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Correspondence : Dr. Anique Ducharme, MD, MSc, FRCP Professor of Medicine, University of Montreal Director Heart Failure Clinic, Montreal Heart Institute Montreal Heart Institue, Research Center (S-2700) 5000 Belanger street, Montreal (QC), H1T 1C8 Tel: 514-376-3330, ext 3947; fax: 514-593-2575
A number of societies produce heart failure (HF) management guidelines, comprising official recommendations based on recent research discoveries, but their applicability to specific situations encountered in daily practice might be difficult. This Clinical Practice Update (CPU) aims to provide responses to fundamental questions facing health care providers, like appropriate timing for the introduction and optimization of different classes of medication according to specific patient phenotypes, when second line therapies and valvular interventions should be considered, and management of difficult clinical scenarios such as cardiorenal syndrome and frailty. A consensus-based methodology was used. Approaches to five different phenotypes are presented: 1) The Wet HF Phenotype is the easiest to manage, decongestion being performed alongside introduction of guideline-directed medical therapy (GDMT); 2) The De-novo HF Phenotype requires the introduction of the four pillars of GDMT, personalizing the order based on individuals’ biological and physiological characteristics; 3) The Worsening HF Phenotype is a marker of poor prognosis, and therefore should motivate optimization of GDMT, start second line therapies and/or re-evaluate goals of care/advanced HF therapies; 4) The Cardiorenal Phenotypes requires correct volume assessment, as renal function usually improves with decongestion; 5) The Frail HF Phenotype require special attention, careful drug titration and consideration of cardiac rehabilitation programs. In conclusion, specific common HF phenotypes call for a personalized approach to improve adoption of the HF Guidelines into clinical practice.
Patients living with heart failure (HF) can have different characteristics, traits and clinical presentation, defined as HF phenotypes. For instance, HF can be classified by the acuity of clinical presentation, duration of disease, etiology, left ventricular ejection fraction (LVEF), and associated comorbid conditions. It is increasingly evident that the clinical management of HF and the trajectory of disease progression also depend on these factors. There are comprehensive guidelines and position statements by the Canadian Cardiovascular Society (CCS) and Canadian Heart Failure Society (CHFS) [
The 2014 Canadian Cardiovascular Society Heart Failure Management Guidelines Focus Update: anemia, biomarkers, and recent therapeutic trial implications.
CCS/CHFS Heart Failure Guidelines: Clinical Trial Update on Functional Mitral Regurgitation, SGLT2 Inhibitors, ARNI in HFpEF, and Tafamidis in Amyloidosis.
] that were updated over the last decade. Unfortunately, widespread adoption of these guidelines has been inadequate, leaving the majority of patients on sub-optimal therapy [
]. Good adherence to the guidelines can be achieved when HF management is managed by a multidisciplinary specialized team, focusing on patients’ physiological and biological limitations in addition to target dosage of the recommended pharmacological agents. [
] In this Clinical Practice Update (CPU), we focus our attention on the important clinical phenotypes of HF and how the health care team can recognize them and provide phenotypic-based care applying the current guidelines to a specific individual. These phenotypes are not necessarily mutually exclusive and may co-exist in the same patient with any given presentation. Also, these are dynamic presentations and potentially modifiable with treatment targeted at the principle hemodynamic derangements.
Specifically, we will focus on the following HF phenotypes: 1) the wet hypertensive HF patient, 2) the patient with de novo HF; 3) the patient with worsening HF (WHF); 4) the HF patient with cardio-renal syndrome (CRS), and 5) the frail HF and/or hypotensive patient. Each of these patients with HF have unique considerations for diagnosis and treatment based on their clinical presentation and their disease prognosis.
Heart Failure Phenotypes: Diagnosis and Management Considerations
1 The Wet Heart Failure Phenotype
Patients with acute HF (AHF) often present with a variety of different clinical features, regardless of LVEF and can be managed in both acute and ambulatory care settings. Early efforts to outline the phenotypes have provided only a rough guide with many overlapping features. In many of the classification systems used, elevated blood pressure (BP) and the presence of volume overload or maldistribution are consistent across definitions.[
The wet hypertensive patients are relatively easier to care for, due to an elevated Systolic Blood Pressure (SBP), which provides for a greater range of options for initial treatment. A higher BP upon presentation is linked to better outcomes [
], even though SBP is dynamic and changes rapidly due to many variables, including ischemia, atrial arrhythmias, renal function, volume loading, and tachypnea.
Most patients with AHF have volume overload or redistribution, as evidenced by the constellation of pulmonary edema, ascites and/or lower extremity edema, which may have been present for hours (in rapid pulmonary edema) to days or weeks (in patients who slowly decompensate at home). The fluid shifts between compartments (e.g., intra- and extravascular spaces) and increase in total body water lend themselves well for approaches to therapy.
Overall, the mainstay of initial treatment remains loop diuretics and/or a combination of loop + thiazide diuretics. [
] Intravenous furosemide is the most common initial diuretic, and time to diuresis has been put forward as a potential quality indicator given the ubiquity of this therapy in the treatment pathways. [
] In the ADVOR trial, the addition of acetazolamide (500 mg bolus and 500 mg /day infusion with 3 g of magnesium for 2 days or until decongestion) to intravenous loop diuretics (prescribed at twofold the oral dose) led to superior decongestion of patients admitted for acute decompensated HF;[
] the incidence of adverse effects was comparable, including renal failure, hypokalemia and hypotension. It is important to note that patients receiving SGLT2i were excluded as their site of action is the same as acetazolamide. [
] Therefore, SGLT2i should be favored over acetazolamide for maintenance treatment.
Other therapies that have been suggested in hospitalized patients include vasodilators (e.g., ularitide, serelaxin, nesiritide, nitroglycerin), inodilators (e.g., levosimendan, TRV027, milrinone in non-shock patients) and other variations on diuretics (e.g., vasopressin antagonists); in patients with severely impaired kidney function, only the combination of hydralazine and nitrates may be considered but has not been tested in large clinical trials conducted in hospital. None of these have been successful in reducing the morbidity or mortality in patients with AHF.
Hospital admission should be an opportunity for early initiation of guideline directed medical therapy (GDMT), especially mineralocorticoid receptor antagonists (MRA) regardless of LVEF, [
Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial.
] which should be favored over potassium supplements. Switching an angiotensin receptor blocker (ARB) or angiotensin converting enzyme inhibitor (ACEi) to angiotensin receptor neprilysin inhibitor (ARNI) should be done early and ideally at the time of clinical presentation for those with HF and reduced EF (HFrEF, LVEF ≤ 40%). [
] The introduction of a SGLT2i should also be considered early, as soon as the patient has been stabilized, and before discharge given the benefits of these agents on hospital readmission, regardless of LVEF.[
Effects of Empagliflozin on Symptoms, Physical Limitations, and Quality of Life in Patients Hospitalized for Acute Heart Failure: Results From the EMPULSE Trial.
Risk stratification, HF pathways of care, and identifying comorbid conditions impacting care alongside dedicated teams to manage patients with AHF are currently the best treatment strategy on top of diuretics and optimizing indicated medications.
2 The De-novo Heart Failure Phenotype
a. Characteristics and Causes
Patients with de-novo HF present with a new onset of symptoms and signs of HF without a previous diagnosis or documentation of HF or left ventricular (LV) dysfunction, [
Clinical Characteristics of De Novo Heart Failure and Acute Decompensated Chronic Heart Failure: Are They Distinctive Phenotypes That Contribute to Different Outcomes?.
] regardless of the clinical setting (ambulatory or in-patient). Important differences in the clinical characteristics and outcomes of patients with de-novo HF have been observed when compared to patients with an exacerbation of chronic HF. Patients with de-novo HF are younger and more likely to present in the context of an acute coronary syndrome. They are also less likely to have significant co-morbid disease such as diabetes (DM), chronic obstructive pulmonary disease (COPD), atrial fibrillation (AF) and a history of vascular disease. [
Differences in clinical characteristics and outcome of de novo heart failure compared to acutely decompensated chronic heart failure - systematic review and meta-analysis.
] When hospitalized, patients with de-novo HF have better dyspnea relief and lower post-discharge and one-year mortality compared to patients with an acute exacerbation of their chronic HF. [
Differences in clinical characteristics and outcome of de novo heart failure compared to acutely decompensated chronic heart failure - systematic review and meta-analysis.
] Patients with de-novo HF may also be in a favorable position to receive GDMT with the associated improvement in outcomes and reduction in re-hospitalization, emphasizing the need for prompt and thorough management of this patient phenotype. [
] Like the previous phenotype, it seems reasonable to manage these patients with GDMT as early as possible and their introduction could be in pairs. For example, diuretics and MRA could be introduced first in hospitalized patients with fluid overload. For those with HFrEF, ARNI and beta-blockers (BB) should be the next modality of treatment, with SGLT2i being introduced last, but ideally before discharge. [
In ambulatory patients with de-novo HF, early initiation of SGLT2i may be considered, even while waiting for an echocardiography to be performed to delineate whether the patients has HFrEF, as these agents are beneficial regardless of LVEF. [
Irrespective of the cause of HF (whether new onset or an exacerbation of chronic HF), guideline directed initiation/optimization of foundational HF treatment including ARNI (ACEi/ARB), BB, MRA, and SGLT2i therapy is an essential part of HFrEF management. How these therapies are introduced in a patient naïve to such treatments will depend on hemodynamic stability, BP, heart rate (HR) and renal function. BB therapy should only be initiated when patients have no residual signs of congestion or signs of low output, particularly if treatment naïve. SGLT2i therapy can be introduced safely in patients with appropriate renal function, once intravenous therapies are stopped, [
Patient profiling in heart failure for tailoring medical therapy. A consensus document of the Heart Failure Association of the European Society of Cardiology.
While the questions of when and how to introduce sacubitril/valsartan has been subject of debates in the early days, its safety and efficacy in de-novo HFrEF patients has been demonstrated both in ambulatory and hospital settings; [
Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study.
] the subgroup with newly diagnosed HF being more likely to achieve target dose of sacubitril/valsartan at 10 weeks with fewer serious adverse reactions when compared to subjects with established HF, [
Initiation of sacubitril/valsartan shortly after hospitalisation for acutely decompensated heart failure in patients with newly diagnosed (de novo) heart failure: a subgroup analysis of the TRANSITION study.
] more substantial decreases in NT-proBNP and lower rates of re-hospitalization without compromising up-titration of other GDMT. Likewise, one-third of patients enrolled in the PIONEER-HF trial had de-novo HF and just over half were RAS inhibitor naïve patients.[
] Even though not the primary goal of the study, an exploratory analysis of its open label extension showed that patients initiated on ARNI in-hospital had a lower incidence of subsequent HF events, including HF hospitalization (HFH) or cardiovascular mortality through the entire 12-week trial period compared to patients converted to ARNI after the first 8 weeks (13.0% vs 18.1%, p=0.03). [
Initiation of Angiotensin-Neprilysin Inhibition After Acute Decompensated Heart Failure: Secondary Analysis of the Open-label Extension of the PIONEER-HF Trial.
First line ARNI introduction must be considered in those patients with adequate BP (systolic >100 mmHg), stable renal function (estimated eGFR >30 ml/min/1.73 m2), and those in whom reliable re-assessment of safety labs (re-check of serum electrolytes, creatinine) can be achieved within one week. For most patients, especially those naïve to previous RAS inhibition therapy, starting at the lowest dose is recommended, with up-titration within one to two weeks as the patient tolerates. The proposed scheme of introduction of the different class of agents for the De Novo Heart Failure Phenotype is presented in Figure 2.
Figure 2De-Novo Heart Failure Practical Tips for Initiation of Therapy.
There is not a universal definition of worsening HF (WHF); indeed, each published trial used its own definition and timeframe, making comparisons difficult for trial results. Nevertheless, WHF is generally defined as worsening HF symptoms and signs requiring an intensification of therapy [
Importance of Clinical Worsening of Heart Failure Treated in the Outpatient Setting: Evidence From the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF).
]; several studies demonstrate that even just an increase in oral diuretics is associated with increased risk of short-term events. So WHF can be a spectrum of increased oral diuretics, outpatient IV diuretics, unscheduled clinic visit, visit to ER or admission. It is difficult to ascertain the exact epidemiology of WHF owing to these varying published definitions, but WHF accounts for anywhere from 5% to 42% of HF admissions. The most common causes of worsening of chronic HF are ischemia, arrhythmias, valvular dysfunction, systemic or pulmonary hypertension, volume overload or fluid retention, high output conditions (infection, anemia, thyrotoxicosis), drugs (Non-Steroidal Anti-Inflammatory agents (NSAIDs)), cyclo-oxygenase (COX) inhibitors, thiazolidinediones) and HF medication change (decrease in diuretics, patient’s noncompliance, etc).
Patients hospitalized with WHF are at high risk for adverse outcomes post-discharge, with high readmission rates (0.7 per patients at 30 days and 2.0 at 24 months post-worsening event). These patients also exhibited a rapid decline in survival starting soon after a WHF event, with almost 30% of the patients not being alive within 2 years. [
] While only a few trials specifically targeted patients with WHF (see below), a first step is to optimize GDMT and see this hospital admission as an opportunity to improve care. The Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) [
Fonarow, G.C., et al., Carvedilol use at discharge in patients hospitalized for heart failure is associated with improved survival: an analysis from Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF). Am Heart J, 2007. 153(1): p. 82.e1-11.
] registry evaluated the relationship between use of carvedilol and early clinical outcomes in patients discharged on BBs (93.3%) 60 and 90 days after discharge, compared to those not receiving BBs therapy at discharge (30.4%).[
] Pre-discharge use of carvedilol was well tolerated with high rates of continued therapy at follow-up and was associated with a significant reduction in mortality at 90 days (HR: 0.46, p ≤ 0.01) and the combination of mortality or re-hospitalization (OR: 0.71, p = 0.02) compared to the group without BB at discharge. More recently, the PIONEER trial discussed above, showed the safety and benefit of introducing/switching to an ARNI compared to enalapril, with significant reduction of NT-proBNP [
Initiation of Angiotensin-Neprilysin Inhibition After Acute Decompensated Heart Failure: Secondary Analysis of the Open-label Extension of the PIONEER-HF Trial.
Despite the high event rate, developing new therapies for these patients has been challenging, in part due to the lack of reliable surrogate markers to predict future risk. Only four trials have enrolled patients with WHF.
In patients with diabetes hospitalized for HF, the SOLOIST trial showed a reduction in cardiovascular events (HR 0.67; 95%CI, 0.52-0.85, p<0.01) of the combined SGLT2 and SGLT1 inhibitor sotaglifozin [
Effects of Empagliflozin on Symptoms, Physical Limitations, and Quality of Life in Patients Hospitalized for Acute Heart Failure: Results From the EMPULSE Trial.
] showed that the SGLT2i inhibitor empagliflozin was beneficial at reducing the composite of death, number of HF events, time to first HF event, and change in Kansas City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS) from baseline to 90 days among 530 acute decompensated HF patients, regardless of EF (median LVEF of 31%) or diabetes status. Clinical stability was defined as SBP ≥100 mmHg and no symptoms of hypotension within 6 hours, no increase in intravenous (IV) diuretic or nitrates dose within 6 hours, and no IV inotropic drugs within 24 hours. In addition, HF was confirmed by elevated NT-proBNP ≥1600 pg/ml or BNP ≥400 pg/ml during hospitalization or within 72 hours prior to admission. The clinical benefit occurred at a rate of 53.9% in the empagliflozin group compared with 39.7% in the placebo group (p <0.01). There was no evidence for treatment interaction among various tested subgroups and the benefit of empagliflozin was independent of symptomatic impairment at baseline. Taken together, these small trials support the early initiation of SGLT2i in patients, a class of drugs which benefits have been shown in ambulatory patients regardless of diabetes and EF.
The VICTORIA trial evaluated the effect of vericiguat, which directly and selectively stimulates the soluble guanylate cyclase (sGC) to increase cGMP production even under low nitric oxide conditions such as HF. They enrolled 5050 patients with AHF on GDMT, randomized either as inpatient or outpatient but must have met criteria for clinical stability (e.g., SBP ≥ 100 mmHg, off IV treatments ≥ 24 hours) and showed a decrease on cardiovascular death or HFH (HR 0.90; 95% CI, 0.82–0.98, p=0.02) after a median follow-up of 10.8 months, despite the majority of patients being on recommended GDMT. [
] The impact on renal function and BP is minimal and this agent should be considered in patients with a current or recent WHF despite GDMT.
Lastly, the selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with HFrEF. Its effect on CV outcomes was studied in the GALACTIC-HF trial [
],which randomized 8256 HFrEF patients (inpatients and outpatients) to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard HF therapy. They showed a reduction in the composite of a first HF event or CV death (HR: 0.92; 95%CI, 0.86-0.99; p=0.03) compared to placebo during a median of 21.8 months, but no significant difference in the change from baseline on the Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score. Therefore, this agent should be considered in patients with WHF. [
WHF is a challenging condition to treat, as many co-morbidities may limit our ability to implement GDMT, such as chronic kidney disease, frailty and low BP. Therefore, treatment needs to be individualized in accordance with each patient’s response to therapy. Other HF therapies should also be sought for the WHF patient, such as ivabradine, hydralazine and nitrates combination, cardiac resynchronization and other interventions described in the HF guidelines. [
] Many options are being developed, but mostly for patients with HFrEF except MRA and SGLT2i. To improve outcomes, one potential solution might be to intervene earlier and potentially avert this HFH. Anderson et al. showed that acutely hospitalized patients with HF consulted a physician multiple times before their incident HFH, particularly in the month before (adjusted RR: 1.28; 95%CI, 1.25-1.31; p<0.01) compared with matched COPD controls and 75% compared with stable HF (RR: 1.75; 95%CI, 1.71 to 1.79; p<0.01). [
] These health care contacts could represent missed opportunities to diagnose HF and provide optimal medical therapy in an ambulatory setting and prevent hospitalizations for HF. Finally, considerations for advanced HF therapies, mainly mechanical circulatory support and heart transplantation, are addressed in the next section. The proposed scheme of introduction of the different class of agents for the patients with Worsening Heart Failure Phenotype is presented in Figure 2 (lower panel).
4 The Heart Failure patient with Cardiorenal Phenotype
Most patients with AHF present with signs and symptoms of volume overload, necessitating the relief of clinical congestion as a primary goal. While patient specific circumstances vary, recent studies suggest 4-8 kg of weight loss during a typical hospitalization, although reduction of cardiac filling pressures and clinical congestion associates most closely with prognosis. [
] Fortunately, most patients rapidly improve with intravenous diuretic therapy. However, approximately 20% of inpatients fail to improve once initially stabilized. These patients are more challenging to treat, experience longer length of stay, and have typically more comorbidities such as CKD. Several patient and treatment factors should be considered in these cases, and a stepwise approach, as outlined below may be of help. It may not be possible to fully decongest such patients without complications of therapy, and a degree of ‘permissive overload’ may be necessary, keeping in mind that it would be associated with worse prognosis.
a. Identifying the Cardiorenal Heart Failure Phenotype
In the absence of a unified definition of clinical improvement in AHF, one may reasonably take known and favorable prognostic patient response to therapy, together with absence of complications Thus, systematic standard daily assessment of each patient, including signs and symptoms, oxygen requirements, weight loss, urine output, electrolytes and creatinine, should be obtained and documented for future comparison.
A major hallmark of this phenotype is the presence of cardiorenal syndrome (CRS), [
] whereby both cardiac and renal disease co-exist, and whilst is common the CRS remains vaguely defined. Acute kidney injury or AKI (rise in serum creatinine >26 umol/L or 1.5 x baseline serum creatinine coupled with <0.5 ml/kg/h urine output for at least 6 hours) is a specific syndrome requiring careful assessment, frequently specialist consultation and close follow up. It is associated with worse in-hospital and outpatient outcomes. While escalation of diuretics may prove useful in this setting, worsening AKI may also result, necessitating decision with respect to renal replacement therapy and goals of care.
b. Management of the Decompensated Cardiorenal Heart Failure Phenotype
A detailed review of this topic is beyond the scope of this CPU but can be found elsewhere. [
Hollenberg, S.M., et al., 2019 ACC Expert Consensus Decision Pathway on Risk Assessment, Management, and Clinical Trajectory of Patients Hospitalized With Heart Failure: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol, 2019. 74(15): p. 1966-2011.
] Practical management of these patients can be achieve using a stepwise approach.
Step 1: Re-confirm volume status
Determination of intravascular fluid volume may be challenging. In the event of inadequate diuresis, it is critical to confirm that clinical congestion exists. More than 20% of patients with AHF may present with discordant right- and left-sided filling pressures.[
] This is particularly important in patients with relatively high right-sided filling pressures, where further diuresis may precipitate low cardiac output and acute kidney injury, or alternatively improve renal function without adversely impacting cardiac output. Also, patients with elevated left filling pressure in the absence of peripheral congestion would benefit from vasodilators rather than excessive diuresis that could precipitate AKI. Hence, disproportional elevation of RV or LV filling pressures requires careful attention to diuretic responsiveness.
Recent studies suggest diagnostic aids, such as the chest X-ray or point-of-care ultrasound where both right-sided (inferior vena cava (IVC) or jugular venous pressure (JVP) diameter) and left-sided (pulmonary B lines, pleural effusions) filling pressures may be estimated. Comprehensive 2D echocardiography may also be used to estimate LV and pulmonary artery (PA) pressures. Invasive measurement of right-sided pressures may be necessary and in small, single-centre studies have been shown to change therapeutic decisions, even when compared to highly experienced HF practitioners, and improved outcomes. [
Step 2: Mitigate Iatrogenic and Patient Contributions
Several concomitant therapies may contribute to inadequate decongestion. Inadvertent administration of solute (via IV infusions) and use of agents which promote volume retention in patients with AHF should be stopped, if possible, along with medications typically avoided in this population. It is also important to acknowledge that extreme salt restriction (< 1500 mmol/24 hours) and water restriction (< 1200 ml/24 hours) have not been shown to improve decongestion, and in several studies have been associated with worse patient outcomes. [
] Many patients with AHF experience water and salt craving and will self-administer increased levels. Clues to this behavior include multiple fluid containers at the bedside, delivered food with high salt content to the patient (instead of hospital diet), frequent patient absences from the ward, especially during mealtimes, and large discrepancies between fluid intake/output balance and daily weights/clinical assessment. Measurement of urinary sodium excretion (lack of weight loss despite serum sodium > 50 meq/L on spot urine) might be useful. One way to mitigate this behavior is to allow a less restrictive intake restriction of a maximum of 2 liters per day in patients without hyponatremia.
It is critically important to identify and address other comorbid conditions such as concomitant infection, anemia, iron-deficiency, hepatic dysfunction, thyroid disease, concomitant cardiac ischemia, valve disease or poor lung function, which otherwise might lead to refractory HF.
Step 3: Escalation of Diuretic Therapy
Nearly all admitted patients with AHF exhibit some degree of diuretic resistance and require increased doses to diuresis adequately. In general, chronic HF patients will require 2x the usual dose of home diuretic given intravenously while newly diagnosed patients will require a lesser dose, such as 40 mg furosemide equivalent. In general, a stepped approach to diuretic therapy is strongly suggested, beginning with doubling of the loop diuretic dose, followed by addition of a second, typically thiazide diuretic, while monitoring for complications of therapy (hyponatremia, hypokalemia). [
] Several additional options are also available to the clinician for add on therapy, none of which are proven superior to any other. They include the addition of thiazide diuretic, use of a vasopressin inhibitor (tolvaptan) or carbonic anhydrase inhibitor (acetazolamide; see ADVOR trial described above, which was not performed specifically in cardiorenal patients however). The addition of MRA may also potentiate the loop diuretic while introducing the GDMT (spironolactone, eplerenone). Use of these agents will often result in additional 2-3 L of diuresis. When goals are met, de-escalation may be undertaken as per CCS Guidelines suggestions. [
Ezekowitz, J.A., et al., 2017 Comprehensive Update of the Canadian Cardiovascular Society Guidelines for the Management of Heart Failure. Can J Cardiol, 2017. 33(11): p. 1342-1433.
] Many clinicians report increased urine output following an infusion of loop diuretic instead of bolus injections. While this strategy appears as safe as bolus injections clinical superiority has not been shown. [
Selected patients with low output HF may benefit from intravenous vasodilation therapy as a means to tailored therapy, lower systemic vascular resistance and improve cardiac output. This afterload reduction strategy is probably underutilized as it has been shown to improve outcomes in small studies from experienced centres. [
] However caution must be employed to avoid excessive hypotension, which will impair renal perfusion pressure and potentially lead to AKI. The ROSE-AHF trial was conducted in participants with AHF and renal dysfunction and showed that neither low-dose dopamine nor low-dose nesiritide enhanced decongestion or improved renal function when added to diuretic therapy. [
] Whether differences in the vasodilator used or the absence of invasive hemodynamic monitoring in ROSE-AHF can explain the apparent discrepancy in the results of these trials is unknown.
Inotropic therapy may be used as either a palliative option to improve symptoms, even for outpatients, or if advanced HF therapies are being considered, as a bridge to a more definitive treatment option. In either case, use of these therapies is highly dependent upon clear starting and stopping rules. However, it is important to recognize early when patients with this phenotype are in cardiogenic shock (CS), by measuring serum blood lactate levels. [
SCAI clinical expert consensus statement on the classification of cardiogenic shock: This document was endorsed by the American College of Cardiology (ACC), the American Heart Association (AHA), the Society of Critical Care Medicine (SCCM), and the Society of Thoracic Surgeons (STS) in April 2019.
] This high mortality of cardiogenic shock patients has remained unchanged for three decades, potentially because early recognition of shock is still sub-optimal, especially in patients with ADHF.
Also, single centre studies have reported that administration of small boluses of hypertonic saline (100 ml of 3% NaCl over 30-60 minutes or 150 mL 3% NaCl to be given over 30 min (300 ml/h) [
] followed by intravenous loop diuretic may increase urine output and fluid loss. Peripheral and central ultrafiltration have been shown to be highly effective in removing fluid, although they have not been shown to preserve renal function or improve clinical outcomes.[
] In highly selected patients, these options may be considered. Removal of loculated fluid collections, such as relief of pleural effusion or paracentesis may offer short term relief of symptoms and are typically limited for this use.
Some patients with the cardiorenal phenotype that are not responding to therapy due to low output may benefit from referral for evaluation for advanced HF therapies, as they have VERY high short-term risk. Regardless of the situation, a simple acronym can be used as a reminder of when the clinicians should consider referral to an advanced heart failure center: I NEED HELP (Figure 3). [
Yancy, C.W., et al., 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol, 2018. 71(2): p. 201-230.
Finally, selected patients may benefit for consideration of transcatheter valvular intervention in patient with severe mitral functional regurgitation [
] even though these trials were not specifically enrolling hospitalized patients with the cardiorenal phenotype, it is not infrequent that progression of valvular disease leads to refractory HF that can be sometimes safely alleviate with such interventions. [
CCS/CHFS Heart Failure Guidelines: Clinical Trial Update on Functional Mitral Regurgitation, SGLT2 Inhibitors, ARNI in HFpEF, and Tafamidis in Amyloidosis.
Frailty is a syndrome characterized by progressive loss of physiological reserve resulting in decreased energy, decreased physical activity, and reduced cognitive ability, and is associated with increased morbidity and mortality. In the FRAIL-HF prospective observational cohort study, 70.2% of 450 patients > 70 years old admitted with HF (mean age 80 ± 6 years) fulfilled the criteria for frailty [
FRAIL-HF, a study to evaluate the clinical complexity of heart failure in nondependent older patients: rationale, methods and baseline characteristics.
]. The frailty phenotype in the HF population is challenging for management because of increased falls risk from multimorbidity and polypharmacy, reduced health care access due to limited mobility, problems with self-care, frequent hospitalizations and decreased quality of life [
].Medication therapy in these patients should be individualized, with shared decision making between prescribers and patients, in the setting where multiple co-morbidities may further limit lifespan and lead to complex medication regimens [
2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee.
GDMT used in the treatment of HF have BP and/or HR lowering effects which may be difficult to tolerate for those who are unsteady in their movement or prone to falls. Doses of GDMT achieved in these patients will often be lower than the target doses used in clinical trials, as well as those tolerated by younger patients [
2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee.
]. Strategies to help mitigate hypotension and risk of falls include initiating medications at small doses and titrating very slowly as tolerated (every 2-4 weeks) and separating administration times of the various medications by at least several hours apart such that the peak antihypertensive effects do not all overlap simultaneously. Certain medications in the different GDMT classes may be less tolerated hemodynamically versus other drugs from the same class, such as carvedilol which has alpha-1 receptor antagonism and ARNI which is associated with significant hypotension. All patients with frailty should be instructed on how to carefully change positions from supine to standing to minimize symptoms of orthostasis. Changing the chronology of administration of drugs might also be useful, favoring those with higher vasodilatory effects at bedtime and separating the timing of administration of the different classes (morning, lunch, supper and bedtime).
Including a pharmacist as a member of the multi-disciplinary HF team is beneficial given issues with polypharmacy and medication adherence that is common in this population. Medications such as eplerenone and ivabradine are substrates of CYP3A4, and many beta blockers are substrates of CYP2D6, and so inhibitors and inducers of these enzymes can increase the risk for side effects or decrease efficacy of these medications, respectively. Carvedilol is an inhibitor of P-glycoprotein and may increase the serum concentrations of other medications that are substrates. Ivabradine can prolong the QT interval and can increase risk of torsade de pointes if combined with other QT-prolonging drugs. Encouraging patients to fill all their prescriptions at the same pharmacy will facilitate pharmacists to better identify these and other clinically significant drug interactions. Clinical pharmacists can also help to improve medication adherence by providing education to patients regarding their medications, monitoring refill dates and dispensing medications in compliance packaging. Furthermore, they are instrumental in optimizing GDMT in a multidisciplinary setting. [
Lastly, frailty can sometimes be reversed with physiotherapy, occupational therapy and nutrition; therefore, referral for cardiac rehabilitation should be considered. Altogether they may be key to prevent HF driven cachexia, clinical deterioration and ultimately autonomy loss.
The REHAB-HF trial randomized 349 geriatric patients hospitalized due to acute decompensated HF. They were subjected to a timely, personalized, and progressive rehabilitation program, which comprised multiple physical-function domains. The intervention group exhibited a significantly greater improvement in physical function compared to the standard care group. Notably, all patients had severely compromised physical function at baseline, with 97% of them being frail or pre-frail. The intervention group maintained an 82% retention rate with good adherence to the sessions (67%). The Short Physical Performance Battery score at 3 months improved more in the intervention than in the control group, (8.3 ± 0.2 and 6.9 ± 0.2 respectively, mean difference between groups: 1.5; 95%CI, 0.9-2.0; p<0.001). At 6 months, there was no difference in rates of rehospitalization for any cause (1.18 and 1.28 for the intervention and control groups respectively; rate ratio, 0.93; 95% CI, 0.66-1.19). [
HF is a complex clinical syndrome, with multiple phenotypic patient presentations. Identifying these varying HF patients is critically important for the subsequent tailoring of therapies to improve their presenting symptoms, their other associated morbidities, and ultimately their lifespan with an acceptable quality of life. Given that not all patients with HF are created alike, it is equally important to understand which of the available therapeutic armamentarium can provide efficacious outcomes with respect to HF symptoms and myocardial function, and so in the event that the patient with HF has a phenotype that is recalcitrant to its therapeutic options, be they pharmacological or non-pharmacological, these patients with HF can be considered for advanced therapeutic options where indicated. This clinical practice update is designed to be used in conjunction with the CCS-CHFS guidelines with the intent to provide a clinical context for practical applicability.
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Funding: No funding from any external organization was received for the development or publishing of this Clinical Practice Update.
Disclosures of Conflicts: The disclosure information of the authors and reviewers is available from the CCS in the Guidelines library at www.ccs.ca. Dr Jonathan Howlett recused himself from decision to approve this CPU due to his role as author and chair of the CCS Guidelines Committee.
Acknowledgments:
The authors acknowledge the contributions and support of Carolyn Gall Casey for contributions and support to the writing and dissemination process. The authors also thank Dr. Pema Raj for his assistance and expertise with document and reference review. The authors acknowledge the volunteer contributions of panel members, the CCS Guidelines Committee, CCS members and individuals involved in the creation and dissemination of best practices since the inception of the Clinical Practice Update process.
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