Nebil

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  • 205 mild hypertensives12 weeks
  • 205 mild hypertensives12 weeks
  • Endurance = ability of an animal to exert itself for a longer period of time.
  • Endurance = ability of an animal to exert itself for a longer period of time.
  • N = 37
  • N = 72HOMA = homeostasis model assessment
  • N = 131
  • N = 131
  • N = 131
  • Nebil

    1. 1. HYPERTENSION ST THE DAJAL OF 21 CENTURY Presented byDR. ABDUL RAB SHAIKHMD CARDIOLOGY ( UK)DIPLOMA IN CARDIOLOGY (UK)C O N S U LTA N T I N T E R V E N T I O N A L C A R D I O L O G I S TR E D C R E S C E N T I N S T I T U T E O F C A R D I O L O G Y.
    2. 2. Cardiovascular Mortality Risk with 20/10 mmHg Increments in SBP/DBP* 8 Cardiovascular mortality risk 8X risk 6 4 4X risk 2 2X 0 1X risk risk 115/75 135/85 155/95 175/105 SBP/DBP (mmHg) Individuals aged 40–69 yearsSBP = systolic blood pressureDBP = diastolic blood pressure Lewington et al. Lancet 2002;360:1903–13
    3. 3. 2 MM HG BP REDUCTIONS CAN SIGNIFICANTLYREDUCE THE RISK OF CV EVENTSMeta-analysis of 61 prospective, observational studies1 million adults 2 mm Hg decrease in mean SBP 7% 10% Lewington S et al. Lancet 2002;360:1903-1913.
    4. 4. Aprovel Vs. Other Antihypertensive
    5. 5. How to get rid of this Dajjal.• Phase 1 – dietary protocols.• Phase 2 - medical therapy.
    6. 6. JNC 7: Treatment Algorithm for Hypertension Lifestyle modifications Not at goal blood pressure (<140/90 mm Hg) (<130/80 mm Hg for those with diabetes or chronic kidney disease) Initial drug choices Without compelling indications With compelling indications Stage 1 hypertension Stage 2 hypertension Drugs for compelling indications (SBP 140–159 or DBP 90–99 mm Hg) (SBP 160 or DBP 100 mm Hg) Other antihypertensive drugs Thiazide-type diuretic for most. Two-drug combination for most (diuretic, ACEI, ARB, BB, CCB) as May consider ACEI, ARB, BB, CCB, (usually thiazide-type diuretic and needed. or combination. ACEI or ARB or BB or CCB). Not at goal blood pressure Optimize dosages or add additional drugs until goal blood pressure is achieved. Consider consultation with hypertension specialist.SBP=systolic blood pressure; DBP=diastolic blood pressure; ACEI=angiotensin- ®converting enzyme inhibitor; ARB=angiotensin receptor blocker; BB= -blocker;CCB=calcium channel blocker © 2003 Thomson Professional Postgraduate Services®JNC 7. May 2003. NIH publication 03-5233. www.lipidhealth.org
    7. 7. • Phase 2 – Medical therapy.
    8. 8. Management of Endothelial DysfunctionRole of Beta Blockers
    9. 9. Beta Blockers and EndothelialClick to edit Master title style Dysfunction • Beta blockers classically do not affect endothelial dysfunction. • Only Nebivolol, a beta blocker with NO donor properties, has been shown to improve endothelial function. Journal of Human Hypertension (2005) 19, S21-S25
    10. 10. Comparison of Beta BlockersClick to edit Master title style Properties Atenolol Metoprolol Bisoprolol Carvedilol Nebivolol Generation 2nd 2nd 2nd 3rd 3rd Cost per day 6 6.2 4.5 11 11.5 100 mg OD Initial but recommended 50mg OD preferably in 5 mg OD 6.25 mg BD 5 mg OD dose divided doses Vasodilatory Y (alpha-1 Y (NO N N N action antagonism) mediated) Half life Up to 7 hrs Up to 7 hrs Up to 12 hrs Up to 10 hrs Up to 30 hrs Bioavailability 50% 80% Up to 35% Up to 96% Sleep Y Y Y N N disturbance Vascular Health and Risk Management 2007:3 (5) 647-654
    11. 11. NebivololHighly selective β1 antagonist & NO mediated vasodilator
    12. 12. Chemical Structure of NebivololClick to edit Master title styleF RSSS (levo-nebivolol) F (R 67 145) O O O O N N O O O O SRRR F (dextro-nebivolol)F (R 67 138) Mangrella et al, Pharmacol Res 1998, 38(6); 419-31
    13. 13. Unique Dual Mode of Action ofClick to edit Master title style Nebivolol Nebivolol d-Nebivolol l-Nebivolol Highly selective Endothelial NO β1 antagonist mediated vasodilator ↓ heart rate Sustained vasodilation ↑ stroke volume ↓ PVR Cardiovasc 2008; 26:115 Am J Cardio 2003; 92: 344-348 Cardiovasc Ther 2008; 26 (3): 189-202
    14. 14. The Cardioselectivity of NebivololClick to edit Master title style 45 40.7 40 35 30 1-selectivity 25 20 15.6 15 10 4.2 5 0.7 0 Carvedilol Metoprolol Bisoprolol Nebivolol Brixius K, et al. Br J Pharmacol 2001; 133:1330-8
    15. 15. Reduction in Systemic Vascular Resistance: Master title styleClick to edit Comparison with Bisoprolol Systemic Vascular Resistance Index 2900 2848 2854 2850 2787 (dyn.sec.cm-5.m2) 2800 2750 2700 2646 2650 2600 2550 2500 Bisoprolol Nebivolol Clin Drug Invest 2002; 22: 355-9
    16. 16. Blood Pressure Lowering Efficacy:Click to edit Master title style Comparison with Atenolol Systolic Diastolic Blood Pressure Blood Pressure 0 -5 -10 -15 -14.6 -14.8 -20 -18.2 -19.2 Atenolol 100mg -25 OD n = 205 hypertensives Duration = 12 weeks Gracie et al. Blood pressure suppl 2003; 2:35
    17. 17. Blood Pressure Lowering Efficacy: Click to edit Master title style Nebivolol, Bisoprolol Multicenter Study (NEBIS) DBP Response AE Lowering Rate Rate Bisoprolol Nebivolol 93% 10% 0 92% 8.9% 92% 9% -2 92% 8% -4 91% 7% 5.8% -6 6% 91% -8 89.6 5%mmHg 90% % 4% -10 90% 3% -12 89% 2% -14 89% 1% -16 88% 0% -16 -16 -18 Bisoprolol Nebivolol Bisoprolol Nebivolol n = 273 Duration = 16 weeks Cardiovasc Drugs Ther 2003; 17:257-63
    18. 18. Blood Pressure Lowering Efficacy:Click to edit Master title style Comparison with Metoprolol Complete Normalization of BP 80% 79% 75% 70% 66% 65% 60% 55% Metoprolol Nebivolol n = 155 Duration = 12 weeks Drug Invest 1991; 3:107-10
    19. 19. Sustained Blood Pressure Control: Click to edit Master title style Comparison with Bisoprolol & CarvedilolEffect on HR During Exercise and Trough to Peak Ratios Bisoprolol Carvedilol Nebivolol First Morn 10mg 50mg 10mg 1 week 5mg OD 25mg BD 5mg OD 0% % change in Heart Rate -5% -10% -15% -15% -20% -17% -25% -24% 85% 91% -30% Column 1: 3 hrs following first dose Column 2: 24 hrs following first dose 58% Column 3: 24 hrs following last dose of 7 days treatment Cardiology 2006; 106:199-206
    20. 20. Haemodynamic Effects ofClick to edit Master title style Nebivolol Nebivolol 5mg OD for 14 days 30 Atenolol 100mg OD for 14 days 25 20 15 10Variation (%) 5 0 -5 -10 -15 -20 EDV ESV SV HR CO LVEF PVR -25 De Crée J et al. Drug Invest 1991; 3:40-50.
    21. 21. Metabolic ProfileNebivolol
    22. 22. Nebivolol and Exercise ToleranceClick to edit Master title style 70 64 59 60 50Endurance time (min) 50 40 30 8% 22% 20 10 0 Placebo Nebivolol 5mg OD Atenolol 100mg OD Van Bortel LMAB. Cardiovasc Drugs Ther 1992;6:239-47.
    23. 23. Nebivolol and Lipid MetabolismClick to edit Master title style 20 n = 27 Duration = 12 weeks 16.3 Nebivolol 5mg OD 15 Atenolol 50mg ODChanges in the lipid profile 10 8.7 5 0 -2.4 -2.7 -2 -5 -4.6 -10 -10.1 -11.5 -15 TC LDL-C LDL-C/HDL-C TG Pesant Y et al. Am J Ther 1999; 8:283-8.
    24. 24. Nebivolol and Carbohydrate Click to edit Master title style Metabolism Insulin resistance Insulin resistance (HOMA index) 3 2.79 2.83 2.67 2.5 2.29 2 1.5 18% 6% 1 6 months 6 months Baseline Baseline 0.5 0n = 72 Nebivolol 5mg OD Metoprolol 100mg ODDuration = 12 weeks Celik T, et al. J Hypertens 2006;24:591-6
    25. 25. Nebivolol and New Onset ofClick to edit Master title style Diabetes New onset diabetes 2.15 2.1 2.1 2.05 14% Event rate % per year 2 1.95 1.9 1.85 1.8 1.8 1.75 1.7 1.65 Placebo Nebivolol Agabiti-Rosei E, et al. Drugs 2007; 67:1097-107.
    26. 26. Nebivolol and Erectile Function Click to edit Master title style Before Nebivolol After NebivololSeverity of ED Severe Moderate 34 18% 5% 27% Mild None % 59 30% 18% % 9% Patients treated previously with beta-blockers switched to nebivolol Doumas M, et al. Asaian J Androl 2006; 8:177-82.
    27. 27. Nebivolol and Sexual ActivityClick to edit Master title style 10 8.8 49% 5% 9 8 Sexual intercourse/month 8 7.6 7 6 5 4.5 4 12 weeks 12 weeks Baseline Baseline 3 2 1 0 Atenolol 50mg OD Nebivolol 5mg OD n = 121 Boydak B, et al. Clin Drug Invest 2005;25:409-16
    28. 28. Role of Nebivolol in HFLandmark Trials
    29. 29. Comparison with CarvedilolClick to edit Master title style CHF patients with LV dysfunction A multicentre, double-blind, head to head clinical trial Study protocol • CHF patients with left ventricular dysfunction • Treatment duration: 6 months • Dosage: Nebivolol 1.25 mg to 5mg OD Carvedilol 3.125 mg to 25 mg BID Lombardo RMR, et al. Am J Cardiovasc Drugs 2006;6:259-63.
    30. 30. Effect on LV end-systolic volumeClick to edit Master title style (ml) 80 79 7.6% 9.1% 75 73 72 70 66 65 6 months 6 months Baseline Baseline 60 55 Carvedilol Nebivolol Lombardo RMR, et al. Am J Cardiovasc Drugs 2006;6:259-63.
    31. 31. Effect on LVEF (%)Click to edit Master title style 39 38 38 37 37 36 12% 12% 35 34 34 33 33 6 months 6 months Baseline Baseline 32 31 30 Carvedilol Nebivolol Lombardo RMR, et al. Am J Cardiovasc Drugs 2006;6:259-63.
    32. 32. The ENECA TrialClick to edit Master title style Efficacy of Nebivolol in the Treatment of Elderly Patients with Chronic cardiac failure NYHA Class II-IV as an Add-on therapy to ACE-inhibitors or A-II antagonists, diuretics and/or digitalis A multicentre, double-blind, placebo-controlled clinical trial ENECA trial: study protocol • Main inclusion criteria: Hospitalised and out-patients aged more than 65 years, chronic heart failure stages (NYHA II – IV), left ventricular ejection fraction (LVEF) ≤ 35%, stable basic medication of heart failure with ACE-inhibitors or angiotensin II A1-receptor antagonists (A-II A), diuretics and/or digitalis for a minimum of 2 weeks prior to inclusion • Number of subjects =260 • Dosage: Nebivolol 1.25 mg OD, increasing over 8 weeks to maximum target dose of 10 mg OD or placebo for 8 months • Primary end point: Change on LVEF from baseline after 8 months of treatment Edes I, et al. Eur J Heart Fail 2005;7:631-9.
    33. 33. The ENECA Trial: ResultsClick to edit Master title style Relative improvement of LVEF 40% 36% 35% LVEF % improvment 30% (visit 1 vs visit 11) 80% 25% 20% 20% 15% 10% 5% 0% Placebo Nebivolol 5mg OD Edes I, et al. Eur J Heart Fail 2005;7:631-9.
    34. 34. The ENECA Trial: ResultsClick to edit Master title style Survival Rate 82% 81% 81% 81% Survival rate (%) 80% 80% 79% 79% 78% 78% 78% 77% 77% Placebo Nebivolol 5mg OD Edes I, et al. Eur J Heart Fail 2005;7:631-9.
    35. 35. The ENECA Trial: ResultsClick to edit Master title style Adverse Events 90% 78% 81% 80% Placebo Incidence of Aes (%) 70% 60% 50% 40% 30% 20% 15% 12.1% 10% 0% Adverse events Severe adverse events Edes I, et al. Eur J Heart Fail 2005;7:631-9.
    36. 36. The SENIORS TrialClick to edit Master title style Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure Double-blind, centrally randomized, placebo controlled, multicentre, international trial SENIORS trial: study protocol • Main inclusion criteria: Age ≥ 70 years (70-96 years), clinical diagnosis of chronic heart failure (CHF) and either of: a) documented LVEF ≤ 35% within previous 6 months or b) hospital admission within previous 1 year for CHF • n = 2128 in from european countries • Dosage: Nebivolol 1.25 mg OD, increasing over 16 weeks to maximum target dose of 10 mg OD or placebo • Primary end point: To evaluate Nebivolol on top of standard therapy on total mortality and morbidity in elderly heart failure patients Flather MD, et al. Eur Heart J 2005;26:215-25.
    37. 37. Epidemiology of CHFClick to edit Master title style 12 10.9 9.8 10 Men Percent of population Women 8 6.2 5.8 6 4.1 4 2.3 1.8 1.5 2 0.3 0.3 0.5 0.4 0 20-34 35-44 45-54 55-64 65-74 75+ Ages Source: CDC/NCHS and NHLBI.
    38. 38. Age and EF of patients in major placebo controlled trials of BBs inClick to edit Master title style CHF Beta Mean Mean Trial n Blocker Age EF US Carvedilol Carvedilol 1094 58 22 Metoprolol MERIT-HF 3991 64 28 XL CIBIS-II Bisoprolol 2647 61 28 COPERNICU Carvedilol 2289 63 20 S 25 Overall -- -- 63 (> 40 SENIORS Nebivolol 2128 75 35 excluded) 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; Flather MD. EHJ 2005; 26:215-5.
    39. 39. SENIORS: distribution of EFClick to edit Master title style Moen MD, et al. Drugs 2006; 66(10):1389-409.
    40. 40. The SENIORS Trial: ResultsClick to edit Master title style Left ventricular remodeling 5 10 4.5 7 5 Change in LVESV (ml) 4Change in LVEF (%) 0 3 Placebo Nebivolol -5 2 -10 1 -15 -0.1 0 -20 -19 Placebo Nebivolol -1 -25 Modified from Ghio S, et al. Eur Heart J 2006;27:562-8.
    41. 41. The SENIORS Trial: Results Click to edit Master title styleAll-cause mortality or cardiovascular hospital admission Placebo 50 Nebivolol Patients having an event (%) 40 30 RRR 14% 20 10 0 0 6 12 18 24 30 Months N. of events: nebivolol 332 (31.1%); placebo 375 (35.3%) et al. Eur Heart J 2005;26:215-25. Flather MD,
    42. 42. The SENIORS Trial: ResultsClick to edit Master title style Sudden cardiac death 25 PlaceboPatients having an event (%) Nebivolol 20 15 RRR 38% 10 5 0 0 6 12 18 24 30 Months Moen MD, et al. Drugs 2006; 66(10):1389-409.
    43. 43. Achievement of Target Dose in BBClick to edit Master title style Trials Patients reaching target doseCIBIS 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% 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; Flather MD. EHJ 2005; 26:215-5.
    44. 44. ConclusionClick to edit Master title style SENIORS provides the first large scale data for a potentially beneficial effect of beta blockade in HF patients: – With preserved EF – In elderly Moen MD, et al. Drugs 2006; 66(10):1389-409.
    45. 45. Results of BB Trials in HFClick to edit Master title style Results for All Cause Mortality Trial Beta Blocker %↓ MERIT-HF Metoprolol XL 34 CIBIS-II Bisoprolol 34 COPERNICUS Carvedilol 35 SENIORS Nebivolol 38 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; Flather MD. EHJ 2005; 26:215-5.
    46. 46. The SENIORS Trial: Sub GroupClick to edit Master title style Analysis Heart Failure and Renal Impairment • Renal impairment is a common finding in patients with HF and is independently associated with an increased risk of death. • No study has previously assessed the interaction between beta blocker response and renal function in elderly HF patients. European Journal of Heart Failure (2009) 11, 872-880
    47. 47. The SENIORS Trial: Sub GroupClick to edit Master title style Analysis • The efficacy of Nebivolol is not reduced in elderly HF patients with mild or moderate renal impairment. • In addition, Nebivolol was safe for use in those with renal dysfunction. European Journal of Heart Failure (2009) 11, 872-880
    48. 48. Click to edit Master title style
    49. 49. • Thanks for listening. But the best medicine available is still free to use,…..wait and watch

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