Presentation on theme: "Pharmacologic Considerations for Reducing Hospital Readmission in Geriatric Patients with Heart Failure Barbara J. Zarowitz, Pharm.D. Chief Clinical Officer,"— Presentation transcript:
Pharmacologic Considerations for Reducing Hospital Readmission in Geriatric Patients with Heart Failure Barbara J. Zarowitz, Pharm.D. Chief Clinical Officer, Vice President of Clinical Services Omnicare, Inc., and Adjunct Professor of Pharmacy Practice College of Pharmacy and Health Sciences Wayne State University November 2013
Disclosures Dr. Zarowitz is an employee of Omnicare, Inc., and holds Omnicare stock She has been awarded numerous research grants for Omnicare Senior Health Outcomes from: AbbVie Amgen Astellas Avanir GlaxoSmithKline Mylan Optimer Sanofi-aventis Savient
Heart Failure in the Elderly Persons older than 65 years account for 80% of heart failure hospitalizations Prevalence doubles with each decade of life over age 75 About 6% to 10% over 65 years have heart failure 88% of newly diagnosed cases occur in patients older than 65 years 49% are older than 80 years
Middle Age Elderly (≥ 65 years) Prevalence<1%≈10% GenderM > FF > M EtiologyCoronary artery diseaseHypertension LVEFReducedNormal ComorbiditiesFewMultiple RCTsManyFew TherapyEvidence-basedEmpiric PhysicianCardiologistPrimary care M=male; F=female; LVEF=left ventricular ejection fraction; RCT=randomized clinical trial Features Distinguishing Heart Failure in the Elderly from Heart Failure Occurring During Middle Age Adapted from Rich RW. Drug therapy for heart failure in the elderly. Am J Ger Cardiol 2003;12:235-42.
Pharmacokinetic and Pharmacodynamic Variants in Older Persons with Heart Failure Absorption Increased gastric pH, delayed gastric emptying, reduced GI blood flow and slowed intestinal transit Decreased bioavailability of medications with acid- dependent absorption (iron) and slowed absorption of medications, especially those that are enteric coated Metabolism 20 – 30% reduction in liver mass and hepatic blood flow but hepatocytes remain intact CYP isozymes may be decreased but do not necessarily result in reduced clearance first-pass metabolism is reduced with age Elimination Clcr declines progressively with age- 0.75 mL/min/year 14
Risk Factors for Heart Failure Strongly and consistently associated with HF Less consistently associated with HF Age Male sex Hypertension Electrocardiographic LV hypertrophy Myocardial infarction Diabetes Valve disease Overweight/obesity Excessive alcohol consumption Smoking Dyslipidemia Renal insufficiency Sleep-disordered breathing Low physical activity Low socioeconomic status Coffee consumption Dietary sodium intake Increased heart rate Impaired pulmonary function Mental stress and depression Kenchaiah S et al. Med Clin N Amer 2004:88;1145-72.
Medications That May Exacerbate Heart Failure AgentsRationale Antiarrhythmic agents (avoid disopyramide and flecanide; amiodarone and dofetilide are acceptable, if necessary, for arrhythmia) Calcium channel antagonists (diltiazem, verapamil) Itraconazole Terbinafine Negative inotropic effects Alcohol (excessive amounts in predisposed patients) Doxorubicin Daunomycin Cyclophosphamide Cardiotoxic Androgens COX-2 inhibitors Estrogens Glucocorticoids Nonsteroidal anti-inflammatory drugs Salicylates (high doses) Sodium-containing drugs (e.g., ticarcillin) Thiazolidinediones (rosiglitazone, pioglitazone) Sodium and water retention Albumin Blood products Osmotic agents
BNP Diagnostic Algorithm Dyspnea Physical Examination, Chest XR, ECG, BNP Level BNP 100-400 pg/ml Baseline LV Dysfunction, Underlying Cor Pulmonale, Or Acute Pulmonary Embolism YesNo BNP <100pg/mlBNP >400pg/ml CHF Very Unlikely (2%) Possible Exacerbation of CHF (25%) CHF Likely (75%) CHF Very Likely (95%) Adapted from: Tabbibizar R, Maisel A. Curr Opin Cardiol. 2002;17:343.
BNP for Diagnosis n = 27n = 34n = 36 BNP Concentration (pg/ml) 186 + 22 791 + 165 2013 + 266 BNP concentration for the degree of heart failure severity Maisel A et al. J Am Coll Cardiol 2001;37(2)379-85.
Evidence-Based Treatment Guidelines Yancy CW, et al. 2013 ACCF/AHA Heart Failure Guidelines http://content.onlinejacc.org Jessup M, et al. 2009 ACCF/AHA guidelines for the diagnosis and management of heart failure in adults. Circulation. 2009;119:1977–2016. 25
31 Medications That May Cause or Exacerbate HF* AgentsHow they cause/exacerbate HF Antiarrhythmics † [e.g., Multaq (dronedarone), Rythmol (propafenone), Tambocor (flecanide)] Non-dihydropyridine Calcium Channel Blockers [e.g., Calan or Isoptin (verapamil) or Cardizem (diltiazem)] Itraconazole or Terbinafine Negative inotropic effects (decrease the force of the hearts contraction) Alcohol (excessive amounts) Some chemotherapy treatments (e.g., doxorubicin, daunomycin, cyclophosphamide) Cardiotoxic Androgens or Estrogens Aspirin (high doses) NSAIDs (e.g., celecoxib, ibuprofen, meloxicam, naproxen) Glucocorticoids (e.g., prednisone) Thiazolidinediones [e.g., pioglitazone, Avandia (rosiglitazone)] Sodium and water retention Albumin Blood products (e.g., transfusion) Osmotic agents * - not all inclusive † - amiodarone or Tikosyn (dofetilide) are acceptable alternatives if necessary for arrhythmias Avoid or minimize use whenever possible. Monitor closely if must be used.
ACE Inhibitors, Heart Failure, and Mortality Reduction STUDYACE-IPatientsDurationResults CONSENSUS Mean age 71 Enalapril 2.5-40 mg/d vs. placebo N=253 Class IV HF 12 months 6 month mortality ↓ 40% 1 year mortality ↓ 31% Death from progressive HF ↓ 50% SOLVD Mean age 60 Enalapril 10 mg bid vs. placebo N=2,589 EF < 35% 42 months 3.5 year mortality ↓ 16% Death or CHF hospitalization ↓26% CV hospitalization ↓ 10% AIRE Mean age 65 Ramipril 2.5-5 mg bid N=2,006 HF post MI 30 months All cause mortality ↓ 17% Risk of 1 st event ↓ 19% SAVECaptopril 12.5-150 mg/d vs. placebo N=2,231 EF < 40% Post MI 42 months All cause mortality ↓ 19% CV death ↓ 21% CHF development ↓ 37% Recurrent MI ↓ 25%
ATLAS Trial Low-dose vs. high dose lisinopril 2.5 to 5 mg QD or 32.5 to 35 mg qd N = 3,164 Average age 63.6 years NYHA II-IV EF ≤ 30% High dose group had: 12% lower risk of death or hospitalization for any reason (P=0.002) for high 24% fewer hospitalizations for heart failure (P=0.002) Risk of death reduced 8% in the high dose group (P=0.128) Packer M et al. Circulation 1999;100:2312-8.
Placebo Enalapril 12111098765 0.1 0.8 0 0.2 0.3 0.7 0.4 0.5 0.6 p< 0.001 p< 0.002 4321 0 CONSENSUS Trial Probability of death Months CONSENSUS. N Engl J Med 1987;316:1429-35.
RENIN Angiotensinogen Angiotensin I ANGIOTENSIN II ACE Other pathways VasoconstrictionProliferative Action Vasodilatation Antiproliferative Action AT1 AT2 AT1 Receptor Blockers AT1 Receptor Blockers RECEPTORS Angiotensin II Receptor Blockers (ARB): Mechanism of Action
ACC/AHA Guidelines on the Role of ARBs in HF Therapy Several clinical trials with ARBs failed to show mortality benefit in heart failure ARBs should not be considered equivalent or superior to ACE inhibitors in the treatment of HF ARBs should not be used for the treatment of HF in patients who have had no prior use of an ACE inhibitor ARBs should be used in patients with angioedema or an intractable cough on an ACE-I. ARBs are as likely as ACE-I to produce hypotension, worsening renal function and hyperkalemia 2013 ACCF/AHA Heart Failure Guidelines. J Am Coll Cardiol. http://content.onlinejacc.org/
Val-HeFT: Comparison of Event Rates Event Valsartan (%) Placebo (%)RR*p All-cause mortality17.327.10.670.017 Morbidity/ mortality 24.942.50.56<0.001 Cardiovascular death 15.722.10.760.074 Sudden death with resuscitation 0.51.10.460.529 Hospital admission for HF 13.026.50.47<0.001 Maggioni AP et al. J Am Coll Cardiol 2002;40:1414-21.
CHARM Trial 3 studies in one CHARM-Alternative: LVEF ≤ 40% and could not tolerate an ACE inhibitor CHARM-Added: LVEF ≤ 40% who were currently taking an ACE inhibitor, with or without a beta-blocker CHARM-Preserved: LVEF > 40% Overall-- showed ARB beneficial in terms of morbidity and mortality in heart failure
Background Therapy ACEI +, Beta Blocker - 3034 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 N P=0.009 Test for heterogeneity Relative Risk of Death Valsartan BetterPlacebo Better Combination of ACEI and ARB in Heart Failure Management ACEI +, Beta Blocker + 1610 ACEI -, Beta Blocker - 228 ACEI -, Beta Blocker + 140 Cohn JN et al. NEJM 2001;345:1667-75
All-Cause Mortality in the VALIANT Study Group All-cause mortality (%) Hazard ratio (95% CI) compared with captopril p value Captopril (n=4909) 19.5-- Valsartan (n=4909) 19.9 1 (0.90-1.11) 0.98 Combination (n=4885) 19.3 0.98 (0.89-1.09) 0.73 Pfeffer MA et al. N Engl J Med 2003; 349:1893-1906.
VALIANT: Cardiovascular Death, Recurrent MI, or Heart Failure Hospitalization Group CV death, re-MI, or heart-failure hospitalization (%) Hazard ratio (95% CI) compared with captoprilp value Captopril (n=4909) 31.9-- Valsartan (n=4909) 31.10.95 (0.88-1.03) 0.20* Combination (n=4885) 31.10.97 (0.89-1.05) 0.37* *Not significant Pfeffer MA et al. N Engl J Med 2003; 349:1893-1906. Secondary End Point
VALIANT: Incidence of Adverse Events Group Any adverse event (%) Any ADE leading to permanent study drug discontinuation (%) Captopril28.47.7 Valsartan29.45.8* Combination34.8*9.0* Pfeffer MA et al. N Engl J Med 2003; 349:1893-1906. * Significant difference from captopril (p<0.05)
52 Beta-Blockers (BBs) (bisoprolol, carvedilol, or metoprolol succinate XL) Prevent the speeding up of the damaged heart “recommended for all patients with current or prior symptoms of HF and reduced LVEF, unless contraindicated” Start only if patients have stable fluid status and gradually increase the dose as tolerated Titrate no sooner than every 2 weeks May initially worsen HF and may need to adjust diuretics to maintain pre- treatment weight Monitor heart rate and blood pressure Typically held if pulse <60 beats per minute Monitor for hypoglycemia if diabetic May block symptoms of hypoglycemia except sweating Carefully assess risk vs. benefit for patients with: Reactive airway disease (e.g., asthma) COPD Peripheral vascular disease 2013 ACCF/AHA guidelines. http://content.onlinejacc.org/http://content.onlinejacc.org/
Dosages of Beta-Blockers in Heart Failure Drug Starting DosageTitration Sequence* Maximum Dosage Bisoprolol (Zebeta ® ) 1.25 mg/dayIncrease to 2.5 mg/day in 2-4 weeks, then increase to 5.0 mg/day in 2-4, weeks, then increase to maximum 10 mg/day Carvedilol (Coreg ® ) 3.125 mg twice daily Increase to 6.25 mg bid in 2-4 weeks, then increase to 12.5 mg bid in 2-4 weeks, then increase to maximum 25 mg twice daily (50 mg twice daily if > 85 kg) Metoprolol extended release (Toprol XL ® ) 12.5 mg/dayIncrease to 25 mg/day in 2-4 weeks, then Increase to 50 mg/day in 2-4 weeks, then increase to 100 mg/day in 2-4 weeks, then increase to maximum 200 mg/day ACC/AHA Heart Failure Guidelines, 2001; Farrell MH et al. JAMA 2002;287:890-97. *Doses should only be increased if resident tolerates current dose. Some residents will not tolerate higher doses or may require slower titration.
54 Diuretics (furosemide, bumetanide, hydrochlorothiazide,metolazone) Reduce fluid volume to decrease workload of the heart Loop diuretics (e.g., furosemide) are generally more effective than thiazide diuretics (e.g., hydrochlorothiazide) Thiazides are less effective with declining kidney function Assess edema and monitor weight frequently Often requires use/adjustment of potassium supplementation Monitor electrolytes and kidney function routinely Monitor for rash/photosensitivity Combination therapy with a loop and thiazide diuretic may be necessary in the presence of diuretic resistance 54 2013 ACCF/AHA guidelines. http://content.onlinejacc.org/http://content.onlinejacc.org/
Action of Diuretics Thiazides Inhibit active exchange of Cl-Na in the cortical diluting segment of the ascending loop of Henle K-sparing Inhibit reabsorption of Na in distal convoluted and collecting tubule Loop Diuretics Inhibit exchange of Cl-Na-K in thick segment of the ascending loop of Henle Collecting Tubule Loop of Henle MEDULLA CORTEX
Loop Diuretics Mechanism of action Act on the ascending limb of loop of Henle Increase potassium, magnesium and calcium excretion More effective than thiazide diuretics Adverse reactions Electrolyte/metabolic disturbances hypokalemia, hypomagnesemia, hyperglycemia, hyperuricemia Metabolic alkalosis Azotemia Hypotension, including orthostasis Ototoxicity Other (rash, photosensitivity)
Thiazide Diuretics Mechanism of action No dose response Increase potassium, magnesium and calcium excretion more than with loop diuretics Increase renal vasoconstriction Increase uric acid excretion Adverse reactions Electrolyte/metabolic disturbances hypokalemia, hypomagnesemia, hyperglycemia, hyperuricemia Metabolic alkalosis Azotemia Hypotension, including orthostasis Other (rash, photosensitivity)
Torsemide Loop diuretic Consistent absorption Reduced fatigue Fewer hospitalizations Lower cost of care Murray MD, Deer MM, Ferguson JA et al. Open-label randomized trial of torsemide compared with furosemide therapy for patients with heart failure. Am J Med. 2001;111:513-20.
Diuretic Resistance: Causes Delayed absorption of the diuretic Reduced secretion of the diuretic into the tubular lumen (its site of action) Compensatory retention of sodium after the effective period of the diuretic Hypertrophy and hyperplasia of epithelial cells of the distal convoluted tubule
Diuretic Resistance: Management Rule out non-compliance Dose adjustment Intravenous bolus injection or continuous infusion of a loop diuretic Combination diuretic therapy Metolazone use in combination with loops Given 30 minutes prior to loop administration Monitor closely for hypokalemia
61 Digoxin Increases the force and velocity of cardiac contraction while also reducing the heart rate “can be beneficial in patients with current or prior symptoms of HF and reduced LVEF to decrease hospitalizations for HF” 2012 Updated Beers Criteria list 0.125 mg/day as the maximum recommended dose Monitor pulse prior to giving each dose Monitor for signs/symptoms of toxicity (nausea, anorexia, visual disturbances, electrolyte abnormalities, impaired cognition, weakness, dizziness, hallucinations, etc) Monitor BMP and digoxin concentration routinely Serum drug concentration of 0.5-0.8 ng/mL is the recommended therapeutic range 2013 ACCF/AHA guidelines. http://content.onlinejacc.org/http://content.onlinejacc.org/
Digoxin Inhibits sodium-potassium adenosine triphosphatase Promotes calcium influx via sodium-calcium exchange mechanism Results in an increase in the contractile state of the heart Stroke volume and cardiac output increase Indirect increase in parasympathetic tone Results in decrease in heart rate Direct and indirect decrease in sympathetic tone Secondary to impaired cardiac output Indirectly decreases sympathetic vasoconstriction
Na + K+K+K+K+ K+K+K+K+ Ca ++ Na-K ATPase Na-Ca Exchange Myofilaments Digoxin CONTRACTILITY Digoxin: Mechanism of Action -
Digoxin: Clinical Use Therapy is initiated at dose of 0.125 mg for heart failure Lower doses such as every other day Some elderly Impaired renal function Caution in patients with significant sinus or atrioventricular block Not indicated for stabilization of acute decompensated heart failure
Serum Digoxin Concentrations Are lower digoxin concentrations effective? Methods Data from PROVED and RADIANCE Both were randomized, multi-center, double-blind clinical trials PROVED – diuretic vs. diuretic + digoxin RADIANCE – ACEI+diuretic vs. ACEI+diuretic+digoxin Compared digoxin withdrawal vs. continuation for worsening heart failure Serum drug concentration (SDCs) obtained at baseline, 4, 8, and 20 weeks Adams KF et al. J Am Coll Cardiol 2002;39:946-53.
Risk of Treatment Failure Based on Randomization SDC Group Treatment Group Relative Risk95% CIP Value Digoxin concentration (SDC) < 0.9 ng/ml0.090.01-0.66 0.018 > 0.9-1.2 ng/ml0.220.08-0.61 0.004 > 1.2 ng/ml0.170.06-0.44 <0.001 Relative risk and p values are based on the adjusted Cox proportional hazards analysis. CI = confidence interval; SDC = serum digoxin concentration Adams KF et al. J Am Coll Cardiol 2002;39:946-53.
Digoxin: Clinical Trials Digitalis Investigation Group (DIG Trial) 6,800 patients with ischemic and non-ischemic cardiomyopathy Mild to moderate heart failure Randomized to placebo or digoxin Digoxin has no effect on mortality Digoxin was associated with decreased risk of hospitalization (28% CHF, 6% all cause) Digoxin level investigation (post-hoc of DIG Trial) SDCs of 1.2 ng/mL and higher may be harmful SDCs of ~ 1.0 ng/mL may not provide any clinical benefit vs. placebo SDC of 0.5 to 0.8 ng/mL likely the optimal therapeutic range The Digitalis Investigation Group. N Engl J Med 1997;336:525-33.
50 40 30 20 10 0 48 0 122436 DIG Clinical Trial The Digitalis Investigation Group. N Engl J Med 1997;336:525-33. Months Percent Mortality n = 6800 NYHA II-III P=0.8 Placebo N=3403 Digoxin N=3397
Digoxin Concerns in the Elderly Narrow therapeutic index Age related decrease in renal function Results in increased serum digoxin concentrations May cause delirium Drug-drug interactions Affect digoxin bioavailability or excretion Increase risk of digoxin toxicity Reduced skeletal mass Reduced volume of digoxin distribution Aronow WS. J Am Geriatr Soc 1997;45:1252-8.
Digoxin and Women Outcome Women digoxin (%) Women Placebo (%)p Absolute diff. between sexes (%)* Death from any cause 33.128.90.078 5.8 Death from CV causes 27.824.10.098 4.3 Death from worsening HF 12.411.90.750 2.8 Hospitalization for worsening HF 30.234.40.079 4.7 *Absolute difference between the effect of digoxin compared with the effect of placebo among women vs the same comparative effect in men; p was significant for death from any cause (p=0.034) and marginally significant for hospitalization for worsening HF (p=0.053). Rathore SS et al. N Engl J Med 2002;347:1403-11.
71 Aldosterone Antagonists (AAs) (e.g., spironolactone, eplerenone) Block aldosterone-induced increases in vasoconstriction and sodium reabsorption “Addition of an aldosterone antagonist is reasonable in selected patients with moderately severe to severe symptoms of HF and reduced LVEF who can be carefully monitored for preserved renal function and normal potassium concentration.” SCr should be 2.5 mg/dL for men and 2.0 mg/dL in women K+ should be 5.0 mEq/L Eplerenone is NOT suggested for those over 75 years of age due to lack of survival benefit Monitor BMP and kidney function routinely Minimize concomitant use of potassium supplements, especially in combination with an ACEI or ARB Monitor for endocrine disturbances (e.g., gynecomastia) 2013 ACCF/AHA guidelines http://content.onlinejacc/orghttp://content.onlinejacc/org
ALDOSTERONE Retention Na + Retention Na + Retention H 2 O Retention H 2 O Excretion K + Excretion K + Excretion Mg 2+ Excretion Mg 2+ Collagen Collagen deposition deposition Fibrosis Fibrosis - myocardium - myocardium - vessels - vessels Spironolactone Edema Edema Arrhythmias Arrhythmias Competitive antagonist of the aldosterone receptor (myocardium, arterial walls, kidney) Aldosterone Antagonists: Mechanism of Action
Recent or current symptoms despite ACEI, diuretics, digoxin, and beta-blockers Recommended in advanced heart failure (II-IV), LVEF of ≤ 35%, in addition to ACEI and diuretics Hypokalemia -ESC HF guidelines 2001 Spironolactone: Indications 2013 ACCF/AHA guidelines http://content.onlinejacc/orghttp://content.onlinejacc/org
Background – The RALES Study Pts with NYHA Class III & IV HF on ACEI’s and loop diuretics were randomized to either 25 mg of spironolactone or placebo (avg dose = 26 mg) Spironolactone group had a 30% reduction in risk of death and 35% reduction in hospitalization for worsening HF Pitt B, et al. N Engl J Med 1999;341:709-17.
Aldactone Placebo Survival 1.0 0.9 0.8 0.7 0.6 0.5 0612 18 243036 months p < 0.0001 Annual Mortality Aldactone 18%; Placebo 23% N = 1663 NYHA III-IV Mean follow-up 2 y RALES Trial: Spironolactone RALES. N Engl J Med 1999;341:709
RALES Results – patients with HF Before RALES After RALES Early 1994 (per 1000) Early 1999 (per 1000) Late 2001 (per 1000) Spiro Rx’s3430149 * Hyper K + adms 2.44.011 * Hyper K + deaths 0.30.72.0 * (* p<0.001)
Spironolactone: Contraindications/ Risk-Benefit Considerations Contraindications Potassium concentration > 5.5 mEq/L Risk-benefit considerations Concomitant use with potassium supplements Life threatening hyperkalemia when used with ACE inhibitors or ARBs
Eplerenone Potassium-sparing diuretic Lower affinity than spironolactone for progesterone and androgen receptors Ephesus trial showed statistically significant reduction in death versus placebo More expensive than spironolactone Those over 75 years did not respond to treatment Pitt B et al. N Engl J Med 2003; 348:1309-21. Pitt B 2003. Circulation 2003;108:1790
79 Hydralazine/Isosorbide Dinitrate Hydralazine is a peripheral arterial vasodilator Isosorbide is a peripheral venous vasodilator Working together they mimic vasodilating action of ACEIs “recommended to improve outcomes for patients self-described as African-Americans, with moderate-severe symptoms on optimal therapy with ACE inhibitors, beta blockers, and diuretics.” “patients with reduced LVEF who cannot be given an ACE inhibitor or ARB because of drug intolerance, hypotension, or renal insufficiency.” Monitor closely for hypotension, worsening edema, or headaches 79 2013 ACCF/AHA guidelines http://content.onlinejacc/orghttp://content.onlinejacc/org
80 Inotropic Support [e.g., Dopamine, Dobutamine, Milrinone (Primacor ® ) Increase force of cardiac contraction May provide symptom improvement but result in overall increase in mortality Central line access required Monitor for: Hypotension Arrhythmias Dizziness/Headache Adequate fluid intake Peripheral blood perfusion 2013 ACCF/AHA guidelines http://content.onlinejacc/orghttp://content.onlinejacc/org
2013 Guidelines for Inotropic Support Until definitive therapy (e.g. coronary revascularization, mechanical circulatory support (MCS), heart transplantation) or resolution of the acute precipitating problems. Patients with cardiogenic shock should receive temporary intravenous inotropic support to maintain systemic perfusion and preserve end-organ performance Continuous inotropic support reasonable as “bridge therapy” in patients with Stage D refractory to medication therapy and device therapy who are eligible for and awaiting MCS or cardiac transplantation Palliative therapy in stage D despite optimal medication therapy and device therapy who are not eligible for MCS or transplantation Potentially Harmful – absence of specific indications noted above 81 2013 ACCF/AHA guidelines http://content.onlinejacc/orghttp://content.onlinejacc/org