Drugs 39 (Suppl. 2): 17-22, 1990

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Clinical Experience with Lisinopril in CongestiveHeart FailureFocus on the Older Patient

Thomas D. GilesCardiovascular Research Laboratory, Department of Medicine, Tulane UniversitySchool of Medicine, New Orleans, Louisiana, USA

Summary Lisinopril, a long acting, non-sulfhydryl-containing angiotensin-converting enzymeinhibitor, produces an increase in exercise capacity and an improvement in symptomswhen administered in a dose of 5 to 20 rug/day to patients with congestive heart failure.There is an increase in left ventricular ejection fraction, and the effectiveness of the drugis not diminished by impairment of renal function (serum creatinine > 71.6 mg/dl),Lisinopril is just as effective in older (> 65 years of age) patients as in younger patientsand is well tolerated among patients of all age groups.

The introduction of angiotensin-converting en­zyme (ACE)inhibitors for the treatment of patientswith congestive heart failure (CHF) [Davis et al.1979; Fitzpatrick et al. 1983] represents a signifi­cant advance in the management of this disorderand was the culmination of several decades of in­vestigation of the pathophysiology of CHF, as wellas the pharmacology and physiology of the renin­angiotensin-aldosterone system. Lisinopril, a newACE inhibitor, has recently been introduced for thetreatment of CHF (Dickstein et al. 1986) and hasseveral beneficial distinguishing pharmacologicaland clinical characteristics.

CHF is a common affiiction among the elderlyand increases in prevalence with age (Smith 1985).In 1985, approximately 28.6 million persons in theUnited States of America (11.9% of the population)were > 65 years of age. Thus, any therapy intro­duced for the treatment of CHF must be viewedas potentially beneficial for this group of patients.

However, it cannot be assumed that drugs in gen­eral, and cardiovascular drugs in particular, areequally effective in younger and older patientgroups. A decreasing inotropic responsiveness tocatecholamines occurs with increasing age,~-adrenoceptor density is decreased, and plasmarenin activity is usually lower in younger than inolder patients (Lakatta 1980; Meade et al. 1983).Additionally, left ventricular (LV) hypertrophy anddiastolic (lusitropic) abnormalities of LV functionare more common in older patients (Lakkata 1979).All of these alterations in the cardiovascular sys­tem occurring with advancing age may account forthe observed differences in response to treatmentin older compared with younger patients with CHF.

1. Lisinopril

ACE inhibitors may be subclassified accordingto several pharmacological characteristics (1987).Lisinopril, for example, does not contain a sulfhy-

18 Drugs 39 (Suppl. 2) 1990

700

3. Comparison of Lisinopril with Placeboin CHF

amic benefit 12 hours after administration (Packeret al. 1986); the degree and time course of ACEinhibition are important for maximum haemodyn­amic unloading of the heart.

1284

Weeks

L~-=~~::::::='"""J:(n = 88)*

o

(n = 86)*

Vi-g 600oCJQ)

2. 500Q)

~5: 400"QQ)

~ 300 L_.- .- ..---__---,,-_

Fig. 1. Exercise duration in patients with congestive heartfailure after 12 weeks of treatm ent with lisinopril 5 to20 rug/day (e) or captopril 37.5 to 150 mg/day (.); no. ofpatients in parenth eses. Significant increase from baseline isindicated by * = p < 0.01.

Lisinopril therapy was compared with placeboin a mult icentre prospective randomised double­blind trial comprising 130 patients with moderateto severe CHF (New York Heart Association ClassII to IV) [Chalmers et al. 1987]. LV systolic dys­function was established by the requirement of aLV ejection fraction of less than 45% as an entrycriterion. Clinical impairment was confirmed byenrolling patients only if they were unable to ex­ercise to more than stage III to IV (4 to 16 min­utes) of a modified Naughton Protocol. Patientscontinued treatm ent with diuretics and digitalis,and after 2 weeks of stabilisation they receivedeither lisinopril 5 rug/day (n = 87) or placebo(n = 43). At the next 2 visits (weeks 4 and 8), thedose oflisinopril was increased to 10 or 20 rug/dayif further clinical improvement was deemed nec­essary and no adverse effects of the drug wereexperienced.

Lisinopril treatment resulted in a significant in­crease in exercise capacity compared with placebowhen measured at 12 weeks. In addition, in the

dryl group and uses a carboxyl group as a zinc li­gand for binding to the enzyme. This drug is thelysine derivative of enalaprilat, the active metab­olite of the prodrug enalapril. Thus, lisinopril ispharmacologically active without being metabol­ised and appears to be highly selective for bindingto the angiotensin-converting enzyme.

Lisinopril is a long acting ACE inhibitor ; a singleoral dose of lisinopril 10mg suppresses serumangiotensin-con verting enzyme for 24 hours (Brun­ner et al. 1981). In contrast, captopril , a shorteracting ACE inhibitor, suppresses serum angioten­sin-converting enzyme for approximately 8 hours(Kostis et al. 1987). Absorption of lisinopril isslightly reduced in patients with CHF comparedwith normal volunteers. Thus , bioavailability isappro ximately 19% in patients with CHF (unpub­lished data ) and 25% in normal subjects (Beermanet al. 1986).

2. Haemodynamic Effects of Lisinoprilin CHF

Beneficial haemodynamic changes in patientswith CHF after administration of an initial doseof lisinopril 2.5, 5, or IOmg include a decrease insystemic arterial pressure, pulmonary artery wedgepressure, right atrial pressure, pulmonary arterypressure, calculated systemic vascular resistance,pulmonary vascular resistance and heart rate, whilecardiac and stroke index are increased (Dicksteinet al. 1986; Stone et al. 1989). The peak haemo­dynamic effect is attained 6 to 8 hours after admin­istration of the drug (Dickstein et al. 1986; Stoneet al. 1989).

After 12 weeks of treatment with lisinopril and24 to 28 hours after administration of the last dose,beneficial haemodynamic changes are still present(Stone et al. 1989). However, at that time, oral dos­ing may have resulted in an additional haemod yn­amic benefit, suggesting incomplete inhibition ofangiotensin-converting enzyme probably resultingfrom the relatively low mean dose (5.5mg) used inthe study. The effects of larger doses of enalapril(20mg twice daily) were studied in a similar wayand showed persistent and complete haemodyn-

Clinical Experience with Lisinopril in CHF

~ 5 l 5~

c c.2 (n = 56) .2 (n = 55)U U~ 4 ~ 4c c.2 0u l;a> 3 a> 3'0; 'ijj

> >...J ...J

.S 2 .S 2a> a><I> <I>., .,.. ..0 0s 1 .!: 1

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19

Fig. 2. Increase in left ventricular ejection fraction after 12 weeks of treatment with lisinopril 5 to 20 mg/day (. ) orcaptopril 37.5 to 150 mg/day (~) in (a) all patients with congestive heart failure and (b) patients with baseline ejectionfractions ~ 35%; significant difference between treatments, p < 0.05.

lisinopril-treated patients, LV ejection fraction in­creased, symptoms improved (as assessed by theYale scale dyspnoea-fatigue index), heart size wasreduced as shown by chest x-ray and bodyweightdecreased.

In another 12-week study with a similar pro­tocol, treatment with lisinopril 5 to 20mg (n = 10)or placebo (n = 6) resulted in a significant increasein exercise capacity as well as an increase in oxygenuptake and peak exercise compared with placebo(Jessup et al. 1987).

4. Comparison 0/ Lisinopril withCaptopril in CHF

A comparison of lisinopril with captopril wasperformed in a 12-week multicentre study with adouble-blind, randomised, parallel design (Giles etal. 1989). 189 patients with CHF (New York HeartAssociation Class II to IV) were enrolled in thisstudy. The clinical diagnosis of CHF was con­firmed by one or more of the following criteria: LVejection fraction < 45%, cardiothoracic ratio > 0.5,presence of an early diastolic gallop rhythm, in­creased pulmonary artery wedge pressure (> 15mmHg) and reduced cardiac index « 2.5 L/min/m2)

within the past year.

During the initial placebo period of 4 to 14 days,all drug treatment for CHF, except digoxin and di­uretics, was withdrawn. After patients were stabil­ised, they were randomly assigned to receive eitherlisinopril (5 mg/d ay, n = 94) or captopril (l2.5mg3 times daily, n = 95). In each instance, matchingplacebo was administered where appropriate. If re­quired, the dose of each drug could be doubled at4-week intervals . Thus, the maximum doses of lis­inopril and captopril were 20 rug/day and ISOmg/day, respectively .

Exercise duration was improved with lisinopriland captopril after 12 weeks of treatment (fig. I)and the drugs were equally effective in black andwhite patients. Furthermore, lisinopril therapy im­proved exercise duration in patients with impairedrenal function (serum creatinine > 1.6 mg/dl) . Noimprovement was shown with captopril and a sim­ilar lack of effectiveness in patients with impairedrenal function has been reported by the Captopril­Digitalis Research Group (1988). The time coursesfor the reduction in systemic arterial blood pres­sure produced by lisinopril and captopril weresimilar to those recorded during invasive haemo­dynamic studies, i.e. the maximum decrease forcaptopril occurred within 2 hours compared with5 to 6 hours for lisinopril. Lisinopril, but not cap-

20 Drugs 39 (Suppl. 2) 1990

U>u 140c0u

'"2- 120c

.Q;U

100:;u

'"oil.(3

80Qj)(

'".s 60

'"'"c'"s: 40uc

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Fig. 3. Mean change in exercise durat ion during 12 weeks oftherap y with lisinopril 5 to 20 mg/day (n = 32) [0] orcaptopril 37.5 to 150 mg/da y (n = 25) [_ ] in patients withcongestive heart failure aged ~ 65 years. Significant differ­ence between treatments. p = 0.08 (after Giles et al. 1988.with permissi on).

planned subgroup analysis of the large multicentretrial described above (Giles et al. 1988). Patients> 65 years ofage comprised 39% of the lisinoprilgroup (n = 37) and 29% of the captopril group(n = 28); the demographics of these groups weresimilar. Exerciseduration improved in both groups,although there was a tendency for lisinopril to bemore effective (p = 0.08) [fig. 3]. Again, LV ejec­tion fraction increased in the lisinopril group, butnot in the captopril group (fig. 4).

6. Adverse Effects

Lisinopril is well tolerated in patients with CHF,and adverse events are similar to those reported inpatients receiving placebo (Chalmers et al. 1987).

40-

30-

Captopril

Baseline Week 12

Lisinopri l

Baseline Week 12

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topril, improved LV ejection fraction (fig. 2a). Thedifference between lisinopril and captopril in theeffect on this parameter of LV systolic function waseven more noticeable in the group of patients withpretreatment LV ejection fractions of ~ 35%(fig. 2b).

There is no clear explanation for the beneficialeffects on exercise duration produced by lisinoprilin patients with impaired renal function and LVejection fraction, and the lack of improvement withcaptopril, although the duration of action of theseagents may be a factor. The chronopharmacologi­cal aspects of the treatment of CHF are important,since the circadian variation in blood pressure orheart rate is lost in CHF; maximal cardiac unload­ing requires that blood pressure and heart rate bedecreased throughout the day.

5. Lisinopril in the Older Patientwith CHF

The effects of lisinopril and captopril in thetreatment of older patients (> 65 years of age) withCHF were compared as part of a prospectively

Fig. 4. Mean left ventricular ejection fraction at baseline andafter 12 weeks of therap y with lisinopril 5 to 20 rug/da y(n = 19) or captopril 37.5 to 150 mg/da y (n = 15) in patientswith congestive heart failure aged ~ 65 years; significantchange from baseline, ** = p < 0.0 I (after Giles et al. 1988,with permi ssion).

Clinical Experi ence with Lisinopril in C H F 21

Table I. Serious adverse effects in patients with congestive heartfa ilure treated with lisinopril or captopril (after Giles et al. 1988,with permission)

The comparative trial of lisinopril and captoprilrevealed a 35.7% incidence of adverse events in thelisinopril group compared with one of 47.7% in thecaptopril group ; the most common adverse eventsoccurring in the lisinopril group were dizziness(6.1%), hypotension (2.1%) and nausea (3.2%)[Gileset al. 1989].

Treatment of CHF with ACE inhibitors may re­sult in an increase in blood urea nitrogen concen­tration ; serum creatinine concentrations increaseto a lesser degree. This pattern of 'pre-renal azo­taemia' has been attributed to a decrease inglomerular filtration secondary to an alteration inglomerular haemodynamics (Packer et al. 1987).The increase in blood urea nitrogen is usually smalland is corrected with a decrease in the dose of aconcomitantl y administered diuretic. Only rarelydoes morbidity result from the effect of ACE in­hibitors on the kidney.

Older patients receiving lisinopril experience asfewadverse events as those experienced by youngerpatients (Giles et al. 1988). Indeed , serious adverseevents are uncommon (table I). Hypotension, ananticipated problem among older patients becauseof blunted baroreceptor reflexes, is also uncom­mon and no more frequent than in other agegroups.

Drug

Lisinopril(n = 37)

Captopril(n = 28)

Adverse effect No. of patients

Death 0

Gastrointestinal pain 1Death 1Hypotension 1Cerebrovascular disease 1Hypertensive crisis 1

in healthy subjects. British Journal of Clinical Pharm acologyII : 461-467. 1981

Captopril-Digita lis Research Gro up: compa rison of effects of cap­topril and digoxin on ejection fraction . exercise tolerance.clinical status. and arrhythmias in patients with mild to mod­erate heart failure. Journ al of the American Medical Associ­at ion 259: 539-544. 1988

Chalmers JP . West MJ. Cyran J. De La Torre D. Englert M. etal. Placebo-controll ed study of lisinopr il in congestive heartfailure: a mult icentre study. Journ al of CardiovascularPhar macology 9 (Suppl. 3): S89-S97. 1987

Davis R. Ribner HS. Keung LS. Sonnen blick EH. LeJemtel T H.Treatment of chro nic congestive heart failure with captopril,an oral inh ibitor of angiotensi n converting enzyme. New Eng­land Journ al of Medicine 301: 117-121. 1979

Dickstein K. Aarsland T. Woie L. Abrahamsen AM. Fyhrqu istF. et al. Acute hemodynamic and hormonal effects of lisinopril(MK-521) in congestive heart failure. American Heart Journal112: 121-129. 1986

Fitzpatr ick D. Nichols MG. Ikram H. Espiner EA. Haemod yn­arnic, hormonal. and electrolyte effects of enalapril in heartfailure. British Heart Journ al 50: 163-169. 1983

Giles TD . Fisher MB. Rush JE. Lisinopr il and captopril in thetreatment of heart failure in older patients. Comparison of along- and short-acting angiotensin-convert ing enzyme inh ibi­tor. American Journa l of Medicine 85: (Suppl. 3B): 44-47,1 988

Giles TD. Katz R. Sullivan JM . Wolfson P. Haughland M. et al.For the Multicenter Lisinopril-Captopril CHF Study Group:short- and long-acting angiotensin converting enzyme inhibi­tors. a randomized trial of lisinopril versus captopril in thetreatm ent of congestive heart failure. Journal of the AmericanCollege of Cardiology 13: 1240. 1989

Jessup M, Spielman S, Hare T. et al. Lisinopril in the treatmentof chronic cardia c failure: a controlled trial. Heart Failure 3:114-127, 1987

Kostis JB. Raia JJ. DeFelica EA. Barone JA. Deeter RG. Com­parati ve clinical pharmacology of ACE inhib itors. In Kost isJB, DeFelica (Eds) Angiotensin converti ng enzyme inhibitors,Alan R. Liss Inc.• New York. 1987

Lakatta EG. Alterations in the cardiovascular system that occurwith age. Federation Proceedings 38: 163-167. 1979

Lakatta EG. Age-related alterat ions in the cardiovascular re­sponse to adrenergic media ted stress. Federat ion Proceedings39: 3 173-3177. 1980

Meale TW. Imerson JH . Gordo n E. Peart WS. The epidemiologyof plasma renin. Clinical Science 64: 273-280. 1983

Packer M. Lee WHo Medin a N. Yushak M. Kessler PD, Func­tional renal insufficiency during long-term therapy with cap­topril and enalapril in severe chronic heart failure. Annals ofInternal Medicine 106: 346-354. 1987

Packer M. Lee WHoYusha k M, Medina N, Comparison of cap­topril and enalapril in patients with severe chronic heart fail­ure. New England Journal of Medieine 3 I5: 847-853. 1986

Smith WM. Epidemiology of congestive heart failure. AmericanJournal of Cardio logy 55: 3A-8A. 1985

Stone CK. Uretsky BF. Linnemeier TJ. Shah PK. Amin DK. etal. Hemodynam ic effects of lisinopril after long-term admin­istra tion in congestive heart failur e. American Journal of Car­diology 63: 567-570. 1989

References

Beerman B. Go mez H. Till AE. Junngren IL. Pharmacokineticsof Iisinopril in healthy volunteers. Acta Pharma cologica etToxicologica 59 (Suppl, 5): 66, 1986

Brunner DB. Despond s G. Biollaz J, Keller I. Ferber F. et al.Effect of a new angiotensin con verting enzyme on the MK421and its lysine analogue on the components of the renin system

Author's address: Dr Thomas D Giles, Department of Medicine,Tulane Medical School. 1430 Tulan e Ave. New Orleans,LA 70112. USA.

22

Resumen

Drugs 39 (Suppl. 2) 1990

Lisinopril, un inhibidor de enzima de actuacion prolongada, carente de sufidrilo ytransformador de angiotensina, produce un aumento en la capacidad de ejercicio y unamejoria de los sintomas si se administra en dosis de desde 5 a 20 rng/dia en pacientescon insuficiencia cardiaca congestiva. Aumenta la frecuencia de eyeccion del ventriculoIzquierdo y la eficacia del medicamento no se ve disminu ida por cualquier empeora­miento de la funcion renal (creatinina serica > 71,6 mg/dl. Ellisinopril es tan eficaz enlos pacientes de edad (> 65 aiios) como en los jovenes. Pacientes de todas las edades 10toleran bien.