Effect of Beta Blockers (Metoprolol or Propranolol) on Effect of Simvastatin in Lowering C-Reactive Protein in Acute Myocardial Infarction
Article Outline
Recent data indicated that statin therapy may fail to reduce the incidence of coronary events in patients concomitantly using β blockers. The aim of the present study was to examine whether the concomitant use of β blockers would modify the anti-inflammatory action of statins. Changes in C-reactive protein (CRP) between days 1 and 5 after myocardial infarction were evaluated in 189 patients treated with simvastatin alone (S), β blockers alone (B; propranolol or metoprolol), S + B, or neither of these 2 medications (N) in a prospective observational cohort. At baseline, median CRP was lower in the S group (0.40 mg/dl, interquartile range 0.1 to 0.6) than the other groups (B: 0.6 mg/dl, interquartile range 0.4 to 1.6; S + B: 0.5 mg/dl, interquartile range 0.3 to 1.2; and N: 0.6 mg/dl, interquartile range 0.2 to 1.5). By day 5, median CRP was 1.3 mg/dl (interquartile range 0.7 to 2.6), 4.3 (interquartile range 1.6 to 8.8), 4.6 (interquartile range 2.8 to 9.5), and 4.4 (interquartile range 1.9 to 9.9) for the S, B, S + B, and N groups, respectively. After adjusting for loge baseline CRP, the difference in loge CRP between days 1 and 5 was significantly lower in the S group compared with the B (−0.74 ± 0.23 [SE], p = 0.001) or S + B group (−0.99 ± 0.20 [SE], p <0.0001). The significance remained after adjustment for age, gender, and baseline CRP. There was no significant difference in change in CRP between the SB and B groups. In conclusion, the present study confirmed the anti-inflammatory action of statins and showed that concomitant use of β blockers may significantly attenuate this effect.
Recently, a report from the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) raised the possibility that the clinical outcome benefit associated with treatment with atorvastatin was attenuated when treatment was combined with atenolol-based treatment.1 In animal models, nonselective β-adrenoceptor antagonism has been shown to exacerbate inflammatory responses.2, 3, 4 Because inflammation and the incidence of coronary events were strongly associated, attenuation of the anti-inflammatory effect of statins by concomitant use of β blockers may be considered among the possible causal links for such clinical observations. However, to date, data were unavailable to support such a hypothesis. In the present study, we used inflammatory response during myocardial infarction (MI) as a model to examine whether such an interaction exists between statins and β blockers.
Methods
Study subjects (n = 189) were subjects in the ongoing Brasilia Heart Study. In this prospective observational cohort, consecutive patients with ST-segment elevation MI were included in the study as of May 2006. Inclusion criteria were (1) <24 hours after the onset of MI symptoms, (2) ST-segment elevation in 2 contiguous leads, and (3) increased creatine kinase-MB and troponin. Medical evaluation and blood sampling were performed on hospital admission and day 5 after MI. Because simvastatin was a standard medication in the Brasilia public health system, this drug was the only statin used by enrolled patients. Medical treatment, including selection of β-blocker and simvastatin dosages, was decided by the attending physicians in the emergency department without influence from the study investigators. Creatine kinase-MB, blood glucose, total cholesterol, triglycerides, high-density lipoprotein cholesterol (Roche Diagnostics, Mannheim, Germany), high-sensitivity C-reactive protein (CRP; Dade Behring, Marburg, Germany), and glycated hemoglobin (Bio-Rad Laboratories, Hercules, California) were measured. The study was approved by the Institutional Ethics Committee, and all patients signed informed consent.
Analysis of covariance was used to assess the effect of treatments on CRP. Adjustment for baseline CRP, age, and gender was performed for comparisons of mean change in CRP across treatments. Mann-Whitney test, analysis of variance, and/or Kruskal Wallis test were used for comparisons between groups. Data were presented as mean ± SD (or SE) for normally distributed data or median and interquartile range for skewed data. A 2-sided p = 0.05 was considered statistically significant. Statistical analyses were performed using SPSS for Windows, version 15.0 (SPSS Inc., Chicago, Illinois). The authors had full access to the data and take responsibility for its integrity. All authors have read and agreed to the report as written.
Results
Patients were divided into 4 groups according to the use of statins and β blockers. There was no significant difference in simvastatin dosages between the 2 statin-treated groups (Table 1). In patients using β blockers, propranolol (50 ± 24 mg/day) was used by 73% (n = 89), and metoprolol (87 ± 54 mg/day), by 27% (n = 33). Those receiving a statin were using simvastatin for >60 days before admission. Thirty-five of 124 patients (28%) receiving a β blocker were already using this drug for >60 days before admission. The others were started on these drugs on admission to the emergency department.
Table 1. Clinical and laboratory characteristics of enrolled patients
| Variable | N (n = 36) | S (n = 29) | S + B (n = 80) | B (n = 44) | p Value |
|---|---|---|---|---|---|
| Men | 31 (86%) | 22(76%) | 57(71%) | 33(75%) | 0.39 |
| Age (yrs) | 63±12 | 60±13 | 58±10 | 59±11 | 0.18 |
| Previous MI | 4(11%) | 4(14%) | 14(17%) | 3(7%) | 0.39 |
| Hypertension | 13(36%) | 16(54%) | 43(54%) | 23(52%) | 0.33 |
| Smoking | 11(31%) | 15(50%) | 37(46%) | 20(46%) | 0.36 |
| No physical activity | 12(33%) | 17(57%) | 38(48%) | 22(50%) | 0.26 |
| Diabetes | 13(36%) | 11(39%) | 26(33%) | 20(46%) | 0.55 |
| Glycated hemoglobin (%) | 6.6±1.4 | 6.4±1.0 | 6.6±1.5 | 6.5±1.2 | 0.95 |
| Reperfusion therapy | 19(53%) | 21(72%) | 58(73%) | 31(71%) | 0.09 |
| Time from symptoms to sampling (min) | 233±291 | 208±240 | 251±339 | 357±271 | 0.90 |
| Systolic blood pressure (mm Hg) | 128±33 | 133±24 | 137±33 | 134±25 | 0.54 |
| Diastolic blood pressure (mm Hg) | 79±20 | 86±17 | 85±18 | 84±22 | 0.48 |
| Heart rate (beats/min) | 74±17 | 73±16 | 79±15 | 75±19 | 0.17 |
| Thrombolysis In Myocardial Infarction risk score (points) | 4.1±2.0 | 3.7±2.0 | 3.7±1.9 | 3.5±1.5 | 0.49 |
| Creatine kinase–MB peak (mg/dl) | 156±166 | 264±185 | 253±232 | 202±217 | 0.08 |
| Body mass index (kg/m2) | 26.6±4.0 | 27.6±3.6 | 26.9±4.2 | 26.7±3.4 | 0.73 |
| Waist circumference (cm) | 95±10 | 98±11 | 96±16 | 95±11 | 0.79 |
| Total cholesterol (mg/dl) | 182±57 | 176±35 | 175±45 | 198±52 | 0.08 |
| High-density lipoprotein cholesterol (mg/dl) | 40±9 | 43±12 | 38±11 | 42±14 | 0.06 |
| Low-density lipoprotein cholesterol (mg/dl) | 118±52 | 115±38 | 109±37 | 132±59 | 0.08 |
| Triglycerides (mg/dl) | 131±83 | 111±61 | 157±131 | 173±161 | 0.14 |
| Simvastatin daily doses (mg) | — | 25±14 | 26±16 | — | 0.7 |
Table 1 lists clinical and laboratory characteristics of patients using simvastatin alone (S), β blocker alone (B), simvastatin plus β blocker (S + B), or none of these drugs (N) during admission. There was a trend for less frequent use of reperfusion therapy and lower peak creatine kinase-MB in patients in the N group. The S and S + B groups showed a tendency toward lower total and low-density lipoprotein cholesterol. Figure 1 shows CRP changes between admission and day 5 after MI. At baseline, there was no significant difference in median high-sensitivity CRP among groups. By day 5, median CRP was significantly lower in the S group compared with the B, S + B, and N groups. This difference remained significant after adjusting for loge baseline CRP and age, gender, and loge baseline CRP (p <0.01). There was no significantly different change in CRP between the S + B and B groups.
Figure 1.
Median baseline and day 5 CRP among groups.
No significant difference was found in simvastatin doses (22 ± 7 vs 26 ± 9 mg/day; p = 0.2) or baseline CRP (0.5 mg/L, interquartile range 0.3 to 1.1 vs 0.4, interquartile range 0.2 to 0.55; p = 0.98) between patients using propranolol or metoprolol, respectively. However, the change in CRP between days 1 and 5 after MI tended to be higher in patients using propranolol (4.6 mg/L, interquartile range 2.2 to 9.5) than in those using metoprolol (2.8, interquartile range 1.35 to 5.2; p = 0.07).
Discussion
In line with our previous study with atorvastatin,5 we found that simvastatin treatment attenuated the intense increase in systemic inflammatory activity during the acute phase of MI. In addition, for the first time, this study indicated that such an anti-inflammatory effect of statins could be attenuated by concomitant treatment with propranolol or metoprolol.
Although there was no previous study investigating such drug interaction on inflammation, some evidence supported our observation. In animal and cellular models of lipopolysaccharide-induced inflammation, catecholamines activated nuclear factor-κB and cyclic adenosine monophosphate response to element-binding protein and stimulated the transcription and release of such proinflammatory cytokines as interleukin-6, interleukin-1β, and tumor necrosis factor-α.6, 7 In these experiments, pretreatment with α- and β1-adrenoceptor antagonists abolished the inflammatory response, whereas propranolol exacerbated it.2, 3, 4 In addition, pretreatment with β2-adrenoceptor agonists suppressed the inflammatory response.4 In accord with these observations, in patients treated with simvastatin, we observed that the magnitude of increase in CRP during MI tended to be higher in those using propranolol compared with those treated with metoprolol (the latter had higher selectivity for β1-adrenoceptors). Thus, the overall effect of β blockers on inflammatory activity may result from the balance between their β1 and β2 antagonism.
There are obvious limitations in the interpretation of drug effects in observational cohorts because treatments are not randomly selected. However, a prospective randomized controlled trial comparing such treatment groups in patients with MI would be unacceptable for ethical reasons. Nevertheless, because statins and β blockers are frequently coadministrated, such a possibility of negative interaction requires additional attention and investigation.
Acknowledgment
The authors thank the Diagnósticos da Amérida S.A. and Clinica Biocardios, which supported the biochemical analyses and cardiovascular imaging tests for the Brasilia Heart Study; and acknowledge the statistical advice of Di Limmie Chang.
References
- Potential synergy between lipid-lowering and blood-pressure-lowering in the Anglo-Scandinavian Cardiac Outcomes Trial. Eur Heart J. 2006;27:2982–2988
- . The beta-adrenoceptor agonist clenbuterol is a potent inhibitor of the LPS-induced production of TNF-alpha and IL-6 in vitro and in vivo. Inflamm Res. 1999;48:497–502
- . Infusion of the beta-adrenergic blocker esmolol attenuates myocardial dysfunction in septic rats. Crit Care Med. 2005;33:2294–2301
- . In search of secreted protein biomarkers for the anti-inflammatory effect of beta2-adrenergic receptor agonists: application of DIGE technology in combination with multivariate and univariate data analysis tools. J Proteome Res. 2005;4:2015–2023
- . Anti-inflammatory effect of atorvastatin (80 mg) in unstable angina pectoris and non-Q-wave acute myocardial infarction. Am J Cardiol. 2003;92:298–301
- . Hemorrhage increases cytokine expression in lung mononuclear cells in mice: involvement of catecholamines in nuclear factor-kappaB regulation and cytokine expression. J Clin Invest. 1997;99:1516–1524
- . Beta(2)-adrenoceptor agonist suppresses renal tumour necrosis factor and enhances interleukin-6 gene expression induced by endotoxin. Nephrol Dial Transplant. 2000;15:1928–1934
PII: S0002-9149(08)01874-2
doi:10.1016/j.amjcard.2008.10.007
© 2009 Elsevier Inc. All rights reserved.
