Br J clin Pharmac 1994; 38: 117-123

Haemodynamic response and pharmacokinetics after thefirst dose of quinapril in patients with congestive heartfailure

IAIN B. SQUIREI, ROBERT J. MACFADYENI, KENNEDY R. LEES', W. STEWART HILLIS1"2 & JOHN L.REID''University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow G 1I 6NT and2Department of Cardiology, Western Infirmary, Glasgow

1 Twenty-four elderly patients with stable, chronic congestive heart failure, NYHAII-IV, requiring addition of an ACE inhibitor to their existing therapy were ran-

domised to receive double-blind a single dose of quinapril 2.5 mg p.o. or match-ing placebo after 24-48 h supervised diuretic withdrawal.

2 The effect of treatment on resting supine blood pressure, heart rate, plasmaangiotensin converting enzyme (ACE) and circulating plasma renin activity was

compared between groups over the first 24 h after dosing. The pharmacokineticprofiles of quinapril and the active metabolite quinaprilat were determined.

3 Compared with placebo, quinapril caused a statistically significant but modest fallin blood pressure from 3 to 10 h post dose. The maximum fall of 12 mm Hg (95%C.I. 5.4-18.5) was seen at approximately 5 h. Circulating ACE activity was 40%inhibited within 1 h. Maximum ACE inhibition (83.6%, 95% C.I. 76.7-90.5) was

observed at 3 h. ACE remained 60% inhibited at 24 h post dose. tmax for quinaprilwas seen at 2.6 ± 1.2 h. while tmax for quinaprilat was at 3.6, ± 0.8 h.

4 Treatment with quinapril was associated with a significant rise in plasma reninactivity (PRA) of 8.83 ng Al ml-' h-' (95% C.I. 0.30-17.96) compared withplacebo.

5 Compared with placebo, quinapril 2.5 mg inhibits plasma ACE by over 60% for24 h and reduces blood pressure for at least 10 h in patients with stable, chroniccongestive heart failure. The blood pressure fall, although moderate and well tol-erated, is more sustained than previously described for quinapril in heart failure.

Keywords quinapril ACE inhibition blood pressure heart failure

Introduction

Angiotensin converting enzyme (ACE) inhibitorsimprove haemodynamic function, disease symptomsand mortality in all grades of severity of congestiveheart failure (CHF) [1, 2] and in comparison withalterative therapies [3]. While various actions on vas-cular and cardiac structure, neurohormonal responses,electrolyte handling and on regional haemodynamicshave been postulated as mechanisms underlyingsudden death in CHF [4], the mechanism for themortality reduction associated with the use of ACEinhibitors remains unclear.One of the perceived difficulties of introducing the

ACE inhibitors in clinical practice is the occurrenceof first-dose hypotension in susceptible patients andthe potential organ damage (brain, heart, kidney)which may result. Symptomatic hypotension may bemore common in patients with heart failure thanthose with hypertension: this phenomenon has beenhighlighted by a number of published case reports[5]. In larger studies of heart failure an incidence ofbetween 10% [6] and 40% [7] is suggested. Factorsinfluencing the blood pressure response are variedbut pre-existing activation of the renin-angiotensinsystem in response to chronic heart failure or con-

Correspondence: Dr I. B. Squire, University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary,Glasgow GIl 6NT

117

118 I. B. Squire et al.

comitant diuretic therapy are particularly important.Hypotensive or hyponatraemic patients are particu-larly at risk. Although some recent studies have sug-gested that the likelihood of a fall in blood pressureis unrelated to the dose of ACE inhibitor adminis-tered [8], others have found a direct correlation withthe dose [1]. Against this background it has becomestandard practice in many units to admit patients withCHF to hospital for introduction of ACE inhibitortherapy at low doses, with variable periods of diureticwithdrawal and blood pressure monitoring [9]. How-ever little detailed information has been gathered onthe pharmacodynamics and pharmacokinetics withlow doses of the drugs in heart failure patients.

Quinapril is a non-sulphhydryl ACE inhibitorwhich is available for the treatment of hypertensionand CHF. The full activity of quinapril depends onconversion to the active diacid metabolite quinaprilat.Quinapril has an intermediate duration of action andin animal experiments is suggested to have a rela-tively high affinity for tissue ACE [10]. While theincidence of first dose hypotension followingquinapril is increased with concomitant diuretic ther-apy, the overall incidence of this side effect withmonotherapy is suggested to be low in comparisonwith captopril or enalapril in patients with hyper-tension [11]. In essential hypertension, the suggestedmaintenance dose of 20 mg quinapril was well toler-ated and was not associated with excessive falls inblood pressure [12].

Previous studies with quinapril in heart failurehave shown beneficial haemodynamic changes bothacutely [13] and with chronic therapy [14]. While thecurrently recommended starting dose of quinapril inCCF is 2.5 mg, the timing and extent of the haemo-dynamic response to this dose are unknown. We haveconducted a double-blind, parallel group, placebocontrolled study of the haemodynamic response andpharmacokinetic profile of a single dose of quinapril2.5 mg orally in elderly patients with stable CHF.

Methods

Patients

Twenty-four patients (mean age 72 years, range54-88 years, M:F= 11:13) with chronic stable con-gestive cardiac failure, New York Heart Associationfunctional class II-IV, were recruited from the generalmedical and cardiology departments of the WesternInfirmary. All patients were symptomatic on diuretictherapy (40 mg frusemide or greater per day) prior tothe study. Patients were admitted to hospital fordiuretic withdrawal and commencement of ACEinhibitor therapy. All had erect and supine systolicblood pressure of .100 mm Hg, normal serumsodium (>135 mmol l-l) and stable hepatic and renalfunction (serum creatinine <250 pmol 1-1) prior to thestudy.The diagnosis of heart failure was confirmed by

clinical history and by physical and radiologicalexamination prior to treatment. All patients had

echocardiography performed and a number had addi-tionally undergone cardiac catheterisation or radio-nuclide scanning for confirmation of impaired leftventricular function.

The study protocol was approved by the localethical review committee and all patients gave writ-ten informed consent to take part in the study.

Procedure

Diuretic therapy was withdrawn for 24, and in mostcases 48 h prior to the study day. All vasodilator (e.g.oral nitrate, calcium channel blocker) and 0-adreno-ceptor blocker therapy (one patient) was withheld onthe day of the study; digoxin, where prescribed, wascontinued. On the morning of treatment, patientsrose, washed and had breakfast as normal (07:00 h).They then returned to bed where they rested supine.A peripheral venous cannula was inserted in an ante-cubital fossa vein for the purpose of blood sampling.Blood pressure was measured at 2 min intervals usinga semi-automatic sphygmomanometer (Sentron, Bard,Sunderland, U.K.) to establish stable baseline values.Baseline blood pressure was taken as the mean ofthree recorded values obtained after 45-60 minsupine rest. Following at least 45 min supine rest,blood was drawn for estimation of baseline drug con-centration, ACE activity, plasma renin activity andaldosterone levels. Study medication (quinapril 2.5mg or matching placebo) was then administeredorally in a double-blind fashion according to a ran-domisation code held by the Pharmacy Department.Blood sampling and triplicate determination of supineblood pressure and heart rate were carried out atintervals until 10 h after administration of the studydrug. Patients remained supine until this time, andwere then allowed to resume normal activity. Bloodsampling and blood pressure measurements wererepeated at 24 h, again after 45-60 min supine rest.

At the end of the 24 h study period the treatmentcode was broken by the Department of Pharmacy.Patients who had received active therapy were con-tinued on open ACE inhibitor therapy (enalapril 5 mgtwice daily) while those who had received placebowere given a test-dose of captopril 6.25 mg orally.Vasodilator and diuretic therapies were reintroducedas required. Blood sampling for routine haematologyand biochemistry was carried out prior to the com-mencement of the study and at the end of the 24 hstudy period.

Laboratory and statistical analyses

Blood pressure and heart rate were measured in tripli-cate at each time point and the mean, both absolutevalue and change from baseline, at each point usedfor statistical analysis. The results are presented asmean ± 1 s.d. in all cases. Treatments were comparedusing repeated measures analysis of variance(ANOVA) followed by multiple Bonferroni correc-tions for comparisons at each time point. Differenceswith a P value of <0.05 were taken as significant.Mean arterial blood pressure (MAP) was calculatedfrom the recorded values using the standard formula

Quinapril in heart failure 119

MAP = Diastolic BP+(Systolic BP-Diastolic BP)/3.Plasma drug concentration and ACE activity weremeasured by assay, using high pressure liquid chro-matography, of hippuric acid produced from theexogenous substrate Hip-His-Leu [15]. Plasma reninactivity was estimated by radioimmunoassay ofangiotensin I formed from exogenous angiotensino-gen [16]. Biochemical indices were compared usingunpaired t-tests. Plasma renin activity was comparedbetween groups after logarithmic transformation.Baseline plasma renin activity is expressed as geo-metric mean (95% confidence intervals). All otherbaseline data are expressed as mean (1 s.d.) The 95%confidence intervals for blood pressure response,plasma ACE inhibition and change in PRA are forbetween group comparisons.

Results

General

The two groups were similar in terms of age, sex andaetiology of CHF, NYHA class (Table 1) and base-line laboratory indices (Table 2). No biochemicalparameter was altered significantly over the studyperiod in either group (Table 2). The small fall inhaemoglobin concentration of approximately 1 g dl-'is similar to that seen in previous studies employ-ing similar protocols and is attributable to bloodsampling.

There were no significant adverse events duringdiuretic withdrawal or the study period. Study treat-ment was well tolerated in all cases. One patient who

Table 1 Patient characteristics

Quinapril (n = 12) Placebo (n = 12)M:F 5:7 6:6

Age (years) (Mean (s.d.)) 75.6 (8.2) 69.1 (10.7)Age (range) 61-88 54-85NYHA Class

II 8 6III 4 4IV - 2

Diuretic dosage 57 (27) 70 (27)(mg frusemide or equivalent/day) (Mean (s.d.))

Atrial fibrillation 6 4

Aetiology ofCHFAlcohol related cardiomyopathy - IIschaemic heart disease 7 7Hypertension 1Combination of above 4 4

Blood pressure and heart rate (Mean (s.d.))

Systolic BP (mm Hg) 142 (18) 125 (20)Diastolic BP (mm Hg) 72 (9) 69 (17)Mean BP (mm Hg) 95 (12) 88 (16)Heart rate (beats min'1) 71 (8) 79 (12)

Table 2 Summary statistics-laboratory data. Baseline values and change over study period(Mean (s.d.))

Quinapril Placebo P value (unpaired t-test)

Sodium (mmol 1-1) 140.7 (3.1) 140.5 (1.9)Sodium (change) -3.2 (3.3) -0.4 (3.5) 0.1

Potassium (mmol 1-') 4.0 (0.4) 4.4 (0.4)Potassium (change) +0.3 (0.4) +0.2 (0.5) 0.39

Urea (mmol 1-1) 9.5 (4.4) 8.1 (3.7)Urea (change) -0.5 (1.6) -0.9 (1.4) 0.42

Creatinine (pmol 1-1) 126.7 (52.4) 114.3 (30.2)Creatinine (change) -0.8 (27.3) -10.8 (17.3) 0.3

Haemoglobin (g dl-1) 12.8 (1.5) 14.3 (1.8)Haemoglobin (change) -1.0 (0.8) -1.1 (0.4) 0.82

Plasma renin activity (baseline) 0.86 (1.21-3.39) 1.85 (1.20-6.81)(ng Al ml-' h-') (Mean (95% C.I.))

Aldosterone (pg ml-') (baseline) 111 (66) 155 (118)

120 I. B. Squire et al.

had received placebo therapy (Subject 23) experi-enced symptomatic hypotension following the firstdose of open ACE inhibitor therapy (captopril 6.25mg) and was unable to tolerate continued therapy.All other patients left hospital following stabilisationon open ACE inhibitor therapy with enalapril 5 mgtwice daily and adjustment of diuretic and othermedication.

Haemodynamic response

Systolic BP was higher in the active treatment group(142 ± 18 mm Hg) than in the placebo group (125 ±20 mm Hg) (Table 1). Mean arterial pressure wasspecified in the study protocol as the primary variableof interest and showed a mean difference of 7 mm Hgbetween groups (quinapril 95 ± 12 mm Hg; placebo88 ± 16 mm Hg). In view of the relatively large dif-ference in baseline systolic blood pressure betweenthe groups, this variable was added to the analysis asa covariate. No influence of baseline blood pressureon response to study medication was apparent. Meanblood pressure and heart rate responses are shown aschange from baseline values.

Baseline heart rate was similar in the two treatmentgroups. There was no change in heart rate over thestudy period in either treatment group and no differ-ence in heart rate response between the active andplacebo groups (Figure 1).

In both treatment groups, mean arterial pressureshowed a transient rise over the 30-45 min following

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arterial pressure (a) and heart rate (b) in patients withcongestive heart failure. *P < 0.05 compared with placebo.

administration of study medication. There was no dif-ference between the groups in terms of the magnitudeor time course of this response. This phenomenonmay reflect a transient stress response to the earlypart of the study. A normal diurnal fall in BP wasconfirmed in the placebo group.Compared with placebo, quinapril 2.5 mg caused a

modest, early and sustained fall in MAP from base-line, the maximal change occurring at 5 h post dose(12 mm Hg, 95% C.I. 5.4-18.5). The change in MAPfrom baseline was significant compared with placebobetween 3 and 10 h (Figure 1). The fall in blood pres-sure was greater for systolic than for diastolic ormean arterial pressure. Although less in absoluteterms, the fall in diastolic BP was of greater durationthan for MAP and the change from baselinesignificant between 1 and 10 h.The maximum fall in MAP, irrespective of its time

course was calculated for each patient. Comparedwith placebo the mean maximum fall in MAP of 7mm Hg (95% C.I. -4-+17) in the active treatmentgroup was not statistically significant.

Hormone responses

Plasma ACE inhibition Baseline plasma ACE activitywas similar in the two treatment groups (placebo 19.9+ 6.8 ng Al ml-' h-'; quinapril 23.5 ± 7.1 ng Al ml-h- ). Plasma ACE activity in the active treatmentgroup showed rapid onset of inhibition and wasstatistically different from placebo by 50 min afterdosing. Compared with placebo maximal mean ACEinhibition was 83.6% (95% C.I. 76.7-90.5) at 3 h(Figure 2). ACE activity remained significantlyinhibited (59.9%, 95% C.I. 41.6-77.0) at 24 h afterdosing.

Plasma renin activity Baseline supine plasma reninactivity (PRA) was similar in the placebo (geometricmean 1.85 ng Al ml-' h-', 95% C.I. 1.20-6.81) andin the active treatment group (0.86 ng Al ml-' h-',95% C.I. 1.21-3.39). The change in plasma reninactivity in the two groups is shown in Figure 3.Compared with placebo the mean maximum rise in

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Quinapril in heart failure 121

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mean time ito pea cocnrto (tax fo quinpriwas2.6 (12 h whil tmax fo qunpia wa 3.6

(0st.8) h. The¢.mea maxmu cocnrto (Cax o*.f.;qunari was 49. (3.9 ngmU'trz8 (rangeeX25.2-138.5).

DThe Cma of quiapilaKt waetLzs51 7ii.0(22X.8 ng m.:U.' .(rng 2.4-103.5). The activ moet qunariawas-§<d tetbl Fin th pama wihi 30mmj and- 5remained detectable at 24 h in all 12 sujets recei ; .,l.v-t.

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259 ng ml-' h. Quinapril concentration was 1.8 ngml-' (range 0.0-7.1) at 24 h and was undetectable atthis time in 3 of 12 subjects.

Discussion

This is the first placebo controlled study of thehaemodynamic response to this relatively small doseof quinapril in patients with congestive cardiac fail-ure. A single dose of quinapril 2.5 mg was well toler-ated with no episode of symptomatic hypotension inthis small study in supine patients following super-vised diuretic withdrawal. The observed fall in meanarterial pressure was modest and of a similar magni-tude to that seen in previously published open studiesof quinapril in CHF. The fall of 12 mm Hg in the pre-sent study compares with 12 mm Hg with 2.5 mgorally [17] and 12 mm Hg seen with doses between2.5-10 mg orally [18]. Each of these studies was con-ducted using invasive haemodynamic monitoring,which is known to influence the nature of the haemo-dynamic response.Our observations record a significant blood

pressure fall up to 10 h post-dose with the maximumfall at 5 h. This contrasts with the earlier times tomaximal blood pressure response of 2-2.5 h reportedin CHF with 5 mg orally by Holt et al. [13] and with2.5-10 mg orally by Nieminen & Kupari [17]. Theseuncontrolled studies reported a shorter duration ofeffect on blood pressure. Holt et al. [13] describedhaemodynamic changes returning towards baselineby 4 h after a single dose of quinapril 5 mg orally.However these authors discontinued haemodynamicmonitoring at 4 h post dose, mean arterial bloodpressure having fallen from 93.1 ± 4.5 mm Hg to77.5 ± 7.5 mm Hg at this time. Any continuing effecton mean arterial pressure after this point would havebeen missed and the time to peak effect under-estimated.The time course of the blood-pressure lowering

effect of quinapril has been equated with that ofcaptopril with a peak effect at 1.5-3 h [13, 19]. Ourcontrolled data suggest that in heart failure patients amore accurate comparison may be with enalapril,with which the maximum haemodynamic changes areseen at 4-6 h post dose [20]. The lack of reflex tachy-cardia characteristic of acute ACE inhibition wasconfirmed with quinapril.

Peak concentrations of quinapril occurred at 2 hpost dose, in agreement with previous reports. Theobserved tmax for quinaprilat (3-4 h) is somewhatlonger than that observed in previous studies in nor-mal volunteers (2 h) [21-23]. The observed meanmaximal concentration of quinaprilat seen in the pre-sent study (51 ± 22.8 ng ml-') is similar to that seenin normal volunteers following a single dose of 2.5mg orally [23]. The mean concentration of drugdetectable at 24 h is higher than seen at the sametime in normal volunteers (4.4 ng ml-U compared with2 ng ml-'). The mean AUC (0-24 h) was greater inthe patients with heart failure (422 ± 259 ng ml-' h)than the AUC (0-24 h) seen in normal volunteers(234 ± 87 ng ml-l h) following a single dose ofquinapril 2.5 mg (Meredith, personal communication).Although no formal comparison can be made betweenthe patient groups from these different studies, thesedifferences are likely to reflect differences in renalfunction and drug clearance between healthy volun-

122 I. B. Squire et al.

teers and the older patient population of the presentstudy.The profile of quinapril and quinaprilat differs

somewhat from that seen with other ester prodrugACE inhibitors in this setting. We observed com-parable profiles for ester and diacid (Figure 4)whereas previous studies from our group have showngreater circulating concentrations of parent ester inrelation to the subsequent appearance of a protractedplateau of the diacid metabolite [25]. The lipophilicester prodrug is weakly active in inhibiting ACE butis not felt to have significant biological activity. Thesignificance of the observed variation in pharmaco-kinetic profile remains to be established.

The profile of plasma ACE inhibition in the presentstudy is broadly comparable with that seen in normalvolunteers apart from greater residual enzyme inhibi-tion at 24 h, 63% compared with 50% inhibition involunteers [23]. This is likely to reflect slower drugclearance in the heart failure patients. Although thereis no well established direct relationship between thedegree of circulating ACE inhibition and the bloodpressure response following introduction of ACEinhibitor therapy, no dissociation between the twoparameters was seen in this study. Doses of quinaprilas low as 0.5 mg orally have been shown to produceup to 70% inhibition of plasma ACE, although theduration of effect is reduced with low doses. Whilebaseline mean PRA in this study is similar to thevalues seen in previous studies in heart failure fromour unit, the rise in PRA in the active treatment groupis greater than seen with other ACE inhibitors [24].

In unselected patients, quinapril has been associ-ated with a lower incidence of first-dose hypotension(0.4%) than either enalapril (1.5%) or captopril(2.2%) [19] in patients with hypertension or CHF,although such comparisons are unlikely to reflectequivalent drug exposure for quinapril in CHF. Theeffects on exercise tolerance in response to quinapril5-20 mg twice daily have been assessed in patientswith CHF [25]. Improvement in NYHA functionalclass was seen with doses of 10-20 mg twice daily,lower doses showing no benefit. A second study ofthe effect of quinapril on exercise tolerance inpatients with heart failure demonstrated that oncedaily dosing with quinapril 5-20 mg day-l was aseffective as 5-20 mg day-' in two divided doses [26].The present study indicates the efficacy of a single

2.5 mg oral dose in inhibiting plasma ACE over 24 hin patients with CHF, and this dose has previouslybeen shown to produce beneficial haemodynamicresponses acutely [14, 18]. No information is avail-able on the haemodynamic response to chronic ther-apy with quinapril in a dosage of 2.5 mg once daily.Further studies would be required to identify theminimum, therapeutically effective dose of quinaprilin heart failure in terms of improved mortality.The angiotensin converting enzyme inhibitors are

of proven benefit in the treatment of CHF of allgrades of severity. Considerable concern remainsconcerning the potentially deleterious side effects oftherapy with these agents in CHF and in particularfirst-dose hypotension. Over 80% of physicians sur-veyed recently commenced ACE inhibitor therapy forCHF within hospital where facilities for prolongedobservation of the patient more easily undertaken andappropriate rescuscitative measures available [9].Captopril and enalapril are now licensed in the U.K.to be started for heart failure in general practice. In adouble-blind, placebo controlled study in patientswith heart failure, no blood pressure reduction wasobserved with perindopril 2 mg orally, in contrast tothe notable fall in MAP seen with both enalapril andcaptopril [24]. The size of the starting dose of capto-pril over the range 6.25-25 mg appears to bear norelation to the magnitude of the blood pressure fall[8]. However, these authors emphasise the unpre-dictability of the response and caution is advisedwhen initiating ACE inhibitor therapy in CHF. In par-ticular, the length of time to which a patient isobserved must be adequate and should reflect thepharmacodynamics of the agent chosen.We have established the haemodynamic response

and the pharmacokinetics of 2.5 mg quinapril in CHF.The treatment was well tolerated and resulted inprolonged inhibition of circulating ACE with a con-trolled fall in blood pressure over 3-10 h afterdosing. Our observations suggest both delayed activa-tion and delayed clearance of quinaprilat in CHF. Theblood pressure response is more protracted than pre-viously reported in uncontrolled studies.

This study was supported by Parke-Davis LaboratoriesU.K. We thank Jane White and Adrian Bibby for drugsupplies and logistical support. The technical assistance ofMr D. M. Hughes is gratefully acknowledged. Ms KateHowie provided assistance with statistical analyses.

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(Received 23 November 1993,accepted 11 April 1994)