twenty-two countries (2006-8), and twenty-six countries (2012-2014). The surveys described the lifestyle and the risk factor management in patients with established coronary artery disease.

The results of EUROASPIRE surveys I to IV demonstrated a high prevalence of modifiable risk factors and inappropriate use of pharmacotherapy for blood pressure and lipid control in patients with established cardiovascular disease.

Moreover, the EUROASPIRE V survey, conducted between 2016 and 2018, among patients from 29 countries, incorporated in addition an assessment of dysglycaemia (impaired fasting glycemia IFG, impaired glucose tolerance IGT, and new diabetes) and kidney function in all patients [33]. A total of 8261 patients (females 26%) were interviewed. Nineteen percent smoked and 55% of them were persistent smokers, 38% were obese (body mass index ≥30 kg/m²), 59% were centrally obese (waist circumference: men ≥102 cm; women ≥88 cm), while 34% were physically inactive (physical activity less than 30 min less than 5 times a week). Forty-two percent had a blood pressure ≥ 140/90 mmHg (≥130/85 if diabetic), 71% had low-density lipoprotein cholesterol (≥70 mg/dL (≥1.8 mmol/L), and 29% reported having diabetes. Antiplatelets were prescribed in 93% of patients, beta-blockers in 81%, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in 75%, and statins in 80% [33].

5. Summary

The main risk factors for cardiovascular atherosclerotic disease are high total and LDL cholesterol, elevated blood pressure, smoking, psychological stress, uncontrolled or poorly controlled diabetes, and obesity. Risk factors are treated based on the goals set by the guidelines.

Regular physical activity is important in secondary prevention.

In general, a reduction of sedentary time and more involvement in activities is recommended for all adults for primary and secondary prevention. Cardiac rehabilitation is encouraged for all patients with established CvAD.

A diet poor in saturated fats and rich in vegetables and fruits lowers the risk of cardiovascular disease.

Maintaining a normal weight may influence favorably other risks such as elevated blood pressure and elevated total and LDL cholesterol, reducing, thus, the CvAD risk.

Mental healthcare, especially management of depression, improves the quality of life and reduces the risk for CvAD.

Stopping smoking reduces the CvAD risk in all persons. Assistance drug therapy and follow-up support should be used to encourage patients to stop smoking if difficulties are observed.

The levels of LDL should be lowered by the use of statins, ezetimibe, and/or PCSK9 inhibitors in all patients with CvAD aiming to achieve the goal of values less than 55 mg/dL (<1.4 mmol/L), or if not achieved, by a reduction of more than 50% compared to baseline.

Lifestyle interventions and antihypertensive drugs, such as beta-blockers, ACE inhibitors, or ARBs, are recommended to lower BP levels based on recent guidelines aiming to achieve levels of 120/80 mmHg or lower.

Antiplatelet therapy with aspirin is indicated in all patients with CvAD.

In patients with CvAD and diabetes, treatment of diabetes with a target of 6.5–7.5% HbA1c is recommended.

Table 7 summarizes the use of cardioprotective medications in CvAD.

Aspirin 75–100 mg is recommended for patients with a previous myocardial infarction or revascularization.	I	A
In patients with chronic coronary syndromes clopidogrel 75 mg daily is recommended, in addition to aspirin, for 6 months following coronary stenting, irrespective of stent type, unless a shorter duration is indicated (1–3 months) due to risk or occurrence of life-threatening bleeding.	I	A
ACE inhibitors (or ARB) are recommended if a patient has other conditions (e.g., heart failure, hypertension, or diabetes)	I	A
Beta–blockers are recommended in patients with left ventricular dysfunction or systolic heart failure.	I	A
In patients with established atherosclerotic cardiovascular disease oral lipid-lowering treatment with an ultimate LDL goal of <55 mg/dL (1.4 mmol/L) and a > 50% reduction in LDL vs. baseline is recommended.	I	A

Table 7.

Recommendations for cardioprotective medical therapy in patients with CvAD (ESC guidelines 2021).

Conflict of interest

The author declares no conflict of interest.