![LOOP DIURETICS
Proximal Convoluted Tubule
• Reversible inhibition of Na-K-2 CL Symporter on the apical
membrane of the epithelial cells in the ascending limb of the
loop of Henle
• They are bound to plasma proteins and their delivery ot the
site of action is limited by filtration
• They need to transported into the lumen by organic acid
transport system in PCT.
Distal Proximal Convoluted Tubule
NaHCO3 NaCl
Glomerulus
• Diabetic patients need a higher dose
• The bio-availability of :
Cortex
Medulla
• Frusemide: 40-70% of the oral dose
• Bumetanide and Torsemide: > 80%
NaCl
Carbonic
anhydrase
inhibitors
Descending
limb
• more effective in advanced HF patients and those
with right-sided HF
• greater cost
• Ethacrynic Acid: Slower onset of action and delayed or partial
reversibility. It is the choice for those with sulfa allergy.
553
MECHANISMS OF ACTION. Loop
diuretics are believed to improve
symptoms of congestion by
several mechanisms. First, loop
diuretics reversibly bind to and
reversibly inhibit the action of the
Na+,K+-2Cl− cotransporter, thereby
preventing salt transport in the
thick ascending loop of Henle.
Inhibition of this symporter also
inhibits Ca2+ and Mg2+ resorption
by abolishing the transepithelial
potential difference that is the
driving force for absorption of
these cations. By inhibiting the
concentration of solute within the
medullary interstitium, these
drugs also reduce the driving force
for water resorption in the collect-ing
duct, even in the presence of
AVP (see Chaps. 25 and 27). The
decreased resorption of water by
the collecting duct results in the
production of urine that is almost
isotonic with plasma. The increase
in delivery of Na+ and water to the
distal nephron segments also
markedly enhances K+ excretion,
particularly in the presence of ele-vated
aldosterone levels.
Loop diuretics also exhibit
several characteristic effects on
intracardiac pressure and systemic
hemodynamics. Furosemide acts
as a venodilator and reduces right
Thiazides
AVP antagonists
Loop
diuretics
Ascending
limb
Ascending
limb
NaCl
gradient
Na+
Loop of Henle
Mineralocorticoid
receptor antagonist
K+
Collecting duct
H2O
H2O
Na+
Na+
K+
FIGURE 28-10 Sites of action of diuretics in the kidney. AVP = arginine vasopressin. (From Bristow MR, Linas S, Port DJ:
Drugs in the treatment of heart failure. In Zipes DP, Libby P, Bonow RO, Braunwald E [eds]: Braunwald’s Heart Disease. 7th ed.
Philadelphia, Elsevier, 2004, p 573.)](https://image.slidesharecdn.com/heartfailure-141001055818-phpapp01/85/Heart-failure-9-320.jpg)
![0.5
0.4
0.3
0.2
0.1
0.0
PROBABILITY TIME SURVIVAL BENEFIT
Hazard ratio 0.85
(95% Cl 0.75–0.96), P = 0.011
Adjusted hazard ratio 0.85,
P <0.010
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
• Carvedilol: a non-selective blocker.
Amongst all three, this has been
able to show the greatest benefit
in mortality reduction.
• COPERNICUS (Carvedilol
Prospective Randomised
Cumulative Survival):
• 38% reduction in the mortality
20
10
0
Time (years)
Effect of candesartan on cardiovascular mortality or hospital
heart failure in the CHARM-Alternative trial (A) and the CHARM-Added
Two groups of patients who were randomized to candesartan
depicted—patients who were not receiving an ACEI (A) and
were receiving an ACEI (B). The effect size of candesartan was
group of patients who were receiving an ACEI. (Modified from
McMurray JJ, Yusuf S, et al: Effects of candesartan in patients with
failure and reduced left-ventricular systolic function intolerant to
converting-enzyme inhibitors: The CHARM-Alternative trial. Lancet
and McMurray JJ, Ostergren J, Swedberg K, et al: Effects of candesar-tan
with chronic heart failure and reduced left-ventricular systolic func-tion
angiotensin-converting-enzyme inhibitors: The CHARM-Added trial.
amongst patients with
advanced HF and euvolemic
status with LVEF < 25%
• 31% reduction in relative risk
of death and hospitalisation
2003.)
bisoprolol on mortality in subjects with symptomatic ischemic
nonischemic cardiomyopathy. CIBIS-I showed a nonsignificant (P =
risk reduction for mortality at 2-year follow-up. Because the
for CIBIS-I was based on an unrealistically high expected
the control group, a follow-up trial with more conservative
estimates and sample size calculations was conducted. In
bisoprolol reduced all-cause mortality by 32% (11.8% versus
0.002), sudden cardiac death by 45% (3.6% versus 6.4%; P =
hospitalizations by 30% (11.9% bisoprolol versus 17.6%
0.001), and all-cause hospitalizations by 15% (33.6% versus
0.002; see Fig. 28-17). The CIBIS-III trial addressed the impor-tant
of whether an initial treatment strategy using the beta
bisoprolol was noninferior to a treatment strategy of using an
100
0 200 400 600 800
FIGURE 28-17 Kaplan-Meier analysis of the probability of survival in patients
in the placebo and beta blocker groups in the MERIT-HF (top), CIBIS II (middle),
and COPERNICUS (bottom) trials. CHF = chronic heart failure. (Data from The
Cardiac Insufficiency Bisoprolol Study II [CIBIS-II]: A randomised trial. Lancet 353:9,
1999; Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Ran-domised
Intervention Trial in Congestive Heart Failure [MERIT-HF]. Lancet 353:2001,
SURVIVAL (% of patients)
COPERNICUS
Placebo
Carvedilol
n = 2289
P = 0.00013 (unadjusted)
P = 0.0014 (adjusted)
(days)
↓34% mortality
Placebo
Bisoprolol
n = 2647
P = 0.00006
90
80
70
60
0
0 3 6 9 12 15 18 21
MONTHS
↓35% mortality](https://image.slidesharecdn.com/heartfailure-141001055818-phpapp01/85/Heart-failure-39-320.jpg)
Heart failure
- 1. CHRONIC HEART FAILURE Alireza Kashani SET 2 Cardiothoracic Surgery
- 2. GENERAL MEASURES • Identification and Correction of Causes: • Hypertension, Diabetes,… • Identification of the causes that cause decompensation of heart failure: • dietary indiscretion • inappropriate reduction in HF management medications • patient-driven • clinician-driven • Advise to : • Stop Smoking • Limit Daily Alcohol to 2 SD for Men and 1 SD for Women and completely cease in those with alcohol-induced cardiomyopathy • avoid exposure to extreme heat and overzealous exercise
- 3. DRUGS TO AVOID IF POSSIBLE • Anti-arrhythmic: cardio-depressant and pro-arrythmic effect and can cause worsening of HF. • only “amiodarone” and “dofetilide” have shown not to adversely affect the survival • CCBs: increased cardiovascular events and worsening of HF • only vasoselective ones have shown to be safe • NSAIDs: • water and salt retention • decrease the efficacy and increase adverse effects of diuretics and ACE-Inhs
- 4. ELECTROLYTE DISTURBANCES • Potassium: • Hypokalemia carries the risk of: • arrythmia • digitalis toxicity • activation of sympathetic nervous system and RAS can cause hypokalemia • most drugs used in treatment of HF can alter potassium concentration • A modest increase in potassium can ameliorate the efficacy of HF treatment • Recommended potassium level: 4-5 mmol/L • Those on ACE-Inh and/or Aldosterone antagonists may not need supplemental K and in fact it might be deleterious.
- 5. ELECTROLYTE DISTURBANCES • Sodium: • Dietary sodium should be limited to 2-3g/d • Further restriction to <2g/d in moderate-severe HF • Fluid Restriction: • Generally unnecessary • Unless the patient is hyponatremic (Na <130 mmol) • RAS activation • Excessive AVP • Loss of salt in excess of water due to diuretic use
- 6. PHARMACOLOGICAL MANAGEMENT OF HFREF PATIENTS • Group of Medications: • Diuretics • Vasodilators • ACE-Inhs/ARBs/Aldosterone Receptor Antagonists • Beta-Blockers • Inotropes/Inodilators • Digoxin
- 7. DIURETICS • Loop Diuretics (Preferred Choice) • Increase sodium excretion by up to 20-25% of filtered load of the sodium • Enhance free water clearance • Maintain their efficacy unless the renal function is severely impaired • Thiazides • Increase sodium excretion by only 5-10% of filtered load • Decrease free water clearance • Lose their effectiveness in patients with impaired renal function (CCL < 40 mL/min)
- 8. DIURETICS - LOOP DIURETICS NaHCO3 NaCl Thiazides AVP antagonists Loop diuretics Ascending limb FIGURE 28-10 Sites of action of diuretics in the kidney. AVP = arginine vasopressin. (From Bristow MR, Linas S, Port Proximal Convoluted Tubule Loop of Henle Mineralocorticoid receptor antagonist Collecting duct Ascending limb NaCl gradient NaCl H2O H2O Na+ Na+ Na+ K+ K+ Descending limb Glomerulus Carbonic anhydrase inhibitors Cortex Medulla Distal Proximal Convoluted Tubule
- 9. LOOP DIURETICS Proximal Convoluted Tubule • Reversible inhibition of Na-K-2 CL Symporter on the apical membrane of the epithelial cells in the ascending limb of the loop of Henle • They are bound to plasma proteins and their delivery ot the site of action is limited by filtration • They need to transported into the lumen by organic acid transport system in PCT. Distal Proximal Convoluted Tubule NaHCO3 NaCl Glomerulus • Diabetic patients need a higher dose • The bio-availability of : Cortex Medulla • Frusemide: 40-70% of the oral dose • Bumetanide and Torsemide: > 80% NaCl Carbonic anhydrase inhibitors Descending limb • more effective in advanced HF patients and those with right-sided HF • greater cost • Ethacrynic Acid: Slower onset of action and delayed or partial reversibility. It is the choice for those with sulfa allergy. 553 MECHANISMS OF ACTION. Loop diuretics are believed to improve symptoms of congestion by several mechanisms. First, loop diuretics reversibly bind to and reversibly inhibit the action of the Na+,K+-2Cl− cotransporter, thereby preventing salt transport in the thick ascending loop of Henle. Inhibition of this symporter also inhibits Ca2+ and Mg2+ resorption by abolishing the transepithelial potential difference that is the driving force for absorption of these cations. By inhibiting the concentration of solute within the medullary interstitium, these drugs also reduce the driving force for water resorption in the collect-ing duct, even in the presence of AVP (see Chaps. 25 and 27). The decreased resorption of water by the collecting duct results in the production of urine that is almost isotonic with plasma. The increase in delivery of Na+ and water to the distal nephron segments also markedly enhances K+ excretion, particularly in the presence of ele-vated aldosterone levels. Loop diuretics also exhibit several characteristic effects on intracardiac pressure and systemic hemodynamics. Furosemide acts as a venodilator and reduces right Thiazides AVP antagonists Loop diuretics Ascending limb Ascending limb NaCl gradient Na+ Loop of Henle Mineralocorticoid receptor antagonist K+ Collecting duct H2O H2O Na+ Na+ K+ FIGURE 28-10 Sites of action of diuretics in the kidney. AVP = arginine vasopressin. (From Bristow MR, Linas S, Port DJ: Drugs in the treatment of heart failure. In Zipes DP, Libby P, Bonow RO, Braunwald E [eds]: Braunwald’s Heart Disease. 7th ed. Philadelphia, Elsevier, 2004, p 573.)
- 10. LOOP DIURETICS • Diuresis • Reduction of Pre-Load and PCWP • This effect is lessened in the presence of NSAIDs (esp. Indomethacin) as it is dependent on the release of vasodilatory PGs • Increase in After-Load as the result of increase in SVR secondary to RAS activation. • Hence, the need for combination with vasodilators. • K, Mg, Ca are all excreted
- 11. THIAZIDE AND THIAZIDE-LIKE • Prevent maximal urine dilution, and decrease the ability of free water clearance. • Dilutional Hyponatremia • Increase Ca resorption • Decrease Mg resorption • Increase K and H excretion as the result of increased NaCl delivery to the distal tubule. NaHCO3 NaCl Thiazides Ascending limb Proximal Convoluted Tubule AVP antagonists Loop diuretics Ascending limb NaCl H2O Na+ Na+ Na+ K+ K+ Descending limb Glomerulus Carbonic anhydrase inhibitors Cortex Medulla Distal Proximal Convoluted Tubule
- 12. Thiazides MINERALOCORTICOID AVP antagonists RECEPTOR ANTAGONISTS Loop diuretics • Mineralocorticoids: Ascending limb • Na and Water retention NaCl • K and H gradient excretion Mineralocorticoid receptor antagonist • Spironolactone • Eplerenone Collecting duct Loop of Henle diuretics in the kidney. AVP = arginine vasopressin. (From Bristow MR, Linas S, Port H2O H2O Na+ Na+ K+ K+
- 13. • Spironolactone: • Antiandrogenic and progesterone-like effects; hence, the gynaecomastia, impotence, and menstrual irregularities • Eplerenone was developed to overcome the side effects above. • Eplerenone also has a shorter half-life • Their benefits are less contributed to the diuretic effects. But their peripheral anti-aldosterone effect plays a more important role in reduction of cardiovascular morbidity and mortality.
- 14. • How does spironolactone/eplerenone work? • blocking the aldosterone receptor which is a cytosolic ligand-dependent transcription factor • these receptors are involved in myocardial fibrosis, inflammation, and calcification. • The mechanisms which have been attributed to spironolactone to improve outcome include: • prevention of extracellular matrix remodelling • prevention of hypokalemia
- 15. MAJOR STUDY SUPPORTING THE ABOVE • RALES (Randomized Aldosterone Evaluation Study)Trial (1999): 554 • Spironolactone 25 mg/d titrated to 50 mg/d if needed vs. Placebo • NYHA Class III and Class IV with LVEF of <35% already CH being treated with ACEI, Loop Diuretics, and Digoxin 28 in majority. • 30% reduction in mortality in the spironolactone group (p=0.001): • lower risk of death from progressive pump failure and sudden death • 35% reduction of hospitalisation • significant improvement in the NYHA functional call (p < 0.001) • Other retrospective trials have also demonstrated a trend of improvement in overall mortality in those with better NYHA functional class when spironolactone was added to the management. 1.00 0.95 0.90 0.85 0.80 0.75 0.70 0.65 0.60 0.55 0.50 0.45 0.00 PROBABILITY OF SURVIVAL A MONTHS Spironolactone Placebo 0 3 6 9 12 15 18 21 24 27 30 33 36 40
- 16. 0.65 PROBABILITY MAJOR STUDY 0.60 0.55 SUPPORTING THE ABOVE • EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) 2003: • A double-blinded placebo-controlled study • Primary End Points: • Death from cardiovascular causes • Hospitalization for HF, AMI, Stroke, Ventricular Arrhythmia • Significant decrease in the death from cardiovascular cause in the group which received Eplerenone • Other end points were also reduced. • EMPHASIS-HF (Mild HF patients with NYHA class II and eplerenone) 0.50 0.45 0.00 A 0 3 6 9 12 15 18 21 24 27 30 33 36 MONTHS CUMULATIVE MORTALITY (%) B Placebo 40 35 30 25 20 15 10 5 0 Placebo Eplerenone P = 0.008 RR = 0.85 (95% CI, 0.75–0.96) 0 3 6 9 12 15 18 21 24 27 30 33 36 RANDOMIZATION (mo) FIGURE 28-11 Kaplan-Meier analysis of the probability of survival in patients in the placebo and treatment groups in the RALES trial (A) with spironolactone, and probability of mortality in patients in the placebo and treatment groups in the EPHESUS (B) trial using eplerenone. (Modified from Pitt B, Zannad F, Remme WJ, et al: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 341:709, 1999; and Pitt B, Remme W, Zannad F, et al: Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunc-tion
- 17. OTHER DIURETICS • Pottasium-Sparing Diuretics: • Amiloride, Triamterene • Their effect in achieving a net negative Na balance is not that great in the patients with HF as their site of action is more in the DCT and sodium retention happens more in the PCT part of the nephrons in this group of patients. • Carbonic Anhydrase Inhibitors: • only should be used to correct the metabolic alkalosis that occurs as the result of other diuretics secondary to: • Volume contraction • Excessive H loss in the DCT • When used repeatedly can cause: • Metabolic Acidosis • Hypokalemia
- 18. OTHER DIURETICS • AVP Antagonists (Vaptans): • As increased circulating AVP in patients with HF lead to positive water balance (V2 receptor) and increased vascular resistance (V1a receptor) • 4 medications : Tolvaptan (V2), Lixivaptan (V2), Satavaptan (V2), Conivaptan (V1a, V2) • None have shown to improve mortality • Their use have been authorised for those who suffer from Hypervolemic or Euvolemic hyponatremia (<125 mmol/L) which is symptomatic and also resistant to conventional therapies (fluid restriction, etc.) Principal cell Collecting duct Synthesis DNA ↑cAMP PKA Transport receptor – Gs V2 AVP Tolvaptan Conivaptan AQP H2O H2O NA+ K+ NA+ NA+ AQP K+ H2O AQP FIGURE 28-12 Mechanism of action of vasopressin antagonists. The binding of AVP to V2 receptors stimulates the synthesis of aquaporin-2 (AQP) water channel proteins and promotes their transport to the apical surface. At the cell
- 19. DIURETICS CH 28 552 TABLE 28-7 Diuretics for Treating Fluid Retention in Chronic Heart Failure DRUG INITIAL DAILY DOSAGE MAXIMUM TOTAL DAILY DOSAGE DURATION OF ACTION (HR) Loop diuretics* Bumetanide 0.5-1.0 mg qd or bid 10 mg 4-6 Furosemide 20-40 mg qd or bid 600 mg 6-8 Torsemide 10-20 mg qd 200 mg 12-16 Ethacrynic acid 25-50 mg qd or bid 200 mg 6 Thiazide diuretics† Chlorothiazide 250-500 mg qd or bid 1000 mg 6-12 Chlorthalidone 12.5-25 mg qd 100 mg 24-72 Hydrochlorothiazide 25 mg qd or bid 200 mg 6-12 Indapamide 2.5 mg qd 5 mg 36 Metolazone 2.5-5 mg qd 20 mg 12-24 Potassium-sparing diuretics Amiloride 12.5-25 mg qd 20 mg 24 Triamterene 50-75 mg bid 200 mg 7-9 AVP antagonists Satavaptan 25 mg qd 50 mg qd NS Tolvaptan 15 mg qd 60 mg qd NS Lixivaptan 125 mg qd 250 mg bid NS Conivaptan (IV) 20-mg IV loading dose, followed by 20-mg continuous IV infusion/day 40-mg IV infusion/day 7-9 Sequential nephron blockade Metolazone 2.5 to 10 mg qd plus loop diuretic Hydrochlorothiazide 25 to 100 mg qd or bid plus loop diuretic Chlorothiazide (IV) 500 to 1000 mg qd plus loop diuretic NOTE: Unless indicated, all doses are for oral diuretics. *Equivalent doses: 40 mg furosemide = 1 mg bumetanide = 20 mg torsemide = 50 mg of ethacrynic acid. †Do not use if estimated glomerular filtration is <30 mL/min or with cytochrome 3A4 inhibitors. NS = not specified. Modified from Hunt SA, Abraham WT, Chin MH, et al: ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 112:e154, 2005.
- 20. COMPLICATIONS • Electrolyte Disturbances: • Hypo- and Hyperkalemia • Hypomagnesemia • Hypo- and Hypercalcemia • Hyponatremia • Hypotension, decreased exercise tolerance, fatigue : dose reduction can improve symptoms • Azotemia: does not need change in dose. In fact, in patients with advanced HFrEF higher levels of Urea and Creatinine should be tolerated to achieve the desired therapeutic effects. • Activation of RAS • Ototoxicity: Ethacrynic acid / tinnitus, hearing impairment, deafness / usually reversible
- 21. DIURETIC RESISTANCE • The effects of diuretics as the disease progresses becomes less and less.
- 22. DIURETIC RESISTANCE • 3 mechanisms that counteract the effects: • Most of the loop diuretics are short acting; therefore, after a period of natriuresis then a period of antinatriuresis ensues which in the setting of excess salt use can lead to a stronger Na retention. This effect is due to RAS and SANS activation. • Reduced response to endogenous natriuretic peptides in patients with progressive HF. • As the result of excessive salt delivery to the DCT the epithelial cells undergo hypertrophy and Na, K, ATP-ase activity increases as so does the the thiazide-sensitive NaCl cotransporters. Hence, the Na resorptive capacity increases by 3 folds. • Development of Cardiorenal Syndrome : Worsening renal function in the setting of worsening heart failure. This should not be dismissed as pre-renal renal impairment.
- 23. DIURETIC RESISTANCE • Strategies: • More Frequent Dosing/ Higher Doses / Continuous Infusion • Addition of Second Line Diuretics • Utilisation of Device-Based Therapies such as Ultrafiltration.
- 24. THERAPIES TO PREVENT DISEASE PROGRESSION ACE-Inh, ARBs, Renin- Inhibtors, Beta-Adrenergic Receptor Blockers, Aldosterone Antagonists
- 25. ACE-INHIBITORS • ACE-Inhs: • Should be used for symptomatic and asymptomatic HFrEF (LVEF <40%) • Interfere with RAS: • reduce AT-II • inhibit kininase II : increase bradykinin which further enhances the AT suppression • Effects: • Stabilise LV remodelling • Improve patient symptoms • Prevent hospitalisation • Prolong life
- 26. • Start with lower dose and titrate up to the recommended dose by doubling every 3-5 days. • For stable patients it is acceptable to add beta-blockers before achieving the full dose. • Higher doses are more effective in preventing hospitalisation. • What to watch? BP, Electrolytes, Renal Function, esp. in those with pre-existing azotemia, hypotension, hyponatremia, diabetes mellitus, and those taking supplemental potassium. • Abrupt withdrawal of treatment should be avoided as this might lead to clinical deterioration.
- 27. SURVIVAL BENEFIT • Meta-analysis of ACE-Inh CH in patients with depressed EF 28 following an AMI • 3 trials 560 40 30 0 A 10 Number at risk ACEI Placebo 2995 2971 ACEI 2250 2184 1617 1521 892 853 223 138 20 Placebo CUMULATIVE MORTALITY (%) 0 1 2 3 4 5 40 30 MORTALITY (%)
- 28. 10 CUMULATIVE SURVIVAL BENEFIT • Meta-analysis of ACE-Inh in HF patients with depressed EF including the post-infarction patients. • 5 trials 0 A B 0 1 2 3 4 5 Number at risk 2250 2184 1617 1521 892 853 223 138 0 1 2 3 4 5 TIME SINCE RANDOMIZATION (yr) ACEI Placebo 2995 2971 40 30 20 10 0 CUMULATIVE MORTALITY (%) FIGURE 28-15 Meta-analysis of ACE inhibitors in HF patients with a depressed EF. A, Kaplan-Meier curves for mortality for HF patients with a depressed EF treated with an ACEI following an acute AMI (three trials). B, Kaplan-Meier curves for mortality for HF patients with a depressed EF treated with an ACEI in five clinical trials, including postinfarction trials. The benefits of ACEIs were observed early and persisted long term. (Modified from Flather MD, Yusuf S, Kober L, et al: Long-term ACE-inhibitor therapy in patients with heart failure or left ventricular dysfunction: A systematic overview of data
- 29. RECOMMENDED DOSE TABLE 28-8 Drugs for the Prevention and Treatment of Chronic Heart Failure AGENTS INITIATING DOSAGE MAXIMAL DOSAGE Angiotensin-Converting Enzyme Inhibitors Captopril 6.25 mg tid 50 mg tid Enalapril 2.5 mg bid 10 mg bid Lisinopril 2.5-5.0 mg qd 20 mg qd Ramipril 1.25-2.5 mg qd 10 mg qd Fosinopril 5-10 mg qd 40 mg qd Quinapril 5 bid 40 mg bid Trandolapril 0.5 mg qd 4 mg qd Angiotensin Receptor Blockers Valsartan 40 mg bid 160 mg bid Candesartan 4-8 mg qd 32 mg qd Losartan 12.5-25 mg qd 50 mg qd
- 30. SIDE EFFECTS • Most adverse effects are related to suppression of the RAS • Mild hypotension and azotemia is well tolerated. • If hypotension is associated with dizziness then: • If fluid retention is significant: reduce the ACE-Inh dose • If fluid retention is not an issue then reduce the diuretic dose. • Potassium Retention: esp. if patient is receiving potassium supplements or potassium-sparing agents. If becomes problematic, dose reduction might be necessary. • Kinin-potentiation related side effects: • Non-productive cough (10-15%) • Angio-edema (1%)
- 31. ANGIOTENSIN-RECEPTOR BLOCKERS • Similar effects on: • LV Remodelling • Improving patient symptoms • Preventing Hospitalisation • Prolonging Life • They work on angiotensin type 1 receptor: the responsible receptor for most of the adverse effects of the RAS on CVS • Their effectiveness is similar to ACE-Inh • They can be well-tolerated in those suffering from adverse effects of ACE-Inh (angioedema, cough) • Those with ACE-Inh induced hyperkalemia, will have the same problem with ARBs and the management should be changed to a combination of Hydralazine and and oral nitrate
- 32. • There are studies that support the addition of ARBs to ACE-Inh. • The same precautions with ACE-Inh also applies to ARBs for routine checking of K, Renal Function, BP, etc.
- 33. SURVIVAL BENEFIT • CHARM (Candesartan Heart Failure : Assessment of Reduction in Mortality and Morbidity)Trial (2003): CH 28 • Candesartan effect on the mortality and hospital admission in patients not receiving ACE-Inh 562 50 40 30 20 10 0 HOSPITAL ADMISSION FOR CHF (%) CARDIOVASCULAR DEATH OR PROPORTION WITH Placebo Hazard ratio 0.77 (95% Cl 0.67–0.89), P = 0.0004 Adjusted hazard ratio 0.70, P <0.0001 Time (years) A Candesartan 0 1 2 3 3.5 50 40 CHF (%) DEATH OR Placebo Candesartan
- 34. 28 HOSPITAL ADMISSION Time (years) 20 PROPORTION CARDIOVASCULAR SURVIVAL BENEFIT • CHARM-Added Trial (2003): • Candesartan effect on the mortality and hospital admission in patients receiving ACE-Inh 10 0 Hazard ratio 0.77 (95% Cl 0.67–0.89), P = 0.0004 Adjusted hazard ratio 0.70, P <0.0001 A PROPORTION WITH HOSPITAL ADMISSION FOR CHF (%) CARDIOVASCULAR DEATH OR B 0 1 2 3 3.5 50 40 30 20 10 0 Placebo Candesartan Hazard ratio 0.85 (95% Cl 0.75–0.96), P = 0.011 Adjusted hazard ratio 0.85, P <0.010 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Time (years) FIGURE 28-16 Effect of candesartan on cardiovascular mortality or hospital admission for heart failure in the CHARM-Alternative trial (A) and the CHARM-Added trial (B). Two groups of patients who were randomized to candesartan or placebo are depicted—patients who were not receiving an ACEI (A) and patients who were receiving an ACEI (B). The effect size of candesartan was
- 35. RECOMMENDED DOSE Captopril 6.25 mg tid 50 mg tid Enalapril 2.5 mg bid 10 mg bid Lisinopril 2.5-5.0 mg qd 20 mg qd Ramipril 1.25-2.5 mg qd 10 mg qd Fosinopril 5-10 mg qd 40 mg qd Quinapril 5 bid 40 mg bid Trandolapril 0.5 mg qd 4 mg qd Angiotensin Receptor Blockers Valsartan 40 mg bid 160 mg bid Candesartan 4-8 mg qd 32 mg qd Losartan 12.5-25 mg qd 50 mg qd Beta Receptor Blockers Carvedilol 3.125 mg bid 25 mg bid (50 mg body weight > Carvedilol-CR 10 mg qd 80 mg qd Bisoprolol 1.25 mg bid 10 mg qd Metoprolol succinate 12.5-25 mg qd 200 mg qd CR
- 36. BETA-BLOCKERS • Beta Blockers interfere with the harmful effects of sustained ANS activation. • Although there are some benefits in blocking all the three adrenergic receptors (alpha-1, beta-1, and beta-2); the deleterious side effects of the activation of adrenergic system is attributed to beta-1 • They provide added benefits to ACE-Inh • Three well-studied Beta-Blockers: • Metoprolol Succinate (CR) (beta-1 selective) • Bisoprolol (beta-1 selective) • Carvedilol (nonselective blockade)
- 37. SURVIVAL BENEFIT • MERIT-HF (Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure) - 2001: 34% reduction in mortality in those with mild-moderate HF and moderate-severe systolic dysfunction. 50 40 30 20 10 0 Placebo Candesartan Hazard ratio 0.77 (95% Cl 0.67–0.89), P = 0.0004 Adjusted hazard ratio 0.70, P <0.0001 0 1 2 3 3.5 Time (years) 50 40 30 Placebo Candesartan CUMULATIVE MORTALITY (%) EFFECT OF β-BLOCKADE ON MORTALITY IN CHF MERIT-HF Placebo Metoprolol CR/XL P = 0.0062 (adjusted) P = 0.00009 (nominal) n = 3991 FOLLOW-UP (mo) ↓34% mortality OF SURVIVAL CIBIS II 20 15 10 5 0 0 3 6 9 12 15 18 21 1.0 0.9 0.8 0.7 0.6
- 38. SURVIVAL BENEFIT Hazard ratio 0.77 (95% Cl 0.67–0.89), P = 0.0004 Adjusted hazard ratio 0.70, P <0.0001 0 1 2 3 3.5 • Bisoprolol: Time a (second years) generation beta1- selective blocker with 120 fold higher affinity to beta1 than to beta2. Placebo • CBIS-Candesartan II (Cardiac Insufficiency Bisoprolol Study) - 1999: • 32% reduction in all cause mortality (p = 0.002) • 45% reduction of sudden cardiac death (p = 0.001) • 30% reduction of HF hospitalisation (p < 0.001) • 15% reduction of all cause hospitalisation (p = 0.002) 20 10 0 Hazard ratio 0.85 (95% Cl 0.75–0.96), P = 0.011 Adjusted hazard ratio 0.85, P <0.010 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Time (years) Effect of candesartan on cardiovascular mortality or hospital heart failure in the CHARM-Alternative trial (A) and the CHARM-Added Two groups of patients who were randomized to candesartan depicted—patients who were not receiving an ACEI (A) and receiving an ACEI (B). The effect size of candesartan was group of patients who were receiving an ACEI. (Modified from McMurray JJ, Yusuf S, et al: Effects of candesartan in patients with failure and reduced left-ventricular systolic function intolerant to CUMULATIVE MORTALITY FOLLOW-UP (mo) ↓34% mortality n = 3991 patients) CIBIS II COPERNICUS PROBABILITY OF SURVIVAL TIME (days) ↓34% mortality Placebo Bisoprolol n = 2647 P = 0.00006 10 5 0 0 3 6 9 12 15 18 21 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 100 90 0 200 400 600 800
- 39. 0.5 0.4 0.3 0.2 0.1 0.0 PROBABILITY TIME SURVIVAL BENEFIT Hazard ratio 0.85 (95% Cl 0.75–0.96), P = 0.011 Adjusted hazard ratio 0.85, P <0.010 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 • Carvedilol: a non-selective blocker. Amongst all three, this has been able to show the greatest benefit in mortality reduction. • COPERNICUS (Carvedilol Prospective Randomised Cumulative Survival): • 38% reduction in the mortality 20 10 0 Time (years) Effect of candesartan on cardiovascular mortality or hospital heart failure in the CHARM-Alternative trial (A) and the CHARM-Added Two groups of patients who were randomized to candesartan depicted—patients who were not receiving an ACEI (A) and were receiving an ACEI (B). The effect size of candesartan was group of patients who were receiving an ACEI. (Modified from McMurray JJ, Yusuf S, et al: Effects of candesartan in patients with failure and reduced left-ventricular systolic function intolerant to converting-enzyme inhibitors: The CHARM-Alternative trial. Lancet and McMurray JJ, Ostergren J, Swedberg K, et al: Effects of candesar-tan with chronic heart failure and reduced left-ventricular systolic func-tion angiotensin-converting-enzyme inhibitors: The CHARM-Added trial. amongst patients with advanced HF and euvolemic status with LVEF < 25% • 31% reduction in relative risk of death and hospitalisation 2003.) bisoprolol on mortality in subjects with symptomatic ischemic nonischemic cardiomyopathy. CIBIS-I showed a nonsignificant (P = risk reduction for mortality at 2-year follow-up. Because the for CIBIS-I was based on an unrealistically high expected the control group, a follow-up trial with more conservative estimates and sample size calculations was conducted. In bisoprolol reduced all-cause mortality by 32% (11.8% versus 0.002), sudden cardiac death by 45% (3.6% versus 6.4%; P = hospitalizations by 30% (11.9% bisoprolol versus 17.6% 0.001), and all-cause hospitalizations by 15% (33.6% versus 0.002; see Fig. 28-17). The CIBIS-III trial addressed the impor-tant of whether an initial treatment strategy using the beta bisoprolol was noninferior to a treatment strategy of using an 100 0 200 400 600 800 FIGURE 28-17 Kaplan-Meier analysis of the probability of survival in patients in the placebo and beta blocker groups in the MERIT-HF (top), CIBIS II (middle), and COPERNICUS (bottom) trials. CHF = chronic heart failure. (Data from The Cardiac Insufficiency Bisoprolol Study II [CIBIS-II]: A randomised trial. Lancet 353:9, 1999; Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Ran-domised Intervention Trial in Congestive Heart Failure [MERIT-HF]. Lancet 353:2001, SURVIVAL (% of patients) COPERNICUS Placebo Carvedilol n = 2289 P = 0.00013 (unadjusted) P = 0.0014 (adjusted) (days) ↓34% mortality Placebo Bisoprolol n = 2647 P = 0.00006 90 80 70 60 0 0 3 6 9 12 15 18 21 MONTHS ↓35% mortality
- 40. OTHER BETA BLOCKERS • Bucindolol: BEST Trial showed survival benefit in non-black patients versus increase mortality in black patients. This was due to a polymorphism in beta1-adrenergic receptor • Nebivolol: • Selective Beta1-Blocker with ancillary vasodilatory effects (via nitric oxide pathways) • SENIOR (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure) • Significant reduction in composite outcome of death and rehospitalisation in older patients (p = 0.04) • The effects were similar in those with depressed and preserved EF (<=35% and >35%)
- 41. Fosinopril 5-10 mg qd 40 mg qd Quinapril 5 bid 40 mg bid Trandolapril 0.5 mg qd 4 mg qd Angiotensin RECOMMENDED Receptor Blockers DOSE Valsartan 40 mg bid 160 mg bid Candesartan 4-8 mg qd 32 mg qd Losartan 12.5-25 mg qd 50 mg qd Beta Receptor Blockers Carvedilol 3.125 mg bid 25 mg bid (50 mg bid if body weight > 85 kg) Carvedilol-CR 10 mg qd 80 mg qd Bisoprolol 1.25 mg bid 10 mg qd Metoprolol succinate CR 12.5-25 mg qd 200 mg qd Aldosterone Antagonists Spironolactone 12.5-25 mg qd 25-50 mg qd Eplerenone 25 mg qd 50 mg qd Other Agents Combination of hydralazine/ isosorbide dinitrate 10-25 mg/10 mg tid 75 mg/40 mg tid
- 42. SIDE EFFECTS • Fluid Retention • General Fatigue : Generally resolves within weeks or months spontaneously • Bradycardia or Exacerbation of Heart Block: • dose reduction if HR < 50, development of 2nd or 3rd degree Blocks • Not recommended for patients with asthma or active bronchospasm.
- 43. RENIN-INHIBITORS • Aliskiren : Orally active renin inhibitor • nonpeptide inhibitor that binds to the active site of renin and prevents conversion of angiotensinogen to angiotensin I • ALOFT Study ( Aliskiren Observation of Heart Failure Treatment): • Aliskiren Vs. Placebo to patients on ACE-Inh and NYHA Class II-IV • End Point : change of base line N-Terminal pro BNP (a prognostic biomarker for HF) in 3 months • The NT-ProBNP levels were significantly lower in the Aliskiren group (p <0.01)
- 44. TRIALS 561 TABLE 28-9 Mortality Rates in Placebo-Controlled Trials* TRIAL NAME AGENT NYHA CLASS NO. OF PATIENTS IN STUDY 12-MO PLACEBO MORTALITY (%) 12-MO EFFECT SIZE (%) P VALUE AT 12 MO (FULL FOLLOW-UP) ACEIs HF CONSENSUS-1 Enalapril IV 253 52 ↓31 0.01(0.0003) SOLVD-Rx Enalapril I-III 2569 15 ↓21 0.02 (0.004) SOLVD-Asx Enalapril I, II 4228 5 0 0.82 (0.30) Post-MI SAVE Captopril — 2231 12 ↓18 0.11 (0.02) AIRE Ramipril — 1986 20 ↓22 0.01 (0.002) TRACE Trandolapril — 1749 26 ↓16 0.046 (0.001) ARBs HF VAL-HeFT Valsartan II-IV 5010 9 0 NS (0.80) CHARM-Alternative Candesartan II-IV 2028 8 ↓14 NS CHARM-Added Candesartan II-IV 2548 8 ↓12 NS Aldosterone Antagonists HF RALES Spironolactone III, IV 1663 24 ↓25 NS (<0.001) Post-MI EPHESUS Eplerenone I 6632 12 ↓15 NS (0.005) Beta Blockers HF CIBIS-I Bisoprolol III, IV 641 21 ↓20† NS (0.22) U.S. Carvedilol Carvedilol II, III 1094 8 ↓66† NS (< 0.001) ANZ-Carvedilol Carvedilol I-III 415 NS NS NS (>0.1) CIBIS-II Bisoprolol III, IV 2647 12 ↓34† NS (0.001) MERIT-HF Metoprolol CR II-IV 3991 10 ↓35† NS (0.006) BEST Bucindolol III, IV 2708 23 ↓10† NS (0.16) COPERNICUS Carvedilol Severe 2289 28 ↓38† NS (0.0001) Post-MI CAPRICORN Carvedilol I 1959 ↓23† NS (0.03) BEAT Bucindolol I 343 NS ↓12† NS (0.06) NOTE: Twelve-month mortality rates were taken from the survival curves when data were not directly available in published material.
- 45. STAGES OF HEART FAILURE CH 28 548 Stage D Refractory symptoms requiring special intervention Inotropes Hospice VAD, transplantation Aldosterone antagonist, nesiritide Consider multidisciplinary team Revascularization, mitral-valve surgery Cardiac resynchronization if bundle-branch block present Dietary sodium restriction, diuretics, and digoxin Stage C Structural disease, previous or current symptoms ACE inhibitors and beta-blockers in all patients Stage B Structural heart disease, no symptoms ACE inhibitors or ARBs in all patients; beta-blockers in selected patients Treat hypertension, diabetes, dyslipidemia; ACE inhibitors or ARBs in some patients Stage A High risk with no symptoms Risk-factor reduction, patient and family education FIGURE 28-6 Stages of heart failure and treatment options for systolic heart failure. Patients with stage A HF are at high risk for HF but do not have structural
- 46. RECOMMENDATIONS CH 28 564 contractility, effects However, is to leading increased Digoxin may therefore with of 0.125 0.125 1.0 ng/renal doses recommended rhythm about pharmacokinetics, drugs supplement Although Diagnosis of HF confirmed Assess for fluid retention Fluid retention Diuretic ICD if NYHA Class II or III CRT if NYHA class III-IV and QRS > 120 ms† (*ARB if ACEI intolerant) Evaluate comorbidities Evaluate precipitating factors No fluid retention ACE inhibitor* NYHA I-IV Persistent symptoms or special populations Beta blocker ARB Aldosterone antagonist Hydralazine/isosorbide Digoxin
- 47. STAGE A • Class I: • Hypertension and lipid disorders should be controlled in accordance with contemporary guidelines to lower the risk of HF (Level of Evidence: A) • Other conditions that may lead to or contribute to HF, such as obesity, diabetes mellitus, tobacco use, and known cardiotoxic agents, should be controlled or avoided. (Level of Evidence: C)
- 48. identify increased HF risk in those receiving chemotherapy may be useful but remain unvalidated as yet (333). Tobacco use is strongly associated with risk for incident HF (92,320,334), and patients should be strongly advised about the hazards of smoking, with attendant efforts at quitting. Cocaine and amphetamines are anecdotally but strongly associated with HF, and their avoidance is mandatory. Although it is recognized that alcohol consumption is associated with subsequent devel-opment STAGE B of HF (92,139,140), there is some uncertainty about the and reduced EF, evidence-based beta blockers used to reduce mortality (346–348). (Level of Evidence: 3. In all patients with a recent or remote history of statins should be used to prevent symptomatic cardiovascular events (104,349–354). (Level of 4. In patients with structural cardiac abnormalities, LV hypertrophy, in the absence of a history of blood pressure should be controlled in accordance clinical practice guidelines for hypertension symptomatic HF (27,94,311–313). (Level of Evidence: Table 12. Recommendations for Treatment of Stage B HF Recommendations COR LOE In patients with a history of MI and reduced EF, ACE inhibitors or ARBs should be used to prevent HF I A In patients with MI and reduced EF, evidence-based beta blockers should be used to prevent HF I B In patients with MI, statins should be used to prevent HF I A Blood pressure should be controlled to prevent symptomatic HF I A 27,94,311–ACE inhibitors should be used in all patients with a reduced EF to prevent HF I A Beta blockers should be used in all patients with a reduced EF to prevent HF I C An ICD is reasonable in patients with asymptomatic ischemic cardiomyopathy who are at least 40 d post-MI, have an LVEF !30%, and on GDMT IIa B Nondihydropyridine calcium channel blockers may be harmful in patients with low LVEF III: Harm C ACE indicates angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; COR, Class of Recommendation; EF, ejection fraction; GDMT, guideline-medical therapy; HF, heart failure; ICD, implantable cardioverter-defibrillator; LOE, Level of Evidence; LVEF, left ventricular ejection fraction; MI, myocardial and N/A, not available.
- 49. STAGE C JACC Vol. 62, No. 16, 2013 Yancy et al. October 15, 2013:e147–239 2013 ACCF/AHA Heart Failure Guideline: Full Text HFrEF Stage C NYHA Class I – IV Treatment: For NYHA class II-IV patients. Provided estimated creatinine >30 mL/min and K+ <5.0 mEq/dL Class I, LOE A ACEI or ARB AND Beta Blocker For persistently symptomatic African Americans, NYHA class III-IV Add Add Add Class I, LOE C Loop Diuretics Class I, LOE A Hydral-Nitrates Class I, LOE A Aldosterone Antagonist For all volume overload, NYHA class II-IV patients e173 Figure 1. Stage C HFrEF: evidence-based, guideline-directed medical therapy. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; HFrEF, heart failure with reduced ejection fraction; Hydral-Nitrates, hydralazine and isosorbide dinitrate; LOE, Level of Evidence; and NYHA, New York Heart Association.