Drugs 49 (4): 5 16-535, 1995 00 12-6067 / 95/0004-0516/$20,00/0

REVIEW ARTICLE

© Adis International Umited. All rights reserved.

Choosing the Right ACE Inhibitor A Guide to Selection Gastone Leonettil and Cesare Cuspidi2 1 Istituto Scientifico Ospedale S. Luca, Centro Auxologico Italiano, and Cattedra Terapia Medica Sistematica, Universita degli Studi, Milan, Italy 2 Istituto Clinica Medica Generale e Terapia Medica, Universita di Milano, Milan, Italy

Contents Summary , , , , , , , , , , , . . . , 1, Pharmacokinetics of ACE Inhibitors 1.1 Ligand of the Zinc Ion , 1.2 Prodrug or Active Drug 1,3 Elimination Half-Life , 1,4 Potency , , , , , , , 1 ,5 Lipophilicity , , . . . 1 ,6 Route of Elimination 2, Pharmacodynamics of ACE Inhibitors , 2,1 Antihypertensive Efficacy 2.2 Treatment Schedule , . .. , 2,3 Combination Therapy , , .. 2.4 Left Ventricular Hypertrophy. 2,5 Insulin Sensitivity , , ,... , . 2,6 Renal Protection (Proteinuria) , 3, ACE Inhibitors and the Elderly Hypertensive Patient , 4. ACE Inhibitors and Quality of Life . 5. ACE Inhibitors and Atherosclerosis , 6, Conclusions . , , . , , , , , , , , , ,

Summary

516 518 518 519 519 520 520 520 521 521 521 523 524 525 526 527 528 529 529

To find out if there are one or more criteria to guide selection among the ACE inhibitors for the treatment of arterial hypertension, we have reviewed the principal pharmacokinetic and pharmacodynamic aspects of the more frequently used agents of this class of antihypertensive drugs. Among the pharmacokinetic aspects that we have considered, terminal halflife, as related to the duration of the antihypertensive effect, and the route of elimination may have an impact in the clinical selection among the various ACE inhibitors. On the other hand, all the other characteristics have no pragmatic clinical relevance or may be corrected by dosage adjustment. Among the pharmacodynamic aspects, the antihypertensive efficacy of the different ACE inhibitors seems to be very similar, and some of the differences found in different studi~s are probably due to the population investigated and to the protocol of the study (time of blood pressure measurements, diet, drug dosage etc.). However, some differences can be found among the various ACE inhibitors

Choosing the Right ACE Inhibitor

517

when the antihypertensive efficacy is evaluated also as trough to peak ratio of blood pressure reduction. Indeed, in respect of the administration schedule of each ACE inhibitor not all the agents of this class have a trough to peak ratio above 50 to 60%, as suggested by the Food and Drug Administration of the US. According to this criterion, especially when blood pressure is measured with 24-hour noninvasive ambulatory blood pressure monitoring, some drugs such as lisinopril, enalapril and trandolapril should be preferred for their higher trough to peak ratios. Left ventricular hypertrophy is significantly reduced by antihypertensive agents, the ACE inhibitors being the most effective. Indeed, the reduction of left ventricle mass for each 1mm Hg reduction in mean blood pressure is greater for ACE inhibitors than for other classes of antihypertensive agents. However, this effect seems more class related than characteristic of one or more among the various ACE inhibitors. Insulin resistance is elevated in hypertensive patients and it has been thought responsible for or associated with other metabolic abnormalities. ACE inhibitors seem to correct the insulin resistance of hypertensive patients, but this effect also appears to be class related more than limited to one ACE inhibitor or another. Our knowledge of this field is still limited and more studies are necessary, especially to understand the prognostic impact of insulin resistance and/or insulin resistance improvement. Renal protection of ACE inhibitors was first evaluated in patients with scleroderma crises, and thereafter has been extensively investigated in patients with renal insufficiency, due to diabetic nephropathy, with or without arterial hypertension. In both clinical diseases ACE inhibitors caused a significant improvement in prognosis. More doubtful are the long term effects of ACE inhibitors in patients with renal insufficiency due to nondiabetic nephropathy. In hypertensive patients with normal renal function and microproteinuria the ACE inhibitors reduce blood pressure and microalbuminuria in short and long term studies, without lowering glomerular filtration rate and renal blood flow. Renoprotection has been investigated predominantly with captopril and enalapril and they seem equipotent. No clinically relevant significant differences have been found among the ACE inhibitors in their use in elderly hypertensive patients and in their impact on quality of life. Finally, the effect of ACE inhibitors on atherosclerotic disease of carotid arteries is the subject of ongoing studies. In conclusion, there is no clinically relevant difference among the various ACE inhibitors for the treatment of patients with uncomplicated essential hypertension, when the agents are administered in the correct dosage regimen. However, if we consider the trough to peak ratio of blood pressure reduction, some of them seem to have a more favourable profile, although the long term impact is still unknown. Hypertensive patients with renal insufficiency, secondary either to hypertension or to other disease, seem to benefit from all ACE inhibitors, but some of them with a double route of excretion could be selected in comparison with those eliminated renally only because they do not need dosage adjustment. The family of ACE inhibitors is already very numerous, but in spite of that many others are under investigation. There is no doubt that many reasons are advocated to justify the development of new ACE inhibitors and among them there is the premise of improving efficacy and tolerability, to © Adis International limited. All rights reserved.

achieve a better control of blood pressure and a higher reduction in cardiovascular complications. However, this abundance of agents belonging to the same family raises a question: how to choose one or another ACE inhibitor for the treatment of arterial hypertension, cardiac failure or patients Drugs 49 (4) 1995

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with myocardial infarction, the present clinical indications for the ACE inhibitors? Many reviews have been published on captopril, enalapril and lisinopril,P-9] the first available ACE inhibitors on the market, and recently Salvetti llO ] has published a review on the pharmacokinetics of the newer ACE inhibitors. In spite of all these reviews, no one of them has focused on the problem of if there is one or more criteria to follow for the selection of one or another ACE inhibitor for a patient with arterial hypertension, cardiac failure or acute myocardial infarction. Arterial hypertension was the first clinical indication for the use of ACE inhibitors, and therefore there is a greater experience with these agents in this clinical condition than for the cardiac failure or acute myocardial infarction and therefore we limit our review to find out whether there is a guide to selection among ACE inhibitors for the treat. ment of hypertension only. The aim of antihypertensive treatment is to lower elevated blood pressure as a means to reduce or prevent the cardiovascular complications of hypertensive patients. However, hypertensive patients do differ among themselves for many characteristics, such as age, sex, organ damage, metabolic pattern, concomitant disease, etc. Furthermore, antihypertensive treatment is symptomatic, that is it does not remove the cause or causes of

blood pressure elevation, but it produces haemodynamic changes, such as decrease in peripheral resistances or in cardiac output, in order to lower blood pressure. However, all these effects vanish when the pharmacological treatment is withdrawn. Therefore, antihypertensive treatment is lifelong and must be well tolerated if we want to obtain a good compliance of the patients to the pharmacological treatment. In this review we try to find out if there are pharmacokinetic or pharmacodynamic differences among the ACE inhibitors, more frequently employed in the field of hypertension that are indicative of a greater or more appropriate antihypertensive efficacy or more suitable for patients as function of age, organ damage, metabolic alteration or concomitant disease. Finally, the problem of the incidence and severity of adverse effects and the impact on quality of life is considered.

1. Pharmacokinetics of ACE Inhibitors 1,1 Ligand of the Zinc Ion

The large family of ACE inhibitors can be subdivided into 3 groups according to the functional group that binds to the ACE-zinc ligand. The most numerous group of ACE inhibitors is the carboxylcontaining,lIl-26] followed by the sulphydrylcontaining[27-31] and finally by the phosphoryl-

Table I. Clinical structure, molecular weight (MW), active state (prod rug/active drug), and lipophilicity of different ACE inhibitors Drug

Chemical group

MW

Prodrug

Lipid solubility

Benazepril

COOH

424 217 389 424 348 453 405 340 396 388 521 430 325

Yes

+ + + ++ ++ +++ 0 + ++ + + ++ +++

Captopril

SH

Cilazapril

COOH

Delapril

COOH COOH Phosphoril

Enalapril Fosinopril Lisinopril Perindopril Quinapril Ramipril Spirapril

COOH COOH COOH COOH COOH

Trandolapril

COOH

Zofenopril

SH

No Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes

Abbreviations: + = slight; ++ = moderate; +++ = high.

©

Adis International Limited. All rights reseNed.

Drugs 49 (4) 1995

Choosing the Right ACE Inhibitor

contammg ACE inhibitors (table 1))32-34] The strength of binding to the zinc ligand and the number of additional binding sites determine the level of inhibition of enzyme activity and therefore the potency of the inhibitor. The different ligands per se do not appear to be associated with different pharmacokinetic characteristics in such a way as to influence their effects on the circulation renin-angiotensin system (RAS), while it has been suggested that these chemical structure differences might be relevant for their effects on the tissue RAS_ 1.2 Prod rug or Active Drug

Whether the ACE inhibitor administered is the active moiety or a prodrug may be relevant either for the time to peak concentration (tmaJ of the active form of the agent or for a lower peak plasma concentration in patients with concomitant liver disease (table I). Indeed, it is known that the liver plays a relevant role in the transformation of the prodrug to the active form and for the metabolism of the active drug to inactive compounds)35-38] Therefore, in patients with liver dysfunction, a minor proportion of the prodrug could be transformed to the active metabolite and a lower degree of inactivation of active drug should be expected. ACE inhibitors can be subdivided into 3 subgroups according to activation or metabolism by the liver as follows: (i) no activation or metabolism (lisinopril alone); (ii) activation of prodrug to active drug and hepatic metabolism (e.g. enalapril); and (iii) active drug with hepatic metabolism (e.g. captopril).[39-41] However, the prevalence of the hypertensionliver disease association is relatively low, and only when liver damage is major are the transformation of the prodrug to the active metabolite and the inactivation of active drugs significantly impaired. Therefore, the selection of one drug instead of another due to the presence of concomitant liver damage is relatively rare. Lisinopril could be selected in patients with hepatic insufficiency. On the other hand it could be more relevant from the clinical point of view to consider the tmax © Adis International Limited. All rights reserved.

519

Table II. Time to peak plasma concentration (Imax) and terminal elimination half-life (l1,1!~) of different ACE inhibitors Drug Benazepril Caplopril Cilazapril Delapril Enalapril Fosinopril Lisinopril Perindopril Quinapril Ramipril Spirapril Trandolapril Zofenopril

tmax (h) 1.5 1.0

4.0 1.3 4.0 3.0 7.0 4.0 2.0 3.0 2.5 4.0 1.0

t\.2~

(h) 21 .0 2.0 4.0 1.5 11.0 12.0 13.0 9.0 3.0

12.0 30.0 16-24 5.5

of the drug (table II), because this could be correlated with the time-course of the antihypertensive effect of the drug. Indeed, in the early phase of treatment, when the antihypertensive action is related to the blockade of the circulation RAS more than to the blockade of the tissue RAS, the earlier appearance of effective plasma concentrations of the drug may cause an earlier antihypertensive action. 1.3 Elimination Half-life

Many ACE inhibitors show a polyphasic elimination kinetics, but what is clinically relevant is the elimination half-life (tl;2~)' which is frequently an index of the duration of the antihypertensive effect. Indeed, the earlier phase, with a short half-life, corresponds to the free or excess drug clearance and reflects a prompt elimination process, which explains the absence of drug accumulation during repeated administration. The tl/2~ (table II) corresponds to the clearance of ACE-bound drug and reflects the affinity and strength of binding of ACE inhibitor to ACE, a phenomenon that explains the duration of action.l42-44 ] The t1;2~ may differ very much from one ACE inhibitor to another (table II), but is not always paralleled by the duration of the antihypertensive effect. However, as is shown in section 2, ACE Drugs 49 (4) 1995

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inhibitors can be subdivided into those which can be administered once a day (because the antihypertensive effect persists up to 24 hours) and those which need twice-daily administration to offer 24hour blood pressure control. This may be a guide to selection among the ACE inhibitors. In the evaluation of plasma concentration of the drugs, it is relevant to offer a reminder that methodological problems (sensitivity, specificity, etc.) may significantly interfere in the detection of plasma concentrations, which can sometimes give rise to wrong conclusions. 1.4 Potency

The pharmacokinetic potency of an ACE inhibitor is measured as the amount of the ACE inhibitor necessary to block 50% of the plasma activity of ACE, and for this pharmacokinetic effect there are large differences among the ACE inhibitors. However, the clinical relevance is limited because a similar degree of inhibition of the activity of ACE can be reached by adjusting the dosage of the drugs. There are also great differences among the ACE inhibitors in the duration of inhibition of the activity of ACE. Indeed, while all ACE inhibitors can block up to 100% of ACE activity at peak concentration, the blockade may disappear at varying rates: some ACE inhibitors block ACE activity for up to 72 hours or longer.l45 ,46] Although this can be a guide for the selection among the different ACE inhibitors in pharmacological studies, the discrepancy with the duration of the antihypertensive effect diminishes its clinical relevance. Furthermore, by administering higher doses it is possible to achieve the same degree of inhibition of ACE activity for all ACE inhibitors. 1.5 Lipophilicity

The degree of lipophilicity of the ACE inhibitors together with the molecular size (table I) can influence the rate of crossing the cellular membrane or the blood-brain barrier. As a consequence of penetration through the cellular membrane, an ACE inhibitor can block the tissue RAS and all © Adls International limited. All rights reserved.

the paracrine and autocrine functions of tissuegenerated angiotensin II. Although data in humans are lacking, experimental data in animals suggest that ACE inhibitors might exert inhibitory effects of different degrees and specificity on the tissue RAS of various organs because of different abilities to cross the cellular membrane. However, the potential clinical relevance seems very important and these differences could help in the future selection of a particular ACE inhibitor. The degree of lipophilicity decreases among the available ACE inhibitors from fosinopril to lisinopril (table I). 1 .6Route of Elimination

The ACE inhibitors, either as parent drug or after transformation of the prodrug, are eliminated predominantly as active compound. This means that when the route of elimination is altered, there is an accumulation of active compound that is equivalent to the effects of an overdose of the ACE inhibitor. The great majority of ACE inhibitors are eliminated predominantly through the kidneys and to a minor extent through the liver (table III). This means that the doses of ACE inhibitors must be reduced in hypertensive patients with renal failure proportionally to the reduction in creatinine clearance. However, fosinopril, ramipril, spirapril and trandolapril have a double route of elimination, and Table III. Route of elimination of ACE inhibitors Drug Benazepril Captopril Cilazapril Delapril Enalapril

Route

Ratio(%)

Renal + hepatic Renal (GF + TS) Renal (GF + TS) Renal + hepatic

Fosinopril Lisinopril

Renal (GF + TS) Renal + hepatic Renal (GF)

Perindopril

Renal (GF + TS)

Quinapril Ramipril

Renal (GF + TS) Renal + hepatic

Spirapril Trandolapril Zofenopril

Renal + hepatic

50/50

70/30

50/50 Renal + hepatic 30/70 Renal + hepatic 65/35 Abbreviations: GF = glomerular filtration; TS = tubular secretion.

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521

Table IV. Some examples of the antihypertensive efficacy of ACE inhibitors Reference

Weinberger[65) Muiesan et al. l66) Andren et al.[67)

Drug dosage regimen (mg)

Change in SBP (mmHg)

Change in DBP (mmHg)

Captopril 25 tid

-21 -22

-16

-13 -23 -18 -15 -16 -20

-10 -11 -10 -9 -12 -11

-20 -17

-13 -11 -14

Captopril 25 tid

-9

Goldstein[75)

Captopril 25-50 tid Enalapril 10-20 od Enalapril10-20 od Enalapril 10-40 od Lisinopril 10-80 od Lisinopril 20-80 od Lisinopril 20-80 od Quinapril 20-80 od Quinapril 20-80 od

Stumpe et al.[76)

Ramipril 5 od

-16

-12

Villamil et al.[77)

Ramipril 2.5-5 od

-9/-13

-7/-9

Anderson et al. [78) POOI[79)

Fosinopril10-80 od Fosinopril 5-80 od Perindopril 4-8 od Cilazapril 5 od Perindopril 4-8 od

-10/-18

-13/-18 -14/-17

-25 -15 -18

-17

Shapiro et al.[68) Frishman et al.[69) Edmonds et alJ70) Pool et al.[71) Kochar et alJ72) Bolzano et al.[73) MacLean[74)

Lees et al. [80) Kogle~81)

Morgan & Anderson[91)

-22

-11 -15

Abbreviations: DBP = diastolic blood pressure; od = once daily; SBP = systolic blood pressure; tid = 3 times daily.

when one route of elimination is reduced there is a compensatory rise in the fractional excretion through the alternative one. Because of this mechanism of elimination these drugs can be administered to patients with renal failure without changing the dose, or only when the renal function is markedly reduced.[45-53]

2. Pharmacodynamics of ACE Inhibitors Many systems play an important role in the regulation of blood pressure homeostasis in normal and hypertensive individuals, and each has been the target of pharmacological intervention. The RAS is one such homeostatic mechanism,[54-56] and has been the target of ~-blockers, which interfere with renin secretion,[57,58] of ACE inhibitors, which block angiotensin II formation,[59-61] and more recently of angiotensin II receptor antagonists, which compete for the same receptor of angiotensin II (AT 1).[62-64] © Adls International Limited. All rights reserved.

2.1 Antihypertensive Efficacy

The short term administration of ACE inhibitors causes inhibition of ACE activity, reduction of angiotensin II and plasma aldosterone levels and a rise in plasma levels of renin and angiotensin I. As consequence of these changes there is a significant reduction in vascular resistance without changes in cardiac output. This causes a lowering of blood pressure in hypertensive patients.[65,66] When administered at effective doses, all ACE inhibitors[67-90] cause a clinically relevant blood pressure reduction in hypertensive patients that is significantly greater than placebo (table IV). The few available studies comparing antihypertensive efficacy among the different ACE inhibitors do not show consistent results for a greater efficacy of one ACE inhibitor versus another of the same or of a different group, provided that all ACE inhibitors are administered at effective doses, which can be different from one ACE inhibitor to another (table V)J92-97] On the other hand, some differences can be observed for the time of appearance (from 0.30 to 2 hours) and of maximum blood pressure reduction (from 1 to 8 hours). As a general rule, the antihypertensive effect is more prompt for the active drugs than for the prodrugs, due to the time necessary to metabolise the prodrug to its active derivative (table VI). Although these differences might be relevant in the emergency situation (where the sublingual route of administration has been suggested to speed up the onset of the antihypertensi ve effect), the earlier or later appearance of the antihypertensive effect (differences in the range of hours) in the long term treatment of arterial hypertension does not make any clinically significant difference. 2.2 Treatment Schedule

More relevant is the duration of a clinically significant antihypertensive effect, because it determines the number of daily doses of the drug. From this point of view, there is an important difference among the ACE inhibitors because some of them Drugs 49 (4) 1995

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Table V. Comparison of antihypertensive efficacy among ACE inhibitors Reference

Drug

Change in systolic/diastolic blood pressure (mmHg)

Lees et al. 1801

Captopril Perindopril

Garanin[821

Captopril Enalapril

De Cesaris et al.[831

Captopril Enalapril

Lai et al.[841

Captopril Enalapril Captopril Enalapril

-21/-14 -25/-17 -14/-13 -14/-13 -12/- 10 -15/-10 -19/-13 -17/-12 0/-26 0/-25 -15/-12 -18/-14" -16/-13 -20/-14 -16/-10 -15/-9 -12/-11 -11/-11 -9/-10 -9/-10 -17/-19 -15/-17 -21/-19 -19/-15 -8/-8 -10/-9

Lewis et al.[851 Gosse et al. [861

Captopril Lisinopril

Witte & Walter871

Captopril Ramipril

Goldstein[891

Enalapril Fosinopril Enalapri[ Ramipril

Zabludowski et al.[901 Frishman[921 Goldstein[931 Schnaper941 Taylor951 a

Quinapril Captopril Quinapril Captopril Quinapril Captopril Quinapril Captopril

p
can be administered once a day to guarantee a 24hour blood pressure reduction, while for others it is necessary to administer the drug at least twice a day. The once-daily administration of a drug does increase patient compliance (although not all authors agree with this conclusion)[98] and can minimise the incidence and severity of adverse effects, frequently correlated with the peak plasma concentration of the drug. Indeed, many drugs administered once daily have a lower peak and a more stable plasma concentration in the therapeutic range. Until recently, the clinical development of an antihypertensive drug was a relatively simple and straightforward procedure in which a drug was deemed suitable for once-daily administration if it © Adis Intemotionol Umited. All rights reserved.

could be shown to cause a statistically significant and clinically relevant fall in blood pressure 24 hours after the previous dose (trough) during steady-state therapy. To improve the profile of blood pressure reduction, which may have an impact on target organ damage, the incidence and severity of adverse effects and the patient's prognosis, the Food and Drug Administration (FDA) of the US[99] has suggested a more definite and comprehensive index of the antihypertensive effect. The guidelines indicate that in addition to maintaining a 'useful' antihypertensive effect at the end of dosage interval, this trough effect should be at least half of the peak effect, once appropriate adjustment has been made for placebo/circadian effects. Furthermore, if the net peak effect of the drug appears relatively modest, for instance a reduction of 5mm Hg at peak, a relatively larger trough/peak ratio of 66% would be required. From a practical point of view, when the trough/ peak ratio is over 50% blood pressure is reduced in a smooth, constant manner, while for a trough/peak ratio below 50% there is a more relatively profound response at the peak time and a higher blood pressure variability. A few studies[91 ,100-105] which have employed the mercury sphygmomanometer for the measureTable VI. Time of onset and of maximum antihypertensive effect of ACE inhibitors Drug

Onset of effect (h)

Time to maximum effect (h)

2-4

Benazepril Captopril

0.2-0.3

1

Cilazapril

1

Delapril

1-2

3-7 4-6 4-6 3-6 4-6 3-4 4 3-6 4-8 6-8 2

Enalapril Fosinopril Lisinopril Perindopril Quinapril

1

Ramipril Spirapril

1-2 2 2

Trandolapril Zofenopril

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Table VII. Ratios of trough: peak (TIP) for systolic and/or diastolic blood pressure reduction of different ACE inhibitors, evaluated with casual blood pressure measurements

Reference Morgan & Anderson l911

Fogari et al.11001 Morgan & Anderson p011 Salvetti et al.11021

Drug Captopril Enalapril Perindopril Captopril Enalapril Perindopril Lisinopril

Guntzel et al.11031

Cilazapril

Kobrin et a1P 041

Cilazapril

Ford et al.11051

Fosinopril

Gomezl1061

Benazepril

Data on file, Warner-Lambert

Quinapril

Regimen (mg/day)a

50 bid 20 4 50 bid 10-20 2-8 5 10 20 2.5 5 2.5 5 10 20 40 10-80 2.5 10 40

Systolic TIP

Diastolic TIP

(%)

(%)

38

59

55 87 57 71

83

76 84

100 76 75 96 62 59 >50 >50 79 48 74 >50 >100 59 76

a Once daily unless specified otherwise. Abbreviation: bid =twice daily.

ments of blood pressure before and during antihypertensive treatment (as suggested by the Food and Drug Administration) have shown that some ACE inhibitors have a satisfactory trough-peak ratio when administered once a day (table VII). However, sometimes the trough/peak ratio is good only for systolic or diastolic blood pressure, and different studies with the same ACE inhibitor can give contrasting results. However, current understanding of the blood pressure profile over a 24-hour period, since the advent of ambulatory blood pressure monitoring,[107] has led to a greater scrutiny of the characteristics of an ideal antihypertensive agent. Ambulatory blood pressure monitoring has first of all allowed a full appreciation of blood pressure variability (although recognised for over 30 years). It has also minimised or completely abolished stress factors such as a visit to doctor's office, which is well known to cause transient increases in blood pressure, in some instances quite dramatically. © Adis International Umited. All rights reserved.

Zannad[108] has recently published a large review of the literature from 1986 to 1992 in which the trough/peak blood pressure reduction ratio of ACE inhibitors has been evaluated with ambulatory blood pressure monitoring. He used very stringent"criteria, such as patients with mild and moderate hypertension untreated or with al least a 2 week wash-out period, who thereafter received ACE inhibitor monotherapy for at least 2 weeks. Furthermore, 24-hour ambulatory blood pressure monitoring had been performed before and at the end of the treatment period, and hourly systolic and diastolic blood pressure values were available. As a result of this accurate selection he was able to select only 19 studies fulfilling all the above criteria out of 136 he examined. The results of his review (table VIII) suggest that not all the ACE inhibitors presently administered once daily produce optimal 24-hour blood pressure reduction. Among the drugs examined it appears that benazepril, perindopril and quinapril had trough/peak ratios below 50%, while enalapril, Drugs 49 (4) 1995

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Table VIII. Trough/peak ratios for diastolic blood pressure calculated from 24-hour blood pressure monitoring[108] Drug

No. of patients

Dosage range (mg)

Trough: peak (%)

Captopril

45

12.5-100 bid

Benazepril

72

5-400d

10-40

0-40 30

Perindopril

21

4-80d

Quinapril

29

20-400d

30-40

Ramipril

76

10-400d

40-50

Lisinopril

148

10-800d

40-70

Enalapril

118

5-200d

50-80

20d

80-100

Trandolapril

54

Abbreviations: bid =twice daily; od

=once daily.

lisinopril and trandolapril had trough/peak ratios above 50% with once-daily administration. On the whole, there is a satisfactory agreement among the trough/peak ratios calculated with ambulatory blood pressure monitoring and casual sphygmomanometer measurements. Some of the discrepancies can be attributed to a higher number of blood pressure measurements during the 24hour period and therefore a better blood pressure profile with ambulatory blood pressure monitoring more than to real differences. For the purposes of this review it could be suggested, according to Zannad's conclusion, that lisinopril, enalapril and trandolapril seem to guarantee a better control of 24-hour blood pressure profile and therefore should be preferred when the once-daily administration schedule is used. 2.3 Combination Therapy

The percentage of hypertensive patients whose blood pressure has been normalised with ACE inhibitor monotherapy ranges from 40 to 80%. The differences found among the studies with different ACE inhibitors can be attributed to the population investigated, the time of blood pressure measurement, pretreatment blood pressure values etc. , more than to differences in antihypertensive efficacy between ACE inhibitors. When monotherapy alone is not sufficient to normalise blood pressure it is advisable to use 2 or more antihypertensive agents. ACE inhibitor therapy can be combined with diuretics, calcium antag© Adis International limited. All rights reserved.

onists and (Xl-adrenoceptor antagonists, while more controversial are the results of combination therapy with ~-blockers. All ACE inhibitors are similarly potentiated by the association with diuretics and calcium antagonists, although that with diuretics is the most employed. In summary, there are no significant differences in antihypertensive efficacy among the different ACE inhibitors either in monotherapy or when associated with other antihypertensive agents. There may be slight differences in the time to peak of antihypertensive effect which may be relevant in emergencies, but not during long term therapy. On the other hand, a clinically relevant difference among the ACE inhibitors concerns the duration of the antihypertensive effect. For this reason, some of them can be administered once daily, while for others it is necessary to administer the ACE inhibitor at least twice daily to obtain 24-hour blood pressure control. This can be an important guide for the selection of the ACE inhibitors. 2.4 Left Ventricular Hypertrophy

The presence of left ventricular hypertrophy (LVH) in hypertensive patients significantly increases the cardiovascular risk.[l09] This conclusion has been reinforced by the advent of echocardiographic devices which allow a better evaluation of the cardiac mass,lllO] ACE inhibitors are able to significantly reduce LVH in hypertensive patients.[lll-l25] According to 2 meta-analyses by Cruickshank et aLllll] and Dahlof et al.,[ll2] ACE inhibitors decrease left ventricle mass, predominantly by reducing the thickness of the posterior wall and interventricular septum, and to a minor extent by shortening the left ventricle diameter. Compared with the other classes of antihypertensive agents, ACE inhibitors caused a greater reduction of left ventricle mass for each Imm Hg reduction in blood pressure. It has been suggested that this positive effect could be due to the modulation of the tissue RAS and of the sympathetic nervous systems, improvement of corDrugs 49 (4) 1995

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Choosing the Right ACE Inhibitor

onary circulation and finally better 24-hour control of blood pressure by this class of antihypertensive agent. Another mechanism for the greater reduction of left ventricle mass with ACE inhibitors could be the improvement of compliance of large arteries caused by these agents, which reduces afterload and the pulse wave velocity, particularly the wave reflection from periphery, thus lowering central systolic pressure. According to the 2 meta-analyses,[lII ,1121the regression of LVH with the various ACE inhibitors was different in different studies (as happened also for all the antihypertensive drugs and also for placebo). This is probably due to the population investigated, the pretreatment ventricular mass, the duration of antihypertensive treatment, etc., more than to different efficacy between the various ACE inhibitors. We have compared the antihypertensive efficacy and the effects on LVH of enalapril and trandolapril to evaluate if ACE inhibitors with different intracellular penetration and binding duration to ACE could have a different impact on blood pressure and/or on left ventricle mass.l l261 Our results showed that the 2 ACE inhibitors caused a similar blood pressure reduction and left ventricle mass regression, in spite of the differences in some pharmacokinetic characteristics. In summary, it appears that ACE inhibitors are particularly effective in causing the regression of LVH in hypertensive patients, and that this regression is greater than that expected from the degree of blood pressure reduction. This suggests a specific property of this class of antihypertensive drugs, probably mediated through different mechanisms such as the blockade of the proliferative action of angiotensin II or the modulation of the sympathetic nervous system. On the other hand, this effect seems to be class related and therefore cannot be considered specific for one ACE inhibitor or another. © Adis International Limited. All rights reserved.

2.5 Insulin Sensitivity Hypertension is frequently characterised by insulin resistance with consequent hyperinsulinaemia, glucose intolerance and dyslipidaemia, all metabolic changes that represent independent risk factors for coronary heart disease.l127-1351 It has therefore been suggested that one way to improve survival in patients with hypertension could be the reduction of the metabolic risk factors by nonpharmacological and pharmacological means. This entails intervention against the increased insulin resistance and its metabolic consequences. It is therefore important that assessment of insulin resistance form the basis of studies on the metabolic action of antihypertensive agents. Some information about insulin sensitivity may be gained from oral or intravenous glucose tolerance tests, but the 'gold-standard' technique is the euglycaemic insulin clamp which, in its simplest form, determines whole-body glucose disposal in response to steady-state elevation of the plasma insulin level. Captopril is the ACE inhibitor which has been more extensively investigated for its effects on insulin sensitivity in hypertensive nondiabetic patients. Short term studies or studies offairly limited duration have shown that captopril improves insulin sensitivity, while during long term studies the fasting plasma insulin and glucose levels decrease.[136-142] Enalapril[143] has been shown to cause a small but significant reduction in fasting plasma glucose, suggestive of increased insulin sensitivity, during long term treatment in hypertensive patients and, finally, cilazapril[I441 has been shown to improve glucose-induced insulin response, but not insulin sensitivity. Although insulin sensitivity is, on average, decreased in hypertensive patients, this is not true for all patients, and therefore patients can be divided into those with or without decreased insulin sensitivity. Captopril has been shown to improve insulin sensitivity in patients with decreased sensitivity and to be neutral in those with normal insulin sensitivity. Drugs 49 (4) 1995

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In a study in 86 elderly hypertensive patients, Paolisso et a1. 1145 ] compared the antihypertensive efficacy and the effects on insulin-sensitivity of 5 different ACE inhibitors (captopril, enalapril, quinapril, ramipril and lisinopril) and of placebo. All ACE inhibitors improved insulin sensitivity compared with placebo, but lisinopril displayed a statistically significantly greater improvement than the other ACE inhibitors. In this study, the improvement in insulin sensitivity was paralleled by a decline in triglycerides and free fatty acids. The clinical and prognostic relevance of the effects of ACE inhibitors on insulin sensitivity is at present unknown, but it is worthwhile to mention that the significant improvement in insulin sensitivity obtained with this class of antihypertensive agent can explain the absence of negative effects on plasma glucose and lipoproteins, other clinical markers of reduced insulin sensitivity. Furthermore, the positive results of ACE inhibitors contrast with the negative impact on insulin sensitivity of other antihypertensive agents such as diuretics and ~-blockers, while calcium antagonists are neutral. This interesting effect of ACE inhibitors on insulin sensitivity is still to be explored for its impact on patient survival, which remains the main goal of antihypertensive therapy. Although prognostic studies are not available, it appears that the improvement of insulin sensitivity is class related and therefore cannot be adapted as a criterion to select among the different ACE inhibitors. 2.6 Renal Protection (Proteinuria)

Recent reports I 146] of an increasing incidence of end-stage renal disease have amplified the interest in the pathophysiology and treatment of patients with chronic renal insufficiency. The demonstration that hypertension constitutes one of the major determinants of this increasing incidence of endstage renal disease has focused interest on this disorder. Although it is clear that renal abnormalities may play an important role in the pathogenesis of systemic hypertension, arterial hypertension compli© Adis International Limited. All rights reserved.

Leonetti & Cuspidi

cates the clinical course of most patients with chronic renal failure.1147-149] Experimental studies have shown that glomerular hypertension plays a key role in the immutable progression of renal disease, and that treatment with ACE inhibitors significantly decreases the glomerular pressure, which results in a marked reduction of renal sclerosis and of renal deterioration.l 150,151] The first reports describing the maintenance of renal function and the control of blood pressure during treatment with captopril were in patients with scleroderma renal crisis.1152-155] Since then many studies have been published on the effects of ACE inhibitors in patients with different kinds of renal disease, with or without arterial hypertension and with different degrees of protein excretion. The most frequent clinical studies of renal protection with antihypertensive agents were undertaken in patients with diabetic nephropathy, characterised by glomerular hypertension and eventually worsened by a systemic elevation of blood pressure. On the basis of a recent metaregression analysis,1156] it has been shown that ACE inhibitors decrease proteinuria and preserve glomerular filtration rate (GFR) in patients with diabetes mellitus. It has been also suggested that the effects of ACE inhibitors are independent of changes in systemic blood pressure, suggesting a unique renoprotective effect of this class of agents. Wee and Epstein l157 ] in a recent meta-regression analysis on the effects of ACE inhibitors on the progression of nondiabetic chronic renal disease subdivided the results according to the duration of the studies. In short term studies (<12 months' duration) GFR was unmodified or slightly increased in the majority of the studies and renal blood flow was almost always unchanged. Renal protein excretion was reduced in 20 of the 23 studies. In comparison with other agents, ACE inhibitors were the most efficacious, and the effect was independent of the response of GFR and/or renal blood flow, pretreatment blood pressure and its reduction. In long term studies (>12 months' duration) the changes in GFR were more variable, but on the whole it was Drugs 49 (4) 1995

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constant. On the other hand, the reduction of protein excretion was less relevant. Indeed, there was a reduction of urinary protein in 6 studies and no change in the remaining 9 studies. Again, there was no parallel between the changes in GFR and protein excretion. Finally, in 2 studies of longer duration (>2 years) it has been found that treatment with ACE inhibitors reduces the decline of renal function and the number of patients who require dialysis.[l58,159 l Several patients with essential hypertension have an abnormal urinary excretion of protein even when renal function is still within the normal range. Since microproteinuria (>30 and <200 mgl24h) or macroproteinuria (>200 mgl24h) are considered independent predictors of cardiovascular morbidity and mortality,D58,159l and are at the same time expressions of increased glomerular pressure, studies have been undertaken to determine the effects of various antihypertensive agents on urinary albumin or protein excretion, on the assumption that a reduction in urinary protein excretion might result in improvement of cardiovascular and/or renal prognosis in patients with essential hypertension. Bianchi et aLl160- 162 l have studied in short and long term studies the effects of ACE inhibitors in patients with arterial hypertension, maintained renal function and urinary protein excretion between 30 and 200 mg/24h. The authors found that enalapril significantly decreased the protein excretion rate. Compared with other antihypertensive agents, such as nitrendipine, nicardipine, atenolol and diuretics, enalapril was the only drug able to significantly correct protein excretion. As expected, all the antihypertensive agents caused a similar blood pressure reduction. Although caution is needed in drawing any conclusions, the few available long term studies in patients with diabetic nephropathy suggest that the benefits of ACE inhibitors in short term studies (more numerous) are maintained, and that the deterioration rate of renal function is reduced also in patients with nondiabetic chronic renal failure. © Adis International limited. All rights reserved.

The mechanism of the antiproteinuric effect of ACE inhibitors has been investigated in animal experiments, while this is not possible in humans. From animal experiments it appears that ACE inhibitors exert a complex action at the glomerular level by: (a) reducing increased intraglomerular pressure; (b) reducing mesangial cells contraction; and (c) improving the filtration coefficient. The antiproteinuric effect of ACE inhibitors seems to be class related and, although captopril and enalapril have been the most extensively investigated, the different ACE inhibitors so far investigated seem equipotent, with the degree of reduction in protein excretion being generally proportional to pretreatment level.

3. ACE Inhibitors and the Elderly Hypertensive Patient Arterial hypertension of mild-to-moderate degree is the most frequent of the chronic health problems among the elderly.l163, 164 l Until recently, many physicians were concerned about the decision to start pharmacological treatment to lower abnormal systolic (:2:160mm Hg) and/or diastolic (:2:90mm Hg) blood pressure. Indeed, there were (and still are for some physicians) many perplexities and concerns about antihypertensive treatment in the elderly. The most difficult to be eradicated was that elevated blood pressure in the elderly was considered an age-dependent phenomenon. Currently, many perplexities and concerns have been answered by epidemiological studies which have shown that pharmacological treatment significantly reduces cardiovascular morbidity and mortality in elderly patients with systolic and/or diastolic hypertension.[l65- 168 l The lower circulating levels of renin in the elderly could theoretically reduce the efficacy of ACE inhibitors.l169,170l In spite of this, different clinical studies have shown a significant blood pressure reduction in the elderly treated with ACE inhibitors.l 17l - 178l The available studies comparing the antihypertensive efficacy of this class of agents in elderly and younger hypertensive patients have Drugs 49 (4) 1995

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shown similar blood pressure reductions in both groupS.[179-181] However, when treating elderly hypertensive patients, it is more relevant to add 'life to years' than 'years to life' , and for this reason the impact of antihypertensive agents on the quality of life is particularly relevant for the selection of an agent or agents for elderly patients. Two postmarketing surveillance studies have shown that the incidence and severity of adverse effects in the elderly treated with captopril[182] and enalapril[183] was similar and eventually lower than that in younger patients. Recently, Suraniti et a1.£I77] have found that perindopril was effective and well tolerated in a large population of elderly hypertensive patients during a 6-month follow-up. Therefore, the available studies in elderly hypertensive patients have shown that ACE inhibitors are effective and well tolerated agents, but there are no comparison studies among the available ACE inhibitors to find out if there are differences in efficacy and tolerability among them.

4. ACE Inhibitors and Quality of Life Quality of life is today widely accepted as an important end-point in therapeutic assessment: indeed successful implementation of treatment strategy for hypertension depends not only on the efficacy and safety of therapeutic agents, but also on their impact on the patient's well-being or quality of lifeJ 184] Antihypertensive therapy is a special situation, in which the primary process being treated usually results in few symptoms. Therefore, it is much easier to decrease than to improve the quality of life of hypertensive patients, especially with pharmacological intervention. As a whole, antihypertensive agents of the same pharmacological class typically produce similar clinical responses with regard to efficacy and major adverse effects. However, changes in the quality of life during therapy depend frequently on more subtle reports by patients of drug effects on overall well-being and functioning, which cannot be accounted for by the pharmacodynamic charac© Adls International Limited. All rights reserved.

Leonetti & Cuspidi

teristics of the drug only and, therefore, differences among drugs can become apparent when the quality of life as a whole is evaluated. Quality of life can be evaluated with scales containing items for the many domains which together contribute to determining quality of life. The work by Croog et a1.£1 85] was the first study aimed at evaluating with a correct and scientific approach the effects of the antihypertensive agents methyldopa, propranolol and captopril on blood pressure and quality of life in hypertensive patients. In that study, methyldopa and propranolol caused the expected frequency and severity of adverse effects and an overall negative effect on many domains of quality of life. On the other hand, global measure of quality of life and many of the individual components of this measurement actually improved from baseline during treatment with captopril. Beto and Bansal[186] performed a meta-analysis of the studies on quality of life of hypertensive patients before and during long term pharmacological treatment. After an exhaustive literature search, covering the period 1970-1990, they found only 9 trials performed with scientific criteria (design, placebo control, methodology, follow-up, etc.). In 4 of these an ACE inhibitor was administered (3 with captopril and 1 with enalapril). The authors concluded that 'although none of the drug groups had a clearly superior effect, a more frequent positive effect with angiotensin converting enzyme inhibitors and ~-blockers was seen for all constructs (of quality of life)' . Other studies excluded from the meta-analysis for less strict selection criteria confirm a positive effect of ACE inhibitors on the quality oflife (or at least on some domains) of hypertensive patients during long term treatment. In a recent comparison of captopril and enalapril by Testa et al.[187] it appeared that although indistinguishable according to clinical assessment of efficacy and safety, the 2 ACE inhibitors differed significantly in their effects on the quality of life, favouring captopril. Drugs 49 (4) 1995

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5. ACE Inhibitors and Atherosclerosis In recent years, several antihypertensive agents have been tested in various animal studies for their effects on the progression of atherosclerosis, and ACE inhibitors and calcium antagonists have shown particularly promising actions.l 188 ] Although these effects on atherosclerosis in animal experiments can today be of no help for the selection among the different ACE inhibitors for the treatment of human arterial hypertension, we have thought that this knowledge could be clinically relevant to understand the background of clinical trials on the effects of ACE inhibitors in human atherosclerosis which are ongoing. The interest in ACE inhibitors for their potential effects in reducing the progression of atherosclerosis begins from the demonstrated ability of angiotensin II to stimulate hypertrophy of cultured arterial smooth muscle cells and to induce the expression of the proto-oncogenes C-fos and Cmyc and of the A-chain of platelet-derived growth factor (PDGF).l189,190] Results from in vivo animal studies confirm the effects of ACE inhibitors on atherosclerosis: (a) Aberg and Ferre[ 191 1 have shown a significant reduction in the progression of arterial lesion in cholesterol-fed monkeys, when treated with captopril: (b) in a study by Powell et aU 1921 cilazapril prevented myointimal proliferation after vascular injury in the rat, as a function of the doses, time and length of administration; (c) Chobanian et aP19 31 demonstrated the antiatherogenic effect of captopril in Watanabe rabbits; (d) several investigations have shown that the new ACE inhibitor fosinopril reduces the extent of the lesion area of the carotid artery of monkeys fed with an atherogenic diet; (e) captopril and fosinopril reduced the percentage of abdominal aorta surface covered by atherosclerotic lesions in pigs; and finally (f) in a hamster model captopril was equipotent to pravastatin, a competitive inhibitor of HMG-CoA reductase, in reducing the area of fatty streaks. The antiatherosclerotic mechanism of ACE inhibitors may only in part be due to the lowering of blood pressure (many experimental animals were © Adis International limited. All rights reserved.

normotensive). The potential additional mechanisms could be: (a) an inhibition of low density lipoprotein (LDL) oxidation; (b) inhibition of smooth muscle cell hypertrophy and proliferation; (c) inhibition of smooth muscle cell migration; (d) inhibition of sympathetic activity; (e) an increase in vascular bradykinin or prostacyclin; and (f) inhibition of macrophage function.[l93] Recently, as an alternative to the invasive angiographic method for the evaluation of the progression and regression of atherosclerotic lesions, there has become available the quantitative B-Mode ultrasonography of superficial arteries. B-Mode ultrasonography can be used to examine, with no risk for the patients, the morphological aspect of both lumen and intima-media thickness of the arterial wall. This allows an early and reliable estimate of both the extent and the severity of peripheral atherosclerosis. Based on this methodology, 2 studies are ongoing on the comparison of the effects of a diuretic and of 2 ACE inhibitors (fosinopril and perindopril) on the evolution of atherosclerosis at the carotid level in hypertensive patients. Although the prognostic effect of these antiatherosclerotic properties is difficult to evaluate today, it seems clinically relevant to find out if the ACE inhibitors do have an antiatherosclerotic effect, while lowering the blood pressure of hypertensive patients. This should further justify their role as a drug of first choice.

6. Conclusions ACE inhibitors are antihypertensive agents that are properly positioned among the first choice drugs: indeed their efficacy and tolerability are such as to justify this position, even with the lack of long term studies on the prevention of cardiovascular events. ACE inhibitors differ among themselves for many pharmacokinetic characteristics, some of which have a clinically relevant counterpart. Indeed the chemical structure, the condition of prodrug or active drug and lipophilicity have no relevance for their use in the treatment of arterial Drugs 49 (4) 1995

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hypertension. In contrast, the t'l:!~ is clinically important as it relates to duration of the antihypertensive effect. The route of elimination is also clinically important: lower doses of renally-eliminated ACE inhibitors will be required in patients with renal insufficiency, or a change to an ACE inhibitor with some hepatic elimination. These aspects may help in the selection of an ACE inhibitor. Similarly disappointing has been the evaluation of the different pharmacodynamic aspects as a guide for the selection of an ACE inhibitor. When the antihypertensive efficacy of an ACE inhibitor is taken into account either in absolute values or in comparison versus other ACE inhibitors, there are no clinically significant differences, although doses and administration schedules may differ among the various ACE inhibitors. However, some differences among the ACE inhibitors can be found when the trough to peak ratios of the antihypertensive effects are taken into account. Indeed, according to this pharmacodynamic characteristic not all ACE inhibitors, as commonly administered, have a trough to peak ratio above 50 to 60% as suggested by the US FDA. Furthermore, by calculating the trough to peak ratio from 24-hour noninvasive ambulatory blood pressure monitoring, only 3 of 9 ACE inhibitors evaluated resulted in a favourable blood pressure reduction. The 'renoprotective' effect of ACE inhibitors, predominantly investigated in patients with diabetic nephropathy with or without arterial hypertension, seems more class related than specific of one ACE inhibitor or another, although the greater experience has been accumulated with captopril and enalapril. A similar consideration can be made for the effects of ACE inhibitors on insulin resistance in hypertensive patients. The ACE inhibitors studied to date seem to produce an equivalent improvement, which can explain the neutral or positive effects of this class on blood glucose and lipoproteins. LVH is significantly reduced by antihypertensive agents, and among them ACE inhibitors have shown a greater potency as expressed by left ven© Adis International Limited. All rights reserved.

tricular mass reduction for each mm Hg of blood pressure reduction. Unfortunately, there are not enough data to compare the various ACE inhibitors and, at the present time, this effect must be considered class related. Age per se cannot be considered a contraindication to the use of ACE inhibitors, and elderly hypertensive patients respond satisfactorily to all ACE inhibitors without clinically important differences among them. Quality oflife during ACE inhibitor therapy has been carefully evaluated in only a few studies, all of which indicate similar improvement. In conclusion, we think that at the present time there is no clinically relevant difference among the various ACE inhibitors more extensively employed for the treatment of arterial hypertension without other complications. The clinical impact of a trough to peak ratio of blood pressure reduction above or below 50 to 60% is unknown, and new studies are necessary for a correct evaluation and eventually a guide to selection among the ACE inhibitors. In patients with renal insufficiency some ACE inhibitors with a double route of elimination may avoid the dosage adjustment necessary for ACE inhibitors only eliminated renally.

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Correspondence and reprints: Professor Gastone Leonetti, Istituto Scientifico Ospedale S. Luca, Via Spagnoletta 3, 20149 Milan, Italy.

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