Bisoprolol In Heart Failure.pdf

Bisoprolol in Heart Failure

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Development Of Neurohormonal Antagonists In Treatment Of CHF AIRE, TRACE

SOLVD V-HeFT II

Landmark Trials

CIBIS III SENIORS

SAVE, ISIS-4

COMET COPERNICUS CONSENSUS Recognition of neurohormonal activation

Potential benefit: vasodilatation

Captopril Propranolol

1975; Sweden Waagstein et al.

MERIT-HF CIBIS II USCP CIBIS I MDC

1978–80; Swedberg et al. Lancet; Br Heart J

BB contraindicated: neg. inotropic effects

1960

1970

1980

1990

2000

2005

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How Well Do Β-blockers Work In HF ? • ± 34 % reduction in mortality • Suggested mechanisms also include reduce remodeling • β-Blockers may be beneficial through resensitization of the down-regulated receptor, improving myocardial contractility. • Acts primarily by inhibiting the sympathetic nervous system.

• Increases beta receptor sensitivity (up regulation). • Anti-arrhythmic properties. • Anti-oxidant properties

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Cardiac Insufficiency Bisoprolol Studies - The CIBIS Story

1994: CIBIS I study

641 patients NYHA III-IV; study period: 03/1989-02/1993, bisoprolol 1.25 – 5 mg on top of standard therapy (diuretic + ACEI)  – 20% mortality (p=0.22), – 32% heart failure hospitalization (p<0.01)

1999: CIBIS II study

2647 patients NYHA III-IV; study period: 11/1995-03/1998, bisoprolol 1.25 – 10 mg on top of standard therapy (diuretic + ACEI)

 CHF a former contraindication turned into an indication

 2005:

CIBIS III study

1010 patients NYHA II-III; study period: 10/2002-05/2005, bisoprolol-first 1.2510 mg o.d. vs. enalapril-first 2.5-10 mg b.i.d. bisoprolol-first was significantly non-inferior to enalapril-first (ITT) with regard to combined primary endpoint (all-cause mortality and hospitalization) (time-to-event analysis)  46% significant sudden death reduction during first year (biso-first vs enalaprilfirst)

 Bisoprolol another option* for starting CHF therapy * Option to start CHF therapy with a beta-blocker (bisoprolol) instead of an ACE inhibitor approved in only some countries.  off-label use in the other countries ! IDN/NONCMCGM/1018/0011 IDN/NONCMCGM/1018/0011

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CIBIS I: Main Results •

•

Reduction of mortality with bisoprolol in patients ... ... in total (n=641) ... without myocardial infarction ... with dilated cardiomyopathy ... with a ventricular rate of over 80 beats/minute

– 20% – 47% – 53% – 42%

p=0.22 p=0.01 p=0.01 p<0.05

Reduction by one NYHA class in patients receiving ... ... bisoprolol ... placebo

21% 15%

p=0.04

– 32%

p<0.01

•

Reduction in heart failure decompensation requiring hospitalisation

•

Tolerability/safety of bisoprolol comparable with placebo (no significant difference in premature dicontinuations)

Lechat Ph at the CIBIS investigators’ meeting at the Journées Européennes de la Société Française de Cardiologie, Paris, 1994

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Conclusion of the authors: “The beneficial effects of bisoprolol on mortality and hospitalization for worsening heart-failure were not modified by baseline eGFRBSA. Renal impairment should not prevent the use of bisoprolol in patients with HF.”

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CIBIS II - Main results at a glance In the bisoprolol-treated group of patients there was a reduction in •

All-cause mortality (independent of etiology) by

34% (p<0.0001)

•

Sudden death by

44% (p<0.0011)

•

All-cause hospital admissions by

20% (p<0.0006)

•

Hospital admissions due to worsening heart failure by

36% (p<0.0001)

Permanent treatment withdrawals similar in both treatment groups

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15% (p=0.98)

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CIBIS II: Bisoprolol reduces mortality in CHF patients at all tolerated dose levels Biso 1.25–3.75 mg/d, n=434

1

0.9 0.8

Survival Probability

Survival Probability

1

0.7 HR 0.66 (0.48–0.92)

0.6 0.5

Biso low dose Plac low dose

0.4

Months

0.3 0

5

10

15

20

Biso 5–7.5 mg/d, n=328

0.9

0.8 0.7 HR 0.33 (0.21–0.51)

0.6

0.5 Biso moderate dose Plac moderate dose

0.4

25

0

Survival Probability

1

its withdrawal increases risk of mortality  Better a low dose than no dose!

5

10

15

20

Biso 10 mg/d, n=565

0.9

0.8 0.7 HR 0.59 (0.40-0.89)

0.6

Simon T et al. Eur Heart J 2003;24:552–59

0.5 Biso high dose Plac high dose

0.4

Months

0.3 0

5

10

15

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Months

0.3

20

25

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25

CIBIS III - Cardiac Insufficiency Bisoprolol Study III Effect On Survival And Hospitalisation Of Initiation Of Treatment For Chronic Heart Failure With Bisoprolol Followed By Enalapril Compared To The Opposite Sequence • Investigator-initiated, Multicentre, Prospective, Randomised, Open-label, Blinded Endpoint Evaluation (Probe) Trial

• 1,010 Patients (NYHA II+III), 128 Centres, 20 Countries (Europe, Tunisia, Australia) • Study Period: 10/2002–05/2005

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CIBIS III:

Worsening Heart Failure Throughout Study (ITT) Requiring Hospitalisation or Occurring in Hospital:

Sudden Death – First Year 46% significant reduction of SD

• Initiating CHF treatment with bisoprolol as effective and well-tolerated as initiating treatment with enalapril • Bisoprolol-first strategy  trend to improved early survival • Bisoprolol as another option for starting CHF therapy • More patients to benefit from early beta-blockade IDN/NONCMCGM/1018/0011 IDN/NONCMCGM/1018/0011

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CIBIS-ELD study

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CIBIS-ELD: results • Primary endpoint

• Tolerability, defined as reaching and maintaining guidelinerecommended target doses after 12 weeks of treatment

• None of the BBs was superior with regard to tolerability (p=0.64): ➢ bisoprolol: 24% (95% CI 20-28) reached endpoint ➢ carvedilol: 25% (95% CI 21-29) reached endpoint

• Overall, 55% of patients tolerated at least half of the target dose. • Mean daily doses reached at follow-up were: ▪ bisoprolol 5,0 mg ▪ carvedilol: 23.9 mg in patients ≤85 kg (47.7 mg in patients >85 kg)

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CIBIS-ELD: results Bisoprolol induced ➢ a greater reduction of heart rate (adjusted mean difference 2.1 bpm, 95% CI 0.5-3.6; p=0.008) ➢ more bradycardic adverse events (16% vs. 11%; p=0.02) ➢ more fatigue/drowsiness adverse events (11% vs. 5%; p=0.003)

Carvedilol led to ➢ a reduction of forced expiratory volume (FEV1; adjusted mean difference 50 ml, 95% CI 4-95; p=0.003

➢ more pulmonary adverse events (10% vs. 4%; p<0.001) ➢ more anemia adverse events (12% vs. 7%; p<0.01)

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CIBIS-ELD:

Conclusion and clinical implications • There was no difference in achieved doses and tolerability to target doses between bisoprolol and carvedilol in elderly patients with heart failure, although the patterns of adverse effects differed. • With both agents, it appears that clinicians should follow an individualized, slower, titration scheme.

• For patients with low resting heart rates, physicians might prefer prescription of carvedilol, and for patients with lung disease, the favourable beta-blocker might be bisoprolol.

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Safety profile of bisoprolol

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AWR (cm H2O/L/s)

Bisoprolol: Beta1-selectivity results in minimal effects on lung function in patients with stable angina pectoris and chronic obstructive lung disease1,2 9

8 b=before dosing N=12 Mean ± SEM

7

Airway resistance (AWR) Heart rate (HR)

HR (beats/min)

90

70

50 b

Graph adapted from reference 1

2

4 8 24 3 6 12 Placebo

b

2 4 8 24 1 3 6 12 Bisoprolol 20 mg

b

1

4 8 24 3 6 12 Atenolol 100 mg

For complete contraindications, warnings and precautions for use please refer to the abbreviated product information at the end of this presentation.

1. Cruickshank JM. The Modern Role of Beta-blockers in Cardiovascular Medicine. Shelton, CT: People's Medical Publishing House-USA;2011, Fig. 1-8 2. Dorow P, Bethge H, Tönnesmann U. Effects of single oral doses of bisoprolol and atenolol on airway function in nonasthmatic chronic obstructive lung disease and angina pectoris. Eur J Clin Pharmacol. 1986;31:143–7. IDN/NONCMCGM/1018/0011

2

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IDN/CONCO/0318/0011

1

Bisoprolol: Beta1-selectivity results in minimal effects on airways resistance in asthmatic hypertensive patients1,2 * N=12 Mean ± SEM *p<0.05 vs. placebo2

1.2 0.8

0.4 0 Airway resistance (AWR)

– 0.4 – 0.8 10 mg Placebo

20 mg Bisoprolol

100 mg Atenolol

Graph adapted from reference 1 For complete contraindications, warnings and precautions for use please refer to the abbreviated product information at the end of this presentation. 1. Cruickshank JM. The Modern Role of Beta-blockers in Cardiovascular Medicine. Shelton, CT: People's Medical Publishing House-USA;2011, Fig. 6-9 2. Chatterjee SS. The cardioselective and hypotensive effects of bisoprolol in hypertensive asthmatics. J Cardiovasc Pharmacol. 1986;8(Suppl 11):S74–S77.

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Change in AWR (cm H2O/L/s)

1.6

Bisoprolol has minimal effects on lipids and glucose1,2 Cholesterol (mg/dL)

Triglycerides (mg/dL)

**p<0.05 vs. placebo

260

*

250

220

200

180

150

140

100

100 Initial value

After 2 weeks of bisoprolol 10 mg daily

Initial value

After 2 weeks of placebo

After 2 weeks of bisoprolol 10 mg daily

After 2 weeks of placebo

* Glucose (mg/dL)

*

HbA1 (%)

180

10

160

9

140

8

120

7

100

6 Initial value

After 2 weeks of bisoprolol 10 mg daily

Graph adapted from reference 1

After 2 weeks of placebo

Initial value

After 2 weeks of bisoprolol 10 mg daily

After 2 weeks of placebo

For complete contraindications, warnings and precautions for use please refer to the abbreviated product information at the e

1. Cruickshank JM. The Modern Role of Beta-blockers in Cardiovascular Medicine. Shelton, CT: People's Medical Publishing House-USA;2011, Fig. 6-13 2. Janka HU, Ziegler AG, Disselhoff G et al. Influence of bisoprolol on blood glucose, glucosuria, and haemoglobin A1 in noninsulin-dependent diabetics. J Cardiovasc Pharmacol. 1986;8(Suppl 11):S96–S99. IDN/NONCMCGM/1018/0011

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Bisoprolol: Beta1-selectivity and lipid metabolism during long-term therapy1-3

0

Mepindolol 10 mg/day (n=16) Bisoprolol 10 mg/day (n=17)

-10

Propranolol 160 mg/day (n=15 Atenolol 100 mg/day (n=22)

**

-20

**

**

**

**

-30

**

*

% change in plasma HDL-cholesterol

+10

**

**

**

12

18

**

-40

Graph adapted from reference 1

*p<0.05 **p<0.01

6

24

30

36

months

vs. baseline

For complete contraindications, warnings and precautions for use please refer to the abbreviated product information at the end of this presentation. 1. Cruickshank JM. The Modern Role of Beta-blockers in Cardiovascular Medicine. Shelton, CT: People's Medical Publishing House-USA;2011, Fig. 1-9 and Fig. 6-14 2. Fogari R, Zoppi A, Tettamanti F, et al. ß-blocker effects on plasma lipids in antihypertensive therapy: importance of the duration of treatment and the lipid status before treatment. J Cardiovasc Pharmacol. 1990;16(Suppl 5):S76–S80. 3. Fogari R, Zoppi A. The clinical benefits of β1-selectivity. Rev Contemp Pharmacother. 1997;8:45–54. IDN/NONCMCGM/1018/0011

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Prevalence of overall sexual dysfunction (%)

Bisoprolol has minimal effect on male sexual function1-3 5.0%

4.0%

3.9% 3.0%

2.9% 2.0%

2.1% 1.8%

1.0%

0.0% Placebo

Enalapril 5-40 mg/day

Amlodipine 2.5-10 mg/day

Bisoprolol 5 mg/day

For complete contraindications, warnings and precautions for use please refer to the abbreviated product information at the end of this presentation. 1. Prisant LM, Weir MR, Frishman WH et al. Self reported sexual dysfunction in men and women treated with bisoprolol, hydrochlorothiazide, enalapril, amlodipine), placebo or bisoprolol/hydrochlorothiazide. J Clin Hypertens. 1999;1:22-26. 2. Broekman CPM , Haensel SM, van de Ven LLM et al. Bisoprolol and hypertension: Effects on sexual functioning in men. J Sex Marital Ther. 1992;18(4):325-31. 3. Erdmann E. Safety and tolerability of beta-blockers: prejudices and reality. Eur Heart J Suppls. 2009;11(Suppl A):A21-A25.

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Problems • Beta Blocker Still Underuse. • Lack Of Awareness To Overcome The Adverse Effect.

• The Naive To Initiate And Uptitrate Beta Blocker In Heart Failure.

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Medications Received – Beta Blockers 100 90 80 70 60

others

50

metoprolol

40

bisoprolol

30

carvedilol

20

no BB

±30%

10 0 prior (2011)

during (2011)

discharge (2011)

prior (2012)

during (2012)

discharge (2012)

BB less prescribed upon discharge? NCCHK Registry of Heart Failure. IDN/NONCMCGM/1018/0011

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Beta Blocker in Asia

Beta Blocker in Asia 10-50% Malaysia (10%), Japan (50%)

Guo Y, et al. Current Cardiology Reviews, 2013, 9, 112-122 IDN/NONCMCGM/1018/0011

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Are We On Target Dose ?

NCCHK Registry of Heart Failure. IDN/NONCMCGM/1018/0011

Siswanto BB, 2011

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Achievement Of Target Dose In Beta-blocker Trials Patients reaching target dose

CIBIS II (bisoprolol 10 mg o.d.)

42%

MERIT-HF (metoprolol 200 mg o.d.)

64%

COPERNICUS (carvedilol 25 mg b.i.d.)

65%

SENIORS (nebivolol 10 mg o.d.)

68%

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CIBIS II Investigators & Committees. Lancet 1999; 353:9-13; MERIT HF Study group. Lancet 1999; 353:2001-7; Packer M, et al. N Eng J Med 2001; 344(22):1651-8; Merck Flather MD. EHJ 2005; 26:215-5.

Adherence to CHF Treatment Guidelines 100

88%

82%

Adherence (%)

80

63% 58%

60

40

20

0

Overall

ACE-I

Diuretics

The Mahler Survey Investigation, European Heart Journal, 2005 IDN/NONCMCGM/1018/0011

beta-blockers

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The Importance Of Adhering To Guidelines

Estimated probability of cardiovascular hospitalisations

1.0

0.9

0.8 Low adherence (0-33%) 0.7

Middle adherence (50-67%) High adherence (100%)

0.6 Log rank test: p=0.002

0.5 0

20

40

60

80

100

120

140

160

180

Days

The Mahler Survey Investigation, European Heart Journal, 2005 IDN/NONCMCGM/1018/0011

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Challenges In Initiating Beta Blocker Initiation Of Treatment With A Beta Blocker May Produce 4 Types Of Adverse Reactions That Require Attention And Management: • • • •

fluid retention and worsening HF Fatigue bradycardia or heart block hypotension The Mahler Survey Investigation, European Heart Journal, 2005

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Overcome The Challenges!!! Fluid retention and worsening HF Occurrence of fluid retention or worsening HF is not generally are as on for the permanent withdrawal of treatment. Euvolemic state.

Fatigue Multifactorial and is perhaps the hardest symptom to address with confidence. Other causes of fatigue should be considered, including sleep apnea, over diuresis, or depression. Yancy et al. 2013. JACC:e147–239. ESC Acute and Chronic Heart Failure. 2012. IDN/NONCMCGM/1018/0011

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Overcome The Challenges!!! Bradycardia or heart block ▪ECG to exclude heart block ▪Consider pacemaker support if severe bradycardia, AV block or SSS early after starting ▪Review : need, reduction or discontinuing other heart rate slowing drugs e.G digoxin, amiodarone, diltiazem ▪Reduce dose ( discontinuation rarely necessary) Hypotension Administer the β-blocker and acei at different times. Reduce/stop other agents that reduce bp (nitrate, ccbs). May also resolve after a decrease in the dose of diuretics in patients who are volume depleted. If accompanied by clinical evidence of hypoperfusion, should be decreased or discontinued.

The Mahler Survey Investigation, European Heart Journal, 2005 IDN/NONCMCGM/1018/0011

Yancy et al. 2013. JACC:e147–239. ESC Acute and Chronic Heart Failure

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Lee HY, Baek SH. Circ J 2016; 80: 565-571 IDN/NONCMCGM/1018/0011

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Summary • CHF Still Becomes Major Health Problem Worldwide • Guidelines Publicized The Importance Of Beta Blocker On Therapeutic Regiment Of CHF (Class 1A) • Beta Blocker Therapy Still Underuse, Both Globally And In Indonesia, Because The Concern Of Adverse Effects After Initiation • Always Consider Adding Β-blocker To Standard Treatment For HF With Impaired Systolic Function, Regardless Of Severity • Do Not With-hold From Patients With Comorbidities (COPD, DM, PAD) • Avoid In Total AV Block, Severe Poorly Controlled Asthma, And Critical Limb Ischaemia • Use Drug Licensed For CHF : Bisoprolol, Carvedilol, Metoprolol, Nebivolol • Start With Small Dose, Titrate Slowly Every 2 Weeks

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Summary • Aim to achieve recommended target dose, but accept the maximum tolerated dose • Check standing and sitting BP and heart rate, bradycardia in the absence of symptoms does not require dose reduction • Try not to stop the β-blocker if the HF deteriorates, try to adjust other drugs to regain control of symptoms and fluid balance • In patients who also have asthma or COPD, monitor symptoms and peak expiratory flow rates closely

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THANK YOU

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