Antihypertensive Efficacy of Candesartan-Lisinopril in Combination vs. Up-Titration of Lisinopril: The AMAZE Trials

Joseph L. Izzo, Jr., MD; Marc S. Weinberg, MD; James W. Hainer, MD, MPH; Joseph Kerkering, MBA; Conrad K.P. Tou, PhD

Disclosures
In This Article

Results

In Study 1, 74 investigational sites screened 945 patients, of whom 543 were randomized; 538 qualified for the ITT population (267 in the lisinopril group and 271 in the candesartan plus lisinopril group). One patient in the combination group was excluded from the ITT/LOCF analysis because all postbaseline values were missing, and therefore, there was not a valid observation to carry forward. Thus, the ITT/LOCF analysis included 267 patients in the monotherapy group and 270 in the combination group. A total of 240 patients (90%) in the lisinopril group and 238 (88%) in the candesartan plus lisinopril group completed the 8-week, double-blind period.

In Study 2, 69 investigational sites screened 852 patients, of whom 560 were randomized; 558 qualified for the ITT population (279 in the lisinopril group and 279 in the candesartan plus lisinopril group). Two patients in the monotherapy group and one patient in the combination group were excluded from the ITT/ LOCF analysis because one patient had a DBP <90 mm Hg, one patient had a serum potassium value outside of previously defined parameters, and one patient had significant renal impairment. Thus, the ITT/LOCF analysis included 277 patients in the monotherapy group and 278 in the combination group. A total of 253 patients (91%) in the lisinopril group and 247 (89%) in the candesartan plus lisinopril group completed the 8-week, double-blind period.

The sample populations were very similar for the two AMAZE studies, and each study's randomization process produced treatment groups well balanced for all baseline characteristics ( Table I ). For Studies 1 and 2, mean ages were 54.4 years and 53.8 years; 17% and 15% were >65 years of age; mean weights were 205.8 lb and 206.1 lb; and mean body mass indices were 31.9 kg/m2 and 31.8 kg/m2, respectively. In Study 1, 17% of patients were black, and in Study 2, 24% were black. The mean trough sitting SBP/DBP at baseline was also nearly identical for the two treatment groups across both studies: 148.7/96.6 mm Hg in Study 1 and 148.6/96.8 mm Hg in Study 2. There were 57 patients with diabetes in Study 1 and 47 in Study 2, all of whom had type II diabetes. For these studies, patients were classified as having diabetes if they cited a positive history for diabetes. Across both studies, the most common prior antihypertensive medications were ACE inhibitors and their combinations with diuretics (40%), calcium channel blockers and their combinations with diuretics (16%), diuretics (14%), ARBs (other than candesartan, which was an exclusion criterion) and their combinations with diuretics (11%), and ß blockers and their diuretic combinations (8.6%). Compliance with the study medication was >96% in both treatment groups for both studies.

In Study 1, DBP, the primary efficacy measure, declined with both treatments: 5.90 mm Hg (95% confidence interval [CI], -7.26 to -4.55 mm Hg) with lisinopril monotherapy and 8.29 mm Hg (95% CI,-9.63 to-6.95 mm Hg) with candesartan plus lisinopril. This was a significant difference of 2.39 mm Hg (95% CI, -3.86 to -0.92 mm Hg; p <0.01). In Study 2, DBP also declined with both treatments: 6.24 mm Hg (95% CI, -7.50 to -4.98 mm Hg) with lisinopril monotherapy and 7.44 mm Hg (95% CI, -8.67 to -6.22 mm Hg) with candesartan plus lisinopril. This was a difference of 1.21 mm Hg (95% CI, -2.57 to 0.16 mm Hg; p = 0.08). Figure 2A and Table II present the least squares mean changes in trough sitting DBP from baseline to Week 8.

Least squares mean changes in trough sitting diastolic blood pressure (DBP) (A) and trough sitting systolic blood pressure (SBP) (B) from baseline to Week (WK) 8 in Studies 1 and 2. Results shown are for the intent-to-treat analysis (last observation carried forward). Bars represent standard error.

Least squares mean changes in trough sitting diastolic blood pressure (DBP) (A) and trough sitting systolic blood pressure (SBP) (B) from baseline to Week (WK) 8 in Studies 1 and 2. Results shown are for the intent-to-treat analysis (last observation carried forward). Bars represent standard error.

In Study 1, for SBP, the least squares mean change from baseline to Week 8 was -6.24 mm Hg (95% confidence interval [CI], -8.53 to -3.95 mm Hg) with lisinopril monotherapy and -11.58 mm Hg (95% CI, -13.84 to -9.32 mm Hg) with candesartan plus lisinopril, a statistically significant difference (-5.34 mm Hg [95% CI, -7.82 to -2.85 mm Hg]; p <0.01). In Study 2, for SBP, the least squares mean change from baseline to Week 8 was -8.72 mm Hg (95% CI, -10.82 to -6.62 mm Hg) with lisinopril monotherapy and -9.48 mm Hg (95% CI, -11.51 to -7.45 mm Hg) with candesartan plus lisinopril, a difference of -0.76 mm Hg (95% CI, -3.03 to 1.50 mm Hg; p = 0.51). Figure 2B and Table II present the least squares mean changes in trough sitting SBP from baseline to Week 8.

Figure 3 illustrates mean DBP levels over the 8-week, double-blind period. Most of the decline in DBP occurred in the first 1-2 weeks, and the difference in BP reduction in the direction favoring candesartan plus lisinopril was evident throughout the treatment periods. A similar pattern was observed for SBP (data not shown).

Mean trough sitting diastolic blood pressure (DBP) over time in Studies 1 and 2. Results shown at baseline and Weeks 1, 2, and 4 are for the intent-to-treat analysis (without carrying forward observations). At Week (WK) 8, results are shown for both intent-to-treat analyses (without carrying forward observations and last observation carried forward [LOCF]). DB=double-blind.

The response and control rates in both studies reflected the findings for mean change in BP, i.e., the rates were slightly greater for the combination treatment and these were statistically significant in Study 1 for the percentage of responders (DBP <90 mm Hg or reduced by >10 mm Hg) and the percentage of patients whose BP was controlled at <140/<90 mm Hg. Table II presents the response and control rates for both studies.

As shown in Figure 4, analysis of antihypertensive efficacy by subpopulations suggests that response to the treatments was in the same direction as the overall population, i.e., in the direction favoring combination treatment. For DBP, the only exception included black patients who exhibited greater BP reduction with lisinopril monotherapy in Study 1. Results were similar when SBP was analyzed by the same subgroups. Of note is the observation that, as a group, black patients tended to exhibit a somewhat lesser degree of BP lowering than non-black patients, while patients with diabetes tended to exhibit greater BP reductions than patients without diabetes.

Subpopulation analyses. Differences in least squares mean changes in trough sitting diastolic blood pressure from baseline to Week 8 in Studies 1 and 2. Results shown are for the intent-to-treat analysis (without carrying forward observations). Point estimate boxes are approximately proportional to sample sizes; bars represent 95% confidence intervals; *p ≤0.05, condensation and lisinopril vs. lisinopril monotherapy.

For both studies, repeated primary analyses based on the ITT population with no imputations on missing values and a per-protocol population (ITT population minus patients with significant protocol violations and poor compliance) were consistent with the primary analyses based on the ITT/LOCF population. Analyses based on patient screening group were also consistent with the overall results, except for Group B (newly diagnosed hypertension or patients off treatment for >30 days). For Group B patients in Study 1, lisinopril monotherapy was more effective than the combination by 1.43 mm Hg for DBP (p = 0.41), while in Study 2 the combination was substantially better (DBP difference of 4.22 mm Hg, p = 0.01).

For the 103 diabetic patients included in the ITT/LOCF analysis in the two studies (one patient had no post-baseline BP measurements), BP declined by 6.68/6.37 mm Hg with lisinopril monotherapy and 11.88/8.94 mm Hg with candesartan plus lisinopril. The difference of 5.20/2.57 mm Hg in favor of combination treatment was not statistically significant (p = 0.07/ p = 0.15) in this small sample size. Microalbuminuria was not assessed in these studies; however, semiquantitative urinary protein levels were recorded by study sites (dipstick method). Only 18 patients with diabetes had demonstrable urinary protein at the baseline visit, and there was no apparent change in the urinary protein distributions in the small diabetic patient group.

The safety findings in the two studies were similar, as were the safety findings in the two treatment groups. The most commonly reported adverse events were respiratory infection (6.2% lisinopril, 8.5% combination), headache (6.2%, 4.4%), cough (4.4%, 5.3%), and dizziness (4.2%, 5.6%) ( Table III ). Serious adverse events occurred in eight patients in the monotherapy group (1.5%) and in six patients in the combination group (1.1%). Only one serious adverse event, angioedema after 11 days of double-blind lisinopril monotherapy, was considered possibly related to study medication. One death occurred during double-blind therapy with candesartan plus lisinopril, which the investigator attributed to acute cocaine toxicity. Adverse events resulted in the discontinuation of 20 patients (3.7%) in the lisinopril group and 33 patients (6.0%) in the candesartan plus lisinopril group. Cough contributed to the discontinuation of five patients in the monotherapy group and six patients in the combination group, dizziness in one and six patients, respectively, and hyperkalemia in zero and four patients, respectively. Eleven patients in the lisinopril group and nine in the candesartan plus lisinopril group experienced hyperkalemia (defined as a serum potassium level of >6.0 mEq/L), had hyperkalemia reported as an adverse event, or were withdrawn from the study because of hyperkalemia. No patient experienced any apparent adverse consequences of hyperkalemia.

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