Journal Logo

ACE Inhibition and Vascular Protection in Hypertension

Efficacy and Safety of Spirapril in Mild-to-Moderate Hypertension

Hayduk, Karl; Kraul, Holger

Editor(s): Lüscher, Thomas F.

Author Information
Journal of Cardiovascular Pharmacology: August 1999 - Volume 34 - Issue - p S19-S23
  • Free


Angiotensin-converting enzyme (ACE) inhibitors have been shown to be effective vasodilators. Therefore, over the last two decades ACE inhibitors have been used for lowering elevated blood pressure and have been recommended as first-line monotherapy in the treatment of mild-to-moderate essential hypertension.

ACE inhibitors exert their effect by preventing the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. At the same time, inhibition of the degradation of kinins (which themselves support the blood pressure lowering effect of ACE inhibitors) has become an integral part of the clinical relevance of ACE inhibitors.

Many different ACE inhibitors are available world-wide. Captopril, the first orally active ACE inhibitor, was introduced to the market in 1981 (1,2). Since 1997, spirapril has been available. It is a non-thiol-containing monoethylester prodrug ACE inhibitor. In the human body, spirapril is converted by hydrolysis to the pharmacologically active spiraprilat.

The antihypertensive efficacy of spirapril has been convincingly proved in a number of clinical trials (3-11). Patients with all degrees of hypertension and concomitant diseases such as nephropathy or diabetes mellitus were involved. Some reviews (12,13) summarize these data. This paper focuses on results yielded in trials with patients suffering from mild-to-moderate hypertension without concomitant diseases.


There are no pharmacodynamically based differences in the efficacy of the individual ACE inhibitors found in any of the studies. Nevertheless, the current knowledge about the individual compounds is disparate. Therefore, it cannot presently be concluded whether these same properties are special features of individual ACE inhibitors or are class effects. In contrast, some clinically relevant pharmacokinetic differences have been shown. These include the elimination half-life (t1/2β) and the affinity to bind to the ACE molecule. In consequence, the duration of action and the possibility of single daily administration is modified. Furthermore, the mode of elimination is different and can be important for the decision to use a certain ACE inhibitor in renal or liver impairment.

The mean bioavailability of spirapril is 50% after oral administration (Table 1). Spirapril is almost completely converted to the active diacid metabolite spiraprilat which reaches maximal plasma concentrations within 2-3 h. The elimination of spiraprilat occurs more or less equally by both renal and hepatic routes. Consequently, in patients with renal dysfunction there is no clinically significant accumulation of spiraprilat. Thus, in these patients no dose adjustment is required (14,15) in contrast to many other ACE inhibitors.

Pharmacokinetic properties of spirapril and spiraprilat

The time-course of spiraprilat in plasma is biphasic beginning with an initial half-life of 1.5-2.2 h. This reflects the fast elimination of the non-bound substance followed by a terminal elimination half-life of about 30-40 h. The high affinity of spirapril to ACE is the reason for the long half-life of spirapril compared with all the other ACE inhibitors and, therefore, for the long duration of action (16)(Table 2). This allows once-daily administration of spirapril. Even if patients miss one administration, they do not fall into a 'non-treated' status. Spirapril is claimed to be a forgiving drug.

Elimination half-life (t1/2β) of different angiotensin-converting enzyme inhibitors


Earlier studies had demonstrated the antihypertensive efficacy of spirapril in doses up to 50 mg once daily (10,17). In further trials, the efficacy of lower once-daily dosages in the treatment of mild-to-moderate hypertension was evaluated.

Hayduk et al. (6) investigated the antihypertensive effect of 1, 6, 12 and 24 mg spirapril once daily in a dose-finding study and compared the results. The randomized, double-blind, multicentre study entered 171 patients with mild-to-moderate hypertension [diastolic blood pressure (DBP) 100-115 mm Hg]. A 3-week single-blind placebo run-in period was followed by a 5-week active-treatment period.

Spirapril in doses of 6, 12 and 24 mg once daily significantly lowered systolic blood pressure (SBP) and DBP compared with 1 mg once daily (Fig. 1). However, there were no significant differences in the extent of blood pressure reduction among the 6, 12 and 24 mg dosages of spirapril once daily. Blood pressure measurements with spirapril 1 mg were not significantly different from those recorded at baseline. At the end of the study, the mean decrease in SBP from baseline was 10-12 mm Hg with the three higher doses compared to only 4 mm Hg found for the 1 mg dose. The mean DBP decrease was 2.9, 11.0, 9.7 and 10.4 mm Hg with the 1, 6, 12 and 24 mg dosages, respectively (Fig. 1).

FIG. 1
FIG. 1:
Dose dependence of the blood pressure lowering effect of spirapril after 5 weeks treatment with once-daily administration. Blood pressure readings were taken 24 h after dosing; *p < 0.05 by F-test. Data from Hayduk et al. (6).

Reduction of DBP to ≤90 mm Hg ('normalizer') 24 h after the last dose at the end of the study was attained in 37.5, 30.8 and 28.9% in the 6, 12 and 24 mg group, respectively. Only 12.5% of the patients taking 1 mg reached this level. Furthermore, another 18.8, 17.9 and 23.7% of the patients taking 6, 12 and 24 mg spirapril, respectively, achieved a DBP decrease of ≤10 mm Hg compared with 12.5% of those taking 1 mg. Thus, the overall responder rates among the three higher dosages (6,12 and 24 mg) were 56.3, 48.7 and 52.6%, respectively, whereas only 25.0% of the patients taking 1 mg reached this goal.

Fairhurst (3) reported another double-blind, parallel-group, randomized, multicentre study on patients with mild-to-moderate hypertension. In contrast to Hayduk et al. (6), this was a placebo-controlled study. A total of 283 patients entered a 3-week placebo-wash-out period followed by a 6-week active-treatment period with either 3, 6, 12 or 24 mg spirapril once daily or placebo.

A significant decrease in mean DBP could be observed in all treatment groups. In the spirapril groups the differences compared to baseline were not dose dependent in the range 8.5-11.1 mm Hg. The blood pressure lowering effect was statistically significant for spirapril with 3, 6 and 12 mg once daily compared with placebo. The strong effect in the 3 mg group was related to the higher number of patients who were older than 60 years compared to the other treatment groups and who exhibited a higher response to spirapril.

The proportion of patients who achieved a blood pressure ≤90 mm Hg ('normalizer') 24 h after the last intake of the drug was between 35 and 40% for those taking spirapril and 15% for those taking placebo.


Several data are available showing that spirapril is as effective as other antihypertensive drugs including ACE inhibitors in the treatment of hypertension (10,11,18-23). In a comparison of spirapril and the calcium antagonist nitrendipine (20-40 mg) after 8 weeks treatment, spirapril was more effective. However, the dosage of spirapril ranged between 12 and 24 mg and patients with severe hypertension were also involved (18). The trial of Weber et al. (10) after a 10-week treatment period revealed a 10 mm Hg reduction in DBP as well as SBP for both 12.5-50 mg spirapril and 50-150 mg captopril.

Only one trial is available comparing the blood lowering efficacy of 6 mg spirapril in comparison with another ACE inhibitor in patients with mild-to-moderate hypertension (11). In a double-blind, placebo-controlled study, 6 mg spirapril once daily produced a blood pressure reduction very similar to that obtained with enalapril titrated between 5 to 20 mg after 8 weeks treatment. Both drugs reduced blood pressure significantly compared with placebo. However, DBP reduction was greater with spirapril than with enalapril both at peak and at trough 24 h after the last drug administration. The blood pressure reduction at trough for spirapril and enalapril was 14.7 and 12.4 mm Hg, respectively. The calculated trough : peak ratio for DBP was 84% for spirapril. Spirapril produced a statistically significant decrease of blood pressure after 4 weeks treatment compared to placebo; maximal effects were achieved after 6 weeks treatment (Fig. 2). About 51% of the patients treated with spirapril 6 mg achieved a blood pressure ≤90 mm Hg ('normalizer') 24 h after the last intake of the drug.

FIG. 2
FIG. 2:
Sitting diastolic blood pressure (DBP) at the end of the 24-h dosing intervals during the treatment of mild-to-moderate hypertension with 6 mg spirapril once daily; *p < 0.001 versus placebo. Data from Guitard et al. (11).

The study confirmed that spirapril 6 mg once daily is an effective and well tolerated choice for the treatment of mild-to-moderate hypertension. In contrast to enalapril it was not necessary to titrate the dose of spirapril to achieve a significant blood pressure lowering effect.


The most common adverse events (AEs) with spirapril in clinical trials on patients with mild-to-moderate hypertension were headache, dizziness and fatigue (3,6,10,11). At the dose of 6 mg once daily, placebo-controlled studies revealed that the frequency of side effects was at the level of placebo (11)(Table 3). There were no significant differences between placebo and spirapril in either frequency or severity of AEs, except for headache, when all data obtained on 6-24 mg spirapril were pooled (3)(Table 3). Headache was more frequently reported with spirapril (5.8%) than with placebo (1.7%); the number of AEs seems to be enhanced by dosages higher than 6 mg spirapril, dosages that are not neccesary as the blood lowering effect cannot be increased by doses higher than 6 mg spirapril. This was shown by Hayduk et al. (6), who observed a dose-AE relationship (Fig. 3). Only 16% of the patients treated with spirapril 6 mg experienced AEs, which corresponded to the incidence of AEs in the group with spirapril 1 mg; 12 and 24 mg of spirapril produced 22.7 and 25.6% AEs, respectively. This is in the range reported by Fairhurst (3) for the pooled data of 6-24 mg spirapril which could not confirm a relationship between dosage and number of AEs.

Frequency of adverse events during treatment with spirapril compared to placebo
FIG. 3
FIG. 3:
Percentage of patients experiencing newly occurring or worsening adverse events with spirapril at four different dosages. Data from Hayduk et al. (6).

In general, the incidence of other class-specific AEs such as cough, first-dose hypotension or angioneurotic oedema was similar to that with placebo or was absent. The occurence of cough was relatively low (0-4%) compared with the average range of 1-10% claimed for other ACE inhibitors (13). It can be assumed that the incidence of cough differs among the various ACE inhibitors because the ability to liberate mediators of inflammation differs (24).

Spirapril induced no reflex tachycardia despite its remarkable effects on blood pressure. This is in accordance with other ACE inhibitors but in contrast to other vasodilatatory drugs such as calcium antagonists.


Spirapril is very simple to dose. The recommended dose is 6 mg spirapril because a dose-related increase of the blood lowering effect of spirapril could only be observed in the range 1-6 mg. The effect of 1 mg was similar to that of placebo and 3 mg caused an inadequate response, although this was sometimes statistically significant not only in patients with mild-to-moderate but also in mild-to-severe hypertension (3,5,9). Dosages over 6 mg spirapril do not lead to any further decrease in elevated blood pressure in all degrees of hypertension (3-6,9). Thus the maximal blood pressure lowering effect is achieved with 6 mg spirapril.

Spirapril at doses of 6 mg is also effective and well tolerated in patients with diabetic nephropathy and other chronic renal diseases of various severity (7,14,25). There was no accumulation of drug even in terminal kidney failure (25), obviously due to the dual elimination of spiraprilat. For that reason, no dose adjustment is necessary in patients with renal impairment.

With the recommended dose of 6 mg spirapril once daily, a normalization rate of about 50% can be achieved in patients with mild-to-moderate hypertension. In patients with mild-to-severe hypertension this range is lower but the responder rate seems not to be influenced by the severity of the blood pressure at baseline (4). On the other hand, Schmidt and Kraul (26) showed that the higher the baseline values of blood pressure the higher the antihypertensive effect. They also confirmed the finding that the blood pressure lowering effect is more pronounced with respect to the DBP than to the SBP (11,26).

In elderly patients (≥60 years of age), the effect on blood pressure seems to be in the same range as in younger patients (27), at least with 6 mg spirapril (3). Fairhurst (3) detected some age-related discrepancies at the dosage of 3 mg with a higher blood pressure lowering effect in the elderly. Vreugdenhil et al. (9) confirmed this in patients with mild-to-severe hypertension. Kantola et al. (27,28) even found that 3 mg and 6 mg spirapril were equally effective in reducing blood pressure in elderly patients. Thus, 3 mg spirapril could be sometimes sufficient in elderly patients to cause a distinct reduction in blood pressure. Nevertheless, 6 mg spirapril can be recommended without any dose adjustment for routine use in the managment of hypertensive patients, because no statistically validated differences related to age and sex occured.

Spirapril at a dose of 6 mg in mild-to-moderate hypertension consistently gives trough : peak ratio values above 0.84 in patients with mild, moderate and also severe hypertension (4,11). These values satisfy Food and Drug Administration (FDA) guidelines for once-daily treatment of hypertension. The efficacy and the tolerability of spirapril were both very good. The drug has a gentle onset of action and achieves maximal efficacy after 3-6 h (13). Therefore, no first-dose phenomenon could be observed (6) in contrast to many other ACE inhibitors which usually have a quicker influx of the drug. The profile of AEs for 6 mg spirapril was not different from that of placebo (4,11) or 1 mg spirapril (6). There was a trend that doses higher than 6 mg spirapril caused more AEs. In all trials reported, there was generally a low incidence of cough. This could be a special feature of spirapril compared to other ACE inhibitors.

In conclusion, spirapril at a dosage of 6 mg once daily is an effective and safe choice for the treatment of mild-to-moderate essential hypertension.


1. Heel RC, Brogden RN, Speight TM, Avery GS. Captopril: a preliminary review of its pharmacological properties and therapeutic efficacy. Drugs 1980;20:409-52.
2. Romankiewicz JA, Brogden RN, Heel RC, Speight TM, Avery GS. Captopril: An update review of its pharmacological properties and therapeutic efficacy in congestive heart failure. Drugs 1983;25:6-40.
3. Fairhurst GJ. A multicentre multidose study of the efficacy and safety of spirapril in mild-to-moderate essential hypertension. Blood Press 1994;3 (suppl 2):77-80.
4. Guitard C, Alvisi V, Maibach E, et al. Placebo-controlled comparison of spirapril at 6, 12 and 24 mg/day in mild to severe essential hypertension. Blood Press 1994;3 (suppl 2):81-87.
5. Guitard C, Sassano P, Tzincoca C, et al. Placebo-controlled crossover comparison of spirapril at 3, 6, 12 and 24 mg once daily in mild to severe essential hypertension. Blood Press 1994;3 (suppl 2):61-68.
6. Hayduk K, Schardt F, Sierakowski B et al. Single daily admininstration of spirapril and spiraprilat in the treatment of essential hypertension. A multicentre double-blind comparison of 1, 6, 12 and 24 mg of spirapril once daily. Blood Press 1994;3 (suppl 2):41-46.
7. Norgaard K, Jensen T, Christensen P, et al. A comparison of spirapril and isradipine in patients with diabetic nephropathy and hypertension. Blood Press 1993;2:301-308.
8. Otterstad JE, Froeland G. Changes in left ventricular dimensions and haemodynamics during antihypertensive treatment with spriapril for 36 months. Blood Press 1994;3 (suppl 2):69-72.
9. Vreugdenhil G, van Montfrans GA, Jacobs MC, et al. 24 hour ambulatory blood pressure monitoring and spirapril in mild to severe essential hypertension: a randomized dose comparison. Blood Press 1994;2 (suppl 3):23-30.
10. Weber MA, Ferraresi RW, Poorvin D. Evaluation of a new angiotensin converting enzyme inhibitor, spirapril, in mild to moderate essential hypertension. J Hypertens 1986;4 (suppl 6):171-173.
11. Guitard C, Lohmann FW, Alfiero R, Ruina M, Alvisi V. Comparison of efficacy of spirapril and enalapril in control of mild-to-moderate hypertension. Cardiovasc Drugs Ther 1997;11:453-461.
12. Schmidt J. Spirapril in der Hochdrucktherapie. Dtsch Med Wochenschr 1997;122 (Beilage zu Heft 38):1-8.
13. Noble S, Sorkin EM. Spirapril: a preliminary review of its pharmacology and therapeutic efficacy in the treatment of hypertension. Drugs 1995;49:750-66.
14. Stein G, Sierakowski B, Grass P, et al. Pharmacokinetics of spirapril and spiraprilat in patients with chronic renal failure. Blood Press 1994;3 (suppl 2):47-53.
15. Grass P, Gerbeau C, Kutz K. Spirapril: Pharmacodynamic properties and drug interactions. Blood Press 1994;3 (suppl 2):7-13.
16. Leonetti G, Cuspidi C. Choosing the right ACE inhibitor. A guide to selection. Drugs 1995;49:516-535.
17. Ikeda M, Arakawa K, Ishii M, Shionoiri H. Spirapril Study Group. The effect of spirapril on blood pressure in patients with essential hypertension [abstract]. Cardiovasc Drug Ther 1989;3 (suppl 2):A593.
18. Carlsen JE, Galloe A, Kober L, et al. Comparison of efficacy and tolerability of spirapril and nitrendipine in arterial hypertension. Drug Invest 1991;3:172-7.
19. Schroeder RJ, Cordes M, Danne O, et al. Left ventricular hypertrophy regression and cardiac function under antihypertensive therapy a comparison of a vasodilating beta adrenoreceptor blocker and an ACE-inhibitor. Perfusion 1994;7:210-8.
20. Schroeder RJ, Cordes M, Del N, et al. Left ventricular hypertrophy regression under therapy with ACE-inhibitors: a comparison of four substances. Perfusion 1994;7:82-90.
21. Steensgaard-Hansen F, Kober L, Torp-Pedersen C, et al. Effect of a new ACE-inhibitor spirapril and nitrendipine on left ventricular mass and function in essential hypertension [abstract]. Eur Heart J 1990;11 (suppl):420.
22. Ram CVS, Tjoa HI, Kaplan NM, et al. Differential racial responses to ACE inhibitors in patients with hypertension (HTN) [abstract]. Am J Hypertens 1990;3:103A.
23. Shieh SM, Jeng CY, Sheu WHH, et al. Randomized double-blinded long-term study of spirapril and hydrochlorothiazide on metabolic effects in patients with hypertension [abstract]. Am J Hypertens 1994;7:49A.
24. Andersson RGG, Persson K. ACE inhibitors and their influence on inflammation, bronchial reactivity and cough. Eur Heart J 1994;15:52-56.
25. Elliott HL. Clinical use of angiotensin-converting enzyme inhibitors in patients with renal impairment. Blood Press 1994;3(suppl 1):48-9.
26. Schmidt J, Kraul H. Clinical experiences with spirapril in human hypertension. J Cardiovasc Pharmacol 1999;33 (suppl 1)S25-S30.
27. Kantola I, Terent A, Honkanen T, et al. Efficacy and safety of spirapril, a new ACE inhibitor, in elderly hypertensive patients. Eur J Clin Pharmacol 1996;50:155-159.
28. Kantola I, Terent A, Honkanen T, et al. Efficacy and safety of small doses of spirapril, and ACE inhibitor, in elderly hypertensive patients [abstract]. J Hypertens 1994;12 (suppl 3):23.

Section Description

A Spirapril symposium held in Vienna, Austria, August 25, 1998

The symposium and the publication of this supplement were supported by an educational grant from ASTA Medica AG, Frankfurt am Main, Germany.


Spirapril; Mild-to-moderate hypertension; Safety; Once daily administration

© 1999 Lippincott Williams & Wilkins, Inc.