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Does the Pro-Hypertensive Effect of Cyclooxygenase-2 Inhibitors Account for the Increased Risk in Cardiovascular Disease?

2005; Elsevier BV; Volume: 96; Issue: 6 Linguagem: Inglês

10.1016/j.amjcard.2005.05.038

1879-1913

Dongze Li, Tina Sichrovsky,

Antiplatelet Therapy and Cardiovascular Diseases

Ever since its beginning >4 years ago, 1Mukherjee D. Nissen S.E. Topol E.J. Risk of cardiovascular events associated with selective COX-2 inhibitors.JAMA. 2001; 286: 954-959Crossref PubMed Scopus (1704) Google Scholar the cyclooxygenase-2 (COX-2) inhibitor controversy has created considerably more heat than light. Not only have the news media hyped the controversy and thereby scared patients and frustrated practicing physicians, but even reputable medical journals have used phraseology that seems much more suitable for the tabloid press than contemporary science. This is unfortunate, because as Sir George Pickering 2Pickering G. The Nature of Essential Hypertension. J. & A. Churchill, London1961Google Scholar stated, controversy is the lifeblood of science and should be welcomed. Very often, it is only through controversy that science advances. Regrettably however, the COX-2 inhibitor controversy has become first and foremost the lifeblood for litigating trial lawyers. The recent thorough article of Sowers et al 3Sowers J.R. White W.B. Pitt B. Whelton A. Simon L.S. Winer N. Kivitz A. van Ingen H. Brabant T. Fort J.G. 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: 161-168Crossref PubMed Scopus (235) Google Scholar elucidates some pathophysiologic aspects of this issue. The investigators conducted a prospective, randomized trial evaluating, with ambulatory blood pressure (BP) monitoring, the effects of celecoxib, rofecoxib, and naproxen in approximately 400 patients with type 2 diabetes mellitus, hypertension, and osteoarthritis and showed that at equally effective doses for osteoarthritis symptoms, patients treated with rofecoxib, but not with celecoxib or naproxen, exhibited significant increases in 24-hour systolic BP of 3 to 4 mm Hg. The destabilization of hypertension control occurred, to some extent, in all 3 treatment groups but significantly more often in patients who were receiving rofecoxib. The recent meta-analysis of Aw et al 4Aw T.J. Haas S.J. Liew D. Krum H. Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure.Arch Intern Med. 2005; 14 (165): 490-496Google Scholar corroborates and amplifies these findings. Clearly, the differences in BP between the 2 COX-2 inhibitors, which support previous findings, 5Whelton A. White W.B. Bello A.E. Puma J.A. Fort J.G. SUCCESS-VII InvestigatorsEffects 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: 959-963Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar seem small, and many clinicians will consider them of questionable clinical significance. However, the 1 million–patient meta-analysis of the BP trialists allows one to calculate that a mere 2 mm Hg decrease in the usual systolic BP would involve an approximately 10% lower stroke mortality rate and an approximately 7% lower mortality rate from ischemic heart disease. 6Lewington S. Clarke R. Qizilbash N. Peto R. Collins R. Prospective Studies CollaborationAge-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: 1903-1913Abstract Full Text Full Text PDF PubMed Scopus (8020) Google Scholar The BP difference in the study of Sowers et al 3Sowers J.R. White W.B. Pitt B. Whelton A. Simon L.S. Winer N. Kivitz A. van Ingen H. Brabant T. Fort J.G. 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: 161-168Crossref PubMed Scopus (235) Google Scholar between celecoxib and rofecoxib was about twice as much, and it is important that the study is unique in that it was performed in patients with type 2 diabetes. In hypertensive diabetic patients, the risks for heart attack and stroke have been shown to be much more dependent on BP than in nondiabetic patients. The Systolic Hypertension in Europe study 7Tuomilheto J. Rastenyte D. Birkenhäger W.H. Thijs L. Antikainen R. Bulpitt C.R. Fletcher A.E. Forette F. Goldhaber A. Palatini P. et al.Effects of a calcium-channel blockade in older patients with diabetes and systolic hypertension.N Engl J Med. 1999; 340: 677-684Crossref PubMed Scopus (863) Google Scholar allows one to estimate that for a similar decrease in systolic BP, the risk for stroke and cardiovascular end points decreases approximately 2 to 3 times, and total mortality decreases approximately 4 times more in diabetic than in nondiabetic patients. One also should consider that in the United States >7 million patients with osteoarthritis have treated hypertension, and an additional 3.8 million have untreated hypertension. Maintaining or achieving BP control in these patients would avoid >70,000 deaths from stroke and 60,000 deaths from coronary heart disease, resulting in 449,000 patient-years of life saved and 3.8 billion dollars in direct health care cost savings. 8Grover S.A. Coupal L. Zowall H. Treating osteoarthritis with cyclooxygenase-2–specific inhibitors what are the benefits of avoiding blood pressure destabilization?.Hypertension. 2005; 45: 92-97Crossref PubMed Scopus (38) Google Scholar According to the not completely unbiased viewpoint of United States Food and Drug Administration official Dr. David Graham and colleagues, rofecoxib, in the >5 years during which it was on the market, may have been responsible for 88,000 to 140,000 excess cases of coronary heart disease in the United States alone, and an estimated 44% of these cases may have been fatal. 9Graham D.J. Campen D. Hui R. Spence M. Cheetham C. Levy G. Shoor S. Ray W.A. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs nested case-control study.Lancet. 2005; 365: 475-481Abstract Full Text Full Text PDF PubMed Scopus (736) Google Scholar Less well known is that patients receiving rofecoxib in the Adenomatous Polyp Prevention on VIOXX trial had excess rates not only of myocardial infarctions but also of strokes. 10Bresalier R.S. Sandler R.S. Quan H. Bolognese J.A. Oxenius B. Horgan K. Lines C. Riddell R. Morton D. Lanas A. et al.Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial InvestigatorsCardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial.N Engl J Med. 2005; 352: 1092-1102Crossref PubMed Scopus (2333) Google Scholar Cerebrovascular events are much more dependent on BP than are coronary events. Also, in the same study, aspirin unexpectedly did not prevent the occurrence of cardiovascular events. These findings indicate that the well-documented excess of cerebrovascular and cardiovascular events seen with certain COX-2 inhibitors, especially rofecoxib, may to a large extent be related to the effects of these drugs on BP. This could be considered a silver lining in this cloudy story, because BP can be monitored and antihypertensive therapy can be initiated or intensified if needed in patients at risk. However, one cannot exclude that this prohypertensive effect is additive or synergistic to other BP-independent detrimental effects. A metabolite of rofecoxib, for example, may inhibit the metabolism of aldosterone, which could lead to fluid retention and vascular remodeling. 11Liew D. Krum H. The role of aldosterone receptor blockade in the management of cardiovascular disease.Curr Opin Investig Drugs. 2002; 3: 1468-1473PubMed Google Scholar Furthermore, COX-2 inhibitors may have different effects on endothelial function and lipid peroxidation, 12Widlansky M.E. Price D.T. Gokce N. Eberhardt R.T. Duffy S.J. Holbrook M. Maxwell C. Palmisano J. Keaney Jr, J.F. Morrow J.D. et al.Short- and long-term COX-2 inhibition reverses endothelial dysfunction in patients with hypertension.Hypertension. 2003; 42: 310-315Crossref PubMed Scopus (145) Google Scholar, 13Chenevard R. Hurlimann D. Bechir M. Enseleit F. Spieker L. Hermann M. Riesen W. Gay S. Gay R.E. Neidhart M. et al.Selective COX-2 inhibition improves endothelial function in coronary artery disease.Circulation. 2003; 107: 405-409Crossref PubMed Scopus (369) Google Scholar and some deleterious effects seem to be dose related, as shown in the Adenoma Prevention With Celecoxib trial. 14Solomon S.D. McMurray J.J. Pfeffer M.A. Wittes J. Fowler R. Finn P. Anderson W.F. Zauber A. Hawk E. Bertagnolli M. Adenoma Prevention With Celecoxib (APC) Study InvestigatorsCardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention.N Engl J Med. 2005; 352: 1071-1080Crossref PubMed Scopus (1925) Google Scholar BP-independent effects not withstanding, clearly, all patients who begin receiving COX-2 inhibitors or nonselective nonsteroidal anti-inflammatory drugs need to have their BP monitored thoroughly and frequently. We should bear in mind that with regard to their prehypertensive effects, not all of these drugs seem to be created equal.