Effect of Selective Cyclooxygenase-2 Inhibitors on Heart Rate in Healthy Young Men Christoph Lamprecht, MD, Ulrike Werner, PhD, Dierk Werner, MD, Simon Schaefer, Bertold Renner, MD, Martin Fromm, MD, and Kay Brune, MD During an investigation of the possible pharmacokinetic interactions of cyclooxygenase-2 (COX-2) inhibitors with metoprolol, we observed that rofecoxib caused a significant reduction in heart rate in young healthy volunteers. The effect of valdecoxib did not reach significance. When these drugs were given together with metoprolol, the effect was continued. The latter effect could not be related to pharmacokinetic interactions. In the light of experimental results claiming a cardioprotective effect of possibly COX-2– derived prostaglandins and clinical observations hinting at an increased risk of sudden cardiovascular death in conjunction with the long-term use of selective cyclooxygenase inhibitors, our results may help to increase awareness and to suggest investigation of the impact of coxibs on heart function. 䊚2005 by Excerpta Medica Inc. (Am J Cardiol 2005;95:1531–1532)
yclooxygenase-2 (COX-2) inhibitors have been intensively discussed recently due to their negaC tive effects on cardiac functions. An increased incidence of myocardial infarction has been observed with long-term treatment of rofecoxib.1 Graham et al2 recently reported an increased incidence of sudden cardiac deaths in patients treated with high doses of rofecoxib. These data are widely disputed, and their clinical importance remains controversial because a plausible mechanism of these unwanted drug effects is lacking. For decades a cardioprotective effect of prostaglandins has been claimed.3 Recent evidence indicates that prostacycline produced from COX-2 may be cardioprotective in dogs.4 In contrast, thromboxane may support arrhythmia.5 Taken together, these clinical and experimental findings indicate that COX-2 inhibitors as a class may be independent risk factors in patients with a damaged cardiac or vascular system. We report the unexpected finding that both, rofecoxib and valdecoxib, given to healthy young male volunteers, reduced heart rate—an effect that is particularly prominent with rofecoxib alone and when given together with metoprolol. We believe that this observation indicates an as yet uninvestigated cardioprotecFrom the Department of Experimental and Clinical Pharmacology and Toxicology, FAU Erlangen-Nuremberg, Erlangen; Department of Cardiology, Helios Clinic, Schwerin; and Department of Anesthesiology, University Hospital Essen, Essen, Germany. Dr. Brune’s address is: Department of Experimental and Clinical Pharmacology and Toxicology, FAU Erlangen-Nuremberg, Fahrstrasse 17, Erlangen, 91054 Germany. E-mail:
[email protected]. Manuscript received November 1, 2004; revised manuscript received and accepted February 15, 2005. ©2005 by Excerpta Medica Inc. All rights reserved. The American Journal of Cardiology Vol. 95 June 15, 2005
MD,
tive or antiarrhythmogenic effect of prostaglandins produced from COX-2. •••
We recently embarked on an investigation of possible pharmacokinetic interactions between 2 widely used cyclooxygenase inhibitors, namely rofecoxib and valdecoxib, with the prevailing -blocking agent metoprolol, because we demonstrated that celecoxib interfered with the metabolization of this  blocker.6 For that purpose, 15 volunteers (12 of them extensive metabolizers at the enzyme CYP2D6) were treated for 1 week with conventional doses of rofecoxib (25 mg/day) or valdecoxib (20 mg/day). They then received on day 7 at 7 A.M. the usual dose of the COX-2 inhibitor and 2 hours later 50 mg of metoprolol. The volunteers were fixed with a continuous electrocardiographic recording system after administration of the coxibs. After 24-hour Holter monitoring, the recorded cardiac frequency was evaluated. To our surprise, the volunteers had a slower heart rate after administration of a COX-2 inhibitor (before metoprolol administration; Table 1). Moreover, the reduction in heart rate caused by metoprolol was augmented when combined with coxibs (Table 1). The effect appeared related to the pharmacokinetics of the drugs (Figure 1). This effect was significant for rofecoxib (Table 1). These effects were not related to a pharmacokinetic interaction (data to be published), becauses both coxibs at the doses given did not interfere with the pharmacokinetics of metropolol in a measurable extent, in contrast to celecoxib.6 Moreover, in a small group of volunteers5 who received 50 (rofecoxib) or 40 (valdecoxib) mg for 1 day, the same effect was observed. However, it did not reach significance. The same holds true for the 3 poor metabolizers. To estimate any possible proarrhythmic risk, we calculated QTc intervals during all 3 study phases at 9.00 A.M. (i.e., 2 hours after administration of the cyclooxygenase inhibitors and immediately before uptake of metoprolol). The QTc time did not change significantly from baseline after receiving rofecoxib or valdecoxib (0.37 ⫾ 0.03 vs 0.36 ⫾ 0.03 vs 0.36 ⫾ 0.02 seconds, respectively, p ⫽ NS), showing that treatment with coxibs does not impose a major proarrhythmic risk in healthy volunteers. •••
We report the unexpected but stable finding that COX-2 inhibitors may cause a reduction in heart rate, per se, and increase the effect of a  blocker (metropolol). This observation has to be regarded as preliminary, because the study design was not aimed at detecting such an effect. In contrast, we acknowledge, for the first time, that coxibs are found to reduce 0002-9149/05/$–see front matter doi:10.1016/j.amjcard.2005.02.033
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TABLE 1 Effect of Coxibs on Heart Rate
Drug Dose Without COX-2 inhibitors Rofecoxib (25 mg) Valdecoxib (20 mg)
Heart Rate (beats/min) After Metoprolol for 23 h
Heart Rate (beats/min) Before Metoprolol for 1 h (n ⫽ 11)*
All Volunteers† (n ⫽ 15)
A.M. (n ⫽ 12)
P.M. (n ⫽ 3)
78.9 ⫾ 9.4 72.8 ⫾ 13.1 (p ⫽ 0.062) 73.8 ⫾ 8.3 (p ⫽ 0.181)
66.9 ⫾ 6.6 64.0 ⫾ 7.0* (p ⫽ 0.017 df ⫽ 1, 14 F ⫽ 7.27) 65.7 ⫾ 7.5 (p ⫽ 0.352 df ⫽ 1, 14 F ⫽ 0.93)
68.2 ⫾ 7.1 65.6 ⫾ 7.7
62.5 ⫾ 5.3 60.0 ⫾ 6.2
67.0 ⫾ 8.5
61.8 ⫾ 5.7
Values are expressed as mean ⫾ SEM. *Recorded 1 hour after administration of coxibs, before administration of metoprolol (Wilcoxon p values). † Effect of treatment (p ⫽ 0.016, df ⫽ 2, 28, F ⫽ 4.82) calculated for GLM for repeated-measures (p values were calculated using contrasts comparing treatments with and without COX-2 inhibitors). The p values were calculated using repeated-measures analysis of variance (the general linear model within subject factor “treatment” threefold and “time” threefold contrasts to treatment without COX-2 inhibitors.
known to reduce the production of prostacyclin from endothelial tissue without inhibiting thromboxane synthesis. This could change the balance between proarrhythmic thromboxane and cardioprotective prostaglandins.7 Taken together, our results may add to an as yet not understood mechanism that increases the vulnerability of the heart after COX-2 inhibition. We report our unexpected observation to suggest investigating whether coxibs may support the development of cardiac arrhythmias and thus cardiac death.2 Obviously, further experimentation should take these possibilities into account. Until then, coxibs as a class, should be administered cautiously to patients with heart disease. FIGURE 1. Mean decrease in heart rate after administration of the COX-2 inhibitors rofecoxib and valdecoxib in 15 healthy male volunteers compared with no treatment or metoprolol only. Heart rate was registered by 24-hour Holter electrocardiography (7 A.M: no drugs or administration of COX-2 inhibitor; 9 A.M: single dose of 50 mg metoprolol. (For statistical data see Table 1).
spontaneous heart rate. Importantly, this phenomenon was seen in young healthy volunteers given relatively low doses of the cyclooxygenase inhibitors for a only few days. It remains to be seen what effect long-term treatment with higher doses in elderly patients might cause. Our observation could therefore be seen as hinting at an antiarrhythmic or cardioprotective effect, or both, of COX-2– dependant prostaglandins blocked by coxibs. These drugs have been shown to enhance the damaged area in experimental cardiac infarction in dogs.4 Thromboxane was demonstrated to be arrhythmogenic in animals.5 Finally, inhibition of COX-2 is
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1. 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, and the VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000;343:1520 –1528. 2. Graham DJ, Campen D, Cheetham C, Hui R, Spence M, Ray WA. Risk of acute cardiac events among patients treated with cyclooxygenase-2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 2005;365:449 – 451. 3. Bolli R, Shinmura K, Tang XL, Kodani E, Xuan YT, Guo Y, Dawn B. Discovery of a new function of cyclooxygenase (COX)-2: COX-2 is a cardioprotective protein that alleviates ischemia/reperfusion injury and mediates the late phase of preconditioning. Cardiovasc Res 2002;55:506 –519. 4. Hennan JK, Huang J, Barrett TD, Driscoll EM, Willens DE, Park AM, Crofford LJ, Lucchesi BR. Effects of selective cyclooxygenase-2 inhibition on vascular responses and thrombosis in canine coronary arteries. Circulation 2001; 104:820 – 825. 5. Wacker MJ, Tehrani RN, Smoot RL, Orr JA. Thromboxane A (2) mimetic evokes a bradycardia mediated by stimulation of cardiac vagal afferent nerves. Am J Physiol Heart Circ Physiol 2002;282:H482–H490. 6. Werner U, Werner D, Rau T, Fromm M, Hinz B. Brune K. Celecoxib inhibits metabolism of cytochrome P450 2D6 substrate metoprolol in humans. Clin Pharmacol Ther 2003;74:130 –137. 7. FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001;345:433– 442.
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