Patients in Whom New Therapies May Not Be Indicated Contraindications may preclude the initiation of some agents among some patients. Additionally, after being presented with all evidence for and against these thera- pies, a well-informed patient may make a personal judg- ment, in terms of bene ts and risks, and decide against initiation. In a patient whose life expectancy is short (<1 year) due to other comorbidities, some therapies (such as implant- able devices) may not be appropriate. Similarly, in pa- tients with NYHA class IV and Stage D HF being considered for advanced therapies (i.e., transplant or LV assist device), home inotropes, hospice, or initiation of new drug therapies may not be appropriate, especially given the absence of evidence addressing their ef cacy in such patients. 5.2. How to Achieve Optimal Therapy Given Multiple Drugs for HF, Including Augmented Clinical Assessment That May Trigger Additional Changes in GDMT (e.g., Imaging Data, Biomarkers, and Filling Pressures) 5.2.1. Target Doses To achieve the maximal bene ts of GDMT in patients with chronic HFrEF, therapies must be initiated and titrated to maximally tolerated doses (16,40 42). Doses of GDMT J Maddox et al. higher than those studied in randomized clinical trials, even if tolerated, are not known to provide incremental bene ts, and are generally not recommended. Strategies for titration are detailed in Figures 2 and 3. Achieving target or maximally tolerated doses of GDMT is the goal of titration. Beta-blocker doses should be adjusted every 2 weeks (43) in a patient with no evidence of decompensated HF and no contraindications to higher doses. Longer time periods may be needed for frail pa- tients or those with marginal hemodynamics, whereas more rapid titration may be reasonable in clinically stable patients without hypotension. Following adjustment, patients should be cautioned that there may be a transient worsening of HF symptoms such as dyspnea, fatigue, erectile dysfunction, or dizziness. An ARNI is the preferred renin-angiotensin inhibitor in the absence of hypotension, electrolyte/renal instability, or prior angioedema on an ACEI or ARB. If administration of an ARNI is not possible, then an ACEI or ARB should be used, barring contraindication. An ARNI/ACEI/ARB may be titrated similarly to beta-blockers with monitoring of renal function, potassium, and blood pressure; more rapid titration is also reasonable in clinically stable patients. For those taking an ARNI, doses can be increased every 2 weeks to allow time for adjustment to the vasodilatory effects of the combined inhibition of the angiotensin receptor and neprilysin while also monitoring renal function, potassium, and especially blood pressure. For optimal titration of an ARNI/ACEI/ARB, lower loop diuretic doses may be necessary to permit titration; in this circumstance, careful attention to potassium concentra- tions is needed, as the kaliuretic effects of loop diuretics may no longer be present, and restriction of supplemental and/or dietary potassium may be necessary. Aldosterone antagonists are added in as part of the therapy for patients with symptomatic chronic HFrEF who are already receiving beta-blockers and an ARNI/ ACEI/ARB and who do not have contraindications to this therapy (3). It is not necessary to achieve target or maxi- mally tolerated doses of other drugs before adding aldo- sterone antagonists. The doses of aldosterone antagonists used in clinical trials, which are typically below those that might in uence blood pressure, are suf cient for clinical ef cacy. Adherence to the guideline recommendations for monitoring of renal function and potassium is required (4). SGLT2 inhibitors are added in as part of the therapy for patients with chronic HFrEF who are already receiving beta-blockers, an ARNI/ACEI/ARB, and aldosterone an- tagonists, if not contraindicated. There is little data addressing the combination of an ARNI and an SGLT2 inhibitor. However, in both DAPA-HF and EMPEROR- Reduced, the bene t of SGLT2 inhibition was consistent in patients already treated with an ARNI, and a meta- analysis of the 2 trials af rms this nding (12,34,44). In the DAPA-HF trial, among the small number of patients receiving an ARNI, additive bene t was seen across each timepoint from the addition of dapagli ozin (45). Achieving target or maximally tolerated doses of other drugs is not necessary before adding SGLT2 inhibitors. The loop diuretic dose may need to be adjusted based on close monitoring of weight and symptoms (46). In pa- tients using insulin or insulin-secretagogues (such as sulfonylureas), coordinating care through the inclusion of endocrinologists and primary care providers may be helpful in order to minimize the risk of hypoglycemia in patients with diabetes. For several reasons, HYD/ISDN-indicated therapy for HF is often neglected in eligible patients. However, given the bene ts of this combination (43% relative reduction in mortality and 33% relative reduction in HF hospitali- zation) and the favorable impact on health status (47), African-American patients should receive these drugs once target or maximally tolerated doses of beta-blocker, ARNI/ACEI/ARB, and aldosterone antagonists are ach- ieved (3). This combination of drugs is especially impor- tant for those patients with NYHA class III to IV symptoms. Finally, in patients whose heart rate remains $70 beats/min on target or maximally tolerated doses of beta- blockers, ivabradine (6) can be added and titrated at 2 weeks to lower the heart rate. 5.2.2. Barriers to Medication Titration In some instances, it may not be possible to titrate GDMT to the target doses achieved in clinical trials. Patients seen in clinical practice may differ substantially from those enrolled in trials. For example, patients seen in clinical practice are typically older, may experience more side effects including hypotension, and are likely to have more comorbidities that will limit titration. Although data are lacking, it is logical to assume that below-target doses of multiple classes of GDMT are likely more effective in reducing risk than large doses of 1 or 2 agents. Abnormal renal function and/or hyperkalemia are common barriers to initiation and titration of GDMT. In patients with hyperkalemia, education regarding a low potassium diet should be provided. In addition, newer potassium binders (patiromer and sodium zirconium cyclosilicate) are now approved by the Food and Drug Administration and may be considered; however, more data are needed regarding use of such agents in patients with HFrEF, as their use has not been shown to increase GDMT use or have an impact on outcomes in patients. Additionally, these agents raise concerns in terms of cost/ access and their contribution to polypharmacy. A trial examining whether a strategy of potassium binding will potentiate GDMT prescription and improve HFrEF Maddox et al. J outcomes is ongoing, and more data may be available in the future. For patients with established renal disease, caution may be necessary when starting GDMT. In patients with ), no adjustment is needed when deciding the starting dose of the ARNI sacubitril/valsar- tan. In those with severe renal impairment (eGFR <30 mL/ ), the starting dose of sacubitril/valsartan should be reduced to 24/26 mg twice daily (Table 4). ACEIs/ARBs are generally considered safe in patients with severe renal impairment, although de nitive data are lacking. Aldosterone antagonists are contraindicated in patients with severe renal impairment (eGFR <30 mL/ , or creatinine >2.5 mg/dL in men or creati- nine >2 mg/dL in women) or with potassium >5.0 mEq/L (Figure 2). Renal function and potassium should be assessed within 1 to 2 weeks after initiation or dose increase of an ARNI/ACEI/ARB. In patients with preserved renal func- tion or mild to moderate renal impairment, renal function and potassium after initiation and titration of aldosterone antagonists should be assessed within 2 to 3 days and again at 7 days. The schedule for subsequent monitoring should be dictated by the clinical stability of renal func- tion and volume status but should occur at least monthly for the rst 3 months and every 3 months thereafter (3). During the initiation and titration of agents that affect renal function, a decrease in eGFR of >30% or the development of hyperkalemia should alert the clinician that a reduction in doses may be necessary, even though short-term changes in eGFR during intense diuretic therapy or with the initiation of an ACEI or ARB do not predict longer-term adverse outcomes (48), and initial mild worsening of renal function after SGLT2 inhibitor initiation may also occur before longer-term renal func- tion preservation (13). In patients with evidence of hypovolemia, the dose of diuretic agents should be reduced. The ARNI dose may also need to be reduced in the setting of renal insuf ciency or hypotension. Hyper- kalemia may also require changes in medical therapy. Among SGLT2 inhibitors for patients with chronic HFrEF, clinical trial experience with dapagli ozin is lacking in , whereas for empagli ozin, there is a similar lack of clinical trial data for those with an eGFR <20 mL/min/1.73 m2 . Volume status should be closely monitored, as intravascular vol- ume contraction may necessitate a reduction in loop diuretic dosing. Clinical assessment and renal stability in each patient dictates whether clinicians may need to monitor certain patients more closely than others. Socioeconomic barriers to care may undermine the ability to achieve GDMT. For example, the cost of thera- pies poses a substantial barrier to care, particularly for an ARNI, SGLT2 inhibitor, and ivabradine (see the discussion on costs of care in Section 5.7). In such cases, if all solu- tions are exhausted, optimizing care with the most nancially manageable program is recommended. Simi- larly, some patients have a limited ability to attend frequent of ce visits for GDMT optimization. For example, homebound patients or those with limited ability to travel may be unable to have blood pressure, heart rate, or renal function assessed in a timely fashion. In these cases, options such as virtual care and home visiting nurse services may aid in remote optimization of GDMT (49). Virtual care in particular may be a more viable strategy, with the recent increases in its use due to the COVID-19 pandemic. Useful guidance exists regarding the use of virtual visits to allow for medical access, moni- toring of symptoms/signs, and adjustments of GDMT (50). 5.2.3. Clinical Assessment Figure 4 details a reasonable strategy for patient evalua- tion and management following a diagnosis of HFrEF. After GDMT is initiated and titrated with the goal of achieving clinical trial doses or maximally tolerated doses, patients with chronic HFrEF should be evaluated on a regularly scheduled basis. For most patients, a reasonable interval is every 3 to 6 months, although many may require more frequent follow-up to monitor clinical stability and revisit opportunities for further GDMT titration. Cardiac rehabilitation is helpful to support drug titration, monitor symptoms, improve health status, and increase exercise tolerance, but remains underused in terms of both prescription and access (51). During the COVID-19 pandemic, virtual care to allow for outpatient GDMT titration has been useful in certain patients (52) and will likely take on a larger role in HFrEF care post- pandemic. High-risk features (conveniently summarized by the acronym I NEED HELP in Figure 4 and Table 6) should trigger consideration for referral for an advanced HF consultation (53). Features triggering referral to advanced HF care are also discussed in Section 5.3 and Table 6. 5.2.4. Imaging When to Order an Echocardiogram An echocardiogram, with strain imaging when available, is recommended in the evaluation of the patient with incident HF to assess LVEF, diastolic function, chamber size, ventricular wall thickness, valvular abnormalities, and hemodynamic parameters including estimated right ventricular systolic pressure, central venous pressure, and LV lling pressures. Once optimal doses of GDMT have been achieved for 3 to 6 months, repeat imaging can be useful in making decisions regarding device therapy (implantable cardioverter de brillator, cardiac resynch- ronization therapy, or transcatheter mitral valve repair) or referral for advanced therapies (ventricular assist device J Maddox et al. or transplant). In some patients, it may be reasonable to wait longer for such decisions if there is an expectation that LV remodeling might further progress. For example, in the PROVE-HF study, increases in LVEF and reduction in LV volumes continued over 12 months in some patients (11). Repeat imaging may also be considered at the time of important changes in clinical status (3). Routine surveil- lance echocardiograms (e.g., annually) in the absence of FIGURE 4 Testing and Medication Titration Following Diagnosis of HFrEF Maddox et al. J change in clinical status or some other signal of risk are unwarranted. If echocardiography does not provide an assessment of LVEF, guidelines recommend other mo- dalities including radionuclide ventriculography or mag- netic resonance imaging (3). When recovery of LVEF to >40% is noted in the setting of prior HFrEF, outcomes improve (54). Clinicians are often faced with the question of whether to continue GDMT or reduce/eliminate it in patients with complete LVEF recovery. The recent TRED-HF (Withdrawal of Pharmacological Treatment for Heart Failure in Patients with Recovered Dilated Cardiomyopathy) study examined this question, nding that nearly 50% of subjects with- drawn from GDMT had an HF event within 6 months (55). Therefore, in the absence of a de ned, reversible cause for HFrEF (e.g., tachycardia-mediated cardiomyopathy), current GDMT should be continued (56). 5.2.5. Biomarkers When to Order Natriuretic Peptides B-type natriuretic peptide (BNP) and NT-proBNP are the most studied biomarkers in HF. They play a role in diag- nosis and prognostication: higher concentrations of BNP or NT-proBNP in an ambulatory patient with HFrEF inform high risk, particularly when the concentrations are rising. Current clinical practice guidelines give a Class I recommendation to measure BNP or NT-proBNP to support a clinical diagnosis of HF, assess disease severity, or establish prognosis (3). More recently, biomarkers have been examined for their role as markers of clinical responsiveness to GDMT. This is due, in part, to the fact that a wide range of GDMTs may reduce BNP and NT-proBNP concentrations in par- allel with the bene ts of these therapies. Patients whose natriuretic peptide concentrations do not fall with GDMT ( nonresponders ) have a worse prognosis and more deleterious LV remodeling (7,57,58). In the GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensi ed Treatment in HF) trial, among patients with HFrEF, lowering NT-proBNP to <1,000 pg/mL was asso- ciated with signi cant reverse remodeling and improved outcomes (59). Similarly, in the PROVE-HF study, the speed and magnitude of NT-proBNP lowering after ARNI initiation were associated with greater degrees of reverse cardiac remodeling and improved outcomes (7,54). Therefore, measurement of BNP or NT-proBNP is useful to monitor risk, assist in decision-making regarding the ordering of imaging studies to evaluate LV remodeling, and to provide helpful objective data regarding decision- making for referral to advanced HF therapies (Figure 4, Table 6). Concentrations of BNP or NT-proBNP are sup- ported with a Class I guideline recommendation to determine prognosis. In the setting of worsening TABLE 6 Triggers for HF Patient Referral to a Specialist/Program Clinical Scenario 1. New-onset HF (regardless of EF): Refer for evaluation of etiology, guideline-directed evaluation and management of recommended therapies, and assistance in disease management, including consideration of advanced imaging, endomyocardial biopsy, or genetic testing for primary evaluation of new-onset HF 2. Chronic HF with high-risk features, such as development or persistence of one or more of the following risk factors: n Need for chronic intravenous inotropes n Persistent NYHA functional class III IV symptoms of congestion or profound fatigue n Systolic blood pressure #90 mm Hg or symptomatic hypotension n Creatinine $1.8 mg/dL or BUN $43 mg/dL n Onset of atrial brillation, ventricular arrhythmias, or repetitive ICD shocks n Two or more emergency department visits or hospitalizations for worsening HF in the prior 12 months n Inability to tolerate optimally dosed beta-blockers and/or ACEI/ARB/ARNI and/or aldosterone antagonists n Clinical deterioration, as indicated by worsening edema, rising biomarkers (BNP, NT-proBNP, others), worsened exercise testing, decompensated hemodynamics, or evidence of progressive remodeling on imaging n High mortality risk using a validated risk model for further assessment and consideration of advanced therapies, such as the Seattle Heart Failure Model 3. Persistently reduced LVEF #35% despite GDMT for $3 months: refer for consideration of device therapy in those patients without prior placement of ICD or CRT, unless device therapy is contraindicated or inconsistent with overall goals of care 4. Second opinion needed regarding etiology of HF; for example: n Coronary ischemia and the possible value of revascularization n Valvular heart disease and the possible value of valve repair n Suspected myocarditis n Established or suspected speci c cardiomyopathies (e.g., hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia, Chagas disease, restrictive cardiomyopathy, cardiac sarcoidosis, amyloid, aortic stenosis) 5. Annual review needed for patients with established advanced HF in which patients/caregivers and clinicians discuss current and potential therapies for both anticipated and unanticipated events, possible HF disease trajectory and prognosis, patient preferences, and advanced care planning 6. Assessment of patient for possible participation in a clinical trial ACEI angiotensin converting enzyme inhibitors; ARB angiotensin receptor blockers; ARNI angiotensin receptor-neprilysin inhibitor; BNP B-type natriuretic peptide; BUN blood, urea, nitrogen; CRT cardiac resynchronization therapy; EF ejection fraction; GDMT guideline-directed medical therapy; HF heart failure; ICD implantable cardioverter- de brillator; LVEF left ventricular ejection fraction; NT-proBNP N-terminal pro-B-type natriuretic peptide; NYHA New York Heart Association; SGLT2 sodium-glucose cotransporter-2. J Maddox et al. symptoms (60), the reassessment of BNP or NT-proBNP may be informative. Severe renal dysfunction may inter- fere with the interpretation of natriuretic peptide con- centrations. Importantly, current evidence does not suggest targeting treatment to speci c BNP or NT-proBNP levels. Although rising natriuretic peptide concentrations are correlated with adverse outcomes, this relationship can be confounded by the use of sacubitril/valsartan. Due to neprilysin inhibition, concentrations of BNP sometimes modestly rise in patients treated with sacubitril/valsartan and tend not to rapidly return to baseline despite chronic therapy. In contrast, NT-proBNP concentrations typically decrease much more consistently than do BNP concen- trations, as NT-proBNP is not a substrate for neprilysin (61). Clinicians should interpret natriuretic peptides in the context of GDMT; caution is advised when attempting to interpret BNP values in the context of ARNI treatment, and NT-proBNP measurement may be preferable in this setting. However, during treatment, either biomarker predicts the risk of major adverse outcomes in patients treated with sacubitril/valsartan (8). 5.2.6. Filling Pressure Assessment When and How to Measure Filling Pressures Whereas routine pulmonary artery catheterization is not recommended to manage congestion, invasive hemody- namic and lling pressure assessment may occasionally be useful to support decision-making. For example, in patients who have refractory symptoms despite perceived adequate use of diuretic agents, those who develop worsening renal function with attempts to increase doses of diuretic agents, or those with repeated hospitalization for congestion, a better understanding of lling pressures and hemodynamics might assist in pivotal changes in HF therapies. Pulmonary artery catheterization results may also help select candidates for advanced therapies, including transplantation or mechanical circulatory support. Recent attention has focused on the use of implantable sensors to guide lling pressure assessment in ambula- tory patients with HF. In the CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III HF Patients) study, patients with NYHA class III HF symptoms were randomly assigned to receive a wireless implantable pulmonary artery pressure monitor versus usual care (62). Patients who were managed with data from implantable pulmo- nary artery pressure monitoring experienced more changes in GDMT and diuretic doses (63). In addition, those managed with implantable pulmonary artery pres- sure monitoring had a 28% relative reduction in HF hos- pitalization (0.49 events/patient/year in the treatment arm versus 0.69 events/patient/year in the control arm; p < 0.001). Such improvement was seen in patients with both HFrEF and HF with preserved EF. This suggests that in well-selected patients with recurrent congestion, this highly specialized monitoring strategy may guide thera- peutic decision-making. The impact on mortality is un- known but is being evaluated in an ongoing randomized clinical trial, GUIDE-HF (Hemodynamic-Guided Manage- ment of HF). A team-based approach may be necessary to best deploy this monitoring strategy (see Section 5.8). Patients on optimal GDMT who have either high-risk features (Section 5.3 and Table 6) or a poor response to therapy should be considered for referral to an advanced HF specialist, as discussed in the next section. 5.3. When to Refer to an HF Specialist Appropriate and timely referral to an HF specialist and/or HF program is essential in selected patients to optimize therapies and evaluate advanced HF care options (Table 6) (3,64). Referrals should be made for consultation and, if indicated, for comanagement as well as consider- ation of advanced therapies (heart transplantation or mechanical circulatory support), recognition and man- agement of speci c or unusual cardiomyopathies, or annual review (3,65 71). Clinical triggers for referral (Table 6) include persistent or worsening symptoms, adverse clinical events, or other features suggesting that the patient is at high risk for disease progression or death (53,72 75). 5.4. How to Address Challenges of Care Coordination Delivering optimal patient-centered HF care is complex. The range of treatments available, particularly those for patients with HFrEF, include multiple medications, car- diac devices, surgery, and lifestyle adaptations, all of which require education, monitoring, and engagement. For example, patients with HFrEF frequently require consultative care delivered by electrophysiology special- ists to implant, monitor, and adjust devices such as implantable cardioverter-de brillator or cardiac resynch- ronization therapy devices. As outlined in Section 5.9, the complexity of HF care is further exacerbated by the frequent coexistence of both cardiac and noncardiac comorbidities found in patients with HF. Comorbidities are particularly common in the elderly. More than 50% of patients with HF on Medicare have 4 or more non-CV comorbidities and more than 25% have 6 or more (76). The care needs for comorbidities can complicate and in some cases prevent the optimal use of HF therapies. Finally, the medical complexity inherent in most patients with HF generally requires the involvement of multiple clinicians across many care settings (e.g., hospitals, rehabilitation facilities, and ambulatory clinics). This raises the risk of inef ciencies in care delivery, miscom- munication, potential drug drug interactions and drug Maddox et al. J disease interactions, and missed opportunities to achieve optimal HF outcomes. As new medications and devices become available that require optimal communication between multiple parties, including the patient, care coordination is especially important. For example, when caring for patients with HF who have comorbid T2D and are being considered for new glucose modifying therapies (SGLT2 inhibitors), possible approaches include a consultative approach or a team approach. In a consultative approach, the CV specialist consults with the diabetes clinician and/or the patient in the provision of their care (31). In a team approach, an interprofessional multidisciplinary group of clinicians (e.g., primary care, endocrinologists, cardiologists, phar- macists, nurses, advanced practice professionals, and di- eticians) consider novel therapies collectively (31). Regardless, all approaches to HFrEF management need to be patient-centered, use shared decision-making, and involve communication across disciplines (31). Randomized trials have demonstrated the superiority of the team-based approach over usual care in patients with HF (77 80) with respect to the risks of death, hos- pitalization, lengths of stay, and quality of life (81 84). These outcomes are generally attributed to greater adherence to GDMT, higher proportions of patients receiving effective medication doses, and earlier recog- nition of HF signs and symptoms (85,86). Team-based HF care is thus recommended in the most recent HF guide- lines (3). Necessary skills for care teams include pro ciency in monitoring for HF progression and exacerbation, care coordination, treatment prescription and monitoring, and education for patients and their caregivers (Table 7). Effective team-based HF care may be possible with small teams as long as the requisite skills are available. Composition of care teams may continue to evolve. For example, transcatheter mitral valve intervention pro- grams require collaboration with cardiology, cardiac sur- gery, anesthesiology, imaging, nursing, and social services. They also require other medical professionals to be involved with preprocedural patient selection, intra- procedural management, postprocedural in-hospital and post-discharge care, and follow-up outcome reporting. Each program will de ne the roles and responsibilities of various care team members in an effort to effectively communicate and obtain optimal patient outcomes (87). In addition, recent innovations in HF care delivery, such as group visits, remote specialist video consultation, and telemonitoring programs, may also be useful (88 93). As previously noted, the COVID-19 pandemic has accelerated the uptake and reimbursement of virtual care, including telephone and video visits. In addition, remote patient monitoring programs to monitor patients with HF for early signs of clinical decompensation have also been accelerated by the pandemic, given their ability to assess patients without unnecessarily exposing them to COVID- 19. These advances may ultimately have an impact on HF care well after the pandemic subsides. For example, communication may be enhanced with telehealth by leveraging remote symptom monitoring captured be- tween visits, which can be used to inform clinical de- cisions through patient engagement in self-care (94). It will be important to rigorously study the ability of tele- health to effectively manage patients with HFrEF. In the interim, virtual visits serve as one avenue to avoid delays in care, including titration of GDMT remotely, if needed, while taking appropriate precautions to keep patients and caregivers safe during the COVID-19 pandemic. Potential infrastructure components to support team- based HF care are detailed in Table 8. Electronic health records are essential to communica- tion and coordination of care. Patient monitoring and engagement tools that can detect early signs of HF decompensation and encourage adherence to effective therapies are also important adjuncts. Many recent tech- nological innovations in this area, such as implantable pulmonary arterial pressure monitoring devices (62), wearable activity monitors (95), and smartphone and other mobile applications (96), have the potential to improve monitoring and patient engagement (96). These advances have been accompanied by new billing codes for remote monitoring activities. However, as previously noted, these innovations are largely unproven, so the focus should remain on the effectiveness and evidence, rather than the form of these tools. In addition, these programs will require a clear and effective way for care teams to receive, analyze, and act on the information. Low-tech approaches, such as daily weights and algo- rithms for management of HF, may be suf cient for some patients to assist in self-management. In all cases, un- derstanding who receives and acts upon the data is as important as having established programs for monitoring patient-generated data. Patient and caregiver educational tools also support team-based HF care. Recent advances in optimizing health literacy and empowering patient engagement and self-management in HF care are TABLE 7 Essential Skills for an HF Team n HF diagnosis and monitoring for progression n Treatment prescription, titration, and monitoring n Patient and caregiver education on disease and treatments n Lifestyle prescription (e.g., diet, exercise), education, and monitoring n Psychological and social support assessment, treatment, and monitoring n Palliative and end-of-life counseling and care n Coordination of care for concomitant comorbidities HF heart failure. J Maddox et al. promising in this respect (97,98). Ongoing monitoring of team-based care implementation, outcomes, and safety through periodic data collection, analysis, benchmarking, and as needed process improvements are an essential aspect of optimal team-based HF care. 5.5. How to Improve Adherence 5.5.1. Medication Nonadherence Patient adherence is fundamental to the therapeutic effectiveness of GDMT. Medication adherence is de ned as the extent to which medications are taken as pre- scribed, such that nonadherence is not dichotomous, but rather a spectrum of types and degrees of discordance with medication prescription (99). Estimates of signi cant nonadherence in patients with HFrEF vary from 20% to 50% (100 103), with some difference by drug (104). Such nonadherence is associated with worse outcomes in HF (105,106). In addition to nonadherence, a large proportion of patients with HFrEF do not receive target doses of medical therapies (107), even in the absence of docu- mented intolerance. Reasons for nonadherence are complex (108,109), as outlined in Table 9. Unintentional nonadherence is thought to be more common than intentional non- adherence (99,110). As Table 9 shows, the ability of pa- tients to follow treatment plans in an optimal manner is frequently compromised by more than 1 barrier (111,112). Patients with HF, especially those with HFrEF, have indications for multiple medication therapies. In addi- tion, the HF population has a rising prevalence of comorbidities that necessitate their own pharmacological therapies. As a result, patients with HF are prescribed an average of 6 different medications totaling more than 10 daily doses (113,114). Consequently, interventions that target adherence in HF must be multidisciplinary, multi- factorial, and personalized to the particular demands experienced by the patient. 5.5.2. General Approaches to Improving Adherence Regularly assessing adherence helps guide individual approaches and tailor the intensity and type of adherence interventions. Notably, however, clinicians tend to over- estimate actual adherence, and no perfect measure of adherence exists. The past decade has seen a transition away from a hi- erarchical approach to medication adherence and more TABLE 8 Potential Infrastructure Components to Support Team-Based HF Care Modality Challenges Potential Bene ts Electronic health records n Ease of access n Interoperability with other electronic data repositories n Data accuracy including missing data n Reduction in errors n Decision support (e.g., ACC TreatHF mobile app) n Accurate medication reconciliation to facilitate guideline adherence n Patient portal to facilitate patient/caregiver engage- ment, including patient-reported outcomes and other patient-generated data (if available) Patient monitoring devices: (e.g., scales, implanted devices, bioimpedance devices, wearable hemodynamic sensors) n Accuracy n False alert n Cost-effectiveness n Infrastructure/resource needs, including accurate data management and triage n Early warning and a reduction in morbidity Wearable activity monitors n Accuracy n Physical activity coaching/adherence n Early detection of arrhythmias (e.g., AF) Smartphones or other mobile technologies n Need for more useful apps or other mobile tech- nologies, including support systems in place for providing equipment and training for use n Potential privacy issues n Activity tracking n Diet records n Weight management n Communication with HF team n Prompts for medication and lifestyle adherence ACC American College of Cardiology; AF atrial brillation; HF heart failure. Reasons for Nonadherence (World Health Organization) Patient n Perceived lack of effect n Poor health literacy n Physical impairment (vision, cognition) n Mental health conditions (depression, anxiety) n Social isolation n Cognitive impairment (dementia) Medical condition n High HF regimen complexity n Impact of comorbidities (e.g., depression) n Polypharmacy due to multiple comorbidities Therapy n Frequency of dosing n Polypharmacy n Side effects Socioeconomic n Out-of-pocket cost n Dif cult access to pharmacy n Lack of social support n Homelessness Health system n Poor communication n Silos of care n No automatic re lls n Dif culty navigating patient assistance programs HF heart failure. Maddox et al. J toward a shared approach, with greater focus on systems solutions (Table 10). As such, the language has shifted from patient compliance to adherence and now to activation, engagement, and empowerment (115). Within this new paradigm, patients are seen as needing support, whereas blame is counterproductive. Shared decision- making, holistic approaches to multiple chronic condi- tions, cost transparency, personal responsibility, and behavioral theories underlie many of the evolving ap- proaches to enhancing medication adherence (116,117). Six categories of interventions have been identi ed: pa- tient education; medication regimen management; clin- ical pharmacist consultation for chronic disease comanagement; cognitive behavioral therapies; medication-taking reminders; and incentives to promote adherence (102). A systematic review and meta-analysis of 771 intervention trials on medication adherence TABLE 10 Ten Considerations to Improve Adherence 1. Capitalize on opportunities when patients are most predisposed to adherence n In-hospital/pre-discharge initiation following decompensation 2. Consider the patient s perspective n Start with the goals of therapy (feeling better and living longer) and then discuss how speci c actions (medication initiation, intensi cation, monitoring, and adherence) support those goals (example: ACC s My Heart Failure Action Plan) n Use decision aids when available (example: CardioSmart Heart Failure Resources) n Ask patient how they learn best and provide education accordingly n Use culturally relevant patient education materials 3. Simplify medication regimens whenever possible 4. Consider costs and access n Become familiar with and advocate for systems that help make cost sharing automatic, immediate, and transparent n Prescribe lower-cost medications if of similar ef cacy n Facilitate access to copay assistance n Discuss out-of-pocket copays proactively n Prescribe 90-day quantities for re lls 5. Communicate with other clinicians involved in care, ideally facilitated by electronic health records 6. Educate using practical, patient-friendly information n Provide a written explanation of the purpose of each medication prescribed n Plan pharmacist visits for complex medication regimens n Use the teach back principle to reinforce education 7. Recommend tools that support adherence in real time n Pill boxes to be lled by patient or care partner a week at a time n Alarms for each time of the day medications are due n Smartphone or other mobile health applications that provide an interactive platform for education, reminders, warnings, and adherence tracking 8. Consider behavioral supports n Motivational interviewing n Participate in engaged bene t designs 9. Anticipate problems n Communicate common side effects n Provide instructions on when to call for re lls or report problems n Remind patients using pharmacy assistance programs that re lls/reorders are not automatic 10. Monitor adherence and target patients at risk n Inquire patients directly (e.g., How many times in a week do you miss taking your medications? Have you run out of your medications recently? )n Carry out medicine reconciliation at visits, with focus on discrepancies n Assess remaining dosage units (i.e., count excess remaining tablets) n Monitor pharmacy lls, using available clinical databases or automated alerts for failed lls and re lls n Review available drug levels (e.g., digoxin, INR) or concentrations of BNP/NT-proBNP n Plan home-based nursing visits for appropriate patients ACC American College of Cardiology; BNP B-type natriuretic peptide; INR international normalized ratio; NT-proBNP N-terminal pro B-type natriuretic peptide. J Maddox et al. demonstrated that the most effective interventions were delivered face-to-face by pharmacists and administered directly to patients, with a speci c focus on habit-based interventions (118). In a systematic review of 57 studies (119), interventions to enhance adherence for patients with HF were associated with lower mortality (relative risk: 0.89; 95% CI: 0.81 to 0.99) and hospital readmission (odds ratio: 0.79; 95% CI: 0.71 to 0.89). A systematic re- view of 27 studies of mobile health interventions for CV diseases including HF (120,121) found that mobile health signi cantly improved adherence to medical therapy (odds ratio: 4.51; p < 0.00001). 5.5.3. Systems and Policies to Promote Adherence Individual patients and clinicians must be supported by systems that help the right patient get the right therapy at the right time (122). Automated screening and assessment tools can identify and target patients who are at the greatest risk for nonadherence (e.g., those with dementia, depression, homelessness, or drug use) (123). Health in- formation technologies increasingly have the ability to collect pooled data on prescription lls as well as to share these data among care providers and across settings. This offers the potential to characterize patient medication adherence in real time and automatically identify prob- lems. Electronic health record-based algorithms to iden- tify and optimize use of GDMT are already in use for these purposes (124 126). Several other mechanisms can help to optimize adherence: 1. Integration of pharmacists, patient navigators, and registered nurses in collaborative practice may help with optimization of GDMT (127 131). 2. Limiting copays has been associated with small in- creases in patient prescription lls (101,132). Value- based insurance designs that tailor cost sharing to value are promising. 3. The CMS Innovation Center s Bene ciary Engagement and Incentives models aim to support patient adher- ence (https://www.cms.gov/newsroom/fact-sheets/ bene ciary-engagement-and-incentives-models-shared- decision-making-model). 4. Monetary incentives or other rewards for adherence to medications may be cost-saving for highly ef cacious and inexpensive drugs, such as beta-blockers, in HFrEF. 5.6. What Is Needed in Speci c Patient Cohorts: African Americans, Older Adults, and the Frail Randomized clinical trials typically enroll only a subset of patients with HFrEF, resulting in limited demographic, economic, and clinical diversity. Consequently, there is uncertainty about the bene ts and risks of HFrEF thera- pies in patients not resembling those studied. As a result, only approximations of risks and bene ts can guide therapy in the least-studied populations (Table 11) (133). Examples of populations that have been relatively understudied in HFrEF trials include African Americans, older adults ($75 years), and frail patients. African Americans. ARNIs, SGLT2 inhibitors, and ivabradine were tested in clinical trial populations with few or no African Americans. In fact, the landmark ivab- radine study SHIFT included almost no African Americans (12,28,135). Nonetheless, no signi cant differences in the ef cacy of ARNIs or SGLT2 inhibitors have been observed by race. Ivabradine is now actively being studied in Afri- can Americans with HF. Given the established bene ts in the general public, we recommend that African Americans receive these newer medications as part of their HF GDMT. TABLE 11 Speci c Patient Cohorts in HF Care Patient Cohorts Description Evidence-based recommendations Risks Uncertainties African-American patients Self-identi ed GDMT n ARNIs, ACEIs, and ARBs: possibly higher risk of angioedema compared with Caucasian patients n Uncertain risk of hypotension when combining new drugs with HYD/ISDN Expected outcomes of ARNI, SGLT2 inhibitors, and/or ivabradine in those treated with HYD/ISDN Older adults $75 years of age n GDMT, but recognize that this pop- ulation is excluded from many trials supporting GDMT n Consider starting with lower doses of GDMT n Potential falls n Worsening of renal function n Polypharmacy n Comorbidity Ef cacy of lower-dose GDMT on outcomes Frail patients Meets established frailty GDMT as tolerated n Uncertain response to GDMT n Possibly increased risk for adverse drug reactions Ability to have an impact on natural history in the frail with HF ACEI angiotensin converting enzyme inhibitors; ARB angiotensin receptor blockers; ARNI angiotensin receptor-neprilysin inhibitor; GDMT guideline-directed medical therapy; HF heart failure; HYD/ISDN hydralazine/isosorbide dinitrate. Maddox et al. J A key therapy among African Americans with HFrEF is HYD/ISDN. However, the combined bene t of HYD/ISDN with an ARNI, SGLT2 inhibitor, and/or ivabradine is less clear nevertheless, this lack of clarity should not prevent prescription of these new medications. African Americans are underprescribed HYD/ISDN, a treatment with survival bene ts isolated to those of self-de ned African-Amer- ican race; it should be a priority to initiate evidence-based medications in all applicable populations. We recommend consideration of both HYD/ISDN and ARNI prescriptions for African-American patients, with the acknowledgment that both purportedly act via upregulation of cyclic gua- nosine monophosphate (cGMP) pathways and could in- crease the risk of hypotension. Additionally, the risk of angioedema with both ACEIs and ARNIs is higher in African-American patients (136). Clinical guidance for treating HF in African-American patients includes: a. Establish GDMT with an ARNI/ACEI/ARB (ARNI preferred, if possible), a beta-blocker, and an aldoste- rone antagonist; if stable, follow with titration of HYD/ ISDN (starting at a low dose, but aim for doses used in the pivotal randomized trials [Table 1, Figure 3G]). For those with persistent NYHA class III to IV symptoms, titration should proceed with careful blood pressure monitoring and close monitoring of other side effects (e.g., headache, dizziness). (Note: HYD/ISDN are avail- able as a xed-dose combination or as individual medi- cations. The ACC/AHA/HFSA guideline considers either form acceptable in this context.) b. Avoid ARNIs in settings of known or hereditary angioe- dema with ACEIs or ARBs. c. If the heart rate remains above goal in sinus rhythm, ivabradine may be considered; however, given the paucity of data in African Americans, optimize beta- blocker dosing preferentially. d. Use of an SGLT2 inhibitor should also be considered as concomitant treatment for HFrEF in African Americans. Importantly, given the risk of HF in African Americans, use of an SGLT2 inhibitor is especially important in the pre-HF stage to reduce the onset of the disease in those with known diabetes. e. Social barriers to GDMT and optimal HFrEF manage- ment should be assessed and, where present, addressed to avoid health inequities in HFrEF outcomes (137). f. All treatment decisions should be determined in the context of an informed, culturally competent, shared decision-making discussion with the patient that con- siders the risks and bene ts of treatment. Older adults. Older adults, especially the very elderly, represent yet another conundrum for treatment of HF. The upper range for inclusion in HF clinical trials has typically been age 75  5 years; in essence, there are no randomized data for drugs or devices in patients older than 80 years of age. And although data from DAPA-HF can inform the use of a SGLT2 inhibitor in persons over the age of 75 years, for other evidence-based therapies in HFrEF, observational data represent the only lines of evidence supporting similar treatment bene ts in older patients. Nevertheless, target doses for GDMT should be attempted in older patients, with close surveillance for any adverse drug reactions. The pharmacokinetic pro le for GDMT as a function of age is not known, and higher risks of adverse events (133) have been described in older populations. Accordingly, optimal doses for older patients may be lower than those studied in trials or tolerated in younger patients. Furthermore, medication and dosing decisions should be made in a holistic context of the pa- tient. At times, deprescribing, or the process of medi- cation withdrawal or dose reduction to correct or prevent medication-related complications, is an appropriate ac- tion (138). Frailty. Frailty is a speci c pathophysiological entity affecting at least 20% of those over the age of 80 years and ampli es cachexia, muscle wasting, and neurological decline. Frailty increases the risk for HF and, when HF is already present, exaggerates both morbidity and mortal- ity. No evidence exists to suggest that any current ther- apies should be withheld or doses modi ed in the setting of frailty. Potential interventions include multidomain rehabilitation along with cognitive and nutritional sup- port programs to accompany standard GDMT for HFrEF (139,140). Standard assessments of frailty are available (134). 5.7. How to Manage Your Patients Costs and Access to HF Medications The economic burden of HF is substantial and is expected to increase markedly in parallel with increases in HF prevalence. Between 2012 and 2030, total direct medical costs for HF are projected to increase from $21 billion to $53 billion (141), while total costs (including indirect outlay) are estimated to increase from $30.7 billion to $69.8 billion (5). After hospital costs, the cost of CV medications is the second most important cost for pa- tients with HF, accounting for 15.6% of direct costs (142). This creates a nancial barrier for many patients, which is compounded by the fact that most patients with HF also have several comorbidities requiring additional medica- tions. For example, diabetes is present in over 40% of all patients with HF, and polypharmacy for diabetes treat- ment is also growing rapidly (143). Cost Reduction Measures: A variety of cost reduction measures should be considered in patients with HF (Table 12). Whenever possible, generic equivalents for GDMT should be considered. Pricing for common generic HF drugs (digoxin, carvedilol, and lisinopril) varies J Maddox et al. widely, even within a limited geographic area (144). This variability in pricing could potentially have negative im- plications for adherence, encouraging patients to shop around for the best price, increasing time and travel costs, and leading patients to obtain drugs at multiple pharmacies. The use of multiple pharmacies prevents the ef ciencies of having a single pharmacist overseeing all of a patient s medications, identifying potential drug in- teractions, performing medication synchronization, and assessing adherence, as well as providing disease man- agement programs and ensuring that vaccinations are current. As such, patients and clinicians should be encouraged to work with pharmacists, social workers, and/or patient navigators to help identify copay assis- tance programs and request price matching, when possible, should another pharmacy be found to have the medication at a lower cost. In addition, price-checker tools (e.g., GoodRx) can be used to assist patients in locating the retailers with the lowest cost medications. Medication Access Measures: Newer HFrEF therapies are often expensive, with higher monthly costs and copays, and frequently more time and effort are required to obtain them. For example, prior authorization from payers is often required before these medications will be covered, which can serve as a signi cant barrier to GDMT. In 2017, the ACC and a coalition of 16 medical or- ganizations called for reform of the prior authorization process and utilization management requirements that increase clinical workload and limit patient access to care (see: https://www.aacap.org/App_Themes/AACAP/docs/ homepage/2017/PA_Reform_Principles.pdf) (145). Managing approvals for medications may be time- consuming; tips for managing such processes are out- lined in Table 13. It is important to consider the cost-effectiveness of any new therapy to justify out-of-pocket costs. Cost- effectiveness analyses of sacubitril/valsartan and ivabra- dine showed an incremental cost-effectiveness ratio that compares favorably to other accepted CV therapies when they were rst adopted or approved (146 148). Pharma- cists can help navigate insurance coverage and patient assistance programs to make sure that patients have ac- cess to the appropriate medications. Standard requests through patient assistance programs allow for 90-day supplies with 3 re lls to provide coverage for 1 year. However, income veri cation and reordering procedures are among the most challenging aspects of patient assis- tance programs for patients and clinicians (149). Many pharmaceutical companies accept signed letters from clinicians indicating that the patient has no known in- come. This can be used in place of of cial income docu- mentation, although this option is not clearly apparent on many of the patient assistance program websites. Like- wise, patients and clinicians need to be cognizant of reordering procedures, which becomes especially impor- tant if doses are changed re lls/reorders are not always sent and, unfortunately, re lls/reorders cannot be requested before the 60-day post-approval date. Supplemental Appendix 2 provides product-speci c in- formation on assistance in payment for newer HF thera- pies and appropriate use criteria to assist in the prior authorization process. 5.8. How to Manage the Increasing Complexity of HF Management The 2017 HF ECDP was motivated by an increasingly complex HFrEF management environment and the need to assist clinicians in navigating it (2). In the 3 years since its publication, GDMT for HFrEF now has additional medications that improve patient outcomes, thus further increasing the complexity of achieving target GDMT in all TABLE 12 Strategies to Reduce Patients Cost of Care n Coordinate care (including labs and imaging) among clinicians to mini- mize unnecessary duplication n Consider limitations of medication coverage (insurance, Medicaid, etc.) when prescribing n Use generic equivalents for GDMT whenever possible n Work with a pharmacist, social worker, or patient navigator to identify and navigate Patient Assistance Programs n Request price matching if a drug is found at a lower cost at another pharmacy GDMT guideline-directed medical therapy. Helpful Information for Completion of Prior Authorization Forms* Patient Criteria n Include HF phenotype: HFrEF; HFpEF n Identify NYHA functional class n Include recent measurement of LVEF with source documentation if requested n Identify the treatment requested or the additional testing required, with indications supported by evidence and/or guideline statements where applicable; clinical judgment, especially for testing requests, is an appropriate rationale n Address previous therapies used and the rationale for switching to or adding the requested treatment n Address known contraindications to use, adverse effects, and steps intended to minimize the risks of drugs or procedures n Document, when appropriate, that delays or interruptions in therapy may cause harm to the patient n Work with local pharmacy resources and pharmacy professionals to jointly address prior authorization requirements; do not hesitate to ap- peal decisions that are contrary to the best patient care. Document all steps taken in the patient s health record. *Required information may vary depending on payer and state. HF heart failure; HFpEF heart failure with preserved ejection fraction; HFrEF heart failure with reduced ejection fraction, LVEF left ventricular ejection fraction; NYHA New York Heart Association. Maddox et al. J patients with HFrEF. As detailed in Table 14, the modu- lation of 12 pathophysiological targets has now been shown to improve symptoms and/or outcomes for pa- tients with HFrEF. These targets include not only those modulated by the recommended treatments in this document, but also emerging treatments. For example, vericiguat, a soluble guanylyl cyclase stimulator, has demonstrated bene t for the combined outcome of death from CV causes or rst hospitalization for HF (150). The large and growing target and therapy list in HFrEF signi cantly complicates HF management for both patients and their care teams. However, several guiding principles can improve decision-making for and adherence to GDMT, which, in turn, is likely to improve patient outcomes. Principle 1: GDMT is the foundation of HF care, and the GDMT with the highest expected bene t should be prioritized. Based on large randomized trials for HFrEF, ARNIs, evidence-based beta-blockers, aldosterone antag- onists, and SGLT2 inhibitors are rst-line medications for all populations. HYD/ISDN is also a rst-line medication for self-identi ed African Americans. Ivabradine is a second-line medication for select populations. Principle 2: Target doses are associated with best outcomes. Attempt to achieve target doses of all recom- mended therapies in the absence of contraindications and/or intolerance. Titration should occur even if the patient appears stable or their symptoms and/or EF improve. Principle 3: Start GDMT immediately. Delayed initia- tion of GDMT is associated with never initiating GDMT (151). Principle 4: Attention to the clinical, social, and nancial barriers to achieving GDMT should be priori- tized. Multidisciplinary care should be targeted to the individual patient s barriers. Consider early referral to an HF team for assistance. Principle 5: Diligent management of volume status will reduce patient symptoms. Congestion drives symp- toms and hospitalizations. If the volume status is unclear, consider performing right heart catheterization and/or referral to an HF specialist. Chronic ambulatory pulmo- nary artery pressure monitoring may be considered in patients with hospitalizations in the past year who have persistent symptoms with minimal exertion. Principle 6: Tolerability and side effects depend, in part, on how and when GDMT is prescribed. Scenario: Worsening renal function or hyperkalemia. Use less than target doses of an ARNI/ACEI/ARB and discontinue aldosterone antagonist if estimated creati- nine clearance <30 ml/min or serum potassium >5.0 mEq/L. Available data support a survival bene t even with a low-dose ACEI, which may be the default choice in the setting of renal insuf ciency and marginal blood pressure. Scenario: Symptomatic hypotension. Hypotensive symptoms may be due to over-diuresis, use of non-CV drugs with hemodynamic effects (e.g., anticholinergic agents, treatments for prostate enlarge- ment, others), autonomic dysfunction, or simultaneous administration of multiple HF medications. All of these should be addressed before deciding to lower doses of evidence-based therapies. After excluding other causes of hypotension, use best-tolerated doses of GDMT, accept- ing that less data exist for the impact of lower doses in HF management. Clinical comorbidities and clinical judge- ment should be used to guide which GDMTs are reduced. For persistent hypotension, consider referral to an advanced HF specialist. Principle 7: Primary prevention implantable cardioverter-de brillator and cardiac resynchronization therapy should be considered after consistent use of optimal doses of all GDMTs for at least 3 to 6 months, followed by reassessment of EF and other indications for device therapy. Principle 8: Transcatheter mitral valve repair may be considered among symptomatic patients with chronic moderate-severe to severe mitral regurgitation despite optimal doses of all GDMTs. Principle 9: Focus on the patient s symptoms, func- tional capacity, and cardiac function. Maintain surveil- lance of the patient s health status using validated symptom questionnaires (e.g., the Kansas City Important Pathophysiological Targets in Chronic, Hemodynamically Stable HFrEF and Treatments Target Therapy Renin-angiotensin-aldosterone system ARNIs/ACEIs/ARBs, aldosterone antagonists Sympathetic nervous system Beta-blockers Natriuretic and other vasodilator peptides Neprilysin inhibitor (ARNI) Balanced vasodilation and oxidative stress modulation HYD/ISDN Elevated heart rate Beta-blocker, ivabradine Guanylyl cyclase Soluble guanylyl cyclase stimulators Relief of congestion Diuretic agents Ventricular arrhythmias Implantable cardioverter- de brillators Ventricular dyssynchrony due to conduction abnormalities Cardiac resynchronization therapy Mitral regurgitation Surgical or percutaneous mitral valve repair Reduced aerobic capacity Aerobic exercise training ACEI angiotensin-converting enzyme inhibitor; ARB angiotensin receptor blocker; ARNI angiotensin receptor-neprilysin inhibitor; HFrEF heart failure with reduced ejection fraction; HYD/ISDN hydralazine/isosorbide dinitrate; SGLT2 sodium- glucose cotransporter-2. J Maddox et al. Cardiomyopathy Questionnaire). This could be achieved during cardiac rehabilitation, which should be used to improve patient-reported outcomes, reduce hospitaliza- tions, and improve aerobic tness. Principle 10: The value of a therapy to a patient is the combination of bene ts and burdens as they relate to that patient s values, goals, and preferences. Shared decision-making will help patients and the healthcare team reach the best treatment plan for the individual patient. Principle 11: Team-based care is critical to optimizing GDMT and may include frequent follow-up visits, tele- health visits, and remote monitoring. Employ multidisciplinary teams that include advanced practice professionals, clinical nurses, and pharmacists to help titrate GDMT. Team management also facilitates se- rial assessments and longitudinal care, including man- agement of comorbidities. 5.9. How to Manage Common Comorbidities In many cases, there is a bidirectional relationship be- tween HF and certain comorbidities whereby the pres- ence of one may increase the risk of the other, and the prognosis for the patient may be worse if both are present simultaneously. Patients with HF, particularly older patients, frequently have other CV and non-CV comorbidities that affect their prognosis. The presence of multiple chronic conditions is associated with increased symptom burden, may contribute to progression of underlying disease, and often plays a role in a large proportion of hospitalizations in patients with HF. Furthermore, these comorbid con- ditions can greatly affect the treatment of HF and the ability to optimize therapies. To optimally manage these patients and improve clinical outcomes, clinicians must increasingly consider diagnosis and treatment of relevant comorbidities alongside the use of evidence-based HF therapies. Appropriate referral to clinicians with experi- ence treating the various comorbidities is another important aspect of management and lays the foundation for effective team-based care. Diabetes is a common comorbidity that deserves care- ful attention (152,153). Diabetes is strongly associated with the risk of both incident HF and adverse clinical outcomes and is also closely linked to other relevant co- morbid conditions such as hypertension, coronary artery disease, and chronic kidney disease. Treatment of pa- tients with T2D with SGLT2 inhibitors improves glycemic control but also signi cantly reduces HF events in pa- tients with established CV disease or CV risk factors (154 156). Among patients with chronic kidney disease, SGLT2 inhibitors also decrease the risk of renal disease progres- sion in a manner additive to renin-angiotensin- aldosterone system inhibitors (145). As already indicated, the recent DAPA-HF and EMPEROR-Reduced trials demonstrated that SGLT2 in- hibitor therapy reduced the risk of the composite of CV death or worsening HF in patients with HFrEF, regardless of whether they had T2D (12,44). Dapagli ozin is now approved for this indication, and the role of empagli ozin is under review by the Food and Drug Administration. SGLT2 inhibitors must now be included among the established, evidence-based therapies available to clini- cians managing patients with HFrEF. Dapagli ozin has also demonstrated ef cacy among patients with chronic kidney disease in reducing the composite of disease pro- gression, end-stage kidney disease, or death from renal or CV causes. This effect was independent of the presence of diabetes (157). In a similar manner, empagli ozin slowed the decline of kidney function among patients treated in the EMPEROR-Reduced study (13). Table 15 classi es comorbidities into CV and non-CV processes and provides guidance on appropriate management options. Finally, the recent COVID-19 pandemic has illustrated an association between underlying CV disease, including HF, and worse clinical outcomes (171). It is now known that in patients with HFrEF, renin-angiotensin- aldosterone system inhibition is not associated with risk of infection or severity of disease and should be continued, even in the setting of COVID-19 infection, as long as hemodynamically tolerated (172 176). As ap- proaches to management continue to evolve, readers are encouraged to follow the scienti c literature for updated evidence and recommendations for optimal management of these patients. 5.10. How to Integrate Palliative Care and Transition to Hospice Care Advances in care have delayed the progression of disease but rarely lead to a cure, such that the palliative care needs of patients, caregivers, and healthcare systems are as great as ever. Most palliative care is provided by non- palliative care specialists. Accordingly, such clinicians shoulder the primary responsibility for coordinating an end-of-life plan consistent with values and goals expressed by patient and family. The following are important points to consider regarding palliative care and transition to hospice. Principle 1: Palliative care strives to reduce suffering through the relief of pain and other distressing symptoms while integrating psychological and spiritual aspects of care. Action: Soliciting goals of care and focusing on quality of life are appropriate throughout the clinical course of HF and become increasingly important as the disease progresses. Principle 2: Good HF management is the cornerstone of symptom palliation. Maddox et al. 