Published online before print June 28, 2004, doi: 10.1161/01.HYP.0000136129.18326.26
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(Hypertension. 2004;44:123.)
© 2004 American Heart Association, Inc.
Editorial Commentaries |
Hypertension Associated With Therapies to Treat Arthritis and Pain
From the Division of Hypertension and Clinical Pharmacology, Center for Cardiology and Cardiovascular Biology, University of Connecticut School of Medicine, Farmington.
Correspondence to William B. White, MD, Professor and Chief, Division of Hypertension and Clinical Pharmacology, Center for Cardiology and Cardiovascular Biology, University of Connecticut School of Medicine, 263 Farmington Ave, Farmington, CT 06030-3940. E-mail wwhite{at}nso1.uchc.edu
Cyclooxygenase-2 (COX-2) inhibitors have become a widely used class of agents for the treatment of arthritis and pain because of their improved gastrointestinal safety and tolerability profile compared with the nonselective NSAIDs.1,2 During the past 4 years, the effects of these agents on destabilization of blood pressure (BP) has become a concern that has led to substantial research and controversy. COX inhibition is associated with antinatriuretic and vasoconstrictor effects mediated through the inhibition of the actions of prostaglandin E2 and prostacylin.3–5 The first 2 studies that evaluated the effects of NSAIDs on BP6,7 demonstrated that mean arterial pressure could rise by as much as 5 to 6 mm Hg in a population of patients with hypertension. The greatest effects of NSAIDs on BP control were observed in patients on monotherapeutic regimens of ß-adrenergic blocking drugs, diuretics, or angiotensin-converting enzyme (ACE) inhibitors.6
Recent clinical trials suggest that patients treated with ß-blockers and ACE inhibitors are particularly susceptible to destabilization of BP control by some COX-2 inhibitors compared with patients controlled with a calcium antagonist.8 For example, in patients on an ACE inhibitor monotherapy regimen, rofecoxib (25 mg daily) increased the systolic BP by 5 mm Hg, whereas in patients on a calcium antagonist alone, there was no increase in systolic BP. However, not all COX-2 inhibitors have the same effect on BP. In a drug interaction trial involving 178 patients with hypertension, 24-hour ambulatory BP monitoring showed that celecoxib (200 mg twice daily) had a modest and nonsignificant increase in systolic BP in patients treated with a stable dose of the ACE inhibitor lisinopril.9
Additionally, the effects of the COX-2 inhibitors have been evaluated in older, hypertensive patients with osteoarthritis in clinical practice trials in which BP had been controlled at stable doses of antihypertensive therapy for at least 3 months.8,10 After 6 to 12 weeks of treatment, significantly more patients treated with rofecoxib 25 mg once daily had clinically important elevations in clinic and 24-hour systolic BP compared with patients treated with celecoxib 200 mg daily. Although these studies have shown that the incidence of edema was significantly higher in the rofecoxib-treated patients compared with the celecoxib-treated patients, most of the patients developing uncontrolled hypertension did not develop edema or significant weight gain. Hence, interference with the vasodilatory actions of certain antihypertensive drugs may be a more common cause of destabilization of BP control than enhanced plasma volume associated with the antinatriuretic effects of the COX-2 inhibitors.8,10
In prior analyses of clinical trials involving nonhypertensive patients with arthritis, nonselective NSAIDs and COX-2 inhibitors have not appeared to have much effect on the development of hypertension.6,7,11 However, studies in these normotensive populations have had small sample sizes, so one could not accurately predict the BP interaction effects of NSAIDs and COX-2 inhibitors for patients who were newly treated for arthritis and pain in clinical practice.4
In this issue of Hypertension, Solomon et al have provided some important insight into the effects of NSAIDs and COX-2 inhibitor therapy on the development of hypertension using a large retrospective case-control study involving >17 000 elderly patients from 2 pharmacy benefit management plans in New Jersey and Pennsylvania.12 To be included in the study, patients were required to have no prior diagnosis of hypertension nor the use of any class of antihypertensive therapy (except loop diuretics). There were 3915 individuals (ie, cases) who developed newly diagnosed hypertension and subsequently were prescribed an antihypertensive drug. A key finding in the study is that the absolute incidence of new onset hypertension during the 2- to 3-year period of observation was 21% in patients prescribed celecoxib, 23% in patients prescribed NSAIDs, and 27% in the patients prescribed rofecoxib. The background incidence rate of new onset hypertension was 22% in 15 711 patients not using anti-inflammatory drugs during the observation period. Further, the odds of developing hypertension was 1.3 to 1.6x greater in patients receiving rofecoxib than in patients receiving conventional NSAIDs or celecoxib.
Unlike the results of a similar case-control study13 that showed a significant impact of dose of rofecoxib and the development of acute myocardial infarction in the Medicare study population, Solomon et al did not find a dose-related increase for the onset of hypertension on rofecoxib. However, this finding may be an artifact of a very small number of patients taking a rofecoxib dose >25 mg daily compared with a large number taking lower doses (
25 mg/d). In the VIoxx Gastrointestinal Outcomes Research (VIGOR) trial that had a median period of observation of 9 months,2 the incidence of hypertension was greater in patients randomized to rofecoxib 50 mg daily compared with naproxen 1000 mg daily.
The implications of the findings of the Solomon et al study involve 2 important issues. Physicians clearly prescribe NSAIDs and COX-2 inhibitors to normotensive patients with pain or arthritis or both and do not recognize that the development of hypertension may be attributable to the newly prescribed therapy. Hence, patients may end up on antihypertensive drug therapy unnecessarily. Alternatively, patients who have known hypertension that is acceptably controlled could become destabilized by the introduction of a COX-2 inhibitor. Small increases in systolic BP over time in an older population are linked to significant increases in coronary heart disease death rates and stroke.14 Furthermore, in the treated hypertensive population, small mean differences from baseline measures could have clinically relevant results, as has been observed in the treatment groups in the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) study.15
Finally, Solomon et al12 reported that the odds of developing hypertension were significantly greater in patients with a history of heart or renal disease or both and who were treated with rofecoxib compared with other NSAIDs and celecoxib. This finding may in part be because of the inability for patients with renal disease to compensate for the antinatriuretic effects of the COX-2 inhibitor.16 Unfortunately, no clinical trials have been conducted using the COX-2 inhibitors in patients with moderate renal insufficiency and, therefore, great caution should be taken with using rofecoxib or any NSAID in patients with renal insufficiency or heart failure, even for short periods of time.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
1. Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, Makuch R, Eisen G, Agrawal NM, Stenson WF, Burr AM, Zhao WW, Kent JD, Lefkowith JB, Verburg KM, Geis GS. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. JAMA. 2000; 284: 1247–1255.
2. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ for the VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000; 343: 1520–1528.
3. McAdam BF, Catella LF, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2 [published erratum appears in Proc Natl Acad Sci U S A. 1999 May 11;96:5890]. Proc Natl Acad Sci U S A. 1999; 96: 272–277.
4. Simon LS, Smolen JS, Abramson SB, Appel G, Bombardier C, Brater DC, Breedveld FC, Brune K, Burmester GR, Crofford LJ, Dougados M, DuBois RN, Fitzgerald GA, Frishman W, Garcia Rodriguez LA, Hochberg MC, Kalden JR, Laine L, Langman MJ, Prescott SM, van de Putte LB, Whelton A, White WB, Williams GH. Controversies in COX-2 selective inhibition. J Rheumatol. 2002; 29: 1501–1510.
5. Morgan TO, Anderson A, Bertram D. Effect of indomethacin on blood pressure in elderly people with essential hypertension well controlled on amlodipine or enalapril. Am J Hypertens. 2000; 13: 1161–1167.[CrossRef][Medline] [Order article via Infotrieve]
6. Pope JE, Anderson JJ, Felson DT. A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure. Arch Intern Med. 1993; 153: 477–484.
7. Johnson AG, Nguyen TV, Day RO. Do nonsteroidal anti-inflammatory drugs affect blood pressure? Ann Intern Med. 1994; 121: 289–300.
8. Whelton A, White WB, Bello AE, Puma JA, Fort JG. 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.[CrossRef][Medline]
[Order article via Infotrieve]
9. 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.
10. Sowers J, White WB, Pitt B, Whelton A, Simon LS, Winer N, Kivitz A, van Ingen J, Fort J. The effects of cyclooxygenase-2 inhibitors and nonsteroidal antiinflammatory therapy on 24-hour blood pressure in hypertensive patients with osteoarthritis and type 2 diabetes mellitus. J Am Coll Cardiol. 2003; 41: 320A.
11. Schwartz JI, Vandormael K, Malice MP, Kalyani RN, Lasseter KC, Holmes GB, Gertz BJ, Gottesdiener KM, Laurenzi M, Redfern KJ, Brune K. Comparison of rofecoxib, celecoxib, and naproxen on renal function in elderly subjects receiving a normal-salt diet. Clin Pharmacol Ther. 2002; 72: 50–61.[CrossRef][Medline] [Order article via Infotrieve]
12. Solomon DH, Schneeweiss S, Levin R, Avorn J. The relationship between COX-2 specific inhibitors and hypertension. Hypertension. 2004; 44: 140–145.
13. Solomon DH, Schneeweiss S, Glynn RJ, Kiyota Y, Levin R, Mogun H, Avorn J. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation. 2004; 109: 2068–2073.
14. Izzo JL, Levy D, Black HR. Importance of systolic blood pressure in older Americans. Clinical advisory statement. Hypertension. 2000; 35: 1021–1024.
15. ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone. The antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). JAMA. 2000; 283: 1967–1975.
16. Cheng HF, Harris RC. Cyclooxygenases, the kidney, and hypertension. Hypertension. 2004; 43: 525–530.
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