Cardiorenal effects of celecoxib as compared with the nonsteroidal anti-inflammatory drugs diclofenac and ibuprofen
2006; Elsevier BV; Volume: 70; Issue: 8 Linguagem: Inglês
10.1038/sj.ki.5001766
ISSN1523-1755
AutoresAndrew Whelton, JB Lefkowith, Christine R. West, Kenneth M. Verburg,
Tópico(s)Eicosanoids and Hypertension Pharmacology
ResumoThe cardiorenal safety database from the Celecoxib Long-term Arthritis Safety Study (CLASS) was analyzed to examine whether supratherapeutic doses of celecoxib are associated with decreased renal function and blood pressure (BP) effects compared with standard doses of diclofenac and ibuprofen in osteoarthritis (OA) and rheumatoid arthritis (RA) patients.In total, 8059 patients were enrolled; 7968 received at least one dose of study drug (RA: N=2183; OA: N=5785). Patients received celecoxib, 400 mg twice a day (b.i.d.). (N=3987); ibuprofen, 800 mg three times a day. (N=1985); or diclofenac, 75 mg b.i.d. (N=1996). Effects measured included: investigator-reported hypertension, edema or congestive heart failure, clinically important BP elevations, incidence of patients starting new antihypertensive medication, and increases in serum creatinine or reductions in creatinine clearance. Celecoxib was associated with a similar incidence of hypertension or edema to diclofenac but significantly lower than ibuprofen. The celecoxib group had significantly fewer initiations of antihypertensives versus ibuprofen. Systolic BP increases of >20 mmHg and above 140 mmHg occurred significantly less often with celecoxib compared with ibuprofen or diclofenac. Changes in serum creatinine or estimated creatinine clearance occurred in a similar percentage of patients taking celecoxib or ibuprofen; modest differences were evident against diclofenac. In patients with mild prerenal azotemia, significantly fewer patients taking celecoxib exhibited clinically important reductions in renal function (3.7%), compared with diclofenac (7.3%; P<0.05) and ibuprofen (7.3%; P 20 mmHg and above 140 mmHg occurred significantly less often with celecoxib compared with ibuprofen or diclofenac. Changes in serum creatinine or estimated creatinine clearance occurred in a similar percentage of patients taking celecoxib or ibuprofen; modest differences were evident against diclofenac. In patients with mild prerenal azotemia, significantly fewer patients taking celecoxib exhibited clinically important reductions in renal function (3.7%), compared with diclofenac (7.3%; P<0.05) and ibuprofen (7.3%; P<0.05). A supratherapeutic dose of celecoxib was associated with an improved cardiorenal safety profile compared with standard doses of either ibuprofen or diclofenac. Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to manage the pain and inflammation associated with arthritis. However, these agents inhibit both isoenzymes of cyclooxygenase (COX): COX-1 and COX-2.1.Gierse J.K. Hauser S.D. Creely D.P. et al.Expression and selective inhibition of the constitutive and inducible forms of human cyclo-oxygenase.Biochem J. 1995; 305: 479-484Crossref PubMed Scopus (369) Google Scholar Therefore, the use of nonselective NSAIDs can result in a spectrum of mild-to-severe and occasionally life-threatening mechanism-based adverse events, particularly within the gastrointestinal tract, effects on platelets, and the cardiorenal axis, which may limit their therapeutic benefit.2.Verburg K.M. Maziasz T.J. Weiner E. et al.Cox-2-specific inhibitors: definition of a new therapeutic concept.Am J Ther. 2001; 8: 49-64Crossref PubMed Scopus (49) Google Scholar, 3.Gabriel S.E. Jaakkimainen L. Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis.Ann Intern Med. 1991; 115: 787-796Crossref PubMed Scopus (1184) Google Scholar, 4.Henry D. Lim L.L. Garcia Rodriguez L.A. et al.Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis.BMJ. 1996; 312: 1563-1566Crossref PubMed Scopus (772) Google Scholar, 5.Griffin M.R. Piper J.M. Daugherty J.R. et al.Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons.Ann Intern Med. 1991; 114: 257-263Crossref PubMed Scopus (708) Google Scholar, 6.Langman M.J. Weil J. Wainwright P. et al.Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs.Lancet. 1994; 343: 1075-1078Abstract PubMed Scopus (803) Google Scholar Celecoxib was the first of the COX-2 selective inhibitors (COXIBs) to be developed. At full therapeutic doses, celecoxib possesses comparable analgesic and anti-inflammatory efficacy to nonselective NSAIDs in the treatment of rheumatoid arthritis (RA) and osteoarthritis (OA), although sparing COX-1 activity, thereby avoiding many of the gastrointestinal- and platelet-related adverse events.7.Bensen W.G. Fiechtner J.J. McMillen J.I. et al.Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial.Mayo Clin Proc. 1999; 74: 1095-1105Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar, 8.Geis G.S. Update on clinical developments with celecoxib, a new specific COX-2 inhibitor: what can we expect?.J Rheumatol. 1999; 26: 31-36Google Scholar, 9.Leese P.T. Hubbard R.C. Karim A. et al.Effects of celecoxib, a novel cyclooxygenase-2 inhibitor, on platelet function in healthy adults: a randomized, controlled trial.J Clin Pharmacol. 2000; 40: 124-132Crossref PubMed Scopus (315) Google Scholar, 10.Goldenberg M.M. Celecoxib, a selective cyclooxygenase-2 inhibitor for the treatment of rheumatoid arthritis and osteoarthritis.Clin Ther. 1999; 21: 1497-1513Abstract Full Text PDF PubMed Scopus (120) Google Scholar, 11.Simon L.S. Nonsteroidal anti-inflammatory drugs and their effects: the importance of COX selectivity.J Clin Rheumatol. 1996; 2: 135-140Crossref PubMed Scopus (39) Google Scholar Nonselective inhibition of COX-1 and COX-2 attenuates the prostaglandin-mediated mechanisms responsible for modulating renal function, including renal vascular tone and electrolyte and water excretion, particularly during renal stress, as manifested by reduced renal perfusion.12.Whelton A. Maurath C.J. Verburg K.M. et al.Renal safety and tolerability of celecoxib, a novel cyclooxygenase-2 inhibitor.Am J Ther. 2000; 7: 159-175Crossref PubMed Scopus (171) Google Scholar, 13.Pope J.E. Anderson J.J. Felson D.T. A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure.Arch Intern Med. 1993; 153: 477-484Crossref PubMed Google Scholar The most common side effect is edema, which is followed by, and frequently linked with, destabilization of blood pressure (BP) control in treated hypertensive individuals. Retention of salt and water is also linked to the blunting of clinical response to diuretic treatment and may subsequently induce congestive heart failure in susceptible individuals. In the setting of reduced renal perfusion and, hence, dependence of renal perfusion upon the compensatory production of prostaglandin synthesis, the use of a nonselective NSAID may result in acute, hemodynamically mediated deterioration in renal function. This is fully reversible following discontinuation of the offending drug. Other renal syndromes are rare to very rare. They include other electrolyte complications, such as hyperkalemia, hyponatremia, nephrotic syndrome with interstitial nephritis, and papillary necrosis. The mechanisms of the induction of these rare events via inhibition of arachidonic acid processing by COX enzymes are reviewed in detail elsewhere.14.Whelton A. Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications.Am J Med. 1999; 106: 13S-24SAbstract Full Text Full Text PDF PubMed Scopus (522) Google Scholar, 15.Atta M.G. Whelton A. Acute renal papillary necrosis induced by ibuprofen.Am J Ther. 1997; 4: 55-60Crossref PubMed Scopus (22) Google Scholar It is remarkable to note that, following exposure to several days' treatment with nonselective NSAIDs, approximately one in five subjects will manifest a renal function abnormality.16.Whelton A. Hamilton C.W. Nonsteroidal anti-inflammatory drugs: effects on kidney function.J Clin Pharmacol. 1991; 31: 588-598Crossref PubMed Scopus (286) Google Scholar COX-1 is expressed abundantly in the kidney. In the early development of celecoxib, it was assumed that COX-2 was not constitutively expressed in the healthy human kidney as was the case in most other tissues with the exception of the brain and the female reproductive system. However, subsequent studies have demonstrated that the COX-2 isoenzyme is indeed constitutively expressed in discrete areas of the adult mammalian kidney.17.Harris R.C. Breyer M.D. Physiological regulation of cyclooxygenase-2 in the kidney.Am J Physiol Renal Physiol. 2001; 281: F1-F11PubMed Google Scholar For example, expression of COX-2 in the macula densa suggests a role in the production of prostaglandins regulating the release of renin. COX-2 expressed in the cortical thick ascending limb and medullary interstitial cells may be involved in the regulation of medullary blood flow. In the medulla, COX-2 expression decreases with salt depletion and increases with a high-salt diet and with dehydration.18.Hao C.M. Yull F. Blackwell T. et al.Dehydration activates an NF-kappaB-driven COX2-dependent survival mechanism in renal medullary interstitial cells.J Clin Invest. 2000; 106: 973-982Crossref PubMed Scopus (138) Google Scholar, 19.Yang T. Singh I. Pham H. et al.Regulation of cyclooxygenase expression in the kidney by dietary salt intake.Am J Physiol. 1998; 274: F481-F489PubMed Google Scholar Thus, as information accumulated, it became increasingly clear that COX-2 may serve an important role in the regulation of renal hemodynamic and/or renal excretory function under physiologic or pathophysiologic conditions.20.Whelton A. Schulman G. Wallemark C. et al.Effects of celecoxib and naproxen on renal function in the elderly.Arch Intern Med. 2000; 160: 1465-1470Crossref PubMed Scopus (264) Google Scholar, 21.Harris Jr, R.C. Cyclooxygenase-2 inhibition and renal physiology.Am J Cardiol. 2002; 89: 10D-17DAbstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar Typically, the use of a selective COX-2 inhibitor in otherwise healthy individuals is associated with mild edema, hypertension, and modest sodium retention for the first 1 or 2 days of therapy followed by a return to baseline excretion levels and elimination of retained salt and water. As the kidney and vasculature are capable of expressing both COX-1 and COX-2, it may be hypothesized that a selective COX-2 inhibitor such as celecoxib may have decreased renal adverse effects relative to nonselective inhibitors. The Celecoxib Long-term Arthritis Safety Study (CLASS) was undertaken to compare the long-term upper gastrointestinal safety of celecoxib 400 mg twice a day (b.i.d.), two to four times the full therapeutic doses for RA and OA, respectively, with normal full therapeutic doses of diclofenac (75 mg b.i.d.) and ibuprofen (800 mg three times a day). A large cardiorenal safety database was accumulated in the CLASS trial, which was determined to be useful for studying cardiorenal-related adverse effects associated with nonselective NSAIDs and celecoxib. A separate publication has detailed the cardiovascular thrombotic complications observed during the CLASS trial.22.White W.B. Faich G. Whelton A. et al.Comparison of thromboembolic events in patients treated with celecoxib, a cyclooxygenase-2 specific inhibitor, versus ibuprofen or diclofenac.Am J Cardiol. 2002; 89: 425-430Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar Patient disposition is outlined in Figure 1. A total of 8059 patients were randomized, of whom 7968 received at least one dose of study drug, and were therefore included in the intent-to-treat (ITT) population (RA: N=2183; OA: N=5785). In the ITT population, 3987 patients received celecoxib and 3981 were treated with either ibuprofen or diclofenac. Baseline demographics, exposure to treatment, mean BP levels, and renal function are shown in Table 1. Mean patient age was 60 years in each treatment group, most (69–71%) patients were female and mean BP was 133/80 mmHg. As determined by medical history, slightly less than 40% of patients in each treatment group had pre-existing hypertension. Overall BP levels and renal function were normal at baseline and comparable between treatment groups.Table 1Baseline characteristics and exposure to treatmentCelecoxib 400 mg b.i.d. (N=3987)Diclofenac 75 mg b.i.d. (N=1996)Ibuprofen 800 mg t.i.d. (N=1985)Exposure to treatment Median (days)273257186 Total (patient-years)232010811122Age Mean (years)60.660.159.5 65–74 years (%)26.926.425.5 ≥75 years (%)12.211.810.9Female (%)68.567.470.8History (%) Hypertension39.038.938.1 Diabetes8.87.58.1Blood pressure (mmHg) Systolic132.7133.0132.6 Diastolic79.479.579.9Creatinine Serum level (mg/dl)0.790.790.77 Clearance (ml/minaEstimated by the Cockcroft–Gault formula.)112.2112.0116.4b.i.d., twice a day; t.i.d., three times a day.a Estimated by the Cockcroft–Gault formula. Open table in a new tab b.i.d., twice a day; t.i.d., three times a day. A summary of antihypertensive and diuretic medication use at baseline is summarized in Table 2. Over 40% of the patients in each treatment group were receiving one or more of these agents, with nearly 20% receiving diuretics. Overall, the frequency and distribution of use of these drugs were similar across the treatment groups.Table 2Summary of antihypertensive and diuretic medication use at baselineDrug N (% of patients)Celecoxib 400 mg b.i.d. (N=3987)Diclofenac 75 mg b.i.d. (N=1996)Ibuprofen 800 mg t.i.d. (N=1985)Any antihypertensive or diuretic medication1688 (42.3)859 (43.0)845 (42.6)ACE inhibitors528 (13.2)266 (13.3)240 (12.1)Alpha adrenergic agonists209 (5.2)95 (4.8)87 (4.4)Angiotensin II receptor antagonists128 (3.2)64 (3.2)70 (3.5)Beta-blockers473 (11.9)238 (11.9)260 (13.1)Calcium channel blockers511 (12.8)283 (14.2)274 (13.8)Diuretics764 (19.2)412 (20.6)393 (19.8)ACE, Angiotensin-converting enzyme; b.i.d., twice a day; t.i.d., three times a day. Open table in a new tab ACE, Angiotensin-converting enzyme; b.i.d., twice a day; t.i.d., three times a day. Celecoxib was associated with an incidence of hypertension (both new-onset and aggravated) that was comparable to standard doses of diclofenac and significantly lower than standard doses of ibuprofen (P<0.05) (Table 3). In patients taking ibuprofen, the increased incidence of hypertension versus celecoxib was accompanied by a corresponding trend towards a mean increase in systolic BP (P=0.09). Both ibuprofen and diclofenac treatments were associated with a significantly (P 20 mmHg and above 140 mmHg as compared with celecoxib (treatment differences 1.6–2.0%). No treatment differences were observed for diastolic BP (Table 3). Withdrawals from study treatment owing to hypertension-related adverse events were uncommon and occurred with similar frequency among the three treatment groups (Table 3).Table 3Blood pressure effects of celecoxib vs diclofenac or ibuprofenEventCelecoxib 400 mg b.i.d. (N=3987)Diclofenac 75 mg b.i.d. (N=1996)Ibuprofen 800 mg t.i.d. (N=1985)Any hypertension adverse event (% of patients)aNew-onset or aggravated.2.72.64.2*P<0.05 versus celecoxib by Fisher exact test. New-onset hypertension (% of patients)2.02.03.1*P 20 mmHg from baseline and absolute value >140 mmHg5.06.6*P<0.05 versus celecoxib by Fisher exact test.7.0*P 15 mmHg from baseline and absolute value >90 mmHg1.91.22.2b.i.d., twice a day; t.i.d., three times a day.a New-onset or aggravated.b Observed at final clinic visit.* P<0.05 versus celecoxib by Fisher exact test. Open table in a new tab b.i.d., twice a day; t.i.d., three times a day. The initiation of new antihypertensive and diuretic therapy was significantly higher with ibuprofen treatment as compared with celecoxib treatment and specifically for initiation of angiotensin II receptor antagonists, calcium channel blockers, and diuretic therapies (Table 4). No significant differences were observed in the use of antihypertensives between the celecoxib and diclofenac treatment groups. Upward adjustments of antihypertensive or diuretic therapies already being administered to patients in order to maintain BP control were not considered in this analysis. Of the patients summarized in Table 4, 59% (229/391) celecoxib-treated patients, 58% (107/184) diclofenac-treated patients, and 56% (133/238) ibuprofen-treated patients were already receiving antihypertensive or diuretic therapy at baseline and, therefore, were being initiated to a second agent concurrently or being switched from one treatment to another. For the remaining approximately 40% of patients in this cohort across the treatment groups, the initiation of antihypertensive or diuretic therapy occurred in the absence of any baseline treatment.Table 4Initiation of antihypertensive and diuretic medicationsDrug N (% of patients)Celecoxib 400 mg b.i.d. (N=3987)Diclofenac 75 mg b.i.d. (N=1996)Ibuprofen 800 mg t.i.d. (N=1985)Any new antihypertensive or diuretic medicationaIf a patient received more than one antihypertensive/diuretic medication, that patient is counted once in the overall incidence for any drug.391 (9.8)184 (9.2)238 (12.0)*P<0.05 versus celecoxib by Fisher exact test.ACE inhibitors108 (2.7)63 (3.2)62 (3.1)Alpha adrenergic agonists45 (1.1)15 (0.8)12 (0.6)Angiotensin II receptor antagonists34 (0.9)17 (0.9)39 (2.0)**P<0.01 versus celecoxib by Fisher exact test.Beta-blockers74 (1.9)36 (1.8)38 (1.9)Calcium channel blockers79 (2.0)34 (1.7)62 (3.1)**P<0.01 versus celecoxib by Fisher exact test.Diuretics153 (3.8)84 (4.2)103 (5.2)*P<0.05 versus celecoxib by Fisher exact test.ACE, Angiotensin-converting enzyme; b.i.d., twice a day; t.i.d., three times a day.a If a patient received more than one antihypertensive/diuretic medication, that patient is counted once in the overall incidence for any drug.* P<0.05 versus celecoxib by Fisher exact test.** P<0.01 versus celecoxib by Fisher exact test. Open table in a new tab ACE, Angiotensin-converting enzyme; b.i.d., twice a day; t.i.d., three times a day. Celecoxib treatment was associated with a similar incidence of investigator-reported edema (including either peripheral or generalized edema) compared with diclofenac and a significantly lower incidence compared with ibuprofen (P<0.05) (Table 5). This higher incidence of edema in patients taking ibuprofen paralleled a significantly greater use of new diuretic use compared with celecoxib-treated patients (P<0.05) (Table 4). No significant differences were noted in diuretic use between patients assigned to celecoxib and diclofenac.Table 5Fluid retention effects of celecoxib versus diclofenac or ibuprofenCelecoxib 400 mg b.i.d. (N=3987)Diclofenac 75 mg b.i.d. (N=1996)Ibuprofen 800 mg t.i.d. (N=1985)Any edema-related adverse event (% of patients)aIncludes investigator reports of edema, generalized edema or peripheral edema.4.14.16.2*P<0.05 versus celecoxib by Fisher exact test.Withdrawals for edema-related adverse events (% of patients)aIncludes investigator reports of edema, generalized edema or peripheral edema.0.70.41.0Congestive heart failure (% of patients)0.30.20.5Withdrawals due to congestive heart failure (% of patients)0.1<0.10.3Increase in body weight of ≥3% (% of patients)20.717.621.1b.i.d., twice a day; t.i.d., three times a day.a Includes investigator reports of edema, generalized edema or peripheral edema.* P 99%) had a serum creatinine ≤1.5 mg/dl, which reflects normal renal function required per protocol. Renal function, as reflected by serum creatinine or estimated creatinine clearance, decreased significantly in patients assigned to diclofenac compared with those receiving celecoxib (P<0.05) (Table 6). A nonsignificant trend towards decreased renal function was observed in patients treated with ibuprofen relative to those patients receiving celecoxib (Table 6).Table 6Renal effects of celecoxib versus diclofenac or ibuprofenCelecoxib 400 mg b.i.d. (N=3987)Diclofenac 75 mg b.i.d. (N=1996)Ibuprofen 800 mg t.i.d. (N=1985)Mean change in serum creatinine (mg/dl)(n=3692) 0.009±0.002(n=1850) 0.027±0.004*P<0.05 versus celecoxib by analysis of covariance or by Fisher exact test.(n=1786) 0.017±0.004Mean change in estimated creatinine clearance (ml/min)(n=3668) 0.08±0.37(n=1846) -2.82±0.51*P<0.05 versus celecoxib by analysis of covariance or by Fisher exact test.(n=1775) -0.96±0.56b.i.d., twice a day; t.i.d., three times a day.* P 0.5 mg/dl relative to baseline or serum creatinine >1.5 mg/dl at any post-baseline assessment or (2) a decrease in estimated creatinine clearance ≥30% relative to baseline are provided in Figure 2. For the entire treatment cohort, one significant treatment difference was detected: the incidence of ≥30% reductions in estimated creatinine clearance from baseline was significantly lower in patients treated with celecoxib as compared with diclofenac. An evaluation of the time course of these changes (data not shown) revealed that the highest frequency occurred early after initiation of treatment (week 4 and 13 clinic visits) and declined thereafter, rather than a progressively increasing risk as a function of duration of treatment in all three treatment groups. It should be noted, however, that a substantial proportion of patients exhibited these changes 6 months or longer after treatment was initiated, suggesting that the hazard, although perhaps diminishing with time, does continue throughout the therapy period. Increases in serum creatinine of >1.0 mg/dl were uncommon, occurring in nine celecoxib-treated patients (0.2%), two diclofenac-treated patients (0.1%), and two patients taking ibuprofen (0.2%). These treatment differences were not significantly different. For those patients characterized by mild prerenal azotemia at baseline (serum blood urea nitrogen >20 mg/dl) but relatively normal renal function (Table 7), the incidence of clinically important changes in renal function was at least twofold lower (P 20 mg/dl)Celecoxib 400 mg b.i.d. (N=592)Diclofenac 75 mg b.i.d. (N=300)Ibuprofen 800 mg t.i.d. (N=260)Baseline serum creatinine (mg/dl)0.930.940.93Estimated baseline creatinine clearance (ml/min)91.191.394.3Mean change in serum creatinine (mg/dl)0.003±0.0070.049±0.012*P<0.05 by analysis of covariance or by Fisher exact test.0.033±0.015*P<0.05 by analysis of covariance or by Fisher exact test.Mean change in estimated creatinine clearance (ml/min)1.27±0.69-1.65±1.03*P<0.05 by analysis of covariance or by Fisher exact test.-1.34±1.28b.i.d., twice a day; BUN, blood urea nitrogen; t.i.d., three times a day.* P 1.5 mg/dl on treatment versus the overall cohort (relative risk, 2.0; P<0.05). When expressed as a percentage of the patients with normal serum creatinine/prerenal azotemia at baseline, the withdrawal rate in patients treated with celecoxib (1.5%) was significantly lower compared with those receiving diclofenac (3.7%; P<0.05) and ibuprofen (4.2%; P<0.05). Changes in mean serum levels of sodium, potassium, chloride, and bicarbonate were minimal between treatment groups and were not of clinical significance (data not shown). The incidence of serious cardiorenal-related adverse events during treatment with celecoxib, ibuprofen, or diclofenac was low. The study investigators reported one case of uremia in an ibuprofen-treated patient. Two cases of hyponatremia were reported in patients treated with celecoxib and one case was reported in a patient taking ibuprofen. No cases of serious adverse events related to nephrotic syndrome, interstitial nephritis, or papillary necrosis were observed. The large cardiorenal database from the CLASS trial has provided the opportunity to observe and compare the natural history of the onset and clinical management of cardiorenal-related adverse events that evolve when exposing a typical adult arthritic population to chronic treatment with a nonselective NSAID or supratherapeutic doses of the COXIB, celecoxib. Thus, the study provides a new and important clinical resource of therapeutic cardiorenal safety information. The data have permitted the description of a clinical paradigm wherein certain key patient characteristics may provide additional predictive clinical information with respect to future drug-specific susceptibility to impairment of cardiorenal function. The present analysis supports the hypothesis that RA and OA patients receiving celecoxib 400 mg b.i.d. (two- to fourfold greater than the maximum effective doses for RA and OA) have an overall reduced risk of cardiorenal-related adverse events compared with standard therapeutic doses of the nonselective NSAIDs, diclofenac 75 mg b.i.d. and ibuprofen 800 mg three times a day. In particular, celecoxib treatment was superior to the nonselective NSAIDs with respect to renal function in patients with prerenal compromise. Some important differences were observed in the cardiorenal safety profiles of celecoxib versus nonselective NSAIDs and between the respective nonselective NSAIDs. Compared with celecoxib, the incidence of adverse events related to hypertension and edema were significantly higher with ibuprofen (but not diclofenac), and decline in renal function was more apparent with diclofenac than with ibuprofen. These data provide a greater understanding of the relative effects of these agents on cardiorenal function and homeostasis. The increased incidence of hypertension in patients taking ibuprofen versus celecoxib appeared to be largely a function of effects on systolic, rather than diastolic, BP. Both diclofenac and ibuprofen were associated with significantly higher incidences of clinically meaningful elevations in systolic BP versus celecoxib. The importance of systolic BP has been highlighted in the Systolic Hypertension in Elderly Program trial,23.Kostis J.B. Davis B.R. Cutler J. et al.Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. SHEP Cooperative Research Group.JAMA. 1997; 278: 212-216C
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