Mending a Broken Heart:

Medications When Your Patient is on Standard Therapy and Still Short of Breath

Dawn M. Waddell, PharmD, BCPS Cardiothoracic Transplant & MCS Pharmacist, BMH - Memphis Associate Faculty, UTHSC College of Pharmacy

No relevant financial relationships to disclose

Objectives

• • • • • Review medication interventions in patients at risk for developing heart failure (HF) Discuss medications that may cause or worsen HF Review current guidelines to optimize medication therapy Review medication options in Stage D patients Evaluate new therapies under investigation for specific populations of HF patients

Prevention

• • • • Treat hypertension – Long-term treatment of systolic and diastolic HTN decreases HF risk by ~50% CAD/Atherosclerosis – Add statin Identify and treat pre-diabetes – Metformin can be added to diet and exercise if Hb A1C 5.7-6.4% Control diabetes – Every 1% increase in HbA1c = 8% increase in HF risk (median follow up 2.2 years) – RR of developing HF in DM patients = 1.85 (median follow up 19 years)

Diabetes and HF

• • • • FDA: metformin can be used in HF without severe LV dysfunction if stable hemodynamics and adequate renal function Metformin decreases all-cause mortality in HF patients Metformin safe in patients with advanced HF Lower 1-year mortality and re-hospitalization rates in HF patients compared to insulin/sulfonylureas

Diabetes and HF

• • • Pioglitazone (Actos®) – Increase in peripheral edema, incidence of new HF, HF progression and hospitalizations – – Increased mortality not shown at this time Recommended with caution in NYHA I-II but avoid in symptomatic HF patients DPP-4 inhibitors – Saxagliptin (Onglyza®) associated with 0.75% and 0.3% increased risk of HF hospitalizations in patients with and without previous HF – Sitagliptin (Januvia®) trial scheduled to report results June 2015 Sodium-glucose cotransporter-2 inhibitors – Dapagliflozin (Farxiga®): long-term studies on CV outcomes underway

Medications to (Ideally) Avoid in HF

• • • • • • Non-dihydropyridine calcium channel blockers – Verapamil/Diltiazem decrease cardiac output – Amlodipine: neutral; preferred > Felodipine/Nifedipine Antiarrhythmics – Avoid class I, class III antiarrhythmics – Amiodarone/Dofetilide recommended in HF NSAIDs – Including COX-2 inhibitors Steroids – Minimize doses Chemotherapy – Anthracyclines, high-dose cyclophosphamide, trastuzumab, bevacizumab TNF-alpha inhibitors – Infliximab (Remicade®), Adalimumab (Humira®)

Optimize Standard Therapy

• • • • • • • Titrate to goal HF doses Beta blockers ACE-Is ARBs Aldosterone antagonists Hydralazine/Isosorbide Digoxin

Beta Blockers

HF approved BB

Carvedilol (Coreg®)

Initial dose

3.125 mg BID

Goal dose

25 mg BID (<85 kg) 50 mg BID (>85 kg)

TennCare Exempt List

Yes

$4 Generic Lists

Yes Metoprolol succinate (Toprol XL®) Bisoprolol (Zebeta®) 12.5 mg DAILY 200 mg DAILY 2.5 mg DAILY 10 mg DAILY Yes Yes No Yes, with HCTZ • Avoid abrupt withdrawal

Beta Blockers

• • •

Carvedilol

Improved BP control Usually improved tolerability compared to metoprolol in regards to fatigue/depressive adverse effects Usually tolerated in COPD (>asthma) unless severe • • •

Metoprolol succinate

May be used in patients who tend to be hypotensive May have advantage in patients with ventricular arrhythmias May be used in patients with COPD/asthma

ACE-Is

Captopril (Capoten®) Enalapril (Vasotec®)

Benazepril (Lotensin®)

Lisinopril (Zestril®) Perindopril (Aceon®) Quinapril (Accupril®) Ramipril (Altace®)

ACE-Inhibitors

Initial Dose

6.25 mg TID

Goal Dose

50 mg TID

TennCare Exempt List

No 2.5 mg BID

5-10 mg DAILY

2.5-5 mg DAILY 10-20 mg BID No

40-80 mg DAILY or divided BID

20-40 mg DAILY

No

No 2 mg DAILY 5 mg BID 8-16 mg DAILY 20 mg BID 1.25-2.5 mg DAILY 10 mg DAILY Yes No No

$4 Generic Lists

No Yes, with HCTZ

Yes

Yes +/- HCTZ No No No

ACE-Inhibitors

• • • • Caution in patients with SBP < 80 mmHg, SCr > 3.0 mg/dL, K > 5.0 meq/L, bilateral renal artery stenosis Check SCr and K every 1-2 weeks with initiation of therapy and dose increases ~20% of patients experience cough Angioedema occurs in <1% but higher rate in African Americans

ARBs

ARBs

Candesartan (Atacand®) Losartan (Cozaar®) Valsartan (Diovan®)

Initial Dose

4-8 mg DAILY

Goal Dose

32 mg DAILY 25-50 mg DAILY 50-150 mg DAILY 20-40 mg DAILY 160 mg BID

TennCare Exempt List

Yes Yes +/- HCTZ Yes +/- HCTZ

$4 Generic Lists

No No No

ARBs

• • • Use in patients intolerant to ACE-Is May be alternative in patients with ACE-I associated angioedema – Cases of patients with angioedema to ARB Similar precautions and monitoring as ACE-Is

Aldosterone Antagonists

AAs Initial Dose Goal Dose

Spironolactone (Aldactone®) Eplerenone (Inspra®) 12.5-25 mg DAILY 25 mg DAILY 25 mg DAILY 50 mg DAILY

TennCare Exempt List

No No

$4 Generic Lists

Yes No

Aldosterone Antagonists

• • • • • Should be considered in NYHA II-IV – NYHA II: prior CV hospitalization or elevated BNP Also following acute MI if EF < 40% and patient with HF symptoms or DM SCr < 2.5 (men) or 2.0 (women), or GFR > 30 mL/min, K < 5.0 mEq/L Check SCr and K in 2-3 days and at 7 days following initiation Decrease dose or discontinue if K > 5.5 mEq/L

Hydralazine/Isosorbide

Vasodilators Initial Dose Goal Dose

Hydralazine/ Isosorbide dinitrate (Bidil®) Hydralazine (Apresoline®) Isosorbide dinitrate (Isordil®) 37.5/20 mg TID 25-50 mg 3-4x DAILY 20-30 mg 3-4x DAILY 75/40 mg TID 300 mg DAILY divided 3-4x 120 mg DAILY divided 3-4x

TennCare Exempt List

No Yes No

$4 Generic Lists

No Yes, only low doses No

Hydralazine/Isosorbide

• • • • Recommended in African American patients who remain symptomatic despite ACE-Is/ ARBs, beta blockers, and aldosterone antagonists May be used in patients intolerant to ACE-Is/ ARBS Titrate slowly Headache, dizziness, GI complaints

Digoxin

• • • • • • May improve symptoms and decrease hospitalizations Avoid in sinus/AV block unless pacemaker Goal level 0.5-0.9 ng/mL; 0.5-0.8 ng/mL preferred Adverse effects include arrhythmias, anorexia, N/V, confusion, visual disturbances Increased toxicity with hypokalemia, hypomagnesemia, hypothyroidism, impaired renal function, lean body mass Potential for drug interactions

Digoxin

• • • • Retrospective subgroup analysis of women in DIG trial – Increase in mortality compared to men including death from CV causes or worsening HF – Unclear if due to slightly higher digoxin concentrations (0.9 ng/mL vs 0.8 ng/mL) Another retrospective analysis showed serum digoxin level to be continuous variable associated with mortality Recommended as add-on therapy to BBs in patients with atrial fibrillation (A. fib) May be used in A. fib with RVR in decompensated HF

Diuretics

• • • • Loop diuretics 1 st line for fluid retention Patients may become intolerant of furosemide and may have improved response to bumetanide or torsemide May require addition of metolazone to maintain euvolemia Must monitor carefully as add or increase doses of BBs, ACE-Is/ARBs, aldosterone antagonists

Pearls

• • • • • • Consider HF medications in patients at risk in need of additional HTN treatment Titrate slowly but get to goal doses May give once-daily blood pressure medications at bedtime to decrease adverse effects Caution patients to hold doses of ACE-Is, ARBs, aldosterone antagonists if significant N/V/D or dehydration Monitor K carefully if diuretic dose decreased and patient on ACE-I, ARB, or aldosterone antagonist ACE-I + ARB + aldosterone antagonist not recommended

Management of Acute Exacerbation

• • • • • IV loop diuretics May increase diuretic dose, consider continuous infusion, and/or add metolazone to achieve diuretic response CO2 will increase d/t contraction alkalosis prior to SCr/BUN trending up – Signal to decrease dose to prevent AKI Maximize vasodilator therapy as BP tolerates Only decrease/hold other HF medications if hypotension/decreased cardiac output

Refractory HF (Stage D)

• • • Short-term intravenous inotropes indicated in cardiogenic shock to maintain perfusion Continuous inotropes may be used as “bridge” to cardiac transplant or ventricular assist device (VAD) therapy Long-term use reserved for palliative care

Inotropes

Inotrope Dose (mcg/kg/min) Half life CO HR SVR PVR Adverse effects

Dobutamine

Stimulates beta 1 receptors leading to increased HR and contractility, little effect on beta 2 or alpha receptors

(Dobutrex®) Initial: 2.5-5 Maintenance: 5-20 2-3 min ↑ ↑ ↓↔ ↔ Tachy arrhythmias Milrinone

Inhibits PDE-3 in cardiac and vascular tissue leading to increased cardiac contractility and decreased vascular tone

(Primacor®) Initial: 0.125-0.375

Maintenance: 0.375-0.75

2.5 h ↑ ↑ ↓ ↓ Tachy arrhythmias

PDE-5 Inhibitors

• • • Sildenafil approved for use in pulmonary arterial hypertension (Group 1) Inhibits PDE-5 leading to pulmonary vascular relaxation Studied in HF patients with secondary pulmonary hypertension (Group 2) – 12 week study: increased peak VO2, improvement in RVEF, improved QOL – 6 month study: decreased PAP, increased peak VO2, improved breathlessness score

Iron Deficiency and Anemia in HF

• • • • Anemia and iron deficiency are comorbidities in HF associated with adverse outcomes Iron deficiency in HF defined for study purposes – Ferritin < 100 ng/mL OR – Ferritin 100-300 ng/mL and Tsat < 20% Prospective study found 37% of HF patients (mean EF 26%) met criteria Intravenous iron regimens under study

FERRIC-HF and FAIR-HF

• • • FERRIC-HF NYHA class II-III and iron deficiency as defined treated with IV iron sucrose versus placebo Noted improvements in QOL and functional class Statistically significant increase in peak VO2 in patients with anemia and IDA • • • FAIR-HF Similar to FERRIC-HF but patients received IV ferric carboxymaltose Improvements in QOL, functional class and 6-minute walk No difference in hospitalizations or mortality at 24 weeks No long-term data

Potential Algorithm

Omega 3 Fatty Acids

• • • • • Omega-3 polyunsaturated fatty acids (PUFA) may be used as adjunctive therapy Decreased mortality observed in post-MI patients receiving omega-3 PUFA 1 g Subgroup analysis showed greatest reduction in patients with reduced EF GISSI-HF study compared omega-3 PUFA 1 g to placebo – Decreased mortality 27% versus 29% in placebo – CV death or hospitalization also decreased Safe and well-tolerated

Paradigm-HF Trial

• • • • • Evaluated angiotensin receptor-neprilysin inhibitor (LCZ696) versus enalapril NYHA II-IV with EF < 40% randomized to LCZ696 or enalapril 10 mg bid Stopped early with median follow up of 27 months due to benefit in LCZ696 group – Death from any cause 17.0% vs 19.8% (p<0.001) – Death from CV cause 13.3% vs 16.5% (p<0.001) – Reduced risk of hospitalization by 21% (p<0.001) Increased rate of hypotension and nonserious angioedema Decreased proportion of renal impairment, hyperkalemia, and cough

Questions?