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Introduction

Although heart disease is sometimes considered a “man’s disease,” similar numbers of women and men in the U.S. die from heart disease each year.¹ Joint guidelines for the management of heart failure (HF) from the American College of Cardiology (ACC), American Heart Association (AHA) and Heart Failure Society of America (HFSA) do not differ significantly in their management recommendations for women in comparison to men.^2,3 The same applies for the European Society of Cardiology (ESC) HF guidelines.⁴ However, it is important to call attention to many issues specific to women with HF. Women remain significantly under-represented in HF clinical trials.⁵ In addition, it has been shown that some clinicians may apply diagnostic and management guidelines differently for women. For example, a myocardial infarction (MI) affecting a woman may be initially overlooked because women typically do not present with clinical characteristics generally associated with early MI signs.^5,6 Women with HF signs and symptoms may be less likely to be referred for diagnostic testing or specialty care.⁵

Clinician adherence to HF guideline recommendations is poor with regard to treatment of both sexes, but appears to be even less stringent for women with HF.^5,7,8 The medication regimen for HF is highly complex involving multiple medications, but these are often prescribed inappropriately or used incorrectly. There are many potential avenues where pharmacist intervention can improve medication safety, adherence, and patient outcomes.⁹

Clinical Inertia: How Are HF Medications Used in Real-World Clinical Practice?

Medical therapy for HF can be highly effective in improving symptoms and mortality risk, but the sequencing of the multi-drug regimen for HF is highly complex to manage. This presents a challenge for healthcare providers to ensure that the correct agents and evidence-based target doses are employed.³ The CHAMP-HF (Change the Management of Patients with Heart Failure) Registry is an observational registry to evaluate how HF patients are being treated in the "real world" outside of clinical trials. A paper from the registry published in July 2018 reported on 3,518 patients with heart failure with reduced ejection fraction (HFrEF).¹⁰ Although HF guideline recommendations have existed for decades, virtually all recommended medication categories were significantly underused. Specifically:

• 27% of patients were not prescribed an angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), or angiotensin receptor-neprilysin inhibitor (ARNI)
• 33% were not prescribed a beta blocker
• 67% were not prescribed a mineralocorticoid receptor antagonist (MRA)

One of the most surprising findings was that only about 1% of HF patients were receiving all appropriate medications at the target doses.¹⁰ The CHAMP-HF study findings present a compelling rationale for pharmacist intervention in HF management. Many HF medications have a recommended starting dose that is up-titrated to the maximum tolerated dose, but this study showed that the majority of patients did not achieve optimal doses of the drug. Pharmacists can guide drug selection, advise on initial and maximum doses, and help to manage the drug regimen to minimize contraindications and adverse events.

Heart Failure Presentation in Women

Some basic gender differences in cardiovascular anatomy and heart disease presentation have been observed in HF. As outlined in Table 1, differences in women include a faster resting heart rate and a presentation of HF that tends to be more symptomatic compared with men. Anatomically, women have smaller, lighter coronary arteries and smaller left ventricular size. Women are more likely to present with heart failure with preserved ejection fraction (HFpEF) compared with men.⁵ Early symptoms of MI may be overlooked because women tend to present less frequently with the characteristic severe substernal chest pain that affects men.¹¹

Hypertension is a key risk factor for HF among women, and for younger women conditions such as diabetes and/or complications of pregnancy can precipitate myocardial damage.^5,6 HF is more likely to affect women in the older age brackets, especially women over age 80, as shown in Figure 1.¹² Reduced estrogen levels in aging women are associated with myocardial effects. On average, women with HF survive longer than men with this disease.^13,14

Classification of Heart Failure

Classifications for HF are key in determining the course of treatment. The New York Heart Association (NYHA) system is the standard system for categorizing patients with cardiac disease by their symptom presentation (Table 2). Class I represents patients with cardiac disease—following an MI, for example—who have no limitation on physical activity. Patients in Class II have slight limitations, while Class III represents marked limitation of physical activity, with subclassifications that involve either no dyspnea or dyspnea at rest. Class IV represents patients with severe disease and symptoms present even at rest.

The ACC/AHA staging system is similar to NYHA except that it incorporates structural disorder and includes a category (Stage A) for patients at risk for HF.² Figure 2 illustrates how the NYHA system compares to the ACC/AHA HF stages A through D.³ Stage A includes patients who have conditions such as hypertension, diabetes, or coronary artery disease that put them at risk for HF, but who do not have evidence of structural heart disease. There is no corresponding NYHA class for Stage A. Stage B corresponds to NYHA Class I, in which patients have structural heart disease but are asymptomatic. Stage C corresponds to NYHA Classes II and III and to some degree Class IV. Stage D, end-stage HF, is similar to NYHA Class IV.

Stratification by Left Ventricular Ejection Fraction (LVEF)

In recent years, a key distinction has emerged in HF presentation based on patient’s left ventricular function as measured by left ventricular ejection fraction (LVEF). This distinction has important implications for treatment, as patients with HFrEF (previously called systolic dysfunction) generally respond well to available pharmacologic therapies.^2,4 HFrEF is characterized by a weakened left ventricle, resulting in less blood being pumped out of the ventricle (Figure 3). The ACC/AHA HF guidelines define reduced left ventricular function as EF <40%.

Heart failure with preserved ejection fraction (diastolic dysfunction) is characterized by a stiff heart muscle resulting in less blood filling the ventricles. HFpEF, defined as EF ≥ 50%, has been shown to be less responsive to pharmacologic treatment.^3,4 Recent guidelines have included a mid-range EF (40%–49%), but further research is needed to determine how HF treatment recommendations apply to this group.⁴ Women with HF appear to be more likely than men to present with HFpEF.⁵

Influence of Staging on Medical Management of HF

Goals of Treatment

Overarching goals of HF management for any patient regardless of gender or classification include:

• Reduce hospitalization/readmission rates
• Increase patient quality of life (QoL)
• Reduce mortality
• Reduce risk of secondary events (MI, stroke)

Stage B Therapeutic Strategy

Where the patient falls in the spectrum of these classification systems partly determines how treatment goals should be individualized. For example, a patient with NYHA Class I (Stage B in ACC/AHA) is asymptomatic, usually with a history of MI with reduced ejection fraction. The main goal of treatment is not necessarily to influence quality of life, but to reduce the risk of long-term morbidity and mortality. These patients should be on a therapy to regulate the renin-angiotensin-aldosterone system (RAAS), such an ACE inhibitor or ARB, as well as a beta blocker. Other goals of treatment include controlling the patient's blood pressure and lipid levels. Use of non-dihydropyridine calcium channel blockers (such as verapamil and diltiazem) is contraindicated in patients with reduced LVEF due to the negative inotropic effects in the presence of reduced cardiac contractility.² If a calcium channel blocker is needed, a dihydropyridine calcium channel blocker (e.g., amlodipine) is a better option. These patients should also avoid nonsteroidal anti-inflammatory drugs, which may contribute to an exacerbation of heart failure.¹⁵

Stage C Therapeutic Strategy

Much of this paper will focus on pharmacologic management of symptomatic HFrEF, ACC/AHA Stage C. Decades of clinical trials have shown that medical therapy is effective in significantly reducing morbidity and mortality for patients with symptomatic HFrEF. Recently, the ACC's Task Force on Expert Consensus Decision Pathways developed a series of flow diagrams outlining the therapy recommendations by addressing 10 pivotal issues about HFrEF (see Figures 4–7).¹⁶ Other management approaches such as left ventricular assist devices and various forms of surgical intervention are not discussed in this paper.

For patients with HF who are symptomatic, the primary goals of management include improving QoL, preventing hospitalization, and reducing mortality risk.² Patients with Stage C HFrEF should again be receiving an ACE inhibitor or ARB and a beta blocker. Patients with symptoms of fluid overload should receive a diuretic. For patients who are African-American in NYHA Classes III or IV, the combination of hydralazine/isosorbide dinitrate may be a consideration.¹⁷ For patients who are still symptomatic despite maximum tolerated doses of an ACE inhibitor or ARB, a switch to an angiotensin-receptor-neprilysin inhibitor (ARNI) combination should be considered. Mineralocorticoid receptor antagonists (MRAs) can be considered for patients with normal renal function who remain symptomatic, and for symptomatic patients in sinus rhythm ivabradine is recommended to lower heart rate.^2,3

Medication Categories for HF Management

Diuretics (Thiazide, Loop)

Diuretics inhibit sodium reabsorption in the nephron, which increases urinary excretion of water, thereby helping to relieve breathlessness and edema in patients with congestion. The diuretics can be broken down into three main pharmacologic categories: thiazide (e.g., hydrochlorothiazide, metolazone), loop (e.g., bumetanide, furosemide, torsemide) and potassium-sparing (e.g., spironolactone, eplerenone). While thiazide diuretics may be used in mild HF, most patients with HF will require a loop diuretic.² Diuretics do not have an impact on mortality and do have adverse effects, so these agents should be reserved for patients with symptoms of fluid overload.³ Electrolyte abnormalities such as hypokalemia may be worsened due to diuretic therapy, so electrolytes including potassium should be monitored frequently. Symptomatic hypotension may be worsened by diuretic-induced hypovolemia.¹⁶

Angiotensin-Converting Enzyme (ACE) Inhibitors

ACE inhibitors were originally studied for their vasodilatory effects in HF. Later, their effects on neurohormonal systems such as the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS) became better understood.¹⁸ ACE inhibitors work by inhibiting the RAAS and decreasing the effects of angiotensin II. Due to concerns about hypotension, ACE inhibitors are usually started at a low dose and titrated upward to the maximum tolerated dose. However, in current practice most patients are receiving suboptimal doses of ACE inhibitors.¹⁰ A transient change in renal function can be expected on this therapy, with serum creatinine becoming elevated and then returning to normal after a few weeks. ACE inhibitors can elevate potassium levels, especially in patients with renal disease or diabetes and in patients who are also on an MRA. ACE inhibitors are commonly associated with cough and angioedema, possibly due to their potentiation of bradykinin. There is evidence suggesting that angioedema may be observed more frequently in women with HF than in men.³

Clinical trials of ACE inhibitors have shown a significant effect on mortality. The CONSENSUS trial in patients with NYHA Class IV showed a 40% reduction in mortality risk compared to placebo, while the SOLVD trial in patients with NYHA Classes II and III demonstrated a 16% reduction in mortality versus placebo.¹⁹ Although there are several ACE inhibitors available (Table 3), those with the most available data in HF include enalapril, lisinopril, ramipril, and trandolapril. Captopril is used less frequently due to the need for thrice-daily dosing and interactions with certain foods.

Although HF primarily affects older women, it is important to note that the agents in the ACE/ARB/ARNI classes are teratogenic, particularly in the first trimester. This is a key consideration in the treatment of any women of child-bearing age with HF.²⁰

Angiotensin Receptor Blockers (ARBs)

When this group of drugs was developed it appeared they might take the place of ACE inhibitors. Because ARBs work at the receptor site and do not enhance bradykinin, they are associated with less angioedema and cough than ACE inhibitors.³ Unfortunately, efficacy studies show a less-robust effect for ARBs compared with ACE inhibitors, so ARBs are used mainly in patients who cannot tolerate an ACE inhibitor. The side effect profile is similar between ARBs and ACE inhibitors, including hypotensive and renal effects. Table 4 shows recommended dosage of available ARBs, per the ACC/AHA HF guidelines. Higher doses have been associated with improved efficacy, as was demonstrated in the HEAAL study comparing low-dose (50 mg) and high-dose (150 mg) losartan in 3,846 patients with NYHA Classes II through IV who were intolerant to an ACE inhibitor.²¹

Beta Blockers

Beta blockers are indicated for all symptomatic patients with HFrEF in conjunction with an ACE inhibitor or an ARB, as well as for asymptomatic patients with left ventricular dysfunction following an MI.²² Beta blockers inhibit activity of the RAAS, have antihypertensive effects, reduce heart rate to improve myocardial contractility, and reduce excessive adrenergic drive on the myocardium.²² It is essential to avoid abrupt discontinuation of a beta blocker to avoid sympathetic rebound. Beta blockers are contraindicated in patients who have second- or third-degree AV block.

Over the course of several decades, many clinical trials have shown the lifesaving benefits of beta blockers in patients with HF.^23-25 Those with evidence in HF include bisoprolol, carvedilol (short-acting and long-acting) and long-acting metoprolol succinate (Table 5). The classic MERIT-HF study showed a 35% reduction in mortality risk with long-acting metoprolol versus placebo over a mean 1-year follow-up period.²⁶ Trials of carvedilol and bisoprolol show similar survival benefits compared with placebo.^23,25,27

Unlike the ACE inhibitors, beta blockers are a highly heterogeneous group of drugs.²⁸ Therefore, beta blocker selection in HF should be limited to those agents with evidence-based benefits. Selection of a specific beta blocker is often influenced by the patient's blood pressure. Carvedilol has alpha blocking effects and thus may lower blood pressure to a greater degree than metoprolol succinate. For a patient who is hypotensive, metoprolol may be a better option. It is important to achieve and maintain target doses of beta blockers in patients with HF, but this can be a significant challenge for patient adherence. Patients must be counseled that these agents are for long-term benefit, but the beta blocker will not make them feel better in the short term and will likely make them feel worse. As patients adjust through the titration period and up to the target dose, the long-term benefits are incredibly important. Beta blocker doses should be reduced if congestion worsens or if the patient's heart rate is low (< 50).

Mineralocorticoid Receptor Antagonists (MRAs)

MRAs, also referred to as aldosterone antagonists, tend to be an underutilized group of drugs in HF. MRAs work on a different part of the RAAS than do ACE inhibitors, by blocking the effects of aldosterone and other steroid hormone receptors.⁴ MRAs are recommended for patients with HFrEF who remain symptomatic despite an ACE inhibitor plus beta blocker (LVEF ≤35%).^2,3 They can be given once daily and have minimal effect on blood pressure. MRAs should be used with caution in patients with impaired renal function or elevated serum potassium. Serum potassium should be monitored closely within the first few days and weeks of MRA therapy. To prevent hyperkalemia, avoid concomitant use with other potassium-retaining drugs, such as potassium-sparing diuretics.³ Pharmacists should counsel patients who use an MRA to avoid salt substitutes, which contain high levels of potassium.²⁹

Clinical trials of the MRAs include the RALES trial of spironolactone which showed a 30% reduction in mortality compared with placebo over a mean follow-up time of 24 months in patients with NYHA Classes III and IV.³⁰ The EMPHASIS-HF trial evaluated eplerenone in patients with NYHA Class II HF and showed a reduction in both the rate of hospitalization and cardiovascular death.³¹ Starting and target doses of MRAs are shown in Table 6. Achieving target doses may be based on potassium levels. In patients with hyperkalemia or reduced renal function (estimated GFR 30–49 mL/min) the guidelines recommend an initial regimen of every other day dosing. Patients developing gynecomastia with spironolactone can be switched to eplerenone.

Angiotensin Receptor–Neprilysin Inhibitor (ARNI)

The combination of valsartan (an ARB) and sacubitril (a newer drug category known as a neprilysin inhibitor) is probably the most significant new addition to chronic HF management in the past decade.³² ARNI therapy is recommended as a replacement to an ACE inhibitor in patients with HFrEF who remain symptomatic despite optimized ACE inhibitor/ARB and beta blocker treatment. It can be considered as part of initial therapy in patients with new-onset HF. In this combination, valsartan acts to inhibit RAAS while sacubitril inhibits neprilysin. Neprilysin inhibition in turn enhances brain natriuretic peptide (BNP) systems shown to be important in HF pathology and progression.^32-34

Approval of this combination was based on results of the PARADIGM-HF trial.³⁵ PARADIGM-HF studied 8,442 patients with chronic HF treated with either sacubitril/valsartan or the active comparator, enalapril. The trial was stopped early due to the substantial benefit of sacubitril/valsartan, which included a significantly reduced rate of cardiovascular death or heart failure hospitalizations (the study's primary end point) by about 20% compared with treatment with enalapril. All-cause mortality, a secondary end point, was also significantly reduced with the ARNI compared with enalapril. Because sacubitril/valsartan can cause hypotension (as was seen in about 10% of patients in PARADIGM-HF), patients require careful blood pressure monitoring.³⁵

A more recent trial of ARNI is the PIONEER-HF study.³⁶ This trial evaluated approximately 900 patients with acute decompensated HF who had been stabilized, comparing sacubitril/valsartan with enalapril. The ARNI group had significantly greater reduction in the primary endpoint of change in NT-proBNP concentration from baseline (50% versus 25% for enalapril). Other endpoints included death and rehospitalization for HF. Rehospitalization was significantly lower for sacubitril/valsartan, and there were no significant differences observed between the groups for worsening renal function, hyperkalemia, hypotension, and angioedema.

Dosage of sacubitril/valsartan is reviewed in Table 7. When starting ARNI therapy, it is essential that ACE inhibitors be discontinued for at least 36 hours to minimize the risk of angioedema. ARNI is contraindicated in combination with another ARB and in patients with history of angioedema.

l_f-Channel Blocker

Ivabradine is indicated for patients with HFrEF who are in sinus rhythm with a resting heart rate ≥70 bpm, and who are either on maximally tolerated doses of a beta blocker or have a contraindication to beta-blocker use.³⁷ This agent regulates heart rate via the I_f  or "funny" channel without an effect on ventricular repolarization or myocardial contractility. Approval for ivabradine was based on the placebo-controlled SHIFT trial, which randomized more than 6,500 patients with NYHA Class II-IV HFrEF.³⁸ Use of ivabradine resulted in a highly significant 18% drop in risk for cardiovascular death or hospitalization for worsening heart failure (the composite primary end point) over an average of 23 months. This was primarily due to a reduction in hospitalizations, with little effect on cardiovascular mortality. Ivabradine is well tolerated; despite bradycardia being recorded in 10% of the study population, the condition lead to study withdrawal in only 1% of these patients.³⁸ Because ivabradine is a substrate of the CYP3A4 enzyme, care should be taken to avoid interaction with strong inhibitors or inducers of 3A4. Before considering ivabradine, beta blocker therapy should be used at the maximally tolerated dose. Ivabradine dose starts at 5 mg titrated to 7.5 mg, to aim for a heart rate in the 50 to 60 BPM range (Table 8). For more cautious initiation, a starting dose of 2.5mg twice a day may be used.

Management of HFpEF

Heart failure with preserved ejection fraction (HFpEF) refers to HF in which LVEF is greater than 50%. HFpEF affects approximately 50% of people with heart failure and a disproportionate number of women.^.39 Unfortunately, clinical trials thus far have not shown a mortality benefit for pharmacologic therapy in this group pf patients. While the TOPCAT trial showed no overall benefit of spironolactone in patients with HFpEF on the composite endpoint of death from cardiovascular causes, aborted cardiac arrest, or hospitalization, , although it did show a modest decrease in hospitalization for heart failure.⁴⁰ A subsequent geographic analysis suggested some potential benefit among the U.S.-based subjects.⁴¹ Due to the lack of evidence for mortality-reducing or disease-modifying therapies in HFpEF, treatment is primarily aimed at managing co-morbidities, improving quality of life and alleviating symptoms. To manage symptoms, many of the medications used in HFrEF are employed. The lack of effective therapies for patients with preserved EF represents an important unmet need in HF treatment.⁴² However, the results of the ongoing PARAGON study are eagerly anticipated. This study compares the effects of sacubitril/valsartan versus valsartan on composite outcomes of cardiovascular death and HF hospitalizations in patients with HFpEF.⁴³

Role of Pharmacists in HF Management

Potentially life-saving HF therapies are often underutilized or used incorrectly. Research suggests that many patients do not receive an adequate dose of HF medications.^9,10 This is a significant opportunity for pharmacist intervention. Pharmacists in many practice areas play a critical role in improving HF management and optimizing outcomes for the HF population.⁹ Both reducing hospitalizations and improving quality of life are goals that can be better achieved with pharmacist involvement in HF treatment plans. Pharmacists can ensure that appropriate drugs are prescribed and may personalize therapy based on patient specific characteristics. Many individual patient factors relating to disease presentation (preserved vs reduced LV function, degree of HF symptoms), age/frailty, organ function, and comorbidities all influence therapeutic selection. Not only do pharmacists prevent medication errors and adverse drug reactions, but they are often involved in educating clinicians and patients. Improving adherence and access to therapy are among the most important pharmacist contributions to management of heart failure and can help ensure that patients are receiving guideline directed medical therapy.⁹ Pharmacists are in an excellent position to advocate for their female patients with HF, bearing in mind that women with HF tend to be even more under-treated than men with this condition.

Case 1. African American Woman with HFrEF The patient is a 72-year-old African American woman with a history of recent myocardial infarction (MI). She has reduced left ventricular function with LVEF < 30%. Her current medications include: Hydrochlorothiazide 12.5 mg/day Atenolol 25 mg/day Captopril 12.5 mg TID She remains symptomatic despite the use of these therapies with fatigue, reduced exercise tolerance when walking and grocery shopping, and moderate fluid retention with ankle swelling. How can this patient’s current treatment be optimized? Dose of diuretic is probably not adequate. Change from thiazide to loop diuretic, better fluid reduction in patients with HF. Change to a different beta blocker with evidence base for heart failure: metoprolol succinate or carvedilol. Change angiotensin converting enzyme (ACE) inhibitor to lisinopril or another with once-daily dosing to reduce pill burden. What other therapies can be considered? Consider replacing ACE inhibitor therapy with angiotensin receptor-neprilysin inhibitor (ARNI). If switching to ARNI, ensure that patient is off ACE inhibitor at least 36 hours before. In African-Americans, hydralazine/isosorbide dinitrate may be considered at some point, but may be too soon for this patient.

Case 2. Frail Elderly Woman with HFrEF The patient is a frail 82-year-old woman with HFrEF who underwent triple bypass grafting 4 years ago. She has a number of medical comorbidities in addition to her history of coronary artery disease, including: Osteoarthritis Hyperlipidemia Hypothyroidism Current medications Aspirin Clopidogrel Digoxin Labetalol Simvastatin Furosemide Levothyroxine Polypharmacy is a concern for this patient. She frequently forgets to take her medications and does not know what each drug is used for. Considerations for management of frail elderly patients with HF Not all older individuals are frail! But, Frailty affects > 70% of patients with HF aged 80 or older. Effect of frailty on medication management Optimize doses of HF medications slowly, monitor status often. Reduce polypharmacy when possible and practical. Consider stopping non-essential medications without immediate effects on symptom relief or quality of life. With frailty/low muscle mass, serum creatinine is typically low and creatinine clearance (CrCl) may be overestimated. Dosage adjustment based on CrCl should be conservative. Review timing and dose of diuretic therapy to reduce risk of incontinence. Cognitive impairment is a common comorbidity in frail elderly patients and can affect ability to manage the medication regimen, report symptoms and adverse effects, etc.

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