Beta - adrenoblockers in the treatment of arterial hypertension and CHF

Transcription

1 Beta - adrenoblockers in the treatment of arterial hypertension and CHF Viacheslav Mareev M.V.Lomonosov Moscow State University, Moscow, Russia HFA ESC Congress, Belgrade, 21 May 2012

2 EPOCH - CHF Relative risk of development of CHF (by Framingham criteria) 14 12,2 11,2 Prevalence of CHF By Framingam criteria = 4,5% (RF) 7 3,9 3,7 3,8 6,4 0 0,1 AH CAD AMI VHD DCMP DM Н / И

3 Frequancy / 1000 pts/years Increased risk of CV cjmplications due AH (>140/90 mm Hg) CAD / AMI STROKE P V D C H F 45,4 Controls Hypertensives Relative Risk Risk ,7 21,3 12,4 9,5 9,9 6,2 7,3 5 3,3 2,4 2 x 4 13,9 6,3 3,5 2,1 Males Females Males Females Males Females Males Females Муж Жен Муж Жен Муж Жен Муж Жен Framingham Heart Study - CV compications due to BP levels (n=4559) years; 36-years of F-U Kannel WB JAMA 1996; 275(24):

4 Influence of antihypertensive therapy: BAB (BAB + Diuretics) on the risk of CV complications (CHF) 0 CHF STROKE CV death AMI % -52 All changes are significant Hebert P., Arch Intern Med, 1993; 153: Moser M et al., J Am Coll Cardiol, 1996; 27:

5 Relative Risk of CHF With BB as a Function of SBP Difference Between Treatment Modalities at Study End Bangalore, S. et al. J Am Coll Cardiol 2008;52:

6 Antihypertensive efficacy (% of pts at goal <140/90 mm Hg) after treatment with different beta- blockers 90 % n= Betaxolol Metoprolol Atenolol Talinolol Bisoprolol 40 mg 100 mg 100 mg 100 mg 10 mg Olbinskay L.I. at al., Kardiologia, 2002;41:56

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8 Proportion of all cause deaths Relation between plasma norepinephrine concentration and risk of death in CHF patients 100 NE > 900 pg/ml 80 p< NE = pg/ml NE < 600 pg/ml M o n t h e s o f f o l l o w u p J.Cohn et al.,1984

9 Survival of patients with DCMP and CHF First analysis of BAB influence on mortality in CHF Digitals + Diuretics + BAB Digitals + Diuretics NO ACEI! years K.Swedberg et al., Lancet,1979 Waagstein F., Hjalmarsson A., Varnauskas E., Wallentin I. Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy. Br. Heart J., 1975: 37,

10 Moscow study with BAB in CHF ( ) Restoration of LV pump function (via increase LVEF and CO) by the time of administration of metoprolol in CHF (no ACEI!) 25 HR 86 Initial drop of CO due to negative inotropic effect of BAB (up to first 2 weeks) 78 * 13 22* Δ LVEF 8 Δ CO n=60; NYHA=1,83-17 * Before 2 weeks 12 weeks 24 weeks LVEF Cardiac Output V.Mareev et al., ESC congress.nice,1993

11 Bisoprolol effects on myocardial viability in CHF (by equilibrium radionuclide scintigraphy) BEFORE treatment 6 months Akinetic (necrosis) - Normokinetic (alive) - Hypokinetic (Hybernation) Lopatin YM et al., Serdechnaya Nedostatochnost,2000

12 Bisoprolol dose titration in CIBIS - II trial to avoid CHF escalation Start with 1,25 and stepwise increase every 2 weeks (or even 4 weeks) only in stable clinical situation and BP > mm Hg 10 мг 8,75 7,5 6,25 5 3,75 2,5 1, weeks Optimal Possible (slow) CIBIS II investigators, Lancet,1999,v.353,p. 9-13

13 B- CONVINCE trial Possibility to keep BAB treatment even in acute worsening of CHF Stop BAB (n=78) Keep BAB (n=69) Jondeau G et al., European Heart Journal (2009) 30,

14 Relation between decrease of HR and improving survival in 12 RCI with BAB (post MI and/or CHF BAB CCB P<0,001 HR (beats/min) HR by 10 beats/min risk of all-cause death by 26% Cucherat et al. ESC 2006

15 Absence of parallelism in HR reduction and clinical effects of BAB in the treatment of patients with CHF 100 Beats/min HR 3 2,8 2,7 NYHA * 72 * 74 * ,3 2,3 2,2 2 * 2,1 * 1,5 60 INI 3 mo 6 mo 12 mo 1 INI 3 mo 6 mo 12 mo Treatment with BAB is not easy, needed accurate dose titration to avoid CHF worsening, BP drop, bradicardia + conduction disturbances and clinical effects appears months after start of therapy and decrease of HR Mareev V. et al., Cardiology, 1999

16 LVEF dynamics during long-term treatment of CHF patients with bisoprolol (n=54) Double-Bind placebo control trial (Substudy of CIBIS-II) 36 % 35,5 34, ,2 30,8 30,1 30,2 29,6 29,8 28 INI 3 mo 6 mo 12 mo Placebo (n=27) Bisoprolo (n=27) Mareev V. et al., Cardiology, 1999

17 Neuro - hormonal activation in CHF and possibiities of treatment (interplay between RAAS and SNS) RENIN ANGIOTENSIN ALDOSTERONE SYSTEM (RAAS) ACEI / ARB Х BAB SYMPATETIC NERVOUS SYSTEM (SNS) LVH, ischemia, hybernation, arrhythmia, cardiac remodeling: fibrosis, apoptosis, necrosis + Sodium and water retention Development (Progression) of CHF

18 Dynamics of SNS (NE level) and RAAS (aldosterone concentration) activity in patients with CHF treated by bisoprolol (n=54) Double-Bind placebo control trial (Substudy of CIBIS-II) NE, pg/ml Aldosterone, pg/ml ** * ** * ИСХ 6 мес 12 мес ИСХ 6 мес 12 мес Placebo(n=27) Bisoprolol (n=27) Mareev V. et al., Cardiology, 1999

19 Decreases of total mortality in BAB trials in CHF Carvedilol Metoprolol Bisoprolol Bucindolol Carvedilol Nebivolol 0 CAPRICORN MERIT-HF CIBIS II BEST COPERNICUS SENIORS

20 CIBIS - II Main end-points of the study: changes in mortality 0 A l l - c a u s e C V C H F S u d d e n р=0, P=0,17-50 % p<0, р=0,0011 CIBIS II investigators, Lancet,1999,v.353,p. 9-13

21 CIBIS - II Calculations of NNT and saving life figures for treatment of clinically relevant CHF by bisoprolol If one will treat 1000 patients (CHF II-IV, LVEF < 35%) during one year he can prevent: 39 deaths (20 from them sudden) 43 Hospitalization (40 due to worsening CHF) To save one life you need to treat with bisoprolol during one year: 25 patients with CHF (NYHA = III-IV) CIBIS II investigators, Lancet,1999,v.353,p. 9-13

22 Meta- analysis of BAB effects on mortality in patients with CHF (23 RCT, pts) BAB dose have no connection with prognosis (p=0>69) of HR on every 5 beats/min Lead to of death in CHF pts By 18% [95 CI 6-29%] McAlister F.A. et al. Ann Intern Med 2009;150:

23 CIBIS - II Mortality depending on the doses of BAB used B I s o p r o l o l P l a c e b o Lowest doses 1,25-3,75 mg Medium dose 5-7,5 mg 1 0,59 (0,32-0,74) p=0,009 Highest doses 10 mg 0,30 (0,19-0,46) p=0,0001 Risk of death : Lowest doses 1,25-3,75 mg Medium dose 5-7,5 mg 1 0,76 (0,54-1,09) p=0,059 Risk reduction in bisoprolol vs placebo: Lowest doses: - 36% (95% CI = 0,47 0,89)* Medium doses: - 68% (95% CI = 0,21-0,50)* Highest doses: -39% (95% CI = 0,41-0,91)* Highest doses 10 mg 0,28 (0,20-0,40) p=0,002

24 CIBIS - III Design of the study (free choice of the frst medications) STEP 2 Bisoprolol 1/day + Enalaprin 2/day Randomisation Bisoprolol 3,75мг 2,5 мг Screening 1,25 мг 5,0 мг 7,5 мг 10,0 мг +2,5 мг +5,0 мг +10,0 мг «Wash out» Enalapril +1,25 мг +2,5 мг +5,0 мг +7,5 мг +10,0 мг +3,75мг 5,0 мг х 2 10,0 мг х 2 2,5 мг х 2 STEP 2 Enalapril 2/day + Bisoprolol 1р/сут Weeks End of the study : 3 years

25 % без осложнений CIBIS - III Primary end-point: Death + hospitalizations BB first ACEI first B/E vs E/B 163 vs 165 pts ОР 0.97 (95% CI ) Not worsе P= % Rsk Reduction months Willenheimer R. et al., Circulation,2005:112;

26 % of sudden death % sudden death CIBIS - III Number of sudden death by the end of monotherapy phase B/E vs E/B 8 vs 16 pts ОР 0.50 (95% CI ) P=0.107 Enalapril Bisoprolol 50% RRR Число случаев месяцы Willenheimer R. et al., Circulation,2005:112;

27 CIBIS III: Subgroups analysis NYHA Gender Age> years II III жен муж 72 >72 LVEF % <28 28 Diabetes Hyperension да нет да нет P = 0,001 HR (beats/ min) <80 80 SBP (mm Hg) Hemoglobin (g/dl) 11.5 > >16 Creatinine (ml/min) <60 Glycosdes 140 > да нет BAB first better ACEI first better Willenheimer R. et al., Circulation,2005:112;

28 Survival of pts with CHF (NYHA) II-IV according to treatment with neurohormonal blockers (30 years retrospective analysis of Moscow study) 1,0 0,9 0,8 Без иапф и БАБ, (n = 432) (дигокс ин +диуретик) иапф, RRR=33%; (n = 344) иапф+баб, (n = 315) p= Выживаемость 0,7 0,6 0,5 RRR=28%; p= RRR=36%; p= ACEI + BAB (n=315) 0,4 ACEI, No BAB (n=344) 0,3 0,2 No ACEI, No BAB (n=432) 0, Дни Beenkov YN & Mareev VY, Cardiologia; 2008

29 Independent predictors of survival in CHF pts (NYHA II-IV), n=835) Multifactorial proportional analysis Parameter Beta -coifficient BAB therapy -0,6120 Low SBP -0,0114 р <0,001 <0,001 NYHA 0,3614 <0,001 Nitrates therapy LVEF 0,3541 0,001-0,0084 0,058 Beenkov YN & Mareev VY, Cardiologia; 2008

30 Real administration of BAB in clinical trials (Russia / World) CORONA (2007): 91%- World ; 93% RF CORONA (2007): 75%- World ; 87% RF ИАПФ БАБ IMPROV ФАСОН ЭПОХА СНЕГОВИК АРХИМЕД ДУЭЛЬ ТРИОЛЯ n= 811 n= 1445 n= 2989 n= 813 n= 448 n= 470 n= 108

31 Real administration of BAB in CHF patients in Europe P. de Groote Eur J Heart Fail 2007; 9:

32 Characteristic and doses of BAB in CHF ,1 mg/day EHS=17, EHS=74,9 51 mg/day EHS=4,7 4,8 mg /day 21,5% 35,5% 16,8% EHS=74,9 69,8 mg/day 69,9 mg/day 15,5% 500 6,1% 1,5% 1,9% 1,2% 0 Ate Beta Biso Carve Meto Succi Meto Tartr Nebovolol Sotalol 73,8% ( 43% of recommended doses)

33 ractical usage of optimal doses of ACEI and BAB in pts with CHF 10,5% > 50% = 20,8% Ulf Dahlstrom1*, European Journal of Heart Failure (2009) 11, 92 98

34 «No one even the best medication will not help, if the patient will not take it» Nobel prize for inventing of BAB in the treatment of CVD