Antihypertensive Treatment with Moexipril Plus HCTZ Vs Metoprolol Plus HCTZ in Patients with Mild-To-Moderate Hypertension

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Antihypertensive treatment with moexipril plus HCTZ vs metoprolol plus HCTZ in patients with mild-to-moderate hypertension

M Stimpel and B Koch for the investigators of the study Department of Clinical Research, Schwarz Pharma AG, Monheim, Germany

Combination therapy with the new ACE inhibitor moexi- −17.6 mm Hg/−12.8 mm Hg and −17.2 mm Hg/−13.9 pril plus hydrochlorothiazide (HCTZ) results in signifi- mm Hg in the moexipril/HCTZ and metoprolol/HCTZ cant blood pressure (BP) reductions. This study com- groups, respectively. The response rate to both kinds pares the efficacy and safety of moexipril plus HCTZ to of combinations were very similar, 69% and 74% in the that of a standard combination treatment in patients moexipril/HCTZ and metoprolol/HCTZ groups, respect- with mild-to-moderate hypertension. ively. The percentage of patients which experienced one After a 1 month placebo run-in period, 140 hyperten- or more AEs were 46% in the moexipril/HCTZ and 61% sive patients whose sitting diastolic BP (DBP) averaged in the metoprolol/HCTZ group. Headache and cough 95–114 mm Hg were randomized to receive either once which are the most frequently reported AEs after treat- daily moexipril 7.5 mg/HCTZ 12.5 mg or metoprolol ment with ACE inhibitors were seen in 9% and 10% of 100 mg/HCTZ 12.5 mg for the following 12-week double- the patients in the moexipril/HCTZ group compared to blind treatment period. At biweekly visits BP was con- 10% and 4% in the metoprolol/HCTZ group. trolled sphygmomanometrically and the occurrence of The study indicates that the combination of moexipril adverse events (AE) was documented. 7.5 mg plus HCTZ 12.5 mg is as efficacious and safe as At study endpoint adjusted mean reductions in sitting metoprolol 100 mg plus HCTZ 12.5 mg in the treatment systolic/diastolic BP seen with both combinations were of mild-to-moderate hypertension.

Keywords: moexipril; metoprolol; hydrochlorothiazide; high blood pressure

Introduction inhibitors may limit the metabolic disturbances induced by the thiazides.8 Fixed dose antihypertensive combinations are This study was designed to compare the efficacy increasingly being used in the management of and safety of the combination of the new ACE- hypertension. These usually combine drugs with inhibitor moexipril plus hydrochlorothiazide to the different mechanisms of action which offer the combination of metoprolol plus hydrochlorothiaz- potential for a synergistic effect on blood pressure ide in the treatment of mild-to-moderate hyperten- (BP) while counteracting the side effects of each sives. other. Numerous studies have shown the efficacy of a combination of a beta-blocker with a diuretic, for Patients and methods example metoprolol plus hydrochlorothiazide, in Patients lowering BP. The hypotensive effects of both are fully additive. In addition, diuretics and beta-block- One hundred and forty men and women with a sit- ers have been shown to reduce morbidity and mor- ting diastolic blood pressure (DBP) of 95–114 tality in hypertensive subjects when used alone or mm Hg were considered for entry into the study if in combination.1–4 The combination of an ACE- aged between 35 and 80 years. Patients had to be inhibitor with a diuretic is increasingly popular. generally healthy and free of secondary hyperten- Addition of even small doses of a thiazide diuretic sion, cardiac disease or a significant impairment of to an ACE-inhibitor has shown far greater additional renal or hepatic function. falls in BP than could be achieved by substantial increases in the ACE-inhibitor dose.5–7 Furthermore, Conduct of the study a potential benefit of this combination is that ACE- After providing informed consent eligible patients entered a 4-week single-blind placebo run-in phase. Those, whose sitting DBP was between 95 mm Hg Correspondence: Michael Stimpel, Department of Clinical Research, Schwarz Pharma AG, Alfred-Nobel-Straβe 10, 40789 and 114 mm Hg (average of three readings) at the last Monheim, Germany two visits of the placebo period were randomized Received 10 December 1996 into one of two treatment regimens: Moexipril/HCTZ vs metoprolol/HCTZ in hypertension M Stimpel and B Koch 134 (1) 7.5 mg moexipril combined with 12.5 mg hyd- HCTZ combination group. A total of 127 (91%) rochlorothiazide (HCTZ); patients completed the double-blind period of the (2) 100 mg metoprolol combined with 12.5 mg study and 13 (9%) were prematurely withdrawn for HCTZ. adverse events. The majority of the patients were men (56%). The The study drugs, contained in capsules for moexi- average age was 59 years and 69% of the patients pril and hydrochlorothiazide or matching placebo were under 65 years of age. There were no clinically and in tablets for metoprolol or matching placebo, relevant differences among treatment groups in any were taken once daily (approximately at the same baseline demographic variables (see Table 1). time of the day) over a 12-week double-blind treatment period. Compliance was assessed by pill coun- ting. Efficacy BP was measured by trained personnel using stan- Figures 1 and 2 show the changes in sitting systolic dard mercury sphygmomanometers. Trough BP and DBP in both treatment groups from baseline to measurements were obtained at each visit (at the endpoint (last valid BP measurement during the end of the 22–26 hour dosing interval before drug double-blind phase). Treatment means at baseline administration). The mean of three sitting readings were very similar: 101.7 mm Hg and 101.5 mm Hg taken 1 min apart was used as the visits sitting BP. in the moexipril combination group and the metop- Afterwards, patients were asked to get up and an rolol combination group, respectively. With respect immediate upon standing and two 2-min standing to adjusted mean reductions from baseline in sitting BP readings were taken. Heart rate was measured in DBP at endpoint (−12.8 mm Hg vs −13.9 mm Hg), no the sitting and 2-min standing position. statistically significant difference was shown The primary variable of efficacy was based on the between the 7.5 mg moexipril/12.5 mg HCTZ combi- mean change from baseline in sitting DBP at the end nation group and the 100 mg metoprolol/12.5 mg of the 12-week double-blind treatment. Sitting sys- HCTZ combination group. Comparable results were tolic BP (SBP) and standing DBPs were recorded as obtained at 1 and 2 h after the initial dose and at all secondary efficacy variables. trough timepoints. Adverse experiences (AEs) as well as pre- vs post- Exploratory analysis of subgroups showed similar treatment results of physical examination, electro- results between the treatment groups among both cardiogram and laboratory tests (biochemistry, hem- men and women, younger patients (Ͻ65 years) and atology and urinalysis) were included in the safety older patients (у65 years) and mild and moderate evaluation. Adverse events were assessed at each hypertensive patients. visit by questioning in a general way. The adverse At endpoint, 69% of the patients showed a good events were graded by the investigator as serious or (sitting DBP у90 mm Hg but reduction of у10 non-serious, as mild, moderate or severe and the mm Hg from baseline) or excellent (sitting DBP Ͻ90 relationship to the study medication was charac- mm Hg) response to treatment in the moexipril plus terized as none, likely, possible, probable or HCTZ group compared to 74% of the patients in the highly probable. metoprolol plus HCTZ group. The difference was not statistically significant. Statistical analysis Changes in sitting SBP paralleled those seen in DBP and changes in systolic and DBP in the stand- An intent to treat analysis which included all ran- ing and 2-min standing position were similar to domized patients who had at least one baseline BP those in the sitting position. No statistically signifi- reading and one post baseline reading was perfor- cant differences between the moexipril and the med to assess efficacy. All randomized patients were metoprolol combination group were detected in included into the safety analysis. The BP data were reducing the sitting SBP (−17.6 mg Hg vs −17.2 analyzed using a two-way analysis of covariance mm Hg) and the standing BP. (ANCOVA). Before utilizing the final ANCOVA model, it was established that generally there were no significant treatment-by-baseline interactions. Safety Therefore the final model included only the main Both combination treatments were generally well effects for treatment and investigator, with the base- tolerated and no unusual or unexpected adverse line measurement of BP as the covariate. The inci- events occurred during the study. The incidence of dence of adverse events was summarized for each patients reporting at least one AE (regardless of drug treatment group in frequency tables and demo- relationship) was 46% in the moexipril/HCTZ and graphic and baseline characteristics were summar- 61% in the metoprolol/HCTZ combination group, ized using descriptive statistics. respectively. Table 2 is a summary of the most frequently reported AEs. Few of these AEs were con- Results sidered drug related by the investigators. Cough was the most frequently reported adverse event that was Of 155 patients initially enrolled, 140 met the entry considered related to moexipril combination treat- criteria and were randomized to treatment. Of the ment (7%) and fatigue, dizziness and headache were 140 patients, 69 (49%) were randomized to the the most common AEs assessed to be at least poss- 7.5 mg moexipril/12.5 mg HCTZ combination group ibly related to treatment with the metoprolol combi- and 71 (51%) to the 100 mg metoprolol/12.5 mg nation (7% each). Moexipril/HCTZ vs metoprolol/HCTZ in hypertension M Stimpel and B Koch 135 Table 1 Summary of demographic and baseline characteristics

Characteristics Moexipril Metoprolol 7.5 mg + 100 mg + HCTZ 12.5 mg HCTZ 12.5 mg

Number of patients 69 71 Age (yrs) Mean (Range) 57.8 (35–76) 61.1 (44–80) Sex Male 40 (58%) 39 (55%) Female 29 (42%) 32 (45%) Sitting systolic blood pressure (mm Hg) Mean (Range) 161.5 (132.7–191.3) 160.8 (124.7–192.0) Sitting diastolic blood pressure (mm Hg) Mean (Range) 101.7 (96.0–110.0) 101.5 (94.3–110.7) Sitting pulse (bpm) Mean (Range) 72 (56–96) 74 (54–96)

Table 2 Main adverse experiences (у5% incidence) regardless of relationship to study drug

Adverse experiences Moexipril 7.5 mg Metoprolol 100 mg + HCTZ 12.5 mg + HCTZ 12.5 mg

N = 69 N = 71 n (%) n (%)

Body as a whole Fatigue 2 (3) 5 (7) Flu Syndrome 2 (3) 4 (6) Headache 6 (9) 7 (10) Pain 7 (10) 7 (10) Pain Back 4 (6) 1 (1) Digestive System Dyspepsia 1 (1) 4 (6) Figure 1 Adjusted mean change from baseline in sitting diastolic Nausea 0 4 (6) blood pressure (mm Hg). Nervous System Dizziness 2 (3) 6 (8) Respiratory System Cough increased 7 (10) 3 (4) Upper respiratory 5 (7) 6 (8) infection Skin and Appendages Rash 3 (4) 5 (7)

Table 3 Adverse events which result in withdrawal

Treatment group Adverse events

Moexipril 7.5 mg + HCTZ Cardiac Arrest 12.5 mg Tachycardia Metoprolol 100 mg + HCTZ Dizziness Figure 2 Adjusted mean change from baseline in sitting systolic 12.5 mg Myocardial infarction blood pressure (mm Hg). Rash Nausea/dizziness Somnolence Thirteen patients were discontinued due to AEs Fatigue (see Table 3). Of these patients two were receiving Atrial fibrillation Vertigo 7.5 mg moexipril plus 12.5 mg HCTZ and 11 Hemoptysis patients were receiving 100 mg metoprolol plus Pain/dizziness/rhinitis 12.5 mg HCTZ. Three of the 13 patients with AEs Syncope leading to discontinuation had serious AEs, one in Moexipril/HCTZ vs metoprolol/HCTZ in hypertension M Stimpel and B Koch 136 the moexipril combination group (cardiac arrest, BP chronic management of hypertension without prior to AE: 160/100 mm Hg) and two in the repeated laboratory tests, modern drugs should com- metoprolol group (myocardial infarction, BP: 180/60 bine high efficacy with a good safety profile. There- mm Hg; atrial fibrillation). fore, the fact that ACE inhibitors are reported to be There were no clinically significant changes nearly metabolically neutral seems to be advan- between pre- and post-treatment results of physical tageous while this is not true for HCTZ or metopro- examination, electrocardiogram or laboratory lol.20–22 Hypokalaemia, hyponatraemia, hypochlor- values, however elevated uric acid levels were aemia or hypercalcaemia as well as increases in reported in six patients (8.7%) in the moexipril com- serum glucose, cholesterine, triglycerides and uric bination group and in 10 patients (14.3%) in the acid are the metabolic disturbances often seen with metoprolol combination group. All of these patients HCTZ.23–27 As the dosage of HCTZ was very low in had at least one uric acid abnormality that was out- this study the metabolic changes seen after 12 weeks side predefined limits. None of these events was of treatment were small and only rarely classified as considered clinically important by the investigators. clinically significant. Although no statistically difference could be detected between the two groups fewer patients in the moexipril combination group Discussion reported noteworthy changes in one of the above Despite the availability of numerous single antihy- mentioned metabolic parameters. Furthermore pertensive agents, combination therapy is required moexipril seemed to be more able than metoprolol in many patients to achieve BP control. As the dose- to counterbalance the negative effects of HCTZ. response curve for antihypertensive agents tends to Overall, adverse experiences occurred in 61% and plateau at higher doses, titration toward maximum 46% of the patients in the metoprolol and moexipril doses of a single agent often leads to only small groups, respectively. Especially peripheral vascular increases in efficacy at the expense of an undesirable disease, dyspepsia, nausea, dizziness, rash and tin- increase in side effects.9 Alternatively, adding of a nitus were reported much more frequent in the second drug from another class with a different metoprolol group causing a higher incidence of AEs mode of action seems to be more recommended if in the cardiovascular system, the digestive system, initial therapy is inadequate.10 This study compared the musculoskeletal system, the nervous system, as the efficacy and safety of two antihypertensive com- well as in the system of skin and appendages and binations, the new ACE inhibitor moexipril com- special senses. As for other ACE inhibitors28–31 bined to HCTZ and metoprolol combined to HCTZ. cough was the adverse experience which was The principal finding was that both combinations reported most frequently in the moexipril group. were equivalent in their effectiveness in reducing Ten per cent of patients reported cough in the moex- BP and that moexipril plus HCTZ was as safe as the ipril group compared to only 4% in the metoprolol metoprolol combination. group, but none of the patients had to discontinue The results confirmed that both fixed combi- from treatment because of this AE. nations administered at a daily dosage of 7.5 mg In conclusion, this study comparing the efficacy moexipril plus 12.5 mg HCTZ and 100 mg metopro- and safety of moexipril plus HCTZ to that of metop- lol plus 12.5 mg HCTZ were able to decrease both rolol plus HCTZ during a 12-week treatment period sitting DBP and sitting SBP for 24 h. Reduction in indicates that the moexipril combination is as effec- sitting SBP and sitting DBP after 12 weeks of treat- tive as the metoprolol combination in treating mild- ment were −17.6/−12.8 mm Hg and −17.2/−13.9 for to-moderate hypertensives. As to be seen from stud- the moexipril and metoprolol combination groups, ies with diuretics and beta-blockers an important respectively. Both combinations also achieved a effect of this BP lowering activity is a reduced risk high and comparable good (sitting DBP у90 mm Hg of cardiovascular diseases, stroke, heart attacks and but reduction of у10 mm Hg from baseline) or excel- heart failure. Although up to now there are no data lent (sitting DBP Ͻ90 mm Hg) BP response of 69% available whether ACE inhibitors may also reduce in the moexipril combination group and 74% in the morbidity and mortality in hypertensive patients, metoprolol combination group. These values are in this short-term study showed that the combination accordance with BP reductions and responses seen of moexipril plus HCTZ has a good safety profile and with other combinations11–14 and the values are was as safe as metoprolol plus HCTZ. clearly higher than those seen in patients treated 15–19 with moexipril, metoprolol or HCTZ alone. Acknowledgements Studies investigating the effect of 7.5 mg moexipril plus 12.5 mg HCTZ vs the components showed sys- The authors would like to thank Mrs Marion Berger tolic and DBP reductions of approximately −10.0 for her excellent assistance in preparing the manu- mm Hg/−8.0 mm Hg for the monotherapies, and of script. −17.0 mm Hg/−12.0 mm Hg for the combination treatment. 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