Vasodilating Beta BlockersThe 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

• B1• Heart• Kidneys• Fat cells

• B2 • 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 insulin-mediated glucose entry and metabolism.

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 point Metoprolol p Carvedilol p

Mean HbA1c change with treatment, % (SD)

0.15 (0.04) <0.001 0.02 (0.04) 0.65

Insulin sensitivity (%)

-2.0 0.48 -9.1 0.004

GEMINI: Progression to microalbuminuria

Bakris GL. American Heart Association Scientific Sessions 2004. Nov 7-10, 2004; New Orleans, LA.

End point Metoprolol Carvedilol

Odds ratio (95% CI)

p

Progression to microalbuminuria (%)

10.3 6.4 0.60 0.04

Lipid Metabolisem

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

Vasodilating Beta Blockers

Improved Efficacy

in CHFin Elderly and Obese Patients

COMET Trial Results

End point Carvedilol (n=1511) (%)

Metoprolol (n=1518) (%)

HR(95% CI)

p

All-cause mortality

33.9 39.5 0.83(0.74-0.93)

0.0017

All-cause mortality or all-cause hospitalization

73.9 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

Coats A. European Society of Cardiology Congress 2004; August 28-September 1, 2004; Munich, Germany.

End point Nebivolol, 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

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.

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).