Angiotensin-Converting Enzyme Inhibitors

General (including evidence of efficacy)

Angiotensin-converting enzyme inhibitors (ACEIs) are a commonly used medication in the current management of various medical conditions, including heart failure, postacute coronary syndrome, nephrotic syndrome and hypertension.

The discoveries leading to the development of such drugs began in 1956 when an extract of snake venom was noted to control hypertension. This agent was found to inhibit the enzyme responsible for the conversion of “hypertensin I” into the potent vasoconstrictor “hypertensin II.”

This enzyme would later become known as angiotensin-converting enzyme and its substrate and product, (both with vascular trophic, procoagulant and vasoconstrictor properties), the peptides angiotensin I, and angiotensin II, respectively. The inhibitor became widely known as angiotensin-converting enzyme inhibitors (ACEIs) and has become one of the best studied and most efficacious therapies in cardiovascular medicine to date.

ACE inhibitors exert their cardiovascular effects through inhibition of the “renin-angiotensin-aldosterone” or RAAS system, which is active in patients with cardiovascular disease. Since RAAS activation leads to increased systemic blood pressure, increased proclivity toward thrombosis and vascular growth, fibrosis, and remodeling (blood vessels, kidneys, and heart), ACEI administration will blunt these effects.

These effects are inhibited both in the peripheral blood as well as local tissue. It is unknown to what degree these effects in the periphery versus tissues are responsible for the positive cardiovascular effects of ACE inhibitors.

Differences between drugs within the class

See Table I.

Table 1.n

Administration

ACE inhibitors are given orally and are variably absorbed. Most ACEIs are administered as prodrugs and are metabolized in the liver into active forms to mediate their inhibition of ACE. There is one form of intravenous ACE inhibitor, enalaprilat, which is used occasionally for hypertensive crises.

It is not recommended for acute heart failure or acute myocardial infarction due to the potential deleterious hypotensive effects in some individuals. An attached algorithm, developed at the University of Alberta by Koshman, Ezekowitz et al, may be used for assistance in administration of ACE inhibitors (Figure 1).

Figure 1.n

Pharmacologic action

Physiology

The renin-angiotensin-aldosterone system in the body functions to maintain plasma volume and renal perfusion by adjusting sodium reabsorption and fluid balance. The synthesis and secretion from the liver of the precursor angiotensinogen is the first step in the system.

When appropriate stimuli are sensed at the renal juxtaglomerular apparatus (stimuli include increased sympathetic nervous activity, decreased vascular pressure/stretch, and decreased NaCl to the macula densa), the kidneys secrete renin into the plasma, which in turn cleaves the angiotensinogen to form angiotensin I.

The active agent angiotensin II is then produced via a conversion reaction of the angiotensin-converting enzyme. This conversion occurs primarily in the pulmonary circulation rather than peripheral blood.

Angiotensin II then mediates its effects, including some direct sodium resorption in the kidney, increased antidiuretic hormone (ADH) release from the pituitary, vasoconstriction of arterioles, and secretion of aldosterone from the adrenal cortex.

Aldosterone is then able to cause increased sodium and water reabsorption in the cortical collecting ducts (and conversely decreased sodium and water excretion), and increase plasma volume. A secondary increase in excreted potassium is also caused by this reaction.

Thus, inhibiting the enzymatic activity and stopping the formation of the angiotensin II and its downstream effects leads to reduced systemic blood pressure, increased serum potassium, and variable effects on the kidney- usually a small 10% reduction in the glomerular filtration rate from direct effects upon renal blood flow.

Indications and contraindications

The primary indications for ACEIs:

• Systemic hypertension. Angiotensin converting enzyme inhibitors are preferred agents for patients with hypertension, ischemic heart disease, renal disease, diabetes and heart failure.

• Following myocardial infarction (MI). It is important to emphasize that the benefit of ACEIs in the post-MI setting, in terms of number needed to treat for benefit (NNT) becomes lower as the patient is more ill. For example, in unselected post-MI patients, a 30-day course of ACEI will confer a 5-10% benefit in survival rate, while in the longer term a 20% benefit is seen. In patients with clinical heart failure or poor left ventricular systolic function (with left ventricular ejection fraction [LVEF]), use of ACEIs is associated with a 25% benefit in survival rate and a 1-1.5 year increase in life expectancy.

• Heart failure. Again, with worsening HF status, the benefit of treatment increases. In patients with advanced heart failure, therapy is associated with a 40% reduction in death, while those with mild to moderate symptoms and LVEF less than 35% will expect a 25% reduction in death and hospitalization, and a 1-year increase in life expectancy. For patients with HF and normal LVEF, the benefit is relatively small, with a 10-15% reduction in hospitalization for heart failure and minimal, if any mortality reduction.

• Renal disease including diabetic nephropathy, nondiabetic nephropathy, and hypertension with proteinuria. In these situations, ACEI therapy has been associated with at least a 20% reduction in progression to renal dialysis, increase in proteinuria, doubling of serum creatinine and hospitalization for heart failure.

Contraindications

Prior to initiating an ACEI in a patient’s management, contraindications need to be assessed. Contraindications to ACEI use include hyperkalemia (>5.5 mmol/L), renal artery stenosis, pregnancy (ACEI or Australian Drug Evaluation Committee [ADEC] pregnancy category D), or prior adverse reaction to an ACEI including angioedema.

Of recent note, a new class of agents called Angiotensin-Neprilysin Receptor Inhibitors (ARNI-LCZ696 or Entresto™) are now available as an alternative to ACEI for selected patients with heart failure and reduced left ventricular ejection fraction. These agents also increase circulating bradykinin levels, which are related to occurrence of angioedema. As such, co-administration of ACEI and ANRIs is CONTRAINDICATED. A separate chapter discussing this class of drugs is available in this program.

Other relative contraindications include renal failure (serum creatinine >2.5 mg/dL ); hyponatremia, especially if below 130 mmol/L (associated with poorer outcomes); hypovolemia/hypotension less than 90 mmHg; aortic stenosis or LV outflow tract obstruction; or patients who may become pregnant or are breast feeding.

Undesirable effects

In addition, here are few practical tips for use of ACE inhibitors:

• It is quite acceptable for creatinine to increase up to 30% while using ACEIs. However, sudden leaps (in only a few days) or more substantial increases in serum creatinine should be cause for concern.

• Baseline creatinine must be less than 2.5 mg/dl and serum potassium should be less than 5.2 mmol/L.

• Concomitant medications known to affect renal function and serum potassium (especially COX-2 inhibitors and NSAIDs) should be stopped before ACE inhibitor use, if at all possible.

• Use of other medications that affect the RAAS system, such as angiotensin receptor blockers, spironolactone, eplerenone and amiloride, will exert synergistic effects with the ACE inhibitor.

• The patient must not be volume depleted; this will worsen and aggravate the hypotensive and renal effects of ACEI. One of the more common scenarios occurs when patients with heart failure, who are over diureses, develop hypotension and/or worsening renal function. When this occurs, one should reduce the diuretic rather than the ACEI.

• Serum creatinine and electrolytes, as well as questioning for symptoms of hypotension/postural hypotension should be performed 7-10 days after drug initiation and titration. If monitoring is not readily available, you should not be using the drug.

• The blood pressure lowering effects of ACEIs are synergistic with other antihypertensives. If the patient experiences symptoms of hypotension and is not volume depleted, try staggering the dose of ACE with other such drugs to mitigate the “bolus” effect of simultaneous drug ingestion.

When starting a medication, it is important to anticipate possible complications and to disclose this to the patient to maximize compliance and alleviate anxiety with the starting of a new medication. Common side effects of ACEIs include a dry cough (quoted as 1:10 patients), symptomatic hypotension (especially with the first dose, so advise patients to take at bed time first), taste disturbance, hyperkalemia, renal impairment that can be worsened with ACEI, urticaria, and angioedema (<1:1,000); rarely they can also cause proteinuria, leucopenia and fatigue.

It is well known that use of ACEI in patients with pre-existing renal disease may lead to worsening renal function, particularly during the in-hospital phase of acute decompensated heart failure. Increases in serum creatinine are associated with worse prognosis for both stable and decompensated heart failure. However, recent analyses of clinical trial as well as acute heart failure registry data indicate that increases of serum creatinine due to ACEI administration (in the absence of severe oliguria) are the exception to this rule. Ongoing titration of ACEI in the setting of increased serum creatinine is safe and effective provided appropriate monitoring is in place.

If a cough develops, it is important to establish the cause as it could genuinely be from the ACEI, or worsening HF, or perhaps a baseline cough just worsening.

If a cough develops that is due to the ACEI and is intractable, a trial of another ACEI and reassessment in 2 weeks should take place. If no alleviation of the cough is documented, then switching to an ARB should be considered. Should angioedema develop, immediate discontinuation of the ACEI is warranted. No further attempts, even with a different ACEI, should be carried out, although an ARB may be considered (with caution).

Should a patient have an unfavorable reaction to any ACEI, it should be properly documented to avoid future exposure to this medication. Women of childbearing age should be advised against conception due to high levels of malformations and defects that can be caused by ACEI use.

Alternative approaches

While ACE inhibitors remain the gold standard for inhibition of the renin-angiotensin-aldosterone system, many patients are unable to take or tolerate these medications. Reasons for discontinuing ACE-I therapy fall into two broad categories: ACE-inhibitor cough and all other reasons.

ACE inhibitor cough may occur in 4-15% of patients, and may be either well tolerated, in which case they should be continued, or poorly tolerated. If an ACEI is stopped due to cough, an angiotensin receptor blocker (ARB) can be substituted.

These agents have been shown to also reduce cardiovascular morbidity and mortality, especially following MI and in patients with renal disease. They have shown efficacy but not equivalence to ACEI for heart failure with reduced LVEF and so are not first line.

While ARBs can be safely used as substitutes for ACEI intolerance due to cough, they cannot be substituted for ACEI intolerance resulting from any other side effect of an ACEI due to their similar effects upon blood pressure, renal function and potassium concentration.

For patients who cannot tolerate ACE inhibitors due to worsening renal function or hyperkalemia, and who have heart failure, a combination of hydralazine (37.5 to 75 mg tid) and isosorbide dinitrate (20 to 40 mg tid) may be used. This combination usually does confer improved symptoms, as well as improved survival rates in chronic systolic heart failure but is not as effective as an ACEI. In addition, this combination usually causes more significant blood pressure reduction than an ACEI (8 vs. 5 mmHg in chronic heart failure).

References

Skeggs, LT, Kahn, JR, Shumway, NP. “The preparation and function of the hypertension-converting enzyme”. JEM. vol. 103. 1956. pp. 295-9. (Original paper published outlining properties of ACE inhibitors.)

Ferreira, SH. “A bradykinin potentiating factor (BPF) present in the venom of Bothrops Jararaca”. Brit J. Pharmacol. vol. 24. 1965. pp. 163-9.

Widmaier, E, Raff, H, Strang, K. “Human Physiology”. 2004. pp. 534-8. (Excellent outline of the RAAS system for reference.)

Ng, KKF, Vane, JR. “Conversion of angiotensin I to angiotensin II”. Nature.. vol. 216. 1967. pp. 762-6.

Chua, D, Ignaszewski, A, Schwenger, E. “Angiotensin-converting enzyme inhibitors: an ACE in the hole for everyone?”. BCMJ. 2011. pp. 53

“Effects of ramipril on cardiovascular and micro vascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE sub study. Heart Outcomes Prevention Evaluation Study Investigators”. Lancet. vol. 355. 2000. pp. 253-9. (Seminal prevention study demonstrating powerful preventative cardio protection of ACE inhibitors for those at high risk of CV events.)

“Canadian Diabetes Association 2008 clinical practice guidelines for the prevention and management of diabetes in Canada”. Can J Diabetes. vol. 32. 2008. pp. S1-S201. (Good reference for role of ACE inhibitors for patients with diabetes.)

Arnold, JMO, Liu, P, Demers, C. “Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: Diagnosis and management”. Can J Cardiol. vol. 22. 2006. pp. 23-45.

Hunt, SA. “ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure)”. J Am Coll Cardiol. vol. 46. 2005. pp. e1-e82. (These last two references relate to the central position of ACE inhibitors for management of heart failure.)

Longmore, M, Wilkinson, IB, Davidson, EH, Foulkes, A, Mafi, AR. “Oxford Handbook of Clinical Medicine”. 2010. pp. 109

Langenickel, TH, Dole, WP. “Angiotensin receptor-neprilysin inhibition with LCZ696: a novel approach for the treatment of heart failure. Drug Discovery Today”. Therapeutic Strategies. vol. 9. 2012.

Clark, H, Krum, H, Hopper, I. “Worsening renal function during renin-angiotensin-aldosterone system inhibitor initiation and long-term outcomes in patients with left ventricular systolic dysfunction”. Eur J Heart Fail. vol. 16. 2014 Jan. pp. 41-8.

Alexander, J., Kula, Jennifer S., Hanberg, F. Perry Wilson, Brisco, Meredith A.. “Influence of Titration of Neurohormonal Antagonists and Blood Pressure Reduction on Renal Function and Decongestion in Decompensated Heart Failure”. Circ Heart Fail. vol. 9. 2016 Jan. pp. e002333

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