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Cardioprotective drugs 

Cardioprotective drugs
Chapter:
Cardioprotective drugs
Author(s):

Johan De Sutter

, Miguel Mendes

, and Oscar H. Franco

DOI:
10.1093/med/9780199656653.003.0019_update_001

Update:

  • Includes ESC guidelines on ACEi in heart failure

  • Updated references

Updated on 23 February 2017. The previous version of this content can be found here.
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date: 07 March 2021

Summary

Cardioprotective drugs are important in the treatment of patients at risk for or with documented cardiovascular disease (CVD). Beta-blockers are indicated for a wide range of patients with cardiac pathologies, including acute coronary syndrome, stable coronary artery disease, heart failure, and arrhythmias. Most evidence on cardiovascular morbidity and mortality is available for post-myocardial infarction (MI) patients and those with chronic systolic heart failure. Ivabradine is a specific heart-rate-lowering agent which acts on the sinoatrial node cells by selectively and specifically inhibiting the pacemaker If current. It can be used for the symptomatic treatment of chronic stable angina pectoris in patients with coronary artery disease (CAD) in sinus rhythm and a heart rate remaining at 70 or more beats/min. Accordingly, in systolic heart failure it reduces the risk of hospitalization for heart failure in patients in sinus rhythm with a heart rate remaining at 70 or more beats/min and persisting symptoms. Angiotensin-converting enzyme inhibitors (ACEi), together with other drugs like beta-blockers, statins, and antiplatelets, are one of the cornerstones of CVD prevention in congestive heart failure, stable angina, and post-acute MI and in secondary prevention after any event or revascularization procedure in CAD. They are also the first-line medication in hypertension, namely in the presence of renal dysfunction, diabetes, or diabetes nephropathy. Angiotensin receptor blockers (ARBs) are mainly alternative drugs for the same indications in case of intolerance to ACEi in stable angina, STEMI, Non-STEMI and after myocardial revascularization. In HF patients, LCZ696, the association of valsartan and sacubitril (a neprilysin inhibitor) demonstrated to be superior to enalapril in reducing the risks of death and of hospitalization for heart failure. ACEi and ARBs should not be used together, except in rare situations, due to the risk of deterioration of renal function and hyperkalaemia. The aldosterone antagonists (AAs) spironolactone and eplerenone are indicated in patients with New York Heart Association class II–IV heart failure or acute MI with impaired left ventricular function, and may also have a role in hypertension. Aliskiren, a direct renin inhibitor (DRi), belongs to the most recent and less studied renin–angiotensin–aldosterone (RAAS) receptor blocker group. It only has a clinical indication for hypertension. Calcium channel blockers (CCBs) are first-line medication in patients with isolated systolic hypertension, black people, and during pregnancy, in the presence of intermittent claudication, asymptomatic atherosclerosis, or metabolic syndrome. They can be used together with diuretics, ACEi, ARBs, or beta-blockers, with the aim of reaching the guideline-recommended blood pressure targets, improving the surrogate end-points, and limiting side effects. CCBs have also shown clinical efficacy in angina pectoris, alone or in combination with beta-blockers and/or with long-acting nitrates. The non-dihydropyridines verapamil and diltiazem are an alternative to beta-blockers in stable CAD, and can be used alone or in association with other drugs to control the ventricular rate in atrial fibrillation or flutter or to prevent some supraventricular tachycardias. Despite great advances in the prevention and treatment of CVD, it remains one of the main causes of mortality and morbidity. Under the principle that a large preventive effect for CVD would require intervention on everyone at increased risk irrespective of their risk factors levels, modifying several risk factors together, and reducing these by as much as possible, in 2003 Wald and Law proposed the polypill concept. A polypill is a pill in which multiple medications effective in the prevention of CVD (e.g. statins, antihypertensives, and aspirin) are combined in a single pill. The concept also includes the strategy of giving this combination pill to everyone over 55 years of age and all those with existing CVD irrespective of age, and stopping all efforts focused on measuring risk factors and screening for CVD. Since the introduction of the concept, much debate has been generated regarding the potential role of a polypill in CVD prevention and treatment, and multiple efforts have focused on developing and testing polypills. Further evaluation on the safety and long-term efficacy of polypills is required, but initial reports are promising and polypills could soon play a crucial role in the treatment and prevention of CVD.

Clinical case

A 63-year-old man with a history of smoking and chronic obstructive pulmonary disease was admitted for a ST-segment elevation myocardial infarction that was treated in the acute phase with primary percutaneous coronary intervention and stenting of the proximal left anterior descending coronary artery. At discharge his echocardiography showed a left ventricular ejection fraction of 45% due to apical hypokinesia without arguments for elevated filling pressures or significant valvular heart disease. He was discharged with a statin, dual antiplatelet therapy, carvedilol 25 mg/day, and lisinopril 10 mg/day.

Two weeks later he is seen for his first out-patient consultation before the start of a cardiac rehabilitation programme. He has no angina and has stopped smoking. However, he mentions complaints of dyspnoea and wheezing. Physical examination shows no signs of fluid retention, but lung auscultation reveals mild wheezing and a prolonged expirium. His blood pressure is 150/90 mmHg and his electrocardiogram shows a regular sinus rhythm 80 beats/min and Q waves in leads V1–V4. The exercise test was stopped because of dyspnoea but no clinical or electrocardiographic signs of ischaemia were noted. His maximal blood pressure was 220/100 mmHg.

Is this patient on an optimal drug treatment? How long should his beta-blocker and angiotensin-converting enzyme inhibitor be continued?

Introduction

This chapter will discuss the important role of beta-blockers, ivabradine, angiotensin-converting enzyme inhibitors (ACEi), angiotensin-receptor blockers (ARBs), and calcium antagonists for either the primary or secondary prevention of cardiovascular disease (CVD). Also the concept of the polypill will be explained as well as our current knowledge on its efficacy, side effects, and cost-effectiveness. Drugs used to prevent thrombosis or for the management of risk factors such as dyslipidaemias, elevated blood pressure, or type 2 diabetes are discussed in Cardioprotective drugs Chapters 17, 15, 14, and 16, respectively. Vitamins, omega-3 fatty acids or other ‘nutriceuticals’ are dealt with in Cardioprotective drugs Chapter 11.

Beta-blockers

Mechanisms and cardiovascular effects

Beta-adrenergic antagonists, or beta-blockers, bind selectively to beta-adrenoreceptors, resulting in competitive and reversible antagonism of the effect of beta-adrenergic stimuli on various organs. Their prevention of the cardiotoxic effects of catecholamines plays a central role in the treatment of different CVDs [1]. Their anti-ischaemic actions are a result of a decrease in myocardial oxygen demand due to the reduction in heart rate, cardiac contractility, and systolic pressure. They may also increase myocardial perfusion by prolongation of diastole caused by the reduction in heart rate. Their antihypertensive action is a result of inhibition of the release of renin and production of angiotensin II, blockade of pre-synaptic alpha-adrenoreceptors that increase the release of norepinephrine from sympathetic nerve terminals, and decrease of central vasomotor activity and peripheral vasodilator activity mediated via alpha-1 adrenoreceptor blockade (e.g. with carvedilol and labetalol). Many additional myocardial effects have been described, such as improvement of myocardial energetics by inhibition of catecholamine-induced release of free fatty acids from adipose tissue, reduction of myocardial oxidative stress, inhibition of cardiac apoptosis, and substantial improvement of cardiac remodelling. Beta-blockers also have anti-arrhythmic effects as a result of their reduction of heart rate, decrease of spontaneous firing of ectopic pacemakers, slowing of conduction, and increase of the refractory period of the atrioventricular (AV) node [2].

Beta-blockers can be classified into non-selective agents (combined beta-1 and beta-2 blockers), cardioselective beta-1 antagonists, and beta-blockers with vasodilatory properties through direct [possibly nitric oxide (NO)-mediated] vasodilation and added alpha-1 adrenergic blockade. Some beta-blockers, such as pindolol and acebutolol, show a weak agonist response (intrinsic sympathicomimetic activity) and can stimulate and block the beta-adrenoreceptor. However, they are used less frequently today. All beta-blockers have anti-arrhythmic properties by their class II activity. Sotalol is an unique long-acting non-selective beta-blocker with added class III anti-arrhythmic activity that is specifically used for the treatment of arrhythmias. Types and typical dosages of the most frequently used beta-blockers for patients with coronary artery disease and heart failure are summarized in Cardioprotective drugs Table 19.1 [1,2].

Table 19.1 Types and typical dosages of the most frequently used beta-blockers

ISA

Lipid solubility

Peripheral vasodilation

Average daily oral dose

Non-selective antagonists:

Pindolol

+ +

+

0

10–40 mg twice a day

Propranolol

0

+ + +

0

40–160 mg twice a day

Sotalol*

0

0

0

80–160 mg twice a day

Timolol

0

+

0

5–40 mg twice a day

Selective beta-1 antagonists:

Atenolol

0

0

0

25–100 mg once a day

Bisoprolol

0

+

0

2.5–10 mg once a day

Celiprolol

+

+

+

200–600 mg once a day

Esmolol

0

0

0

IV only

Metoprolol-SR

0

+

0

50–200 mg once/twice a day

Nebivolol

0

+ + +

+

2.5–10 mg once a day

Alpha-1 and beta antagonists:

Carvedilol

0

+

+

3.125–50 mg twice a day

Labetalol

+

+++

+

200–800 mg twice a day

0, no effect; +, mild effect; ++, moderate effect; +++, strong effect.

ISA, intrinsic sympathicomimetic activity; IV, intravenous administration possible; SR, slow release.

*For ventricular arrhythmias and atrial fibrillation.

Source: data from Lopez-Sandon J, Swedberg K, McMurray J, Tamargo J, Maggioni A, Dargie H, Tendera M, Waagstein F, Kjekshus J, Lechat P, Torp-Pedersen C. Expert consensus document on β‎-adrenergic receptor blockers. The Task Force on Beta-Blockers of the European Society of Cardiology. Eur Heart J 2004; 25: 1341–1362 and Opie LH and Gersh BJ. Drugs for the heart, 7th Edition, 2009. Chapter 1, pages 1–37. Saunders, Elsevier Inc.

Indications

The indications for beta-blockers are summarized in Cardioprotective drugs Boxes 19.1 and 19.2. Beta-blockers are indicated for a wide range of patients with cardiac pathologies, including acute coronary syndrome (ACS), stable coronary artery disease (CAD), heart failure, and arrhythmias. Their place in the treatment of hypertension is discussed in Cardioprotective drugs Chapter 14.

Acute coronary syndrome

Several trials and meta-analyses have demonstrated that beta-blockers reduce mortality and reinfarction by 20–25% in those who have recovered from an infarction. The best studied beta-blockers for this indication are propranolol, metoprolol, carvedilol, and timolol, of which only carvedilol has been studied in the reperfusion era [2]. The European Society of Cardiology (ESC) ST-segment elevation myocardial infarction (STEMI) guidelines [3] state that beta-blockers should be used indefinitely in all patients who have recovered from a STEMI, especially in the presence of left ventricular (LV) dysfunction. Accordingly, the ESC non-STEMI guidelines [4] advocate the use of beta-blockers in all patients with reduced systolic function [left ventricular ejection fraction (LVEF) ≤ 40%] with or without symptoms of heart failure. They may be useful in other patients, but evidence for their long-term benefit is not established.

Stable coronary artery disease

Beta-blockade is a very effective symptomatic treatment, alone or combined with another drug, in the majority of patients with classic effort angina [2,5]. It has been extrapolated from the post-infarction trials that beta-blockers may also reduce major outcomes in patients with stable CAD. However, this has not been proven in a placebo-controlled trial.

An analysis of the ACTION trial showed no mortality benefit of beta-blocker treatment for patients with stable angina pectoris [6]. Data from the Reduction of Atherothrombosis for Continued Health (REACH) Registry showed that in the CAD-without-myocardial infarction (MI) group, rates of the primary end-point (composite of cardiovascular death, non-fatal MI, or non-fatal stroke) were not significantly different in patients with versus those without beta-blockers [12.9% versus 13.6%; hazard ratio (HR) 0.92, p = 0.31]. In fact, for the secondary end-point (primary outcome plus hospitalization for atherothrombotic events or a revascularization procedure), outcomes were actually worse among those who used beta-blockers compared with those who did not [30.6% versus 27,8%, odds ratio (OR) 1.14, p = 0.01] [7]. The latest American Heart Association (AHA)/American College of Cardiology Foundation (ACCF) secondary prevention guidelines also stress the fact that evidence supporting the use of beta-blockers is greatest among patients with recent MI (<3 years) and/or left ventricular systolic dysfunction (LVEF ≤ 40%). For patients without these class I indications, beta-blocker therapy is considered optional (class IIa or IIb) [8]. In this era of modern medical and reperfusion therapy there is clearly a need for randomized trials to actually define which patients with stable CAD are best suited to beta-blocker therapy and to identify the optimal duration of treatment.

Larger studies (including APSIS and TIBET) comparing beta-blockers with calcium antagonists for stable angina have shown that treatment with a calcium antagonist such as verapamil SR or nifedipine SR resulted in similar cardiovascular event rates compared with treatment with metoprolol CR or atenolol [5,9,10].

Finally, only one randomized controlled trial has examined the use of beta-blockers in a general post-coronary artery bypass graft (CABG) population; it found no differences in cardiovascular outcomes at 2-year follow-up [11]. Therefore, in the absence of a history of MI or heart failure, there is little evidence to suggest that beta-blockers should be used routinely after CABG [12].

Heart failure

Several randomized trials with bisoprolol [13], carvedilol [14], and metoprolol CR/XL [15] in patients with mild to severely symptomatic heart failure and reduced ejection fraction have shown that treatment with beta-blockers reduces mortality (relative risk (RR) reduction ∼ 34% in each trial) and heart failure hospitalizations (RR reduction 28–36%) within about a year of starting treatment. These findings are supported by the SENIORS study in which elderly patients with heart failure (≥70 years, 36% with a LVEF > 35%) were randomized to nebivolol versus placebo [16]. This trial showed a reduction in the RR of 14% in the primary composite end-point of death or cardiovascular hospitalization, but did not reduce mortality. However, bucindolol, a beta-blocker with partial agonist properties, did not show a significant reduction in mortality and short-acting metoprolol tartrate (different from the long-acting succinate formulation used in the MERIT-HF trial) was inferior to carvedilol for increasing survival [17]. The 2012 ESC guidelines for heart failure [18] recommend a beta-blocker in addition to an ACEi (or ARB if ACEi is not tolerated) for all patients with a LVEF ≤ 40% to reduce the risk of heart failure hospitalization and of premature death. They should usually be initiated in stable patients starting with a low dose and up-titrated over several weeks.

No treatment has yet been shown to significantly reduce morbidity and mortality in patients with heart failure and preserved ejection fraction (diastolic heart failure). In these patients beta-blockers may be used to control the ventricular rate of atrial fibrillation or improve myocardial ischaemia.

Arrhythmia

Beta-blockers can be used to slow the heart rate in different arrhythmias including sinus tachycardia, supraventricular tachycardias, and atrial flutter or atrial fibrillation [1,19] Beta-blockers are also effective in the control of ventricular arrhythmias related to sympathetic activation, ACS, and heart failure, including the prevention of sudden cardiac death [1,3,4,18].

Other indications

Beta-blockers can have a place in the treatment of other clinical entities such as aortic dissection, hypertrophic cardiomyopathy, and vasovagal syncope [1]. In the setting of non-cardiac surgery they are recommended in patients scheduled for high-risk surgery (such as vascular surgery) and in some patients scheduled for intermediate-risk surgery. In these patients, treatment should be initiated optimally between 30 days and at least 1 week before surgery, with a target heart rate of 60–70 beats/min and a systolic blood pressure > 100 mmHg [20].

Finally, for patients with only risk factors for CAD, data from the REACH Registry showed that the rates of the primary end-point (composite of cardiovascular death, non-fatal MI, or non-fatal stroke) were actually higher in patients taking beta-blockers with versus those without (14.2.% versus 12.1%; HR 1.18, p = 0.02) [7]. Therefore, beta-blockers cannot be routinely recommended for such patients.

Contraindications and side effects

Treatment with beta-blockers may result in adverse events, especially when they are used in large doses (Cardioprotective drugs see Boxes 19.1 and 19.2). The most important cardiovascular adverse effects are extreme bradycardia and AV block (especially in patients with impaired sinus node or AV node function) as well as hypotension with dizziness or fatigue. Cold extremities and Raynaud’s phenomenon may also occur, although this is less pronounced with cardioselective agents [1,2]. In patients with heart failure, continuation during an episode of heart failure exacerbation has been shown to be safe, although dose reduction may be necessary. Temporal discontinuation is advised in shocked or severely hypoperfused patients. Reinstitution of treatment should be attempted before discharge [18].

Increased insulin resistance and a higher incidence of new-onset diabetes were reported in early trials with beta-blockers, although newer agents such as bisoprolol and carvedilol have no negative effects on glucose metabolism [2]. In patients with insulin-dependent diabetes some warning symptoms of hypoglycaemia (tremor, tachycardia) may be masked by non-selective beta-blockers, and therefore cardioselective agents are preferred [1]. Importantly, ESC guidelines recommend treatment with beta-blockers for all diabetic patients with ACS, post-MI, and heart failure [21].

Beta-blockers can lead to a life-threatening increase in airway resistance, and are therefore contraindicated in patients with asthma. However, chronic obstructive pulmonary disease (COPD) in which airway obstruction is irreversible is not a contraindication. There is evidence from randomized controlled trials that beta-blockers reduce mortality by 15–43% in patients with coexistent COPD and CAD [22,23]. In these patients beta-1-selective beta-blockers should be started at a low dose and up-titrated slowly. As asthma and COPD may coexist, lung function should be monitored. Mild deterioration in pulmonary function and symptoms should not lead to prompt discontinuation, but if symptoms worsen a reduction of the dosage or withdrawal may be necessary [24].

Central effects of beta-blockers include fatigue, headache, sleep disturbances, vivid dreams, and depression. Beta-blockers may also cause or aggravate impotence and loss of libido. However, some studies suggest that erectile dysfunction is no more common with beta-blockers than with other drugs prescribed for heart failure or hypertension and that the anxiety of knowing that beta-blockers may cause erectile dysfunction may be enough to produce this supposed side effect [24].

Ivabradine

Mechanisms and cardiovascular effects

Ivabradine is a specific heart-rate-lowering agent which acts on the sinoatrial node cells by selectively and specifically inhibiting the pacemaker If current in a dose-dependent manner. As a result, it reduces heart rate while preserving the force of contraction, cardiac conduction, and blood pressure [25]. Heart rate reduction with ivabradine reduces angina symptoms and improves exercise tolerance [26], and these effects were at least comparable (and even better for exercise tolerance) to treatment with atenolol [27]. The ASSOCIATE trial showed that these beneficial effects persisted on top of atenolol (50 mg) [28].

The prognostic value of ivabradine in patients with CAD was evaluated in the BEAUTIFUL study, a randomized, double-blind, parallel-group trial carried out in 10 917 patients with documented stable CAD, LVEF < 40% and a resting heart rate ≥ 60 beats/min. Patients were randomized to either ivabradine or matching placebo on top of optimal preventive therapy and were followed up for 19 months. There was no measurable effect of treatment on the primary end-point in the overall population, but in patients with elevated heart rate (≥70 beats/min) ivabradine reduced the risk of fatal and non-fatal MI by 36% (p = 0.001) and coronary revascularization by 30% (p = 0.016) [29]. A post hoc subgroup analysis in 1507 patients in the BEAUTIFUL study with limiting angina at baseline confirmed a 24% reduction of the primary end-point in patients randomized to ivabradine [30]. The on-going SIGNIFY trial is testing the hypothesis that ivabradine improves the prognosis of patients with CAD and normal LV function with a heart rate ≥ 70 beats/min [31].

The SHIFT trial evaluated the prognostic value of ivabradine in patients with systolic heart failure. In this randomized, double-blind, placebo-controlled, parallel-group trial, 6558 patients with symptomatic heart failure, LVEF ≤ 35%, sinus rhythm with a heart rate ≥ 70 beats/min, and a stable background treatment including a beta-blocker if tolerated were randomized between ivabradine and placebo. After a median follow-up of 23 months, there was an 18% (p < 0.0001) reduction in the primary end-point (composite of cardiovascular death or hospital admission for worsening heart failure) in the ivabradine group. The effects were mainly driven by hospital admissions for worsening heart failure and deaths due to heart failure [32].

Indications

Based on the studies mentioned in ‘Mechanisms and cardiovascular effects’, the European Medicines Agency (EMA) stated in 2012 that ivabradine is indicated for symptomatic treatment of chronic stable angina pectoris in CAD patients with normal sinus rhythm, in patients unable to tolerate or with a contraindication to the use of beta-blockers, and in combination with beta-blockers in patients who are inadequately controlled with an optimal dose of beta-blockers and whose heart rate is > 60 beats/min.

The 2012 ESC guidelines for chronic heart failure [18] state that ivabradine should be considered to reduce the risk of heart failure hospitalization in patients in sinus rhythm with a LVEF ≤ 35%, a heart rate remaining at 70 or more beats/min, and persisting symptoms (NYHA class II–IV) despite optimal medical treatment including beta-blockers (class IIa, level of evidence B). In patients who are unable to tolerate a beta-blocker, it may be considered to reduce the risk of heart failure hospitalization in patients in sinus rhythm, with a LVEF ≤ 35% and a heart rate remaining at 70 beats/min or more (class IIb, level of evidence C).

Contraindications and side effects

The most common side effects with ivabradine are visual side effects or ‘phosphenes’ (a temporary brightness in the field of vision). Ivabradine must not be used in patients who have a resting heart rate below 60 beats/min, very low blood pressure, various types of heart disorder (including cardiogenic shock, rhythm disorders, heart attack, acute heart failure, and unstable angina), or severe liver problems.

Renin–angiotensin–aldosterone receptor blockers (ACEi, ARBs, renin blockers, and aldosterone antagonists)

Mechanisms and cardiovascular effects

There are four classes of RAAS receptor blockers: ACEi, ARBs, aldosterone antagonists (AAs), and direct renin inhibitors (DRi) [33,34] (see Cardioprotective drugs Table 19.2).

Table 19.2 RAAS blockers

Class

Drug

Usual daily dose

Heart failure

Hypertension

ACEi

Captopril

6.25–50 mg, t.i.d.

12.5–50 mg, t.i.d.

Zofenopril

7.5–30 mg, b.i.d.

30 mg, b.i.d. or 60 mg, o.d.

Benazepril

10–40 mg, o.d. or b.i.d.

Enalapril

2.5–20 mg, b.i.d.

2.5–20 mg, b.i.d.

Lisinopril

2.5–40 mg, b.i.d.

2.5–40 mg, b.i.d.

Perindopril

2–16 mg, o.d.

4–16 mg, o.d.

Quinapril

5–20 mg, b.i.d.

10–40 mg, o.d.

Ramipril

1.25–10 mg, o.d.

2.5–20 mg, o.d.

Fosinopril

10–40 mg, o.d.

10–80 mg, o.d.

ARB

Candesartan

4–32 mg, o.d.

8–32 mg, o.d.

Eprosartan

400–800 mg, o.d.

Irbesartan

150–300 mg, o.d.

Losartan

25–100 mg, o.d.

Olmesartan

20–40 mg, o.d.

Telmisartan

20–80 mg, o.d.

DRi

Aliskiren

150–300 mg, o.d.

AA

Spironolactone

12.5–50 mg, o.d.

25–50 mg, o.d. or b.i.d.

Eplerenone

25–50 mg, o.d.

50–100 mg, o.d.; 50 mg, b.i.d.

RAAS, renin–angiotensin–aldosterone system; ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker; AA, aldosterone antagonist; DRi, direct renin inhibitors; t.i.d., three times a day; b.i.d., twice a day; o.d., once a day.

ACEi, the most used and studied type of RAAS blocker, have a class I indication in the ESC guidelines in hypertension [35], diabetes mellitus [21], heart failure [36], secondary prevention for stable CAD [37], in the acute phase and post-STEMI or Non-STEMI [3,4], and after myocardial revascularization [38].

ARBs have similar properties to ACEi, but with a better tolerability profile. Since they are more expensive and appeared later, they are usually considered as an alternative for patients intolerant to ACEi due to non-productive cough or any other reason. They share most of the indications and contraindications for ACEi.

DRi (e.g. aliskiren) have a clinical indication in hypertension. Aliskiren has not been studied in heart failure, secondary prevention after myocardial infarction, stroke, or stable angina.

AAs (e.g. spironolactone and eplerenone) have a good evidence of benefits in heart failure (NYHA class II to IV) and in acute MI with LVEF <40%.

ACEi, ARBs, and DRi act by blockade of the RAAS, with beneficial effects through the cardiovascular risk continuum, either in the presence of only cardiovascular risk factors (hypertension, hypercholesterolaemia, diabetes, and chronic kidney disease) or in the context of clinical entities such as stable CAD, acute MI (STEMI or Non-STEMI), stroke, and heart failure, and after myocardial revascularization,. Recently, LCZ, the association of valsartan and sacubitril (a neprilysin inhibitor) demonstrated to be superior to enalapril in reducing the risks of death and of hospitalization for heart failure, as has now a class IB in heart failure (39).

The end result of the activation of the RAAS is the production of angiotensin II at the renal level, which in the short term results in vasoconstriction, retention of sodium and water, and increased arterial pressure and myocardial contractility with the aim of preserving blood pressure. Vascular smooth muscle and cardiac hypertrophy and fibrosis are deleterious effects related with RAAS system activation.

Renin production, the first step in this chain of reactions, occurs at the level of the juxtaglomerular apparatus when its perfusion decreases. Renin catalyses the conversion of angiotensinogen to angiotensin I, which is hydrolysed by angiotensin-converting enzyme (ACE) into angiotensin II. At the end of the process angiotensin II will act at the suprarenal cortex releasing aldosterone, which is a potent vasoconstrictor and will increase the circulating volume by retention of salt and water. Should an increase in perfusion occur at the juxtaglomerular apparatus, the release of renin will be inhibited by a negative feedback mechanism.

ACEi act by inhibiting the transformation of angiotensin I into angiotensin II, ARBs by blocking the angiotensin II receptor subtype 1, and AAs antagonize the effects of aldosterone.

There are also alternative pathways, the so-called non-ACE pathways, to convert angiotensinogen into angiotensin II, through tissue plasminogen activator, cathepsin, and tonin, and angiotensin I to angiotensin II by chymase and cathepsin, explaining the so-called ‘angiotensin II escape’ to ACEi.

As well as the already described classical RAAS pathway in the circulation it also exists at the tissue level and works in a complementary manner to the former by paracrine or autocrine activity.

Indications

Cardioprotective drugs Table 19.3 shows the recommendations for RAAS blockers in the ESC guidelines.

Table 19.3 Class of recommendation for RAAS blockers in the ESC guidelines

Class

ESC guideline

Acute MI with ST-elevation, 2012 [3]

ACS without ST-elevation, 2015 [4]

Stable CAD, 2013 [37]

Myocardial Revascularization, 2014 [38]

Acute and chronic HF, 2016 [36]

ACEi

  • IA: within 24 hours of STEMI in pts with evidence of heart failure or LV systolic dysfunction, diabetes or anterior infarct

  • IIaA: In all patients without contraindication

IA: in pts with LVEF ≤ 40% after stabilization, to reduce the risk of death, recurrent MI and hospitalization for heart failure

  • IA: if presence of other conditions (e.g, heart failure, hypertension or diabetes)

  • IIbB: may be considered for the treatment of microvascular angina in pts with refractory symptoms

  • IA: if presence of other conditions (e.g, heart failure, hypertension or diabetes)

  • IA: in all patients with heart failure or myocardial infarction with LVEF ≤ 40% unless contraindicated

  • IA: in pts with LV dysfunction and with or without a history of MI in order to prevent or delay the onset of heart failure.

  • IA: in addition to a beta-blocker, for symptomatic pts with HFrEF ro reduce the risk of HF, hospitalizations and death

ARB

IB: preferably valsartan, in in pts with evidence of heart failure or LV systolic dysfunction particularly in those intolerant to ACEi

IA: in pts intolerant to ACEi with LVEF ≤ 40% after stabilization, to reduce the risk of death, recurrent MI and hospitalization for heart failure

IA: if presence of other conditions (eg, heart failure, hypertension or diabetes) in alternative to ACEi

  • IA: as an alternative to ACEi if other conditions present (eg, heart failure, hypertension or diabetes)

  • IA: in all patients with heart failure or myocardial infarction with LVEF ≤ 40%, intolerant to ACEi

  • IB: To reduce hospitalizations and cardiovascular death in addition to a beta-blocker, in patients intolerant to an ACEi or AA

  • IIb: To reduce the risk of HF hospitalizations and death in addition to a beta-blocker, in symptomatic despite treatment with a beta-blocker who are unable to tolerate an AA

  • IB: Sacubirtil/valsartan as a replacement for an ACEi to further reduce the risk of HF and death in ambulatory pts with HFrEF who remain symptomatic despite optimal treatment with an ACEi, a beta-blockerand a AA

DRi

No indication

No indication

No indication

No indication

No indication

AA

IB: in pts with an LVEF ≤ 40% and heart failure or diabetes provided no renal failure or hyperkalaemia

  • IA: to reduce the risk of HF hospitalization and death in all pts with persistent symptoms (NYHA II-IV) and LVEF<35% despite treatment with an ACEi (or ARB) and a beta-blocker

  • IB: an AA, preferably eplerenone, is recommended to reduce the risk of cardiovascular hospitalization and death in pts with LVEF ≤ 40%

No indication

IA: in pts with persisting symptoms (NYHA class II-IV) and an LVEF<35% despite treatment with an ACEi (or ARB)

IA: In pts with HFrEF, who remains symptomatic despite treatment with an ACEi and a beta-blocker, to reduce the risk of hospitalizations and death

ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker; AA, aldosterone antagonist; DRi, direct renin inhibitors; LVEF, left ventricular ejection fraction; HF, heart failure; CKD, chronic kidney disease; IA, general agreement that the treatment is beneficial/useful/effective, based on data derived from multiple randomized clinical trials or meta-analysis; IB, general agreement that the treatment is beneficial/useful/effective, based on data derived from a single randomized clinical trial or large non-randomized studies.

High-risk individuals and patients with diabetes

The HOPE trial [40] (ramipril versus placebo) studied 9297 high-risk patients (with vascular disease or diabetes plus at least one more risk factor) and demonstrated reductions of 26% for cardiovascular death, 20% for MI, 32% for stroke, and 33% for heart failure with even better results in the diabetes cohort [41].

ACEi also proved to be beneficial in hypertension, reducing mortality (HYVET [42]) and/or cardiovascular events (HYVET-Pilot [43], HYVET [42]), although some trials like CAPP [44] (captopril versus diuretics or beta-blockers) and STOP 2 [45] [diuretic or beta-blockers versus ACEi or calcium channel blockers (CCBs)] did not show any benefit regarding the comparator regime. ACEi are also recognized as one of the best pharmacological groups for diminishing LV hypertrophy [46], a parameter implicated in cardiovascular risk.

Regarding ARBs, losartan showed superiority versus atenolol in the LIFE study [47], by reducing the risk of cardiovascular death, stroke, or acute MI, while decreasing blood pressure and LV hypertrophy. In the VALUE trial [48], valsartan was compared with amlodipine in hypertensive or high-risk patients and demonstrated to be equivalent in lowering cardiac mortality and morbidity. In both the LIFE and VALUE studies, ARBs showed a lower incidence of new cases of diabetes.

In the ONTARGET study [49], which enrolled high-risk cardiovascular patients, telmisartan showed similar cardioprotection when compared with ramipril with the advantage of being better tolerated. In a meta-analysis published in 2012 by McAlister et al. [50] it was shown that ACEi or ARBs are beneficial in patients with, or at an increased risk for, atherosclerotic disease even if their systolic pressure is <130 mmHg before treatment.

The cardiovascular benefits of ACEi and ARBs seem to be related to their ability to reduce blood pressure and insulin resistance and to provide renal protection. Insulin resistance was decreased in HOPE [40] and CHARM [51], respectively, by ramipril and candesartan.

In summary, ACEi or ARBs are widely used in the presence of hypertension, diabetes, or chronic kidney disease to prevent cardiovascular events and progression of nephropathy.

Aliskiren, a DRi, was tested in several hypertension trials alone or in association with an ACEi or an ARB and showed clinical efficacy by itself, which increased when in combination with ramipril or valsartan. Aliskiren was also used in the AVOID study [52] in combination with losartan in patients with diabetes, hypertension, and proteinuria and reduced the albumin/creatinine ratio by 20% compared with losartan alone.

In resistant hypertension, spironolactone, as part of a combination therapy, may provide further reductions in blood pressure as shown in the ASCOT study [53].

Coronary artery disease

The EUROPA study [54] randomized stable CAD patients for perindopril versus placebo. The composite end-point of non-fatal acute MI, cardiovascular death, and resuscitated cardiac arrest was modestly lower. PEACE [55] and ACCOMPLISH [56] both demonstrated similar results.

The mid 1990s saw the first generation of trials in acute MI using an ACEi in unselected patients, for example ISIS-4 [57], (captopril versus placebo) and GISSI-3 [58] (lisinopril versus open control), where unequivocal but mild mortality benefits were obtained. In a second generation of trials on LV dysfunction or overt congestive heart failure, like SAVE [59] (captopril versus placebo), AIRE [60] (ramipril versus placebo), and TRACE [61] (trandolapril versus placebo), larger benefits were detected on mortality, hospitalization, and CHF progression.

In summary, interesting reductions in mortality and cardiovascular events were demonstrated with the use of ACEi in post-acute MI patients, with or without LV dysfunction, with or without overt congestive heart failure, probably due to their anti-LV remodelling and anti-atherosclerotic effects.

ARBs are less studied in the post-acute MI setting. In the OPTIMAAL trial [62], which enrolled patients with congestive heart failure, losartan demonstrated similar outcomes to captopril, although it was slightly better tolerated. In the VALIANT trial [63], valsartan was compared with captopril and showed similar mortality.

Heart failure

The benefits of ACEi in heart failure were demonstrated in several randomized controlled trials using enalapril (CONSENSUS [64], V-HeFT II [65], and SOLVD prevention [66] and treatment [67]), which showed improvement in clinical symptoms and reductions in mortality and hospitalizations.

ARBs were compared with ACEi in patients with heart failure, alone or in combination. In ELITE I [68] losartan was similar to captopril in terms of mortality and renal dysfunction, and in HEAAL [69] it was shown that a higher dose of 150 mg provided larger reductions in mortality and readmissions compared with a lower dose (50 mg). In CHARM, candesartan was studied alone [51] and as an alternative [70] to ACEi: a 30% reduction in cardiovascular death or heart failure hospitalizations was demonstrated. Lee et al. [71] found in a meta-analysis that ARBs reduce mortality and heart failure hospitalizations in patients with congestive heart failure by a similar magnitude to ACEi. More recently in Paradigm HF [6], LCZ696 a the first drug of a new class, which is the association of sacubitril (a neprilysin inhibitor) and valsartan (a ARB), shown to be superior to enalapril in reducing the risks of death and of hospitalization for heart failure in HFrEF patients. The 2016 ESC guidelines on HF recommend Sacubitril/valsartan to replace ACEIs in ambulatory HFrEF patients who remain symptomatic despite optimal therapy and who fit within the trial strict inclusion/exclusion criteria.

Aliskiren, a DRi, was tested versus placebo in the ALOFT trial [72], a surrogate end-points study, and showed to lower N-terminal pro-brain natriuretic peptide, brain natriuretic peptide, and urinary aldosterone more than placebo.

The AAs spirolactone and eplerenone are useful complements in patients with heart failure to the RAAS blockade provided by ACEi or ARBs. They provide additional protection because they counteract the so-called ‘angiotensin II escape’ and block the direct effect of aldosterone, which has additional deleterious effects to angiotensin II on the heart. Spironolactone was used in RALES [73], a trial in patients having NYHA class III and IV heart failure, and produced a 30% reduction in RR of death over 2 years, with a decreased number of readmissions and improvement in NYHA class. Eplerenone, a drug similar to spironolactone, was tested in EPHESUS [74] in patients with acute MI and also reduced mortality at 1 year. They are now recommended for HFrEF, patients who remain symptomatic despite treatment with an ACE-I and a beta-blocker, to reduce the risk of HF hospitalization and death.

Other indications

ACEi and ARBs were evaluated in some small trials for other indications like prevention of new onset and recurrence of atrial fibrillation, in association with amiodarone for maintenance of sinus rhythm after electrical cardioversion, with the rationale that they could counteract atrial remodelling, but the scientific evidence at present is not fully conclusive.

With regard to stroke prevention, there is much evidence in favour of ACEi used alone or in combination with a diuretic or a CCB, after trials like HOPE [40] where ramipril reduced the RR (32% for any stroke and 61% for fatal stroke) and PROGRESS [75] (perindopril ± indapamide versus placebo), in patients with a previous stroke or transient ischaemic attack, which showed a 28% (for perindopril alone) and 43% (perindopril ± indapamide) reduction of recurrent stroke.

ARBs have also been studied in primary and secondary prevention trials like LIFE [47] (losartan), SCOPE [76] (candesartan), MOSES [77] (eprosartan), TRANSCEND [78], and ONTARGET [79] (telmisartan) for stroke prevention and demonstrated important reductions in RR for stroke and acute MI. Besides these unquestionable benefits, there is some evidence after the PRoFESS [49] trial that ARBs should be considered as an alternative in ACEi-intolerant patients for stroke prevention, but not as first choice medication.

Contraindications and side effects

Box 19.3 lists practical tips and tricks for RAAS blockers in daily practice.

Contraindications

ACEi and ARBs are formally contraindicated in previous severe aortic stenosis, angio-oedema, or bilateral renal artery stenosis. ACEi can also produce teratogenic effects, which implicates their interruption in pregnancy.

Moderate renal insufficiency (serum creatinine < 3 mg/dl), mild hyperkalaemia (K+ < 6.0 mEq/L), and asymptomatic low blood pressure are not formal contraindications to ACEi or ARBs, but in these cases they must be started at low doses, small dosage increases must be performed, and renal function closely monitored. If potassium rises to over 6.0 mEq/L or creatinine increases by more the 50% over the baseline value or exceeds 3 mg/dl the drugs must be stopped.

Side effects

Non-productive cough is the most frequent side effect related to ACEi, being present in 5–10% of patients, starting a week to several months after drug initiation. It is frequently unnoticed by patients. It may be related to increased levels of bradykinin and/or substance P in the lungs due to ACE inhibition. This side effect is not dose dependent and disappears in 1 or 2 weeks after drug interruption. The alternative use of ARBs to an ACEi is mainly justified by their lower incidence of this side effect.

Angio-oedema is a rare but potentially life-threatening side effect of ACEi. It is easy to recognize in the presence of severe dyspnoea due to oedema of the larynx, but it can be more difficult to recognize if it becomes overt by mild gastrointestinal symptoms, like nausea, vomiting, diarrhoea, and colic.

ACEi and ARBs may have other important side effects like hypotension, deterioration of renal function, and hyperkalaemia. Hypotension and acute impairment of renal function occur more frequently after the first dose, due to angiotensin II withdrawal in salt- and volume-depleted patients (e.g. patients under high doses of diuretics) or patients with congestive heart failure who have high plasma renin activity. Deterioration of renal function occurs in the same type of patients (hyponatraemic or elderly). Usually, if significant renal dysfunction is found upon starting an ACEi or an ARB the presence of bilateral renal artery stenosis or single kidney artery stenosis must be ruled out. Renal dysfunction normalizes a few days after drug interruption in almost all patients.

Hyperkalaemia, due to a decrease in aldosterone secretion secondary to an ACEi, an ARB, or an AA, typically occurs in patients with some degree of renal or hepatic dysfunction and can be relatively common in patients with congestive heart failure, the elderly, or diabetic patients, especially if they are under potassium supplements, any combination of AA/ACEi/ARB, or a non-steroidal anti-inflammatory drug (NSAID).

ACEi can produce some degree of proteinuria. The presence of proteinuria previously to starting an ACEi or an ARB is not a contraindication.

High doses of captopril have been related to cutaneous rash, neutropenia, taste abnormalities, and nephrotic syndrome. These manifestations were presumed to be due to the sulphydryl group of captopril and are much rarer with daily doses below 100–150 mg.

AAs can induce oligomenorrhoea in women and men can experience gynaecomastia, breast pain, or impotence (more common with spironolactone then with eplerenone). Special caution must be taken in the presence of increased levels of potassium (>5 mEq/L) or creatinine, namely in type 2 diabetic patients with hypertension and microalbuminuria, due to the risk of hyperkalaemia.

After ONTARGET [79] the double or triple drug combination regime of ACEi/ARBs/AAs showed to be contra-indicated due to the risk of severe hyperkalaemia and renal dysfunction.

Calcium antagonists

Mechanisms and cardiovascular effects

CCBs are a heterogeneous group of drugs that have in common the ability to produce vasodilatation in coronary and peripheral arteries, where they can markedly lower peripheral resistance. This property makes them very useful in hypertension and CAD, namely in stable angina pectoris and vasospasm angina [82,83].

CCBs can be divided in two main classes of drugs: dihydropyridines (DHPs) and non-dihydropyridines (non-DHPs), subdivided into benzothiazepines (e.g. diltiazem) and phenylethylamines (e.g. verapamil).

DHPs (e.g. nifedipine, amlodipine, felodipine, isradipine, lacidipine, lercanidipine, and nisoldipine) are almost pure vasodilators without any significant effect on LVEF or the heart conduction system. The last five have increased arteriolar selectivity compared with nifedipine and amlodipine.

The non-DHPs (diltiazem and verapamil), although not so potent as vasodilators, can slow heart rate and AV conduction and decrease myocardial contractility, similarly to beta-blockers to which they are an alternative in management of angina pectoris or supraventricular arrhythmias in case of contraindication such as asthma.

The main indication for CCBs is in the treatment of arterial hypertension, where they have been shown to decrease LV hypertrophy, stroke incidence, and progression of atherosclerosis and ameliorate endothelial dysfunction. CCBs are neutral regarding metabolic cardiovascular risk factors such as diabetes and hypercholesterolaemia.

In the context of stable CAD, CCBs can be used to control angina when the classical drug regime involving a beta-blocker and a long-acting nitrate fails. They are also specifically indicated in the presence of uncontrolled hypertension, intermittent claudication, or Raynaud’s phenomenon.

Indications

Cardioprotective drugs Tables 19.4 and 19.5 show the indications/magnitude of effect by pharmacological class and dosages, respectively, for CCBs.

Table 19.4 Calcium channel blockers: indications/magnitude of effect by pharmacological class

Indication

Class of calcium channel blocker

Phenylethylamines (verapamil)

Benzothiazepines (diltiazem)

Dihydropyridines (amlodipine)

Hypertension

+ +

+

+ + +

Angina (vasospasm or effort)

+ + +

+ + +

+ + +

Paroxysmal supraventricular tachycardia

+ + +

+ +

Atrial flutter and fibrillation

+ +

+ +

Hypertrophic cardiomyopathy

+ +

Raynaud’s syndrome

+ +

+ +

+ +

–, no effect/not indicated; +, mild effect/efficacy; + +, moderate effect/efficacy; + + +, intense effect/efficacy.

Table 19.5 Calcium channel blocker (CCB) drug dosing

CCB class

Drug

Form, dose, and frequency

Short acting

Long acting

Phenylethylamines

Verapamil

40–80 mg, t.i.d.

120–480 mg, o.d.

Benzothiazepines

Diltiazem

60–90 mg, t.i.d.

120–480 mg, o.d.

Dihydropyridines

Amlodipine

2.5–10 mg, o.d.

Felodipine

2.5–20 mg, o.d.

Isradipine

2.5–10 mg, b.i.d.

5–20 mg, o.d.

Lacidipine

2–4 mg, o.d.

Lercanidipine

10–20 mg, o.d.

Nicardipine

20–40 mg, t.i.d.

30–120 mg, o.d.

Nifedipine

5–10 mg, t.i.d.

30–120 mg, o.d.

Nisoldipine

10–40 mg, b.i.d.

o.d., once a day; b.i.d., twice a day; t.i.d., three times a day.

High-risk individuals and patients with diabetes

DHP-type CCBs are relatively well tolerated and can be combined with other antihypertensive drugs, they can be used in the presence of end-stage chronic kidney disease, and they do not have any serious side effects. Like other groups of antihypertensive drugs, they reduce LV hypertrophy, an important risk factor for cardiovascular events in the context of hypertension. Nifedipine reduced progression of asymptomatic atherosclerosis in the INTACT trial [84] and improved endothelial function in the ENCORE II study [85].

CCBs are especially indicated for the treatment of isolated systolic hypertension, hypertension in black people, and high blood pressure during pregnancy [86]. They do not have any limitation in chronic kidney disease, even in end-stage disease or in patients under haemodialysis.

Unlike diuretics and beta-blockers, CCBs are neutral in terms of cardiovascular metabolic risk factors, which make them very useful in the setting of diabetes, metabolic syndrome, hypercholesterolaemia, and gout [87].

CCBs act synergistically with the other drugs like ACEi or ARBs, or less frequently with diuretics and beta-blockers, in treatment of hypertension. Their efficacy is increased and the secondary effects reduced.

Several large randomized controlled trials like ALLHAT [88], ASCOT [89], ACCOMPLISH [90], and VALUE [91], showed consistent results to support amlodipine, the most used DHP in the field of hypertension, as a safe and efficacious drug alone or in combination with an ACEi (perindopril in ASCOT and benazepril in ACCOMPLISH) or an ARB (valsartan in VALUE). The amlodipine groups showed significantly reduced mortality and major cardiovascular events like stroke against the comparator groups.

CAFÉ [92], a sub-study of ASCOT, showed that the amlodipine + perindopril regimen lowered central aortic blood pressure to a greater extent than the atenolol/thiazide regimen (by 4 mmHg systolic). Central pressure was related to cardiovascular and renal outcomes, and in another sub-study it was shown that the combination of amlodipine + perindopril was associated with lower variability in blood pressure then the other regime [93,94]. Both mechanisms, lower central blood pressure and lower variability, may explain the better results of the amlodipine + perindopril combination.

The most recent European Society of Hypertension/ESC guidelines for the management of arterial hypertension recommend an association of two drugs as initiating therapy when blood pressure is beyond 20 mmHg of the systolic goal or 10 mmHg above diastolic target, or in milder degrees if multiple risk factors, subclinical organ damage, diabetes, renal disease, or CAD are present. Knowing that doubling the dose of a DHP CCB (amlodipine) is more efficacious than doubling the dose of an ACEi or ARB, it is recommended to increase the CCB first.

Non-DHPs are recommended in patients who are intolerant to beta-blockers and DHP and are an alternative to ACEi and ARBs in patients with severe renal failure or at risk of hyperkalaemia. It has been advocated to use a combination of CCBs, including a non-DHP (like verapamil or diltiazem) and a DHP (like amlodipine) to lower blood pressure, but no outcome data or long-term safety data are available. Unlike diuretics, ACEi, and ARBs, CCBs do not lose their effect by concomitant therapy with NSAIDs—frequently used by elderly hypertensive patients [95,96].

Coronary artery disease

The main indication for CCBs in patients with CAD is control of angina in stable or vasospasm angina when beta-blockers and nitrates fail [97,98]. Non-DHP proved to have a similar efficacy to beta-blockers to release symptoms in stable angina [99]. DHP and non-DHP drugs have similar efficacy in vasospasm angina [100,101].

Although CCBs have been shown to delay progression of atherosclerosis and improve endothelial function in small mechanistic studies, in the ACTION trial [102], a multicentre, randomized controlled trial with long-acting nifedipine (60 mg, once a day) compared with placebo in patients with CAD, no positive effects could be demonstrated for CCBs as secondary prevention drugs (unlike ACEi or ARBs).

The DAVIT-I and DAVIT-II studies taken together demonstrated that verapamil has positive effects in non-ST elevation ACS [103] in patients with preserved LV function, showing significant reductions in sudden death, reinfarction, and total mortality [38]. Moss et al. described similar results for diltiazem in the Multicenter Diltiazem Postinfarction Trial [104].

CCBs have not been shown to be useful in ST elevation ACS. On the contrary, in the HINT trial (nifedipine versus metoprolol) an excess rate of reinfarction was found in the nifedipine group, necessitating premature stoppage of the trial [105].

Heart failure

CCBs are not recommended in the ESC heart failure guidelines, probably as a consequence of the negative inotropism of non-DHPs and the lack of a specific indication for non-DHPs [18,106]. In the PRAISE [107] and V-HeFT III [108] trials, amlodipine and felodipine, respectively, were shown to cause no harm to patients with heart failure if there is still a requirement to treat hypertension or angina after the use of ACE/ARBs and diuretics for hypertension or a beta-blocker with a long-acting nitrate for angina pectoris.

Other indications

Nifedipine has proved to be useful in hypertension during pregnancy without causing teratogenic effects or complications of the peripartum [109]. Nifedipine and diltiazem have been shown to improve symptoms in pulmonary arterial hypertension in some cases when vasoreactivity is still present [110].

Due to their peripheral vasodilatation properties, CCBs can be used in intermittent claudication and Raynaud’s syndrome. They may be chosen as a first-line drug or as an alternative to beta-blockers, which frequently worsen the complaints.

Non-DHPs like verapamil and diltiazem have been shown to be an alternative to beta-blockers in the setting of hypertrophic cardiomyopathy [111,112]. They are also useful for controlling the ventricular rate in the setting of multifocal atrial tachycardia, atrial flutter, or fibrillation [113,114], alone or in combination with digoxin or a beta-blocker due to their property of slowing conduction and prolonging refractoriness in the AV node. In paroxysmal supraventricular tachycardia verapamil and diltiazem can be used intravenously to abort the tachycardia or orally to prevent the recurrence of arrhythmia. They should not be used in unstable patients with supraventricular tachycardia due to the risk of hypotension or in wide QRS complex tachycardia (which can have ventricular origin), and are contraindicated in tachycardia related to pre-excitation.

Contraindications and side effects

Cardioprotective drugs Box 19.4 lists practical tips and tricks for the use of CCBs in daily practice.

Contraindications

CCBs are contraindicated in the presence of heart failure and severe aortic stenosis. The non-DHP compounds are contraindicated in the presence of sick sinus disease and AV block grade II or III due to AV conduction increase, in the absence of a pacemaker. They should not be used added to beta-blockers, amiodarone, or digoxin, especially if there is any degree of AV block.

With the exception of nifedipine and verapamil, CCBs are contraindicated during pregnancy or breast feeding [109].

Side effects

The main side effects of DHPs are facial flush, headache, dizziness or light-headedness, tachycardia angina, and pedal oedema present in 10–20% of patients. These side effects are more frequent with immediate release formulations at high doses [115]. Pedal oedema is minimized by combining the CCB with an ACEi or an ARB. Verapamil is associated with constipation in 10–25% of patients.

Worsening or induction of AV block can be expected with non-DHP drugs. They should be used with great caution in the presence of grade I AV block and their use is not recommended in combination with other dromotropic negative drugs, like beta-blockers, amiodarone, or digoxin.

Polypills

The polypill concept

Changes in the twentieth century characterized by technological advances combined to increase food availability; this, together with subsequent deteriorations in levels of physical activity, has increased the prevalence of risk factors for CVD [116]. Consequently, in an increasing number of populations there is a high level of the risk factors for CVD, especially for many of those living in high-income countries [116]. Although effective therapy for treating CVD is available, due to high costs, low compliance, and poor identification of those at risk many individuals who could benefit from treatment remain untreated or inadequately treated. It seems evident that new and innovative strategies will be indispensable for controlling the global epidemic of heart disease. With this in mind, Wald and Law [116] proposed the concept of the polypill as a population CVD prevention strategy based on mass treatment. The concept proposes a radical approach based on the principle that high risk is common and a large preventive effect for CVD would require intervention in everyone at increased risk irrespective of their risk factor levels, modifying several risk factors together and reducing these risk factors by as much as possible. The authors wrote: ‘it is time to discard the view that risk factors need to be measured and treated individually if found to be abnormal’ [116]. A polypill is a theoretical combination of six pharmacological compounds that, together, could modify four different risk factors for CVD (cholesterol modification with statins, lowering of blood pressure with three different antihypertensives, antiplatelet aggregation with aspirin, and reduction of hyperhomocysteinaemia with folic acid) and theoretically reduce CVD by more than 80% [116].

The specific components of the originally proposed polypill included: one statin (e.g. atorvastatin 10 mg/day, or simvastatin or lovastatin 40 mg/day taken in the evening or 80 mg/day taken in the morning), three different classes of antihypertensives at half standard dose, folic acid (0.8 mg/day), and aspirin (75 mg/day) [116]. The concept also includes the strategy of giving this combination pill to everyone over 55 years of age and all those with existing CVD irrespective of age, hence stopping all efforts focused on the measurement of risk factors and screening for CVD. Since the introduction of the concept, much debate has been generated regarding the potential role of a polypill in CVD prevention and treatment, and multiple efforts have focused on developing and testing potential polypills.

Strengths, limitations, and efficacy

The proposed polypill could have multiple advantages [116,117]. Among these, one of the most relevant is facilitating the delivery of effective medications for the prevention and treatment of CVD. Having multiple medications combined in a single pill could dramatically improve adherence to medication and improved compliance could greatly contribute to a reduction in CVD events. Other strengths of the polypill include: facilitation of prescription and dose titration, reduction of costs by combining generic components, and provision of a platform for other widespread CVD prevention approaches (e.g. lifestyle advice) [117]. This is further supported given that such a combination pill appears to have high levels of tolerability, bioavailability, and no pharmacokinetic drug–drug interactions among the individual components [118]. Considering these combined strengths, a polypill could in theory provide great gains in terms of prevention of cardiovascular events, even among those free from CVD (see Cardioprotective drugs Fig. 19.1).


Fig. 19.1 Effects of 10 years of intervention with a polypill. Number of events prevented per 1000 people treated. Moderate risk refers to a 10–20% risk of coronary heart disease (CHD) in 10 years according to the Framingham risk score. High risk refers to a 10-year risk of CHD of ≥20%. YLS (Disc 4%), years of life saved discounted at 4%.

Fig. 19.1
Effects of 10 years of intervention with a polypill. Number of events prevented per 1000 people treated. Moderate risk refers to a 10–20% risk of coronary heart disease (CHD) in 10 years according to the Framingham risk score. High risk refers to a 10-year risk of CHD of ≥20%. YLS (Disc 4%), years of life saved discounted at 4%.

The polypill concept is still under evaluation and these potential advantages require further investigation. Besides the lack of evidence (given that this is still a concept in the process of development and testing), adverse effects and the costs of medicalizing large proportions of the population could limit the prospects of a future polypill era in CVD prevention. Also it is still unclear whether a polypill would be a safe alternative to individual drugs, and the optimal combination to be included in a polypill is still under debate [117]. Furthermore, after the key medications to be incorporated in a polypill have been identified its registration could also pose a challenge, particularly so for primary prevention as the efficacy of the combination still requires demonstration. Finally, a major concern remains regarding the effect of the availability of a polypill on the communication and implementation of healthy lifestyles (individuals might rely on a polypill to be effective and abandon healthy lifestyle habits).

Despite the uncertainties, the prospects are promising. A polypill could theoretically prevent over 80% of CVD and increase by more than 11 years the CVD-free life expectancy of people aged over 55 taking a polypill daily [116]. If a polypill was to be given to all US adults aged over 55 and those with a history of CVD it could contribute to the prevention of 4 million coronary heart disease events and more than 2 million stroke events over 10 years of treatment [119].

Since the original polypill publication, different combination pills have been developed [117]. A combination of amlodipine 2.5 mg, losartan 25 mg, hydrochlorothiazide 12.5 mg, and simvastatin 40 mg in a polypill was tested among individuals aged over 50 who were free from CVD and compared with placebo on a crossover trial [120]. This polypill effectively reduced systolic blood pressure by 17.9 mmHg (12% reduction), diastolic blood pressure by 9.8 mmHg (11% reduction), and low-density lipoprotein (LDL) cholesterol by 1.4 mmol/L (39% reduction), effects which were very similar to those originally predicted [116,120].

Another proposed polypill is the polycap, which was tested in the Indian Polycap Study (TIPS) [121]. TIPS was a phase II double-blind randomized trial conducted among 2053 individuals in India aged 45–80 years and without CVD, in which the efficacy of the polycap (a combination of thiazide 12.5 mg, atenolol 50 mg, ramipril 5 mg, simvastatin 20 mg, and aspirin 100 mg) was tested against its individual components and specific combinations of antihypertensives. The polycap had similar effects on risk factors and was tolerated in a similar way to the individual components, with a potential combined effect of a 62% reduction in coronary heart disease events and a 48% reduction in stroke events [126]. Although below the originally expected level of CVD reduction of 80%, the effects calculated are still substantial [1,6].

In TIPS-2 (the second Indian Polycap Study) 8 weeks’ treatment with a low-dose polycap (one capsule per day) versus full-dose polycap treatment (two capsules per day) with potassium supplementation was tested among 518 individuals at high risk of CVD [122]. The two formulations had similar tolerability while the full-dose polycap was more effective in reducing blood pressure and LDL cholesterol [122].

New evidence and new studies are required to confirm the efficacy and safety of the polypill in preventing hard events (MI and stroke) for both the primary and secondary prevention of CVD.

Side effects and cost-effectiveness

Although a polypill could be effective, medicalizing a large proportion of the population could have a great impact in terms of costs and side effects.

Despite the prevalence of participants in randomized trials reporting symptoms attributable to the polypill components being low (ranging from less than 0.1% for some antihypertensives to 3.9% for aspirin), it could be expected that up to 15% of those taking the polypill would experience an adverse effect, and these could be sufficient for permanent discontinuation in up to 2% [116]. Side effects of a polypill would depend on the individual components selected, among which aspirin could generate the most serious adverse effects including haemorrhagic stroke, extracranial haemorrhage, upper abdominal discomfort, and gastrointestinal bleeding. The specific probabilities of experiencing adverse effects while taking a polypill remain unknown, and studies with longer periods of polypill treatment will be necessary to obtain a better estimate. The levels of adverse effects would play a key role in the level of adherence to a polypill as well as in the cost-effectiveness of this treatment.

The potential costs of a polypill have been estimated to be rather low, given that the combination will include only generic components. The costs could range from $1 a day in developed countries to even less than 20 cents a day in developing countries [117]. However, since a polypill is not yet commercially available actual costs are still unknown and will depend on multiple factors, including levels of adverse effects, the cost of the ingredients to be included in the combination, costs of packaging and commercializing, and the costs of research, development, registration, marketing, and distribution, and profit margins for the manufacturers [117]. Given that the costs are unknown, the existing calculations on the cost-effectiveness of a polypill are only speculative; however, since all the individual components have proven to be cost-effective in multiple populations no major differences would be expected for a polypill. The first evaluation of the cost-effectiveness of a polypill calculated how much it should cost in order to be cost-effective for the primary prevention of CVD among men aged 50 years or above [123]. To be cost-effective in populations having levels of 10-year coronary heart disease risk over 20%, the annual cost of a polypill should not exceed €300, taking into account the costs of the medication and costs of care for prescription, evaluation, titration, and treatment of adverse effects [123]. For populations at lower levels of risk this cost should not be above €100 a year for a polypill to be considered cost-effective, at a threshold for cost-effectiveness of €20 000 per year of life saved (see Cardioprotective drugs Fig. 19.2). More recently, using the Dutch primary healthcare setting, different potential polypill combinations were tested and found to be cost-effective compared with usual care [124]. The levels of cost-effectiveness ranged between €7900 and €12 300 per quality-adjusted life year (QALY) [124]. The best levels of cost-effectiveness were found for polypill combinations without aspirin and with a double dose of statins [124].


Fig. 19.2 Maximum annual cost of a polypill for primary prevention of CVD at different levels of cost-effectiveness. Annual drug costs are presented in Euros (€). Moderate risk refers to a 10–20% risk of CHD in 10 years according to the Framingham risk score. High risk refers to a 10-year risk of CHD of ≥20%. YLS, years of life saved.

Fig. 19.2
Maximum annual cost of a polypill for primary prevention of CVD at different levels of cost-effectiveness. Annual drug costs are presented in Euros (€). Moderate risk refers to a 10–20% risk of CHD in 10 years according to the Framingham risk score. High risk refers to a 10-year risk of CHD of ≥20%. YLS, years of life saved.

Although these initial reports indicate that it is very probable that a polypill will be cost-effective for the secondary prevention of CVD, the actual costs of a polypill once it becomes available and its cost-effectiveness for the primary prevention of CVD need further evaluation.

Whether a polypill could be a safe and cost-effective alternative to current methods of preventing CVD remains unknown, and is one of the key challenges for its implementation for the prevention of CVD.

Future prospects

The polypill is a promising concept that has the potential to dramatically change and improve current strategies for preventing CVD. Questions remain regarding its long-term efficacy, safety, tolerability, and cost-effectiveness, especially for primary prevention of CVD. In addition, the impact that the availability of a ‘super-pill’ on people’s willingness to follow a healthy lifestyle and the consequences of medicalizing large proportions of the population remain under debate.

Multiple trials aiming to clarify the role that a polypill could have in the treatment and prevention of CVD are currently being conducted. One of these, TIPS-3, will evaluate a polycap preparation without aspirin versus placebo over 5 years in 5000 individuals free from CVD in China and India [117]. It might take some time before sufficient evidence is accumulated to permit the full incorporation of the polypill concept in clinical practice, but from initial reports the concept seems a promising and potentially effective and affordable solution to the current epidemic of CVD: ‘No other preventive method would have so great an impact on public health in the Western world’ [116].

Once a polypill becomes available, instead of replacing a healthy lifestyle it should be combined with adequate levels of physical activity, smoking cessation, and an optimal diet to further reduce the levels of CVD.

Solution for the clinical case

The problem of dyspnoea and wheezing of this patient does not seem to be related to heart failure/elevated filling pressures or ischaemia. It is probably caused by his COPD and current intake of a non-selective beta-blocker. His blood pressure is also still too high.

In this case the non-selective beta-blocker should be replaced by a selective beta-blocker (e.g. bisoprolol 5 mg/day up-titrated to 10 mg/day). If beta-blockers are not tolerated at all, ivabradine may be considered.

For his hypertension problem, the dose of the ACEi is still suboptimal and can be increased to 20 mg/day. If the blood pressure is still above 140/90 mmHg, amlodipine 5 mg/day could be added. The combination of an ACEi with an ARB is not recommended in this patient in addition to the treatment with aliskiren.

Both the treatment with the ACEi and the beta-blocker should be continued as the patient suffered from a significant MI with left ventricular dysfunction.

Further reading

Beta-blockers

Erdmann E. Safety and tolerability of beta-blockers: prejudices and reality. Eur Heart J 2009; 11 (Suppl. A): A21–A25. [An excellent and critical overview of the absolute and relative contra-indications for beta-blockers in daily practice. The subchapters on asthma/COPD and impotence are especially worth reading.]Find this resource:

Lopez-Sandon J, Swedberg K, McMurray J, et al. Expert consensus document on β‎-adrenergic receptor blockers. The Task Force on Beta-Blockers of the European Society of Cardiology. Eur Heart J 2004; 25: 1341–62. [This expert consensus document provides detailed information for the different indications for β‎-blocker treatment.]Find this resource:

McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Eur Heart J 2012; 33: 1787–847. [These latest ESC guidelines on heart failure describe the place and the practical use of beta-blockers for patients with heart failure.]Find this resource:

Opie LH, Gersh BJ. Drugs for the heart, 7th edn, 2009. Philadelphia, PA: Saunders Elsevier, pp. 1–37. [Excellent textbook on cardiovascular drugs. The chapter on beta-blockers provides a detailed description on the pharmacology, types of beta-blockers, indications, and contraindications.]Find this resource:

Ivabradine

Fox K, Ford I, Steg PG, et al. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet 2008; 372: 807–16. [Landmark study on the effect of ivabradine in patients with stable coronary artery disease and left-ventricular systolic dysfunction.]Find this resource:

McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Eur Heart J 2012; 33: 1787–847. [These latest ESC guidelines on heart failure describe the place and the practical use of ivabradine for patients with heart failure.]Find this resource:

Swedberg K, Komajda M, Böhm M, et al. SHIFT investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010; 376: 875–85. [Landmark study on the effect of ivabradine in patients with chronic systolic heart failure.]Find this resource:

RAAS blockers

Abdulla J, Barlera S, Latini R, et al. A systematic review: effect of angiotensin converting enzyme inhibition on left ventricular volumes and ejection fraction in patients with a myocardial infarction and in patients with left ventricular dysfunction. Eur J Heart Fail 2007; 9: 129–35.Find this resource:

Abdulla J, Pogue J, Abildstrøm SZ, et al. Effect of angiotensin-converting enzyme inhibition on functional class in patients with left ventricular systolic dysfunction—a meta-analysis. Eur J Heart Fail 2006; 8: 90–6.Find this resource:

Anand IS, Bishu K, Rector TS, et al. Proteinuria, chronic kidney disease, and the effect of an angiotensin receptor blocker in addition to an angiotensin-converting enzyme inhibitor in patients with moderate to severe heart failure. Circulation 2009; 120: 1577–84.Find this resource:

Brugts JJ, Ninomiya T, Boersma E, et al. The consistency of the treatment effect of an ACE-inhibitor based treatment regimen in patients with vascular disease or high risk of vascular disease: a combined analysis of individual data of ADVANCE, EUROPA, and PROGRESS trials. Eur Heart J 2009; 30: 1385–94.Find this resource:

Calhoun DA. Aldosterone and cardiovascular disease. Circulation 2006; 114: 2572–4.Find this resource:

Desai A. Hyperkalemia associated with inhibitors of the renin-angiotensin-aldosterone system. Circulation 2008; 118: 1609–11.Find this resource:

Leopold JA. Aldosterone, mineralocorticoid receptor activation, and cardiovascular remodeling. Circulation 2011; 124: e466–e468.Find this resource:

Maron BA, Leopold JA. Aldosterone receptor antagonists. Circulation 2010; 121: 934–9.Find this resource:

van Vark LC, Bertrand M, Akkerhuis KM, et al. Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158 998 patients. Eur Heart J 2012; 33: 2088–97.Find this resource:

Calcium antagonists

Collier DJ, Poulter NR, Dahlof B, et al. Impact of amlodipine-based therapy among older and younger patients in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA). J Hypertens 2011; 29: 583–91.Find this resource:

Epstein M. Calcium antagonists in clinical medicine, 2nd edn, 1998. Philadelphia, PA: Hanley & Helfus, pp. 1–26.Find this resource:

Jerums G, Allen TJ, Campbell DJ, et al. Long-term renoprotection by perindopril or nifedipine in non-hypertensive patients with Type 2 diabetes and microalbuminuria. Diabet Med 2004; 21: 1192–9.Find this resource:

The polypill

Indian Polycap Study (TIPS), Yusuf S, Pais P, Afzal R, et al. Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Lancet 2009; 373: 1341–51.Find this resource:

Lonn E, Bosch J, Teo KK, et al. The polypill in the prevention of cardiovascular diseases: key concepts, current status, challenges, and future directions. Circulation 2010; 122: 2078–88.Find this resource:

Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. Br Med J 2003; 326: 1419.Find this resource:

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