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Celecoxib associated with lower rate of renal dysfunction compared to nonspecific inhibitor NSAIDs
96A
POSTERS: Clinical Trials
P-250 EFFICACY AND SAFETY OF FIXED COMBINATIONS OF IRBESARTAN/HCTZ IN PATIENTS WITH UNCONTROLLED SBP ON MONOTHERAPY, ACCORDING TO PREVIOUS ANTIHYPERTENSIVE DRUG CLASS, IN THE INCLUSIVE TRIAL Michael A Weber, The INCLUSIVE Investigators. Department of Cardiology, SUNY Downstate College of Medicine, Brooklyn, NY. Objective: To determine the efficacy and safety of irbesartan/HCTZ fixed combinations in diverse patient populations with uncontrolled SBP on monotherapy who were enrolled in the Irbesartan/HCTZ Blood Pressure Reductions In Diverse Patient Populations (INCLUSIVE) trial, analyzed by previous antihypertensive drug class. Methods: This subgroup analysis of a multicenter, prospective, openlabel, single-arm study with forced titration to SBP response included patients, ⱖ18 years of age, with hypertension and uncontrolled SBP (140-179 mmHg; 130-179 mmHg for patients with diabetes) after ⱖ4 weeks of antihypertensive monotherapy. Treatment was sequential, with placebo (4 weeks), HCTZ 12.5 mg (2 weeks), irbesartan/HCTZ 150/12.5 mg (8 weeks), and irbesartan/HCTZ 300/25 mg (8 weeks). Mean changes in SBP and DBP from baseline to study end, SBP and DBP control rates, and safety were evaluated. Results: A total of 844 subjects completed the placebo wash-out phase and were enrolled in the study. Patients had previously failed to achieve SBP control on monotherapy with ACE inhibitors (34%), angiotensin receptor blockers (ARBs; 20%), calcium channel blockers (CCBs; 20%), diuretics (14%), and beta-blockers (11%). Few patients were previously on alpha-blockers (1%) and other antihypertensives (1%), and were excluded from further analysis. Mean change in SBP/DBP from baseline for the ITT population (n⫽736) was -21.5⫾14.3/-10.4⫾8.7 mmHg (P⬍0.001). Mean SBP changes by previous monotherapy ranged from -24.2⫾16.0 mmHg (P⬍0.001) in patients uncontrolled on beta-blockers to -20.1⫾14.8 mmHg (P⬍0.001) in those uncontrolled on ACE inhibitors. Mean DBP changes ranged from -12.9⫾9.2 mmHg (P⬍0.001; beta-blockers) to -9.3⫾8.3 mmHg (P⬍0.001; CCBs). SBP control (⬍140 mmHg; ⬍130 mmHg for patients with diabetes) rates ranged from 72% (ACE inhibitors) to 84% (beta-blockers). DBP control (⬍90 mmHg; ⬍80 mmHg for patients with diabetes) rates ranged from 80% (ACE inhibitors; diuretics) to 91% (beta-blockers). Treatments were well tolerated. Conclusions: Titration from HCTZ monotherapy to low- and highdose irbesartan/HCTZ fixed combinations allows SBP control to be attained in over 70% of patients previously uncontrolled on any antihypertensive monotherapy. Key Words: Blood Pressure Control, Combination Drug Therapy, Irbesartan/HCTZ
P-251 NEBIVOLOL IN THE TREATMENT OF PATIENTS WITH STAGE 1 AND STAGE 2 HYPERTENSION: RESULTS OF A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY Robert J Weiss, Michael A Weber, Albert A Carr, Betty S Riggs. Androscoggin Cardiology Associates, Auburn, ME; SUNY Downstate College of Medicine, Brooklyn, NY; Southern Clinical Research & Management, Augusta, GA; Mylan Bertek Pharmaceuticals, Morgantown, WV. The purpose of this study was to establish the antihypertensive efficacy and safety of nebivolol – a novel, highly selective 1 blocker with nitric-oxide mediated vasodilatory effects – in patients with Stage 1 or 2 hypertension. In this 12-week, multicenter, double-blind study, 909 hypertensive patients (mean sitting diastolic blood pressure [siDBP] 95 to 109 mm Hg) were randomized and treated with either placebo or nebivolol 1.25 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, or 40 mg once daily. Statistically significant reductions in blood pressure (BP) were evident at doses of 10, 20 and 40 mg approx-
AJH–May 2005–VOL. 18, NO. 5, PART 2
imately 2 to 3 hours after administering the first dose. Furthermore, treatment with nebivolol resulted in a dose-dependent reduction in both trough siDBP and trough sitting systolic blood pressure (siSBP), with a statistically significant treatment effect (vs. placebo) for all nebivolol doses at all visits from 2 to 12 weeks. At the end of the 12-week treatment period, the placebosubtracted numerical reductions in siDBP at trough ranged from -5.1 mmHg for nebivolol 1.25mg to -8.3 mmHg for nebivolol 40 mg. The placebosubtracted numerical reductions in siSBP at trough ranged from -6.6 mmHg for nebivolol 1.25 mg to -11.7 mmHg for nebivolol 40 mg. The placebosubtracted trough-to-peak ratios for the reduction in SiDBP were 0.9 or above for all doses of nebivolol. Heart rate was statistically significantly reduced in the nebivolol treatment groups in a dose dependent manner. The incidence of adverse events was not statistically different from placebo for doses of nebivolol up to and including 10 mg. In summary, nebivolol reduced BP and had an adverse event profile comparable to placebo. Key Words: Beta-Blocker, Nebivolol, Nitric Oxide
P-252 CELECOXIB ASSOCIATED WITH LOWER RATE OF RENAL DYSFUNCTION COMPARED TO NONSPECIFIC INHIBITOR NSAIDS Andrew Whelton, Ken Verburg. Dept of Medicine, Universal Clinical Research Center Inc, and The Johns Hopkins University School of Medicine, Baltimore, MD; Pain and Inflammation, Pfizer Global R&D, Ann Arbor, MI. Both the COX-1 and COX-2 isoforms are expressed by the human kidney and vasculature. Therefore, it is important to evaluate the renovascular effects of COX-2 specific inhibitors and NSAIDs, particularly in patients with preexisting renal dysfunction. The Celecoxib Long-term Arthritis Safety Study (CLASS) assessed gastrointestinal outcomes associated with supratherapeutic doses of the COX-2 specific inhibitor celecoxib (400mg bid), and standard doses of NSAIDs, ibuprofen (800mg tid) and diclofenac (75mg bid), in patients with rheumatoid arthritis (RA) or osteoarthritis (OA). The trial’s full database provided a large cardiorenal database for studying renal-related adverse events associated with nonspecific NSAIDs and celecoxib. Complete methods and gastrointestinal and cardiovascular results are published elsewhere. Enrolled patients had a serum creatinine ⱕ1.5mg/dL reflecting normal renal function. Renal function was assessed in all patients including those with mild prerenal azotemia defined by a baseline blood urea nitrogen (BUN) level of ⬎20mg/dL. The renovascular effects measured in these patients were clinically important reductions in renal function (defined as an increase in serum creatinine ⬎0.5mg/dL from baseline) and mean serum creatinine/estimated creatinine clearance. In patients with mild prerenal azotemia significantly fewer patients taking celecoxib exhibited clinically important reductions in renal function (3.4%) compared with either diclofenac (8.3%;P ⱕ0.05) or ibuprofen (7.7%;P ⱕ0.05). In patients with mild renal compromise, celecoxib was associated with a significantly lower rate of renal dysfunction at supratherapeutic doses compared with diclofenac and ibuprofen at standard doses. These data suggest that celecoxib may be a more suitable alternative to treat chronic pain and inflammation than nonspecific NSAIDs in patients with compromised renovascular function. Patients with baseline serum creatinine <1.5mg/dL and BUN >20mg/dL Baseline (mean) Serum creatinine (mol/L) Estimated creatinine clearance (mL/min) Mean change in serum creatinine (mol/L)
Celecoxib 400mg bid (n ⴝ 592)
Diclofenac 75mg bid (n ⴝ 300)
Ibuprofen 800mg tid (n ⴝ 260)
82.2 91.1
83.2 91.3
82.1 94.3
0.3 ⫾ 0.6
4.3 ⫾ 1.1*
2.9 ⫾ 1.3*
* P ⱕ 0.05; ANCOVA, Fisher’s exact test
Key Words: Celecoxib, NSAIDs, Prerenal Azotemia
POSTERS: Clinical Trials
P-250 EFFICACY AND SAFETY OF FIXED COMBINATIONS OF IRBESARTAN/HCTZ IN PATIENTS WITH UNCONTROLLED SBP ON MONOTHERAPY, ACCORDING TO PREVIOUS ANTIHYPERTENSIVE DRUG CLASS, IN THE INCLUSIVE TRIAL Michael A Weber, The INCLUSIVE Investigators. Department of Cardiology, SUNY Downstate College of Medicine, Brooklyn, NY. Objective: To determine the efficacy and safety of irbesartan/HCTZ fixed combinations in diverse patient populations with uncontrolled SBP on monotherapy who were enrolled in the Irbesartan/HCTZ Blood Pressure Reductions In Diverse Patient Populations (INCLUSIVE) trial, analyzed by previous antihypertensive drug class. Methods: This subgroup analysis of a multicenter, prospective, openlabel, single-arm study with forced titration to SBP response included patients, ⱖ18 years of age, with hypertension and uncontrolled SBP (140-179 mmHg; 130-179 mmHg for patients with diabetes) after ⱖ4 weeks of antihypertensive monotherapy. Treatment was sequential, with placebo (4 weeks), HCTZ 12.5 mg (2 weeks), irbesartan/HCTZ 150/12.5 mg (8 weeks), and irbesartan/HCTZ 300/25 mg (8 weeks). Mean changes in SBP and DBP from baseline to study end, SBP and DBP control rates, and safety were evaluated. Results: A total of 844 subjects completed the placebo wash-out phase and were enrolled in the study. Patients had previously failed to achieve SBP control on monotherapy with ACE inhibitors (34%), angiotensin receptor blockers (ARBs; 20%), calcium channel blockers (CCBs; 20%), diuretics (14%), and beta-blockers (11%). Few patients were previously on alpha-blockers (1%) and other antihypertensives (1%), and were excluded from further analysis. Mean change in SBP/DBP from baseline for the ITT population (n⫽736) was -21.5⫾14.3/-10.4⫾8.7 mmHg (P⬍0.001). Mean SBP changes by previous monotherapy ranged from -24.2⫾16.0 mmHg (P⬍0.001) in patients uncontrolled on beta-blockers to -20.1⫾14.8 mmHg (P⬍0.001) in those uncontrolled on ACE inhibitors. Mean DBP changes ranged from -12.9⫾9.2 mmHg (P⬍0.001; beta-blockers) to -9.3⫾8.3 mmHg (P⬍0.001; CCBs). SBP control (⬍140 mmHg; ⬍130 mmHg for patients with diabetes) rates ranged from 72% (ACE inhibitors) to 84% (beta-blockers). DBP control (⬍90 mmHg; ⬍80 mmHg for patients with diabetes) rates ranged from 80% (ACE inhibitors; diuretics) to 91% (beta-blockers). Treatments were well tolerated. Conclusions: Titration from HCTZ monotherapy to low- and highdose irbesartan/HCTZ fixed combinations allows SBP control to be attained in over 70% of patients previously uncontrolled on any antihypertensive monotherapy. Key Words: Blood Pressure Control, Combination Drug Therapy, Irbesartan/HCTZ
P-251 NEBIVOLOL IN THE TREATMENT OF PATIENTS WITH STAGE 1 AND STAGE 2 HYPERTENSION: RESULTS OF A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY Robert J Weiss, Michael A Weber, Albert A Carr, Betty S Riggs. Androscoggin Cardiology Associates, Auburn, ME; SUNY Downstate College of Medicine, Brooklyn, NY; Southern Clinical Research & Management, Augusta, GA; Mylan Bertek Pharmaceuticals, Morgantown, WV. The purpose of this study was to establish the antihypertensive efficacy and safety of nebivolol – a novel, highly selective 1 blocker with nitric-oxide mediated vasodilatory effects – in patients with Stage 1 or 2 hypertension. In this 12-week, multicenter, double-blind study, 909 hypertensive patients (mean sitting diastolic blood pressure [siDBP] 95 to 109 mm Hg) were randomized and treated with either placebo or nebivolol 1.25 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, or 40 mg once daily. Statistically significant reductions in blood pressure (BP) were evident at doses of 10, 20 and 40 mg approx-
AJH–May 2005–VOL. 18, NO. 5, PART 2
imately 2 to 3 hours after administering the first dose. Furthermore, treatment with nebivolol resulted in a dose-dependent reduction in both trough siDBP and trough sitting systolic blood pressure (siSBP), with a statistically significant treatment effect (vs. placebo) for all nebivolol doses at all visits from 2 to 12 weeks. At the end of the 12-week treatment period, the placebosubtracted numerical reductions in siDBP at trough ranged from -5.1 mmHg for nebivolol 1.25mg to -8.3 mmHg for nebivolol 40 mg. The placebosubtracted numerical reductions in siSBP at trough ranged from -6.6 mmHg for nebivolol 1.25 mg to -11.7 mmHg for nebivolol 40 mg. The placebosubtracted trough-to-peak ratios for the reduction in SiDBP were 0.9 or above for all doses of nebivolol. Heart rate was statistically significantly reduced in the nebivolol treatment groups in a dose dependent manner. The incidence of adverse events was not statistically different from placebo for doses of nebivolol up to and including 10 mg. In summary, nebivolol reduced BP and had an adverse event profile comparable to placebo. Key Words: Beta-Blocker, Nebivolol, Nitric Oxide
P-252 CELECOXIB ASSOCIATED WITH LOWER RATE OF RENAL DYSFUNCTION COMPARED TO NONSPECIFIC INHIBITOR NSAIDS Andrew Whelton, Ken Verburg. Dept of Medicine, Universal Clinical Research Center Inc, and The Johns Hopkins University School of Medicine, Baltimore, MD; Pain and Inflammation, Pfizer Global R&D, Ann Arbor, MI. Both the COX-1 and COX-2 isoforms are expressed by the human kidney and vasculature. Therefore, it is important to evaluate the renovascular effects of COX-2 specific inhibitors and NSAIDs, particularly in patients with preexisting renal dysfunction. The Celecoxib Long-term Arthritis Safety Study (CLASS) assessed gastrointestinal outcomes associated with supratherapeutic doses of the COX-2 specific inhibitor celecoxib (400mg bid), and standard doses of NSAIDs, ibuprofen (800mg tid) and diclofenac (75mg bid), in patients with rheumatoid arthritis (RA) or osteoarthritis (OA). The trial’s full database provided a large cardiorenal database for studying renal-related adverse events associated with nonspecific NSAIDs and celecoxib. Complete methods and gastrointestinal and cardiovascular results are published elsewhere. Enrolled patients had a serum creatinine ⱕ1.5mg/dL reflecting normal renal function. Renal function was assessed in all patients including those with mild prerenal azotemia defined by a baseline blood urea nitrogen (BUN) level of ⬎20mg/dL. The renovascular effects measured in these patients were clinically important reductions in renal function (defined as an increase in serum creatinine ⬎0.5mg/dL from baseline) and mean serum creatinine/estimated creatinine clearance. In patients with mild prerenal azotemia significantly fewer patients taking celecoxib exhibited clinically important reductions in renal function (3.4%) compared with either diclofenac (8.3%;P ⱕ0.05) or ibuprofen (7.7%;P ⱕ0.05). In patients with mild renal compromise, celecoxib was associated with a significantly lower rate of renal dysfunction at supratherapeutic doses compared with diclofenac and ibuprofen at standard doses. These data suggest that celecoxib may be a more suitable alternative to treat chronic pain and inflammation than nonspecific NSAIDs in patients with compromised renovascular function. Patients with baseline serum creatinine <1.5mg/dL and BUN >20mg/dL Baseline (mean) Serum creatinine (mol/L) Estimated creatinine clearance (mL/min) Mean change in serum creatinine (mol/L)
Celecoxib 400mg bid (n ⴝ 592)
Diclofenac 75mg bid (n ⴝ 300)
Ibuprofen 800mg tid (n ⴝ 260)
82.2 91.1
83.2 91.3
82.1 94.3
0.3 ⫾ 0.6
4.3 ⫾ 1.1*
2.9 ⫾ 1.3*
* P ⱕ 0.05; ANCOVA, Fisher’s exact test
Key Words: Celecoxib, NSAIDs, Prerenal Azotemia