Angiotensin‐Converting Enzyme Inhibitor Use in the Year 2005

Abstract

The angiotensin‐converting enzyme (ACE) inhibitor drug class is one with considerable staying power. ACE inhibitors are not only well established antihypertensive agents but also are compounds that fairly regularly provide end‐organ protection. Several of the ACE inhibitors are entangled in an active debate regarding class effect. Class effect for ACE inhibitors is a hopelessly confused term because its definition is not standardized and is subject to interpretation that in many cases is self‐serving. For the most part, ACE inhibitor side effects are readily identifiable, and management strategies put in place can be logical and sequential. The future of this drug class remains bright. Other drug classes, such as angiotensin receptor blockers, have narrowed—but not entirely closed—the outcomes gap that exists between these two drug classes.

In 1981, the first orally active angiotensin‐converting enzyme (ACE) inhibitor, captopril, was introduced. Shortly thereafter, the more long‐acting compounds enalapril maleate and lisinopril became available. In 1991, the ACE inhibitors fosinopril, quinapril, benazepril, and ramipril were almost simultaneously released. Over the next several years, the compounds moexipril, trandolapril, and perindopril entered the US marketplace. As such, there are now 10 ACE inhibitors available in the United States and several more to be had worldwide. ¹

Although ACE inhibitors were originally introduced as antihypertensive agents, they were soon recognized for their ability to check progressive renal, cardiac, and/or vascular disease. ¹ , ² Thus, it was a logical step in their development to seek additional usage indications in conditions such as heart failure (HF), post‐myocardial infarction (post‐MI), and diabetic nephropathy. ¹ Most recently, a treatment indication has been granted to the ACE inhibitor ramipril for reducing cardiovascular (CV) events in high‐risk cardiac patients without obvious left ventricular dysfunction, ³ and a similar indication is being considered for the compound perindopril. ⁴ , ⁵

ACE inhibitors are considered a suitable first‐step option in the treatment of hypertension in a diversity of patient types. The enthusiasm for the use of ACE inhibitors extends beyond the issue of effectiveness, since they are at best comparably efficacious to most other drug classes, including diuretics, β blockers, and calcium channel blockers (CCBs). Response rates with ACE inhibitors range from 40%–70% in stage I or II hypertension, with level of sodium intake and ethnicity having an effect on the observed response rate. ⁶

The blood pressure (BP)‐lowering ability of an ACE inhibitor is bettered with the concurrent administration of a diuretic, particularly when the hypertensive phenotype is a salt‐sensitive one. ⁷ The underlying principle for combining these two drug classes is one of diuretic‐induced sodium depletion activating the renin‐angiotensin‐aldosterone axis and shifting BP to a mode dependent on angiotensin‐II. Adding a peripheral a antagonist, such as doxazosin, to an ACE inhibitor can further reduce BP, albeit without a clear mechanistic basis. ⁸ Finally, the combination of an ACE inhibitor and a CCB is particularly effective in reducing BP, and recently has been shown to provide a superior outcomes benefit compared with a diuretic and β‐blocker‐based regimen. ⁹

PREDICTORS OF RESPONSE

In the interpretation of clinical trials results with ACE inhibitors, a distinction should be made between the mean reduction in BP (which is typically significant) and the percentage of individuals who are poor, average, and excellent responders (which may vary considerably in different studies). In that regard, there are no reliable predictors of the vasodepressor response to ACE inhibition. ¹⁰ Although ACE gene polymorphism (and specific genotypes), among other genetic determinants, have been suggested to predict the antihypertensive response to ACE inhibitors, such findings have not been consistent enough to justify routine use of genotyping. There has also been an inconsistent relationship between the preand /or post‐treatment plasma renin activity value (used as a marker of renin‐angiotensin‐aldosterone axis activity) and the level of fall in BP with an ACE inhibitor; however, when hypertension is marked by significant renin‐angiotensin‐aldosterone axis activation, such as in renal artery stenosis, the early response to an ACE inhibitor can be profound. ¹¹ The elderly generally respond well to ACE inhibitors at usual doses, ¹² though senescence‐related renal failure, which reduces the elimination of most ACE inhibitors, confounds analysis of dose‐specific treatment successes.

If the BP response is a modest one with an ACE inhibitor, the daily dose may be increased (this can occur by shifting to twice‐daily drug administration or increasing an individual dose), understanding that the dose‐response curve for ACE inhibitors, like many antihypertensive agents, is relatively steep at starting doses and thereafter levels. ⁶ Increasing the dose of an ACE inhibitor typically does not increase the peak effect; rather, it prolongs the duration of response. In fact, several of the shorter‐acting ACE inhibitors, such as enalapril, can function as true once‐a‐day medications if sufficiently high doses are given. ¹

CV OUTCOMES

Several trials have been completed that assess the utility of ACE inhibitors in modifying cardiac and cerebrovascular end points. ³ , ⁴ , ¹² , ¹³ , ¹⁴ These trials have either compared ACE inhibitor therapy to placebo ³ , ⁴ , ¹⁴ or to an active comparator such as a thiazide diuretic. ¹³ The ACE inhibitor perindopril has been shown to reduce CV risk in a low‐risk population with stable coronary artery disease (CAD) and no apparent HF; ⁴ however, in a similarly styled study—The Prevention of Events with Angiotensin‐Converting Enzyme Inhibition (PEACE)—the effect of adding the ACE inhibitor trandolapril to a contemporary therapeutic regimen of patients with stable CAD and preserved left ventricular function did not confer any additional benefit in terms of reducing the incidence of CV death, MI, or coronary revascularization. The neutral findings in PEACE add a new wrinkle to the concept of class effect for CV protection with ACE inhibitors in patients with CAD. ¹⁴

CLASS EFFECT

Given the large number of ACE inhibitors that are available, a not unexpected development has been the application of the concept of class effect to this grouping of drugs. Class effect is a phrase often invoked to justify use of a less costly and/ or not similarly studied ACE inhibitor when a higher‐priced agent in the class has been the one specifically studied in disease states, such as HF, diabetic nephropathy, or circumstances of high‐risk CAD. ¹ , ³ , ⁴ The concept of class effect, already fuzzy in its definition, becomes even more hazy when “true” dose equivalence for a non‐BP end point, such as rate of progression to end‐stage renal disease or survival in the setting of HF and/or post‐MI, is being determined for the various ACE inhibitors. ¹ Determining ACE inhibitor dose equivalence from outcomes trials is befuddled by differing dose frequency, titration requirements, and level of renal function in individual disease‐state studies. A sensible approach regarding the concept of ACE inhibitor class effect is to assume that the benefits (or not) in outcomes trials are gained from the compound tested, for the outcome studied, at the per protocol dose. ³ , ⁴

SIDE EFFECTS

A number of side effects are associated with ACE inhibitors—including cough, angioedema, anemia, acute renal failure, and hyperkalemia. ¹⁵ One side effect of ACE inhibition does not beget another except in the instance of acute or subacute renal failure, wherein anemia and hyperkalemia often coexist. Angioedema is the most life‐threatening of ACE inhibitor side effects, and its occurrence mandates permanent discontinuation of the offending agent. It is important not to restart ACE inhibitor therapy in any patient who has previously experienced an episode of angioedema, since the rate of recurrence with other ACE inhibitors is quite high. Acute or subacute renal failure proves the most bothersome of all ACE inhibitor side effects, in that its occurrence leads to premature and oftentimes ill‐advised permanent discontinuation of the involved drug. An understanding of the pathophysiology of this form of renal failure will often allow the compound in question to be restarted. ¹ , ¹⁵

Functional renal insufficiency with ACE inhibitors was first reported in patients with extensive renovascular disease. Other conditions predisposing to a similar process include dehydration, nonsteroidal anti‐inflammatory drug use, and/or HF. ¹⁶ A fall in glomerular afferent arteriolar flow is what mechanistically sets off this condition. When this occurs, glomerular filtration transiently declines if a kidney is hemodynamically vulnerable. In response to this reduction in glomerular filtration, angiotensin‐II production increases within the kidney and postglomerular arteriolar (efferent) constriction occurs. This restores hydrostatic (and thereby filtering) pressures within the more proximal glomerular capillary bed.

The abrupt removal of angiotensin‐II, as occurs with an ACE inhibitor (or an angiotensin receptor blocker), will give rise to sudden dilation of the efferent arteriole. In combination with a reduction in systemic BP, this hemodynamic adjustment reduces hydrostatic pressures such that glomerular filtration plummets. This type of functional renal insufficiency is best treated by discontinuation of the offending agent, prompt (yet careful) volume expansion (if intravascular volume contraction is a contributing factor), and if warranted on clinical grounds, evaluation for the presence of renal artery stenosis (Figure). ¹⁶

A situation analogous to that of functional renal insufficiency is exposure to ACE inhibitors during the second and third trimester of pregnancy (Black Box Warning for use). With such exposure, BP and renal perfusion drop in tandem, and in utero acute renal failure can develop. Oligohydroamnios develops thereafter, together with specific abnormalities thought to be secondary to reduced amniotic fluid volume (limb deformities, cranial ossification deficits, lung hypoplasia, and tubular dysgenesis).

Given the lack of documented teratogenicity, inadvertent use of an ACE inhibitor in the first trimester is not a justifiable reason for abortion.

CONCLUSION

With over 25 years of experience with ACE inhibition, this drug class has fully matured. These drugs remain effective antihypertensive agents—either as monotherapy or as a component of a multi‐drug regimen—and are firmly entrenched as compounds of choice for CV and renal end‐organ protection. The compendium of papers provided in this supplement provides a picture of how a particular compound, such as perindopril, reaches a stage where it is a viable choice in a crowded marketplace. This is not to say that other ACE inhibitors could not provide a similar portfolio of results; rather it is to point out that a certain blueprint of experimental findings is needed for physicians to consider use of a particular drug in a class. Most importantly, for any ACE inhibitor to succeed, it must have positive outcomes data as a part of its experimental dossier, as is the case for ramipril in the Heart Outcomes Prevention Evaluation (HOPE) study ³ and perindopril in the EUROPA study. ⁴