Cardiac Rehabilitation to Optimize Medication Regimens in Heart Failure

INTRODUCTION

Heart failure (HF) is a disease with high morbidity and mortality and high impact on function and quality of life.^1,2 Although numerous pharmacologic agents have demonstrated improvements in clinical outcomes among adults with HF,^1,2 the concept of an optimal medication regimen remains inherently ambiguous because clinical priorities can conflict with one another. For example, polypharmacy, commonly defined as the use of at least 5 medications,^3,4 is nearly universal in older adults with HF,⁵ but it is associated with myriad adverse outcomes, including falls,^6–9 disability,^10–12 and hospitalizations.^13–15 The presence of polypharmacy reflects HF prescriptions as well as medications prescribed for the many other comorbid chronic conditions that are endemic in an older HF population.¹⁶ Diuretics, neurohormonal antagonists, and vasodilators are commonly prescribed for pathophysiologic processes and symptoms related to HF,^1,2 and multiple noncardiovascular medications are almost always prescribed as well.

Although there is a rich tradition of evidence-based rationale for any one medication in HF, there is little evidence regarding the optimal administration of medications in aggregate. Moreover, it is not clear how to best balance divergent management priorities, especially in the broader context of noncardiovascular priorities. Important challenges remain with regard to optimizing medication regimens amidst such clinical complexity. Accordingly, there is an ongoing need to address the challenge of optimizing medication regimens in older adults with HF through novel patient-centered strategies and to establish platforms wherein medication optimization is actionable.

Cardiac rehabilitation (CR) was recently approved by the Centers for Medicare & Medicaid Services for management of HF patients and provides a multifaceted secondary prevention program that combines a supervised exercise program with education and counseling to encourage lifelong health and fitness, improve self-care, facilitate self-efficacy, and ultimately improve clinical outcomes and quality of life.¹⁷ Given its comprehensive nature and patient-centered focus,¹⁸ CR has the potential to enhance several other aspects of chronic disease management, such as diet, lifestyle, and stress management, and presents a remarkable opportunity to address medication optimization as a port of an expanded model of CR care. Because most CR programs target enrollment shortly after a cardiac event when changes in HF medications are common, CR provides an ideal platform for important medication management interventions.¹⁷ In this review, 4 major challenges to optimizing medication regimens in HF are reviewed and strategies offered for leveraging CR toward addressing these important challenges (Table 1).

Table 1.

Challenges and potential strategies for optimizing medication regimens in older adults with heart failure

Challenge	Potential Strategies	Cardiac Rehabilitation–Related Strategies
Diuretic management
Chronic congestion and chronically elevated intracardiac pressures are common.	Maintain euvolemia, avoid hypovolemia.	Conduct history and physical examination to identify congestion or signs of over-diuresis. Titrate diuretic dose at CR or relay information to patients’ physicians for dose titration. Co-localize HF program.
Electrolyte abnormalities can result from diuretic use and are associated with adverse outcomes.	Avoid and/or treat electrolyte abnormalities.	Check blood work routinely. Replete electrolytes at CR or relay information to patients’ physicians for repletion. Develop algorithm to address electrolyte abnormalities.
Guideline-directed Medical Therapy (GDMT)
GDMT is frequently under-prescribed. GDMT can cause adverse effects.	Initiate and/or up-titrate GDMT. Down-titrate and/or discontinue GDMT; reinitiate GDMT if can be tolerated at later date.	Introduce nuanced approach to GDMT with close monitoring for tolerance and adverse effects over course of CR.
Review and reconciliation of noncardiovascular medications
An increasing number of medications is associated with increased risk of adverse drug reactions from drug-drug interactions, drug-disease interactions, and drug-patient interactions	Conduct medication review Identify potentially harmful prescribing patterns Discontinue/deprescribe potentially harmful agents	Provide comprehensive review of medications by CR personnel Utilize pharmacist to review and reconcile medications Apply implicit or explicit criteria to identify potentially harmful medications
Medication adherence
Nonadherence is common, undermining the goals of pharmacotherapy.	Provide patient education Ensure safe medication regimen management Provide clinical pharmacist consultation Offer medication-taking reminders Award incentives to promote adherence	Incorporate medication adherence into usual educational program. Manage medications with close monitoring for tolerance and adverse effects Incorporate pharmacist into CR. Incorporate mobile health technologies. Provide tangible incentives for adherence at CR.

CHALLENGE #1: DIURETIC MANAGEMENT

State of the Problem

Patients with HF are at risk for episodes of congestion, defined as signs and symptoms of extracellular fluid accumulation from increased intracardiac filling pressures.¹⁹ Congestion is associated with reduced quality of life, hospitalization, and death.²⁰ Accordingly, diuretics are a cornerstone in the management of HF, targeting congestion.²¹ Loop diuretics are recommended in chronic HF and are used in more than 90% of patients¹⁹; thiazides may be used as adjunctive therapy for those with persistent congestion despite loop diuretic use; and mineralocorticoid receptor antagonists (MRAs) may be used to augment diuresis by modulating the expression and activity of sodium and potassium channels in the distal nephron^19,20 and to combat neurohormonal-mediated adverse remodeling.

To ensure diuretic effectiveness, titrating to doses that can maintain euvolemia is critically important. This is frequently a major challenge, however, for clinicians. Recent data suggest that a large proportion of adults hospitalized with HF is inadequately decongested by hospital discharge²²; and among ambulatory patients, a significant proportion experiences chronically elevated intracardiac pressures.²³ Although under-diuresis is associated with adverse outcomes,²³ over-diuresis is also important because it can lead to hypovolemia and symptoms such as dizziness and lightheadedness, predisposing older adults to falls.²⁴ In addition, adverse effects from diuretics, including electrolytes abnormalities such as hypokalemia and hyperkalemia (which are both linked to adverse outcomes),²⁵ must be monitored. These issues highlight the importance of close monitoring when managing diuretics to achieve euvolemia without adverse effects.

Cardiac Rehabilitation as a Solution

CR constitutes a potential platform for both the recognition and management of congestion. CR personnel typically include capable exercise physiologists, physical therapists, and/or nurses under the direction of physician leadership. These personnel could be tasked with identifying congestion through history taking and physical examination, and such information could then be used to titrate diuretic dose. Many CR programs already assume a similar role in managing lipid lowering therapy. Although the effectiveness of CR clinical staff to titrate diuretics has not yet been explored, the concept represents an opportunity for future study. Alternatively, clinical data regarding volume status obtained during a CR session could be routinely relayed to patients’ usual physicians for proper diuretic titration. Co-localizing HF programs with CR could also provide a potential strategy for leveraging CR toward improving diuretic management in this population. With increasing evidence to support the use of continuous ambulatory pulmonary artery pressure monitoring to ensure euvolemia and prevent HF hospitalizations,²⁶ incorporating this new technology into CR represents yet another strategy that warrants investigation.

Because CR occurs over several sessions across a span of several weeks, CR can facilitate repeat evaluations during diuretic titration to ensure both effectiveness and safety. Routinely eliciting symptoms of congestion like shortness of breath and conducting a physical examination to assess for signs of congestion could help to ensure the effectiveness of the diuretic regimen. At the same time, an assessment for hypovolemia could easily be achieved during CR sessions by routinely inquiring about suggestive symptoms like dizziness and lightheadedness and by obtaining a blood pressure (already routinely performed in CR). CR programs could also incorporate routine collection and review of blood work for patients taking diuretics to assess for electrolyte abnormalities. Algorithms could be developed to address electrolyte disturbances by supplementing electrolytes and/or communicating directly with patients’ physicians about abnormal results. With additional training of personnel, CR has the potential to offer an adjunctive platform to ensure euvolemia through careful monitoring and thoughtful decision making.

CHALLENGE #2: GUIDELINE-DIRECTED MEDICAL THERAPY

State of the Problem

Several pharmacologic agents have demonstrated their potential to improve outcomes in HF. β-blockers, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), angiotensin receptor–neprilysin inhibitors (ARNIs), MRAs, and vasodilators (hydralazine/nitrates) have robust data to indicate that they improve mortality, supporting their use in HF with reduced ejection fraction.^1,2 A summary of these agents is shown in Table 2. Although they are included in clinical practice guidelines as class I indications, many of these agents are under-prescribed, especially among older adults.^27,28 In response to low prescribing rates, national quality improvement programs, such as Get With The Guidelines,²⁹ were created to improve the use of guideline-directed medical therapy (GDMT) in adults with HF. Additionally, the Centers for Medicare & Medicaid Services have incorporated the use of GDMT into their quality metrics for hospitalized HF patients as part of a national effort to facilitate broader use of these disease-modifying mortality-reducing agents. Despite these efforts, GDMT use remains suboptimal—in a recent study from the Change the Management of Patients with Heart Failure registry, composed of 3518 ambulatory HF patients with a reduced ejection fraction from 150 primary care and cardiology practices across the United States, 33%, 27%, and 67% were not prescribed β-blocker, ACEI/ARB/ARNI, and MRA therapy, respectively.³⁰ Moreover, among those who were prescribed GDMT, few were taking the recommended target doses (β-blockers: 28%; ACEIs/ARBs/ARNIs: 17%; and MRAs: 67%). This is important because lower doses may not provide maximal benefit. Thus, there remains a need for strategies to combat issues like clinical inertia and a lack of prescriber awareness to optimize the use of GDMT among those who can tolerate it and ultimately improve outcomes.

Table 2.

Guideline-directed medical therapy for heart failure and their potential adverse effects

Medication	Landmark Randomized Controlled Trial	Mean Age in Landmark Randomized Controlled Trial (y)	Target Dose	Potential Adverse Effects
β-Blockers
Metoprolol succinate	MERIT-HF	64	200 mg daily	Hypotension, bradycardia, dizziness, fatigue, depressed mood, confusion, erectile dysfunction
Carvedilol	COPERNICUS	63	25–50 mg bid
Bisoprolol	CIBIS II	61	10 mg daily
ACEIs
Enalapril	SOLVD	61	10–20 mg bid	Hypotension, dizziness, syncope, fatigue, hyperkalemia, acute kidney injury, cough
Lisinopril	ATLAS	64	20–40 mg daily
Captopril	ELITE	74	50 mg tid
ARBs
Candesartan	CHARM	66	32 mg daily	Hypotension, dizziness, syncope, hyperkalemia, acute kidney injury
Losartan	ELITE	74	150 mg daily
Valsartan	Val-HeFT	63	160 mg bid
ARNI
Valsartan-sacubitril	PARADIGM	64	97 mg/103 mg BID	Hypotension, dizziness, falling, hyperkalemia, acute kidney injury, cough
MRAs
Spironolactone	RALES	65	25 mg daily	Dizziness, hyperkalemia, hyponatremia, acute kidney injury
Eplerenone	EMPHASIS	64	50 mg daily
Vasodilators
Hydralazine	V-HeFT	58	75 mg QID	Hypotension, dizziness, tachycardia, palpitations
Isosorbide dinitrate	V-HeFT	58	40 mg QID	Hypotension, dizziness

Juxtaposed to under-prescribing and under-titration of GDMT is the observation that GDMT may be poorly tolerated in some individuals. For example, the Cardiac Insufficiency Bisoprolol Study in Elderly (CIBIS-ELD) trial, which specifically enrolled older adults aged at least 65 years, revealed that overall β-blocker tolerability was lower compared with the tolerability observed in prior β-blocker trials composed of younger participants. In addition, CIBIS-ELD showed that advanced age was associated with reduced tolerability.³¹ These observations are likely the result of multiple factors, including age-related changes in cardiovascular structure and function,³² and unpredictable alterations in pharmacokinetics and pharmacodynamics observed with aging, both of which can have an impact on medication effects.³³ Older adults frequently experience impairments in cognition and function,³⁴ which increase the risk for adverse drug reactions.^35,36 Given their exclusion from major clinical trials,^37,38 less is known about how older adults with impairments in cognition and/or function tolerate HF medications and how much benefit they derive. A recent study of adults with HF revealed that individuals with significant functional impairment (impairments in their activities of daily living) took the same number of medications as those without such impairments, suggesting that clinicians may not consider factors like function and cognition when prescribing medications.⁵ Given that the risk-benefit ratio of HF medications for older adults with HF could vary based on several different factors, there is a rationale for implementing a nuanced approach to GDMT in which patients are closely monitored for untoward effects, and down-titration or even discontinuation (also known as deprescribing³⁹) is strongly considered for those who develop concerning signs and symptoms like dizziness, postural instability, orthostatic hypotension, or even worsened fatigue.

Cardiac Rehabilitation as a Solution

CR offers an excellent opportunity to optimize GDMT. For those not yet on GDMT who do not have apparent contraindications, this is an opportune time to start evidence-based agents like β-blockers, ACEIs/ARBs/ARNIs, MRAs, and/or vasodilators. Given that CR typically occurs over the span of weeks, initiation and/or up-titration of GDMT during CR is sensible because it provides a platform for monitoring as doses are changed. Moreover, it provides opportunity to systematically inquire about symptoms like increased fatigue or dizziness and to objectively evaluate changes in function, balance, and/or gait that provide important insight into GDMT tolerance. Vital signs, which are routinely assessed during CR, also can provide important information about GDMT tolerability. For example, bradycardia or hypotension could prompt changes to GDMT. For scenarios where GDMT is either decreased or discontinued, CR should additionally offer the opportunity for restarting or increasing GDMT if/when there is an improvement in function. This notion may be especially relevant for post-hospitalization patients, whose balance and gait speed as well as symptoms of dizziness and fatigue may improve with CR.

Although implementation of this model represents an ambitious undertaking, leveraging CR to introduce nuance into the management of GDMT could substantially alter the paradigm of HF management. Given potential benefits, future studies should examine whether such a model is feasible, effective, and pragmatic.

CHALLENGE #3: REVIEWING AND RECONCILING NONCARDIOVASCULAR MEDICATIONS

State of the Problem

Multimorbidity, or the condition of having multiple chronic conditions,⁴⁰ is nearly universal in HF. Among Medicare beneficiaries, 90% have at least 3 other chronic conditions and more than 60% have at least 5 other chronic conditions.¹⁶ Consequently, a large number of medications taken by adults with HF are frequently noncardiovascular in nature. This is important because as the number of medications increases, the risks for drug-drug interactions, drug-disease interactions, and drug-patient interactions increase.⁴¹ In routine care, the process of optimizing medication regimens may be undermined by several factors, including limitations in the time and resources of clinicians to conduct a thorough review, the disease-specific focus of many clinicians where medications outside the scope of their expertise may be overlooked, and fragmentation of care where multiple clinicians prescribe multiple medications with sub-optimal communication with one another. This supports the need for an improved process of medication reconciliation. Consequently, potentially harmful medications often remain even after a patient sees a clinician. In a recent study of adults with HF from National Health and Nutrition Examination Survey, almost half of ambulatory adults with HF took a medication that could potentially exacerbate HF; most were noncardiovascular medications.⁴² These issues underscore the importance of conducting comprehensive reviews of all medications (not just those that pertain to HF or cardiovascular conditions) during patient encounters.

Cardiac Rehabilitation as a Solution

CR offers a platform for conducting a detailed medication reconciliation to reduce the risk of medication errors and to eliminate agents that could cause harm. Medication review using implicit and explicit criteria to identify harmful prescribing patterns⁴³ and medication reviews performed by pharmacists⁴⁴ have demonstrated improvements in medication prescribing quality. CR could be leveraged to provide these services. A thorough medication review could be performed where duplicate medications and medications for resolved indications are eliminated and potentially harmful interactions are identified through the aid of the electronic medical record, a checklist, and/or a pharmacist. Although there has been significant national focus on adding appropriate medications (GDMTs) that can improve outcomes in HF, eliminating agents that can cause harm in HF may be equally important.⁴² Although this would require additional resource allocation, CR could offer an opportunity to identify medications that can exacerbate HF⁴⁵ (Box 1), thereby facilitating discontinuation of agents that may contribute to adverse outcomes in this vulnerable population.

Box 1. List of major heart failure exacerbating medications.

Therapeutic Class	Subclass/Drug
Analgesics	COX, nonselective inhibitors (NSAIDs; COX, selective inhibitors (COX-2 inhibitors)
Anesthesia medications	Desflurane; enflurane; halothane; isoflurane; sevoflurane; ketamine
Diabetes mellitus medications	Thiazolidinediones; saxagliptin; sitagliptin
Antiarrhythmic medications	Flecainide; disopyramide; sotalol; dronedarone
Antihypertensive medications	Diltiazem; verapamil; moxonidine
Anti-infective medications	Itraconazole; amphotericin B
Anticancer medications	Doxorubicin; daunorubicin; epirubicin; idarubicin; mitoxantrone; cyclophosphamide; ifosfamide; 5-FU; capecitabine; bevacizumab; interferon; interleukin-2; lapatinib; pertuzumab; trastuzumab; lenalidomide
Hematologic medications	Anagrelide; cilostazol
Neurologic and psychiatric medications	Carbamazepine; citalopram; bromocriptine; pergolide; pramipexole; clozapine; ergotamine; methysergide; lithium
Ophthalmologic medications	Topical β-blockers
Pulmonary medications	Albuterol; bosentan; epoprostenol
Rheumatologic agents	TNF-α inhibitors; chloroquine; hydroxychloroquine

Abbreviations: 5-FU, 5-fluorouracil; COX, cyclooxygenase; NSAID, nonsteroidal anti-inflammatory drug; TNF, tumor necrosis factor.

CHALLENGE #4: MEDICATION ADHERENCE

State of the Problem

Among the self-care behaviors required for HF treatment, medication adherence is critical for achieving positive health outcomes. Unfortunately, medication adherence in patients with HF is suboptimal. In a study of 178,000 Medicare beneficiaries, just 52% were considered adherent to HF medications.⁴⁶ Reasons for this observation are multifactorial. Patient-related factors include cognitive impairment, which can lead to forgetfulness about taking medications; low health literacy, which can lead to an underappreciation about the importance of taking medications; and low motivation, which can lead to disinterest in taking medications. Medication regimen–related factors contributing to nonadherence include pill burden, regimen complexity, medication intolerance, and cost.^47,48 Given the link between improvements in medication adherence and outcomes,^49,50 the need to address medication adherence persists for older adults with HF.

Several interventions aimed at improving adherence have been studied, demonstrating their potential for improving clinical outcomes.^49,50 A systematic review and meta-analysis of interventions to improve HF medication adherence revealed that they significantly reduced mortality risk (relative risk, 0.89; 95% CI 0.81–0.99) and decreased the likelihood for hospital readmission (odds ratio, 0.79; 95% CI 0.71–0.89).^49,50 Interventions to improve medication adherence may be grouped into 6 categories, each of which requires varying levels of time and resources: patient education, medication regimen management, clinical pharmacist consultation for chronic disease comanagement, cognitive behavioral therapies, medication-taking reminders, and incentives to promote adherence. To effectively implement medication adherence interventions, there is a need to appropriately measure adherence, understand the underlying reason(s) for nonadherence, and then subsequently tailor an intervention that can address the underlying issue. A major challenge for achieving these objectives is that although self-report is an inexpensive way to measure nonadherence, questions about adherence are infrequently asked in routine patient encounters. Another important challenge is that that the time and resources necessary to implement an effective intervention may not be available. These issues highlight the importance of developing novel strategies that can leverage preexisting infrastructure and resources to implement interventions that can improve adherence.

Cardiac Rehabilitation as a Solution

CR offers an excellent opportunity to improve medication adherence. The structure of CR, which includes episodic interactions with CR personnel over the course of several weeks, is particularly well-suited for multifaceted initiatives that frequently are required to change complex health behaviors.¹⁸ Also, a key component of CR is tailored education and counseling to provide patient-centered care. This concept is directly aligned with the current literature on medication adherence interventions, which promotes a patient-tailored approach to address adherence barriers rather than one-size-fits-all.⁵¹

Through a team-based approach involving CR personnel, CR could offer the opportunity to better understand patterns of medication adherence and elicit barriers to adherence. Once these issues have been identified, CR personnel could potentially implement patient-centered interventions to improve medication adherence. Selection of the intervention may be drawn from several different intervention categories that may be applicable in the CR setting. Patient education about the importance of pharmacotherapy and medication adherence could be incorporated into the education already provided as part of the CR program. Nuanced approaches to medication regimen management, as described previously, could provide an additional strategy to improve medication adherence. Clinical pharmacist consultation could be incorporated into CR to ensure drug safety, as described previously, as well as to improve medication adherence. Medication-taking reminders, such as through the use of mobile health (mHealth) strategies (eg, text messaging), is currently being studied among patients enrolled in CR⁵² and offers a novel avenue for improving adherence. Finally, incentives to promote adherence through recognition and/or financial reward also could be incorporated into CR. Given the number of possible strategies that could be adapted to the CR setting, leveraging CR toward maximizing medication adherence seems to be a fruitful area for further investigation, with great potential for improving the health outcomes of older adults with HF.

SUMMARY

CR is an inherently patient-centered program that provides holistic care to adults with cardiovascular conditions to promote lifelong health and fitness, facilitate self-care and self-efficacy, and ultimately improve clinical outcomes.¹⁷ As described in this review, CR offers an excellent platform for patient-centered optimization of medication regimens for older adults with HF through its potential to address several aspects of care that have historically served as major challenges to clinicians—diuretic management, the use of GDMT, review and reconciliation of noncardiovascular medications, and medication adherence. Given the link between pharmacotherapy and outcomes in this vulnerable population, the effectiveness of CR may be greatly enhanced by incorporating formal processes, such as those discussed in this article, for optimizing medication regimens. Little is known about how best to incorporate these aspects into CR, and many challenges exist impeding potential benefits of medication management within CR programs. Given the degree of benefit that could result from optimizing medication regimens in HF patients, future work should explore how CR can pragmatically be leveraged toward this purpose and how CR can further maximize both clinical outcomes and quality of life for this highly vulnerable population.

KEY POINTS.

• Given its comprehensive nature and patient-centered focus, cardiac rehabilitation (CR) presents a remarkable opportunity to address medication optimization in older adults with heart failure (HF) as a port of an expanded model of cardiac rehabilitation care.

• With additional training of personnel and potential collaboration with HF clinicians, CR has the potential to offer an adjunctive platform to ensure euvolemia and safe use of diuretics through careful monitoring and thoughtful decision making.

• Utilizing CR to introduce nuance into the management of guideline-directed medical therapy for older adults with HF has the potential to alter the paradigm of HF medication management.

• CR offers a platform for conducting a detailed medication reconciliation to reduce the risk of medication errors and to eliminate agents that could cause harm.

• Through a team-based approach involving CR personnel, CR offers the opportunity to better understand patterns of medication adherence, to elicit barriers to adherence, and to implement strategies to improve adherence.