Dr. Khairy Abdel Dayem. Professor of Cardiology Ain-Shams University

Transcription

1 Dr. Khairy Abdel Dayem Professor of Cardiology Ain-Shams University

2 RALES Randomized Aldactone Evaluation Study 1. NEJM Bertram Pitt Class III and IV HF patients 4. EF 35% placebo spironolactone 25 mg. 7. F/U 3 2 years

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4 EPLERONONE Competitive antagonist of aldosterone at the mineralocorticoid receptor level. Has much higher degree of selectivity for the aldosterone receptor. Has low binding affinity for progesterone, androgen and glucocorticoid receptors.

5 E P H E S U S Epleronone (Inspira) Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study 1. NEJM Bertram Pitt patients with acute MI 4. Systolic LV dysfunction: EF 40%, or D.M. 5. Randomized 3-14 D after acute event placebo epleronone mg. 8. F/U up-to 2.5 y

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7 Adverse Effects of Raised Levels of Plasma Aldosterone Soduim retention Postassium depletion Magnesium depletion Catecholamine potentiation Reduced compliance of aorta and branches Baroreceptor dysfunction Reduced heart-rate variability Higher incidence of arrhythmias Higher incidence of cardiac mortality Myocardial remodeling/fibrosis Mechanical: Due to fluid retention and ventricular wall stress Fibroblast activation

8 Effects of Myocardial Fibrosis 1. Increased wall stiffness resulting in LVDD then ultimately LVSD. 2. Increased distance between myocyte and blood vessel less availability of Q 2 and nutrients. 3. Separates myocytes from each other impeding cell to cell communication and ultimately cell survival. 4. Predisposes for: Ventricular arrhythmias Apoptosis and necrosis 5. All these changes result in: Progressive HF SCD

9 How Does Aldosterone Induce Cardiac and Vascular Fibrosis? 1. Aldosterone binds to and activates mineralocorticoid receptors present in the cardiomyocyte, endothelial cells and fibroblasts of the human heart and vessels. It promotes the entry of sodium in the fibroblast by activating Na/K ATPase and the sodium pump. This promotes the growth of fibroblasts and the synthesis of collagen. 2. It also increases gene expression of fibrillar collagen. 3. It also increases TGFβ 1 and PDGF.

10 How Does Aldosterone Induce Cardiac and Vascular Fibrosis? 4. It upregulates AT 1 receptors thus enhancing Ang. II action (ARBs may be beneficial in counteracting this effect). 5. It may act through upregulating ET A (endothelin) receptors. Endothelin antagonists e.g. bosentan (Tracelear) may be useful.

11 Beneficial Effects of Mineralocorticoid Receptor Blockade 1. Inhibits aldoesterone induced interstitial fibrosis both myocardial and arterial. 2. Decreases cardiac and arterial stiffness. 3. Improves endothelial dysfunction. 4. Attenuates platelet aggregation 5. Improves heart rate variability and. QT dispersion. 6. Decreases cardiac arrhythmias. 7. Decreases BNP and ANP.

12 Aldosterone Escape Usual doses of ACE inhibitors do not completely block production of aldosterone and the level of aldosterone may rise after several months of ACE inhibitors therapy. Mechanisms: 1. Ang. II production independent of ACE inhibition e.g. through chymase pathway 2. Aldosterone production that is independent of Ang. II activity.

13 Stimuli for Aldosterone Secretion 1. Angtiotensin II is the principal stimulator when intravascular volume is reduced. 2. Hyperkalemia: Aldosterone secretion increases after consumption of K. rich food and after vigorous physical activity. 3. Hypermagnesemia: 4. Corticotrophin, endothelin, vasopressin and catecholamines are minor stimuli. Patients with ACE genotype DD have higher levels of tissue aldosterone.

14 Characteristics of Patients in RALES and EPHESUS Cause of CHF Randomized to Receive Study Patients Age Ischemic Non- Spirono- Placebo Baseline Mean ischemic lactone EF Duration RALES ± % 24 months Randomized to Receive Eplerenone Placebo EPHESUS ± % 16 months

15 Number and Cause of Deaths from Therapy in the RALES and EPHESUS Trials Placebo RALES Study Spironolactone RR (95% CI) P value No. of deaths/ no. in group (%) No. of deaths/ no. in group (%) Total deaths 386/841 (46) 284/822 (35) 0.70( ) <.001 Death due to progression of heart failure 189/841 (22) 127/822 (15) 0.64( ) <.001 Sudden death 110/841 (13) 82/822 (10) 0.71( ).02 Placebo EPHESUS Study Eplerenone RR (95% CI) P value No. of deaths/ no. in group (%) No. of deaths/ no. in group (%) Total deaths 554/3313 (18) 478/3319 (14) 0.85( ).008 Death due to progression of heart failure 127/3313 (4) 104/3319 (3) 0.80( ).10 Sudden death 201/3313 (6) 162/319 (4.88) 0.79( ).03

16 Effects of Aldosterone Receptor Antagonists on the Number of Hospitalizations in Patients with Heart Failure in the RALES and EPHESUS RALES Study Reason for Hospitalization Placebo Spironolactone P value No. of episodes/ no. in group No. of episodes/ no. in group Cardiovascular events 753/ /822 <.001 Heart Failure 663/ /822 <.001 EPHESUS Study Reason for Hospitalization Placebo Eplerenone P value No. of episodes/ no. in group No. of episodes/ no. in group Cardiovascular events 1004/ / Heart Failure 618/ /

17 Incidence of Hyperkalemia and Gynecomastia in the RALES and EPHESUS RALES Study Placebo % Spironolactone % P value Hyperkalemia 1.0% 2.0% <.42 NS Gynecomastia 1.0% 10.0% <.001 Breast Pain 0.1% 2.0%.006 EPHESUS Study Placebo % Eplerenone % P value Hyperkalemia 3.9% 5.5%.002 Gynecomastia 0.6% 0.5%.70 NS Breast Pain 0.3% 0.1%.63 NS

18 DROSPIRONE A potent progesterone with blocking effects of the mineralocorticoid receptors equivalent to 25 mg. aldosterone. Best used in conjunction with estrogen in women with postmenopausal symptoms plus hypertension.

19 Dosage Adjustment of Aldosterone After Initiation of Therapy Based on Serum Potassium Levels Serum Potassium (mmol/l) Action Dosage Adjustment <5.0 Increase 25 mg QD to 50 mg QD Maintain No adjustment Decrease 50 mg QD to 25 mg QD 25 mg QD to 25 mg QOD 6.0 Withhold