A presentation made by Dr. Akshay Mehta on the topic- Beta blockers in SIHD: yes, all patients should receive them !. This was presented at the SIHD conference, Mumbai, 2015.

1. Beta Blockers in SIHD :
Yes, All Patients Should Receive
Them !
- Dr. Akshay Mehta

2. Spectrum of SIHD
• Stable HF with reduced EF (HFrEF)
• Stable MI with reduced EF
• Stable MI with preserved EF
• Stable angina
• Asymptomatic CAD
• HF with preserved EF (HFpEF)

3. Stable HF with reduced EF (HFrEF)
Stable MI with reduced EF
Beta-blocker therapy should be used in all
patients with LV systolic dysfunction (ejection
fraction ≤40%) with heart failure or prior MI,
unless contraindicated.
(Class I, Level of Evidence: A) ACC/AHA 2012
SIHD Guidelines
(Unchanged in 2014 update)

4. Stable MI with normal EF

5. FAST-MI 2014
French registry of STEMI and NSTEMI patients from 2005
to 2010
• In post STEMI pts with EF > 40 % and without HF:
• After one year, survival was 95.3% for patients on beta-
blockers and 87.8% in those off the drug.
• At five years more patients in the off-beta-blocker group
were alive
• Both results not statistically significant.
• Thus, in post MI pts with near normal EF, early beta-blocker
treatment might be beneficial

6. The American Journal of
Medicine (2014) 127, 939-953

7. Results of the Meta-analysis
• In the pre-reperfusion :b-blockers reduced
mortality
• In the reperfusion era : no mortality benefit but
reduced recurrent myocardial infarction and
angina (short-term) at the expense of increase in
heart failure and, cardiogenic shock

8. However
• Results of the meta-analysis heavily driven by COMMIT &
other trials (IV, then oral BB)
• Lack of patient-level data analysis reduces the generalizability
of these findings
• Significant clinical heterogeneity : many different beta-
blockers were given in various dosages, which precludes
identification of potentially harmful regimens
• Registry data have found significant differences in outcomes
according to timing and route of beta-blocker administration
in myocardial infarction patients.

9. Choo EH, et al. Heart 2014;100:492–499
The association between β-blocker use after
discharge and mortality (all-cause death
and cardiac death) within 3 years
was examined.

10. Kaplan-Meier curves of all cause mortality
according to β-blocker treatment

12. Hence, for post MI, Normal EF :
• Beta-blocker therapy should be started and
continued for 3 years
• Class I, Level of Evidence: B- ACC/AHA 2012
(Unchanged in 2014 update)
• For 1 year – 2013 ESC guidelines

13. Should a patient with stable
angina without MI or LV dysfun be
on BB ?
Beta blockers should be prescribed as initial
therapy for relief of symptoms in patients with
SIHD (Class I, Level of Evidence: B)
ACC-AHA 2012

14. Why not IVABRADINE ?
• “SIGNIFY”'s Most Surprising Finding ! …2014
• Ivabradine associated with significantly worse
outcomes in more than half the population : ie
those with CCS angina class ≥2
• Author recom : Consider adjusting beta-blocker
doses to effective levels before initiating
ivabradine

15. Should an asymptomatic person, with SIHD
without LV dysfn be on BB ?
• REACH…2012
• CHARISMA…..2014
• Andersson et al - Kaiser Permanente Northern
California….2014
• FAST AMI……2014

16. REACH registry 2012
• known prior MI
• known CAD without MI
• CAD risk factors only
No benefit in any group
CHARISMA 2014
• prior MI ,
• known atherothrombotic disease
• risk factors only
Benefit in prior MI group
Andersson etal 2014
• New CAD
Benefit in pts with prior MI
FAST-MI 2014
• Post MI, EF > 40%
Benefit at 1 year, not at 5 yrs

17. Limitations of all these studies :
• Older beta blockers used
• Not RCT’s
• Observational – with propensity matching, many
residual confounders missed
• No information on several factors, such as the extent of
coronary artery disease, LVEF, and patient’s functional
capacity.
• No information on whether patients continued to take
their beta-blockers over the entire follow-up or,
indeed, whether patients in the no-beta-blocker group
started taking them during this same period

18. What about SIHD with
silent ischemia ?

19. The Heart and Soul Study
• A prospective study in patients with
established CHD defined by :
• A h/o MI,
• angiographic evidence of at least 50% stenosis
in 1 or more major coronary vessels,
• prior evidence of exercise-induced ischemia
• or a h/o PTCA or CABG

20. Conclusions:
• Out of all patients with inducible ischemia > 80% did
not report angina.
• The presence of inducible ischemia without self-
reported angina was associated with > 2-fold
increased rate of recurrent CHD events
• WOULD YOU NOT GIVE BB FOR SILENT ISCHEMIA ?

21. What about SIHD with CTO ?
HEART 2013
Data from 295 chronic total occlusions using the collateral flow
index (CFI).

22. Clinical parameters and CFI

23. What about HFpEF ?
Association Between Use of β-Blockers and
Outcomes in Patients With Heart Failure
and Preserved Ejection Fraction

24. Swedish Heart Failure Registry
• JAMA. 2014, November 19
• 19 083 patients with HFPEF
• After a median of 755 days, 36% of patients who
received a beta-blocker had died compared with
46% of those who did not receive one (P<0.001).

25. So, BB’s indicated in :
SIHD WITH :
• HFrEF
• MI with r EF
• MI with p EF
• Anginal symptoms
• Silent Ischemia
• CTO
• HFpEF
• Co morbidities like Hypertension, Arrhythmia, MVP, microvascular
angina, Migraine ……etc etc
So is there any SIHD patient in whom they are not
indicated ?

26. THERE IS HARDLY ANY SUCH PATIENT

27. CONCLUSION
• No strong evidence against time tested
benefits of BB’s – NO RCT’s
• Whatever weak evidence : is with old BB’s
• Evidence of atherosclerosis regression
(even in the era of statins, ACEI)
• No serious harm

28. QED : All Patients with SIHD
Should
Receive
Beta Blockers

29. Thank you for your vote in
favor of beta blockers !!

30. "Art is a passion pursued with
discipline; science is a discipline
pursued with passion"
- Sir James Black
Discoverer of Beta Blockers and Nobel Prize laureate for medicine

31. ESC 2013
• In summary, there is evidence for prognostic
benefits from the use of b-blockers in post-MI
patients, or in heart failure.
• Extrapolation from these data suggests that b-
blockers may be the first line anti-anginal
therapy in stable CAD patients without
contraindications

32. Post-hoc analysis of participants
without HF from the CHARISMA trial
• 4,772 participants with prior MI, 7,804 with known
atherothrombosis and 2,101 with risk factors for CVD.
• Stratified within their cohort based on beta-blocker use at baseline
• The primary outcome was a composite of nonfatal MI, stroke and
CV mortality.
• Mean follow-up was 28 months.
• Propensity score analysis used within each of the three cohorts to
better control for confounding and bias.

33. Results
• In participants with prior MI, beta-blocker use was associated with lower
risk for the primary outcome compared with nonuse (7.1% vs. 10.2%;
HR=0.69; 95% CI, 0.5-0.94).
• This result was primarily driven by a lower rate of recurrent MI (3.4% vs.
4.9%; HR=0.62; 95% CI, 0.39-1), and there was no difference in mortality
(users, 5.3%; nonusers, 6.7%; P=.2), according to the results.
• In the cohorts of participants with known atherothrombosis and with CV
risk factors alone Beta-blocker use was not associated with a lower rate of
CV events
• In the risk-factor-alone cohort, there was a trend toward higher risk for
stroke associated with beta-blocker use (users, 3.5%; nonusers, 1.5%;
HR=2.13; 95% CI, 0.92-4.92)

34. FAST-MI trial
• FAST-MI is a nationwide French registry that tracked STEMI and NSTEMI patients
over a five-year period, 2005 to 2010, at 223 hospitals at the European Society of
Cardiology (ESC) 2014 Congress .
• 142 patients no longer taking beta-blockers matched with 280 patients who were
still on the drugs at 12 months.
• After one year, survival was 95.3% among patients still taking their beta-blockers
and 87.8% among those who had discontinued (HR 0.76, 95% CI 0.53–1.10). While
the survival advantage did not meet statistical significance
• After five years, however this pattern was reversed, with continued beta-blocker
use associated with a trend toward increased mortality, although here again the
numbers did not meet statistical significance (HR 1.18, 95% CI 0.67–2.08).

35. What do the guidelines say ?
Most recent ACC/AHA guidelines for STEMI and for
secondary prevention give extended beta-blocker
therapy post-AMI in patients without HF or
hypertension a class I recommendation (for at least
three years), but recent ESC guidance in STEMI
downgraded their recommendation from I to IIa

37. • No prospective, randomized, controlled trial
to test the prognostic benefit of beta-blockade
in asymptomatic patients with stable CAD esp
with NEW BB

39. Limitations of REACH
• No data on the type of BB, the medication dosage, or the
reason patients were without BB use.
• No data on type of MI or prior B-blocker use.
• Ejection fraction was not recorded.
• Not RCT
• Observational – with propensity matching, many
unmeasured confounders missed

40. Limitations to the CHARISMA analysis
• It’s a post hoc analysis
• Use of older beta-blockers
• No information whether patients continued to take
their beta-blockers over the entire follow-up or,
indeed, whether patients in the no-beta-blocker
group started taking them during this same period.

41. REACH REGISTRY

42. Conclusion
• In this 44 month longitudinal observational study of
patients with either
• CAD risk factors only,
• Known prior MI, or
• Known CAD without MI,
• The use of -blockers was not associated with a lower risk
of composite cardiovascular events.
JAMA. 2012;308(13):1340-1349

43. Clopidogrel for High Atherothrombotic
Risk and Ischemic Stabilization,
Management and Avoidance
(CHARISMA)
Deepak L. Bhatt M.D., Keith A. A. Fox M.B.Ch.B., Werner Hacke M.D., Peter B. Berger M.D.,
Henry R. Black M.D., William E. Boden M.D., Patrice Cacoub M.D., Eric A. Cohen M.D., Mark A.
Creager M.D., J. Donald Easton M.D., Marcus D. Flather M.D., Steven M. Haffner M.D., Christian
W. Hamm M.D., Graeme J. Hankey M.D., S. Claiborne Johnston M.D., Koon-Hou Mak M.D., Jean-
Louis Mas M.D., Gilles Montalescot M.D., Ph.D., Thomas A. Pearson M.D., P. Gabriel Steg M.D.,
Steven R. Steinhubl M.D., Michael A. Weber M.D., Danielle M. Brennan M.S., Liz Fabry-Ribaudo
M.S.N., R.N., Joan Booth R.N., Eric J. Topol M.D., on behalf of the CHARISMA Investigators

44. CHARISMA- a post hoc analysis
September 30, 2014 Circulation: Cardiovascular Quality and Outcomes
• Patients grouped according to whether they’d had
• a prior MI ,
• known atherothrombotic disease or
• risk factors only,
• but no heart failure at the study outset.
• Each group was divided according to whether or not they
were taking beta-blockers at baseline.

45. Over 28 months of follow-up
• Baseline beta-blocker use was associated with a 31%
reduced risk of the primary composite outcome
among patients with prior MI
• driven mainly by reduced risk of new MI
• No advantage of BB in other 2 groups

46. Analysis of 19,843 pts on whom beta-blocker treatment
initiated within 7 days of discharge from their initial CHD event.
An average of 3.7 years of follow-up.
J Am Coll Cardiol 2014; 64 : 247- 52

47. Association of BB use with cardiac events, overall
and according to presence or absence of a prior
MI

48. • No data on extent of CAD, LVEF, and patient’s
functional capacity.
• No information on why a patient was on or off beta-
blockers at any particular time.
• Observational- unmeasured confounders not
accounted for

49. But….
• Several confounders
• A nonrandomized registry study
• Used a select subgroup.

50. Extent or reperfusion therapies in
India
• Approximately 59% received fibrinolytic therapy and
• only 9% underwent primary PCI
• during their hospitalization, suggesting substantial
room for improvement in the use of acute
reperfusion therapy in STEMI patients in India
• CREATE registry data : Lancet 2008;371:1435-1442.

51. Conclusions- CTO & Collaterals
• In CTOs, collaterals provide an average of 39% of the blood flow
• Use of β blockers was associated with well-developed collaterals
• In line with studies showing that a low heart rate is positively
associated with collateral artery development
• Counteraction on catecholamines -important mediators of the
inflammatory response-another mechanism by which β blockers
could induce arteriogenesis

52. Of course, like any other drug, BB’s
have :
• Side effects
• Contraindications
• Precautions

53. Should a SIHD patient with HFpEF
be on BB ?

54. Thank you!!!