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β-Blockers and Progression of Coronary Atherosclerosis: Pooled Analysis of 4 Intravascular Ultrasonography Trials

Ilke Sipahi, MD; E. Murat Tuzcu, MD; Katherine E. Wolski, MPH; Stephen J. Nicholls, MBBS, PhD; Paul Schoenhagen, MD; Bo Hu, PhD; Craig Balog, BS; Mehdi Shishehbor, DO; William A. Magyar, BS; Timothy D. Crowe, BS; Samir Kapadia, MD; and Steven E. Nissen, MD
[+] Article and Author Information

From The Cleveland Clinic Foundation, Cleveland, Ohio.


Acknowledgments: The authors thank Jordan Andrews, Eva Balazs, Sorin Brener, Tammy Churchill, Anne Colagiovanni, Kelly Emerick, Teresa Fonk, Jessica Fox, Marlene Goormastic, Thomas Ivanc, Karilane King, Aaron Loyd, Kara McInturff, Roman Poliszczuk, Rhiannon Regal, Troy Schweitzer, Andrea Winkhart, and Jay Zhitnik at the Cleveland Clinic Cardiovascular Coordinating Center; David J. Frid, Michele Norton, Fady Ntanios, Harry Shi, and Kamlesh Thakker at Pfizer; James Hanyok and Laurent Kassalow at Sankyo Pharma; and Valerie Cain and Joel Raichlen at AstraZeneca for their contributions.

Grant Support: The REVERSAL and CAMELOT studies were funded by Pfizer. The ACTIVATE study was funded by Sankyo. The ASTEROID study was funded by AstraZeneca. Dr. Nicholls is supported by a Ralph Reader Overseas Research Fellowship from the National Heart Foundation of Australia.

Potential Financial Conflicts of Interest: Dr. Sipahi has received an educational grant from Pfizer and lecture honoraria from AstraZeneca. All honoraria are paid directly to charity so that neither income nor any tax deduction is received. Dr. Tuzcu received grant support from Pfizer and Takeda and lecture honoraria from Pfizer. Dr. Nicholls has received lecture honoraria from Pfizer and AstraZeneca. Dr. Schoenhagen has consulted for Takeda without financial compensation. All honoraria are paid directly to higher education so that neither income nor any tax deduction is received. Dr. Nissen has received research support from AstraZeneca, Eli Lilly, Pfizer, Takeda, Sankyo, and Sanofi-Aventis. He has also consulted for a number of pharmaceutical companies without financial compensation. All honoraria, consulting fees, or other payments from any for-profit entity are paid directly to charity so that neither income nor any tax deduction is received.

Requests for Single Reprints: Steven E. Nissen, MD, The Cleveland Clinic Foundation, Department of Cardiovascular Medicine, 9500 Euclid Avenue, Desk F15, Cleveland, OH 44195; e-mail, nissens@ccf.org.

Current Author Addresses: Drs. Sipahi, Nicholls, and Schoenhagen; Ms. Wolski; Mr. Balog; Mr. Magyar; and Mr. Crowe: The Cleveland Clinic Foundation, Department of Cardiovascular Medicine, 9500 Euclid Avenue, Desk JJ65, Cleveland, OH 44195.

Drs. Tuzcu and Kapadia: The Cleveland Clinic Foundation, Department of Cardiovascular Medicine, 9500 Euclid Avenue, Desk F25, Cleveland, OH 44195.

Dr. Hu: The Cleveland Clinic Foundation, Department of Quantitative Health Sciences, 9500 Euclid Avenue, Desk Wb4, Cleveland, OH 44195.

Drs. Shishehbor and Nissen: The Cleveland Clinic Foundation, Department of Cardiovascular Medicine, 9500 Euclid Avenue, Desk F15, Cleveland, OH 44195.

Author Contributions: Conception and design: I. Sipahi, E.M. Tuzcu, S.J. Nicholls, S. Kapadia.

Analysis and interpretation of the data: I. Sipahi, E.M. Tuzcu, K.E. Wolski, S.J. Nicholls, B. Hu, S. Kapadia.

Drafting of the article: I. Sipahi, S.J. Nicholls, P. Schoenhagen, S. Kapadia.

Critical revision of the article for important intellectual content: I. Sipahi, E.M. Tuzcu, S.J. Nicholls, P. Schoenhagen, M. Shishehbor, T.D. Crowe, S. Kapadia, S.E. Nissen.

Final approval of the article: I. Sipahi, E.M. Tuzcu, K.E. Wolski, S.J. Nicholls, P. Schoenhagen, C. Balog, M. Shishehbor, W.A. Magyar, T.D. Crowe, S. Kapadia, S.E. Nissen.

Provision of study materials or patients: I. Sipahi, E.M. Tuzcu, W.A. Magyar.

Statistical expertise: I. Sipahi, K.E. Wolski, B. Hu, C. Balog.

Administrative, technical, or logistic support: E.M. Tuzcu, W.A. Magyar.

Collection and assembly of data: I. Sipahi, W.A. Magyar.


Ann Intern Med. 2007;147(1):10-18. doi:10.7326/0003-4819-147-1-200707030-00003
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Clinical trials have demonstrated that β-blockers substantially reduce recurrent myocardial infarction, sudden cardiac death, and total mortality rates in patients with myocardial infarction (15, 16). A suggested mechanism for the long-term beneficial effects of β-blockers is their possible antiatherosclerotic effect. Many animal models have provided evidence that β-blockers can slow the development of atherosclerosis (1721). However, the antiatherosclerotic effects of β-blockers have not been demonstrated in the human coronary artery. Our study suggests that β-blockers have considerable coronary antiatherosclerotic effects. According to the linear effects models, atheroma volume statistically significantly decreased by 2.4 mm3/y in patients who received β-blocker treatment, corresponding to a regression of atheroma volume of approximately 1.3% per year. A nonsignificant decrease of 0.4 mm3/y occurred in patients who did not receive β-blockers. No direct data exist about the amount of differential change in atheroma volume that is associated with better clinical outcomes. However, indirect evidence from the REVERSAL (7) and PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) (22) studies, which used the same treatment regimens (atorvastatin, 80 mg/d, vs. pravastatin, 40 mg/d), suggests that the annual difference in change in atheroma volume of approximately 3.5 mm3 favoring atorvastatin, 80 mg, found in REVERSAL should be clinically important. This is because atorvastatin, 80 mg, in the PROVE-IT study was associated with a statistically significant 16% reduction in the clinical end point (23). In our analysis, the effect size of β-blockers (difference of 2.0 mm3/y) was smaller than that of intensive lipid-lowering therapy compared with moderate lipid-lowering therapy in REVERSAL.

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Figure.
Yearly atheroma progression rates.

Values are means, and error bars represent SEs. P < 0.001 by linear-effects model. The median low-density lipoprotein (LDL) cholesterol level was 2.2 mmol/L (86 mg/dL). Plus signs mean that patients were receiving β-blocker treatment, and minus signs mean that patients were not receiving β-blocker treatment.

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Sympathetic nervous tone and atherosclerosis
Posted on July 6, 2007
Yujiro Kida
University of Southern California, Department of Surgery
Conflict of Interest: None Declared

To the Editor,

Sipahi and coworkers firstly reported the regressive effect of beta- blockers on the progression of coronary atherosclerosis in patients (1). As the authors discussed, reduced heart rate by beta-blockers is thought to be one of mechanisms explaining such effect of beta-blockers. Sata et al. showed that bone-marrow derived cells including hematopoietic stem cells (HSCs) differentiated into neointimal smooth-muscle cells and endothelial cells and contributed to arterial atherogenesis in experimental animal models (2). In addition, it was demonstrated that decrease of sympathetic nerve tone down-regulated HSCs mobilization from bone marrow to peripheral blood (3). From these results, it is possible that beta-blockers retard the growth of coronary atherosclerosis through diminishing of HSCs mobilization. On the other hand, statin was reported to potently augment endothelial progenitor cells and CD34-positive HSCs in peripheral blood (4). It would be helpful to determine whether anti- atherosclerotic effect of beta-blockers depends on decrease of HSCs mobilization if the authors would give information about the HSCs' number in peripheral blood of eligible patients. References

(1) Sipahi I, Tuzcu EM, Wolski KE, et al. Beta-blockers and progression of coronary atherosclerosis: Pooled analysis of 4 intravascular ultrasonography trials. Ann Intern Med 2007;147:10-18

(2) Sata M, Saiura A, Kunisato A, et al. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med 2002;4:403-409

(3) Katayama Y, Battista M, Kao WM, et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 2006;124:407-421.

(4) Dimmeler s, Aicher a, Vasa M, et al. HMG-CoA reductase inhibitors (statins) increase endothelial progenitorcells via the PI 3-kinase/AKT pathway. J Clin Invest 2001;108:391-397.

Conflict of Interest:

None declared

Reason to question conclusion of meta analysis
Posted on July 12, 2007
L Joe Dunaway
None
Conflict of Interest: None Declared

Why do we not see this proposed mechanism of decreased atherosclerosis progression attributed to beta blockers as in this meta analysis when beta blockers are used in the treatment of hypertension? Prospective studies have shown no decreased incidence of MI and stroke in patients treated with beta blockers verses placebo. How can this mechanism of decreased atherosclerosis progression be active in a post MI patient treated with beta blockers and obviously not in a hypertensive patient treated with beta blocker? I think this contradiction demonstrates a fatal flaw in the conclusion reached by this meta analysis.

Conflict of Interest:

None declared

Beta-blockers and progression of coronary atherosclerosis
Posted on August 4, 2007
Gaetano A Lanza
Istituto di Cardiologia - Università Cattolica del Sacro Cuore - Roma
Conflict of Interest: None Declared

Analyzing data from four clinical trials, Sipahi et al. show that treatment with beta-adrenergic blocking agents is associated with a reduction of coronary atherosclerotic plaques, as assessed by intravascular ultrasound imaging (1). Among the possible mechanisms responsible for the antiatherosclerotic effect of beta-blockers, Sipahi et al. include an improvement of vascular function related to a reduced mechanical stress on the vessels, consequent to the reduction of heart rate and blood velocity, a reduced affinity of LDL cholesterol to vessel wall proteoglycans and blunting of the catecholamine-induced increase in endothelial permeability to lipoproteins. In recent years, however, it has become evident that inflammation is a major cause of coronary atherosclerosis. Accordingly, markers of inflammation (e.g., C-reactive protein [CRP]) are associated with an increased risk of coronary artery disease and coronary events as well as with progression of coronary atherosclerosis. Moreover, some data also suggest that statin-induced reduction of CRP levels may result in a lower progression of coronary atherosclerosis (2). Interestingly, recent experimental data have suggested that inflammatory reactions can be modulated by the activity of the autonomic nervous system (3). Specifically, vagal activation is associated with a reduction of inflammatory cell reactivity, whereas chronic adrenergic activation may favor inflammation. Accordingly, recent clinical studies in unselected subjects and in patients with various cardiac diseases, have suggested an association between sympatho-vagal imbalance toward adrenergic predominance, as assessed by heart rate variability (HRV), and increased markers of inflammation (4). Importantly, in a small randomized trial involving 21 type-1 diabetic patients with evidence of impaired cardiac autonomic function, we have recently shown that a 3-4 week treatment with atenolol (50 mg/die) was not only associated with an improvement of HRV, but also with a significant reduction of serum CRP levels (5). Thus, we would like to suggest that a further possible mechanism by which beta-blockers may exert a favorable effect on coronary atherosclerosis may consist of an anti-inflammatory action mediated by the improvement of the autonomic sympatho-vagal balance.

References

1. Sipahi I, Tuzcu EM, Wolski KE, Nicholls SJ, Schoenhagen P, Hu B, Balog C, Shishehbor M, Magyar WA, Crowe TD, Kapadia S, Nissen SE. Beta-blockers and progression of coronary atherosclerosis: pooled analysis of 4 intravascular ultrasonography trials. Ann Intern Med 2007;147:10-8.

2. Schoenhagen P, Tuzcu EM, Apperson-Hansen C, Wang C, Wolski K, Lin S, Sipahi I, Nicholls SJ, Magyar WA, Loyd A, Churchill T, Crowe T, Nissen SE. Determinants of arterial wall remodeling during lipid-lowering therapy: serial intravascular ultrasound observations from the Reversal of Atherosclerosis with Aggressive Lipid Lowering Therapy (REVERSAL) trial. Circulation 2006 ;113(24):2826-34.

3. Tracey KJ. The inflammatory reflex. Nature 2002;420:853-9.

4. Lanza GA, Sgueglia GA, Cianflone D, Rebuzzi AG, Angeloni G, Sestito A, Infusino F, Crea F, Maseri A; SPAI (Stratificazione Prognostica dell'Angina Instabile) Investigators. Relation of heart rate variability to serum levels of C-reactive protein in patients with unstable angina pectoris. Am J Cardiol 2006;97:1702-6.

5. Lanza GA, Pitocco D, Navarese EP, Sestito A, Sgueglia GA, Manto A, Infusino F, Musella T, Ghirlanda G, Crea F. Association between cardiac autonomic dysfunction and inflammation in type 1 diabetic patients: effect of beta-blockade. Eur Heart J 2007;28:814-20.

Conflict of Interest:

None declared

Re: Sympathetic nervous tone and atherosclerosis
Posted on August 16, 2007
ILKE SIPAHI
Cleveland Clinic
Conflict of Interest: None Declared

We thank Dr.Kida for suggesting an additional mechanism for the anti- atherosclerotic effects of beta-blockers. Because information on hematopoietic stem cells was not collected in the trials, we are not able to provide an insight into this mechanism using our dataset.

Conflict of Interest:

None declared

Re: Reason to question conclusion of meta analysis
Posted on August 15, 2007
ILKE SIPAHI
Cleveland Clinic
Conflict of Interest: None Declared

Dr. Dunaway's statement "Prospective studies have shown no decreased incidence of myocardial infarction (MI) and stroke in patients treated with beta blockers verses placebo" is not true. The meta-analyses by Lindholm et al. (1) and Bradley et al. (2) involving more than 20.000 patients with hypertension showed that beta-blockers significantly reduce the incidence of stroke by 19% as compared to placebo (95% confidence interval for relative risk 0.71-0.93). While there was only a statistical trend for reduced incidence of MI in these meta-analyses (relative risk 0.83-1.05), beta-blockers reduce the incidence of MI significantly by 28- 41% in patients with history of MI (3, 4). Recently, it has been recommended that in primary prevention patients beta-blockers should not be preferred over other antihypertensives as a first line agent. However, in our article (5) we have stated ""¦ our analysis involved only patients with established coronary artery disease. Therefore, no conclusion about the effects of ß-blocker use can be drawn for primary prevention (for example, hypertensive patients without coronary artery disease)." in order to limit the implications of our study to secondary prevention patients.

REFERENCES

1. Lindholm LH, Carlberg B, Samuelsson O. Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet. 2005;366(9496):1545-53.

2.Bradley HA, Wiysonge CS, Volmink JA, Mayosi BM, Opie LH. How strong is the evidence for use of beta-blockers as first-line therapy for hypertension? Systematic review and meta-analysis. J Hypertens. 2006;24(11):2131-41.

3.Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med. 1981;304(14):801-7.

4.Julian DG, Prescott RJ, Jackson FS, Szekely P. Controlled trial of sotalol for one year after myocardial infarction. Lancet. 1982;1(8282):1142-7.

5.Sipahi I, Tuzcu EM, Wolski KE, et al. Beta-blockers and progression of coronary atherosclerosis: pooled analysis of 4 intravascular ultrasonography trials. Ann Intern Med. 2007;147(1):10-8.

Conflict of Interest:

Dr. Sipahi has received an educational grant from Pfizer and lecture honoraria from AstraZeneca. Dr. Nissen has received research support from AstraZeneca, Eli Lilly, Pfizer, Takeda, Sankyo, and Sanofi-Aventis. He has also consulted for a number of pharmaceutical companies without financial compensation. All honoraria, consulting fees, or other payments from any for-profit entity are paid directly to charity so that neither income nor any tax deduction is received.

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