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The effects of COX-2 specific inhibitors on edema and systolic blood pressure in elderly patients with osteoarthritis and treated hypertension: a pooled analysis on 1,902 patients
118A
POSTERS: Clinical Trials
AJH–April 2002–VOL. 15, NO. 4, PART 2
domised into the trial and their demographics were recently reported (J.Hypertension 2001;19:1139-47). Mean blood pressures at randomisation (representing a mixture of both untreated 20% and previously treated 80% patients) were 164 mmHg systolic and 95 mmHg diastolic. Target pressures are⬍140 mmHg systolic and ⬍90 mmHg diastolic, except for a subgroup of patients with type 2 diabetes in whom targets are lowered to ⬍130 mm Hg systolic and ⬍80 mmHg diastolic. Blood pressure changes during the first 2.5 years of follow up (treatment groups combined) are shown in the accompanying table. Patients will be followed up for a further 2.5 years on average. Mean BP & BP change by visit-all patients
Randomisation 6 Weeks 3 Months 6 Months 1 Year 1.5 Years 2 Years 2.5 Years
Number
mmHg
Difference
19332 18890 18721 18584 18275 17003 12127 6930
164/95 155/88 150/86 147/86 145/85 143/83 142/83 141/82
⫺ 10/7 14/9 17/9 9/10 21/12 22/12 24/14
By 2.5 years 27 % of patients remained on one antihypertensive drug and the remainder (73%) required 2 or more antihypertensive drugs. These data emphasize that to achieve currently recommended BP targets, at least 2 drugs are required for most hypertensives but that using clear treatment algorithms as in the ASCOT trial, acceptable BP control is achievable for a large proportion of patients. Key Words: Hypertension, RCT, ASCOT
P-243 ASSESSMENT OF THE NOVEL SELECTIVE ALDOSTERONE BLOCKER EPLERENONE USING AMBULATORY AND CLINIC BP IN 400 PATIENTS WITH SYSTEMIC HYPERTENSION: RESULTS FROM A PIVOTAL MULTINATIONAL TRIAL W. B. White, W. Oigman, D. Mion, A. Lewin, B. Roniker, R. Jordan, J. Kleiman, I. Nusbaum†, on behalf of the Eplerenone 049 Investigators. Section of Hypertension and Clinical Pharmacology, University of Connecticut Health Center, Farmington, CT, United States; Hospital Universitario Pedro Ernesto, Rio de Janeiro, Brazil; Hospital das Clinicas da Faculdade de Medicina da USP, Sao Paulo, Brazil; National Research Institute, Los Angeles, CA, United States; Pharmacia Corporation, Skokie, IL, United States; Pharmacia Corporation, Skokie, IL, United States; Pharmacia Corporation, Skokie, IL, United States; †Deceased. For more than a decade, new antihypertensive agents have been evaluated using both clinic and ambulatory BP recordings in pivotal trials that determine dose ranges, level of efficacy, and pharmacodynamic benefits. Eplerenone is a novel selective aldosterone blocker that is being developed for the treatment of both hypertension and congestive heart failure. To evaluate its utility in systemic hypertension, we performed a 12-week double-blind, placebo-controlled, parallel arm, fixed-dose study over a range of doses in the treatment of stage I-III hypertension. Following single-blind placebo therapy for 3-4 weeks to obtain baseline clinic and ambulatory BP measures, 400 patients were randomized to receive placebo or 1 of 4 doses of eplerenone (25, 50, 100, and 200 mg QD). Patients were reassessed using clinic and ambulatory BP at the end of 12 weeks of therapy (see Table) Changes from Baseline in the Clinic and Ambulatory BP on Eplerenone:
There were no reports of gynecomastia, menstrual abnormalities, or breast pain in patients on eplerenone. AEs attributed to eplerenone and withdrawal rates were similar to those of placebo. Thus, these data demonstrate that eplerenone was effective at doses as low as 25 mg daily for ABPM. Furthermore, the top effective dose in stage I-III hypertension based on both clinic and ambulatory BP was 100 mg daily. Key Words: Eplerenone, Aldosterone, Selective Aldosterone Blocker
P-244 THE EFFECTS OF COX-2 SPECIFIC INHIBITORS ON EDEMA AND SYSTOLIC BLOOD PRESSURE IN ELDERLY PATIENTS WITH OSTEOARTHRITIS AND TREATED HYPERTENSION: A POOLED ANALYSIS ON 1,902 PATIENTS Joseph A. Puma, Alfonso E. Bello, Jennifer J. Rodriguez, John G. Fort. The Heart & Vascular Center, Winston-Salem, North Carolina, United States; Illinois Bone and Joint Institute, Chicago, Illinois, United States; Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina, United States; Pharmacia Corporation, Peapack, New Jersey, United States. Elderly patients with hypertension (HTN) and osteoarthritis (OA), who are already at high risk of cardiovascular events, may be particularly vulnerable to the cardiorenal side effects of COX-2 specific inhibitors. Controversy exists over the prevalence of these side effects and whether they are a class effect of these drugs or molecule specific. To compare the cardiorenal effects of celecoxib and rofecoxib, we used pooled data of two similar, double-blind, randomized, controlled trials. Patients ⱖ65 years old with OA and stable, treated HTN were randomized to treatment with celecoxib 200 mg/day or rofecoxib 25 mg/day. A total of 1,902 patients were randomized; standardized assessments of edema and BP were performed at baseline and at weeks 1, 2 and 6. Significant destabilization in SBP was defined as change from baseline ⬎20 mm Hg and over 140 mm Hg; significant destabilization in DBP was defined as change from baseline ⬎15 mm Hg and over 90 mm Hg. Edema was assessed by a 5-point scale from 0 to 4⫹ along with changes in weight (3% or greater). Baseline demographics were similar for each group. Edema and blood pressure results are shown in Table 1. This pooled analysis of two large randomized trials demonstrates statistically significant destabilization of SBP and increased edema in elderly patients with OA and HTN treated with rofecoxib compared with celecoxib. Further investigation of these molecule-specific differences and their clinical importance is warranted.
Outcome
Rofecoxib n ⴝ 942
Celecoxib n ⴝ 960
Relative Risk, Rofecoxib vs. Celecoxib (95% CI)
Increased edema SBP destabilization DBP destabilization
80 (8.5%) 147 (15.6%) 21 (2.2%)
46 (4.8%) 84 (8.8%) 13 (1.4%)
1.85 (1.27–2.70) 1.79 (1.39–2.27) 1.64 (1.21–3.23)
P (Fisher exact test) 0.001 ⬍0.001 0.168
Disclosure: Sponsored by Pharmacia Corporation and Pfizer Inc. Key Words: COX-2 Specific Inhibitors, Hypertension, Edema and Systolic Blood Pressure
POSTERS: Clinical Trials
AJH–April 2002–VOL. 15, NO. 4, PART 2
domised into the trial and their demographics were recently reported (J.Hypertension 2001;19:1139-47). Mean blood pressures at randomisation (representing a mixture of both untreated 20% and previously treated 80% patients) were 164 mmHg systolic and 95 mmHg diastolic. Target pressures are⬍140 mmHg systolic and ⬍90 mmHg diastolic, except for a subgroup of patients with type 2 diabetes in whom targets are lowered to ⬍130 mm Hg systolic and ⬍80 mmHg diastolic. Blood pressure changes during the first 2.5 years of follow up (treatment groups combined) are shown in the accompanying table. Patients will be followed up for a further 2.5 years on average. Mean BP & BP change by visit-all patients
Randomisation 6 Weeks 3 Months 6 Months 1 Year 1.5 Years 2 Years 2.5 Years
Number
mmHg
Difference
19332 18890 18721 18584 18275 17003 12127 6930
164/95 155/88 150/86 147/86 145/85 143/83 142/83 141/82
⫺ 10/7 14/9 17/9 9/10 21/12 22/12 24/14
By 2.5 years 27 % of patients remained on one antihypertensive drug and the remainder (73%) required 2 or more antihypertensive drugs. These data emphasize that to achieve currently recommended BP targets, at least 2 drugs are required for most hypertensives but that using clear treatment algorithms as in the ASCOT trial, acceptable BP control is achievable for a large proportion of patients. Key Words: Hypertension, RCT, ASCOT
P-243 ASSESSMENT OF THE NOVEL SELECTIVE ALDOSTERONE BLOCKER EPLERENONE USING AMBULATORY AND CLINIC BP IN 400 PATIENTS WITH SYSTEMIC HYPERTENSION: RESULTS FROM A PIVOTAL MULTINATIONAL TRIAL W. B. White, W. Oigman, D. Mion, A. Lewin, B. Roniker, R. Jordan, J. Kleiman, I. Nusbaum†, on behalf of the Eplerenone 049 Investigators. Section of Hypertension and Clinical Pharmacology, University of Connecticut Health Center, Farmington, CT, United States; Hospital Universitario Pedro Ernesto, Rio de Janeiro, Brazil; Hospital das Clinicas da Faculdade de Medicina da USP, Sao Paulo, Brazil; National Research Institute, Los Angeles, CA, United States; Pharmacia Corporation, Skokie, IL, United States; Pharmacia Corporation, Skokie, IL, United States; Pharmacia Corporation, Skokie, IL, United States; †Deceased. For more than a decade, new antihypertensive agents have been evaluated using both clinic and ambulatory BP recordings in pivotal trials that determine dose ranges, level of efficacy, and pharmacodynamic benefits. Eplerenone is a novel selective aldosterone blocker that is being developed for the treatment of both hypertension and congestive heart failure. To evaluate its utility in systemic hypertension, we performed a 12-week double-blind, placebo-controlled, parallel arm, fixed-dose study over a range of doses in the treatment of stage I-III hypertension. Following single-blind placebo therapy for 3-4 weeks to obtain baseline clinic and ambulatory BP measures, 400 patients were randomized to receive placebo or 1 of 4 doses of eplerenone (25, 50, 100, and 200 mg QD). Patients were reassessed using clinic and ambulatory BP at the end of 12 weeks of therapy (see Table) Changes from Baseline in the Clinic and Ambulatory BP on Eplerenone:
There were no reports of gynecomastia, menstrual abnormalities, or breast pain in patients on eplerenone. AEs attributed to eplerenone and withdrawal rates were similar to those of placebo. Thus, these data demonstrate that eplerenone was effective at doses as low as 25 mg daily for ABPM. Furthermore, the top effective dose in stage I-III hypertension based on both clinic and ambulatory BP was 100 mg daily. Key Words: Eplerenone, Aldosterone, Selective Aldosterone Blocker
P-244 THE EFFECTS OF COX-2 SPECIFIC INHIBITORS ON EDEMA AND SYSTOLIC BLOOD PRESSURE IN ELDERLY PATIENTS WITH OSTEOARTHRITIS AND TREATED HYPERTENSION: A POOLED ANALYSIS ON 1,902 PATIENTS Joseph A. Puma, Alfonso E. Bello, Jennifer J. Rodriguez, John G. Fort. The Heart & Vascular Center, Winston-Salem, North Carolina, United States; Illinois Bone and Joint Institute, Chicago, Illinois, United States; Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina, United States; Pharmacia Corporation, Peapack, New Jersey, United States. Elderly patients with hypertension (HTN) and osteoarthritis (OA), who are already at high risk of cardiovascular events, may be particularly vulnerable to the cardiorenal side effects of COX-2 specific inhibitors. Controversy exists over the prevalence of these side effects and whether they are a class effect of these drugs or molecule specific. To compare the cardiorenal effects of celecoxib and rofecoxib, we used pooled data of two similar, double-blind, randomized, controlled trials. Patients ⱖ65 years old with OA and stable, treated HTN were randomized to treatment with celecoxib 200 mg/day or rofecoxib 25 mg/day. A total of 1,902 patients were randomized; standardized assessments of edema and BP were performed at baseline and at weeks 1, 2 and 6. Significant destabilization in SBP was defined as change from baseline ⬎20 mm Hg and over 140 mm Hg; significant destabilization in DBP was defined as change from baseline ⬎15 mm Hg and over 90 mm Hg. Edema was assessed by a 5-point scale from 0 to 4⫹ along with changes in weight (3% or greater). Baseline demographics were similar for each group. Edema and blood pressure results are shown in Table 1. This pooled analysis of two large randomized trials demonstrates statistically significant destabilization of SBP and increased edema in elderly patients with OA and HTN treated with rofecoxib compared with celecoxib. Further investigation of these molecule-specific differences and their clinical importance is warranted.
Outcome
Rofecoxib n ⴝ 942
Celecoxib n ⴝ 960
Relative Risk, Rofecoxib vs. Celecoxib (95% CI)
Increased edema SBP destabilization DBP destabilization
80 (8.5%) 147 (15.6%) 21 (2.2%)
46 (4.8%) 84 (8.8%) 13 (1.4%)
1.85 (1.27–2.70) 1.79 (1.39–2.27) 1.64 (1.21–3.23)
P (Fisher exact test) 0.001 ⬍0.001 0.168
Disclosure: Sponsored by Pharmacia Corporation and Pfizer Inc. Key Words: COX-2 Specific Inhibitors, Hypertension, Edema and Systolic Blood Pressure