Can Natriuretic Peptide Levels Predict the Cardiovascular Complications of COX-2 Inhibitors and Nonsteroidal Anti-inflammatory Drugs?
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《家庭医学美国版》
From the Department of Family Medicine, Case Western Reserve University School of Medicine, Berea, OH
There is evidence that fluid retention, whether due to a disease process or due to a medication, is associated with a number of cardiovascular diseases, including heart failure, strokes, coronary artery disease, and cardiovascular death. There is additional evidence that fluid retention that manifests as increased intravascular volume adversely affects cardiovascular outcomes. Because natriuretic peptide levels reflect intravascular volume and pressure, it is hypothesized that when patients are prescribed medications that promote fluid retention—such as non-selective nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors—monitoring natriuretic peptide levels before and after initiating the medication may allow these medications to be used more safely.
Several diseases that are associated with fluid retention are also associated with cardiovascular diseases. Likewise, some medications that promote fluid retention are associated with, and in some instances contribute to, cardiovascular morbidity and mortality. Because natriuretic peptide levels reflect intravascular volume, and because elevated natriuretic peptide levels are a risk factor for a number of adverse cardiovascular outcomes, there is a scientifically based rationale for the hypothesis of this paper that monitoring natriuretic peptide levels before and after starting medications that cause fluid retention—such as non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors—might allow these medications to be used more safely.
Data involving natriuretic peptides provides the primary evidence that fluid retention in the form of increased intravascular volume is a cardiovascular risk factor. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are secreted by the myocytes of the atria and ventricles in response to stretch and pressure. Serum levels of ANP and BNP reflect intravascular volume or pressure, with higher levels of ANP and BNP indicating increased intravascular volume or pressure.
While abnormally elevated levels of natriuretic peptides imply a diagnosis of heart failure, even when natriuretic peptide levels fall within the normal range, higher than average levels of BNP and ANP predict a number of adverse cardiovascular events: death from any cause, first major cardiovascular event, heart failure, atrial fibrillation, and stroke or transient ischemic attack, but not coronary heart disease.1
Heart Failure
Heart failure is characterized by fluid retention. Patients with heart failure are more likely to die suddenly compared with persons with normal left ventricular ejection fractions,2,3 and the lower the left ventricular ejection fraction, the higher the mortality rate.4 In addition, heart failure increases the risk for the development of a stroke,2,3,5–8 with the risk increasing as the left ventricular ejection fraction decreases.9,10
Sleep-disordered Breathing
Obstructive sleep apnea (OSA) is associated with, and can cause, fluid retention.11,12 OSA is associated with increased levels of ANP, primarily during the hours of sleep.13–19 Following appropriate treatment of OSA with nasal continuous positive airway pressure, ANP levels decrease.16–19
Prospective studies indicate that OSA is a risk factor for hypertension, heart failure, strokes, fatal cardiovascular disease, and coronary artery disease, whereas treating the OSA reduces the risk of developing these cardiovascular diseases.20–24
Diabetes Mellitus II and the Metabolic Syndrome
Insulin resistance with concomitant hyperinsulinemia is a hallmark of type 2 diabetes mellitus and the metabolic syndrome.25 One of the properties of insulin is fluid and sodium retention.26,27 Fluid retention may help explain why diabetes mellitus II is associated with increased levels of ANP.28
Heart failure, OSA, and type 2 diabetes mellitus are all associated with endothelial dysfunction.28–33 Stimulation of the sympathetic nervous system, activation of the renin-angiotensin system, effects on endothelial nitric oxide, and, in the case of type 2 diabetes mellitus, atherogenic properties of insulin itself, have been invoked as possible explanations as to why these disease states are associated with endothelial dysfunction.28–34
Antihypertensive Medications
Antihypertensive medications that are associated with fluid reduction (diuretics and angiotensin-converting enzyme inhibitors [ACEIs]) are associated with better cardiovascular outcomes than antihypertensive medications that promote fluid retention (calcium channel blockers [CCBs] and -adrenergic receptor blockers [-blockers]).35 Thiazide diuretics are more effective than ACEIs, CCBs, and -blockers at preventing heart failure, and thiazide diuretics are more effective than ACEs and -blockers at preventing strokes.36–40 When compared with ?-adrenergic receptor blockers and ACEIs, CCBs are less effective at reducing myocardial infarctions and heart failure.36,37
Non-selective NSAIDs
Non-selective NSAIDs cause fluid retention, raise blood pressure,41,42 are associated with the development of heart failure,43–45 and are associated with an increased likelihood of having an ischemic stroke.46 A number of studies have failed to identify a relationship between non-selective NSAIDs and myocardial infarctions.47–55
Rofecoxib
The COX-2 inhibitor rofecoxib (Vioxx) causes more fluid retention than either non-selective NSAIDs or celecoxib (Celebrex).56,57 In the prospective Vioxx Gastrointestinal Outcomes Research (VIGOR) study, rofecoxib was associated with a higher frequency of myocardial infarctions than naproxen,58 and a different prospective study found that subjects treated with rofecoxib had more than twice the incidence of cardiovascular death, myocardial infarctions, unstable angina, and cerebrovascular disease as subjects in the placebo group.59 A meta-analysis combining 18 prospective and 11 retrospective studies found that rofecoxib increases the risk of myocardial infarctions compared with placebo, naproxen, or non-naproxen NSAIDs.60
Celecoxib
One prospective study showed that, compared with placebo, celecoxib increased the risk of myocardial infarction, stroke, heart failure, or death from cardiovascular causes.61 However, a pooled analysis of prospective studies found that, compared with placebo and compared with non-selective NSAIDs, celecoxib is not associated with an increased incidence of cardiovascular events (myocardial infarctions, strokes, and cardiovascular death).62
Valdecoxib
A pooled analysis found that valdecoxib (Bextra) does not increase the risk of cardiovascular thrombotic events (cardiac, cerebrovascular and peripheral vascular, or arterial thrombotic events) compared with non-selective NSAIDs and compared with placebo.63 However, coronary bypass graft surgery subjects treated with intravenous parecoxib (an intravenous prodrug of valdecoxib) followed by oral valdecoxib had increased cardiovascular and thromboembolic events (cardiovascular death, myocardial infarctions, strokes, deep venous thrombosis, and pulmonary emboli) compared with subjects treated with placebo.64
Although it has been argued that the adverse cardiovascular events resulting from selective COX-2 inhibitors are due to their mechanism of action,65–67 it is equally plausible that fluid retention is to blame. If it were possible to predict which patients are at increased risk for adverse cardiovascular events following the use of NSAIDs or selective COX-2 inhibitors, prescribing these medications would become safer. One might expect that measuring markers of endothelial dysfunction before and after initiating the medication might help to identify those patients at increased risk. However, because rofecoxib can lower levels of C-reactive protein and interleukin-6,68 this approach is fallible.
A more promising strategy might be to measure natriuretic peptide levels in patients before and after they start using selective COX-2 inhibitors and non-selective NSAIDs. One would anticipate that persons who experience an increase in natriuretic peptide levels would be the ones most at risk for adverse cardiovascular outcomes. If a rise in natriuretic peptide levels does predict an increased risk for cardiovascular disease, patient safety could be improved by monitoring natriuretic peptide levels before and after starting non-selective NSAIDs and selective COX-2 inhibitors. Physicians could then discontinue the medication for those persons who experience an increase in the level of natriuretic peptide.
There is evidence linking fluid retention with coronary heart disease, heart failure, strokes, and cardiovascular death, but a causal relationship between fluid retention and these cardiovascular diseases has not been established. It is hypothesized that because increased intravascular fluid volume may heighten the risk of adverse cardiovascular events, then monitoring natriuretic peptides before and after patients use medications that cause fluid retention—such as COX-2 inhibitors or non-selective NSAIDs—may allow these medications to be used more safely.
Conflict of interest: none declared.
Received for publication April 13, 2005. Revision received June 5, 2005. Accepted for publication June 8, 2005.
References
Wang TJ, Larson MG, Levy D, et al. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med 2004; 350: 718–20.
Gottdiener JS, McClelland RL, Marshall R, et al. Outcome of congestive heart failure in elderly persons: influence of left ventricular systolic function. Ann Intern Med 2002; 137: 631–9.
Kaplan RC, Heckbert SR, Furberg CD, Psaty BM. Predictors of subsequent coronary events, stroke, and death among survivors of first hospitalized myocardial infarction. J Clin Epidemiol 2002; 55: 654–64.
Gradman A, Deedwania P, Cody R, et al. Predictors of total mortality and sudden death in mild to moderate heart failure. J Am Coll Cardiol 1989; 14: 564–70.
Kannel WB, Wolf PA, Verter J. Manifestations of coronary disease predisposing to stroke. The Framingham Study. JAMA 1983; 250: 2942–6.
Davis PH, Dambrosia JM, Schoenberg BS, et al. Risk factors for ischemic stroke: a prospective study in Rochester, Minnesota. Ann Neurol 1987; 22: 319–27.
Sharma JC, Fletcher S, Vassallo M, Ross I. Cardiovascular disease and outcome of acute stroke: influence of pre-existing cardiac failure. Eur J Heart Fail 2000; 2: 145–50.
Dries DL, Rosenberg YD, Waclawiw MA, Domanski MJ. Ejection fraction and risk of thromboembolic events in patients with systolic dysfunction and sinus rhythm: evidence for gender differences in the studies of left ventricular dysfunction trials. J Am Coll Cardiol 1997; 29: 1074–8.
Loh E, Sutton MS, Wun CC, et al. Ventricular dysfunction and the risk of stroke after myocardial infarction. N Engl J Med 1997; 336: 251–7.
Pullicino PM, Halperin JL, Thompson JL. Stroke in patients with heart failure and reduced left ventricular ejection fraction. Neurology 2000; 54: 288–94.
Blankfield RP, Ahmed M, Zyzanski SJ. Idiopathic edema is associated with obstructive sleep apnea in women. Sleep Med 2004; 5: 583–7.
Blankfield RP, Ahmed M, Zyzanski SJ. Effect of nasal continuous positive airway pressure on edema in patients with obstructive sleep apnea. Sleep Med 2004; 5: 589–92.
Schafer H, Ehlenz K, Ewig S, et al. Atrial natriuretic peptide levels and pulmonary artery pressure awake, at exercise and asleep in obstructive sleep apnoea syndrome. J Sleep Res 1999; 8: 205–10.
Baruzzi A, Riva R, Cirignotta F, Zucconi M, Cappelli M, Lugaresi E. Atrial natriuretic peptide and catecholamines in obstructive sleep apnea syndrome. Sleep 1991; 14: 83–6.
Krieger J, Laks L, Wilcox I, et al. Atrial natriuretic peptide release during sleep in patients with obstructive sleep apnoea before and after treatment with nasal continuous positive airway pressure. Clin Sci 1989; 77: 407–11.
Krieger J, Follenius M, Sforza E, Brandenberger G, Peter JD. Effects of treatment with nasal continuous positive airway pressure on atrial natriuretic peptide and arginine vasopressin release during sleep in patients with obstructive sleep apnea. Clin Sci 1991; 80: 443–9.
Lin CC, Tsan KW, Lin CY. Plasma levels of atrial natriuretic factor in moderate to severe obstructive sleep apnea. Sleep 1993; 16: 37–9.
Kita H, Ohi M, Chin K, et al. The nocturnal secretion of cardiac natriuretic peptides during obstructive sleep apnoea and its response to therapy with nasal continuous positive airway pressure. J Sleep Res 1998; 7: 199–207.
Svatikova A, Shamsuzzaman AS, Wolk R, Phillips BG, Olson LJ, Somers VK. Plasma brain natriuretic peptide in obstructive sleep apnea. Am J Cardiol 2004; 19: 529–32.
Peppard PE, Young TB, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000; 342: 1378–84.
Pepperell JC, Ramdassingh-Dow S, Crosthwaire N, et al. Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnea: a randomized parallel trial. Lancet 2001; 359: 204–10.
Shahar E, Whitney CW, Redline S, et al. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the sleep heart health study. Am J Resp Crit Care Med 2001; 163: 19–25.
Becker HF, Jerrentrup A, Ploch T, et al. Effect of nasal continuous positive airway pressure treatment on blood pressure in patients with obstructive sleep apnea. Circulation 2003; 107: 68–73.
Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005; 365: 1046–53.
Deen D. Metabolic syndrome. Am Fam Physician 2004; 69: 2867–82.
Hamilton BP. Diabetes and hypertension. Am J Kidney Dis 1990; 16: 20–9.
Nannipieri M, Seghieri G, Catalano C, Prontera T, Baldi S, Ferranninni E. Defective regulation and action of atrial natriuretic peptide in type 2 diabetes. Horm Metab Res 2002; 34: 265–70.
Semplicini A, Ceolotto G, Massimino M. Interactions between insulin and sodium homeostasis in essential hypertension. Am J Med Sci 1994; 307: S43–6.
Nieto FJ, Herrington DM, Redline S, Benjamin E, Robbins JA. Sleep apnea and markers of vascular endothelial function in a large community sample of older adults. Am J Resp Crit Care Med 2004; 169: 354–60.
Sj?holm ?, Nystr?m T. Endothelial inflammation in insulin resistance. Lancet 2005; 365: 610–2.
Katz SD, Biasucci L, Sabba C. et al. Impaired endothelial-mediated vasodilation in the peripheral vasculature of patients with congestive heart failure. J Am Coll Cardiol 1992; 19: 918–25.
Treasure CB, Vita JA, Cox DA, et al. Endothelium-dependent dilation of the coronary microvasculature is impaired in dilated cardiomyopathy. Circulation 1990; 81: 772–9.
Chong AY, Blann AD, Patel J, Freestone B, Hughes E, Lip GY. Endothelial dysfunction and damage in congestive heart failure: relation of flow-mediated dilation to circulating endothelial cells, plasma indexes of endothelial damage, and brain natriuretic peptide. Circulation 2004; 110: 1794–8.
Warnholtz A, Tsilimingas N, Wendt M, Münzel T. Mechanisms underlying nitrate-induced endothelial dysfunction: insight from experimental and clinical studies. Heart Fail Review 2002; 7: 335–45.
Blankfield RP. Fluid matters in choosing antihypertensive therapy: a hypothesis that the data speak volumes. J Am Board Fam Pract 2005; 18: 113–24.
Pahor M, Psaty BM, Alderman MH, et al. Health outcomes associated with calcium antagonists compared with other first-line antihypertensive therapies: a meta-analysis of randomized controlled trials. Lancet 2000; 356: 1949–54.
Blood Pressure Lowering Trialists Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood pressure-lowering drugs: results of prospectively designed overviews of randomized trials. Lancet 2000; 356: 1955–64.
The ALLHAT Officers and Coordinators for the 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: 1967–75.
The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288: 2981–97.
Psaty BM, Lumley T, Furberg CD, et al. Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA 2003; 289: 2534–44.
Frishman WH. Effects of nonsteroidal anti-inflammatory drug therapy on blood pressure and peripheral edema. Am J Cardiol 2002; 89: 18D–25D.
Johnson AG, Nguyen TV, Day RO. Do nonsteroidal anti-inflammatory drugs affect blood pressure? a meta-analysis. Ann Intern Med 1994; 121: 289–300.
Mamdani M, Juurlink DN, Lee DS et al. Cyclo-oxygenase-2 inhibitors versus non-selective anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study. Lancet 2004; 363: 1751–6.
Page J, Henry D. Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an unrecognized public health problem. Arch Intern Med 2000; 160: 777–84.
Garcia Rodriguez LA, Hernandez-Diaz S. Nonsteroidal antiinflammatory drugs as a trigger of clinical heart failure. Epidemiology 2003; 14: 240–6.
Bak S, Andersen M, Tsiropoulos I, et al. Risk of stroke associated with nonsteroidal anti-inflammatory drugs: a nested case-control study. Stroke 2003; 34: 379–86.
Rahme E, Pilote L, LeLorier J. Association between naproxen use and protection against myocardial infarction. Arch Intern Med 2002; 27: 1111–5.
Watson DJ, Rhodes T, Bing C, Guess HA. Lower risk of thromboembolic cardiovascular events with naproxen among patient with rheumatoid arthritis. Arch Intern Med 2002; 162: 1105–10.
Solomon DH, Glynn RJ, Levin R, Avorn J. Nonsteroidal anti-inflammatory drug use and acute myocardial infarction. Arch Intern Med 2002; 162: 1099–104.
Schlienger RG, Jick H, Meier CR. Use of nonsteroidal anti-inflammatory drugs and the risk of first-time acute myocardial infarction. Br J Clin Pharmacol 2002; 54: 327–32.
Ray WA, Stein CM, Hall K, Daugherty JR, Griffin MR. Non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease: an observational cohort study. Lancet 2002; 359: 118–23.
Garcia Rodriguez LA, Varas-Lorenzo C, Maguire A, Gonzalez-Perez A. Nonsteroidal anti-inflammatory drugs and the risk of myocardial infarction in the general population. Circulation 2004; 109: 3000–6.
Reicin AS, Shapiro D, Sperling RS, Barr E, Yu Q. Comparison of cardiovascular thrombotic events in patients with osteoarthritis treated with refecoxib versus nonselective nonsteroidal anti-inflammatory drugs (ibuprofen, diclofenac, and nabumetone). Am J Cardiol 2002; 89: 204–9.
Garcia Rodriguez LA, Varas C, Patrono C. Differential effects of aspirin and non-aspirin nonsteroidal antiinflammatory drugs in the primary prevention of myocardial infarction in postmenopausal women. Epidemiology 2000; 11: 382–7.
Mamdani M, Rochon P, Juurlink DN, et al. Effect of selective cyclooxygenase 2 inhibitors and naproxen on short-term risk of acute myocardial infarction in the elderly. Arch Intern Med 2003; 163: 481–6.
Wolfe R, Zhao S, Pettitt D. Blood pressure destabilization and edema among 8538 users of celecoxib, rofecoxib, and nonselective nonsteroidal anti-inflammatory drugs (NSAID) and nonusers of NSAID receiving ordinary clinical care. J Rheumatol 2004; 31: 1143–51.
Whelton A, White WB, Bello AE, Puma JA, Fort JG, the SUCCESS-VII Investigators. Effects of celecoxib and rofecoxib on blood pressure and edema in patients > or = 65 years of age with systemic hypertension and osteoarthritis. Am J Cardiol 2002; 90: 959–63.
Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000; 343: 1520–8.
Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005; 352: 1092–102.
Juni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet 2004; 364: 2021–9.
Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005; 352: 1071–80.
White WB, Faich G, Borer JS, Makuch RW. Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib. Am J Cardiol 2003; 92: 411–8.
White WB, Strand V, Roberts R, Whelton A. Effects of cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis. Am J Ther 2004; 11: 244–50.
Nussmeier NA, Whelton AA, Brown MT, et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005; 352: 1081–91.
Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001; 286: 954–9.
FitzGerald GA. Coxibs and cardiovascular disease. N Engl J Med 2004; 351: 1709–11.
Topol EJ. Arthritis medicines and cardiovascular events—"House of coxibs." JAMA 2005; 293: 366–8.
Monakier D, Mates M, Klutstein MW, et al. Rofecoxib, a COX-2 inhibitor, lowers C-reactive protein and interleukin-6 levels in patients with acute coronary syndromes. Chest 2004; 125: 1610–5.(Robert P. Blankfield, MD,)
There is evidence that fluid retention, whether due to a disease process or due to a medication, is associated with a number of cardiovascular diseases, including heart failure, strokes, coronary artery disease, and cardiovascular death. There is additional evidence that fluid retention that manifests as increased intravascular volume adversely affects cardiovascular outcomes. Because natriuretic peptide levels reflect intravascular volume and pressure, it is hypothesized that when patients are prescribed medications that promote fluid retention—such as non-selective nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors—monitoring natriuretic peptide levels before and after initiating the medication may allow these medications to be used more safely.
Several diseases that are associated with fluid retention are also associated with cardiovascular diseases. Likewise, some medications that promote fluid retention are associated with, and in some instances contribute to, cardiovascular morbidity and mortality. Because natriuretic peptide levels reflect intravascular volume, and because elevated natriuretic peptide levels are a risk factor for a number of adverse cardiovascular outcomes, there is a scientifically based rationale for the hypothesis of this paper that monitoring natriuretic peptide levels before and after starting medications that cause fluid retention—such as non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors—might allow these medications to be used more safely.
Data involving natriuretic peptides provides the primary evidence that fluid retention in the form of increased intravascular volume is a cardiovascular risk factor. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are secreted by the myocytes of the atria and ventricles in response to stretch and pressure. Serum levels of ANP and BNP reflect intravascular volume or pressure, with higher levels of ANP and BNP indicating increased intravascular volume or pressure.
While abnormally elevated levels of natriuretic peptides imply a diagnosis of heart failure, even when natriuretic peptide levels fall within the normal range, higher than average levels of BNP and ANP predict a number of adverse cardiovascular events: death from any cause, first major cardiovascular event, heart failure, atrial fibrillation, and stroke or transient ischemic attack, but not coronary heart disease.1
Heart Failure
Heart failure is characterized by fluid retention. Patients with heart failure are more likely to die suddenly compared with persons with normal left ventricular ejection fractions,2,3 and the lower the left ventricular ejection fraction, the higher the mortality rate.4 In addition, heart failure increases the risk for the development of a stroke,2,3,5–8 with the risk increasing as the left ventricular ejection fraction decreases.9,10
Sleep-disordered Breathing
Obstructive sleep apnea (OSA) is associated with, and can cause, fluid retention.11,12 OSA is associated with increased levels of ANP, primarily during the hours of sleep.13–19 Following appropriate treatment of OSA with nasal continuous positive airway pressure, ANP levels decrease.16–19
Prospective studies indicate that OSA is a risk factor for hypertension, heart failure, strokes, fatal cardiovascular disease, and coronary artery disease, whereas treating the OSA reduces the risk of developing these cardiovascular diseases.20–24
Diabetes Mellitus II and the Metabolic Syndrome
Insulin resistance with concomitant hyperinsulinemia is a hallmark of type 2 diabetes mellitus and the metabolic syndrome.25 One of the properties of insulin is fluid and sodium retention.26,27 Fluid retention may help explain why diabetes mellitus II is associated with increased levels of ANP.28
Heart failure, OSA, and type 2 diabetes mellitus are all associated with endothelial dysfunction.28–33 Stimulation of the sympathetic nervous system, activation of the renin-angiotensin system, effects on endothelial nitric oxide, and, in the case of type 2 diabetes mellitus, atherogenic properties of insulin itself, have been invoked as possible explanations as to why these disease states are associated with endothelial dysfunction.28–34
Antihypertensive Medications
Antihypertensive medications that are associated with fluid reduction (diuretics and angiotensin-converting enzyme inhibitors [ACEIs]) are associated with better cardiovascular outcomes than antihypertensive medications that promote fluid retention (calcium channel blockers [CCBs] and -adrenergic receptor blockers [-blockers]).35 Thiazide diuretics are more effective than ACEIs, CCBs, and -blockers at preventing heart failure, and thiazide diuretics are more effective than ACEs and -blockers at preventing strokes.36–40 When compared with ?-adrenergic receptor blockers and ACEIs, CCBs are less effective at reducing myocardial infarctions and heart failure.36,37
Non-selective NSAIDs
Non-selective NSAIDs cause fluid retention, raise blood pressure,41,42 are associated with the development of heart failure,43–45 and are associated with an increased likelihood of having an ischemic stroke.46 A number of studies have failed to identify a relationship between non-selective NSAIDs and myocardial infarctions.47–55
Rofecoxib
The COX-2 inhibitor rofecoxib (Vioxx) causes more fluid retention than either non-selective NSAIDs or celecoxib (Celebrex).56,57 In the prospective Vioxx Gastrointestinal Outcomes Research (VIGOR) study, rofecoxib was associated with a higher frequency of myocardial infarctions than naproxen,58 and a different prospective study found that subjects treated with rofecoxib had more than twice the incidence of cardiovascular death, myocardial infarctions, unstable angina, and cerebrovascular disease as subjects in the placebo group.59 A meta-analysis combining 18 prospective and 11 retrospective studies found that rofecoxib increases the risk of myocardial infarctions compared with placebo, naproxen, or non-naproxen NSAIDs.60
Celecoxib
One prospective study showed that, compared with placebo, celecoxib increased the risk of myocardial infarction, stroke, heart failure, or death from cardiovascular causes.61 However, a pooled analysis of prospective studies found that, compared with placebo and compared with non-selective NSAIDs, celecoxib is not associated with an increased incidence of cardiovascular events (myocardial infarctions, strokes, and cardiovascular death).62
Valdecoxib
A pooled analysis found that valdecoxib (Bextra) does not increase the risk of cardiovascular thrombotic events (cardiac, cerebrovascular and peripheral vascular, or arterial thrombotic events) compared with non-selective NSAIDs and compared with placebo.63 However, coronary bypass graft surgery subjects treated with intravenous parecoxib (an intravenous prodrug of valdecoxib) followed by oral valdecoxib had increased cardiovascular and thromboembolic events (cardiovascular death, myocardial infarctions, strokes, deep venous thrombosis, and pulmonary emboli) compared with subjects treated with placebo.64
Although it has been argued that the adverse cardiovascular events resulting from selective COX-2 inhibitors are due to their mechanism of action,65–67 it is equally plausible that fluid retention is to blame. If it were possible to predict which patients are at increased risk for adverse cardiovascular events following the use of NSAIDs or selective COX-2 inhibitors, prescribing these medications would become safer. One might expect that measuring markers of endothelial dysfunction before and after initiating the medication might help to identify those patients at increased risk. However, because rofecoxib can lower levels of C-reactive protein and interleukin-6,68 this approach is fallible.
A more promising strategy might be to measure natriuretic peptide levels in patients before and after they start using selective COX-2 inhibitors and non-selective NSAIDs. One would anticipate that persons who experience an increase in natriuretic peptide levels would be the ones most at risk for adverse cardiovascular outcomes. If a rise in natriuretic peptide levels does predict an increased risk for cardiovascular disease, patient safety could be improved by monitoring natriuretic peptide levels before and after starting non-selective NSAIDs and selective COX-2 inhibitors. Physicians could then discontinue the medication for those persons who experience an increase in the level of natriuretic peptide.
There is evidence linking fluid retention with coronary heart disease, heart failure, strokes, and cardiovascular death, but a causal relationship between fluid retention and these cardiovascular diseases has not been established. It is hypothesized that because increased intravascular fluid volume may heighten the risk of adverse cardiovascular events, then monitoring natriuretic peptides before and after patients use medications that cause fluid retention—such as COX-2 inhibitors or non-selective NSAIDs—may allow these medications to be used more safely.
Conflict of interest: none declared.
Received for publication April 13, 2005. Revision received June 5, 2005. Accepted for publication June 8, 2005.
References
Wang TJ, Larson MG, Levy D, et al. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med 2004; 350: 718–20.
Gottdiener JS, McClelland RL, Marshall R, et al. Outcome of congestive heart failure in elderly persons: influence of left ventricular systolic function. Ann Intern Med 2002; 137: 631–9.
Kaplan RC, Heckbert SR, Furberg CD, Psaty BM. Predictors of subsequent coronary events, stroke, and death among survivors of first hospitalized myocardial infarction. J Clin Epidemiol 2002; 55: 654–64.
Gradman A, Deedwania P, Cody R, et al. Predictors of total mortality and sudden death in mild to moderate heart failure. J Am Coll Cardiol 1989; 14: 564–70.
Kannel WB, Wolf PA, Verter J. Manifestations of coronary disease predisposing to stroke. The Framingham Study. JAMA 1983; 250: 2942–6.
Davis PH, Dambrosia JM, Schoenberg BS, et al. Risk factors for ischemic stroke: a prospective study in Rochester, Minnesota. Ann Neurol 1987; 22: 319–27.
Sharma JC, Fletcher S, Vassallo M, Ross I. Cardiovascular disease and outcome of acute stroke: influence of pre-existing cardiac failure. Eur J Heart Fail 2000; 2: 145–50.
Dries DL, Rosenberg YD, Waclawiw MA, Domanski MJ. Ejection fraction and risk of thromboembolic events in patients with systolic dysfunction and sinus rhythm: evidence for gender differences in the studies of left ventricular dysfunction trials. J Am Coll Cardiol 1997; 29: 1074–8.
Loh E, Sutton MS, Wun CC, et al. Ventricular dysfunction and the risk of stroke after myocardial infarction. N Engl J Med 1997; 336: 251–7.
Pullicino PM, Halperin JL, Thompson JL. Stroke in patients with heart failure and reduced left ventricular ejection fraction. Neurology 2000; 54: 288–94.
Blankfield RP, Ahmed M, Zyzanski SJ. Idiopathic edema is associated with obstructive sleep apnea in women. Sleep Med 2004; 5: 583–7.
Blankfield RP, Ahmed M, Zyzanski SJ. Effect of nasal continuous positive airway pressure on edema in patients with obstructive sleep apnea. Sleep Med 2004; 5: 589–92.
Schafer H, Ehlenz K, Ewig S, et al. Atrial natriuretic peptide levels and pulmonary artery pressure awake, at exercise and asleep in obstructive sleep apnoea syndrome. J Sleep Res 1999; 8: 205–10.
Baruzzi A, Riva R, Cirignotta F, Zucconi M, Cappelli M, Lugaresi E. Atrial natriuretic peptide and catecholamines in obstructive sleep apnea syndrome. Sleep 1991; 14: 83–6.
Krieger J, Laks L, Wilcox I, et al. Atrial natriuretic peptide release during sleep in patients with obstructive sleep apnoea before and after treatment with nasal continuous positive airway pressure. Clin Sci 1989; 77: 407–11.
Krieger J, Follenius M, Sforza E, Brandenberger G, Peter JD. Effects of treatment with nasal continuous positive airway pressure on atrial natriuretic peptide and arginine vasopressin release during sleep in patients with obstructive sleep apnea. Clin Sci 1991; 80: 443–9.
Lin CC, Tsan KW, Lin CY. Plasma levels of atrial natriuretic factor in moderate to severe obstructive sleep apnea. Sleep 1993; 16: 37–9.
Kita H, Ohi M, Chin K, et al. The nocturnal secretion of cardiac natriuretic peptides during obstructive sleep apnoea and its response to therapy with nasal continuous positive airway pressure. J Sleep Res 1998; 7: 199–207.
Svatikova A, Shamsuzzaman AS, Wolk R, Phillips BG, Olson LJ, Somers VK. Plasma brain natriuretic peptide in obstructive sleep apnea. Am J Cardiol 2004; 19: 529–32.
Peppard PE, Young TB, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000; 342: 1378–84.
Pepperell JC, Ramdassingh-Dow S, Crosthwaire N, et al. Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnea: a randomized parallel trial. Lancet 2001; 359: 204–10.
Shahar E, Whitney CW, Redline S, et al. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the sleep heart health study. Am J Resp Crit Care Med 2001; 163: 19–25.
Becker HF, Jerrentrup A, Ploch T, et al. Effect of nasal continuous positive airway pressure treatment on blood pressure in patients with obstructive sleep apnea. Circulation 2003; 107: 68–73.
Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005; 365: 1046–53.
Deen D. Metabolic syndrome. Am Fam Physician 2004; 69: 2867–82.
Hamilton BP. Diabetes and hypertension. Am J Kidney Dis 1990; 16: 20–9.
Nannipieri M, Seghieri G, Catalano C, Prontera T, Baldi S, Ferranninni E. Defective regulation and action of atrial natriuretic peptide in type 2 diabetes. Horm Metab Res 2002; 34: 265–70.
Semplicini A, Ceolotto G, Massimino M. Interactions between insulin and sodium homeostasis in essential hypertension. Am J Med Sci 1994; 307: S43–6.
Nieto FJ, Herrington DM, Redline S, Benjamin E, Robbins JA. Sleep apnea and markers of vascular endothelial function in a large community sample of older adults. Am J Resp Crit Care Med 2004; 169: 354–60.
Sj?holm ?, Nystr?m T. Endothelial inflammation in insulin resistance. Lancet 2005; 365: 610–2.
Katz SD, Biasucci L, Sabba C. et al. Impaired endothelial-mediated vasodilation in the peripheral vasculature of patients with congestive heart failure. J Am Coll Cardiol 1992; 19: 918–25.
Treasure CB, Vita JA, Cox DA, et al. Endothelium-dependent dilation of the coronary microvasculature is impaired in dilated cardiomyopathy. Circulation 1990; 81: 772–9.
Chong AY, Blann AD, Patel J, Freestone B, Hughes E, Lip GY. Endothelial dysfunction and damage in congestive heart failure: relation of flow-mediated dilation to circulating endothelial cells, plasma indexes of endothelial damage, and brain natriuretic peptide. Circulation 2004; 110: 1794–8.
Warnholtz A, Tsilimingas N, Wendt M, Münzel T. Mechanisms underlying nitrate-induced endothelial dysfunction: insight from experimental and clinical studies. Heart Fail Review 2002; 7: 335–45.
Blankfield RP. Fluid matters in choosing antihypertensive therapy: a hypothesis that the data speak volumes. J Am Board Fam Pract 2005; 18: 113–24.
Pahor M, Psaty BM, Alderman MH, et al. Health outcomes associated with calcium antagonists compared with other first-line antihypertensive therapies: a meta-analysis of randomized controlled trials. Lancet 2000; 356: 1949–54.
Blood Pressure Lowering Trialists Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood pressure-lowering drugs: results of prospectively designed overviews of randomized trials. Lancet 2000; 356: 1955–64.
The ALLHAT Officers and Coordinators for the 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: 1967–75.
The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288: 2981–97.
Psaty BM, Lumley T, Furberg CD, et al. Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA 2003; 289: 2534–44.
Frishman WH. Effects of nonsteroidal anti-inflammatory drug therapy on blood pressure and peripheral edema. Am J Cardiol 2002; 89: 18D–25D.
Johnson AG, Nguyen TV, Day RO. Do nonsteroidal anti-inflammatory drugs affect blood pressure? a meta-analysis. Ann Intern Med 1994; 121: 289–300.
Mamdani M, Juurlink DN, Lee DS et al. Cyclo-oxygenase-2 inhibitors versus non-selective anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study. Lancet 2004; 363: 1751–6.
Page J, Henry D. Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an unrecognized public health problem. Arch Intern Med 2000; 160: 777–84.
Garcia Rodriguez LA, Hernandez-Diaz S. Nonsteroidal antiinflammatory drugs as a trigger of clinical heart failure. Epidemiology 2003; 14: 240–6.
Bak S, Andersen M, Tsiropoulos I, et al. Risk of stroke associated with nonsteroidal anti-inflammatory drugs: a nested case-control study. Stroke 2003; 34: 379–86.
Rahme E, Pilote L, LeLorier J. Association between naproxen use and protection against myocardial infarction. Arch Intern Med 2002; 27: 1111–5.
Watson DJ, Rhodes T, Bing C, Guess HA. Lower risk of thromboembolic cardiovascular events with naproxen among patient with rheumatoid arthritis. Arch Intern Med 2002; 162: 1105–10.
Solomon DH, Glynn RJ, Levin R, Avorn J. Nonsteroidal anti-inflammatory drug use and acute myocardial infarction. Arch Intern Med 2002; 162: 1099–104.
Schlienger RG, Jick H, Meier CR. Use of nonsteroidal anti-inflammatory drugs and the risk of first-time acute myocardial infarction. Br J Clin Pharmacol 2002; 54: 327–32.
Ray WA, Stein CM, Hall K, Daugherty JR, Griffin MR. Non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease: an observational cohort study. Lancet 2002; 359: 118–23.
Garcia Rodriguez LA, Varas-Lorenzo C, Maguire A, Gonzalez-Perez A. Nonsteroidal anti-inflammatory drugs and the risk of myocardial infarction in the general population. Circulation 2004; 109: 3000–6.
Reicin AS, Shapiro D, Sperling RS, Barr E, Yu Q. Comparison of cardiovascular thrombotic events in patients with osteoarthritis treated with refecoxib versus nonselective nonsteroidal anti-inflammatory drugs (ibuprofen, diclofenac, and nabumetone). Am J Cardiol 2002; 89: 204–9.
Garcia Rodriguez LA, Varas C, Patrono C. Differential effects of aspirin and non-aspirin nonsteroidal antiinflammatory drugs in the primary prevention of myocardial infarction in postmenopausal women. Epidemiology 2000; 11: 382–7.
Mamdani M, Rochon P, Juurlink DN, et al. Effect of selective cyclooxygenase 2 inhibitors and naproxen on short-term risk of acute myocardial infarction in the elderly. Arch Intern Med 2003; 163: 481–6.
Wolfe R, Zhao S, Pettitt D. Blood pressure destabilization and edema among 8538 users of celecoxib, rofecoxib, and nonselective nonsteroidal anti-inflammatory drugs (NSAID) and nonusers of NSAID receiving ordinary clinical care. J Rheumatol 2004; 31: 1143–51.
Whelton A, White WB, Bello AE, Puma JA, Fort JG, the SUCCESS-VII Investigators. Effects of celecoxib and rofecoxib on blood pressure and edema in patients > or = 65 years of age with systemic hypertension and osteoarthritis. Am J Cardiol 2002; 90: 959–63.
Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000; 343: 1520–8.
Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005; 352: 1092–102.
Juni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet 2004; 364: 2021–9.
Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005; 352: 1071–80.
White WB, Faich G, Borer JS, Makuch RW. Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib. Am J Cardiol 2003; 92: 411–8.
White WB, Strand V, Roberts R, Whelton A. Effects of cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal anti-inflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis. Am J Ther 2004; 11: 244–50.
Nussmeier NA, Whelton AA, Brown MT, et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005; 352: 1081–91.
Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001; 286: 954–9.
FitzGerald GA. Coxibs and cardiovascular disease. N Engl J Med 2004; 351: 1709–11.
Topol EJ. Arthritis medicines and cardiovascular events—"House of coxibs." JAMA 2005; 293: 366–8.
Monakier D, Mates M, Klutstein MW, et al. Rofecoxib, a COX-2 inhibitor, lowers C-reactive protein and interleukin-6 levels in patients with acute coronary syndromes. Chest 2004; 125: 1610–5.(Robert P. Blankfield, MD,)