ACE Inhibitors:When-and For Which Patients?

Q:Should I avoid angiotensin-converting enzyme (ACE) inhibitors in my patients with progressive renal insufficiency?A:This issue is extremely bothersome to clinicians. ACE inhibitors representa dual-edged sword with respect to their impact on renal function. On onehand, major clinical trials have clearly demonstrated their benefit in patients withcongestive heart failure (CHF) and in patients with diabetic and nondiabetic renaldisease. In multiple large clinical trials, ACE inhibitors reduce the risk of hospitalizationsand death in patients with severe systolic dysfunction. In patients withproteinuric renal disease, ACE inhibitors significantly reduce proteinuria andslow the rate of progressive loss in renal function. Multiple benefits have beenobserved in older patients with cardiovascular disease, with or without hypertension-and with and without renal disease.¹ These data, taken together, suggestthat a significant segment of the population may benefit from this class of agents.

Nevertheless, clinicians remain wary of prescribing ACE inhibitors for patientswith any degree of renal dysfunction-particularly when initiation is associatedwith evidence of further renal dysfunction. Consequently, many patientswho could profit greatly from long-term treatment with ACE inhibitors are deniedtheir potential benefit.

EFFECT OF ACE INHIBITORS ON RENAL CIRCULATIONThe renin-angiotensin system plays an important role in the autoregulationof both renal blood flow and particularly of glomerular filtration rate (GFR). Thebalance between afferent and efferent arteriolar tone in the renal glomerulus determinesglomerular hydrostatic pressure and, therefore, GFR. Suppression ofangiotensin II generation by ACE inhibitors, and the resulting decrease of efferentarteriolar tone, causes a reduction in glomerular hydrostatic pressure, inGFR, and in proteinuria. These changes are a predictable effect of ACE inhibitorswithin the kidney and are reflected clinically by a decrease in GFR, a decrease inquantitative proteinuria, and an increase in the serum creatinine concentration.These observations, however, do not preclude the cautious administrationof ACE inhibitors in patients with renal insufficiency.

WHAT IS THE RISK OF FURTHER RENAL INSUFFICIENCY?
A postmarketing study observing prescription-related events in patients receivingenalapril showed an increase in serum creatinine of greater than 50% inonly 8.2% of cases.² In multiple studies of ACE inhibitors in patients with CHF,the incidence of increased serum creatinine requiring discontinuation of themedication ranged from 5% to 11%. These studies included patients with stages1 to 4 heart failure, acute myocardial infarction, and baseline serum creatinineconcentrations as high as 3.4 mg/dL.

In a meta-analysis of almost 1600 patients with nondiabetic renal disease,ACE inhibitors did not increase overall mortality.³ Baseline serum creatinineconcentrations in this meta-analysis ranged as high as 4.4 mg/dL.

In an earlier study in patients with type 1 diabetes mellitus who were treatedwith captopril, slower progression of renal disease was observed in patientswith serum creatinine levels up to and exceeding 4 mg/dL.In fact, in patients with diabetic and nondiabetic renal disease,those with the highest levels of urine protein excretionand higher levels of creatinine derived particularbenefit from ACE inhibitor therapy. However, renal protectionis maximized when ACE inhibition is started earlierand when long-lasting treatment can result in stabilizationof renal function and subsequent prevention of end-stagerenal disease.

OTHER CONTRIBUTING CONDITIONS
There are a number of clinical conditions in which increasedactivity of the renin-angiotensin system may play akey role in maintaining GFR. In these settings, ACE inhibitorscan contribute to an acute but usually reversibledecrease in renal function. At the same time, ACE inhibitorsmay be considered desirable therapy, if not a treatmentof choice; this dichotomy of effects can complicateuse of this class of agents. In bilateral, high-grade renalartery stenosis, angiotensin-mediated autoregulation ofGFR can be acutely reduced when angiotensin II postglomerularvasoconstriction is inhibited. The subsequentincrease in serum creatinine is usually modest but on occasioncan result in acute but reversible oliguric renal failure.Obviously, an acute decrease in renal function following theinitiation of an ACE inhibitor should trigger further evaluationto identify possible high-renin states, including renalartery stenosis.

Evidence from many clinical trialsinvolving more than 10,000 patientswith CHF suggests that elevatedserum creatinine levels associated withACE inhibitor therapy necessitateddrug withdrawal in 5% to 11% of patients.The higher incidence is observedin patients with more severeand symptomatic CHF and the lowestejection fractions. In patients withasymptomatic left ventricular dysfunction,initiation of ACE inhibitors may beassociated with only minimal increasesin serum creatinine. In many patients,the decline in renal function may resolvewhen the diuretic dosage is loweredand the ACE inhibitor dosagemaintained. Patients with severe volumedepletion or hyponatremia-bothof which increase activity of the reninangiotensin-aldosterone system-mayprecipitate acute decreases in bloodpressure and renal function followingthe initiation of an ACE inhibitor.

Other conditions susceptible toACE inhibitor-induced renal insufficiencyinclude:

• Hypertensive arteriolarnephrosclerosis.
• Progressive renal insufficiencyassociated with polyarteritis nodosaor systemic vasculitis.
• Advanced and decompensatedcirrhosis of the liver.

Other conditions that may be associatedwith hypotension followingACE inhibitor therapy include autosomaldominant polycystic kidney dis-ease with large kidneys. Use caution when recommendingACE inhibitors for elderly patients with intercurrentillnesses that may contribute to reductions in effectivevascular volume.

A WORD ABOUT HYPERKALEMIAWITH ACE INHIBITORS
An increase in the serum potassium concentration isa well recognized effect of ACE inhibitor therapy and isrelated to suppressed aldosterone levels. In hypertensivepatients with normal renal function, this increase is usuallyno more than 0.5 to 1 mg/dL. Use potassium-sparingdiuretics and/or potassium supplements judiciously, evenin patients with normal renal function. In the presence of adeclining GFR, the risk of hyperkalemia increases inverselyto declining GFR. In patients with mild renal insufficiency,the kaliuretic effect of thiazide or loop diuretics mayoffset the increase in serum potassium levels seen withthe ACE inhibitor.

RECOMMENDATIONS FORADMINISTRATION
In view of the rapidly expanding indications for ACEinhibitors, physicians increasingly will be asked to decidewhether to prescribe this class of agents. The recommendationsthat appear in Table 1 should facilitate relativelysafe initiation of therapy with an ACE inhibitor.

In short, the clinical use of ACE inhibitors has beengreatly impaired by concerns about adverse effects in patientswith progressive renal disease. Physicians who areaware of the risks and benefits of ACE inhibitors in renaldisease, and who have knowledge of other contributingconditions, can safely expand their use of these agents. Acautious approach to initiation of an ACE inhibitor-as wellas careful serial monitoring of renal function and electrolytes-should facilitate expanding usage of this importantclass of drugs.

FOR MORE INFORMATION:

• Garg R, Yusuf S, for the Collaborative Group on ACE Inhibitor Trials.Overview of randomized trials of angiotensin-converting enzyme inhibitors onmortality and morbidity in patients with heart failure. JAMA. 1995;273:1450-1456.
• Ruggenenti P, Perna A, Remuzzi G, for the GISEN Study Group. ACE inhibitorsto prevent end-stage renal disease: when to start and why possibly never tostop: a post hoc analysis of the REIN trial results. Ramipril Efficacy in Nephropathy.J Am Soc Nephrol. 2001;12:2832-2837.

References:

REFERENCES:1. Yusuf S, Sleight P, Pogue J, et al, for the Heart Outcome Prevention EvaluationStudy Investigators. Effects of an angiotensin-converting-enzyme inhibitor,ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145-153.
2. Speirs CJ, Dollery CT, Inman WH, et al. Postmarketing surveillance of enalapril,II: investigation of the potential role of enalapril in deaths with renal failure.Br Med J. 1988;297:830-832.
3. Jafar TH, Schmid CH, Landa M, et al. Angiotensin-converting enzyme inhibitorsand progression of nondiabetic renal disease: a meta-analysis of patientleveldata. Ann Intern Med. 2001;135:73-87.
4. Moser M. Lower Your Blood Pressure and Live Longer. New York: Berkley, PutnamBooks; 1992.