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Chapter 16 / Role of ACE Inhibitors 321

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From: Clinical Hypertension and Vascular Diseases: Hypertension in the ElderlyEdited by: L. M. Prisant © Humana Press Inc., Totowa, NJ

16 Assessment of the Role of ACEInhibitors in the Elderly

Domenic A. Sica, MD

CONTENTS

INTRODUCTION

PHARMACOLOGY

MECHANISM OF ACTION AND HEMODYNAMIC EFFECTS

BLOOD PRESSURE-LOWERING EFFECT

ACE INHIBITORS IN COMBINATION WITH OTHER

AGENTS

ACE INHIBITORS IN HYPERTENSION ASSOCIATED

WITH OTHER DISORDERS

END-ORGAN EFFECTS

SIDE EFFECTS OF ACE INHIBITORS

CONCLUSIONS

REFERENCES

INTRODUCTION

In the treatment of hypertension and cardiovascular disease (CVD),multiple treatment strategies have come and gone over the last severaldecades. The stepped care approach was popular for some time. How-ever, adopting a stepped care approach to the treatment of hypertensionper se neglected the diverse individualized pathophysiology of hyper-tension. Its advocates appreciated the purity of a standardization ofhypertension treatment; others were disenchanted with its rigid nature.Yet, the stepped care approach to hypertension therapy, with diureticsand/or β-blockers, was supported by strong outcomes data from numer-ous randomized controlled trials (RCTs) (1).

322 Hypertension in the Elderly

However, for the elderly hypertensive such debate was always lessrelevant, in part because of the overwhelming comorbid disease stateburden and the ever-present need to individualize treatment regimens(2). Into this arena entered angiotensin-converting enzyme (ACE) inhibi-tors. This drug class at first was viewed as an acceptable alternative to thetreatment of hypertension in the elderly but soon was recognized ashaving unique end-organ protective effects. Now, in many instances theselection of an agent to treat hypertension in the elderly is predicated firston the end-organ protection aspect of their use, and the accompanyingblood pressure (BP) reduction is viewed as a secondary benefit (3).However, although there exists a growing advocacy for ACE inhibitoruse in the elderly, in practice many elderly patients with appropriateindications for ACE inhibitor therapy may not routinely receive one ofthese compounds (4).

This chapter discusses the pharmacology, mechanism of action, andresponse data for ACE inhibitors, particularly as relates to their use in theelderly. If necessary, the reader will be directed to sources that providemore comprehensive discussion on particular themes.

PHARMACOLOGY

The first orally active ACE inhibitor was the sulfhydryl-containingcompound captopril, which was introduced in 1981. Subsequently, themore long-acting compound enalapril maleate became available.Enalapril, a prodrug requiring in vivo hepatic and intestinal wallesterolysis to yield the active diacid inhibitor enalaprilat, and lisinoprilbecame available shortly thereafter. All orally administered ACE inhibi-tors are prodrugs with the exception of lisinopril and captopril (5).Although it was originally thought that formation of the active diacidmetabolite of an ACE inhibitor, such as enalapril, could be inhibited inthe presence of hepatic impairment, as may develop in advanced conges-tive heart failure (CHF), this appears not to occur in a clinically relevantmanner (6).

ACE inhibitors are structurally heterogeneous, with the chemicalstructure of their binding ligand serving as a criterion for dividing ACEinhibitors into three groups: sulfhydryl, carboxyl, and phosphinylcontaining. The purported advantages with sulfhydryl-containing ACEinhibitors, such as captopril, are to date clinically unsubstantiated.Likewise is the belief that the phosphinyl group, found on fosinopril,might favorably alter its myocardial penetration and thereby improvemyocardial energetics (7). However, the sulfhydryl group found oncaptopril is believed the cause of the more frequent skin rashes—usually


maculopapular—and the dysgeusia seen with this compound (8). Thelatter can prove particularly troubling in the elderly.

ACE inhibitors can be distinguished by differences in rate and extentof absorption, plasma protein binding, systemic half-life, and mode ofdisposition; however, they behave quite similarly in the way they lowerBP (Table 1) (5,9,10). Beyond the issue of frequency of dosing, seldomare any of these pharmacological differences sufficiently important togovern selection of an agent (3,10). Two pharmacological consider-ations for the ACE inhibitors, route of systemic elimination and tissuebinding, have generated considerable recent debate and deserve somecomment in the context of the elderly (11,12).

Route of EliminationRamipril, enalapril, fosinopril, trandolapril, and benazepril do not

accumulate in the presence of chronic kidney disease (CKD), suggestingthat these prodrugs either undergo intact biliary clearance or their con-version to an active diacid form is not influenced by CKD (13–15).These ACE inhibitor prodrugs are marginally active, making their accu-mulation (or not) in CKD less pertinent. The absence of ACE inhibitorprodrug accumulation in CKD should not be viewed as the existence ofa clinically relevant dual route of elimination for these drugs. The activediacid forms fosinoprilat and trandolaprilat are the only two ACE inhibi-tors that undergo combined renal and hepatic elimination (14,15). For allother ACE inhibitors, systemic elimination is almost exclusively renal,with varying degrees of filtration and tubular secretion occurring (11).ACE inhibitor accumulation generally begins early in the course of CKD;thus, elderly patients can be expected to experience ACE inhibitor accu-mulation either in relationship to their age-related decline in renal func-tion or as the result of comorbid conditions that have a negative impacton renal function.

In the elderly patient with CKD, adverse effects from ACE inhibitoraccumulation have yet to be identified. However, the longer drug con-centrations remain elevated (once a response occurs), the more likely itis that BP will remain reduced. Thus, the major adverse effect of ACEinhibitor accumulation may be that of protracted hypotension and itsorgan-directed sequelae (16).

Tissue BindingThe second unsettled pharmacological feature of ACE inhibitors is

that of tissue binding (12,17). The physicochemical differences amongACE inhibitors, including binding affinity, potency, lipophilicity, anddepot effect, permit the arbitrary classification of ACE inhibitors accord-

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ing to affinity for tissue ACE (12,18). The level of tissue ACE inhibitionproduced by an ACE inhibitor parallels both the inhibitor’s bindingaffinity and the free inhibitor concentration contained within that tissue.The free inhibitor concentration represents a state of dynamic equilib-rium between ACE inhibitor conveyed to tissues and residual ACEinhibitor released from tissues and returned to the bloodstream.

The quantity of ACE inhibitor shuttled to tissues is dictated by tradi-tional pharmacological variables, including dose frequency/amount,absolute bioavailability, plasma half-life, and tissue penetration. Whenblood levels of an ACE inhibitor are high (typically in the first third tohalf of the dosing interval), tissue retention per se of an ACE inhibitoris not needed for functional ACE inhibition. However, toward the end ofthe dosing interval, as ACE inhibitor blood levels fall, two factors—inhibitor binding affinity and tissue retention—assume added impor-tance in prolonging functional ACE inhibition.

The question arises whether the degree of tissue ACE inhibition mayextend to differences in the efficacy of various ACE inhibitors. First,there appears to be little—beyond differences that may arise based onhalf-life considerations—to distinguish one ACE inhibitor from anotheras far as BP reduction is concerned. Moreover, in the elderly, even withearly stages of CKD the accumulation and thereby prolonged half-life ofmost ACE inhibitors further reduces the chances of any intraclass differ-ences in BP reduction.

Second, an alternative question is whether these drugs differ in theirability to provide end-organ protection in a BP-independent fashion, aswas speculated in the Heart Outcomes Prevention Evaluation (HOPE)study (19). In this regard, it should be noted that consistent improvementin endothelial function is reported with those ACE inhibitors with highertissue ACE affinity, such as quinapril and ramipril. If improvement inendothelial dysfunction can be used as a surrogate for protection fromend events, then it is possible that relevant intraclass differences existamong ACE inhibitors. Yet, there have been few direct head-to-headtrials between ACE inhibitors, which have varying tissue affinity. Whensuch comparisons have occurred, the results have not convincingly sup-ported the claim of overall superiority for lipophilic ACE inhibitors(20,21). Moreover, in the elderly relevant differences for BP-indepen-dent effects of the various ACE inhibitors are even less likely in the faceof CKD-related ACE inhibitor accumulation.

Application of Pharmacological DifferencesBecause there is very little that truly separates one ACE inhibitor from

another in the treatment of hypertension, the cost of an ACE inhibitor has


assumed added importance (22). For pricing to be a major selectionfactor is not unreasonable if ACE inhibitors were only used for thecontrol of BP. ACE inhibitors, however, are also extensively used fortheir cardiorenal benefits, and therein only a limited number of ACEinhibitors have been studied for their ability to modify specific end-organ disease states. The term class effect has entered into the discussionof both of these facets of ACE inhibitor use, relevant to one and not theother.

Class effect is a phrase often invoked to legitimatize use of a less-costly ACE inhibitor when a higher priced agent in the class has been theone specifically studied in a disease state, such as CHF or diabetic neph-ropathy (19,23–25). The concept of class effect may be best suited forapplication to the BP effects of ACE inhibitors, for which scant differ-ence exists among the various ACE inhibitors.

Alternatively, the concept of class effect, already vague in its defini-tion, becomes even more ambiguous when “true” dose equivalence fora non-BP end point, such as rate of progression to end-stage renal diseaseor survival in the setting of CHF, is being established between the vari-ous ACE inhibitors. Determining ACE inhibitor dose equivalence fordisease state end points other than BP is further confused by differingdose frequency, titration attempts, and level of renal function (26–31).The last is particular relevant to the elderly because senescence-relatedchanges in renal function extend ACE inhibitor functional half-life andmake it virtually impossible to determine equivalence for various ACEinhibitors.

A prudent action regarding the concept of ACE inhibitor class effectis to assume that the benefits of a particular ACE inhibitor apply prima-rily to the investigated indication, dose amount, dose frequency, andoutcomes.

MECHANISM OF ACTIONAND HEMODYNAMIC EFFECTS

The locus of activity of ACE inhibitors within the renin–angiotensin–aldosterone (RAA) axis is at the pluripotent ACE, which catalyzes theconversion of angiotensin (Ang) I to Ang II and facilitates bradykinindegradation to various vasoactive peptides (32). However potent an ACEinhibitor is in this regard, it still only manages to suppress the Ang-IIgenerated by ACE (19). Other pathways for Ang-II production (e.g.,chymase and other tissue-based proteases) remain functional despiteadministration of an ACE inhibitor (33). These alternative pathwaysrepresent the principal mode of Ang-II generation in myocardial and


vascular tissue (34,35). Interestingly, the long-term administration of anACE inhibitor is marked by a gradual return of Ang-II to pretherapylevels. This phenomenon is termed angiotensin escape and is presum-ably caused by an upregulation in the capacity of these alternative path-ways. Substrate for these alternative pathways at least partly comes fromthe increase in Ang-I levels when ACE inhibition disinhibits renin secre-tion from the juxtaglomerular apparatus (35,36).

Because ACE inhibitors reduce Ang-II levels only on the order ofweeks (36,37), alternative mechanisms for their persistent BP-loweringeffect need to be considered; these include an increase in the concentra-tion of the vasodilator bradykinin (38,39), which in turn stimulates theproduction of endothelium-derived relaxing factor and the release ofprostacyclin. However, the exact contribution of prostaglandins to theantihypertensive effect of ACE inhibitors, particularly in the elderly, isstill debated (40).

Alternatively, it has been recognized for some time that nonsteroidalanti-inflammatory drugs blunt the BP-lowering effect of ACE inhibitors(41). This phenomenon is more common in salt-sensitive hypertensives,as is the case with the elderly (42). Low-dose aspirin (100 mg/day or less)has minimal effect on the BP reduction seen with ACE inhibition (43).For example, in the Hypertension Optimal Treatment study, long-term,low-dose aspirin did not interfere with the BP-lowering effect of antihy-pertensive agents, including combinations with ACE inhibitors, in eld-erly subjects 65 years or older (44). However, higher doses, generallyabove 236 mg/day, can blunt the antihypertensive response to an ACEinhibitor (45).

A variable portion of ACE inhibitor effect is caused by a reduction inboth central and peripheral sympathetic nervous system activity (Table 2)(46,47). ACE inhibitors also preserve circulatory reflexes and barorecep-tor function; thus, they do not reflexly increase heart rate when BP islowered (48). This last property explains why this drug class is seldomassociated with postural hypotension and provides an important safetyadvantage in elderly subjects, who as a group are typically prone toorthostatic hypotension (49). ACE inhibitors also improve endothelialfunction, facilitate vascular remodeling, and favorably alter the vis-coelastic properties of blood vessels (50,51). These vascular propertiesof ACE inhibitors are the likely explanation for the incremental reduc-tion in BP with the long-term use of these drugs.

BLOOD PRESSURE-LOWERING EFFECT

Diuretics are still commonly employed as first-step therapy for hyper-tension, although increasingly ACE inhibitors are viewed as a suitable


Table 2Predominant Hemodynamic Effects of Angiotensin-Converting Enzyme Inhibitors

Hemodynamic parameter Effect Clinical significance

Cardiovascular• Total peripheral resistance Decreased• Mean arterial pressure Decreased• Cardiac output Increased These parameters contri-

or no change bute to a general decrease• Stroke volume Increased in systemic blood pressure• Preload and afterload Decreased• Pulmonary artery pressure Decreased• Right atrial pressure Decreased• Diastolic dysfunction Improved

Renal• Renal blood flow Usually increased Contributes to the

renoprotective effect ofthese agents

• Glomerular filtration rate Variable, usuallyunchanged butmay decrease inrenal failure

• Efferent arteriolar resistance Decreased• Filtration fraction Decreased

Peripheral nervous system• Biosynthesis of noradrenaline Decreased Enhances blood pressure-

lowering effect and resetsbaroreceptor function

• Reuptake of adrenaline Inhibited• Circulating catecholamines Decreased

first-step alternative, particularly in light of the positive outcomes asso-ciated with their use in high-risk elderly patients (52,53). The enthusi-asm for the use of ACE inhibitors is not purely a matter of efficacybecause they have a pattern of efficacy comparable to (and no betterthan) most other drug classes, with response rates from 40 to 70% instage I or II hypertension (54). Physician preference for these drugs inthe elderly also derives from their favorable side-effect profile and theirhighly touted end-organ protection features in at-risk cardiac and renalpatients. The latter is not based on the BP-lowering ability of thesedrugs but rather on proposed tissue-based anti-inflammatory andantiproliferative effects, which are probably class and not agent specific.

There are very few predictors of the BP response to ACE inhibitors,whether it be in the elderly or not. When hypertension is accompanied


by significant activation of the RAA axis, such as in renal artery stenosis,the response to an ACE inhibitor can be immediate and profound (55).In most other instances, there is a limited relationship between the pre-and the posttreatment plasma renin activity value—used as a marker ofRAA axis activity—and the vasodepressor response to an ACE inhibi-tor. Certain patient types are presumed to be less responsive to ACEinhibitor monotherapy, including low-renin, salt-sensitive individualssuch as the diabetic and African-American or elderly hypertensive (56).The low-renin state characteristic of the elderly hypertensive differsfrom other low-renin forms of hypertension in that it develops not as aresponse to volume expansion but rather because of senescence-relatedchanges in the activity of the axis (57). The elderly generally respondwell to ACE inhibitors at conventional doses (58), although senescence-related renal failure that slows the elimination of these drugs compli-cates interpretation of dose-specific treatment successes.

All 10 ACE inhibitors marketed in the United States are currentlyapproved by the Food and Drug Administration for the treatment ofhypertension with several others available on a global basis (Table 3).The Seventh Report of the Joint National Committee on the Detection,Evaluation, and Treatment of High Blood Pressure (JNC 7), the WorldHealth Organization/International Society of Hypertension, and theEuropean Society of Hypertension/European Society of Cardiology nowrecognize ACE inhibitors as an option for first-line therapy in patientswith essential hypertension, especially in those with a high coronarydisease risk profile, diabetes with renal disease/proteinuria, or CHF orwho are postmyocardial infarction (MI) (59,60). Results from a numberof head-to-head trials support the comparable antihypertensive efficacyand tolerability of the various ACE inhibitors if similar doses of theindividual ACE inhibitors are given (Table 1). However, there are dif-ferences among the ACE inhibitors regarding the time to onset of effector the time to maximum BP reduction, which may relate to the absorp-tion characteristics of a compound.

Considerable dosing flexibility exists with the orally available ACEinhibitors, whereas enalaprilat is the lone ACE inhibitor available in anintravenous form (3). ACE inhibitors labeled as “once-daily” vary intheir ability to reduce BP for a full 24 hours, as defined by a trough:peakratio greater than 50% (61). Consequently, the dosing frequency forACE inhibitors is arbitrary and should consider the fact that these drugsoften lose their effect at the end of the dosing interval, thereby requiringa second dose. However, in the elderly, senescence-related changes inrenal function (and reduced ACE inhibitor renal clearance) and/or giv-ing a high dose may obviate a second ACE inhibitor dose during the 24-


Table 3Food and Drug Administration-Approved Indications for Angiotensin-

Converting Enzyme Inhibitors

High-riskpatients without

Diabetic left ventricularDrug HTN CHF nephropathy dysfunction

Captopril • • (post-MI) a •Benazepril •Enalapril • • b

Fosinopril • •Lisinopril • • (post-MI) a

Moexipril •Perindopril •Quinapril • •Ramipril • • (post-MI) •Trandolapril • • (post-MI)

aCaptopril and lisinopril are indicated for CHF treatment both post-MI and asadjunctive therapy in general heart failure therapy.

bEnalapril is indicated for asymptomatic left ventricular dysfunction.CHF, congestive heart failure; HTN, hypertension; MI, myocardial infarction.

hour treatment period (62). Likewise, in the treatment of CHF, ACEinhibitors indicated for once-daily dosing can be split dosed if BP dropsexcessively with a single dose.

An often asked question is what to do if an ACE inhibitor fails tonormalize BP. One approach is simply to raise the dose; however, thedose–response curve for ACE inhibitors, like many antihypertensiveagents, is fairly steep at the beginning doses and thereafter becomesshallow to flat (63,64). Responders to ACE inhibition typically do so atdoses well below those necessary for complete 24-hour suppression ofACE.

If a partial response has occurred with an ACE inhibitor, then therapycan be continued because an additional drop in BP usually follows overthe next several weeks. This late-stage response may involve factors (e.g.,vascular remodeling and improvement in endothelial function) above andbeyond inhibition of ACE (51). Thus, only with complete failure torespond to an ACE inhibitor does an alternative drug class need to beconsidered. Alternatively, an additional compound, such as a diuretic,calcium channel blocker (CCB), or peripheral α-blocker can be combinedwith an ACE inhibitor to effect BP control (see the next section).


ACE INHIBITORS IN COMBINATIONWITH OTHER AGENTS

The BP-lowering effect of an ACE inhibitor is enhanced with theconcurrent administration of a diuretic, particularly in the salt-sensitiveform of hypertension characteristic of the elderly, African-American, ordiabetic hypertensive (65). This pattern of response has encouraged thedevelopment of several fixed-dose combination products comprised ofan ACE inhibitor and varying doses (as low as 12.5 mg) of a thiazide-type diuretic (65). The rationale for combining these two drug classesarises from the observation that diuretic-related sodium depletion acti-vates the RAA axis; therein, BP shifts to an Ang-II-dependent mode,which is the most favorable circumstance for an ACE inhibitor toreduce BP.

β-Blockers have been administered in conjunction with ACE inhibi-tors, an approach that was commonly used per protocol in the Antihy-pertensive and Lipid-Lowering Treatment to Prevent Heart AttackTrial (53). The physiological basis for this combination is that of β-block-ade blunting the rise in plasma renin activity, which is a feature of ACEinhibitor therapy; however, in the elderly the reactive hyperreninemicresponse to ACE inhibitors is nominal (66). Thus, in principle this com-bination (if intended for BP control) would seem to offer little chance ofadditivity in elderly hypertensives.

When a meaningful drop in BP follows from the addition of a β-blocker to an ACE inhibitor, it often occurs in tandem with a reductionin pulse rate. Alternatively, adding a peripheral α-antagonist, such asdoxazosin, to an ACE inhibitor can further reduce BP, albeit without aclear mechanistic basis (67).

Finally, the BP-lowering effect of an ACE inhibitor is reinforced withthe addition of a CCB, whether a dihydropyridine or a nondihydropyridine,and this additivity has been the basis for several products combiningboth drug classes (68–70). Adding an ACE inhibitor to a CCB is alsohelpful in attenuating the peripheral edema commonly seen with CCBtherapy. This is germane to the elderly because CCB-related edema ismore frequent in the elderly (71). In addition, preliminary evidenceexists in support of CCB therapy attenuating the drop in glomerularfiltration rate (GFR) that can accompany ACE inhibitor therapy (72).This is of potential importance to the elderly because one reason forunderuse of ACE inhibitors in older subjects is fear of a further declinein renal function when baseline function is already reduced. This CCBand ACE inhibitor hemodynamic interaction at a renal level may alsooccasionally result in false-positive captopril renography studies (73).


The efficacy of both ACE inhibitors and angiotensin-receptor blockers(ARBs) as antihypertensive agents is well established. This has fueledthe belief that in combination these two drug classes may provide anincremental benefit in both BP reduction and end-organ protection.However, there is insufficient evidence to support a general recommen-dation for the combination of these two drug classes (74,75).

Finally, studies have established the utility of ACE inhibitors in themanagement of hypertensive patients otherwise unresponsive to mul-tiple drug combinations, such as a diuretic together with minoxidil, aCCB and a peripheral α-blocker (76). In addition, if an acute reductionin BP is needed, oral or sublingual captopril—with an onset of action assoon as 15 minutes after administration—can be given. An additionaloption for the management of hypertensive emergencies is that of intra-venous enalaprilat (77). ACE inhibitors should be administered cau-tiously in patients suspected of a marked activation of the RAA axis (e.g.,prior treatment with diuretics). In such subjects, sudden and extreme dropsin BP—so-called first-dose hypotension—have been observed (78).

ACE INHIBITORS IN HYPERTENSION ASSOCIATEDWITH OTHER DISORDERS

ACE inhibitors effectively regress left ventricular hypertrophy (79).This is an important characteristic of ACE inhibitors in that the presenceof left ventricular hypertrophy portends a significant future risk of sud-den death or MI (80). ACE inhibitors can be safely utilized in patientswith coronary artery disease and are indicated for secondary preventionin coronary heart disease after acute MI. Also, the ACE inhibitorperindopril has been shown to reduce cardiovascular risk in a low-riskpopulation with stable coronary artery disease and no apparent heart fail-ure (81). Although they are not coronary vasodilators, they do improvehemodynamic factors that influence myocardial oxygen consumptionand thereby have a favorable impact on ischemia development (Table 2).For example, ACE inhibitors do not reflexly increase myocardial sym-pathetic tone in hypertensive patients with angina, as can take place withother antihypertensives (82). These issues are only as relevant as the useof ACE inhibitors and to that end a prescribing inertia often surroundsthe use of ACE inhibitors after MI, particularly in the elderly (83).

ACE inhibitors are also useful in the treatment of either isolated sys-tolic hypertension or systolic-predominant forms of hypertension, whichpartly relates to their ability to improve artery compliance (51,84). Inaddition, ACE inhibitors are of value in the treatment of patients withcerebrovascular disease because they preserve cerebral autoregulatory


ability despite their reducing BP (85). This is particularly noteworthy inthe treatment of the elderly hypertensive (85). ACE inhibitors dilate bothsmall and large arteries and can be used safely in patients with peripheralarterial disease (PAD) disease and on occasion favorably modify thepattern and/or the course of intermittent claudication (86). For example,4051 of the 9297 patients in the HOPE study had PAD—defined by ahistory of PAD, claudication, or an ankle–brachial index less than 0.90.These patients had a similar reduction in the primary end point whencompared with those without PAD, thus demonstrating that an ACEinhibitor, in this case ramipril, lowered the risk of fatal and nonfatalischemic events in patients with PAD (19).

ACE inhibitors are also viewed as preferred agents—but not exclu-sively so—in the hypertensive diabetic patient (87,88). ACE inhibitorsare used in the hypertensive diabetic patient for two purposes: (a) organprotection, an occurrence presumably independent of BP; and (b) for BPreduction. In the instance of the latter, diuretic coadministration is oftenrequired because the BP-lowering effects of an ACE inhibitor are mod-est in the typically low-renin, volume-expanded hypertensive diabetic.A final consideration with ACE inhibitors in the hypertensive diabeticrelates to their effect on hyperlipidemia and insulin resistance. In thisregard, ACE inhibitors have yet to demonstrate an unambiguous effecton serum lipids or insulin resistance (89). However, in both the CAPtoprilPrevention Project (CAPPP) and the HOPE studies, the ACE inhibitorscaptopril and ramipril, respectively, decreased the incidence of new-onset type 2 diabetes mellitus (90,91).

END-ORGAN EFFECTS

RenalJNC 7 advises the use of ACE inhibitors in patients with hypertension

and chronic renal disease both to control hypertension and to slow therate of progression of CKD (59). Irrespective of the renoprotectiveeffects of ACE inhibitors, the most important element in the manage-ment of the patient with hypertension and CKD remains tight BP control.JNC 7 recommendations advise a goal BP of 130/80 mmHg in albuminu-ric patients (>300 mg/day) with or without CKD (59). In CKD, ACEinhibitor monotherapy is seldom able to achieve goal BP, partly becauseof the volume dependency of this form of hypertension. For example, inthe African-American Study of Kidney Disease, the ACE inhibitorramipril was used, and the average number of medications required toachieve BP control was approximately three (92).


Proteinuria has emerged as a strong marker for the rate of CKD progres-sion as well as an independent risk factor for CVD (93). Microalbuminuriatypically foreshadows the progression of diabetic nephropathy and is nowroutinely measured in all diabetics (94). Screening for microalbuminuriais recommended in diabetes and increasingly in others perceived to beat high risk for renal or CVD (95). Most guidelines now advise effortsbe undertaken to reduce proteinuria in both diabetic and nondiabeticrenal disease (96). In this regard, ACE inhibitors and more recentlyARBs have been shown to reduce protein excretion and are importanttreatment components in the patient (with or without hypertension) withmicro- or macroalbuminuria.

ACE inhibitors have proved useful in the setting of established type 1insulin-dependent diabetic nephropathy (24), type 2 non-insulin-depen-dent diabetic nephropathy (97), normotensive type 1 patients withmicroalbuminuria (98), and a variety of nondiabetic renal diseases (99–101). However, renal outcomes with ACE inhibitors have occasionallybeen negative. The Ramipril Efficacy in Nephropathy study did notidentify a renoprotective effect with ramipril in type 2 diabetic nephr-opathy patients. Of note, in the Ramipril Efficacy in Nephropathy studyramipril-treated patients lost renal function at a significantly faster ratethan did patients treated with a conventional non-ACE inhibitor antihy-pertensive regimen (102). Conversely, ramipril prevented or delayed theprogression of albuminuria in the HOPE trial (103). ACE inhibitor regi-mens shown to slow the rate of CKD progression include 25 mg ofcaptopril three times a day, 5 to10 mg per day of enalapril, 10 mg per dayof benazepril, and 2.5 to 5 mg of ramipril per day (3). These compoundsare all renally cleared; thus, it can be presumed that reduced renal clear-ance under these circumstances enhances the pharmacological effect ofeach of these compounds (104). The beneficial effect of ACE inhibitorsis typically greatest when preexisting high rates of urinary protein excre-tion (>3 g/24 hours) can be substantially reduced because, if left untreated,these patients generally progress quite rapidly (105).

Therapies directed at reducing the production or effects of Ang IIprovide a mixture of potentially beneficial renal, hemodynamic, cellu-lar, and possibly lipid-related effects. For example, in chronic nephro-pathies, ACE inhibitor uptitration to maximum tolerated doses improveshypertriglyceridemia by a direct, dose-dependent effect and hypercho-lesterolemia through amelioration of the nephrotic syndrome (106). ACEinhibitors also transiently reduce GFR in parallel with reduction of glom-erular capillary pressures (107). Such decrements are typically modestand on the order of a 10 to 15% drop in GFR; moreover, these changesare reversible and actually predictive of long-term renal protection (108).


The elderly are prone to greater reductions in GFR with ACE inhibitorsat least partly because of their frequent micro- and macrovascular renaldisease (see Side Effects of Angiotensin-Converting Enzyme Inhibi-tors). A question commonly posed with ACE inhibitors, particularly inthe elderly, is whether there is a specific level of renal function at whichan ACE inhibitor cannot be started. Current practice considerationssuggest that there is not a specific level of renal function that precludesstarting an ACE inhibitor unless significant hyperkalemia is expected todevelop.

Three factors can be considered as potential modifiers of the renalresponse to ACE inhibition. First, a low sodium intake enhances theantiproteinuric and antihypertensive effects of ACE inhibition (109).Second, short-term studies suggested that dietary protein restrictioncomplements the ACE inhibitor effect on protein excretion in nephroticpatients. This would seem to imply that the combination of ACE inhibi-tion and protein restriction could prove more effective than an ACEinhibition alone in slowing the progression of renal failure (110). How-ever, this approach may be ill advised in the elderly, for whom nutritionalintake may already be suboptimal.

A third factor is that of inherited variation in the activity of ACE. Twocommon forms of the ACE gene I (insertion) and D (deletion) give riseto three potential genotypes: II, ID, and DD. The DD phenotype is asso-ciated with higher levels of circulating ACE and a heightened pressorresponse to infused Ang-I as compared to the Ang-II phenotype, with theID phenotype exhibiting intermediate characteristics (111). The findingthat DD patients are at increased risk for MI and ischemic cardiomyopa-thy first established the clinical significance of inherited variation inACE activity (112). Studies suggested that the GFR declines more rap-idly in DD than II nephropathic patients, and that such patients do notshow significant reductions in proteinuria or slowing in the rate of CKDprogression when given ACE inhibitors (113). Although a promisingconcept, pharmacogenetic studies performed to date have not provideda definitive answer regarding whether the antiproteinuric effect of ACEinhibition is influenced by the ACE genotype (114).

CardiacData from both placebo-controlled and open-label trials suggested

that ACE inhibitors substantially reduce the risk of death and hospital-ization for CHF while improving its symptomatology, making ACEinhibitors first-line therapy for the treatment of CHF (115). ACE inhibi-tors reduce Ang-II generation (at least in the short term) and thereby alterthe pathophysiological consequences of neurohumoral change in CHF


(116,117). Even at low doses, ACE inhibitors improve exercise toler-ance and symptomatology in CHF; however, successfully altering thestatus of these surrogates does not imply that similar success will beobtained relating to the mortality of CHF. Improvement in CHF mortal-ity at least partly requires high-dose ACE inhibitor therapy. One aspectof ACE inhibitor dosing relative to the elderly relates to CHF-relatedweight loss or the cachexia of CHF. Weight loss is a common finding inthe elderly CHF patient, and its presence often prompts a diagnosticworkup to seek other causes of weight loss. In this regard, effective ACEinhibitor therapy will arrest the weight loss otherwise seen with progres-sive CHF (118).

Several ACE inhibitors—including captopril, fosinopril, lisinopril,quinapril, ramipril, and trandolapril—now have favorable outcome datain various forms of CHF (115,119). Although ACE inhibitors are almostuniversally recommended as a cost-effective strategy for the treatment ofCHF, physician prescribing practice is such that only a modest number(50–70%) of those patients eligible for treatment with ACE inhibitorsactually receive them (120). Moreover, the dosages used in “real-worldpractice” are substantially lower than those proven effective in RCTs. Forexample, in a retrospective review of 554 elderly hospital-dischargedCHF patients older than 65 years, target (dosage recommended in prac-tice guidelines), subtarget (dosages used in clinical trials but lower thanguideline recommendations), and low-dose ACE inhibitor doses weregiven in 19, 63, and 18% of the patients, respectively. Few demographicor clinical criteria were related to the use of lower dosages (121).

On average, overall mean doses of ACE inhibitors are less than one-half the targeted dose. Factors forecasting either the use or optimal doseadministration of ACE inhibitors include variables relating to the treat-ment setting (prior hospitalization and/or specialty clinic follow-up), theprescribing physician (cardiology specialty vs family practitioner/gen-eral internist), the patient status (increased severity of symptoms, male,younger), and the drug (lower frequency of administration) (120).

Enalapril, captopril, lisinopril, and trandolapril have also been shownto significantly reduce morbidity and mortality rates in the post-MIpatient with a wide range of ventricular function. In a hemodynamicallystable patient after an MI, an oral ACE inhibitor should be initiated,generally within 24-hours of the event, particularly if the MI is anteriorand accompanied by depressed left ventricular function. The hemody-namic effects and overall benefit of ACE inhibition are seen early with40% of the increase in 30-day survival seen in the first day, 45% in days2 through 7, and approximately 15% after day 7 (122). Currently, onlycaptopril, lisinopril, ramipril, and trandolapril are specifically approved


in post-MI left ventricular dysfunction, although enalapril is approvedin asymptomatic left ventricular dysfunction. Trends show an increasein ACE inhibitor prescriptions in patients discharged followed an acuteMI (123).

There are presently insufficient data to determine if clinically signifi-cant differences exist among the ACE inhibitors in the post-MI settinggiven the paucity of head-to-head trials among these agents and the factthat study-specific conditions for particular ACE inhibitors have beenquite variable (124,125). However, as in patients with CHF, numerousACE inhibitors have established benefits in the post-MI patient, suggest-ing a class effect for this phenomenon (125).

Several dosing strategies have been demonstrated as effective in reduc-ing morbidity and mortality in patients with left ventricular systolic dys-function. In this regard, a systematic effort must be made to reach targetACE inhibitor doses shown effective in the randomized therapeutic CHFtrials. Emerging data would seem to suggest that the doses of ACEinhibitors used in clinical practice (range of 50 and 10 mg/day forcaptopril and enalapril, respectively) are less effective than the relativelyhigh doses (captopril and enalapril doses approaching 150 and 40 mg,respectively) used in the RCTs (28,31).

Until incontrovertible evidence otherwise becomes available, thetreatment of CHF should include sequential dose titration to those ACEinhibitor doses shown successful in RCTs. The ability to reach thesedoses in the CHF patient can sometimes prove challenging because amajor deterrent is the development of systemic hypotension and/or adecline in GFR (126,127). Thus, reaching goal ACE inhibitor dosesnecessitates a keen understanding of the critical relationship amongvolume status, BP, and the final desired ACE inhibitor dose. Probablythe single most important variable that allows effective dose titration isthe understanding of the relationship between volume status and BP(126–128).

StrokeGiven the significant public health impact of stroke and the identifi-

cation of both nonmodifiable (age, gender, race/ethnicity) and modifi-able (BP, diabetes, lipid profile, and lifestyle) risk factors, earlyprevention strategies are increasingly implemented. When an elderly ordiabetic patient suffers a stroke, the focus of care becomes the preven-tion of secondary events. This can be accomplished with antiplatelet andlipid-lowering as well as BP reduction strategies.

Despite the clear risk reduction with effective implementation of thesepreventative strategies, new approaches are needed. In particular, it is


unclear whether the stroke benefit gained from BP reduction is uniqueto the agent employed (e.g., an ACE inhibitor or an ARB) or a simpleconsequence of upgrading the hemodynamic profile (129–131).

The Perindopril Protection Against Recurrent Stroke Study (PROG-RESS) reported for the first time that antihypertensive therapy with acombination of the ACE inhibitor perindopril and the thiazide diureticindapamide reduced the stroke recurrence rate even in patients withnormal BP (129). In this study, 6105 hypertensive and nonhypertensivepatients who had sustained a stroke without a major disability within thepast 5 years were randomly assigned to a 4-mg dose of perindopril withor without a 2.5-mg dose of indapamide (diuretic therapy was at thediscretion of the treating physician). After 4 years of follow-up (40%received perindopril alone and 60% combination therapy) in the sub-group of patients receiving perindopril and indapamide, BP was reducedby 12/5 mmHg, and the risk of stroke fell by 43%, and those receivingperindopril monotherapy (BP reduced by 5/3 mmHg) had no significantreduction in the risk of stroke (129). Based on the degree of BP reductionin the perindopril-only group, a 20% reduction in stroke risk would havebeen anticipated; thus, the absence of a positive stroke effect is puzzling.Of note, in the PROGRESS trial, treatment with perindopril andindapamide was associated with reduced risks of dementia and cognitivedecline associated with recurrent stroke (132).

A similar observation to that of the PROGRESS study was made inthe CAPPP trial, for which—despite its design problems—fatal or non-fatal stroke was 1.25 times more common in patients randomly assignedto captopril than in those assigned to conventional therapy with diureticsand/or β-blockers (133). Nevertheless, the beneficial effect of combina-tion therapy with perindopril and indapamide is consistent with priorstudies showing a positive effect of diuretics on recurrent stroke rate.

In contradistinction to the PROGRESS and CAPPP studies, the HOPEstudy provided compelling evidence that treatment with the ACE inhibi-tor ramipril can further reduce the risk of stroke in high-risk patientswithout left ventricular dysfunction by mechanisms presumably aboveand beyond simple BP reduction (19). Ramipril at a dose of 10 mg/dayachieved a highly significant 32% reduction in total stroke rate, andrecurrent strokes were reduced by 33%. In a subanalysis of this trial,nonfatal stroke was reduced by 24% and fatal stroke by 61%. Interest-ingly, in the HOPE study ramipril was given at night, and therefore itspeak effect, whether hemodynamic or otherwise, occurred in the morn-ing hours, a time when strokes occur more frequently (134).

Based on the HOPE study, the American Heart Association guide-lines for the primary prevention of stroke recommend ramipril to prevent


stroke in high-risk patients and in patients with diabetes and hyperten-sion (135). Thus, it would appear that ACE inhibitor therapy is war-ranted if primary prevention is contemplated in a high-risk patient orsecondary prevention is under consideration in a patient already havingsustained a cerebrovascular event.

SIDE EFFECTS OF ACE INHIBITORS

Soon after their release, a syndrome of functional renal insufficiencywas observed as a class effect with ACE inhibitors (136). This phenom-enon was initially reported in patients with renal artery stenosis and asolitary kidney or in the presence of bilateral renal artery stenosis. Pre-disposing conditions to this process include dehydration, CHF, and ei-ther macro- or microvascular renal disease. All of these conditions arecommon occurrences in the elderly.

The mechanistic prompt in these conditions is a fall in afferent arte-riolar flow. When this occurs, glomerular filtration temporarily declines.In response to this reduction in glomerular filtration, local production ofAng-II rises. In concert with this increase in Ang-II, the efferent orpostglomerular arteriole constricts, restoring upstream hydrostatic pres-sures within the glomerular capillary bed.

The abrupt removal of Ang-II, as occurs with an ACE inhibitor (or anARB), will suddenly dilate the efferent arteriole in tandem with a reduc-tion in systemic BP. In combination, these hemodynamic changes dropglomerular hydrostatic pressure to do away with glomerular filtration.This type of functional renal insufficiency is best treated by discontinu-ation of the offending agent, careful volume expansion if intravascularvolume contraction exists, and if suspected on clinical grounds, evalu-ation for the presence of renal artery stenosis (126).

An additional ACE inhibitor-associated side effect relevant to theelderly is hyperkalemia (137). ACE inhibitor-related hyperkalemia isuncommon unless a specific predisposition to hyperkalemia is present,such as in a diabetic or CHF patient with renal failure receiving potas-sium-sparing diuretics or potassium supplements (138). Alternatively,ACE inhibitors will minimize the potassium loss accompanying diuretictherapy.

A dry, irritating, nonproductive cough is a common complicationwith ACE inhibitors, with its incidence estimated at between 0% and44% (139). Cough is a class phenomenon with ACE inhibitors and hasostensibly been attributed to an increase in bradykinin or other vasoac-tive peptides, such as substance P, which may play a second messengerrole in triggering the cough reflex (343). Although numerous therapies


have been tried, few have had any lasting success in eliminating ACEinhibitor-induced cough. The onset of cough with an ACE inhibitor isproblematic in an elderly patient, particularly one with a past history ofsmoking, because it may instigate an unnecessary search for malig-nancy. The more prudent maneuver in such a case is to reassess the coughseveral weeks after discontinuing ACE inhibitor therapy.

ACE inhibitor-related nonspecific side effects are generally uncom-mon, with the exception of taste disturbances, leucopenia, skin rash, anddysgeusia, which are almost exclusively seen in captopril-treated patients(140). The taste disturbance observed with captopril can be particularlytroubling in the elderly, for whom taste abnormalities are already quitecommon (141). Angioneurotic edema is a potentially life-threateningcomplication of ACE inhibitors that is more common in blacks (142).ACE inhibitor-related angioedema is not more common in the elderly(defined as �65 years of age) (143). ACE inhibitor-induced angioedemaof the intestine can also occur. This typically presents with acute ab-dominal symptoms with or without facial or oropharyngeal swelling.Angioedema of the intestine is more common in females, and its occur-rence is independent of age.

A final consideration with ACE inhibitors is that of anemia. ACEinhibitors suppress the production of erythropoietin in a dose-dependentmanner, which is a particular problem when ACE inhibitors are admin-istered in the presence of renal failure (144).

CONCLUSIONS

ACE inhibitors are commonly used drugs in the elderly patient. Thesecompounds are employed in their capacity either to reduce BP or to takeadvantage of their cardio- and/or renoprotective effects. ACE inhibitorscan be expected to provide the greatest end-organ protection in the eld-erly with CHF or proteinuric renal disease or in the post-MI setting.Dosing guidelines exist for each of these scenarios, although such guide-lines may not be followed as closely in clinical practice as is advised.ACE inhibitor-related side effects are for the most part easily recognizedand, other than functional renal insufficiency, which is occasionallyseen with their use, do not occur more commonly in the elderly.

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