Edema and Related Medical Conditions

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Saturday, January 14, 2006

COX Inhibition, Hypertension, and Edema Effect

Vibeke Strand, MD
Even if they are mechanistically different, cyclooxygenase-2 (COX-2) inhibitors have effects on hypertension (HTN) similar to those observed with conventional nonsteroidal anti-inflammatory drugs (NSAIDs). According to Pope et al, use of nonselective NSAIDs in treated hypertensive patients, including those taking angiotensin-converting enzyme (ACE) inhibitors and beta-blockers, results in an average unadjusted increase in mean arterial pressure (MAP) ranging from 0.61 mm Hg with aspirin to 6.10 mm Hg with naproxen. After adjusting for dietary salt intake, the effect ranged from an increase of just over 3.5 mm Hg for naproxen and indomethacin to a decrease in MAP with sulindac, aspirin, and ibuprofen.1 This is a common problem in the osteoarthritis (OA) population. Singh et al report that 40% of the 24.3 million people in the US with OA have HTN.2

All coxibs induce salt and water retention and destabilization of blood pressure (BP), as do conventional NSAIDs. Additionally, there is a dose-related effect with rofecoxib at doses between 12.5 mg and 50 mg (with a markedly increased percentage of patients with BP elevation at the 50-mg dose). There are also dose-related increases with valdecoxib at 40 mg and 80 mg. Bensen et al3 report that 2.7% of rheumatoid arthritis (RA) patients taking 40 mg/day of valdecoxib develop HTN.

In the Celecoxib Rofecoxib Efficacy and Safety in Comorbidities Evaluation Trial (CRESCENT),4 rofecoxib significantly increased 24-hour BP during and at landmarks after 6 weeks of therapy, while celecoxib and naproxen did not, as determined by ambulatory BP measurements. While reductions in OA symptoms were similar across all groups, patients taking rofecoxib had a mean 4 mm Hg increase in 24-hour systolic BP. Patients taking rofecoxib also had increases in pulse pressure. The mean change in 24-hour ambulatory systolic BP from baseline to week 6 between rofecoxib and celecoxib was 3.78 mm Hg and 3.85 mm Hg between rofecoxib and naproxen. There were no significant differences between celecoxib and naproxen. Moreover, the percentage of patients who developed HTN in the study was higher for people taking rofecoxib than celecoxib. In CRESCENT, patients using rofecoxib, but not celecoxib or conventional NSAIDs, had an increased rate of edema (23.3% versus 18.0%), while the rates for celecoxib and conventional NSAIDs were 17.5% and 18.2%, respectively. The adjusted risk of edema was significantly increased for rofecoxib compared with celecoxib.

The Celexcoxib Long-term Arthritis Safety Study (CLASS), the Vioxx Gastrointestinal Outcome Research (VIGOR) trial, and the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) all suggest that COX-2 inhibitors can increase BP. In CLASS, there was a relatively low, non-dose-dependent incidence of HTN with celecoxib when compared with diclofenac and ibuprofen.

In a 6-week, randomized, double-blind study of edema and HTN during treatment with rofecoxib 25 mg daily and celecoxib 200 mg daily in OA patients with HTN, Whelton et al5 found that edema and BP destabilization (systolic pressure increase) were more common in patients receiving rofecoxib than celecoxib.

NSAID use is not associated with incident congestive heart failure (CHF); however, once CHF is present, there is a substantial increase in risk with NSAID use, according to Feenstra et al.6 Nevertheless, compared with HTN there is markedly less data with regard to CHF and edema. In one study by Mamdani et al,7 patients taking rofecoxib and nonselective NSAIDs (but not celecoxib) had an increased risk of hospital admission for CHF relative to non-NSAID users. Compared with celecoxib users, admission was significantly more likely in users of nonselective NSAIDs and rofecoxib. Risk of admission for rofecoxib users was higher than for nonselective NSAID users. Of patients who had not been admitted to a hospital in the past 3 years, only rofecoxib users were at increased risk of subsequent admission relative to controls.

Moreover, two epidemiologic studies in the Netherlands showed an increased incidence of CHF, and new-onset CHF, with NSAIDs versus patients taking diuretics. In a study by Garcia Rodriguez and Hernandez-Diaz,8 the estimated adjusted relative risk of heart failure associated with prescription of NSAIDs was 1.6. The relative risk was greater during the first month of therapy and was independent of treatment indication. Further, the relative risk was 1.9 among patients with a prior history of HTN, diabetes, or renal failure and 1.3 among individuals without these conditions. In TARGET, CHF occurred with similar frequency among lumiracoxib users (0.24%) and NSAID users (0.34%), respectively.9

BP and edema effects differ among the medications. With rofecoxib, greater frequencies of edema and increased BP are observed in patients with HTN versus celecoxib. Moreover, there is an increase in BP among OA patients with treated HTN compared with celecoxib and naproxen. There is no dose-related increase in HTN, edema, or CHF with celecoxib. Celecoxib has a more modest effect on HTN, edema, and CHF than rofecoxib (even in OA patients receiving antihypertensives). It is not yet known whether BP is the surrogate marker for an increase in CV events; however, such events are rare and must be considered in the context of the risk/benefit profile of these agents.

Key Points

HTN among OA patients is a significant problem

All coxibs result in salt and water retention and destabilization of BP, as do conventional NSAIDs
BP and edema effects differ among the medications; for example, edema and increase in BP are seen in rofecoxib-treated patients with HTN versus celecoxib; there are also dose-related increases with valdecoxib at 40 mg and 80 mg

CV events are rare and must be considered in the context of the risk/benefit profile of these agents


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.

Singh G, Miller JD, Lee FH, Pettitt D, Russell MW. Prevalence of cardiovascular disease risk factors among US adults with self-reported osteoarthritis: data from the Third National Health and Nutrition Examination Survey. Am J Manag Care. 2002;8(suppl 15):S383-S391.

Bensen W, Weaver A, Espinoza L, et al. Efficacy and safety of valdecoxib in treating the signs and symptoms of rheumatoid arthritis: a randomized, controlled comparison with placebo and naproxen. Rheumatology (Oxford). 2002;41:1008-1010.

Sowers JR, White WB, Pitt B, et al; Celecoxib Rofecoxib Efficacy and Safety in Comorbidities Evaluation Trial (CRESCENT) Investigators. The effects of cyclooxygenase-2 inhibitors and nonsteroidal anti-inflammatory therapy on 24-hour blood pressure in patients with hypertension, osteoarthritis, and type 2 diabetes mellitus. Arch Intern Med. 2005;165:161-168.
Whelton A, Fort JG, Puma JA, Normandin D, Bello AE, Verburg KM; SUCCESS VI Study Group. Cyclooxygenase-2-specific inhibitors and cardiorenal function: a randomized, controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients. Am J Ther. 2001;8:85-95.

Feenstra J, Heerdink ER, Grobbee DE, Stricker BH. Association of nonsteroidal anti-inflammatory drugs with first occurrence of heart failure and with relapsing heart failure: the Rotterdam Study. Arch Intern Med. 2002;162:265-270.

Mamdani M, Juurlink DN, Lee DS, et al. Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study. Lancet. 2004;363:1751-1756.

Garcia Rodriguez LA, Hernandez-Diaz S. Nonsteroidal anti-inflammatory drugs as a trigger of clinical heart failure. Epidemiology. 2003;14:240-246.

Farkouh ME, Kirshner H, Harrington RA, et al; TARGET Study Group. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: randomised controlled trial. Lancet. 2004;364:675-684.

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