1. Vasodilating Beta Blockers The New Frontier Abdul H Sankari, MD FACC FCCP

2. Disclosure No major Holdings or Financial Assets in Pharmaceutical Co. Speakers Bureau for Abott Astra-Zeneca Forest Novartis Schering

3. OBJECTIVES Identify the scope of Hypertensive Heart Disease. Identify the shortcomings of traditional (non-vasodialating Beta Blockers). Identify the advantages of the Vasodialating Beta Blockers.

4. Beta Blockers The legacy

6. Beta Blockers INDICATIONS CAD CHF HTN ATRIAL AND VENTRICULAR ARRHYTHEMIAS

12. Beta Receptors B1 Heart Kidneys Fat cells B2 Lungs Skeletal Muscles Liver/Pancreas

13. Nebivolol

14. Vasodilating Beta blockers Better side effect profile Better Tolerability Better efficacy

15. Side Effects of Traditional Beta Blockers Fatigue Sexual Dysfunction Depression Cold extremities Decrease Exercise Tolerance Metabolic side effects

22. But WHY? Fatigue / DecreaseExercise Tolerance Reduced CO & SV Increased PVR (at least in the beginning of therapy)

24. Sexual Dysfunction Decreased blood flow in the Corpora Cavernosa due to Vasoconstriction

27. Metabolic Changes Increased insulin resistance Lipid Metabolisem

28. Increased Insulin Resistance Vasoconstriction causes decrease in micro-vascular surface area in skeletal muscle causing reduction in the insulin- mediated glucose entry and metabolism.

30. Bakris GL. American Heart Association Scientific Sessions 2004. Nov 7-10, 2004; New Orleans, LA. GEMINI: Relative to metoprolol, treatment with carvedilol stabilized hemoglobin A1c (HbA1c), a measure of glycemic control; improved insulin resistance; and slowed the development of microalbuminuria. End pointMetoprololpCarvedilolp Mean HbA1c change with treatment, % (SD) 0.15 (0.04)<0.0010.02 (0.04)0.65 Insulin sensitivity (%) -2.00.48-9.10.004

31. GEMINI: Progression to microalbuminuria Bakris GL. American Heart Association Scientific Sessions 2004. Nov 7-10, 2004; New Orleans, LA. End pointMetoprololCarvedilolOdds ratio (95% CI) p Progression to microalbuminuria (%) 10.3 6.40.600.04

32. Lipid Metabolisem Decreased Lipoprotein Lipase activity results in Increased LDL and Triglyceride levels, and decreased HDL.

34. Vasodilating Beta Blockers Improved Efficacy in CHF in Elderly and Obese Patients

35. COMET Trial Results End pointCarvedilol (n=1511) (%) Metoprolol (n=1518) (%) HR (95% CI) p All-cause mortality 33.939.50.83 (0.74-0.93) 0.0017 All-cause mortality or all-cause hospitalization 73.976.40.93 (0.86-1.10) 0.1222 Poole-Wilson P. European Heart Failure 2003 meeting; June 21-24, 2003; Strasbourg, France.

36. Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure (SENIORS) European Society of Cardiology Congress 2004

37. Main results of SENIORS trial Coats A. European Society of Cardiology Congress 2004; August 28-September 1, 2004; Munich, Germany. End pointNebivolol, n (%) Placebo, n (%) Hazard ratio (95% CI) p All-cause mortality/ cardiovascular hospitalizations 332 (31.1)375 (35.3) 0.86 (0.73-0.99) 0.039 All-cause mortality 169 (15.8)192 (18.1) 0.88 (0.71-1.08) 0.214

38. SIGNIFICANT NOTE around one third of heart-failure patients are actually receiving BB in clinical practice, because clinical trials have generally included younger patients (average age 61), whereas the average age of heart-failure patients in the real world was 76.

39. Elderly Patients Decreased density of Beta receptors results in decreased efficacy in the elderly. Vasodilating BB do not just work by blocking the Beta Receptors.

40. Obese patients Traditional Beta Blockers results in 1.2 Kg/Yr weight gain due to reduced resting energy expenditure, and thermogenesis (by as much as 10% in some trials).