Drugs

, Volume 67, Issue 9, pp 1359–1378

Imidapril

A Review of its Use in Essential Hypertension, Type 1 Diabetic Nephropathy and Chronic Heart Failure

Authors

    • Wolters Kluwer Health / Adis
    • Wolters Kluwer Health
  • Monique P. Curran
    • Wolters Kluwer Health / Adis
    • Wolters Kluwer Health
  • Katherine A. Lyseng-Williamson
    • Wolters Kluwer Health / Adis
    • Wolters Kluwer Health
Adis Drug Evaluation

DOI: 10.2165/00003495-200767090-00008

Cite this article as:
Robinson, D.M., Curran, M.P. & Lyseng-Williamson, K.A. Drugs (2007) 67: 1359. doi:10.2165/00003495-200767090-00008

Summary

Abstract

Imidapril (Tanatril™), through its active metabolite imidaprilat, acts as an ACE inhibitor to suppress the conversion of angiotensin I to angiotensin II and thereby reduce total peripheral resistance and systemic blood pressure (BP).

In clinical trials, oral imidapril was an effective antihypertensive agent in the treatment of mild to moderate essential hypertension. Some evidence suggests that imidapril also improves exercise capacity in patients with chronic heart failure (CHF) and reduces urinary albumin excretion rate in patients with type 1 diabetes mellitus. Imidapril was well tolerated, with a lower incidence of dry cough than enalapril or benazepril, and is a first choice ACE inhibitor for the treatment of mild to moderate essential hypertension.

Pharmacological Properties

The active metabolite of imidapril is imidaprilat, which inhibits the conversion of angiotensin I to angiotensin II. Lowering of plasma and tissue angiotensin II levels results in peripheral vasodilation, reduced systemic BP, renoprotective effects in patients with type 1 diabetes, and decreased renal sodium and water retention.

After multidose oral administration in patients with hypertension, steady-state maximum plasma concentrations of imidapril (≈30 ng/mL) and imidaprilat (≈20 ng/mL) are achieved in a median time of 2 and 5 hours. In healthy men 25.5% of a single dose of imidapril 10mg was excreted in the urine within 24 hours. Elimination occurs primarily through excretion in the urine (≈40%) and faeces (≈50%); after oral administration in healthy volunteers, the terminal elimination half-life of imidaprilat is ≈24 hours.

Therapeutic Efficacy

In randomised controlled trials, oral imidapril was effective in the treatment of adults with mild to moderate essential hypertension. In short-term (2- and 4-week) dose-finding trials, imidapril dosages of 10–40 mg/day were significantly more effective than placebo, inducing 11–15mm Hg reductions in sitting diastolic BP (sDBP; primary endpoint). In comparative 12- and 24-week trials, imidapril 5–20 mg/day induced reductions in mean sDBP of 10–15mm Hg that did not differ significantly from those induced by hydrochlorothiazide 12.5–50 mg/day or captopril 50–100 mg/day (primary endpoint), nor those induced by enalapril 5–10 mg/day or nifedipine sustained release (SR) 40–80 mg/day (secondary endpoint). In addition, reductions in sDBP and sitting systolic BP (co-primary endpoints) with imidapril did not differ from those induced by candesartan 4–16 mg/day. Favourable reductions in sDBP were maintained during 6-month and 52-week noncomparative trials.

In patients with type 1 diabetes, the urinary albumin excretion rate (a marker of nephropathy) increased by 72% in placebo recipients, but declined by 41% in imidapril 5 mg/day and by 6% in captopril 37.5 mg/day recipients during a mean treatment period of 1.5 years.

In patients with CHF, mean total exercise time increased from baseline in imidapril 2.5–10 mg/day recipients in a dose-related manner after 12-weeks of treatment; a 9.7% increase with imidapril 10 mg/day was significantly greater than the change with placebo (+0.7%).

Tolerability

Overall, imidapril was relatively well tolerated, with an incidence of adverse events in pooled analyses of data from clinical trials and post-marketing surveillance (n = 6632) of 6.6%. The most commonly reported adverse events were cough, hypotension, dizziness and pharyngeal discomfort. During 2- and 4-week trials, the overall incidence of adverse events was 26% and 40% in recipients of imidapril 2.5–40 mg/day compared with 35% and 37% in placebo recipients. In comparative trials, the incidence of treatment-related adverse events in imidapril versus enalapril recipients in two 12-week trials were 5.6% versus 12.2% and 12.0% versus 14.1%; in other 12-week trials treatment-related adverse events were observed in 24.2% of imidapril versus 41.7% of nifedipine SR, and 20.7% of imidapril versus 46.4% of captopril recipients, while the overall incidence of adverse events in imidapril versus candesartan recipients was 11.7% versus 16.1%. The incidences of adverse events in a 24-week trial were 46.0% with imidapril and 52.8% with hydrochlorothiazide. In longer-term trials, adverse events were reported by 61.6% of imidapril recipients in the 52-week trial; however, only 1.7% of imidapril recipients in a 6-month field trial experienced adverse events considered related to ACE inhibitor treatment.

In prospective investigations in hypertensive patients, switching to imidapril did not reduce the incidence of cough (a class effect of ACE inhibitors) in a small open-label trial in hypertensive patients already experiencing ACE-inhibitor induced cough; however, in a large crossover trial, the incidence of cough with imidapril (15.2%) was less than half that with enalapril (38.6%). In addition, cough disappeared in 52.9% of enalapril recipients switched to imidapril, and in patients without cough during imidapril treatment, switching to enalapril induced cough in 20.9%. In contrast, in patients without cough during initial enalapril treatment, only 0.9% developed cough during subsequent imidapril treatment. In a second large, double-blind crossover trial, the incidence of cough was significantly lower in imidapril than benazepril recipients.

1. Introduction

For several decades, a variety of ACE inhibitors have been used to inhibit the renin-angiotensin-aldosterone system, and have been effective in reducing hypertension, lowering the risk of mortality in patients with heart failure, and preventing and delaying the progression of diabetic nephropathy.[1]

Hypertension has been estimated to annually contribute to 7.1 million premature deaths and 4.4% of the global disease burden (64 million disability-adjusted life-years).[2] Even modest reductions in blood pressure (BP), particularly diastolic BP (DBP) [5–6mm Hg over 2–3 years], decrease the risk of stroke by ≈35–40%, while the risk of coronary heart disease is reduced by ≈20–25% and that of chronic heart disease by 14%.[3]

Heart failure is also a significant public health issue, occurring in ≈5 million US residents and ≈10 million Europeans.[4,5] The prognosis for patients with this condition is poor; ≈50% of those diagnosed with heart failure die within 4 years.[4]

In patients with type 1 or type 2 diabetes mellitus, diabetic nephropathy is a major cause of morbidity, occurring in 20–30% of patients, with the earliest clinical evidence of its existence being microalbuminuria, the appearance of abnormal levels of albumin in the urine (≥30 mg/day).[6] Overt nephropathy or clinical albuminuria (≥300 mg/day), with associated hypertension, develops over a 10- to 15-year period. Thereafter, the glomerular filtration rate declines over several years; end-stage renal disease develops in 50% of patients within 10 years.[6]

Imidapril (Tanatril™)1 is an oral ACE inhibitor currently in pre-registration in the US, and which is approved in multiple countries around the world including Japan,[7] Austria, France, Germany,[8] Spain, Portugal, Greece[9] and the UK[10] for the treatment of essential hypertension. In Japan, China, Korea and several other Asian countries, it is also approved for the treatment of renal parenchymal hypertension.[7,9] It is also approved for diabetic nephropathy associated with type 1 diabetes in Japan, Korea and Pakistan,[7,9] and for chronic heart failure (CHF) in the Czech Republic.[9] This review focuses on the use of imidapril in essential hypertension, type 1 diabetic nephropathy and CHF.

2. Pharmacodynamic Properties

Imidapril (figure 1) is a non-sulfhydryl ACE inhibitor prodrug, whose active diacid metabolite imidaprilat is responsible for the major pharmacodynamic effects of the drug after oral administration, through inhibition of the conversion of angiotensin I to angiotensin II.[44] As with other ACE inhibitors, the reduction of angiotensin II in the plasma is responsible for the majority of the pharmacodynamic effects of imidapril (table I), including peripheral vasodilation, reduced BP and decreased sodium and water retention by the kidney.[44]
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Fig. 1

Structures of imidapril and imidaprilat.

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Table I

Summary of the pharmacodynamic properties of imidapril

In a trial in patients with essential hypertension[15] (see section 4.1 for trial details), inhibition of plasma ACE activity after imidapril 2.5–20 mg/day demonstrated a non-linear relationship to plasma imidaprilat concentrations, with the inhibition of ACE activity continuing after plasma imidaprilat concentrations had declined.[15] Prolonged inhibition of ACE is thought to result from a small fraction of total plasma imidaprilat that remains bound to ACE.[15] In rats, imidapril also reduced ACE activity in the brain, lung and aorta.[14] In patients with hypertension receiving imidapril 10mg once daily, maximal ACE inhibition after 4 weeks was 75%, whereas immediately prior to the next dose it was 50%.[45]

Repeated administration of imidapril lowered BP for over 24 hours in patients with essential hypertension, with a time profile that more closely follows that of ACE inhibition than plasma imidaprilat concentrations.[15] Based on an analysis of data from the 2-week dose-finding study described more fully in section 4.1,[15] the trough-to-peak ratios for sitting DBP (sDBP) were 0.78, 0.84 and 0.63 for imidapril doses of 5, 10 and 20 mg/day, respectively.[46] In a small phase I study, dosages as low as 2.5 mg/day for 2 weeks significantly reduced BP from levels recorded during baseline placebo administration.[9]

Imidapril improved endothelial function in animal models[27] and in patients with hypertension.[29,30] In addition, it reduced measures of left ventricular (LV) hypertrophy in hypertensive patients[17,4749] and in patients after an acute myocardial infarction (MI),[11,38,39] and reduced plasma fibrinolytic activity in patients after an acute MI.[11,39] Imidapril also demonstrated renoprotective effects in patients with type 1 diabetes[50] and chronic glomerulonephritis.[37]

3. Pharmacokinetic Properties

The pharmacokinetic profile of imidapril has been examined in a variety of populations (table II).
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Table II

Pharmacokinetics of imidapril and imidaprilat after single or repeated doses of oral imidapril 10mg.[44,45,51,52] Mean or range values are reported, unless otherwise stated

Imidapril is absorbed from the gastrointestinal tract in proportion to dose, and is then rapidly converted to the active metabolite imidaprilat.[7]

In healthy volunteers (n = 6) after administration of single oral doses of imidapril 2.5–20mg, the imidapril and imidaprilat peak plasma concentrations (Cmax) [5.8–54.9 ng/mL and 1.2–28.8 ng/mL] and their respective areas under the plasma drug concentration-time curve from 0 to 24 hours (AUC24) [30.2–238.2 ng ⋅ h/mL and 18–304.1 ng ⋅ h/mL] increased in a linearly dose-related manner.[53]

In patients with mild to moderate hypertension receiving oral imidapril 10 mg/day,[45] the multidose imidapril Cmax was reached after a median of ≈2 hours; steady-state imidaprilat Cmax was reached after 5 hours (table II).[45] After 4 weeks, the trough imidaprilat concentration was 4.4 ng/mL, giving a trough : peak concentration ratio of 0.21.[45]

The absolute bioavailability of imidapril is ≈42%, while 85% of imidapril and 53% of imidaprilat is bound to plasma protein.[10]

In addition to de-esterification to the active metabolite imidaprilat, imidapril is also metabolised in the liver into three inactive metabolites.[7] When a single dose of imidapril 10mg was administered to healthy adult men, 25.5% of the dose was excreted in the urine within 24 hours. Following administration of an oral dose of radiolabelled imidapril, ≈40% of the radioactivity was recovered in the urine and ≈50% was recovered in the faeces.[10]

Based on limited sampling (24–48 hours) in healthy volunteers, the multidose elimination half-life of imidapril is ≈2–4 hours,[44,51,52] while imidaprilat declines in a biphasic manner with an initial half-life of ≈8–15 hours[10,45,5153] and a terminal elimination half-life, based on single-dose administration, of 16–23 hours[53] or >24 hours.[10]

After a single dose of imidapril 10mg, the imidaprilat Cmax was significantly reduced in patients with impaired liver function (Child-Pugh grade A) compared with patients with normal liver function (table II), suggesting a delayed conversion of imidapril into imidaprilat.[52] However, no significant between-group difference in steady-state imidapril or imidaprilat pharmacokinetics or accumulation of either drug were observed after repeated doses of imidapril 10mg.

Accumulation of imidaprilat occurred in patients with severe renal dysfunction (mean creatinine clearance [CLCR] 18 mL/min) when compared with healthy volunteers (mean CLCR 116 mL/min), with significantly higher mean Cmax and AUC values (table II).[51] There was no significant difference in imidapril or imidaprilat pharmacokinetics between patients with moderate renal dysfunction (mean CLCR 64 mL/min) and those with normal renal function.[51]

There were no significant pharmacokinetic interactions when imidapril was co-administered with hydrochlorothiazide, bisoprolol or nilvadipine.[54] Concomitant administration of imidapril and digoxin reduced the Cmax of imidapril by 15% and of imidaprilat by 20%, while AUC was reduced by 19% and 10%. Co-administration had no effect on the pharmacokinetics of digoxin.[12]

Imidapril, like other ACE inhibitors, may inhibit aldosterone production and decrease potassium secretion; thus, concomitant use of potassium-sparing diuretics or potassium supplements is not recommended.[7] Imidapril may increase reabsorption of lithium in the renal tubules and increase the toxicity of lithium if co-administered with lithium preparations.[7]

4. Therapeutic Efficacy

Randomised, double-blind comparative trials have examined the therapeutic use of oral imidapril once daily in the treatment of mild to moderate essential hypertension (section 4.1), nephropathy in patients with type 1 diabetes (section 4.2) and CHF (section 4.3). Additional longer-term noncomparative trials have also been conducted in patients with mild to moderate essential hypertension (section 4.1.3).

Imidapril is approved in Japan and several other Asian countries for the treatment of renal parenchymal hypertension,[7] although published data in this indication are limited. A clinical study involving patients with renal parenchymal hypertension is reported in the manufacturer’s Japanese prescribing information, in which imidapril was deemed effective (criteria not defined) in 25 of 31 patients.[7]

4.1 In Essential Hypertension

The therapeutic efficacy of imidapril in the treatment of adults with mild to moderate essential hypertension has been examined in randomised, double-blind, placebo-controlled, multicentre, dose-finding, 2- and 4-week trials (reported together in one paper)[15] and in randomised, double-blind, parallel-group, comparative, multicentre, 12-[2023,55] and 24-week[8] trials. Additional data have been obtained from noncomparative, multicentre, 6-month[56] and 52-week[24] trials. Some additional unpublished data have been derived from an expert report obtained from the manufacturer.[46] See table III for study design details.
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Table III

Trial design details of multicentre trials of oral imidapril (IMI) in patients (pts) with mild to moderate essential hypertension[8,15,2024,55,56]

Prior to active treatment, patients underwent a placebo run-in period of 2–4 weeks.[8,15,2024,55] In all but the dose-ranging trials,[15] medication doses were titrated upwards after 4[8,2024,55] and 8[8] weeks if sDBP was still ≥90mm Hg[8,20,2224] (with additional furosemide [frusemide] 20 mg/day if necessary in one trial),[24] or if sitting systolic BP (sSBP)/sDBP was ≥140/90mm Hg[55] or >149/89mm Hg or had declined by <20/10mm Hg.[21]

Intent-to-treat (ITT) analyses in patients receiving at least one dose of imidapril examined the effects on the primary endpoints of sDBP,[8,15,20,24] sSBP and sDBP[55] or response rate.[2123] In most trials, BP measurements were made immediately prior to the next due medication dose (trough).[8,15,20,2224,55] Secondary endpoints included changes in sSBP, standing DBP and SBP, and the proportion of patients with an sDBP response (decrease ≥10mm Hg) or sDBP normalisation (sDBP ≤90mm Hg),[8,15,2024] or a response defined as an sSBP/sDBP <140/90mm Hg, sSBP reduced by ≥20mm Hg and/or sDBP reduced by ≥10mm Hg.[55]

Patients had a mean age of 52–61[15,2024,55,56] or 72[8] years, and 40–67% were female.[15,2024,55,56] Mean baseline sDBP was 97–103mm Hg.[15,2024,55,56]

At the end of two of the 12-week comparative trials, 47%[23] and 49%[22] of imidapril recipients were still receiving the initial dosage (5 mg/day), as were 45% of enalapril recipients,[22] while 58% of nifedipine sustained release (SR) recipients were receiving the initial 20 mg twice-daily dosage.[23] In the 24-week study in elderly patients,[8] 48% of imidapril recipients were receiving 5 mg/day, 28% were receiving 10 mg/day and 24% were receiving 20 mg/day; hydrochlorothiazide recipients were receiving 12.5 mg/day (46%), 25 mg/day (23%) or 50 mg/day (32%).

4.1.1 Versus Placebo

In general, imidapril reduced sDBP in a dose-dependent manner and induced significantly greater reductions in BP than placebo at dosages of 10–40 mg/day (table IV).[15] In the 2-week trial, mean sDBP declined significantly (p ≤ 0.05) from baseline in all treatment groups with a significantly (p = 0.003) linear dose response, and to a significantly greater extent (p ≤ 0.05) in imidapril 20 mg/day than in placebo or imidapril 2.5 or 5 mg/day recipients.[15]
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Table IV

Efficacy of oral imidapril (IMI) in patients (pts) with mild to moderate essential hypertension. Mean baseline and change from baseline in sitting diastolic blood pressure (sDBP) and sitting systolic blood pressure (sSBP) in randomised, double-blind, placebo-controlled, multicentre, 2- or 4-week dose-finding trials[15,46]

While reductions in standing DBP differed significantly (p < 0.05) between placebo and imidapril 20 mg/day treatment groups, and reductions in standing SBP differed (p < 0.05) between placebo and imidapril 10 and 20 mg/day treatment groups (data not shown), there was no linear- or multiple-comparison difference between treatment groups in sSBP in the 2-week trial (table IV).[15] Favourable responses to treatment occurred in 42–83% of imidapril 5–20 mg/day recipients (table IV), while the response rate in the imidapril 2.5 mg/day treatment group did not differ from that in placebo recipients.

In the larger 4-week trial, mean sDBP declined from baseline by 5mm Hg in placebo recipients and by 8–12mm Hg in imidapril recipients (table IV), with significantly (p ≤ 0.05) greater reductions with imidapril 10, 20 and 40 mg/day than with placebo.[15] Reductions in sDBP of ≥10mm Hg were observed in 42–65% of imidapril and 40% of placebo recipients, while reductions in sSBP (table IV) and standing DBP and SBP (data not shown) were greater with imidapril 10, 20 and 40 mg/day than with placebo.[15]

4.1.2 Versus Other Antihypertensives

Overall, imidapril induced a reduction in mean sDBP of 10–15mm Hg after 12–24 weeks of treatment (table V) that did not differ significantly from that induced by candesartan,[55] captopril,[20] hydrochlorothiazide[8] (primary endpoints), enalapril[21,22] or nifedipine SR[23] (secondary endpoints). In one of the 12-week trials, the decline in the coprimary endpoint sSBP did not differ between imidapril and candesartan recipients (10.5% vs 11.7%).[55]
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Table V

Efficacy of oral imidapril (IMI) in patients (pts) with mild to moderate essential hypertension. Mean baseline and change from baseline in sitting diastolic blood pressure (sDBP), sitting systolic blood pressure (sSBP) and response rate in randomised, double-blind, parallel-group, comparative, multicentre 12- or 24-week trials[8,2023,55]

In trials that reported the time-course of sDBP reductions, the decline from baseline in mean sDBP was significant (p < 0.05) after 2 weeks of treatment with imidapril, captopril or enalapril, and the reductions were sustained for 12 weeks.[20,21] Reductions in sDBP were sustained for up to 24 weeks in elderly patients receiving imidapril or hydrochlorothiazide.[8]

The response rate in imidapril recipients did not differ significantly from that observed with comparators in trials where it was a primary[2123] or secondary endpoint[8,20,55] (table V).

Changes in other endpoints did not differ between imidapril and active comparators. Decreases from baseline in mean sSBP (table V), standing DBP, standing SBP or mean BP occurring with imidapril and comparator drugs did not differ significantly amongst treatment groups (specific data not shown).[8,21,22]

Normalisation of sDBP (≤90mm Hg)[20,22,23] or sSBP/sDBP (<140/90mm Hg)[55] occurred in 46%,[20] 50%,[23] 55%[55] or 70%[22] of imidapril recipients, and in 40% of captopril,[20] 45% of candesartan,[55] 52% of nifedipine SR[23] and 68% of enalapril[22] recipients, with no significant differences between imidapril and comparator response rates.[23]

4.1.3 Longer-Term Noncomparative Trials

Overall, favourable initial reductions in BP with imidapril treatment were maintained over 6–12 months of treatment.[24,56]

In the 6-month field trial, mean sSBP/sDBP values declined by 12–13% (21/11mm Hg; p < 0.01 vs baseline) with imidapril 2.5–20 mg/day; mean pulse pressure declined by 18% (from 74 to 61mm Hg; p < 0.01).[56] A reduction in sDBP of >10mm Hg was observed in 64% of patients and a >15mm Hg reduction in sSBP in 71% of patients at trial end, while a BP of ≤140/90mm Hg was achieved by 29% of patients after a mean of 26 days of treatment and was maintained to trial end.[56]

After 52 weeks of treatment with imidapril 5–20 mg/day, mean sDBP was significantly (p < 0.001) reduced from 102 to 88mm Hg (primary endpoint), while mean sSBP declined significantly (p < 0.001) from 166 to 147mm Hg.[24] During this period, sDBP was normalised (≤90mm Hg) or declined by ≥10mm Hg in 85% of patients, while mean standing DBP declined from 104 to 90mm Hg and mean standing SBP from 166 to 146mm Hg (both p < 0.001).

4.2 In Nephropathy with Type 1 Diabetes Mellitus

In a randomised, double-blind, placebo- and comparator-controlled trial, 79 Japanese patients with type 1 diabetes with a urinary albumin excretion (UAE) rate >30 mg/day and a glycosylated haemoglobin (HbA1c) level <10% received imidapril 5 mg/day (n = 26), captopril 37.5 mg/day (n = 26) or placebo (n = 27) for a mean of 1.48 years.[50] Patients with a serum creatinine level >177 μmol/L or other renal, liver, endocrine, cardiovascular, gastrointestinal or connective tissue diseases were excluded. Patients had a mean age of 33 years, 65% were female and the mean baseline UAE rate was 711 mg/day.

Treatment with imidapril reduced albuminuria in patients with type 1 diabetes.[50] The UAE rate (primary endpoint) increased in placebo recipients (figure 2), but was reduced by imidapril (p < 0.001 vs placebo) and captopril (p < 0.043 vs placebo). At baseline, sSBP/sDBP was 129/80mm Hg in imidapril, 126/76mm Hg in captopril and 127/78mm Hg in placebo recipients, while at trial end the values were 130/79mm Hg, 129/79mm Hg and 135/79mm Hg, respectively, with no differences among treatment groups. However, an analysis of covariance indicated that changes in sSBP may be related to changes in UAE rate, with a Spearman correlation coefficient of 0.37 (p = 0.001) across all treatment groups. Serum creatinine, CLCR and HbA1c values did not differ amongst treatment groups at trial end.[50]
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Fig. 2

Percentage change in urinary albumin excretion (UAE) in Japanese patients with type 1 diabetes with a UAE rate >30 mg/day receiving imidapril 5 mg/day (n = 26), captopril 37.5 mg/day (n = 26) or placebo (n = 27) for a mean of 1.48 years.[50] * p < 0.05, ** p < 0.001 vs placebo.

4.3 In Chronic Heart Failure

In a randomised, double-blind, placebo-controlled, dose-ranging, multicentre, 12-week trial,[16] 244 patients with stable (on digoxin and diuretics) mild to moderate CHF (New York Heart Association functional class II–III) received imidapril 2.5, 5 or 10 mg/day or placebo. Patients aged 21–75 years were eligible if they had a LV ejection fraction (LVEF) <0.45 and a total exercise duration on a cycle ergometer of between 2 and 12 minutes, but were excluded if they had other pre-existing cardiac disorders, severe hypertension or hypotension, right-sided CHF or impaired renal function. After a 2-week placebo run-in period, imidapril treatment commenced at a dosage of 2.5 mg/day and was increased to the assigned dosage during the first 3 weeks of treatment.[16]

Primary analysis was conducted on the ITT population. Demographic profiles were well matched across treatment groups; 77% of patients were male, mean age was 61 years and mean sSBP/sDBP was 137/83mm Hg.[16]

After 12 weeks of treatment, mean total exercise time (primary endpoint) was increased in imidapril recipients in a dose-related manner, with a 9.7% (45s) increase (figure 3) from baseline values in patients receiving imidapril 10 mg/day.[16] Changes in exercise duration in the imidapril 2.5 (2.5%; 11s) and 5 mg/day (3.5%; 16s) treatment groups did not differ significantly from those in the placebo group (0.7%; 3s). No significant changes in heart rate or BP were observed.
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Fig. 3

Effect of oral imidapril (IMI) on exercise duration in patients with chronic heart failure (CHF). Mean (± SD where reported) total exercise time on a cycle ergometer in 244 patients with mild to moderate CHF (New York Heart Association functional class II–III) receiving placebo (PL; n = 62) or IMI 2.5mg (n = 65), 5mg (n = 57) or 10mg (n = 60) once daily (some data estimated from a graph).[16] * p < 0.05 vs change with placebo; † p < 0.05 vs change with IMI 2.5 mg/day.

Changes in the physical working capacity at a heart rate of 110 beats/min (secondary endpoint) were also observed in imidapril recipients, with ≈2–3 watt increases in the imidapril 5 and 10 mg/day treatment groups (p = 0.02 and p = 0.005 vs placebo).[16]

Progressive CHF leading to discontinuation occurred less frequently with imidapril than with placebo (3 of 182 [2%] vs 6 of 62 [10%] patients; p < 0.05).[16]

5. Tolerability

Adverse events occurring during the use of imidapril (section 5.1) have been reported in several of the studies discussed in section 4[8,15,2024,56] and in pooled analyses of clinical trials and post-marketing surveillance reported in the manufacturer’s prescribing information.[7] With the exception of one trial,[20] only descriptive analyses were reported. Additional studies[5759] have investigated the effect of imidapril on persistent dry cough, a class effect of ACE inhibitors (section 5.2).

5.1 General Profile

In pooled data from clinical trials (n = 858) and post-marketing surveillance (n = 5774),[7] adverse events occurred in a total of 440 (6.6%) patients. The most commonly reported adverse events were cough, hypotension, dizziness and pharyngeal discomfort (figure 4).
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Fig. 4

Tolerability of oral imidapril. Common adverse events reported in pooled data from clinical trials (n = 858) and post-marketing surveillance data (n = 5774) reported in the manufacturer’s prescribing information.[7]

Abnormal laboratory findings suspected to be drug related occurred in 56 (6.5%) patients in pooled clinical trial data and included increased ALT (2.0% of patients), AST (1.8%) and creatinine (0.8%) levels.[7]

Overall, imidapril was relatively well tolerated when compared with placebo[15] or other antihypertensive agents.[8,2023]

The incidence of adverse events with imidapril was numerically similar to that with placebo in the 2- and 4-week placebo-controlled trials (26% vs 35% and 40% vs 37%).[15] The most commonly reported adverse events were headache in the 2-week trial and headache and dizziness in the 4-week trial.

In both the 2- and 4-week placebo-controlled trials, statistically but not clinically significant rises in serum potassium levels were observed in imidapril 20 mg/day recipients (from 4.0 to 4.3 and from 4.2 to 4.4 mmol/L; p < 0.05) [reference range 3.6–5.0 mmol/L].[15]

The overall incidence of adverse events did not differ between imidapril and hydrochlorothiazide[8] or enalapril[21,22] (table VI). Adverse events considered causally related to treatment occurred in significantly fewer imidapril than captopril recipients.[20]
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Table VI

Tolerability of imidapril (IMI). Percentage incidences of the most frequent selected adverse events in patients (pts) receiving imidapril or comparator drugs in randomised, double-blind, parallel-group, comparative, multicentre, 12- or 24-week trials[8,2023]

Withdrawals as a result of adverse events in imidapril versus comparator recipients occurred as follows: 0.0% versus 1.7% of enalapril,[22] 1.7% versus 3.2% of candesartan,[55] 2.4% versus 5.7% of placebo,[15] 3.8% versus 16.0% of nifedipine SR[23] and 8.4% versus 9.8% of hydrochlorothiazide[8] recipients.

In the placebo-controlled trials no serious adverse events were reported.[15] In the comparative trials serious adverse events occurred in one imidapril and one nifedipine SR recipient,[23] one imidapril and six enalapril recipients,[21] two imidapril and four enalapril recipients,[22] nine imidapril and seven hydrochlorothiazide recipients[8] and zero imidapril and one candesartan recipient.[55] In two trials, these adverse events were considered remotely related or unrelated to study medication.[22,23]

Three elderly patients receiving imidapril died during one comparative trial;[8] one death caused by MI was considered not treatment related, and two other deaths (probable cerebrovascular accident, respiratory failure and shock)[9] were not considered more than possibly treatment related.[8]

In longer-term noncomparative trials, adverse events were reported by 61.6% of imidapril recipients in the 52-week trial;[24] 13.6% of patients reported adverse effect during a 2-week placebo run-in period. The most commonly reported events during the active treatment phase were cough (12.7%), headache (9.3%) and bronchitis (6.8%). In the 6-month field trial, 1.7% of imidapril recipients experienced adverse events considered related to ACE inhibitor treatment.[56] As a result of adverse events, 1.0%[56] and 7.9%[24] of patients in the longer-term trials discontinued treatment.

5.2 Cough

A common adverse event associated with the use of ACE inhibitors is persistent dry cough, which is sometimes severe enough to require drug withdrawal.[60] Although the precise mechanism is uncertain, it is thought that ACE inhibitors promote accumulation of bradykinin or tachykinins and substance P, with the subsequent formation of arachidonic acid metabolites and nitric oxide. In vitro data suggest that the degree of inhibition of bradykinin-metabolising enzymes by imidaprilat may be less than that with enalaprilat.[43]

In comparative trials versus other ACE inhibitors (table VI), the incidences of cough in imidapril and enalapril recipients were 0.9% versus 6.9%[21] and 2.9% versus 4.0%.[22] The only trial to statistically compare the incidence of cough with another ACE inhibitor was small (n = 47) and the difference between imidapril and captopril was nonsignificant (13.8% vs 35.7%; p = 0.055).[20] In longer-term noncomparative trials, the incidence of ACE inhibitor-related cough was 1.1%[56] and 1.7%.[24]

Three randomised crossover trials have further examined this aspect of imidapril tolerability.[5759] In a small, open-label crossover trial in 60 hypertensive patients with pre-existing ACE inhibitor-induced cough, imidapril 5 or 10 mg/day for 6 weeks did not reduce the incidence of cough or pharyngeal/laryngeal irritation (not defined).[57]

A larger (n = 566), double-blind crossover trial in Chinese patients with essential hypertension, reported that the incidence of cough was significantly (p < 0.05) lower in imidapril 5–20 mg/day than in benazepril 10–40 mg/day recipients; the incidence of cough was 14.5% versus 24.6% during an initial 6-week treatment period, and 16.9% versus 23.0% during a subsequent 6-week crossover period.[58]

In another large (n = 489), crossover trial in patients with mild to moderate essential or renal parenchymal hypertension, patients received imidapril 2.5–10 mg/day or enalapril 2.5–10 mg/day for 12 weeks, followed by crossover to the alternative treatment arm.[59] In this trial, the incidence of cough in patients initially treated with imidapril was less than half that of patients initially receiving enalapril (32 of 210 [15.2%] vs 85 of 220 [38.6%]; p < 0.001).[59] In patients with cough during the first treatment period, cough disappeared in 37 of 70 (52.9%) enalapril recipients who subsequently switched to imidapril, but persisted in all 21 (100%) imidapril recipients who switched to enalapril. In patients who did not develop cough during initial treatment with imidapril, switching to enalapril induced cough in 20.9% (31 of 148). In contrast, in enalapril recipients without cough during initial enalapril treatment, only 0.9% (1 of 110) developed cough during subsequent imidapril treatment.[59]

6. Dosage and Administration

In patients with essential hypertension[7,10] once daily oral imidapril is initiated at 5 mg/day, with the dosage titrated depending on efficacy to 10 mg/day[7,10] or, in a small number of patients, to a maximum of 20 mg/day.[10] In elderly patients, those with impaired renal or hepatic function, those at an increased risk of first-dose hypotension,[10] and in patients with renal parenchymal hypertension,[7] the initial dosage should be 2.5 mg/day. Where approved, the dosage in patients with type 1 diabetic nephropathy is 5 mg/day, with initiation at 2.5 mg/day in patients with serious renal dysfunction.[7]

Local prescribing information should be consulted for dosage reduction guidelines, dosage recommendations in special populations, contraindications and precautions.

7. Place of Imidapril in the Management of Essential Hypertension, Type 1 Diabetic Nephropathy and Chronic Heart Failure

A major goal of hypertension treatment is the reduction of associated cardiovascular and renal morbidity and mortality;[61] 13% of deaths, 49% of ischaemic heart disease and 62% of cerebrovascular disease are associated with suboptimal BP control.[2]

Treatment of hypertension has been associated with a reduction in the risk of stroke and MI,[3] and reductions in the incidence of stroke, coronary heart disease, major cardiovascular event risk, cardiovascular death and total mortality appear to be dependent on the magnitude of BP reduction, particularly SBP reduction.[62] Treatment is maximally protective when SBP/DBP is lowered to ≤140/85mm Hg;[63] however, many patients with identified hypertension are untreated or undertreated, and only about one-third of hypertensive patients have BP controlled to <140/90mm Hg.[64]

In fact, all-cause mortality remains higher in treated hypertensive patients than in a nonhypertensive population of similar age.[65] In a prospective observational study in Sweden, despite hypertension treatment for up to 23 years that reduced mean supine SBP/DBP from 169/109 to 145/89mm Hg after 15 years, all-cause mortality in treated hypertensive men remained higher than in normotensive men (odds ratio 1.6; 95% CI 1.4, 2.1), primarily as a result of higher mortality from coronary heart disease (1.9; 95% CI 1.6, 2.3) and stroke (2.1; 95% CI 1.4, 2.7).

In addition, a very large meta-analysis of prospective data from almost 1 million adults has suggested a relationship of BP to the risk of vascular death that declines in proportion to BP down to at least 115/75mm Hg, with no apparent threshold for risk-reduction.[66] Thus the simple premise of ‘the lower the pressure the better’ may become a cornerstone of hypertension management.[67]

According to EU,[68] UK,[69] US[61] and WHO[70] guidelines, the threshold for drug therapy is ≥140–160/90–100mm Hg in low-risk (no target organ damage) hypertensive patients, and ≥130–140/85–90mm Hg in high-risk patients (target organ damage, cardiovascular complications or diabetes). Lifestyle interventions are recommended in all patients receiving drug therapy,[61,6870] and in low-risk patients with a BP of 120–139/80–89mm Hg.[61,68]

Recommended lifestyle modifications include cessation of smoking, weight loss in obese patients, increased physical activity, moderation of alcohol intake, a reduced dietary intake of sodium and saturated fats and an increased intake of potassium and fresh fruit and vegetables.[61,6870]

Although the subject of continuing controversy,[62,7174] convincing evidence of any advantage conferred by use of a particular pharmacological antihypertensive therapy amongst ACE inhibitors, calcium channel antagonists, angiotensin II receptor antagonists, diuretics and β-adrenoceptor antagonists is lacking. It should also be noted that the relative risk of an MI during treatment with ACE inhibitors or angiotensin II receptor antagonists is the subject of ongoing debate.[7582]

International guidelines suggest similar efficacy of most classes of antihypertensive agents, and a frequent requirement for multidrug therapy to achieve BP goals.[61,6870] Both the US[61] and WHO[70] guidelines recommend, in the absence of a compelling indication or contraindication, the first choice use of a low-dose diuretic, particularly of the thiazide type, on the basis of equivalent efficacy, good tolerability and generally lower cost than other antihypertensive agents.

However, UK guidelines[69] and recently revised British National Institute of Clinical Excellence[83] guidelines recommend initiating therapy with an ACE inhibitor in patients <55 years of age, in order to suppress renin levels, which are more likely to be elevated in this population, and a calcium channel antagonist or thiazide-type diuretic in those aged ≥55 years, in whom renin levels tend to be lower.[69,83] If a second antihypertensive agent is required, the addition of a calcium channel antagonist or thiazide-type diuretic to an ACE inhibitor is recommended.[83] The use of β-adrenoceptor antagonists for initial or combination therapy is not recommended based on lower efficacy and an increased risk of developing diabetes, particularly in combination with a thiazide-type diuretic.[83]

Imidapril is a prodrug, whose active metabolite imidaprilat inhibits the conversion of angiotensin I to angiotensin II. The resulting decline in plasma angiotensin II levels is primarily responsible for the majority of the pharmacodynamic effects of imidapril (section 2), including peripheral vasodilation, reduced BP, decreased sodium and water retention by the kidney, and renoprotective effects in patients with type 1 diabetes.

Once absorbed, imidapril is rapidly converted to imidaprilat in the liver, with steady-state imidaprilat Cmax levels achieved after 7 hours (section 3). The initial elimination half-life of imidaprilat is 8–15 hours and the terminal elimination half-life is ≈24 hours, allowing for once-daily administration, with an imidapril concentration trough : peak ratio of 0.21 and sDBP trough : peak ratios of 0.63–0.84 (section 2).

In clinical trials, imidapril was effective in the treatment of mild to moderate essential hypertension (section 4.1). In short-term trials (2–4 weeks) imidapril 10–40 mg/day induced 11–15mm Hg reductions in sDBP that were significantly greater than those achieved with placebo (section 4.1.1). In 12- or 24-weeks trials, imidapril 5 to 20 mg/day reduced sDBP by 10–15mm Hg, reductions which did not differ significantly from those induced by hydrochlorothiazide 12.5–50 mg/day, candesartan 4–16 mg/day, captopril 50–100 mg/day, enalapril 5–10 mg/day or nifedipine SR 40–80 mg/day (section 4.1.2). The efficacy of imidapril was confirmed in longer-term trials (section 4.1.3).

Additional data from an unpublished randomised, double-blind 12-week study in patients aged 18–75 years receiving oral imidapril 5–10 mg/day (n = 158) or atenolol 50–100 mg/day (n = 159), suggest that the decline in supine DBP was greater in atenolol than in imidapril recipients (9.3 vs 12.1mm Hg; p = 0.0003), whereas the difference in the decline in supine SBP (12.8 vs 15.2mm Hg), response rate (63% vs 73%) and the proportion of patients with a normalised BP at study end (51% vs 62%) did not differ between treatment groups.[46] Further data from this study or from other comparisons with β-adrenoceptor antagonists are necessary for a complete evaluation of the relative efficacies of these agents.

In patients with type 1 diabetes who have sustained microalbuminuria, ≈80% will develop diabetic nephropathy in the absence of specific treatment.[6] Patients with type 1 diabetes are advised to undergo annual screening tests for microalbuminuria and, if confirmed, treatment should focus on the optimisation of blood glucose control and the aggressive management of hypertension, with a target BP of <130/80mm Hg.[6,61,68,70,84] In patients with type 1 diabetic nephropathy, both ACE inhibitors and angiotensin II receptor antagonists are recommended as the primary options to retard renal deterioration, with ACE inhibitors regarded somewhat more favourably as they may have specific renoprotective actions.[6,61,6870]

In a single, small clinical trial, imidapril reduced microalbuminuria in patients with type 1 diabetes (section 4.2). The UAE rate increased in placebo recipients, but was reduced by both imidapril 5 mg/day and captopril 37.5 mg/day over a mean treatment period of 1.5 years (section 4.2), suggesting a reduction in the progression of nephropathy and a delay in the development of end-stage renal disease with imidapril. However, UAE is a surrogate endpoint in diabetic nephropathy and larger trials evaluating the development of end-stage renal disease or other hard clinical endpoints are needed to support the use of imidapril in the treatment of nephropathy associated with type 1 diabetes.

Heart failure is a complex clinical syndrome that results from conditions that impair the filling or ejection of blood from the ventricle.[5] Treatment options include lifestyle modifications (as suggested for hypertension), mechanical devices (i.e. resynchronisation therapy and ventricular assist devices) and drug therapy.[4,5,85] Patients with reduced LV systolic function should be treated with an ACE inhibitor and a β-adrenoceptor antagonist as first-line therapy, with the addition of a diuretic in patients with fluid retention.[4,5,85] Aldosterone antagonists and angiotensin II receptor antagonists are generally regarded as secondary treatment options in patients intolerant of ACE inhibitors or with more severe or treatment-intransigent symptoms.[4,85]

In patients with CHF, imidapril increased mean total exercise time (section 4.3). Exercise tolerance was increased in imidapril 2.5–10 mg/day recipients in a dose-related manner, with an increase from baseline values in mean exercise time of 9.7% in patients receiving imidapril 10 mg/day (section 4.3). In patients with an acute MI, imidapril improved LVEF and was more effective than bisoprolol, while in patients with hypertension it reduced LV hypertrophy (section 2). Collectively, these data suggest functional benefits of imidapril in patients with CHF, which may reflect underlying changes in cardiac structure;[86] however, further trials are needed to firmly established the efficacy of imidapril in the treatment of CHF.

In a series of observational studies[41,42,87] in elderly Japanese patients, oral imidapril 0.25–1.25[41] or 5–10[42,87] mg/day for 12 weeks reduced the incidence of symptomless dysphagia/silent aspiration in imidapril recipients (63–73% ), but no change was observed in losartan 10–100 mg/day recipients.[42] This reduction is presumed to occur through the inhibition of substance P breakdown,[41,42] which is normally degraded by angiotensin-converting enzyme, and is thought to play a role in both the coughing and swallowing sensory pathways.[88] Another observational study in elderly patients (n = 576),[89] indicates that the incidence of pneumonia, a major consequence of symptomless dysphagia in older debilitated patients,[90] was significantly lower in elderly hypertensive patients who received imidapril for 3 years than in those who received an unspecified calcium-channel antagonist (3.3% vs 8.9%; p = 0.025); the incidence in nonhypertensive controls was 8.3%.[89] Randomised, controlled clinical trials are necessary to fully evaluate a possible role for imidapril in the treatment of symptomless dysphagia/silent aspiration and the prevention of aspiration pneumonia.

Although imidapril is approved in Japan for the treatment of renal parenchymal hypertension, few published data are available to support its use in this indication.

Overall, imidapril was well tolerated, with an incidence of adverse events generally similar to that with placebo or other antihypertensive agents (section 5.1). In comparative 12- to 24-week trials, the overall incidence of adverse events or the incidence of adverse events considered causally related to treatment was less than or did not differ from that observed in candesartan, captopril, enalapril, hydrochlorothiazide or nifedipine SR recipients (section 5.1). In pooled data from clinical trials plus post-marketing surveillance, the most commonly reported adverse events were cough, hypotension, dizziness and pharyngeal discomfort.

In prospective investigations, data from a small trial suggest that imidapril may not reduce the incidence of cough in patients already susceptible to ACE inhibitor-induced cough. However, in two large crossover trials the incidence of cough in patients receiving imidapril was significantly less than that in patients receiving enalapril or benazepril (section 5.2). Reductions in the incidence of ACE inhibitor-induced dry cough may increase quality of life and minimise the rate of treatment withdrawal. It should be noted that the incidence of ACE inhibitor-induced cough may differ between Asian and non-Asian populations, possibly as a result of differences in ACE insertion/deletion polymorphisms,[90] and therefore differences in the incidence of cough induced by imidapril versus other ACE inhibitors may be population dependent.

In conclusion, oral imidapril is an effective antihypertensive agent in the treatment of mild to moderate essential hypertension, and some evidence suggests that imidapril improves exercise capacity in patients with CHF and reduces UAE in patients with type 1 diabetes. Imidapril was well tolerated, with a lower incidence of dry cough than enalapril or benazepril, and is a first choice ACE inhibitor for the treatment of mild to moderate essential hypertension.

Disclosure

During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article; changes based on any comments received were made on the basis of scientific and editorial merit.

Footnotes
1

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