Beta Blockers in SIHD : Yes, All Patients Should Receive

Them !

- Dr. Akshay Mehta

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)

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)

Stable MI with normal EF

FAST-MI 2014French 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

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

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

However

• Results of the meta-analysis heavily driven by COMMIT & other trials (IV, then oral BB)

• Lack of patient-level data analysis reduces the generalizabilityof 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.

Choo EH, et al. Heart 2014;100:492–499

The association between β-blocker use afterdischarge and mortality (all-cause death and cardiac death) within 3 years was examined.

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

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

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

Why not IVABRADINE ?

• “SIGNIFY”'s Most Surprising Finding ! …2014

• Ivabradine associated with significantly worse outcomes in more than half the population : iethose with CCS angina class ≥2

• Author recom : Consider adjusting beta-blocker doses to effective levels before initiating ivabradine

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

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

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

What about SIHD with silent ischemia ?

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% stenosisin 1 or more major coronary vessels,

• prior evidence of exercise-induced ischemia

• or a h/o PTCA or CABG

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 ?

What about SIHD with CTO ?

HEART 2013

Data from 295 chronic total occlusions using the collateral flow index (CFI).

Clinical parameters and CFI

What about HFpEF ?

Association Between Use of β-Blockers and

Outcomes in Patients With Heart Failure

and Preserved Ejection Fraction

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).

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, microvascularangina, Migraine ……etc etc

So is there any SIHD patient in whom they are not indicated ?

THERE IS HARDLY ANY SUCH PATIENT

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

QED : All Patients with SIHD Should Receive Beta Blockers

Thank you for your vote in

favor of beta blockers !!

"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

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-anginaltherapy in stable CAD patients without contraindications

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.

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)

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).

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

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

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

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.

REACH REGISTRY

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

Clopidogrel for High AtherothromboticRisk 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

CHARISMA- a post hoc analysisSeptember 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.

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

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

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

MI

• 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

But….

• Several confounders

• A nonrandomized registry study

• Used a select subgroup.

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.

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

Of course, like any other drug, BB’s have :

• Side effects

• Contraindications

• Precautions

Should a SIHD patient with HFpEFbe on BB ?

Thank you!!!