Angiotensin converting enzyme inhibitors and angiotensin receptor blockers

Learning objectives.

By reading this article you should be able to:

• •Describe evidence-based indications for angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) therapy in common clinical conditions.
• •Explain the basic pathways through which angiotensin II exerts its pathological effects.
• •Discuss how ACEI and ARB therapy confers therapeutic benefit.
• •Consider the current evidence for perioperative management of ACEIs and ARBs.

Key points.

• •Angiotensin II is pivotal in the pathogenesis of hypertension through multifactorial pathological effects.
• •Acute and chronic therapy with angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) improves clinical outcomes in cardiometabolic disease.
• •Combined treatment with angiotensin receptor neprilysin inhibitors (ARNIs) and ARBs will increasingly feature in the perioperative management of high-risk patients.
• •Perioperative ACEI and ARB therapy needs careful consideration and should be made on a case-by-case basis

Angiotensin II (Ang-II) plays a key pathological role in the development and maintenance of essential hypertension, but blocking this neuropeptide has more effects than simply lowering arterial BP. The development of drugs to inhibit Ang-II began in the 1970s, initially for the management of heart failure; in 1981, captopril was the first angiotensin converting enzyme inhibitor (ACEI) approved for clinical use.¹ Research into the physiological effects of ACEIs and angiotensin receptor blockers (ARBs) has shown a decrease in cardiac remodelling, fibrosis and inflammation, in addition to their antihypertensive effects. Evidence from large clinical trials has substantially expanded the clinical indications for these agents; ACEIs and ARBs are now first line therapy in the management of hypertension, chronic renal disease, stroke, diabetes mellitus and postmyocardial infarction. As such, many high-risk patients presenting for noncardiac surgery are taking ACEIs or ARBs.² The emergence of angiotensin receptor neprilysin inhibitors (ARNIs) for management of patients with chronic heart failure means that an understanding of the basic physiology and pharmacology of the renin-angiotensin system (RAS) will be required even more frequently in the perioperative setting.

The RAS

Circulating prorenin, initially considered to be an inactive precursor of renin, is present in high concentrations in the plasma. The discovery of the (pro)renin receptor, a receptor that binds both renin and prorenin and is distributed throughout many organs in the body, has led to a better understanding of the physiological importance of prorenin, but a full description is beyond the scope of this article.³ Prorenin undergoes proteolytic conversion to renin by removal of 43 amino acids in response to reduced renal blood flow (detected by stretch receptors in the juxtaglomerular apparatus), or decreased sodium concentration in the tubular fluid (sensed by the macula densa) (Fig. 1). Renin subsequently cleaves 10 amino acids from angiotensinogen to produce Ang-I. Angiotensin converting enzyme, which is found predominantly in the lungs, converts the majority of Ang-I to Ang-II. Angiotensin II principally acts on the Ang-II type 1 (AT₁) G protein-coupled receptor; activation of AT₁ produces the hypertensive effects, increased sympathetic outflow, increased aldosterone release, myocyte hypertrophy, myocardial remodelling, fibrosis and oxidative stress, which are associated with increased morbidity and mortality. Angiotensin converting enzyme also plays a role in the breakdown of bradykinin, a potent vasodilator and mild diuretic.

Fig 1.

The renin-angiotensin system. Red arrow and negative (−) symbol indicates inhibition. ANP, atrial natriuretic peptide; CNP, C-natriuretic peptide; Na⁺, sodium concentration.

Angiotensin II 2 (AT₂) receptors are found in very low concentrations throughout the body and are mostly of embryonic origin. Activation of AT₂ receptors decreases cell proliferation, fibrosis and myocardial remodelling, but because of their low distribution throughout the body, high concentrations of Ang-II predominantly affect the AT₁ receptor (Table 1).

Table 1.

Pathophysiological effects of angiotensin II and natriuretic peptides. SVR, systemic vascular resistance

Physiological effects of angiotensin II
	AT1 receptors	AT2 receptors
Cardiovascular	Vasoconstriction	Vasodilatation
	↑ Cardiac remodelling	↓ Cardiac remodelling
	Myocyte hypertrophy
Autonomic	↑ Fibrosis	↓ Fibrosis
	↑ Sympathetic outflow
Immune	↑ Inflammation	↓ Inflammation
	↑ Oxidative stress	↓ Oxidative stress
	↑ Cell proliferation	↓ Cell proliferation
Renal	↑ Aldosterone
	↑ Vasopressin

Physiological effects of natriuretic peptides
Cardiovascular	↓ SVR
	↓ Sympathetic outflow
	Vasodilatation
Renal	Diuresis
	Natriuresis
	Renin release inhibition
	↑ Glomerular filtration rate
	↓ Circulating angiotensin II
	↓ Circulating aldosterone

Natriuretic peptides

The heart plays an essential role in regulating endocrine control of cardiovascular homeostasis.⁴ An increased circulating volume (e.g. cardiac failure, fluid overload) increases both preload and afterload, activating myocardial stretch receptors. The increased stretch detected by the atria and ventricles causes release of atrial natriuretic peptide and brain natriuretic peptide (BNP), respectively. Confusingly, although BNP was originally discovered in the brain of pigs, the cardiac ventricles are the predominant source for release of BNP. Stretch receptors release C-natriuretic peptide in endothelial cells, and urodilatin in the kidney. Natriuretic peptides are upregulated to decrease intravascular circulating volume; the natriuretic peptides increase renal sodium excretion (natriuresis) causing an accompanying diuresis, decreased sympathetic outflow, decreased vasopressin release, vasodilation via the action of nitric oxide and inhibit the RAS (Table 2).⁵

Table 2.

Physiological effects of natriuretic peptides. SVR, systemic vascular resistance

Physiological effects of natriuretic peptides
Cardiovascular	↓ SVR
	↓ Sympathetic outflow
	Vasodilatation
Renal	Diuresis
	Natriuresis
	Inhibition of renin release
	↑Glomerular filtration rate
	↓ Circulating angiotensin II
	↓ Circulating aldosterone

The natriuretic peptides are secreted as prohormones; proBNP is cleaved to active BNP and the physiologically inactive N-terminal prohormone of brain natriuretic peptide (NT-proBNP); the concentrations of BNP, proBNP and NT-proBNP are used clinically in the diagnosis of heart failure. The membrane-bound endopeptidase neprilysin is responsible for the breakdown of the nature to peptides and bradykinin. Neprilysin converts a small proportion of Ang-I to the mediator Ang (1–7), which acts on AT₂ receptors. Activation of the AT₂ receptors conveys a cellular protective effect but neprilysin is also responsible for the breakdown of atrial natriuretic peptide, BNP and bradykinin. The net effect of neprilysin is to reduce the antihypertensive and protective properties of the natriuretic peptides.

Drugs affecting the RAS and neprilysin pathways

ACEIs

Most of the deleterious physiological effects of the RAS system are mediated by the action of Ang-II on AT₁ receptors (Fig. 2). Initial RAS therapies were primarily designed to counteract Ang-II production. Angiotensin converting enzyme inhibitors competitively inhibit the conversion of Ang-I to Ang-II, which decreases activation of the harmful AT₁ receptors and also the protective AT₂ receptors. Angiotensin converting enzyme inhibitors also decrease ACE-mediated bradykinin degradation; the resultant increased bradykinin concentration has an added antihypertensive effect but may be offset by a bradykinin-mediated refractory dry cough (experienced by up to 20% of patients taking an ACEI) and less commonly angioedema. A refractory cough is one of the main reasons for switching therapy from an ACEI to an ARB. Inactivation of the RAS reduces aldosterone release, and the resultant natriuresis causes potassium retention, increasing the risk of hyperkalaemia—a further adverse effect associated with both ACEIs and ARBs.

Fig 2.

Pathological mechanisms through which angiotensin II and neprilysin promote end-stage cardiovascular disease, either directly or through multiple morbidities (the presence of two or more chronic medical conditions). Blue boxes indicate therapeutic agents; red box indicates injurious components of the pathway (neprilysin, angiotensin II, AT₁R). Negative symbols (−) highlight inhibitory effect. Green box indicates protective cellular signalling pathways. ANP, atrial natriuretic peptide; CKD, chronic kidney disease; CNP, C-natriuretic peptide.

ARBs (AT₁ receptor antagonists)

Identification of the AT₁ receptor as the main target for the harmful effects of Ang-II led to the development of ARBs. These drugs became available in the 1990s and have a similar structure to Ang-II. Angiotensin receptor blockers selectively inhibit binding of Ang-II at the AT₁ receptor but do not block the protective effects mediated by the AT₂ receptor or inhibit bradykinin breakdown.

ARNIs (e.g. sacubitril/valsartan)

Natriuretic peptides counteract the deleterious effect of Ang-II, but exogenous BNP did not improve outcomes in patients with heart failure.⁶ Neprilysin inhibitors were subsequently developed to decrease the breakdown of endogenous natriuretic peptides. Initial attempts at blocking neprilysin alone, or in combination with an ACEI, proved unsuccessful. When combined with an ACEI, both ACE and neprilysin-mediated breakdown of bradykinin were inhibited, which resulted in increased concentrations of bradykinin and high rates of serious angioedema.⁵

The combination of valsartan (an ARB) with the neprilysin inhibitor sacubitril overcame the adverse effects of increased concentrations of bradykinin, leading to the better tolerated ‘angiotensin receptor neprilysin inhibitor’ (ARNI) class of drug. After the publication of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) RCT, the introduction of ARNI therapy is likely to revolutionise the management of patients with heart failure with reduced ejection fraction (see below).

Clinical evidence for ACEIs and ARBs

Over the past 40 yrs, multiple large clinical trials have demonstrated a beneficial effect of ACEIs and ARBs across a wide range of cardiometabolic diseases (other than hypertension of pregnancy).¹ This evidence is briefly highlighted below.

Hypertension

The systolic blood pressure intervention trial (SPRINT) open-label RCT (2015) enrolled 9361 patients to investigate whether tighter BP control decreased cardiovascular morbidity and mortality. The SPRINT trial was stopped early, as patients in the intervention arm (targeting a BP of <120 mmHg) had a 25% reduction in non-fatal cardiovascular events (hazard ratio 0.75; 95% confidence interval [CI] 0.64–0.89), and a 27% reduction in death from any cause (hazard ratio 0.73; 95% CI 0.60–0.90) over a median follow up period of 3.26 yrs.⁷ Current National Institute for Health and Care Excellence (NICE) guidelines for hypertension recommend an ACEI or ARB as first-line therapy for hypertension in patients with diabetes, and in patients under the age of 55 yrs who are not of Afro-Caribbean family origin. Given the compelling results of SPRINT, many more patients are likely to be encountered in the perioperative period receiving ACEIs or ARBs.

Diabetes and vascular disease

The heart outcomes prevention evaluation (HOPE) trial, published in 2000, studied the effect of ramipril vs placebo in 9297 high-risk patients aged >55 yrs who had diabetes or vascular disease, plus another cardiovascular risk factor, but no evidence of heart failure.⁸ Over a 5-yr follow-up period, this double-blind trial demonstrated a significant relative risk (RR) reduction of cardiovascular death (RR 0.74; 95% CI 0.64–0.87), myocardial infarction (RR 0.80; 95% CI 0.70–0.90), stroke (RR 0.68; 95% CI 0.56–0.84), cardiac arrest (RR 0.62; 95% CI 0.41–0.94), heart failure (RR 0.77; 95% CI 0.67–0.87) and diabetic complications (RR 0.84; 95% CI 0.72–0.98) in the ramipril compared with the placebo group.

Stroke

The perindopril protection against recurrent stroke study (PROGRESS) trial in 2001 assigned 6105 patients, with a history of stroke or transient ischaemic attack in the past 5 yrs, to either perindopril (plus indapamide) or placebo.⁹ This double-blind RCT found a 28% RR reduction of stroke in the perindopril group over a 4-yr follow-up period (95% CI 0.62–0.83). Similar to the SPRINT trial, tighter BP control is considered to reduce the risk of further strokes.

Heart failure

RCTs examining a role for ACEIs and ARBs in heart failure have evolved rapidly since the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) and Studies of Left New York Heart AssociationVentricular Dysfunction (SOLVD) trials, which reported dramatic reductions in deaths for patients randomised to receive enalapril.^10,11 Similarly, the Val-HeFT trial reported a 13.2% decrease in the combined endpoint of mortality and morbidity in heart failure patients randomised to valsartan therapy (RR 0.87; 95% CI 0.77–0.97).¹² Most recently, the PARADIGM-HF trial randomised 8442 patients with heart failure and reduced ejection fraction to receive either enalapril (standard treatment) or the ARNI sacubitril/valsartan.¹³ PARADIGM-HF was stopped early because of a 20% relative risk reduction in cardiovascular death or hospitalisation (hazard ratio 0.80; 95% CI 0.73–0.87), and a 16% reduction in all-cause mortality in the sacubitril/valsartan group compared with enalapril (hazard ratio 0.84; 95% CI 0.76–0.93). Consequently, sacubitril/valsartan has been recommended as the first-line treatment of patients with heart failure with reduced ejection fraction New York Heart Association (NYHA grades II–IV), although it has been a suggested a validation study may be required to ensure the effect detected is as great as reported. The perioperative consequences of the likely rapid introduction of ARNIs remain unclear.

Perioperative use of ACEIs and ARBs

Current guidelines from the European and American cardiology societies differ in their recommendations regarding perioperative management of patients with ACEI and ARB therapy.^14,15 The US guidelines suggest that continuation of ACEIs or ARBs is reasonable during the perioperative period, without stating whether this applies to specific pre-existing types of cardiovascular disease (class of recommendation: Grade IIa). However, they also recommend that if ACEIs or ARBs are withheld before surgery, it is reasonable to restart as soon as clinically feasible after operation (class of recommendation: Grade IIa). By contrast, the European guidelines suggest that continuation of ACEIs or ARBs, under close monitoring, should be considered during non-cardiac surgery in stable patients with heart failure and left ventricular systolic dysfunction, but advise in hypertensive patients that transient discontinuation of ACEIs or ARBs before non-cardiac surgery should be considered (class of recommendation for both: Grade IIa). During preoperative preparation, the European guidelines also recommend that the initiation of ACEIs or ARBs should be considered at least 1 week before surgery in cardiac-stable patients with heart failure and left ventricular systolic dysfunction (class of recommendation: Grade IIa).

This uncertainty reflects a widespread discordance amongst clinicians as to how ACEIs and ARBs should be managed perioperatively.¹⁶ This lack of agreement in recommendations for clinical practice largely reflects a lack of RCTs, which contrasts with the available evidence to help guide the perioperative management of patients with other cardiometabolic disease. Current guidelines rely on observational studies that cannot account for confounding factors which may contribute to variable clinical outcomes. The most recent and comprehensive systematic review exploring whether to continue or withhold ACEIs and ARBs before non-cardiac surgery analysed five RCTs and four cohort studies, which included 6022 patients (chiefly comprised of patients enrolled in the Vascular Events In Noncardiac Surgery Patients Cohort Evaluation Study (VISION) cohort study).^17,18 This systematic review found no difference in mortality or major cardiac events in patients who continued or withheld these medications. While the impact of stopping ACEIs and ARBs preoperatively on intraoperative hypotension remains unclear, failing to restart these medications has been shown to be associated with excess mortality after both noncardiac and cardiac surgery.19, 20, 21 Strikingly, a similar observation has been made in patients admitted to hospital with cardiac failure.²² The withdrawal of ACEIs/ARBs during hospitalisation for heart failure is associated with higher rates of post-discharge mortality and readmission, even after adjustment for severity of illness. Ongoing pragmatic (NCT03374449) and Phase III (ISRCTN17251494) trials specifically examining perioperative management of ACEIs and ARBs may provide further clinical guidance. Until the results of these trials have been published, robust evidence-based recommendations for the management of perioperative ACEIs and ARBs are not possible. Whether to continue ACEIs or ARBs throughout the perioperative period needs careful consideration on a case-by-case basis. If ACEIs or ARBs are temporarily discontinued during the early perioperative period, current observational data suggest they should be restarted as soon as possible after surgery guided by clear MAP thresholds.

Conclusions

Many high-risk patients presenting for major noncardiac surgery are taking ACEIs and ARBs. There is strong clinical evidence demonstrating a beneficial effect of ACEIs and ARBs in patients with a wide variety of chronic cardiometabolic conditions; failure to restart these medications after operation is associated with increased mortality. The beneficial effects of the ARNI sacubitril/valsartan are likely to transform treatment in reduced ejection fraction heart failure. There remains a lack of robust evidence regarding perioperative management of ACEIs and ARBs; however, there are ongoing preoperative trials that will hopefully better guide us in the future.

Declaration of interests

The authors declare that they have no conflicts of interest.

MCQs

The associated MCQs (to support CME/CPD activity) are accessible at www.bjaed.org/cme/home by subscribers to BJA Education.

Biographies

Andrew Shrimpton FRCA is an academic clinical fellow in anaesthesia at the University of Bristol.

Sophie Walker MBBS is a National Institute for Health Research clinical research PhD fellow at the William Harvey Research Institute.

Gareth Ackland PhD FRCA FFICM is a reader in perioperative medicine and NIHR advanced fellow in translational medicine and therapeutics at the William Harvey Research Institute, and an honorary consultant in anaesthesia and perioperative medicine at the Royal London Hospital, London.

Matrix codes: 1A02, 2A03, 3I00