Clinical Pharm acology
Cardiology 1992;80:34-41
Pharma Division, F. HofFmann-La Roche Ltd.. Basel, Switzerland, and the Cardiovascular Research Foundation, Bad Schwalbach, FRG
Cilazapril: An Overview of Its Efficacy and Safety in Hypertension
Keyw ords
Abstract
Cilazapril ACE inhibitors Hypertension
Cilazapril is a new once-daily angiotensin-converting (ACE) enzyme inhibitor which has been administered to 4,500 patients with mainly mild to moderate essential hypertension in a multinational clinical research program. Sitting diastolic blood pressure was reduced by about 9 mm Hg from baseline (p < 0.01 ) after 4 weeks of treatment with cilazapril 1.2510 mg/day in double-blind placebo-controlled studies. Total responder rates to cilazapril were usually 50-60% compared with 30% to placebo. Adding hydrochlorothiazide 12.5 mg/day to cilazapril 5.0 mg/day in creased the total responder rate from 52 to 71 %. Double-blind dose titra tion studies for 8 weeks showed that cilazapril 2.5-5 mg/day possessed equivalent efficacy to usual therapeutic regimens of sustained release pro pranolol, captopril, hydrochlorothiazide, atenolol and enalapril. Cilaza pril did not affect heart rate. During long-term open administration for 52 weeks, or longer, cilazapril, either alone or in combination with hydro chlorothiazide, effectively maintained control of blood pressure. Treat ment of patients with severe hypertension with cilazapril plus hydrochlo rothiazide achieved a total responder rate of 73%. Adverse events were mostly observed within the first 8-16 weeks of treatment, with headache, dizziness, fatigue, nausea, cough and chest pain being the most frequent. Non-life-threatening angioedema, facial edema and mild hypotension occurred in < 0.2% of patients, and orthostatic hypotension was reported in 2 %. Abnormal laboratory test values were rarely found with cilazapril treatment. Of the 2.3% of patients with elevated scrum creatinine, at any time point during the study and irrespective of outcome on continuation with cilazapril therapy, about two thirds had prior renal impairment. This was also the situation in 5 of 23 patients (0.6%) with proteinuria. Overall, < 6% of patients withdrew from treatment because of adverse events. In conclusion, the results show that cilazapril possesses good efficacy and excellent tolerability in the treatment of essential hypertension.
Received: August 15, 1991 Accepted: August 21, 1991
Dr. Thomas Szucs Pharma Division F. Hoffmann-La Roche Ltd. CH-4002 Basel (Switzerland)
© 1992 S. Karger AG, Basel 0008-6312/92/ 0801-0034Î2.75/0
Downloaded by: UCL 144.82.238.225 - 7/10/2018 6:25:53 PM
Thomas Szucs Adam Schneeweiss
Methods Trial Designs
Placebo- and active agent-controlled studies (five of each) used a randomized, double-blind, parallel group design with treatment initiated after a 4-week placebo run-in period. Placebo-controlled trials used either fixed dosages of cilazapril in the range 1-10 mg once daily or dose titration from a starting dose of 2.5 mg/day increased to 5 mg/day. if required, after 4 weeks of therapy. The same dose titration procedure was used in the active agent-controlled trials. Several of the dose titration studies allowed the addition of hydrochlorothiazide 12.5 or 25 mg/day after 8 weeks on cilazapril monotherapy, if blood pressure remained uncontrolled. The eleven open-label studies were conducted either to evaluate cilazapril during long-term use (up to 1 year or longer) or to address specific questions on the use of cilazapril. such as in patients with severe hyper tension or renal impairment or in the elderly.
Patients
The hypertension research program enrolled male or female patients, generally between 18 and 75 years of age, and most were outpatients. Mild to moderate essential hypertension (sitting diastolic blood pressure. SDBP. of 95-114 mm Hg) was the primary diagnosis in 4.348 patients, while 31 patients presented with renal hypertension and 148 with severe hypertension (SDBP >115 mm Hg). Before entering the studies, all patients underwent a thorough baseline examination. The majority of exclusion criteria were common to virtually all studies: pregnant or lactating females: severe malignant or complicated hypertension; sec ondary hypertension; clinically relevant other diseases; sensitivity or allergy to ACE inhibitors: history of alco hol or drug abuse; unstable diabetes; above normal serum creatinine; proteinuria (> 150 mg/24h). and the use of concomitant drugs which may affect blood pressure. In some studies, the following additional exclusion criteria were applied: specific cardiovascular disorders (such as clinically significant rhythm distur bances, heart failure, angina pectoris, myocardial in farction within the previous 6 months and cerebrovas cular disease); autoimmune disease: electrolyte distur bance; drugs which interact with ACE inhibitors: spec ified drug classes (antiarrhythmics, aminophyllinc analogs, monoamine oxidase inhibitors, cyclic antide pressants. sympathomimetics or long-acting nitrates). Treatment
Cilazapril w'as administered orally mostly at a dose of 2.5-5 mg. once daily, in the morning, either before or after a light breakfast. Assessment o f Efficacy and Safety
In trials of up to 3 months of duration, sitting and standing blood pressure and heart rate were measured every 2-4 weeks: in the long-term studies > 1 year, measurements were performed at intervals of 1-2 months. All adverse events were graded by the investigators for severity and categorized according to the relation ship with treatment. Blood and urine were routinely sampled to monitor for hematologic and biochemical abnormalities. Body weight was recorded at each as sessment and any end-of-treatment electrocardiogram abnormalities w'ere documented. Analyses o f Efficacy and Safely
The primary indicator of efficacy' was the reduction in SDBP from baseline. Standard analyses included results from patients who w'ere prematurely withdrawn because of lack of efficacy but not those withdrawn for
35
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Cilazapril is a new nonsulfhydryl angioten sin-converting enzyme (ACE) inhibitor which is now at an advanced stage of clinical devel opment for the treatment of hypertension. Like enalapril, cilazapril is a prodrug which is rapidly hydrolyzed to the pharmacologically active cilazaprilat following absorption into the bloodstream [1], In clinical pharmacology studies, administration of cilazapril resulted in potent, reversible, selective and competi tive ACE inhibition [2-4], The drug has a long duration of action with plasma ACE activity reduced by about 70% at 24 h following ad ministration of single (1.25-10 mg) doses in normal volunteers [3]. Over 4.500 patients have been treated with cilazapril in an inter national research and development program from which the drug has emerged as an effec tive and well-tolerated once-daily treatment for various grades of hypertension, comparing favorably with several established antihyper tensive agents.
Table 1. Double-blind dose-titration studies comparing cilazapril with several other agents in patients with mild to moderate essential hypertension
Treatment mg/day
Duration weeks
Patients
SDBP. mm Hg
CLZ 2.5-5 PROP 80-160
8
93 47
101.3 101.1
8.9” 9.7**
59 67
CLZ 2.5-5 CAPT 25-50 b.i.d.
8
101 50
101.6 101.6
7.5** 5.6**
49 39
CLZ 2.5-5 HCTZ 25-50
8
67 65
102.5 103.0
14 3 *** 13.3***
64 58
CLZ 2.5-5 ATEN 50-100
8
100 98
103.4 103.7
11.8*** 14.3***
57 68
CLZ 2.5-5 ENAL 10-20
8
64 71
102.1 101.8
15.5*** 16.7***
79 90
baseline
, mean reduction
Cumulative response rates, 7o . .. .. , (normalization)
Treatment: once daily regimen, unless otherwise stated. ATEN = Atenolol; CAPD = Captopril; CLZ = Cilaza pril; ENAL = enalapril; HCTZ = hydrochlorothiazide; PROP = propranolol. ** p < 0.0I. *** p < 0.001. vs. baseline.
Results
Demographics Almost half (46%) of the total of 4.527 patients were enrolled at centers in the USA. The UK and continental and Nordic Europe accounted for the same proportion (43%),
36
Szucs/Schneeweiss
with the remainder from South America, the South Pacific, the Middle East and Africa. Most patients were aged between 41 and 65 (mean 53) years, with 509 aged over 65 years. There were slightly more males (59%) than females, and a large proportion of the popula tion (70%) was overweight. About 12% of the patients were black. Previous antihyperten sive treatment had been administered to ap proximately 70% of patients, and 13% took nonsteroidal anti-inflammatory drugs during the studies. Efficacy Placebo-controlled trials positively dem onstrated the antihypertensive efficacy of var ious dosages of cilazapril covering the range 1.25-5 mg once daily. Total responder rates (SDBP normalized and/or reduced by at least 10 mm Hg) were generally between 50 and 60% in cilazapril groups compared with
Cilazapril in Hypertension
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other reasons. Intent-to-treat analyses were also per formed. including end point results from all enrolled patients who provided blood pressure data. Differ ences in SDBP. both from baseline and between treat ments. were tested for statistical significance using analyses of covariance. In addition, certain subgroup analyses were performed on a post hoc basis. Re sponding patients (= total response) were defined as those whose SDBP decreased to 90 mm Hg or less (normalization), or was reduced by at least 10 mm Hg from the baseline value. Patients with different adverse events occurring within the same body system were counted once, whereas those with adverse events in more than one body system w'ere counted for each system involved.
80 J
1 8 Baseline (734) (739)
about 30% in placebo groups. In a 12-week dose titration study of cilazapril (2.5-5.0 mg/ day), it was shown that the addition of hy drochlorothiazide ( 12.5 mg once daily for the last 4 weeks of treatment) increased the total responder rate from 52% at week 8 to 71% at week 12. Corresponding values for the pla cebo group were 33 and 32%. respectively, at these time points. Overall, 17 patients (2%) withdrew from the placebo-controlled trials because of lack of efficacy while taking cilaza pril. and 20 patients (6%) stopped taking pla cebo for this reason. In double-blind dose titration studies of 8 weeks of duration, cilazapril (2.5-5.0 mg/day) displayed antihypertensive effects which were comparable with those of sustained release propranolol (80-160 mg once daily), captopril (25-50 mg twice daily), hydrochlorothia zide (25-50 mg once daily), atenolol (50-100 mg once daily) and enalapril (10-20 mg once daily). These results are summarized in ta ble 1. There were no statistically or clinically sig nificant effects on heart rate during cilazapril treatment in any of the placebo- or active agent-controlled studies.
16 (739)
24 (707)
32 (707)
40 (697)
48 52 Weeks (688X492)
The 24-hour duration of the antihyperten sive effect of cilazapril was demonstrated in two studies. In a comparative trial with enala pril, it was shown that the blood pressure-low ering effect measured 24 h following adminis tration at week 8 of treatment was at least two thirds of the mean peak effect for both cilaza pril and enalapril. An open-label dose titra tion study, which enrolled 87 patients, found that total cumulative response rates were 16, 31, 42 and 57% when assessed 24 h after administration of cilazapril 0.5, 1, 2.5 and 5 mg, respectively, at the 10th week of treat ment. Thus, in the recommended therapeutic dose range of 2.5-5 mg daily, cilazapril achieves satisfactory antihypertensive effi cacy which is sustained for the 24-hour inter val between doses. In long-term use. cilazapril has been ad ministered to a total of 756 patients (either as monotherapy or in combination with hy drochlorothiazide) for 52 weeks or longer. Nearly all these patients were enrolled in one study and, as shown in figure 1, SDBP re mained controlled throughout the 1 year of therapy. Low-dose cilazapril monotherapy
37
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Fig. 1. SDBP (mean ± SEM) during 52 weeks of therapy with cilazapril, either alone or in combi nation with hydrochlorothiazide, in patients with mild to moderate essential hypertension. The num bers of patients who were treated for > 50 weeks are given in paren theses.
Event
Placebo (n= 324)
CilazapriF (n = 785)
Headache Dizziness Fatigue Nausea Chest pain
7.1 2.8 1.5 0.9 0.9
5.5 3.6 1.9 1.5 1.0
a All doses of cilazapril.
(2.5 mg/day) was sufficient to maintain blood pressure control in 37% of patients. The with drawal rate because of lack of efficacy was 10%.
Safety Placebo-controlled studies revealed that adverse events remotely, possibly or probably related to the treatment occurred in 18.7% of patients given cilazapril compared with 19.4% of those on placebo. Those which oc curred in at least 1% of patients are presented in table 2. Overall, the incidence of adverse events did not appreciably increase with doses of cilazapril up to 5 mg/day (the recommended daily maximum). Compared with other active agents, the risk of adverse events occurring during cilaza pril therapy was not greater than with pro pranolol, captopril and enalapril. There were statistically less adverse events compared to atenolol and less laboratory abnormalities with hydrochlorothiazide. Overall, no major differences in the type or incidence of adverse events associated with these agents and other ACE inhibitors were found. The adverse event profile derived from all 3,769 patients treated with cilazapril mono
38
Szucs/Schnecwciss
therapy for a mean duration of 131 days in multiple-dose studies was essentially the same as that described in placebo-controlled trials with the exception that nausea was reported in less than 1% of patients and cough in 1.6%. Rash, of mild or moderate severity, was asso ciated with cilazapril in 0.6% of patients. During combination treatment with hydro chlorothiazide (12.5-25 mg/day) in 1.068 pa tients, the only notable change to the adverse event profile was the occurrence of dizziness in 4.6% of patients compared with 3.3% dur ing monotherapy. The greatest incidence of adverse events occurred within the first 8-16 weeks of cilazapril administration, either alone or in combination with hydrochloro thiazide. Angioedema, facial edema and hypoten sion are potentially serious adverse events which have occurred during treatment with other ACE inhibitors. In the cilazapril pro gram, angioedema and facial edema occurred in 0.16% of patients, with no signs of associ ated respiratory distress or laryngeal stridor. Hypotension of 65 year of age. Orthostatic hypotension occurred in 2% of patients during multiple-dose cilaza pril monotherapy. Low white blood cell and neutrophil counts and high aspartate aminotransferase and y-glutamyl transferase values were the most frequently recorded laboratory test ab normalities during either cilazapril mono therapy or combination treatment with hy drochlorothiazide. but the majority were con sidered to be unrelated to treatment. In no case was there any relationship of cilazapril to low neutrophil or leukocyte count. None of
Cilazapril in Hypertension
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Table 2. Incidence of adverse events (%) occurring in at least I % of patients treated with cilazapril in pla cebo-controlled trials
Table 3. Summary of patients who withdrew from treatment because of adverse events
Cilazapril alone (n= 3.769)
Cilazapril + hydrochlorothiazide (n ■= 1,068)
n
%
n
%
Adverse events Abnormal laboratory values
183 27
4.9 0.8
44
4.1 1.2
Events most frequently responsible for withdrawal
Headache, nausea. cough, fatigue
Discussion
The benefits of long-term effective antihy pertensive therapy in terms of decreased mor tality from cardiovascular diseases are now well accepted [5, 6], Traditional drugs used in the treatment of hypertension, such as diuret ics and ß-blockers, effectively reduce blood pressure, but long-term exposure to some of their adverse metabolic effects, including di uretic-induced hypokalemia and blood lipid alterations, may negate the benefits of re
Cough, dizziness, chest pain
duced blood pressure [6], In the continuing search for effective and safer antihypertensive drugs, ACE inhibitors represent a major ad vance [7-9], In general, ACE inhibitors are as effective as diuretics and ß-blockers, but do not cause the adverse effects described above. Thus, these drugs do not increase the potential for cardiac arrhythmia, as with non-potassiumsparing diuretics [10], In addition, ACE in hibitors may be administered to patients with asthma or congestive heart failure, whereas ßblockers are best avoided. Reduced renal blood flow is common in patients with hypertension; however, with ACE inhibitor treatment, renal blood flow tends to increase or remain unchanged in spite of decreased blood pressure [11-13]. It appears that reduced proteinuria with treat ment is a useful criterion for predicting bene ficial renal effects of ACE inhibitor therapy [14. 15], Other attributes of ACE inhibitors include a lack of associated central nervous system effects, fewer orthostatic effects and increased exercise tolerance in comparison with other antihypertensive agents [ 16], Given the wealth of clinical evidence which has accumulated in support of the favorable therapeutic profile of ACE inhibi tors. it is not surprising that this class of drugs
39
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the patients with renal impairment or colla gen diseases had any leukopenia and/or neu tropenia. Of 64 patients (2.3%) treated with cilazapril alone or in combination with hy drochlorothiazide who had increases in serum creatinine to > 2m g/dl. 41 had prior renal impairment. These increases usually reversed after discontinuing therapy. Proteinuria in as sociation with cilazapril alone or in combina tion occurred in 23 patients (0.6%), 5 of whom had prior renal impairment. A summary of patients who withdrew from therapy because of adverse events is pre sented in table 3. Although 0.8% of patients stopped taking cilazapril because of abnormal laboratory values, these were rarely of poten tial clinical significance.
12
40
Szucs/Schneeweiss
slightly greater extent than 2.5 mg/day. and this was confirmed in dose titration studies in patients who did not achieve a satisfactory response to 2.5 mg/day. Those patients who do not respond to cilazapril 5 mg/day are likely to do so if a low dose of hydrochloro thiazide is added to the regimen. Although there appear to be fewer risks associated with ACE inhibitors compared with other classes of antihypertensive drugs, there are certain class-specific safety issues. These include the potential for hypotension (especially as a first-dose effect) in salt-de pleted patients and renin-dependent hyper tension [22], renal failure (mainly in patients with renal artery stenosis) [23] and angioedema, cough, rash and low white blood cell counts [24], These events occurred in small numbers of patients taking cilazapril, but the incidences attributed to the drug were compa rable or less than those seen with other ACE inhibitors [20, 25-32], No adverse conse quences. such as infections associated with leukopenia, respiratory distress or laryngeal stridor in association with angioedema, were reported. With more than 4.000 patients treated, no specific safety issue specific to cilazapril has yet emerged. In conclusion, the clinical evidence accu mulated to dale shows that cilazapril is an effective and well-tolerated new ACE inhibi tor in the treatment of hypertension.
Cilazapril in Hypertension
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is now recommended for consideration as first-choice treatment in the USA [17], and a similar guideline has been suggested for Eu rope [18]. Placebo-controlled trials demonstrated that cilazapril in the dose range of 2.5-5 mg/ day significantly reduced SDBP during 4 weeks of therapy. Differences in SDBP com pared with placebo were similar to those ob served in placebo comparisons with usual therapeutic dosages of captopril [19] and lisinopril [20]. Comparable efficacy with other ACE inhibitors, as well as propranolol, hy drochlorothiazide and atenolol, was sup ported by the results of the active agent-con trolled trials. The 24-hour duration of action of cilaza pril has been described in human volunteer studies in terms of ACE inhibition [3], which translates into satisfactory blood pressure control with once-daily administration in hy pertensive patients. This favors a high rate of compliance, which is an important factor in the long-term management of hypertensive patients who are otherwise asymptomatic. Compared with other long-acting ACE inhibi tors. such as cnalapril and lisinopril. cilazapril has been shown to possess superior absorp tion and bioavailability, thus permitting a better prediction of the antihypertensive ef fect of a given dose [unpubl. data]. Like cila zapril [19]. enalapril [21] and lisinopril [20]. cilazapril maintains blood pressure control during long-term use. Based on the results of clinical pharmacol ogy studies and the therapeutic trials, the usual recommended dosage of cilazapril is 2.5-5 mg once daily. Cilazapril 2.5 mg daily attained clinically significant reductions in SDBP in placebo-controlled trials and a 24hour cumulative responder rate following ad ministration comparable to other antihyper tensive monotherapy. In fixed-dose studies, cilazapril 5 mg/day reduced SDBP by a
References 10 Multiple Risk Factor Intervention Trial Research Group: Baseline rest ing electrocardiographic abnormali ties. antihypertensive treatment and mortality in the Multiple Risk Fac tor Intervention Trials. Am J Car diol 1985;55:1-15. 11 Bauer JH, Reams GP: Hemody namic and renal function in essen tial hypertension during treatment with enalapril. Am .1 Med 1985: 79(suppl 30:10-13. 12 de Leeuw PW. Birkenhager WH: Renal blood flow in essential hyper tension. J Cardiovasc Pharmacol 1987; 10
Cardiology 1992;80:34-41
Pharma Division, F. HofFmann-La Roche Ltd.. Basel, Switzerland, and the Cardiovascular Research Foundation, Bad Schwalbach, FRG
Cilazapril: An Overview of Its Efficacy and Safety in Hypertension
Keyw ords
Abstract
Cilazapril ACE inhibitors Hypertension
Cilazapril is a new once-daily angiotensin-converting (ACE) enzyme inhibitor which has been administered to 4,500 patients with mainly mild to moderate essential hypertension in a multinational clinical research program. Sitting diastolic blood pressure was reduced by about 9 mm Hg from baseline (p < 0.01 ) after 4 weeks of treatment with cilazapril 1.2510 mg/day in double-blind placebo-controlled studies. Total responder rates to cilazapril were usually 50-60% compared with 30% to placebo. Adding hydrochlorothiazide 12.5 mg/day to cilazapril 5.0 mg/day in creased the total responder rate from 52 to 71 %. Double-blind dose titra tion studies for 8 weeks showed that cilazapril 2.5-5 mg/day possessed equivalent efficacy to usual therapeutic regimens of sustained release pro pranolol, captopril, hydrochlorothiazide, atenolol and enalapril. Cilaza pril did not affect heart rate. During long-term open administration for 52 weeks, or longer, cilazapril, either alone or in combination with hydro chlorothiazide, effectively maintained control of blood pressure. Treat ment of patients with severe hypertension with cilazapril plus hydrochlo rothiazide achieved a total responder rate of 73%. Adverse events were mostly observed within the first 8-16 weeks of treatment, with headache, dizziness, fatigue, nausea, cough and chest pain being the most frequent. Non-life-threatening angioedema, facial edema and mild hypotension occurred in < 0.2% of patients, and orthostatic hypotension was reported in 2 %. Abnormal laboratory test values were rarely found with cilazapril treatment. Of the 2.3% of patients with elevated scrum creatinine, at any time point during the study and irrespective of outcome on continuation with cilazapril therapy, about two thirds had prior renal impairment. This was also the situation in 5 of 23 patients (0.6%) with proteinuria. Overall, < 6% of patients withdrew from treatment because of adverse events. In conclusion, the results show that cilazapril possesses good efficacy and excellent tolerability in the treatment of essential hypertension.
Received: August 15, 1991 Accepted: August 21, 1991
Dr. Thomas Szucs Pharma Division F. Hoffmann-La Roche Ltd. CH-4002 Basel (Switzerland)
© 1992 S. Karger AG, Basel 0008-6312/92/ 0801-0034Î2.75/0
Downloaded by: UCL 144.82.238.225 - 7/10/2018 6:25:53 PM
Thomas Szucs Adam Schneeweiss
Methods Trial Designs
Placebo- and active agent-controlled studies (five of each) used a randomized, double-blind, parallel group design with treatment initiated after a 4-week placebo run-in period. Placebo-controlled trials used either fixed dosages of cilazapril in the range 1-10 mg once daily or dose titration from a starting dose of 2.5 mg/day increased to 5 mg/day. if required, after 4 weeks of therapy. The same dose titration procedure was used in the active agent-controlled trials. Several of the dose titration studies allowed the addition of hydrochlorothiazide 12.5 or 25 mg/day after 8 weeks on cilazapril monotherapy, if blood pressure remained uncontrolled. The eleven open-label studies were conducted either to evaluate cilazapril during long-term use (up to 1 year or longer) or to address specific questions on the use of cilazapril. such as in patients with severe hyper tension or renal impairment or in the elderly.
Patients
The hypertension research program enrolled male or female patients, generally between 18 and 75 years of age, and most were outpatients. Mild to moderate essential hypertension (sitting diastolic blood pressure. SDBP. of 95-114 mm Hg) was the primary diagnosis in 4.348 patients, while 31 patients presented with renal hypertension and 148 with severe hypertension (SDBP >115 mm Hg). Before entering the studies, all patients underwent a thorough baseline examination. The majority of exclusion criteria were common to virtually all studies: pregnant or lactating females: severe malignant or complicated hypertension; sec ondary hypertension; clinically relevant other diseases; sensitivity or allergy to ACE inhibitors: history of alco hol or drug abuse; unstable diabetes; above normal serum creatinine; proteinuria (> 150 mg/24h). and the use of concomitant drugs which may affect blood pressure. In some studies, the following additional exclusion criteria were applied: specific cardiovascular disorders (such as clinically significant rhythm distur bances, heart failure, angina pectoris, myocardial in farction within the previous 6 months and cerebrovas cular disease); autoimmune disease: electrolyte distur bance; drugs which interact with ACE inhibitors: spec ified drug classes (antiarrhythmics, aminophyllinc analogs, monoamine oxidase inhibitors, cyclic antide pressants. sympathomimetics or long-acting nitrates). Treatment
Cilazapril w'as administered orally mostly at a dose of 2.5-5 mg. once daily, in the morning, either before or after a light breakfast. Assessment o f Efficacy and Safety
In trials of up to 3 months of duration, sitting and standing blood pressure and heart rate were measured every 2-4 weeks: in the long-term studies > 1 year, measurements were performed at intervals of 1-2 months. All adverse events were graded by the investigators for severity and categorized according to the relation ship with treatment. Blood and urine were routinely sampled to monitor for hematologic and biochemical abnormalities. Body weight was recorded at each as sessment and any end-of-treatment electrocardiogram abnormalities w'ere documented. Analyses o f Efficacy and Safely
The primary indicator of efficacy' was the reduction in SDBP from baseline. Standard analyses included results from patients who w'ere prematurely withdrawn because of lack of efficacy but not those withdrawn for
35
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Cilazapril is a new nonsulfhydryl angioten sin-converting enzyme (ACE) inhibitor which is now at an advanced stage of clinical devel opment for the treatment of hypertension. Like enalapril, cilazapril is a prodrug which is rapidly hydrolyzed to the pharmacologically active cilazaprilat following absorption into the bloodstream [1], In clinical pharmacology studies, administration of cilazapril resulted in potent, reversible, selective and competi tive ACE inhibition [2-4], The drug has a long duration of action with plasma ACE activity reduced by about 70% at 24 h following ad ministration of single (1.25-10 mg) doses in normal volunteers [3]. Over 4.500 patients have been treated with cilazapril in an inter national research and development program from which the drug has emerged as an effec tive and well-tolerated once-daily treatment for various grades of hypertension, comparing favorably with several established antihyper tensive agents.
Table 1. Double-blind dose-titration studies comparing cilazapril with several other agents in patients with mild to moderate essential hypertension
Treatment mg/day
Duration weeks
Patients
SDBP. mm Hg
CLZ 2.5-5 PROP 80-160
8
93 47
101.3 101.1
8.9” 9.7**
59 67
CLZ 2.5-5 CAPT 25-50 b.i.d.
8
101 50
101.6 101.6
7.5** 5.6**
49 39
CLZ 2.5-5 HCTZ 25-50
8
67 65
102.5 103.0
14 3 *** 13.3***
64 58
CLZ 2.5-5 ATEN 50-100
8
100 98
103.4 103.7
11.8*** 14.3***
57 68
CLZ 2.5-5 ENAL 10-20
8
64 71
102.1 101.8
15.5*** 16.7***
79 90
baseline
, mean reduction
Cumulative response rates, 7o . .. .. , (normalization)
Treatment: once daily regimen, unless otherwise stated. ATEN = Atenolol; CAPD = Captopril; CLZ = Cilaza pril; ENAL = enalapril; HCTZ = hydrochlorothiazide; PROP = propranolol. ** p < 0.0I. *** p < 0.001. vs. baseline.
Results
Demographics Almost half (46%) of the total of 4.527 patients were enrolled at centers in the USA. The UK and continental and Nordic Europe accounted for the same proportion (43%),
36
Szucs/Schneeweiss
with the remainder from South America, the South Pacific, the Middle East and Africa. Most patients were aged between 41 and 65 (mean 53) years, with 509 aged over 65 years. There were slightly more males (59%) than females, and a large proportion of the popula tion (70%) was overweight. About 12% of the patients were black. Previous antihyperten sive treatment had been administered to ap proximately 70% of patients, and 13% took nonsteroidal anti-inflammatory drugs during the studies. Efficacy Placebo-controlled trials positively dem onstrated the antihypertensive efficacy of var ious dosages of cilazapril covering the range 1.25-5 mg once daily. Total responder rates (SDBP normalized and/or reduced by at least 10 mm Hg) were generally between 50 and 60% in cilazapril groups compared with
Cilazapril in Hypertension
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other reasons. Intent-to-treat analyses were also per formed. including end point results from all enrolled patients who provided blood pressure data. Differ ences in SDBP. both from baseline and between treat ments. were tested for statistical significance using analyses of covariance. In addition, certain subgroup analyses were performed on a post hoc basis. Re sponding patients (= total response) were defined as those whose SDBP decreased to 90 mm Hg or less (normalization), or was reduced by at least 10 mm Hg from the baseline value. Patients with different adverse events occurring within the same body system were counted once, whereas those with adverse events in more than one body system w'ere counted for each system involved.
80 J
1 8 Baseline (734) (739)
about 30% in placebo groups. In a 12-week dose titration study of cilazapril (2.5-5.0 mg/ day), it was shown that the addition of hy drochlorothiazide ( 12.5 mg once daily for the last 4 weeks of treatment) increased the total responder rate from 52% at week 8 to 71% at week 12. Corresponding values for the pla cebo group were 33 and 32%. respectively, at these time points. Overall, 17 patients (2%) withdrew from the placebo-controlled trials because of lack of efficacy while taking cilaza pril. and 20 patients (6%) stopped taking pla cebo for this reason. In double-blind dose titration studies of 8 weeks of duration, cilazapril (2.5-5.0 mg/day) displayed antihypertensive effects which were comparable with those of sustained release propranolol (80-160 mg once daily), captopril (25-50 mg twice daily), hydrochlorothia zide (25-50 mg once daily), atenolol (50-100 mg once daily) and enalapril (10-20 mg once daily). These results are summarized in ta ble 1. There were no statistically or clinically sig nificant effects on heart rate during cilazapril treatment in any of the placebo- or active agent-controlled studies.
16 (739)
24 (707)
32 (707)
40 (697)
48 52 Weeks (688X492)
The 24-hour duration of the antihyperten sive effect of cilazapril was demonstrated in two studies. In a comparative trial with enala pril, it was shown that the blood pressure-low ering effect measured 24 h following adminis tration at week 8 of treatment was at least two thirds of the mean peak effect for both cilaza pril and enalapril. An open-label dose titra tion study, which enrolled 87 patients, found that total cumulative response rates were 16, 31, 42 and 57% when assessed 24 h after administration of cilazapril 0.5, 1, 2.5 and 5 mg, respectively, at the 10th week of treat ment. Thus, in the recommended therapeutic dose range of 2.5-5 mg daily, cilazapril achieves satisfactory antihypertensive effi cacy which is sustained for the 24-hour inter val between doses. In long-term use. cilazapril has been ad ministered to a total of 756 patients (either as monotherapy or in combination with hy drochlorothiazide) for 52 weeks or longer. Nearly all these patients were enrolled in one study and, as shown in figure 1, SDBP re mained controlled throughout the 1 year of therapy. Low-dose cilazapril monotherapy
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Fig. 1. SDBP (mean ± SEM) during 52 weeks of therapy with cilazapril, either alone or in combi nation with hydrochlorothiazide, in patients with mild to moderate essential hypertension. The num bers of patients who were treated for > 50 weeks are given in paren theses.
Event
Placebo (n= 324)
CilazapriF (n = 785)
Headache Dizziness Fatigue Nausea Chest pain
7.1 2.8 1.5 0.9 0.9
5.5 3.6 1.9 1.5 1.0
a All doses of cilazapril.
(2.5 mg/day) was sufficient to maintain blood pressure control in 37% of patients. The with drawal rate because of lack of efficacy was 10%.
Safety Placebo-controlled studies revealed that adverse events remotely, possibly or probably related to the treatment occurred in 18.7% of patients given cilazapril compared with 19.4% of those on placebo. Those which oc curred in at least 1% of patients are presented in table 2. Overall, the incidence of adverse events did not appreciably increase with doses of cilazapril up to 5 mg/day (the recommended daily maximum). Compared with other active agents, the risk of adverse events occurring during cilaza pril therapy was not greater than with pro pranolol, captopril and enalapril. There were statistically less adverse events compared to atenolol and less laboratory abnormalities with hydrochlorothiazide. Overall, no major differences in the type or incidence of adverse events associated with these agents and other ACE inhibitors were found. The adverse event profile derived from all 3,769 patients treated with cilazapril mono
38
Szucs/Schnecwciss
therapy for a mean duration of 131 days in multiple-dose studies was essentially the same as that described in placebo-controlled trials with the exception that nausea was reported in less than 1% of patients and cough in 1.6%. Rash, of mild or moderate severity, was asso ciated with cilazapril in 0.6% of patients. During combination treatment with hydro chlorothiazide (12.5-25 mg/day) in 1.068 pa tients, the only notable change to the adverse event profile was the occurrence of dizziness in 4.6% of patients compared with 3.3% dur ing monotherapy. The greatest incidence of adverse events occurred within the first 8-16 weeks of cilazapril administration, either alone or in combination with hydrochloro thiazide. Angioedema, facial edema and hypoten sion are potentially serious adverse events which have occurred during treatment with other ACE inhibitors. In the cilazapril pro gram, angioedema and facial edema occurred in 0.16% of patients, with no signs of associ ated respiratory distress or laryngeal stridor. Hypotension of 65 year of age. Orthostatic hypotension occurred in 2% of patients during multiple-dose cilaza pril monotherapy. Low white blood cell and neutrophil counts and high aspartate aminotransferase and y-glutamyl transferase values were the most frequently recorded laboratory test ab normalities during either cilazapril mono therapy or combination treatment with hy drochlorothiazide. but the majority were con sidered to be unrelated to treatment. In no case was there any relationship of cilazapril to low neutrophil or leukocyte count. None of
Cilazapril in Hypertension
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Table 2. Incidence of adverse events (%) occurring in at least I % of patients treated with cilazapril in pla cebo-controlled trials
Table 3. Summary of patients who withdrew from treatment because of adverse events
Cilazapril alone (n= 3.769)
Cilazapril + hydrochlorothiazide (n ■= 1,068)
n
%
n
%
Adverse events Abnormal laboratory values
183 27
4.9 0.8
44
4.1 1.2
Events most frequently responsible for withdrawal
Headache, nausea. cough, fatigue
Discussion
The benefits of long-term effective antihy pertensive therapy in terms of decreased mor tality from cardiovascular diseases are now well accepted [5, 6], Traditional drugs used in the treatment of hypertension, such as diuret ics and ß-blockers, effectively reduce blood pressure, but long-term exposure to some of their adverse metabolic effects, including di uretic-induced hypokalemia and blood lipid alterations, may negate the benefits of re
Cough, dizziness, chest pain
duced blood pressure [6], In the continuing search for effective and safer antihypertensive drugs, ACE inhibitors represent a major ad vance [7-9], In general, ACE inhibitors are as effective as diuretics and ß-blockers, but do not cause the adverse effects described above. Thus, these drugs do not increase the potential for cardiac arrhythmia, as with non-potassiumsparing diuretics [10], In addition, ACE in hibitors may be administered to patients with asthma or congestive heart failure, whereas ßblockers are best avoided. Reduced renal blood flow is common in patients with hypertension; however, with ACE inhibitor treatment, renal blood flow tends to increase or remain unchanged in spite of decreased blood pressure [11-13]. It appears that reduced proteinuria with treat ment is a useful criterion for predicting bene ficial renal effects of ACE inhibitor therapy [14. 15], Other attributes of ACE inhibitors include a lack of associated central nervous system effects, fewer orthostatic effects and increased exercise tolerance in comparison with other antihypertensive agents [ 16], Given the wealth of clinical evidence which has accumulated in support of the favorable therapeutic profile of ACE inhibi tors. it is not surprising that this class of drugs
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the patients with renal impairment or colla gen diseases had any leukopenia and/or neu tropenia. Of 64 patients (2.3%) treated with cilazapril alone or in combination with hy drochlorothiazide who had increases in serum creatinine to > 2m g/dl. 41 had prior renal impairment. These increases usually reversed after discontinuing therapy. Proteinuria in as sociation with cilazapril alone or in combina tion occurred in 23 patients (0.6%), 5 of whom had prior renal impairment. A summary of patients who withdrew from therapy because of adverse events is pre sented in table 3. Although 0.8% of patients stopped taking cilazapril because of abnormal laboratory values, these were rarely of poten tial clinical significance.
12
40
Szucs/Schneeweiss
slightly greater extent than 2.5 mg/day. and this was confirmed in dose titration studies in patients who did not achieve a satisfactory response to 2.5 mg/day. Those patients who do not respond to cilazapril 5 mg/day are likely to do so if a low dose of hydrochloro thiazide is added to the regimen. Although there appear to be fewer risks associated with ACE inhibitors compared with other classes of antihypertensive drugs, there are certain class-specific safety issues. These include the potential for hypotension (especially as a first-dose effect) in salt-de pleted patients and renin-dependent hyper tension [22], renal failure (mainly in patients with renal artery stenosis) [23] and angioedema, cough, rash and low white blood cell counts [24], These events occurred in small numbers of patients taking cilazapril, but the incidences attributed to the drug were compa rable or less than those seen with other ACE inhibitors [20, 25-32], No adverse conse quences. such as infections associated with leukopenia, respiratory distress or laryngeal stridor in association with angioedema, were reported. With more than 4.000 patients treated, no specific safety issue specific to cilazapril has yet emerged. In conclusion, the clinical evidence accu mulated to dale shows that cilazapril is an effective and well-tolerated new ACE inhibi tor in the treatment of hypertension.
Cilazapril in Hypertension
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is now recommended for consideration as first-choice treatment in the USA [17], and a similar guideline has been suggested for Eu rope [18]. Placebo-controlled trials demonstrated that cilazapril in the dose range of 2.5-5 mg/ day significantly reduced SDBP during 4 weeks of therapy. Differences in SDBP com pared with placebo were similar to those ob served in placebo comparisons with usual therapeutic dosages of captopril [19] and lisinopril [20]. Comparable efficacy with other ACE inhibitors, as well as propranolol, hy drochlorothiazide and atenolol, was sup ported by the results of the active agent-con trolled trials. The 24-hour duration of action of cilaza pril has been described in human volunteer studies in terms of ACE inhibition [3], which translates into satisfactory blood pressure control with once-daily administration in hy pertensive patients. This favors a high rate of compliance, which is an important factor in the long-term management of hypertensive patients who are otherwise asymptomatic. Compared with other long-acting ACE inhibi tors. such as cnalapril and lisinopril. cilazapril has been shown to possess superior absorp tion and bioavailability, thus permitting a better prediction of the antihypertensive ef fect of a given dose [unpubl. data]. Like cila zapril [19]. enalapril [21] and lisinopril [20]. cilazapril maintains blood pressure control during long-term use. Based on the results of clinical pharmacol ogy studies and the therapeutic trials, the usual recommended dosage of cilazapril is 2.5-5 mg once daily. Cilazapril 2.5 mg daily attained clinically significant reductions in SDBP in placebo-controlled trials and a 24hour cumulative responder rate following ad ministration comparable to other antihyper tensive monotherapy. In fixed-dose studies, cilazapril 5 mg/day reduced SDBP by a
References 10 Multiple Risk Factor Intervention Trial Research Group: Baseline rest ing electrocardiographic abnormali ties. antihypertensive treatment and mortality in the Multiple Risk Fac tor Intervention Trials. Am J Car diol 1985;55:1-15. 11 Bauer JH, Reams GP: Hemody namic and renal function in essen tial hypertension during treatment with enalapril. Am .1 Med 1985: 79(suppl 30:10-13. 12 de Leeuw PW. Birkenhager WH: Renal blood flow in essential hyper tension. J Cardiovasc Pharmacol 1987; 10
