- Email: [email protected]
Effects of Naproxcinod on Blood Pressure in Patients With Osteoarthritis
Effects of Naproxcinod on Blood Pressure in Patients With Osteoarthritis William B. White, MDa,*, Thomas J. Schnitzer, MD, PhDb, George L. Bakris, MDc, Hayet Frayssinet, MScd, Brigitte Duquesroix, MDd, and Michael Weber, MDe Nonsteroidal anti-inflammatory drugs are associated with increases in blood pressure (BP), particularly in patients treated with antihypertensive therapy. Naproxcinod is a nitric oxide-donating cyclooxygenase inhibitor in development for osteoarthritis (OA). Thus, we characterized the effects of naproxcinod on BP in an integrated safety analysis of 3 pivotal trials of patients with OA of the hip or knee involving 2,734 patients. The changes from baseline in the systolic BP after 13 weeks of therapy with naproxcinod (375 and 750 mg), naproxen 500 mg (equipotent to naproxcinod 750 mg), or placebo twice daily were evaluated in all patients and in the subgroup taking renin-angiotensin system inhibitors. Heterogeneity testing showed no treatment-by-study interaction. The effects of naproxcinod 750 mg on the systolic BP was not different from placebo (mean change from baseline vs placebo ⴚ0.4 mm Hg, 95% confidence interval ⴚ1.6 to 0.8). Naproxen increased the systolic BP relative to placebo (mean change from baseline vs placebo ⴙ1.4 mm Hg, 95% confidence interval 0.1 to 2.7). In the renin-angiotensin system inhibitor–treated patients, the effect of naproxcinod 750 mg compared to naproxen 500 mg in the changes from baseline in the systolic BP was ⴚ4.3 mm Hg (95% confidence interval ⴚ8.5 to ⴚ0.0). In conclusion, naproxcinod had effects on BP similar to that of placebo in patients with OA. These results imply that naproxcinod would be less likely to alter systolic BP control in patients with OA than a conventional nonsteroidal anti-inflammatory drug, particularly in those treated with renin-angiotensin system inhibitor agents. © 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;107:1338 –1345) Naproxcinod is a cyclooxygenase-inhibiting compound with analgesic and anti-inflammatory effects that has nitric oxide (NO)-donating properties (cyclooxygenase-inhibiting nitric oxide donator) that has been developed for the treatment of osteoarthritis (OA).1 After absorption, the molecule is rapidly cleaved into naproxen and a NO-donating moiety. Because NO has vasodilator actions, as well as causing inhibition of vascular smooth muscle proliferation that serves to maintain normal vascular tone,2,3 we hypothesized that naproxcinod might not induce the blood pressure (BP) increases typically seen with conventional nonsteroidal antiinflammatory drugs (NSAIDs). BP data were integrated from the pivotal phase III OA clinical trials, and the effects of 2 doses of naproxcinod (375 and 750 twice daily), a
Pat and Jim Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington, Connecticut; bDivision of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois; c Hypertension Center, University of Chicago Pritzker School of Medicine, Chicago, Illinois; dClinical Development and Medical Affairs, NicOx SA, Sophia-Antipolis, France; and eState University of New York Downstate Medical Center, Brooklyn, New York. Manuscript received November 14, 2010; manuscript received and accepted December 21, 2010. This study was funded by Nicox, SA, Sophia-Antipolis, France. The principal author and co-authors contributed to the defined analytic plan reported and had access to all data derived from these analyses. The principal author wrote and edited the manuscript with input from the coauthors. The research physician (B.D.) and statistician (H.F.) from the sponsor participated in the design of the original 3 pivotal trials detailed in the report with authors W.B. White. and T.J. Schnitzer. *Corresponding author: Tel: (860) 679-2104; fax: (860) 679-1250. E-mail address: [email protected] (W.B. White). 0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2010.12.046
naproxen 500 mg (the equipotent dose of naproxcinod 750 mg1) twice daily, and placebo were assessed. The BP treatment effects were studied within the entire population and in patients taking renin-angiotensin system (RAS) inhibitor drugs. Methods Three large OA clinical trials4 – 6 meeting the following criteria were included in the integrated analysis: phase III development, parallel, randomized, placebo-controlled, double-blind, and multicenter studies conducted to evaluate the efficacy and safety of naproxcinod in patients with OA of the knee (2 studies) or hip (1 study). To be included in these 3 studies, the patients were required to be men or women ⱖ40 years old with a confirmed diagnosis of OA of the knee or hip in accordance with the American College of Rheumatology guidelines. They also had to be current chronic users of NSAIDs or acetaminophen for OA pain and to have experienced a flare of pain after a discontinuation period of ⱖ5 half lives of the previous analgesic or anti-inflammatory therapy. A flare was defined as a visual analog pain scale score at baseline of ⱖ50 mm and an increase of ⱖ15 mm compared to the screening visit. The patients were excluded if they had uncontrolled diabetes, clinically important liver or renal impairment (serum creatinine ⬎176 mol/L at screening), or gastrointestinal bleeding or ulceration within the previous 6 months. Patients with hypertension were included if their hypertension control at study entry was acceptable according to the judgment of the study physician and their antihypertensive drug regimen had been stable for ⱖ3 months. www.ajconline.org
Systemic Hypertension/Effects of Naproxcinod on Blood Pressure
1339
Figure 1. Entry, randomization, and follow-up of patients after randomization in integrated safety population. Table 1 Patient characteristics at baseline Characteristic
Age (years) Women Race Black Nonblack Geographic location Europe North America Body mass index (kg/m2) Baseline systolic blood pressure (mm Hg) Baseline diastolic blood pressure (mm Hg) Patients taking antihypertensive agents Patients taking renin-angiotensin system blockers Patients taking renin-angiotensin system blockers and various diuretics
Naproxcinod 750 mg Twice Daily (n ⫽799)
Naproxcinod 375 mg Twice Daily (n ⫽ 487)
Naproxen 500 mg Twice Daily (n ⫽ 637)
Placebo Twice Daily (n ⫽ 811)
Overall (n ⫽ 2,734)
61.6 ⫾ 9.7 534 (66.8%)
60.5 ⫾ 9.5 359 (73.7%)
60.9 ⫾ 9.7 439 (68.9%)
61.7 ⫾ 9.4 557 (68.7%)
61.3 ⫾ 9.6 1,889 (69.1%)
80 (10.0%) 719 (90.0%)
79 (16.2%) 408 (83.8%)
82 (12.9%) 555 (87.1%)
90 (11.1%) 721 (88.9%)
331 (12.1%) 2,403 (87.9%)
199 (24.9%) 600 (75.1%) 31.8 ⫾ 7.2 127.3 ⫾ 14.7 77.9 ⫾ 9.4 349 (43.7%) 101 (12.6%) 74 (21.2%)
N/A 487 (100%) 33.9 ⫾ 8.0 125.4 ⫾ 12.9 77.1 ⫾ 8.4 207 (42.5%) 55 (11.3%) 58 (28.0%)
98 (15.4%) 539 (84.6%) 32.5 ⫾ 7.4 125.8 ⫾ 13.5 77.6 ⫾ 8.3 279 (43.8%) 64 (10.0%) 78 (28.0%)
203 (25.0%) 608 (75.0%) 31.9 ⫾ 7.1 127.9 ⫾ 13.9 78.3 ⫾ 8.9 365 (45.0%) 112 (13.8%) 91 (24.9%)
500 (18.3%) 2,234 (81.7%) 32.4 ⫾ 7.4
1,200 (43.9%) 332 (12.1%) 301 (25.1%)
Data are presented as mean ⫾ SD or n (%).
In 2 of the 3 studies involving 1,938 patients with OA of the knee at 238 clinical sites in the United States, the patients were randomized in a 1:1:1:1 ratio to receive 1 of 4 treatments, comprising naproxcinod 750 mg, naproxcinod 375 mg, naproxen 500 mg, or placebo twice daily, for the 13-week study treatment period. In the third study, 810 patients with hip OA at 105 clinical sites in Europe and North America were randomized to receive naproxcinod 750 mg, placebo, or naproxen 500 mg twice daily in a 2:2:1 ratio. An unbalanced distribution of patients among the treatment groups occurred because naproxcinod 375 mg was not included in the hip OA study and a lesser number of patients were randomized to naproxen. The focus of the present study was the effect of therapy on BP. The complete efficacy findings and other secondary end
points for each of the 3 trials have been previously reported.4 – 6 To determine that no clinically relevant difference in pain control was observed among the active treatment groups, one of the co-primary end points for pain (Western Ontario and McMaster Universities Osteoarthritis Index visual analog scales for pain) is provided in the present report. In each of the 3 studies, the seated clinic BP was measured in a standardized manner7 using mercury column or aneroid manometry in triplicate in the same arm and by the same examiner at baseline and 2, 6, and 13 weeks of the double-blind treatment period. The clinic BP was measured in the morning 2 to 4 hours after a dose of the study drug and, if applicable, antihypertensive drugs that had been taken in the morning. For patients treated with antihyperten-
1340
The American Journal of Cardiology (www.ajconline.org)
Table 2 Evaluation of efficacy for 3 trials pooled in blood pressure (BP) analysis using change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index pain subscale score Intention to Treat Population Study 301 (osteoarthritis of knee) Patients at baseline (n) Mean ⫾ SD Change from baseline at week 13 Least squares mean ⫾ SEM* 95% Confidence interval Efficacy vs placebo for 301 Difference in least squares mean ⫾ SEM† 95% Confidence interval for difference in least squares mean p Value for treatment effect‡ Study 302 (osteoarthritis of knee) Patients at baseline (n) Mean ⫾ SD Change from baseline at week 13 Least squares mean ⫾ SEM* 95% Confidence interval Efficacy vs placebo for 302 Difference in least squares mean ⫾ SEM† 95% Confidence interval for difference in least squares mean p Value for treatment effect‡ Study 303 (osteoarthritis of hip) Patients at baseline (n) Mean ⫾ SD Change from baseline at week 13 Mean ⫾ SD Least squares mean ⫾ SEM* 95% Confidence interval Efficacy vs placebo for 303 Difference in least squares mean ⫾ SEM† 95% Confidence interval for difference in least squares mean p Value for treatment effect§
Naproxcinod 750 mg Twice Daily
Naproxcinod 375 mg Twice Daily
Naproxen 500 mg Twice Daily
Placebo Twice Daily
223 73.4 ⫾ 14.9
234 73.5 ⫾ 15.5
219 71.3 ⫾ 17.3
215 72.2 ⫾ 16.0
⫺35.0 ⫾ 1.8 ⫺38.5 to ⫺31.5
⫺33.8 ⫾ 1.7 ⫺37.2 to ⫺30.4
⫺37.1 ⫾ 1.8 ⫺40.6 to ⫺33.6
⫺24.3 ⫾ 1.8 ⫺27.9 to ⫺20.8
⫺10.7 ⫾ 2.5 ⫺15.7 to ⫺5.7
⫺9.5 ⫾ 2.5 ⫺14.4 to ⫺4.5
⫺12.8 ⫾ 2.6 ⫺17.8 to ⫺7.7
— —
⬍0.0001
0.0002
⬍0.0001
—
241 70.2 ⫾ 17.4
247 71.3 ⫾ 16.9
254 73.6 ⫾ 15.8
256 71.4 ⫾ 16.8
⫺31.3 ⫾ 1.7 ⫺34.6 to ⫺28.0
⫺28.1 ⫾ 1.6 ⫺31.3 to ⫺24.8
⫺29.5 ⫾ 1.6 ⫺32.7 to ⫺26.3
⫺20.4 ⫾ 1.6 ⫺23.5 to ⫺17.2
⫺10.9 ⫾ 2.3 ⫺15.5 to ⫺6.4
⫺7.7 ⫾ 2.3 ⫺12.2 to ⫺3.2
⫺9.2 ⫾ 2.3 ⫺13.7 to ⫺4.7
— —
⬍0.0001
0.0008
⬍0.0001
—
323 66.3 ⫾ 16.2
— —
156 64.0 ⫾ 15.9
331 65.5 ⫾ 15.7
⫺29.1 ⫾ 26.6 ⫺25.8 ⫾ 1.7 ⫺29.2 to ⫺22.5
— — —
⫺27.1 ⫾ 26.1 ⫺24.3 ⫾ 2.2 ⫺28.7 to ⫺19.9
⫺20.8 ⫾ 27.0 ⫺18.0 ⫾ 1.7 ⫺21.3 to ⫺14.7
⫺7.8 ⫾ 1.9 ⫺11.6 to ⫺4.1
— —
⫺6.3 ⫾ 2.4 ⫺11.0 to ⫺1.7
— —
—
⬍0.001
—
⬍0.0001
* Negative change represents improvement. Differences were calculated as active versus placebo. ‡ p Values and 95% confidence intervals were from pairwise contrasts from an analysis of covariance model with baseline as covariate and treatment as factor. § Center also included in analysis of covariance as factor. †
sive drugs, the interval between the intake of antihypertensive medication, the intake of the study medication, and the BP measurements remained the same throughout for each subject in all 3 studies. The times of medication dosing and BP measurements were recorded in the case report forms. The comparability of the 4 treatment groups was determined from the demographic data and baseline BP values. Continuous variables were analyzed using the analysis of variance with treatment as the factor. Discrete variables were analyzed using the chi-square test. The mean changes from baseline at week 13 in systolic and diastolic BP were assessed in a meta-analysis of the individual patient data using mixed linear models, with the study and treatment as categorical fixed effects and the baseline BP as a continuous fixed effect and assuming heterogeneous within-study variance. The 3 active treatment groups were compared to the placebo group using one-sided 95% confidence intervals (CIs) of the differences in the mean changes. The naproxcinod doses were
compared to the naproxen dose using 2-sided 95% CIs. Post hoc, 2-sided CIs of the comparisons with placebo and the associated p values for all pairwise comparisons were calculated. Treatment-by-study interaction was added to the model as an additional random effect to test for heterogeneity across studies. These analyses of the changes from baseline in BP during the study were performed for the entire safety population and for those patients taking renin-angiotensin system (RAS) inhibitors at baseline, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers,  blockers, and renin inhibitors. The rationale for studying the RAS blocker subgroup was based on previous work,8 which showed a larger effect of NSAIDs on BP destabilization in patients taking these classes of antihypertensive agents. For the interpretation of the comparisons between the active treatment groups and the placebo group, a threshold of 2 mm Hg9 for the upper limit of the CI for the systolic BP differences and 1.5 mm Hg9 for the upper limit of the CI for the diastolic BP differences were used based on
Systemic Hypertension/Effects of Naproxcinod on Blood Pressure
1341
Figure 2. Least square mean changes from baseline in (A) systolic BP (mm Hg) and (B) diastolic BP (mm Hg) during 13-week treatment period in integrated safety population. Number of patients enrolled shown at various points in trials.
the relations to both cardiovascular outcomes and the clinical effect of these BP differences. The distributions of the categorized systolic BP changes from baseline (increases in varying individual thresholds of BP) were calculated. The post hoc analyses of these categorized changes were done using the same fixed effect meta-analysis as described and performed on the log odds ratios estimated for each study individually in a logistic regression analysis.10 Treatment differences are presented using odds ratios, 2-sided 95% CIs, and associated p values. The analyses were conducted post hoc to determine the estimated probability of destabilizing systolic BP (i.e., reaching a systolic BP of ⱖ140 mm Hg at week 13 given a
baseline systolic BP of ⬍140 mm Hg). In these analyses, the p values for the treatment comparisons were obtained from the pairwise contrasts from a logistic regression analysis with study and treatment as categorical fixed effects and baseline systolic BP as a continuous fixed effect. The mean constant curves were provided for graphic purpose and were determined from the results from the logistic regression analysis for the 3 individual studies. Results A total of 2,734 patients were included in the integrated safety population. As shown in Figure 1, 2,079 of the
1342
The American Journal of Cardiology (www.ajconline.org)
Table 3 Least square mean change from baseline versus placebo and naproxen in systolic blood pressure Integrated Safety Population Week 2 Comparison vs placebo Patients (n) Mean difference (mm Hg) p Value Comparison vs naproxen Patients (n) Mean difference (mm Hg) p Value Week 6 Comparison vs placebo Patients (n) Mean difference (mm Hg) p Value Comparison vs naproxen Patients (n) Mean difference (mm Hg) p Value Week 13 Comparison vs placebo Patients (n) Mean difference (mm Hg) p Value Comparison vs naproxen Patients (n) Mean difference (mm Hg) p Value
Naproxcinod 750 mg Twice Daily
783 vs 786 0.18 (0.86 to 1.23) 0.7302 783 vs 623 ⫺1.93 (⫺3.04 to ⫺0.81) 0.0007
724 vs 693 ⫺0.13 (⫺1.24 to 0.96) 0.8132 724 vs 587 ⫺2.73 (⫺3.91 to ⫺1.55) ⬍0.0001
662 vs 607 ⫺0.37 (⫺1.57 to 0.84) 0.5505 662 vs 522 ⫺1.78 (⫺3.05 to ⫺0.51) 0.0059
Naproxcinod 375 mg Twice Daily
Naproxen 500 mg Twice Daily
474 vs 786 0.72 (⫺0.53 to 1.97) 0.2564
623 vs 786 2.11 (0.99 to 3.23) 0.0002
474 vs 623 ⫺1.39 (⫺2.66 to 0.12) 0.0323
— — —
445 vs 693 0.81 (⫺0.57 to 2.18) 0.2486
587 vs 693 2.60 (1.41 to 3.79) ⬍0.0001
445 vs 587 ⫺1.79 (⫺3.17 to ⫺0.41) 0.0110
— — —
405 vs 607 0.67 (⫺0.79 to 2.13) 0.3654
522 vs 607 1.42 (0.12 to 2.71) 0.0321
405 vs 522 ⫺0.74 (⫺2.20 to 0.72) 0.3176
— — —
Data in parentheses are 95% CIs.
patients (76.0%) completed the trial, with similar proportions in the active treatment groups. Fewer patients completed the study in the placebo group (70.8%), primarily owing to a lack of efficacy and the worsening of OA symptoms. The baseline characteristics of the study population are listed in Table 1. Most patients were women and white, and the mean age of the study population was 61 years. The mean body mass index for the population was 32 kg/m2 and was similar across the treatment groups. Statistically significant differences were observed among the 4 treatment groups for race (black vs nonblack, p ⫽ 0.007), geographic location (Europe vs North America, p ⬍0.0001), and body mass index (p ⬍0.0001). A total of 1200 patients (44%) had both a history of hypertension and were receiving antihypertensive drug therapy. Of the patients treated with antihypertensive agents, 332 (27.7%) were taking a RAS inhibitor drug as a single agent for hypertension. In each of the 3 studies, all active treatments produced significant improvements from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale score at 13 weeks (Table 2). The changes from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale score at week 13 were similar for naproxcinod 750 mg and naproxen 500 mg. Smaller reductions in the pain subscale score were seen for naproxcinod 375 mg versus naproxcinod 750 mg and naproxen 500 mg twice daily. Both doses of naproxcinod and naproxen 500 mg were significantly superior statistically to placebo (Table 2). The number of patients who discontinued because of a lack of arthritis efficacy was similar for the active treatment groups
(naproxcinod 750 mg, 4.9%; naproxcinod 375 mg, 6.7%, and naproxen 500 mg, 4.8%; Figure 1). The changes from baseline in the systolic BP at each study visit during the 13-week period are shown in Figure 2. The systolic BP in the naproxcinod 750-mg group decreased from baseline to a nadir of ⫺3 mm Hg at week 6 and was of a similar magnitude to the BP changes in the placebo treatment group. In contrast, the systolic BP in the naproxen 500-mg group was unchanged from baseline during the 13-week period. Similar patterns of changes were seen for diastolic BP (Figure 2). Additionally, differences in the mean changes from baseline to week 13 for both naproxcinod doses were similar to those with placebo (upper bound of 95% CI was 0.8 mm Hg and 2.1 mm Hg for naproxcinod 750 mg and 375 mg, respectively). The changes in systolic BP with naproxen 500 mg were significantly greater than those with placebo at week 13 (1.4 mm Hg, 95% CI 0.1 to 2.7, p ⫽ 0.032; Table 3). At weeks 6 and 13, the mean changes from baseline in diastolic BP were significantly lower for both doses of naproxcinod versus naproxen 500 mg twice daily (p ⬍0.05 at both points). The mean systolic BP changes from baseline were significantly greater for naproxen 500 mg than for naproxcinod 750 mg and placebo at 2, 6, and 13 weeks, as well as for naproxcinod 375 mg at weeks 2 and 6 (p ⱕ0.03; Table 3). The differences between groups in the least square mean changes from baseline in the systolic BP at week 13 are shown in Figure 3. The changes from baseline in the systolic BP with naproxcinod 750 mg were significantly less than those with naproxen 500 mg (⫺1.8 mm Hg, 95% CI ⫺3.1
Systemic Hypertension/Effects of Naproxcinod on Blood Pressure
1343
Figure 3. Differences in systolic BP (mm Hg) between treatment groups in integrated safety population after 13 weeks of therapy (total n ⫽ 2,196). Comparisons were 2-sided with threshold of 2 mm Hg for upper limit of 95% CI for comparison versus placebo.
Figure 4. Differences in systolic BP (mm Hg) between treatment groups according to presence of RAS inhibitors at study entry. Comparisons were 2-sided.
to ⫺0.5) but not for naproxcinod 375 mg (⫺0.7 mm Hg, 95% CI ⫺2.2 to 0.7). The differences in the mean changes from baseline in systolic BP among the treatment groups in the subgroup of RAS inhibitor users at week 13 are shown in Figure 4. In patients taking a RAS inhibitor alone for hypertension, the mean changes from baseline were less for both doses of naproxcinod relative to naproxen 500 mg twice daily (naproxcinod 750 mg, ⫺4.3 mm Hg, 95% CI ⫺8.5 to ⫺0.03, p ⫽ 0.048; naproxcinod 375 mg, ⫺4.9 mm Hg, 95% CI ⫺9.8 to 0.01, p ⫽ 0.050). The mean changes from baseline versus placebo for both doses of naproxcinod were 1.0 mm Hg (95% CI ⫺2.4 to 4.3) and 0.4 mm Hg (95% CI ⫺4.4 to 5.1) for 750
mg and 375 mg, respectively, and were greater for naproxen 500 mg at 5.3 mm Hg (95% CI 1.0 to 9.5, p ⫽ 0.016; Figure 4). In the subgroup of patients taking RAS inhibitors combined with various diuretics (n ⫽ 301), the changes from baseline versus placebo in the systolic BP at week 13 was ⫺2.4 mm Hg (95% CI ⫺6.2 to 1.4, p ⫽ 0.220) for naproxcinod 750 mg and 0.4 mm Hg (95% CI ⫺3.4 to 4.2, p ⫽ 0.824) for naproxen 500 mg. The number of patients taking other classes of antihypertensive therapy was too small to analyze. The proportion of patients with increases from baseline in systolic BP of ⱖ5 and ⱖ10 mm Hg at week 13 was greater in the naproxen 500 mg group than in the naproxcinod 750 mg, naproxcinod 375 mg, and placebo groups
1344
The American Journal of Cardiology (www.ajconline.org)
Table 4 Proportions of patients with increases in systolic blood pressure at week 13 Characteristic Integrated safety population at week 13 (n) ⱖ5 mm Hg increase from baseline (n) Comparisons vs placebo OR 95% CI p Value Comparisons vs naproxen OR 95% CI p Value ⱖ10 mm Hg increase from baseline (n) Comparisons vs placebo OR 95% CI p Value Comparisons vs naproxen OR 95% CI p Value ⱖ20 mm Hg increase from baseline (n)
Naproxcinod 750 mg Twice Daily
Naproxcinod 375 mg Twice Daily
Naproxen 500 mg Twice Daily
Placebo
662 177 (26.7%)
405 109 (26.9%)
522 179 (34.3%)
607 162 (26.7%)
0.99 0.76 to 1.28 0.926
0.96 0.71 to 1.31 0.811
1.40 1.07 to 1.83 0.014
0.71 0.54 to 0.92 0.010 101 (15.3%)
0.69 0.51 to 0.93 0.016 73 (18.0%)
108 (20.7%)
0.94 0.69 to 1.29 0.706
1.17 0.81 to 1.68 0.401
1.36 0.99 to 1.87 0.055
0.69 0.51 to 0.94 0.020 15 (2.3%)
0.86 0.61 to 1.21 0.384 17 (4.2%)
31 (5.9%)
96 (15.8%)
22 (3.6%)
naproxen 500 mg twice daily. The proportion of patients with serious cardiovascular adverse events was low in all the 4 treatment groups (0.3% and 0.5% for naproxcinod 750 mg and 375 mg, respectively, 0.3% for naproxen 500 mg, and 0.6% for placebo). The discontinuation rates for adverse events were similar among the 4 treatment groups (Figure 1). Destabilization of BP (defined as at least a 50% increase in the antihypertensive medications or a change in antihypertensive medication because of worsening of hypertension or the occurrence of hypertension as an adverse event) occurred in ⬍20 patients (range 4.4% to 5.7% per treatment group). Figure 5. Probability curves illustrating likelihood for becoming hypertensive (systolic BP ⱖ140 mm Hg) at week 13 when entering trial with normal systolic BP (⬍140 mm Hg) by treatment group. All patients meeting these criteria at baseline (n ⫽ 1,820) shown.
(Table 4). The proportion of patients with increases from a baseline systolic BP of ⱖ20 mm Hg at week 13 were too small to formally analyze (Table 4). The estimated probability of becoming hypertensive (systolic BP ⱖ140 mm Hg when the baseline systolic BP was ⬍140 mm Hg) is shown in Figure 5. Naproxcinod at both doses was less likely than naproxen 500 mg to destabilize systolic BP to hypertensive values, although statistical significance was not reached. The probability of developing hypertension appeared to be differentiated between naproxen and the other treatment groups for baseline systolic BP ⬎125 mm Hg. For example, in patients entering the trial with a baseline systolic BP of 130 mm Hg, the probability for patients taking naproxcinod and placebo to become hypertensive at week 13 was 0.08 to 0.09 versus 0.15 for patients treated with naproxen (Figure 5). One postoperative death (aortic intramural hematoma) occurred 104 days after randomization in 1 patient treated with
Discussion The key finding of the present study was that naproxcinod has BP effects similar to that of placebo in patients with OA. After 13 weeks of therapy, the mean changes from baseline in the systolic BP with naproxcinod were similar to those with placebo. The changes from baseline in the naproxcinod 750 mg-treated patients were significantly less than the changes in the patients treated with naproxen 500 mg but had similar efficacy for pain control. In a subgroup of patients with hypertension treated with drugs of the RAS inhibitor classes, the mean change in systolic BP at week 13 in the naproxen 500 mg twice daily group was 4 to 5 mm Hg greater than in the naproxcinod groups. In addition, the proportion of patients whose systolic BP had increased by ⱖ10 mm Hg after 13 weeks of therapy was larger with naproxen 500 mg (20.7%) than that with an equally potent dose of naproxcinod 750 mg (15.3%). These findings demonstrate that naproxcinod has an effect similar to that of placebo on BP when used for the treatment of OA. Previous nonclinical work suggested that naproxcinod might not affect BP to the same extent as other conventional NSAIDs.11 In a mechanistic study, naproxen increased the BP significantly compared to naproxcinod and vehicle.11
Systemic Hypertension/Effects of Naproxcinod on Blood Pressure
After the administration of N-nitro-L-arginine methyl ester (L-NAME) to rats, naproxen potentiated the hypertension caused by the administration of L-NAME, and naproxcinod partially inhibited the L-NAME–induced hypertension. These results suggested that NO and prostaglandins act synergistically on the regulation of BP and that in the absence of endogenous NO, an increase occurs in the sensitivity to naproxcinod-released NO, as shown by the disparate effects of naproxcinod and naproxen in the absence and presence of concomitant L-NAME administration. The clinical trials of patients with OA of the knee and hip1,12 confirmed that patients treated with naproxcinod had reductions in systolic BP relative to naproxen 500 mg and rofecoxib 25 mg. The lesser effect of naproxcinod on BP was likely due to its NO donor properties. After absorption, naproxcinod is rapidly cleaved to naproxen and an NOdonating moiety. The exogenous release of NO would be expected to reduce vascular smooth muscle contractility, leading to a reduction in systemic vascular resistance and BP.11 This property of naproxcinod could provide an effective mechanism to counter the antiprostacylin effects typically seen with the traditional NSAIDs. The potential for loss of BP control in hypertensive patients receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers,  blockers, and diuretics has been documented for several years by both clinic and 24-hour BP monitoring.13–17 In patients treated with RAS inhibitors, some of the NSAIDs and cyclooxygenase-2 inhibitors have been shown to increase the systolic BP by 3 to 8 mm Hg.14 –17 In the present study, the effect of RAS inhibitors on the differential changes from baseline in the systolic BP between naproxcinod and naproxen was greater (Figure 4) and was not altered when diuretics were co-administered with the RAS inhibitors. These results suggest that RAS inhibitors depend on vascular prostacyclin and/or NO as a part of their mechanism of action.13,14 Calcium antagonists and other non-RAS blockers might not be as influenced as the RAS blocking drugs by the increases in total body sodium associated with the antinatriuretic effects of NSAIDs.8 The importance of relatively small differences (⬍3 to 5 mm Hg) in systolic BP in patient populations with hypertension and cardiovascular diseases has been demonstrated in both observational and randomized clinical trials.9,18 Increases in the systolic BP levels of 3 to 4 mm Hg in older populations of hypertensive patients with vascular diseases can result in significant relative increases in cardiac events within 4 to 6 months.19 Our present analysis demonstrated that naproxcinod was not as likely to increase the systolic BP compared to naproxen in those with a baseline systolic BP of ⱖ125 mm Hg and was similar to placebo in the entire study group, as well as in patients treated with RAS inhibitors. This is important, because RAS inhibitors are typically one of the agents most commonly used in antihypertensive regimens in contemporary clinical practice.18 From the present large-scale analysis, we can conclude that some of the hypertensive burden induced by most NSAIDs in patients with OA can be reduced by the NO-donator agent naproxcinod.
1345
1. Schnitzer TJ, Kivitz AJ, Lipetz RS, Sanders N, Hee A. Comparison of the COX-inhibiting nitric oxide donator AZD3582 and rofecoxib in treating the signs and symptoms of osteoarthritis of the knee. Arthritis Rheum 2005;53:827– 837. 2. Rees DD, Palmer RM, Moncada S. Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci USA 1989;86:3375–3378. 3. Moncada S, Higgs EA. The discovery of nitric oxide and its role in vascular biology. Br J Pharmacol 2006;147(Suppl 1):S193–S201. 4. Schnitzer TJ, Kivitz A, Frayssinet H, Duquesroix B. Efficacy and safety of naproxcinod in the treatment of patients with osteoarthritis of the knee: a 13-week prospective, randomized, multicenter trial. Osteoarthritis Cartilage 2010;18:629 – 639. 5. Schnitzer TJ, Hochberg MC, Marrero CE, Duquesroix B, Frayssinet H, Beekman M. Efficacy and safety of naproxcinod in patients with osteoarthritis of the knee: a 53-week prospective randomized multicenter study. Semin Arthritis Rheum 2010;40:285–297. 6. Baerwald C, Verdecchia P, Duquesroix B, Frayssinet H, Ferreira T. Efficacy, safety and effects of BP of naproxcinod 750 mg b.i.d. compared with placebo and naproxen 500 mg b.i.d. in patients with osteoarthritis of the hip. Arthritis Rheum 2010;62:3635–3644. 7. Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J, Hill MN, Jones DW, Kurtz T, Sheps SG, Roccella EJ. Recommendations for Blood Pressure Measurement in Humans and Experimental Animals. Part 1: blood pressure measurement in humans. A statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Hypertension 2005;45:142–161. 8. Whelton A, White WB, Bello AE, Puma JA, Fort JG; SUCCESS-VII Investigators. Effects of celecoxib and rofecoxib on blood pressure and edema in patients ⬎65 years of age with systemic hypertension and osteoarthritis. Am J Cardiol 2002;90:959 –963. 9. Lewington S, Clarke R, Qizibash N, Peto R, Collins R; Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903–1913. 10. Van Houwelingen HC, Arends LR, Stijinen T. Tutorial in biostatistics—advanced methods in meta-analysis: multivariate approach and meta-regression. Stat Med 2002;21:589 – 624. 11. Muscara MN, McKnight W, Del Soldato P, Wallace JL. Effect of a nitric oxide-releasing naproxen derivative on hypertension and gastric damage induced by chronic nitric oxide inhibition in the rat. Life Sci 1998;62:235–240. 12. Karlsson J, Pivodic A, Aguirre D, Schnitzer TJ. Efficacy, safety, and tolerability of the cyclooxygenase-inhibiting nitric oxide donator naproxcinod in treating osteoarthritis of the hip or knee. J Rheumatol 2009;36:1290 –1297. 13. White WB, Schnitzer TJ, Fleming R, Duquesroix B, Beekman M. Effects of the cyclooxygenase inhibiting nitric oxide donator naproxcinod versus naproxen on systemic blood pressure in patients with osteoarthritis. Am J Cardiol 2009;104:840 – 845. 14. White WB. Cardiovascular effects of the cyclooxygenase inhibitors. Hypertension 2007;49:408 – 418. 15. Izhar M, Alausa T, Folker A, Hung E, Bakris GL. Effects of COXinhibition on blood pressure and kidney function in ACE inhibitortreated blacks and Hispanics. Hypertension 2004;43:574 –577. 16. White WB, Kent J, Taylor A, Verburg KM, Lefkowith JB, Whelton A. Effects of celecoxib on ambulatory blood pressure in hypertensive patients on ACE inhibitors. Hypertension 2002;39:929 –934. 17. MacDonald TM, Reginster JY, Littlejohn TW, Richard D, Lheritier K, Krammer G, Rebuli R. Effect on blood pressure of lumiracoxib versus ibuprofen in patients with osteoarthritis and controlled hypertension: a randomized trial. J Hypertens 2008;26:1695–1702. 18. McInnis NH, Fodor G, Lum-Kwong MM, Leenan FH. Antihypertensive medication use and blood pressure control: a community-based cross-sectional survey (ON–BP). Am J Hypertens 2008;21:1210 – 1215. 19. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, Hua T, Laragh J, McInnes GT, Mitchell L, Plat F, Schork A, Smith B, Zanchetti A; VALUE Trial Group. Outcomes in hypertensive patients at high CV risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004;19:2002–2031.
Pat and Jim Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington, Connecticut; bDivision of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois; c Hypertension Center, University of Chicago Pritzker School of Medicine, Chicago, Illinois; dClinical Development and Medical Affairs, NicOx SA, Sophia-Antipolis, France; and eState University of New York Downstate Medical Center, Brooklyn, New York. Manuscript received November 14, 2010; manuscript received and accepted December 21, 2010. This study was funded by Nicox, SA, Sophia-Antipolis, France. The principal author and co-authors contributed to the defined analytic plan reported and had access to all data derived from these analyses. The principal author wrote and edited the manuscript with input from the coauthors. The research physician (B.D.) and statistician (H.F.) from the sponsor participated in the design of the original 3 pivotal trials detailed in the report with authors W.B. White. and T.J. Schnitzer. *Corresponding author: Tel: (860) 679-2104; fax: (860) 679-1250. E-mail address: [email protected] (W.B. White). 0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2010.12.046
naproxen 500 mg (the equipotent dose of naproxcinod 750 mg1) twice daily, and placebo were assessed. The BP treatment effects were studied within the entire population and in patients taking renin-angiotensin system (RAS) inhibitor drugs. Methods Three large OA clinical trials4 – 6 meeting the following criteria were included in the integrated analysis: phase III development, parallel, randomized, placebo-controlled, double-blind, and multicenter studies conducted to evaluate the efficacy and safety of naproxcinod in patients with OA of the knee (2 studies) or hip (1 study). To be included in these 3 studies, the patients were required to be men or women ⱖ40 years old with a confirmed diagnosis of OA of the knee or hip in accordance with the American College of Rheumatology guidelines. They also had to be current chronic users of NSAIDs or acetaminophen for OA pain and to have experienced a flare of pain after a discontinuation period of ⱖ5 half lives of the previous analgesic or anti-inflammatory therapy. A flare was defined as a visual analog pain scale score at baseline of ⱖ50 mm and an increase of ⱖ15 mm compared to the screening visit. The patients were excluded if they had uncontrolled diabetes, clinically important liver or renal impairment (serum creatinine ⬎176 mol/L at screening), or gastrointestinal bleeding or ulceration within the previous 6 months. Patients with hypertension were included if their hypertension control at study entry was acceptable according to the judgment of the study physician and their antihypertensive drug regimen had been stable for ⱖ3 months. www.ajconline.org
Systemic Hypertension/Effects of Naproxcinod on Blood Pressure
1339
Figure 1. Entry, randomization, and follow-up of patients after randomization in integrated safety population. Table 1 Patient characteristics at baseline Characteristic
Age (years) Women Race Black Nonblack Geographic location Europe North America Body mass index (kg/m2) Baseline systolic blood pressure (mm Hg) Baseline diastolic blood pressure (mm Hg) Patients taking antihypertensive agents Patients taking renin-angiotensin system blockers Patients taking renin-angiotensin system blockers and various diuretics
Naproxcinod 750 mg Twice Daily (n ⫽799)
Naproxcinod 375 mg Twice Daily (n ⫽ 487)
Naproxen 500 mg Twice Daily (n ⫽ 637)
Placebo Twice Daily (n ⫽ 811)
Overall (n ⫽ 2,734)
61.6 ⫾ 9.7 534 (66.8%)
60.5 ⫾ 9.5 359 (73.7%)
60.9 ⫾ 9.7 439 (68.9%)
61.7 ⫾ 9.4 557 (68.7%)
61.3 ⫾ 9.6 1,889 (69.1%)
80 (10.0%) 719 (90.0%)
79 (16.2%) 408 (83.8%)
82 (12.9%) 555 (87.1%)
90 (11.1%) 721 (88.9%)
331 (12.1%) 2,403 (87.9%)
199 (24.9%) 600 (75.1%) 31.8 ⫾ 7.2 127.3 ⫾ 14.7 77.9 ⫾ 9.4 349 (43.7%) 101 (12.6%) 74 (21.2%)
N/A 487 (100%) 33.9 ⫾ 8.0 125.4 ⫾ 12.9 77.1 ⫾ 8.4 207 (42.5%) 55 (11.3%) 58 (28.0%)
98 (15.4%) 539 (84.6%) 32.5 ⫾ 7.4 125.8 ⫾ 13.5 77.6 ⫾ 8.3 279 (43.8%) 64 (10.0%) 78 (28.0%)
203 (25.0%) 608 (75.0%) 31.9 ⫾ 7.1 127.9 ⫾ 13.9 78.3 ⫾ 8.9 365 (45.0%) 112 (13.8%) 91 (24.9%)
500 (18.3%) 2,234 (81.7%) 32.4 ⫾ 7.4
1,200 (43.9%) 332 (12.1%) 301 (25.1%)
Data are presented as mean ⫾ SD or n (%).
In 2 of the 3 studies involving 1,938 patients with OA of the knee at 238 clinical sites in the United States, the patients were randomized in a 1:1:1:1 ratio to receive 1 of 4 treatments, comprising naproxcinod 750 mg, naproxcinod 375 mg, naproxen 500 mg, or placebo twice daily, for the 13-week study treatment period. In the third study, 810 patients with hip OA at 105 clinical sites in Europe and North America were randomized to receive naproxcinod 750 mg, placebo, or naproxen 500 mg twice daily in a 2:2:1 ratio. An unbalanced distribution of patients among the treatment groups occurred because naproxcinod 375 mg was not included in the hip OA study and a lesser number of patients were randomized to naproxen. The focus of the present study was the effect of therapy on BP. The complete efficacy findings and other secondary end
points for each of the 3 trials have been previously reported.4 – 6 To determine that no clinically relevant difference in pain control was observed among the active treatment groups, one of the co-primary end points for pain (Western Ontario and McMaster Universities Osteoarthritis Index visual analog scales for pain) is provided in the present report. In each of the 3 studies, the seated clinic BP was measured in a standardized manner7 using mercury column or aneroid manometry in triplicate in the same arm and by the same examiner at baseline and 2, 6, and 13 weeks of the double-blind treatment period. The clinic BP was measured in the morning 2 to 4 hours after a dose of the study drug and, if applicable, antihypertensive drugs that had been taken in the morning. For patients treated with antihyperten-
1340
The American Journal of Cardiology (www.ajconline.org)
Table 2 Evaluation of efficacy for 3 trials pooled in blood pressure (BP) analysis using change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index pain subscale score Intention to Treat Population Study 301 (osteoarthritis of knee) Patients at baseline (n) Mean ⫾ SD Change from baseline at week 13 Least squares mean ⫾ SEM* 95% Confidence interval Efficacy vs placebo for 301 Difference in least squares mean ⫾ SEM† 95% Confidence interval for difference in least squares mean p Value for treatment effect‡ Study 302 (osteoarthritis of knee) Patients at baseline (n) Mean ⫾ SD Change from baseline at week 13 Least squares mean ⫾ SEM* 95% Confidence interval Efficacy vs placebo for 302 Difference in least squares mean ⫾ SEM† 95% Confidence interval for difference in least squares mean p Value for treatment effect‡ Study 303 (osteoarthritis of hip) Patients at baseline (n) Mean ⫾ SD Change from baseline at week 13 Mean ⫾ SD Least squares mean ⫾ SEM* 95% Confidence interval Efficacy vs placebo for 303 Difference in least squares mean ⫾ SEM† 95% Confidence interval for difference in least squares mean p Value for treatment effect§
Naproxcinod 750 mg Twice Daily
Naproxcinod 375 mg Twice Daily
Naproxen 500 mg Twice Daily
Placebo Twice Daily
223 73.4 ⫾ 14.9
234 73.5 ⫾ 15.5
219 71.3 ⫾ 17.3
215 72.2 ⫾ 16.0
⫺35.0 ⫾ 1.8 ⫺38.5 to ⫺31.5
⫺33.8 ⫾ 1.7 ⫺37.2 to ⫺30.4
⫺37.1 ⫾ 1.8 ⫺40.6 to ⫺33.6
⫺24.3 ⫾ 1.8 ⫺27.9 to ⫺20.8
⫺10.7 ⫾ 2.5 ⫺15.7 to ⫺5.7
⫺9.5 ⫾ 2.5 ⫺14.4 to ⫺4.5
⫺12.8 ⫾ 2.6 ⫺17.8 to ⫺7.7
— —
⬍0.0001
0.0002
⬍0.0001
—
241 70.2 ⫾ 17.4
247 71.3 ⫾ 16.9
254 73.6 ⫾ 15.8
256 71.4 ⫾ 16.8
⫺31.3 ⫾ 1.7 ⫺34.6 to ⫺28.0
⫺28.1 ⫾ 1.6 ⫺31.3 to ⫺24.8
⫺29.5 ⫾ 1.6 ⫺32.7 to ⫺26.3
⫺20.4 ⫾ 1.6 ⫺23.5 to ⫺17.2
⫺10.9 ⫾ 2.3 ⫺15.5 to ⫺6.4
⫺7.7 ⫾ 2.3 ⫺12.2 to ⫺3.2
⫺9.2 ⫾ 2.3 ⫺13.7 to ⫺4.7
— —
⬍0.0001
0.0008
⬍0.0001
—
323 66.3 ⫾ 16.2
— —
156 64.0 ⫾ 15.9
331 65.5 ⫾ 15.7
⫺29.1 ⫾ 26.6 ⫺25.8 ⫾ 1.7 ⫺29.2 to ⫺22.5
— — —
⫺27.1 ⫾ 26.1 ⫺24.3 ⫾ 2.2 ⫺28.7 to ⫺19.9
⫺20.8 ⫾ 27.0 ⫺18.0 ⫾ 1.7 ⫺21.3 to ⫺14.7
⫺7.8 ⫾ 1.9 ⫺11.6 to ⫺4.1
— —
⫺6.3 ⫾ 2.4 ⫺11.0 to ⫺1.7
— —
—
⬍0.001
—
⬍0.0001
* Negative change represents improvement. Differences were calculated as active versus placebo. ‡ p Values and 95% confidence intervals were from pairwise contrasts from an analysis of covariance model with baseline as covariate and treatment as factor. § Center also included in analysis of covariance as factor. †
sive drugs, the interval between the intake of antihypertensive medication, the intake of the study medication, and the BP measurements remained the same throughout for each subject in all 3 studies. The times of medication dosing and BP measurements were recorded in the case report forms. The comparability of the 4 treatment groups was determined from the demographic data and baseline BP values. Continuous variables were analyzed using the analysis of variance with treatment as the factor. Discrete variables were analyzed using the chi-square test. The mean changes from baseline at week 13 in systolic and diastolic BP were assessed in a meta-analysis of the individual patient data using mixed linear models, with the study and treatment as categorical fixed effects and the baseline BP as a continuous fixed effect and assuming heterogeneous within-study variance. The 3 active treatment groups were compared to the placebo group using one-sided 95% confidence intervals (CIs) of the differences in the mean changes. The naproxcinod doses were
compared to the naproxen dose using 2-sided 95% CIs. Post hoc, 2-sided CIs of the comparisons with placebo and the associated p values for all pairwise comparisons were calculated. Treatment-by-study interaction was added to the model as an additional random effect to test for heterogeneity across studies. These analyses of the changes from baseline in BP during the study were performed for the entire safety population and for those patients taking renin-angiotensin system (RAS) inhibitors at baseline, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers,  blockers, and renin inhibitors. The rationale for studying the RAS blocker subgroup was based on previous work,8 which showed a larger effect of NSAIDs on BP destabilization in patients taking these classes of antihypertensive agents. For the interpretation of the comparisons between the active treatment groups and the placebo group, a threshold of 2 mm Hg9 for the upper limit of the CI for the systolic BP differences and 1.5 mm Hg9 for the upper limit of the CI for the diastolic BP differences were used based on
Systemic Hypertension/Effects of Naproxcinod on Blood Pressure
1341
Figure 2. Least square mean changes from baseline in (A) systolic BP (mm Hg) and (B) diastolic BP (mm Hg) during 13-week treatment period in integrated safety population. Number of patients enrolled shown at various points in trials.
the relations to both cardiovascular outcomes and the clinical effect of these BP differences. The distributions of the categorized systolic BP changes from baseline (increases in varying individual thresholds of BP) were calculated. The post hoc analyses of these categorized changes were done using the same fixed effect meta-analysis as described and performed on the log odds ratios estimated for each study individually in a logistic regression analysis.10 Treatment differences are presented using odds ratios, 2-sided 95% CIs, and associated p values. The analyses were conducted post hoc to determine the estimated probability of destabilizing systolic BP (i.e., reaching a systolic BP of ⱖ140 mm Hg at week 13 given a
baseline systolic BP of ⬍140 mm Hg). In these analyses, the p values for the treatment comparisons were obtained from the pairwise contrasts from a logistic regression analysis with study and treatment as categorical fixed effects and baseline systolic BP as a continuous fixed effect. The mean constant curves were provided for graphic purpose and were determined from the results from the logistic regression analysis for the 3 individual studies. Results A total of 2,734 patients were included in the integrated safety population. As shown in Figure 1, 2,079 of the
1342
The American Journal of Cardiology (www.ajconline.org)
Table 3 Least square mean change from baseline versus placebo and naproxen in systolic blood pressure Integrated Safety Population Week 2 Comparison vs placebo Patients (n) Mean difference (mm Hg) p Value Comparison vs naproxen Patients (n) Mean difference (mm Hg) p Value Week 6 Comparison vs placebo Patients (n) Mean difference (mm Hg) p Value Comparison vs naproxen Patients (n) Mean difference (mm Hg) p Value Week 13 Comparison vs placebo Patients (n) Mean difference (mm Hg) p Value Comparison vs naproxen Patients (n) Mean difference (mm Hg) p Value
Naproxcinod 750 mg Twice Daily
783 vs 786 0.18 (0.86 to 1.23) 0.7302 783 vs 623 ⫺1.93 (⫺3.04 to ⫺0.81) 0.0007
724 vs 693 ⫺0.13 (⫺1.24 to 0.96) 0.8132 724 vs 587 ⫺2.73 (⫺3.91 to ⫺1.55) ⬍0.0001
662 vs 607 ⫺0.37 (⫺1.57 to 0.84) 0.5505 662 vs 522 ⫺1.78 (⫺3.05 to ⫺0.51) 0.0059
Naproxcinod 375 mg Twice Daily
Naproxen 500 mg Twice Daily
474 vs 786 0.72 (⫺0.53 to 1.97) 0.2564
623 vs 786 2.11 (0.99 to 3.23) 0.0002
474 vs 623 ⫺1.39 (⫺2.66 to 0.12) 0.0323
— — —
445 vs 693 0.81 (⫺0.57 to 2.18) 0.2486
587 vs 693 2.60 (1.41 to 3.79) ⬍0.0001
445 vs 587 ⫺1.79 (⫺3.17 to ⫺0.41) 0.0110
— — —
405 vs 607 0.67 (⫺0.79 to 2.13) 0.3654
522 vs 607 1.42 (0.12 to 2.71) 0.0321
405 vs 522 ⫺0.74 (⫺2.20 to 0.72) 0.3176
— — —
Data in parentheses are 95% CIs.
patients (76.0%) completed the trial, with similar proportions in the active treatment groups. Fewer patients completed the study in the placebo group (70.8%), primarily owing to a lack of efficacy and the worsening of OA symptoms. The baseline characteristics of the study population are listed in Table 1. Most patients were women and white, and the mean age of the study population was 61 years. The mean body mass index for the population was 32 kg/m2 and was similar across the treatment groups. Statistically significant differences were observed among the 4 treatment groups for race (black vs nonblack, p ⫽ 0.007), geographic location (Europe vs North America, p ⬍0.0001), and body mass index (p ⬍0.0001). A total of 1200 patients (44%) had both a history of hypertension and were receiving antihypertensive drug therapy. Of the patients treated with antihypertensive agents, 332 (27.7%) were taking a RAS inhibitor drug as a single agent for hypertension. In each of the 3 studies, all active treatments produced significant improvements from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale score at 13 weeks (Table 2). The changes from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale score at week 13 were similar for naproxcinod 750 mg and naproxen 500 mg. Smaller reductions in the pain subscale score were seen for naproxcinod 375 mg versus naproxcinod 750 mg and naproxen 500 mg twice daily. Both doses of naproxcinod and naproxen 500 mg were significantly superior statistically to placebo (Table 2). The number of patients who discontinued because of a lack of arthritis efficacy was similar for the active treatment groups
(naproxcinod 750 mg, 4.9%; naproxcinod 375 mg, 6.7%, and naproxen 500 mg, 4.8%; Figure 1). The changes from baseline in the systolic BP at each study visit during the 13-week period are shown in Figure 2. The systolic BP in the naproxcinod 750-mg group decreased from baseline to a nadir of ⫺3 mm Hg at week 6 and was of a similar magnitude to the BP changes in the placebo treatment group. In contrast, the systolic BP in the naproxen 500-mg group was unchanged from baseline during the 13-week period. Similar patterns of changes were seen for diastolic BP (Figure 2). Additionally, differences in the mean changes from baseline to week 13 for both naproxcinod doses were similar to those with placebo (upper bound of 95% CI was 0.8 mm Hg and 2.1 mm Hg for naproxcinod 750 mg and 375 mg, respectively). The changes in systolic BP with naproxen 500 mg were significantly greater than those with placebo at week 13 (1.4 mm Hg, 95% CI 0.1 to 2.7, p ⫽ 0.032; Table 3). At weeks 6 and 13, the mean changes from baseline in diastolic BP were significantly lower for both doses of naproxcinod versus naproxen 500 mg twice daily (p ⬍0.05 at both points). The mean systolic BP changes from baseline were significantly greater for naproxen 500 mg than for naproxcinod 750 mg and placebo at 2, 6, and 13 weeks, as well as for naproxcinod 375 mg at weeks 2 and 6 (p ⱕ0.03; Table 3). The differences between groups in the least square mean changes from baseline in the systolic BP at week 13 are shown in Figure 3. The changes from baseline in the systolic BP with naproxcinod 750 mg were significantly less than those with naproxen 500 mg (⫺1.8 mm Hg, 95% CI ⫺3.1
Systemic Hypertension/Effects of Naproxcinod on Blood Pressure
1343
Figure 3. Differences in systolic BP (mm Hg) between treatment groups in integrated safety population after 13 weeks of therapy (total n ⫽ 2,196). Comparisons were 2-sided with threshold of 2 mm Hg for upper limit of 95% CI for comparison versus placebo.
Figure 4. Differences in systolic BP (mm Hg) between treatment groups according to presence of RAS inhibitors at study entry. Comparisons were 2-sided.
to ⫺0.5) but not for naproxcinod 375 mg (⫺0.7 mm Hg, 95% CI ⫺2.2 to 0.7). The differences in the mean changes from baseline in systolic BP among the treatment groups in the subgroup of RAS inhibitor users at week 13 are shown in Figure 4. In patients taking a RAS inhibitor alone for hypertension, the mean changes from baseline were less for both doses of naproxcinod relative to naproxen 500 mg twice daily (naproxcinod 750 mg, ⫺4.3 mm Hg, 95% CI ⫺8.5 to ⫺0.03, p ⫽ 0.048; naproxcinod 375 mg, ⫺4.9 mm Hg, 95% CI ⫺9.8 to 0.01, p ⫽ 0.050). The mean changes from baseline versus placebo for both doses of naproxcinod were 1.0 mm Hg (95% CI ⫺2.4 to 4.3) and 0.4 mm Hg (95% CI ⫺4.4 to 5.1) for 750
mg and 375 mg, respectively, and were greater for naproxen 500 mg at 5.3 mm Hg (95% CI 1.0 to 9.5, p ⫽ 0.016; Figure 4). In the subgroup of patients taking RAS inhibitors combined with various diuretics (n ⫽ 301), the changes from baseline versus placebo in the systolic BP at week 13 was ⫺2.4 mm Hg (95% CI ⫺6.2 to 1.4, p ⫽ 0.220) for naproxcinod 750 mg and 0.4 mm Hg (95% CI ⫺3.4 to 4.2, p ⫽ 0.824) for naproxen 500 mg. The number of patients taking other classes of antihypertensive therapy was too small to analyze. The proportion of patients with increases from baseline in systolic BP of ⱖ5 and ⱖ10 mm Hg at week 13 was greater in the naproxen 500 mg group than in the naproxcinod 750 mg, naproxcinod 375 mg, and placebo groups
1344
The American Journal of Cardiology (www.ajconline.org)
Table 4 Proportions of patients with increases in systolic blood pressure at week 13 Characteristic Integrated safety population at week 13 (n) ⱖ5 mm Hg increase from baseline (n) Comparisons vs placebo OR 95% CI p Value Comparisons vs naproxen OR 95% CI p Value ⱖ10 mm Hg increase from baseline (n) Comparisons vs placebo OR 95% CI p Value Comparisons vs naproxen OR 95% CI p Value ⱖ20 mm Hg increase from baseline (n)
Naproxcinod 750 mg Twice Daily
Naproxcinod 375 mg Twice Daily
Naproxen 500 mg Twice Daily
Placebo
662 177 (26.7%)
405 109 (26.9%)
522 179 (34.3%)
607 162 (26.7%)
0.99 0.76 to 1.28 0.926
0.96 0.71 to 1.31 0.811
1.40 1.07 to 1.83 0.014
0.71 0.54 to 0.92 0.010 101 (15.3%)
0.69 0.51 to 0.93 0.016 73 (18.0%)
108 (20.7%)
0.94 0.69 to 1.29 0.706
1.17 0.81 to 1.68 0.401
1.36 0.99 to 1.87 0.055
0.69 0.51 to 0.94 0.020 15 (2.3%)
0.86 0.61 to 1.21 0.384 17 (4.2%)
31 (5.9%)
96 (15.8%)
22 (3.6%)
naproxen 500 mg twice daily. The proportion of patients with serious cardiovascular adverse events was low in all the 4 treatment groups (0.3% and 0.5% for naproxcinod 750 mg and 375 mg, respectively, 0.3% for naproxen 500 mg, and 0.6% for placebo). The discontinuation rates for adverse events were similar among the 4 treatment groups (Figure 1). Destabilization of BP (defined as at least a 50% increase in the antihypertensive medications or a change in antihypertensive medication because of worsening of hypertension or the occurrence of hypertension as an adverse event) occurred in ⬍20 patients (range 4.4% to 5.7% per treatment group). Figure 5. Probability curves illustrating likelihood for becoming hypertensive (systolic BP ⱖ140 mm Hg) at week 13 when entering trial with normal systolic BP (⬍140 mm Hg) by treatment group. All patients meeting these criteria at baseline (n ⫽ 1,820) shown.
(Table 4). The proportion of patients with increases from a baseline systolic BP of ⱖ20 mm Hg at week 13 were too small to formally analyze (Table 4). The estimated probability of becoming hypertensive (systolic BP ⱖ140 mm Hg when the baseline systolic BP was ⬍140 mm Hg) is shown in Figure 5. Naproxcinod at both doses was less likely than naproxen 500 mg to destabilize systolic BP to hypertensive values, although statistical significance was not reached. The probability of developing hypertension appeared to be differentiated between naproxen and the other treatment groups for baseline systolic BP ⬎125 mm Hg. For example, in patients entering the trial with a baseline systolic BP of 130 mm Hg, the probability for patients taking naproxcinod and placebo to become hypertensive at week 13 was 0.08 to 0.09 versus 0.15 for patients treated with naproxen (Figure 5). One postoperative death (aortic intramural hematoma) occurred 104 days after randomization in 1 patient treated with
Discussion The key finding of the present study was that naproxcinod has BP effects similar to that of placebo in patients with OA. After 13 weeks of therapy, the mean changes from baseline in the systolic BP with naproxcinod were similar to those with placebo. The changes from baseline in the naproxcinod 750 mg-treated patients were significantly less than the changes in the patients treated with naproxen 500 mg but had similar efficacy for pain control. In a subgroup of patients with hypertension treated with drugs of the RAS inhibitor classes, the mean change in systolic BP at week 13 in the naproxen 500 mg twice daily group was 4 to 5 mm Hg greater than in the naproxcinod groups. In addition, the proportion of patients whose systolic BP had increased by ⱖ10 mm Hg after 13 weeks of therapy was larger with naproxen 500 mg (20.7%) than that with an equally potent dose of naproxcinod 750 mg (15.3%). These findings demonstrate that naproxcinod has an effect similar to that of placebo on BP when used for the treatment of OA. Previous nonclinical work suggested that naproxcinod might not affect BP to the same extent as other conventional NSAIDs.11 In a mechanistic study, naproxen increased the BP significantly compared to naproxcinod and vehicle.11
Systemic Hypertension/Effects of Naproxcinod on Blood Pressure
After the administration of N-nitro-L-arginine methyl ester (L-NAME) to rats, naproxen potentiated the hypertension caused by the administration of L-NAME, and naproxcinod partially inhibited the L-NAME–induced hypertension. These results suggested that NO and prostaglandins act synergistically on the regulation of BP and that in the absence of endogenous NO, an increase occurs in the sensitivity to naproxcinod-released NO, as shown by the disparate effects of naproxcinod and naproxen in the absence and presence of concomitant L-NAME administration. The clinical trials of patients with OA of the knee and hip1,12 confirmed that patients treated with naproxcinod had reductions in systolic BP relative to naproxen 500 mg and rofecoxib 25 mg. The lesser effect of naproxcinod on BP was likely due to its NO donor properties. After absorption, naproxcinod is rapidly cleaved to naproxen and an NOdonating moiety. The exogenous release of NO would be expected to reduce vascular smooth muscle contractility, leading to a reduction in systemic vascular resistance and BP.11 This property of naproxcinod could provide an effective mechanism to counter the antiprostacylin effects typically seen with the traditional NSAIDs. The potential for loss of BP control in hypertensive patients receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers,  blockers, and diuretics has been documented for several years by both clinic and 24-hour BP monitoring.13–17 In patients treated with RAS inhibitors, some of the NSAIDs and cyclooxygenase-2 inhibitors have been shown to increase the systolic BP by 3 to 8 mm Hg.14 –17 In the present study, the effect of RAS inhibitors on the differential changes from baseline in the systolic BP between naproxcinod and naproxen was greater (Figure 4) and was not altered when diuretics were co-administered with the RAS inhibitors. These results suggest that RAS inhibitors depend on vascular prostacyclin and/or NO as a part of their mechanism of action.13,14 Calcium antagonists and other non-RAS blockers might not be as influenced as the RAS blocking drugs by the increases in total body sodium associated with the antinatriuretic effects of NSAIDs.8 The importance of relatively small differences (⬍3 to 5 mm Hg) in systolic BP in patient populations with hypertension and cardiovascular diseases has been demonstrated in both observational and randomized clinical trials.9,18 Increases in the systolic BP levels of 3 to 4 mm Hg in older populations of hypertensive patients with vascular diseases can result in significant relative increases in cardiac events within 4 to 6 months.19 Our present analysis demonstrated that naproxcinod was not as likely to increase the systolic BP compared to naproxen in those with a baseline systolic BP of ⱖ125 mm Hg and was similar to placebo in the entire study group, as well as in patients treated with RAS inhibitors. This is important, because RAS inhibitors are typically one of the agents most commonly used in antihypertensive regimens in contemporary clinical practice.18 From the present large-scale analysis, we can conclude that some of the hypertensive burden induced by most NSAIDs in patients with OA can be reduced by the NO-donator agent naproxcinod.
1345
1. Schnitzer TJ, Kivitz AJ, Lipetz RS, Sanders N, Hee A. Comparison of the COX-inhibiting nitric oxide donator AZD3582 and rofecoxib in treating the signs and symptoms of osteoarthritis of the knee. Arthritis Rheum 2005;53:827– 837. 2. Rees DD, Palmer RM, Moncada S. Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci USA 1989;86:3375–3378. 3. Moncada S, Higgs EA. The discovery of nitric oxide and its role in vascular biology. Br J Pharmacol 2006;147(Suppl 1):S193–S201. 4. Schnitzer TJ, Kivitz A, Frayssinet H, Duquesroix B. Efficacy and safety of naproxcinod in the treatment of patients with osteoarthritis of the knee: a 13-week prospective, randomized, multicenter trial. Osteoarthritis Cartilage 2010;18:629 – 639. 5. Schnitzer TJ, Hochberg MC, Marrero CE, Duquesroix B, Frayssinet H, Beekman M. Efficacy and safety of naproxcinod in patients with osteoarthritis of the knee: a 53-week prospective randomized multicenter study. Semin Arthritis Rheum 2010;40:285–297. 6. Baerwald C, Verdecchia P, Duquesroix B, Frayssinet H, Ferreira T. Efficacy, safety and effects of BP of naproxcinod 750 mg b.i.d. compared with placebo and naproxen 500 mg b.i.d. in patients with osteoarthritis of the hip. Arthritis Rheum 2010;62:3635–3644. 7. Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J, Hill MN, Jones DW, Kurtz T, Sheps SG, Roccella EJ. Recommendations for Blood Pressure Measurement in Humans and Experimental Animals. Part 1: blood pressure measurement in humans. A statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Hypertension 2005;45:142–161. 8. Whelton A, White WB, Bello AE, Puma JA, Fort JG; SUCCESS-VII Investigators. Effects of celecoxib and rofecoxib on blood pressure and edema in patients ⬎65 years of age with systemic hypertension and osteoarthritis. Am J Cardiol 2002;90:959 –963. 9. Lewington S, Clarke R, Qizibash N, Peto R, Collins R; Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903–1913. 10. Van Houwelingen HC, Arends LR, Stijinen T. Tutorial in biostatistics—advanced methods in meta-analysis: multivariate approach and meta-regression. Stat Med 2002;21:589 – 624. 11. Muscara MN, McKnight W, Del Soldato P, Wallace JL. Effect of a nitric oxide-releasing naproxen derivative on hypertension and gastric damage induced by chronic nitric oxide inhibition in the rat. Life Sci 1998;62:235–240. 12. Karlsson J, Pivodic A, Aguirre D, Schnitzer TJ. Efficacy, safety, and tolerability of the cyclooxygenase-inhibiting nitric oxide donator naproxcinod in treating osteoarthritis of the hip or knee. J Rheumatol 2009;36:1290 –1297. 13. White WB, Schnitzer TJ, Fleming R, Duquesroix B, Beekman M. Effects of the cyclooxygenase inhibiting nitric oxide donator naproxcinod versus naproxen on systemic blood pressure in patients with osteoarthritis. Am J Cardiol 2009;104:840 – 845. 14. White WB. Cardiovascular effects of the cyclooxygenase inhibitors. Hypertension 2007;49:408 – 418. 15. Izhar M, Alausa T, Folker A, Hung E, Bakris GL. Effects of COXinhibition on blood pressure and kidney function in ACE inhibitortreated blacks and Hispanics. Hypertension 2004;43:574 –577. 16. White WB, Kent J, Taylor A, Verburg KM, Lefkowith JB, Whelton A. Effects of celecoxib on ambulatory blood pressure in hypertensive patients on ACE inhibitors. Hypertension 2002;39:929 –934. 17. MacDonald TM, Reginster JY, Littlejohn TW, Richard D, Lheritier K, Krammer G, Rebuli R. Effect on blood pressure of lumiracoxib versus ibuprofen in patients with osteoarthritis and controlled hypertension: a randomized trial. J Hypertens 2008;26:1695–1702. 18. McInnis NH, Fodor G, Lum-Kwong MM, Leenan FH. Antihypertensive medication use and blood pressure control: a community-based cross-sectional survey (ON–BP). Am J Hypertens 2008;21:1210 – 1215. 19. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, Hua T, Laragh J, McInnes GT, Mitchell L, Plat F, Schork A, Smith B, Zanchetti A; VALUE Trial Group. Outcomes in hypertensive patients at high CV risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004;19:2002–2031.