The Different Patterns of Blood Pressure Elevation by Rofecoxib and Nabumetone

Home , Nabumetone

Journal of Human Hypertension (2002) 16, 431–434  2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh ORIGINAL ARTICLE The different patterns of blood pressure elevation by rofecoxib and nabumetone

T Reitblat1, D Zamir2, L Estis2, R Priluk3, T Drogenikov4 and JR Viskoper3 1Rheumatology Outpatient Clinics, Barzilai Medical Centre, affiliated with the Faculty of Health Science, Ben-Gurion University of The Negev, Ashkelon, Israel; 2Internal Medicine Department ‘D’, Barzilai Medical Centre, affiliated with the Faculty of Health Sciences, Ben-Gurion University of The Negev, Ashkelon, Israel; 3WHO Collaborative Centre for Prevention of Cardiovascular Diseases and Internal Medicine Department ‘B’, Barzilai Medical Centre, affiliated with the Faculty of Health Sciences, Ben- Gurion University of The Negev, Ashkelon, Israel; 4Internal Medicine Department ‘A’, Barzilai Medical Centre, affiliated with the Faculty of Health Sciences, Ben-Gurion University of The Negev, Ashkelon, Israel

Hypertension and knee osteoarthritis (OA) are frequent the mean systolic and diastolic characteristics of BP in comorbidities. Nonsteroidal anti-inflammatory drugs the rofecoxib treatment group during day time (delta (NSAIDs) are often used to relieve pain in such patients. systolic BP −0.4 mm Hg and delta diastolic BP −0.4 In the last decade selective NSAIDs are used more com- mm Hg), while nocturnal BP increased significantly: monly since they lead to less gastrointestinal compli- delta systolic BP +15.7 mm Hg and delta diastolic BP cations. As has been shown, the treatment with NSAIDs +8.5 mm Hg. The mean systolic arterial pressure in the may cause a mild rise of arterial blood pressure (BP). nabumeton group raised delta systolic BP 2.9 mm Hg in The influence of selective NSAIDs on BP, particularly in the daytime and 5 mm Hg during the night-time after the hypertensive patients has still to be investigated. The treatment. The mean diastolic arterial pressure also rose aim of this study was to determine arterial BP changes delta diastolic 3.2 mm Hg and 4.9 mm Hg at day and in patients suffering from stable arterial hypertension night hours respectively. In conclusion rofecoxib treat- and knee OA and treated with rofecoxib or nabumetone. ment did not change arterial BP during day time hours, Two groups of patients with knee OA and stable arterial however, there was a distinct increase in night-time sys- hypertension received either 25 mg rofecoxib once daily tolic and diastolic BP leading to a disappearance of the or namebutone 2000 mg once daily during the first week physiological diurnal variation. Nabumetone caused a of treatment and 1000 mg for the following 3 weeks. moderate increase of day and night BP, without Twenty-four hour arterial BP monitoring was performed changes in biological diurnal variation. prior to initiation of treatment and at the end of a 4-week Journal of Human Hypertension (2002) 16, 431–434. DOI: period. The results were that no changes were found in 10.1038/sj/jhh/1001411

Keywords: blood pressure; osteoarthritis; non-steroidal antiinﬂammatory drugs; COX-2 inhibitors

Introduction inhibit ‘inducible’ cyclooxygenase at the site of the inflammation, and do not influence ‘constitutional’ Hypertension and knee osteoarthritis (OA) are com- cyclooxygenase. COX-2 on the other hand, is consti- mon comorbidities among the elderly population. tutively expressed in the kidney and is responsible, Nonsteroidal anti-inflammatory drugs (NSAIDs) are at least in part, for the synthesis of some renal often used to relieve pain in such patients. Because prostaglandins,2,3 thus influencing the sodium hand- of the untoward effect of non-selective NSAIDs on ling and renin release. the upper gastrointestinal tract, mainly among the 1 Nabumetone a non-acidic compound of alkanone elderly population, there is a trend to use NSAIDs class is a weak inhibitor of prostaglandin synthesis. of newer generation such as highly selective It is well absorbed after oral administration and cyclooxygenase-2 (COX-2) inhibitors. These new undergoes extensive hepatic first-class metabolism COX-2 inhibitors (rofecoxib and celecoxib) mainly to form major metabolite 6-methoxy-2-naphtylacetic acid (6MNA), which is a more potent inhibitor of prostaglandin synthesis and is responsible for the Correspondence: T Reitblat, Barzilai Medical Centre, Rheuma- 4 tology Outpatient Clinics, Hystadrut st, 3, Ashkelon, Israel. E- anti-inflammatory activity of nabumetone. Studies mail: alexȰbarzi.health.gov.il on endoscopy of the gastrointestinal tract have Received 3 January 2002; revised and accepted 16 February 2002 shown that all these drugs cause lower irritation of The different pattern of blood pressure T Reitblat et al 432 the gastric mucosa then indometacin and nap- Table 1 Demographic and clinical characteristics of patients roxen.5–7 Previous studies have shown that treatment with Patients Rofecoxib Nabumetone NSAIDs may blunt the influence of some antihyper- tensives and cause a mild rise of arterial blood press- Number 10 10 8 Gender f f ure. The influence of rofecoxib and nabumetone on Age (s.d.) 56.7 (9.6) 55.6 (10) blood pressure, particularly among patients with Mean body mass index, 29.3 (4.3) 29.6 (4.7) hypertension, has still to be investigated. kg/m2 (s.d.) The objective of this study was to determine the Creatinine, mg/dl (s.d.) 1.1 (0.2) 1.13 (0.1) Systolic arterial pressure 132.2 (17.6) 125.3 (17.7) arterial blood pressure changes in patients treated before treatment, mm Hg with rofecoxib or nabumetone and suffering from (s.d.) stable arterial hypertension. Diastolic arterial pressure 78.6 (10.5) 70 6 (6.8) before treatment, mm Hg (s.d.) Patients and methods Beta-receptor blockers 10 10 treatment (n) Twenty patients suffering from stable essential ACE inhibitors treatment (n)1010 arterial hypertension and knee OA were included in the study. Exclusion criteria included any contra- indication to the use of rofecoxib or nabumetone, uncontrolled hypertension, creatinine range more mm Hg, P Ͼ 0.05), while nocturnal blood pressure then 1.5 mg/ml and likelihood of poor compliance was significantly increased: delta systolic BP was with trial requirements. Ten patients (group 1) +15.7 mm Hg and delta diastolic BP was +8.5 mm Hg received 25 mg rofecoxib once daily in the morning (P Ͻ 0.05). for 30 days. Ten other patients received nabumetone In the nabumetone group the mean systolic 1.0 g twice daily in the first week of the treatment arterial pressure before treatment was 129.1 mm Hg and 1.0 g once a day in the evening for the following in the daytime and 121.0 mm Hg during the night. 3 weeks. The medicine was given in accordance After the treatment the mean systolic arterial press- with manufacturers’ instructions. All patients ure raised to 132.0 mm Hg in the daytime and to underwent 24-h ambulatory blood pressure monitor- 126.0 mm Hg at night (delta systolic BP was 2.9 ing (ABPM) at baseline and after 1 month using mm Hg in the daytime and 5 mm Hg at night, P Ͼ equipment validated by the Association for the 0.05). The mean diastolic arterial pressure also Advancement of Medical Instrumentation raised after the treatment: from 72.6 mm Hg to 75.8 (Profilomat, Disetronic Medical Systems AG, Burg- mm Hg during the daytime and from 66.7 mm Hg to dorf, Switzerland).9 72.0 mm Hg at night (delta diastolic BP −3.2 mm Hg ABPM was performed on a regular working day and −4.9 mm Hg at day and night hours respectively, with readings every 15 min throughout the daytime P Ͼ 0.05). The data is shown in Table 2. period and every 30 min throughout the night. Discussion Statistical analysis Many studies have evaluated the effect of NSAIDs Results are presented as mean and standard devi- on blood pressure and on blood pressure control in ation (s.d.). The mean quantitative values for the treated hypertensive subjects. The mechanism of the groups were compared using the one-tailed Stud- pressor effect of NSAIDs remains speculative. Salt ent’s t-test. A P value of Ͻ0.05 was considered stat- and water retention,10 increased total peripheral vas- istically significant. cular resistance due to inhibition of PGE2 and PGI211 or increased endothelin-1 secretion12 are Results potentially important. It seems, that NSAID treatment increases blood pressure by 3–5 mm Hg.13,14 Demographic and clinical data of the patients These effects are not the same for all NSAIDs. appears in Table 1. Among the drugs studied, indometacin and pirox- Patients treated with rofecoxib showed a mean icam seem to be associated with the largest increase systolic arterial pressure before treatment of 134.2 in blood pressure,15,16 whereas ibuprofen was shown mm Hg, and 141.3 mm Hg (P = 0.1) afterwards, mean to have no effect on blood pressure in normotensive diastolic blood pressure before and after the treat- subjects.17 There have recently been a few studies ment was 78.6 mm Hg and 82.7 mm Hg respectively that investigated the affect of COX-2 specific NSAID (P = 0.13). While analysing systolic and diastolic on blood pressure. Some studies have shown an blood pressure on daytime and night-time hours increase in blood pressure for both drugs celecoxib separately, we found that the mean systolic and and rofecoxib.18,19 We did not find any other studies diastolic characteristics of blood pressure showed about the influence of nabumetone on blood press- no changes in the day time after the treatment (delta ure. systolic BP −0.4 mm Hg and delta diastolic BP 0.4 In our study we specifically investigated the affect

Journal of Human Hypertension The different pattern of blood pressure T Reitblat et al 433 Table 2 Mean results of ambulatory arterial blood pressure monitoring before and after the treatment

Rofecoxib delta P Nabumeton delta P

before after before after

Systolic AP-day, mm Hg 137.8 (18.5) 137.3 (15.8) −0.4 (−0.2) 0.4 129.1 (15) 132 (10) 2.9 (2) 0.6 (s.d.) Systolic AP-night, mm Hg 130.7 (17.6) 145.4 (25.3) 15.7 (12) 0.04 121 (17.7) 126 (13.7) 5 (4) 0.4 (s.d.) Diastolic AP-day, mm Hg 81.4 (11.3) 81 (10.4) −0.4 (−0.4) 0.4 72.6 (6.8) 75.8 (8.4) 3.2 (4) 0.4 (s.d.) Diastolic AP-night, mm Hg 75.9 (9.2) 84.4 (13.8) 8.5 (11) 0.04 66.7 (5.8) 72 (10.3) 4.9 (7) 0.2 (s.d.)

AP = arterial pressure. of chronic rofecoxib and nabumetone treatment on References patients with knee OA and comorbidity such as hypertension—the common combination in the gen- 1 Aalykke C, Lauritsen K. Epidemiology of NSAID- eral clinical practice. Our study showed that related gastroduodenal mucosal injury. Best Pract Res rofecoxib treatment blunted the effect of antihyper- Clin Gastroenterol 2001; 15: 705–722. tensive treatment during night-time hours, further- 2 Brooks P et al. Interpreting the clinical significance of more, it led to the disappearance of biological diur- the differential inhibition of cyclooxygenase-1 and nal variation. cyclooxygenase-2. Rheumatology 1999; 38: 779–788. In most individuals, there is a circadian rhythm 3 Fitzberald GA, Patrono C. The Coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001; 345: of blood pressure, with daytime levels being higher 433–442. than night-time levels. This is related in part to 4 Bayle EA, Freeman PC. Nabumetone (BRL 147777), changes in posture as well as diurnal changes of hor- 4-(6-methoxy-2-naphtyl-butan-2-one): a new antiin- mone activity, including renin-angiotensin system. flammatory agent. J Pharm Pharmacol 1982; 34: 562– It was shown earlier that elevated blood pressure 569. during early morning hours could contribute to 5 Creb WH. Endoscopic studies of nabumetone (Relifex) increased frequency of acute coronary events, stroke in patients with rheumatoid arthritis: a comparative and sudden death.20 The inhibition of COX-2 by endoscopic and histologic evaluation. Am J Med 1987; rofecoxib, and thus inhibition of prostaglandin syn- 83 (Suppl 4B): 19–24. thesis in the kidney of our patients may lead to the 6 Roth SH. Endoscopy-controlled study of the safety of nabumetone (Relifex) compared with naproxen in changes of renin-angiotensin and natrium homeo- arthritis therapy. Am J Med 1987; 83 (Suppl 4B): 25– stasis adversely influencing blood pressure control. 30. Nabumetone treatment caused moderate elevation 7 Bombardier C et al. Comparison of gastrointestinal tox- in systolic and diastolic blood pressure during day- icity of rofecoxib and naproxen in patients with rheu- and night-time hours, but did not change the physi- matoid arthritis. N Engl J Med 2000; 343: 1520–1529. ologic pattern of blood pressure. Probably because 8 Brook RD, Kramer MB, Blaxall BC, Bisognano JD. Non- of the mild COX-2 inhibition activity of nabume- steroidal Anti-Inflammatory Drugs and Hypertension. tone, there was no strong influence on the renal J Clin Hypertens (Greenwich) 2000; 2: 319–323. prostaglandins and thus renin-angiotensin system. 9O’Brien E, Atkins N, Staessen J. State of the market. A Therefore we did not see circadian rhythm changes review of ambulatory blood pressure monitoring devices. Hypertension 1995; 26: 835–842. in the patients treated with nabumetone. 10 Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal antiinflammatory drugs. N Engl J Med Conclusions 1984; 310: 563–572. 11 Aiken JW, Vane JR. Intrarenal prostaglandin release Rofecoxib treatment did not change mean arterial attenuates the renal vasoconstrictor activity of angio- blood pressure during day time hours in patients tensin. J Pharmacol Exp Ther 1973; 184: 678–687. with stable arterial hypertension, however, during 12 Jonson AG et al. Potential mechanisms by which non- night-time hours systolic and diastolic blood press- steroidal anti-inflammatory drugs elevate blood pressure raised significantly, leading to a disappearance ure: the role of endothelin-1. J Hum Hypertens 1996; of physiological diurnal variation of blood pressure. 10: 257–261. 13 Johnson AG, Nguyen TV, Day RO. Do nonsteroidal Nabumetone treatment caused a moderate anti-inflammatory drugs affect blood pressure? A increase of day- and night-time blood pressure, meta-analysis. Ann Intern Med 1994; 121: 289–300. without changes in biological diurnal variation. 14 Pope JE, Anderson JJ, Felson DT. A meta-analysis of Our study was carried out on a small number of the effects of nonsteroidal anti-inflammatory drugs on the patients. Further studies are needed in order to blood pressure. Arch Intern Med 1993; 153: 477–484. confirm these observations. 15 Morgan TO, Anderson A, Bertam D. Effect of indome-

Journal of Human Hypertension The different pattern of blood pressure T Reitblat et al 434 thacin on blood pressure in elderly people with essen- 18 Muscara MN et al. Selective cyclo-oxygenase-2 inhi- tial hypertension well controlled on amlodipine or bition with celecoxib elevates blood pressure and pro- enalapril. Am J Hypertens 2000; 13: 1161–1167. motes leukocyte adherence. Br J Pharmacol 2000; 129: 16 Brown J, Dollery C, Valdes G. Interaction of nonster- 1423–1430. oidal anti-inﬂammatory drugs with antihypertensive 19 Graves JW, Ingebog A, Hunder RN. Worsening of and diuretic agents. Control of vascular reactivity by hypertension by Cyclo-oxygenase-2 inhibitors. J Clin endogenous prostanoids. Am J Med 1986; 81:43–57. Hypertens 2000; 2: 396–398. 17 McKenney JM et al. Effect of high-dose ibuprofen on 20 Muller JE. Morning increase of onset of myocardial 14-hour blood pressure in healthy women. Drug Intell infarction. Implications concerning triggering events. Clin Pharm 1987; 21: 517–521. Cardiology 1989; 76:96–104.

Journal of Human Hypertension