Vasodilating Beta Blockers The New Frontier Abdul H

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

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

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.

Beta Blockers • The legacy

Beta Blockers • INDICATIONS • CAD • CHF • HTN • ATRIAL AND VENTRICULAR ARRHYTHEMIAS

Beta Receptors • B 1 • Heart • Kidneys • Fat cells • B 2 • Lungs • Skeletal Muscles • Liver/Pancreas

Nebivolol

Vasodilating Beta blockers • Better side effect profile • Better Tolerability • Better efficacy

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

But WHY? • Fatigue / Decrease Exercise Tolerance • Reduced CO & SV • Increased PVR (at least in the beginning of therapy)

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

Metabolic Changes • Increased insulin resistance • Lipid Metabolisem

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

GEMINI: Relative to metoprolol, treatment with carvedilol stabilized hemoglobin A 1 c (Hb. A 1 c), a measure of glycemic control; improved insulin resistance; and slowed the development of microalbuminuria. End point Metoprolol p Carvedilol p Mean Hb. A 1 c change with treatment, % (SD) 0. 15 (0. 04) <0. 001 0. 02 (0. 04) 0. 65 0. 48 -9. 1 0. 004 Insulin -2. 0 sensitivity (%) Bakris GL. American Heart Association Scientific Sessions 2004. Nov 7 -10, 2004; New Orleans, LA.

GEMINI: Progression to microalbuminuria End point Progression to microalbuminuri a (%) Metoprolol Carvedilo Odds l ratio (95% CI) 10. 3 6. 4 0. 60 Bakris GL. American Heart Association Scientific Sessions 2004. Nov 7 -10, 2004; New Orleans, LA. p 0. 04

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

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

COMET Trial Results End point Carvedilol Metoprolol HR (n=1511) (n=1518) (95% CI) (%) p All-cause mortality 33. 9 39. 5 0. 83 (0. 74 -0. 93) 0. 0017 All-cause 73. 9 mortality or all -cause hospitalization 76. 4 0. 93 (0. 86 -1. 10) 0. 1222 Poole-Wilson P. European Heart Failure 2003 meeting; June 21 -24, 2003; Strasbourg, France.

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

Main results of SENIORS trial End point Nebivolol, n (%) Placebo, Hazard ratio n (%) (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 Coats A. European Society of Cardiology Congress 2004; August 28 -September 1, 2004; Munich, Germany.

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 61), whereas the average of heart-failure patients in the real world was 76.

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.

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).