Accepted Manuscript

Regional Variability in Beta-Blockers Efficacy and Safety: a Question of “Location,Location, Location”?

Simon de Denus , B.Pharm, MSc, PhD Eileen O’Meara , MD Jean-Lucien Rouleau ,MD

PII: S0828-282X(14)00342-0

DOI: 10.1016/j.cjca.2014.05.008

Reference: CJCA 1219

To appear in: Canadian Journal of Cardiology

Received Date: 2 May 2014

Revised Date: 8 May 2014

Accepted Date: 8 May 2014

Please cite this article as: de Denus S, O’Meara E, Rouleau J-L, Regional Variability in Beta-BlockersEfficacy and Safety: a Question of “Location, Location, Location”?, Canadian Journal of Cardiology(2014), doi: 10.1016/j.cjca.2014.05.008.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service toour customers we are providing this early version of the manuscript. The manuscript will undergocopyediting, typesetting, and review of the resulting proof before it is published in its final form. Pleasenote that during the production process errors may be discovered which could affect the content, and alllegal disclaimers that apply to the journal pertain.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

Regional Variability in Beta-Blockers Efficacy

and Safety: a Question of “Location, Location,

Location”?

Simon de Denus, B.Pharm, MSc, PhD,a, b Eileen O’Meara, MD,a, c and

Jean-Lucien Rouleau, MDa, c

a Montreal Heart Institute, Montreal, Qc

b Faculty of Pharmacie, Université de Montréal, Montréal, Qc

c Faculty of Medicine, Université de Montréal, Montréal, Qc

Disclosures: SdeD served as a consultant for Servier.

Acknowledgment: SdeD holds the Université de Montréal Beaulieu-Saucier Chair in

Pharmacogenomics.

Words: 1998

Corresponding author: Simon de Denus, 5000 Belanger, Montreal, QC, H1T1C8. Tel:

514-376-3330. Fax: 514-376-1355. E-mail: simon.dedenus@icm-mhi.org

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

In the world of real estate, a familiar expression states that three things are critical to a

property’s worth: “location, location, location”.1 Does this motto apply to the value of

drugs commonly used to treat cardiovascular diseases? Geographic differences have

certainly become a matter of concern in cardiovascular trials.2 In this issue of the journal,

Chatterjee and collaborators published a meta-analysis of 16 randomized controlled trials

(RCTs) to determine whether geographical differences exist in terms of beta-blockers

efficacy and tolerability.3 They found that “there is no evidence to suggest that

geographic region is a significant moderator of clinical outcome with beta blocker

therapy in patients with heart failure and reduced ejection fraction (HFrEF)”. Their

results differ from those of a previous meta-analysis by O’Connor et al4 which found that

US participants had less survival benefit from beta-blockers compared to the rest of the

world (ROW).4 What are we to make of these differences?

Meta-analyses have become a precious tool in identifying answers to clinical questions

that have not been adequately answered by individual RCTs, and in identifying the most

appropriate way of addressing the care of subgroups of patients for which only the

pooling of data from various trials provides adequate power to guide therapy. Meta-

analyses can also be used to gage the consistency of results across different trials, which

in and of itself can alert the clinician to the need to individualize care. Indeed, meta-

analyses, particularly since the availability of the Cochrane library, are considered an

essential step in the development of a RCT, and their results are now an important

element in applying evidence-based care in the clinical setting. This having been said,

work by LeLorier would suggest that, depending on the rigor with which the meta-

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

analysis is performed, and the strength of the data that it is based upon, meta-analyses

may all too frequently lead to erroneous conclusions.5 The meta-analyses of Chatterjee

and of O’Connor both help illustrate some of the pitfalls of meta-analyses that need to be

considered in order to optimize their use. Moreover, they illustrate for the reader of such

work the importance of a careful scrutiny of the studies selected to be part of a meta-

analysis, as well as differences between the individual trials in regards to their design, the

treatment regimens investigated, the patient populations involved and their results.

O’Connor’s meta-analysis included only four large multicenter trials, MERIT-HF

(Metoprolol Controlled-Release Randomized Intervention Trial in Heart Failure),

COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival Trial), BEST

(β-blocker Evaluation of Survival Trial) and CIBIS II (Cardiac Insufficiency Bisoprolol

Study). As these were the four major RCTs that tested the role of beta blockers in patients

with HFrEF, at first glance, this would appear to be an appropriate choice of trials.

However, this approach led to nearly two thirds of US patients and roughly 80% of US

deaths in their meta-analysis coming from the BEST trial. BEST is the only beat-blocker

trial in which the beta-blocker, bucindolol, was not found to reduce the risk all-cause

mortality of patients with HFrEF.4 In BEST, only a handful of patients were recruited

outside the US, therefore including this trial created a bias against the benefit of beta-

blockers in the US4,6 Bucindolol is a unique beta-blocker, as it is the only beta-blocker to

possess central sympatholytic activity.7 It had initially been hypothesized that because

bucindolol decreases norepinephrine concentrations, it could represent a more effective

beta-blocker.8 However, the results of the BEST trial,7 as well as data from a RCT

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

investigating the central sympatholytic moxonidine,9 would suggest that this

sympatholytic effect may in fact have a deleterious impact on clinical outcomes in

patients with HFrEF.

Despite the clear bias created by the proportion of patients in the BEST trial coming from

the US versus the ROW, other potential explanations could help understand regional

differences. These include differences in baseline characteristics of the populations,4,10

differences in the care of patients between the US and the ROW, treatment adherence,11

as well as nutritional, social, cultural and genetic factors.4 Of particular interest, there

was a much higher proportion of individuals of African descent in BEST (23%) than in

MERIT-HF (5%), COPERNICUS (5%) or CIBIS II (0.3%).10 Indeed, existing data

indicate that African-Americans are more likely to carry genetic variations in the

adrenergic pathway (e.g. the beta1-adrenergic-coding gene ADRB1) and related systems

(e.g. the G protein-coupled receptor kinase-5 coding gene GRK5) that may be associated

with a lesser response to beta-blocker, and could thus contribute to regional differences in

results.12,13

Consistent with these concerns, Chatterjee found that a significant heterogeneity existed

between studies in the North American subgroup for many of the analyses conducted.

One has to appreciate the fact that in most cases, this heterogeneity is related to the more

modest benefits observed in the BEST trial. Again, this suggests that the potential

geographic heterogeneity observed by O’Connor could largely be a reflection of the

singular pharmacological properties of bucindolol, rather than an actual difference in

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

efficacy of beta-blockers between individuals established in two different geographic

locations.

The meta-analysis by Chatterjee et al.3 includes a much broader scope of studies. They

include other well-known large multicenter studies, such as the US Carvedilol Heart

Failure Study14 and SENIORS (Study of the Effects of Nebivolol Intervention on

Outcomes and Rehospitalisation in Seniors with Heart Failure),15 as well as smaller trials.

Although this could represent a strength, it also muddies the water by adding studies that

present significant differences from the four large RCTs included in the O’Connor meta-

analysis. Moreover, the inclusion of some of these trials may have underestimated the

benefits of beta-blockers in the ROW population which may have paradoxically served to

compensate for the effect of the BEST trial in the US. For example, in SENIORS,

nebivolol was used in a heterogeneous population of elderly patients with HFrEF and HF

with preserved left ventricular ejection fraction (HFpEF),15 the latter in which the

benefits of beta-blockers remain uncertain and untested. In COMET, the comparator of

carvedilol was metoprolol tartrate and not placebo,16 while in CARMEN, the comparator

was enalapril,17 which may have minimized the apparent benefits of beta-blockers in the

ROW population. Finally, in the original CIBIS trial,18 a more conservative bisoprolol

dosing approach was used than in CIBIS II, which again could minimize the benefit of

the beta-blocker in the ROW population. Thus, despite its strengths, the Chatterjee meta-

analysis exposes other potential weaknesses of meta-analyses, such as the inclusion of

heterogeneous treatment approaches, populations and comparators.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

Finally, other artificial regional differences of more concern could result from regional

differences in the inclusion of patients in trials, such as appears to have happened in the

TOPCAT (Treatment of Preserved Cardiac function Heart Failure with an Aldosterone

Antagonist) trial, in which marked differences in clinical outcomes and spironolactone

efficacy were reported between the Americas (the United States, Canada, Brazil, and

Argentina) and Russia and Georgia.19

So where does that leave us? From the totality of the data available, it would appear that,

although inter-individual variability in the response to beta-blockers, and to most drugs

for that matter, exists, there does not appear to be significant variations in the response to

beta-blockers in patients with HFrEF in regards to their geographical location. Rather, if

regional differences in response to beta-blockers exist, they are likely the reflection of a

wide variety of factors between these populations, which cannot be simply summarized

by the geographic location of an individual. Until useful tools (biomarkers, genetic

markers, or others) to personalize the management of HF patients are identified, the take-

home message is that three beta-blockers (carvedilol, bisoprolol and metoprolol

succinate) are effective in reducing all-cause mortality and morbidity in patients with

HFrEF and that these three agents should be used according to clinical guidelines in all

appropriate patients with careful consideration to reach target doses in a timely manner,

or at least, the highest dose tolerated by the patient. Unfortunately, more than a decade

after the publication of these pivotal trials, the use of these life-saving drugs in patients

with HFrEF remains alarmingly heterogeneous in clinical practice, with many centers

showing suboptimal use.20,21

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

References

1. Marr G. Location, location, location — and other timeless real estate ‘principles’.

Financial Post 2013. Available at: http://business.financialpost.com/2013/05/18/location-

location-location-and-other-timeless-real-estate-principles/. Accessed on April 11th, 2014

2. Mentz RJ, Kaski JC, Dan GA, et al. Implications of geographical variation on

clinical outcomes of cardiovascular trials. Am Heart J 2012;164:303-12.

3. Chatterjee S, Udell JA, Sardar P, Lichstein E, Ryan JJ. Comparable benefit of

beta-blocker therapy across regions of the world: meta-analysis of randomized clinical

trials. Can J Cardiol.

4. O'Connor CM, Fiuzat M, Swedberg K, et al. Influence of global region on

outcomes in heart failure beta-blocker trials. J Am Coll Cardiol 2011;58:915-22.

5. LeLorier J, Grégoire G, Benhaddad A, Lapierre J, Derderian F. Discrepancies

between Meta-Analyses and Subsequent Large Randomized, Controlled Trials. N Engl J

Med 1997;337:536-42.

6. A trial of the beta-blocker bucindolol in patients with advanced chronic heart

failure. N Engl J Med 2001;344:1659-67.

7. Bristow MR, Krause-Steinrauf H, Nuzzo R, et al. Effect of baseline or changes in

adrenergic activity on clinical outcomes in the beta-blocker evaluation of survival trial.

Circulation 2004;110:1437-42.

8. The BEST Steering Committee. Design of the Beta-Blocker Evaluation Survival

Trial (BEST). Am J Cardiol 1995;75:1220-3.

9. Cohn JN, Pfeffer MA, Rouleau J, et al. Adverse mortality effect of central

sympathetic inhibition with sustained-release moxonidine in patients with heart failure.

Eur J Heart Fail 2003;5:659-67.

10. Domanski MJ, Krause-Steinrauf H, Massie BM, et al. A comparative analysis of

the results from 4 trials of beta-blocker therapy for heart failure: BEST, CIBIS-II,

MERIT-HF, and COPERNICUS. J Card Fail 2003;9:354-63.

11. Wu JR, Moser DK, Chung ML, Lennie TA. Objectively measured, but not self-

reported, medication adherence independently predicts event-free survival in patients

with heart failure. J Card Fail 2008;14:203-10.

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

12. Liggett SB, Mialet-Perez J, Thaneemit-Chen S, et al. A polymorphism within a

conserved beta1-adrenergic receptor motif alters cardiac function and beta-blocker

response in human heart failure. PNAS 2006;103:11288-93.

13. Liggett SB, Cresci S, Kelly RJ, et al. A GRK5 polymorphism that inhibits beta-

adrenergic receptor signaling is protective in heart failure. Nat Med 2008;14:510-7.

14. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and

mortality in patients with chronic heart failure. N Engl J Med 1996;334:1349-55.

15. Flather MD, Shibata MC, Coats AJ, et al. Randomized trial to determine the effect

of nebivolol on mortality and cardiovascular hospital admission in elderly patients with

heart failure (SENIORS). Eur Heart J 2005;26:215-25.

16. Poole-Wilson PA, Swedberg K, Cleland JG, et al. Comparison of carvedilol and

metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or

Metoprolol European Trial (COMET): randomised controlled trial. Lancet 2003;362:7-

13.

17. Komajda M, Lutiger B, Madeira H, et al. Tolerability of carvedilol and ACE-

Inhibition in mild heart failure. Results of CARMEN (Carvedilol ACE-Inhibitor

Remodelling Mild CHF EvaluatioN). Eur J Heart Fail 2004;6:467-75.

18. CIBIS Investigators and Committees. A randomized trial of beta-blockade in heart

failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation 1994;90:1765-

73.

19. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for Heart Failure with

Preserved Ejection Fraction. N Engl J Med 2014;370:1383-92.

20. Fonarow GC, Yancy CW, Albert NM, et al. Heart failure care in the outpatient

cardiology practice setting: findings from IMPROVE HF. Circ Heart Fail 2008;1:98-106.

21. Peterson PN, Chan PS, Spertus JA, et al. Practice-Level Variation in Use of

Recommended Medications Among Outpatients With Heart Failure: Insights From the

NCDR PINNACLE Program. Circulation: Heart Failure 2013;6:1132-8.