abchf abchf ABC Heart Fail Cardiomyop ABC Heart Fail Cardiomyop 2764-3107 Sociedade Brasileira de Cardiologia - SBC abchf.20220021 10.36660/abchf.20220021 Review Article Pharmacological Treatment in Patients with Advanced Heart Failure: Recommendations and Challenges 0000-0002-0265-7474 Scussel Fernanda 1 Santa Casa de Misericórdia de Curitiba Curitiba PR Brazil Santa Casa de Misericórdia de Curitiba, Curitiba, PR – Brazil Mailing Address: Fernanda Scussel • Rua Nunes Machado, 471, apto 1402. Postal Code 80250-000, Curitiba, PR - Brazil E-mail: ferscussel@gmail.com

Author Contributions

Writing of the manuscript: Scussel F

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

 12 04 2022 Jan-Mar 2022 2 1 109 115 29 01 2022 01 02 2022 25 02 2022 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract

Heart failure is a highly prevalent condition, and a series of new therapies have emerged over the past years, improving patients’ survival and quality of life, simultaneously making its management more complex. When treating patients with advanced heart failure, that is, with persistent limiting symptoms and recurrent hospitalizations, it is usually even more challenging to manage cases, given that, in addition to frequently having characteristics that would exclude them from most clinical studies, they pose a series of difficulties to optimizing therapies, mainly due to symptomatic hypotension and renal dysfunction, but also due to difficulty in adhering to the growing list of medications, high costs, and poor understanding of their own disease. The concept that is currently in vogue is that therapeutic optimization, including the 4 fundamental drugs for the treatment of heart failure with reduced ejection fraction (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors, beta-blockers, aldosterone receptor antagonists, and sodium-glucose cotransporter-2 inhibitors), should be carried out quickly, within 4 weeks after diagnosis or hospitalization for decompensation, in the event that the patient is not already using the 4 classes. This may be a somewhat “daring” goal when treating patients in more advanced stages. In these cases, some strategies can help to achieve the best tolerated treatment possible, with good control of symptoms and improved survival. Furthermore, intolerance to clinical treatment is also a marker of advanced disease in itself and should be considered a reason for referral to centers specializing in advanced heart failure whenever possible.

 Heart Failure Drug Therapy Introduction

Heart failure (HF) is a highly prevalent condition, for which a series of pharmacological treatments and devices have been developed, with significant improvement in patient survival and quality of life. In spite of this, a portion of patients follow the natural course of the disease, reaching more advanced stages, defined as stage D.1 Even patients who initially benefit from available therapies may eventually progress to the advanced form.

Definitions of HF differ according to the source analyzed, but they all agree on the point of persistent severe symptoms (New York Heart Association functional class [NYHA FC] III to IV) and repeated hospitalizations, in spite of optimized maximum tolerated therapy.2 - 5 It is necessary to keep in mind that the concept of advanced HF goes beyond the presence of left ventricular dysfunction, given that patients with preserved ejection fraction (EF) can also be characterized as such, as well as those with congenital heart disease, severe valve disease without the possibility of intervention, and isolated right ventricular dysfunction.3 That notwithstanding, the therapeutic options discussed in the following text are applied to patients with reduced EF. Another point of convergence in the majority of documents that deal with advanced HF is the issue of intolerance to maximal therapeutic optimization, generally due to symptomatic hypotension and renal dysfunction, with or without hyperkalemia. Moreover, as suggested by the guidelines,3 , 6 - 8 other issues that are frequently present in this group of patients also render clinical optimization difficult, such as advanced age, associated comorbidities, and polypharmacy, with consequent difficulty in adherence, in addition to increasing costs.

The objective of this review is to bring together data from evidence on pharmacological treatment in this specific group of patients, as well as challenges in daily clinical practice.

Classical pharmacological treatment

In general, patients with more advanced disease characteristics end up being underrepresented in most clinical studies. In the PARADIGM-HF study, which randomized more than 8000 patients with EF < 40% (subsequently changed to ≤ 35%) to receive either sacubitril/valsartan (S/V) or enalapril, showing an important reduction in all-cause mortality, deaths due to cardiovascular causes, and hospitalization for HF, in addition to a reduction in sudden death, < 1% of patients were categorized as NYHA FC IV.9 Approximately 20% of patients screened during the run-in period (4 to 6 weeks, to test drug tolerance) could not be included due to intolerance to the target drug dose, hypotension, or worsening renal function. In the PIONEER study, which evaluated the use of S/V in patients with decompensated HF, only 9% were in NYHA FC IV.10

The LIFE study was developed in an attempt to fill this gap in relation to the use of S/V in patients with advanced HF (defined as EF ≤ 35%, NYHA FC IV, BNP ≥ 250 pg/mL or NT-proBNP ≥ 800 pg/mL, and ≥ 1 objective finding of advanced disease).11 Patients were randomized to receive S/V or valsartan alone after a 7-day run-in period to evaluate tolerance to the initial S/V dose of 24/26 mg twice daily. The primary endpoint included proportional change in NT-proBNP at 24 weeks, evaluated by the area under the curve. Secondary outcomes included cardiovascular mortality, hospitalization for HF, hypotension, and other markers of drug tolerance. It was necessary to interrupt the study early due to the COVID-19 pandemic, and the analysis of the results was performed with the 335 patients included up to the moment the study was interrupted; the initial objective had been 400 patients. There were no differences between the groups in any of the outcomes evaluated, and the achieved medication dose was < 50% of the target dose for both groups. In spite of the study limitations, it is starting to become clear that patients in this group do in fact have their own peculiarities in terms of management, and they should not be treated in the same way as patients in earlier stages. Intolerance to clinical treatment should be considered a reason for referral to centers specializing in advanced HF to evaluate indication of other (non-pharmacological) therapies.

Among the studies evaluating the effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with HF and reduced EF, with or without type 2 diabetes, < 1% of patients in the DAPA-HF study12 were in NYHA FC IV. Compared to this, patients included in the EMPEROR-REDUCED study13 had lower EF, higher levels of NT-proBNP, and lower glomerular filtration rate (GFR), reflecting a population with greater severity. A meta-analysis that included both studies showed a 13% reduction in all-cause mortality, a 14% reduction in cardiovascular mortality, and an important reduction in hospitalizations for HF, which had already been demonstrated by both studies individually. However, in subgroup analysis, the effect was shown to be attenuated, although still significant, in patients in NYHA FC III to IV.14 Because these medications have modest effects on blood pressure, in addition to an excellent safety profile, they tend to be well tolerated, even by the most borderline patients, and their initiation in conjunction with beta-blockers has been proposed as a first step in treatment-naive patients or patients whose treatment has been suspended due to more severe decompensation, because, thanks to their natriuretic effect, they can help to counterbalance the symptoms of clinical worsening that may arise at the beginning of beta-blocker therapy.15

In relation to older treatments for HF, there are some studies available that have included outpatients in more advanced stages,16 - 20 demonstrating consistently beneficial results. The COPERNICUS study17 was the largest study that evaluated patients with NYHA FC III to IV and EF < 25%, with a significant reduction in deaths and hospitalizations due to HF, in addition to good patient tolerance to the drug. Meta-analysis of randomized trials evaluating the effect of beta-blockers in patients in NYHA FC IV reiterated this concept.21

In spite of this, concerns still exist in relation to beta-blocker use, especially at the recommended doses, in patients with more advanced disease. A non-randomized study that evaluated the use of carvedilol in patients in NYHA FC IV showed that, although patients were more likely to experience worsening HF soon after starting the medication, the majority were able to continue with the therapy after an initial period of adjustments, and they showed a greater magnitude of symptomatic improvement after 3 months of treatment.22 , 23 Hypotension and hyponatremia, which are conditions that reflect more severe and possibly more congested patients, are predictors of worsening HF after starting carvedilol.22 Patients in more advanced stages require closer follow-up when starting beta-blockers, often requiring a temporary increase in diuretic dose, but these patients tolerate the therapy well and they benefit even more from it. Prior to initiation or progression of the beta-blocker dose, patients must be minimally compensated in order to tolerate the elevated filling pressures and reduced cardiac output, which are mild, yet relevant in these cases.

Aldosterone receptor antagonists are one of the most underused classes in patients with HF and reduced EF,24 - 27 although they have shown 15% to 30% reduction in mortality and up to 40% reduction in rehospitalization in the main studies.19 , 28 , 29 The main precautions are related to worsening renal function, hyperkalemia, and eventually hypotension. Regarding this last issue, an interesting study retrospectively analyzed patients included in the RALES and EPHESUS studies (4396 patients in total), subdivided according to baseline systolic blood pressure (≤ 105, > 105 and ≤ 115, > 115 and ≤ 125, > 125 and ≤ 135, and > 135 mmHg) showing no significant reduction in blood pressure between the drug and placebo, in contrast to what occurs in the treatment of hypertensive patients.30 Furthermore, the benefit of relative reduction in mortality was consistent across all subgroups analyzed. Taking into account that patients with systolic blood pressure ≤ 105 mmHg were more severe patients due to several characteristics analyzed, these patients benefit even more from the proposed treatment. The concern regarding a possible worsening of renal function and hyperkalemia is justified; however, we currently have some strategies to minimize these effects, which will be described subsequently.

In patients with refractory symptoms, the use of digoxin can also be considered, especially as an adjunct to heart rate control in cases of atrial fibrillation, paying attention to the risk of toxicity, especially in women, patients with low weight, and patients with renal dysfunction.31 , 32 The therapy should ideally be adjusted according to drug serum level. Data from more contemporary cohorts of patients with HF are conflicting in relation to the benefits and safety of using digoxin, especially when in sinus rhythm.31 , 33 Discontinuation of digoxin in patients hospitalized for HF seems to be associated with higher rates of rehospitalization, even when they are receiving optimized treatment with other therapies.34

The study that evaluated the effects of ivabradine in patients with HF and reduced EF did not include patients on NYHA FC IV.35 However, the drug seems interesting for the profile of more advanced patients in certain contexts, as it reduces heart rate, without a negative inotropic effect.36 A subanalysis of the SHIFT study using echocardiography assessment showed an increase in systolic volume, by improving ventricular-arterial coupling with a reduction in heart rate.37 It has been postulated that ivabradine may be useful in patients with sinus tachycardia induced by the use of inotropes, especially dobutamine.38 Sinus tachycardia is usually a compensatory mechanism, which attempts to maintain minimally adequate cardiac output. However, the direct physiological relationship between increased heart rate and increased myocardial contractility observed in normal hearts is lost when there is myocardial dysfunction, a condition in which there is a paradoxical reduction in contractile force with higher frequencies.39 Accordingly, ivabradine could contribute to mitigating excessive tachycardia in patients using an inotrope, controlling heart rate without causing negative inotropism and potentially improving hemodynamics. This hypothesis has only been tested in animal studies and small studies in patients with HF, evaluating short-term hemodynamic effects, and the data cannot be extrapolated to clinical practice.40 , 41 Formally, the indication for the use of ivabradine in patients with advanced HF is the same as that applied to other profiles of patients with HF and reduced EF.

Given the various therapeutic options with proven positive impact on HF with reduced EF, taking into account that the benefit of each drug is independent of the presence of the others and that the mechanisms of action are complementary, individualization appears to be the best strategy.42 Patients present with different phenotypes, which reflect different needs, and it seems to be a suitable method define the pharmacological strategy in a more personalized manner, maintaining the objective of including all of the fundamental classes (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors [ACEI/ARB/ARNI], beta-blockers, aldosterone antagonists, and SGLT2 inhibitors).

 New pharmacological treatments

Omecamtiv mecarbil is a more recent medication that has been tested in HF. It acts as a specific ligand of cardiac myosin, optimizing the actin-myosin interaction in the heart muscle, promoting improved contractility (known as the “myotropic” effect). Unlike other medications that increase myocardial contractility, omecantiv does not increase the influx of calcium into the myocyte, considerably reducing the risk of arrhythmias and myocardial ischemia. Initial pharmacokinetic studies showed an increase in ventricular ejection time and systolic volume, in addition to a reduction in left ventricular end-systolic and diastolic volumes.43

The first study to evaluate clinical outcomes of omecantiv mecarbil in HF was the GALACTIC-HF, which randomized more than 8000 patients between 18 and 85 years of age, NYHA FC II to IV (although there were only 124 NYHA FC IV patients in each group), with EF < 35%, who were hospitalized or had been hospitalized during the last year, to receive placebo or omecantiv, with dose guided by serum level measurement. Patients using inotropes, patients with systolic blood pressure < 85 mmHg, and patients with GFR < 20 mL/min/1.73 m2 were excluded. The primary endpoint included time to first HF-related event (hospitalization, urgent emergency room, or outpatient visit) or death due to cardiovascular causes. There was an 8% reduction in the primary outcome (hazard ratio 0.92, 95% confidence interval 0.86 to 0.99; p = 0.03), with no reduction in cardiovascular mortality. There was no difference in the number of adverse events between the groups. Hypotension, worsening of renal function, and hyperkalemia also did not occur.44

Subgroup analysis was performed according to EF (divided into quartiles: EF ≤ 22%, EF 23% to 28%, EF 29% to 32%, and EF ≥ 33%); this analysis had already been pre-specified in the initial study design. The primary endpoint event rate was significantly higher (up to 80% higher) in the quartile with the lowest EF compared to the one with the highest EF, and the benefit of therapy was significantly greater in patients with EF ≤ 28% (hazard ratio 0.84; 95% confidence interval: 0.77 to 0.92; p = 0.0003), when compared to patients with EF > 28% (hazard ratio 1.04; 95% confidence interval: 0.94 to 1.16; p = 0.45). This difference was due to the reduction in hospitalizations rather than cardiovascular mortality.45 In spite of the observed drop in natriuretic peptide levels, there was no symptomatic improvement (evaluated by the Kansas City Cardiomyopathy Questionnaire).

With these data, it is possible to speculate regarding the potential use of this medication in patients with advanced HF, considering the pathophysiological rationale behind its functioning, the evidence of greater benefit in subgroups with greater ventricular dysfunction, and the absence of side effects that are common in this group of patients, such as hypotension and renal dysfunction, but more studies will be needed to confirm these conclusions.

Vericiguat is a molecule that acts by stimulating soluble cyclic guanosine monophosphate through a mechanism that is independent of nitric oxide, but it also increases the sensitivity of cyclic guanosine monophosphate to endogenous nitric oxide, stabilizing the binding of nitric oxide with its receptor, finally improving myocardial function and exerting a vasodilating effect. The medication was approved by the United States Food and Drug Administration in January 2021, following the favorable results of the VICTORIA study,46 which randomized patients with EF < 45%, NYHA FC II to IV, and elevated natriuretic peptides (NT-proBNP > 1000 pg/mL or > 1600 pg/mL with atrial fibrillation), with recent worsening (hospitalization during the past 6 months or use of parenteral diuretic therapy on an outpatient basis) to receive placebo or vericiguat, at a target dose of 10 mg/day. Patients with systolic blood pressure < 100 mmHg and patients who were receiving inotropes were excluded. It is interesting to note that patient recruitment occurred more rapidly than expected, and the number of primary outcome events was also higher than initially calculated, thus representing a more severe population. There was a significant reduction in the outcome of rehospitalization for HF at a mean follow-up of 10 months. Symptomatic hypotension was more frequent in patients using the drug, but there was no significant difference with the placebo group. Anemia was a more common adverse event in patients receiving vericiguat, and the mechanism of this change is not well understood. Subgroup analysis according to NT-proBNP levels (divided into quartiles) showed no benefit in the quartile with higher dosages (> 5314 pg/mL), possibly reflecting a population with very advanced disease, with indication for other non-pharmacological therapies, or even palliative care. Vericiguat became a class IIb recommendation in the 2021 European HF Guideline, for patients with HF with reduced EF, NYHA FC II to IV, and worsening HF in spite of treatment with beta-blockers, ACEI/ARB or ARNI, and aldosterone antagonists.7

 Renal dysfunction and hyperkalemia in patients with advanced HF

The presence of renal dysfunction in patients with HF is a marker of higher morbidity and mortality, as well as advanced disease, when considering that the loss of renal function is secondary to the hemodynamic changes imposed by HF. In spite of this, these patients are known to receive the therapies classically indicated for this condition,47 , 48 mainly renin-angiotensin-aldosterone system antagonists, less frequently.49 Moreover, patients with chronic kidney disease are at an increased risk of developing HF, regardless of the presence of coronary artery disease.50 In relation to patients with more advanced chronic kidney disease (grades 3 or 4), they are also extremely underrepresented in clinical studies. Data on the benefits and safety of the use of ACEI/ARB in these cases come mostly from observational studies. In general, the use of ACEI/ARB can worsen renal function, especially in the short term, and this implies worse prognosis; however, the benefit of therapy with ACEI/ARB is maintained, and it may even be greater.51 In patients who initially present with chronic kidney disease (GFR ≤ 30 mL/min/m2 or creatinine > 2.5 mg/dL), the benefit of using this class of drugs, when tolerated, is maintained.52 Thus, the presence of renal dysfunction should not exclude the patient from trying to use ACEI/ARB and, more recently, ARNI, given that these patients, who are a at higher risk of events, tend to benefit more from treatments, even if at low doses, below those defined as target doses by classical studies, provided that they are followed more closely, with more frequent clinical and laboratory reassessments.

With respect to more recent therapies, subsequent analysis of the PARADIGM study showed that the reduction in GFR was smaller in the S/V group compared to patients who received enalapril, regardless of baseline renal function, in spite of an increase in urine albumin-creatinine ratio caused by S/V.53 This increase was shown to be mild, and it stabilized after a few weeks of treatment. It is worth noting that the study excluded patients with GFR < 30 mL/min/1.73 m2.

SGLT2 inhibitors have also been shown to be very favorable in this scenario, with results of less progression of renal dysfunction in long-term use,54 , 55 in addition to a lower risk of hyperkalemia when used in conjunction with aldosterone antagonists.56

In relation to aldosterone receptor antagonists, recommendations tend to be more conservative when there is renal dysfunction, and their use is contraindicated when creatinine is > 2 mg/dL in women or > 2.5 mg/dL in men, due to the greater risk of worsening of renal function and hyperkalemia, without a clear accompanying benefit.57 Once a patient already using an aldosterone antagonist develops more important renal dysfunction (GFR ≤ 30 mL/min/1.73 m2), the medication should not routinely be discontinued, and each case may be individualized.58

Hyperkalemia is another frequent challenge during management of patients with HF, especially in those with some degree of impaired renal function, and it is associated with worse outcomes, mainly due to the lower use of therapies that block the renin-angiotensin-aldosterone system.59 - 61 When there is mild hyperkalemia, routine non-suspension of these therapies was proposed by Ferreira JP et al.62 in a recent review, where an algorithm for managing these patients was proposed to minimize the underutilization of therapies that have been proven to improve prognosis. The risk of hyperkalemia associated with the concomitant use of aldosterone antagonists is lower when using S/V when compared to enalapril,63 which is one of the strategies proposed if the patient is not already using ARNI. The risk of hyperkalemia is also lower when an SGLT2 inhibitor is associated with treatment.56

The use of potassium chelators is another possibility. The use of patiromer (potassium ligand) has been tested in patients with HF, showing to be effective for this purpose,64 and it is approved for management of hyperkalemia secondary to the use of renin-angiotensin-aldosterone system blockers in the United States and Europe, but it is still unavailable in Brazil. There are no data on efficacy and safety for calcium polystyrene sulfonate in this context. Studies are underway with the objective of evaluating whether the use of chelators, with a consequent increase in the use of renin-angiotensin-aldosterone system blockers, improves outcomes in patients with HF.

 Hypotension and difficulty in dose progression

Optimizing therapy and managing symptoms in patients with more advanced disease can be quite challenging. One of the most limiting issues in this regard is symptomatic hypotension. When this occurs, it is important to assess the possibility of hypovolemia, with the eventual need to reduce diuretic use65 and carefully review all medications in use to check if there are any that are not related to the treatment of HF that may be contributing to hypotension, such as calcium channel blockers and medications for benign prostatic hyperplasia, among others. Fractioning the administration of medications throughout the day, avoiding simultaneous intake of ACEI/ARB/ARNI and beta-blockers can also be useful. It is possible to prioritize beta-blockers without alpha-adrenergic effect (metoprolol and bisoprolol), which therefore have less potential to cause hypotension.

Intolerance to ACEI/ARB use due to circulatory limitation (symptomatic hypotension) or renal limitation (significant worsening of renal function) is an important marker of severity and high risk of death, as well as need for mechanical circulatory support or heart transplantation within 6 months.66 In this manner, these patients should ideally be referred for specialized evaluation.

Initiation of beta-blocker therapy in more advanced patients, although safe, when the disease is minimally compensated, can be more difficult for the patient to tolerate, as patients often experience a feeling of “clinical worsening,” with fatigue, tiredness and drowsiness. In these cases, it is worthwhile to warn patients about this possible feeling of worsening and inform them that, with persistent use, it tends to improve. While more stable patients may have their medication titrated every 7 days, in patients with advanced HF, a longer interval between beta-blocker dose increments may be prudent.67

Beta-blocker intolerance is not a class effect; therefore, it is valid to try more than one option before defining a patient as intolerant to the drug.68

The benefits of fundamental pharmacological therapies (ACEI/ARB/ARNI, beta-blockers, and aldosterone antagonists) are evident and significant, even at low doses, and they are seen in the short term, on average in 30 days.69 - 73 Thus, the association of therapies, even at doses below those considered as target doses, is a superior strategy for reducing outcomes in patients with HF,74 and it often ends up being used in patients with more severe disease. The concept that using a low dose is better than not using the drug should always be taken into account when dealing with a more severe patient who does not tolerate progression.75

 Reconsidering therapeutic goals in advanced HF

Keeping in mind the scarcity of quality data related to the real benefit of classically recommended therapies for HF with reduced EF in the subgroup of patients with advanced disease, much of daily practice ends up being based on the personal experience of professionals who routinely treat these patients.

As a rule, the treatments instituted aim to reduce disease progression and increase survival, but, when treating patients in more advanced stages, improvement of symptoms and quality of life should become one of the goals to be pursued, given that the vast majority will end up not being eligible or will not have access to advanced therapies, such as heart transplantation or circulatory assist devices.

In most cases, the hemodynamic alteration that generates limiting symptoms is the increase in resting filling pressures, caused by hypervolemia. When there is systemic congestion, gastrointestinal symptoms, such as loss of appetite, abdominal discomfort, and early satiety may predominate. A good part of referred patients with refractory symptoms can improve with adequate volume adjustment, which can be difficult to assess, especially in chronic patients.76 In some cases, in addition to dose optimization and eventual association of diuretics, the use of nitrates can be both beneficial and symptomatic.77

Refractory congestion, with resistance to diuretics, is a scenario commonly found in patients with advanced disease, and it requires a targeted and specific approach for this purpose, which is not within the scope of this review.

Finally, it is important to discuss expectations regarding treatment with patients who have advanced HF. In some cases, symptom control becomes a priority, to the detriment of prolonging survival, and pharmacological treatment should be guided by prioritizing this objective.

 Conclusion

Patients with advanced HF present several particularities in pharmacological management and optimization, with increasing complexity. This group of patients is expected to grow progressively, with increased survival promoted by the therapies that are currently available. Therefore, it is essential for there to be more studies focused on this profile of patients, as well as greater representation in clinical trials. Given that it is a marker of worse prognosis, difficulty in pharmacological management should be considered a reason for referral to specialized centers.

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Am J Manag Care. 2015;21(11 Suppl):212-20. Epstein M Reaven NL Funk SE McGaughey KJ Oestreicher N Knispel J Evaluation of the Treatment Gap Between Clinical Guidelines and the Utilization of Renin-Angiotensin-Aldosterone System Inhibitors Am J Manag Care 2015 21 11 Suppl 212 220 60. Beusekamp JC, Tromp J, van der Wal HH, Anker SD, Cleland JG, Dickstein K, et al. Potassium and the Use of Renin-Angiotensin-Aldosterone System Inhibitors in Heart Failure with Reduced Ejection Fraction: Data from BIOSTAT-CHF. Eur J Heart Fail. 2018;20(5):923-30. doi: 10.1002/ejhf.1079. Beusekamp JC Tromp J van der Wal HH Anker SD Cleland JG Dickstein K et al Potassium and the Use of Renin-Angiotensin-Aldosterone System Inhibitors in Heart Failure with Reduced Ejection Fraction: Data from BIOSTAT-CHF Eur J Heart Fail 2018 20 5 923 930 10.1002/ejhf.1079. 61. Lund LH, Pitt B. Is hyperkalaemia in Heart Failure a Risk Factor or a Risk Marker? Implications for Renin-Angiotensin-Aldosterone System Inhibitor Use. Eur J Heart Fail. 2018;20(5):931-2. doi: 10.1002/ejhf.1175. Lund LH Pitt B Is hyperkalaemia in Heart Failure a Risk Factor or a Risk Marker? Implications for Renin-Angiotensin-Aldosterone System Inhibitor Use Eur J Heart Fail 2018 20 5 931 932 10.1002/ejhf.1175. 62. Ferreira JP, Butler J, Rossignol P, Pitt B, Anker SD, Kosiborod M, et al. Abnormalities of Potassium in Heart Failure: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020;75(22):2836-50. doi: 10.1016/j.jacc.2020.04.021. Ferreira JP Butler J Rossignol P Pitt B Anker SD Kosiborod M et al Abnormalities of Potassium in Heart Failure: JACC State-of-the-Art Review J Am Coll Cardiol 2020 75 22 2836 2850 10.1016/j.jacc.2020.04.021. 63. Desai AS, Vardeny O, Claggett B, McMurray JJ, Packer M, Swedberg K, et al. Reduced Risk of Hyperkalemia During Treatment of Heart Failure With Mineralocorticoid Receptor Antagonists by Use of Sacubitril/Valsartan Compared With Enalapril: A Secondary Analysis of the PARADIGM-HF Trial. JAMA Cardiol. 2017;2(1):79-85. doi: 10.1001/jamacardio.2016.4733. Desai AS Vardeny O Claggett B McMurray JJ Packer M Swedberg K et al Reduced Risk of Hyperkalemia During Treatment of Heart Failure With Mineralocorticoid Receptor Antagonists by Use of Sacubitril/Valsartan Compared With Enalapril: A Secondary Analysis of the PARADIGM-HF Trial JAMA Cardiol 2017 2 1 79 85 10.1001/jamacardio.2016.4733. 64. Pitt B, Anker SD, Bushinsky DA, Kitzman DW, Zannad F, Huang IZ, et al. Evaluation of the Efficacy and Safety of RLY5016, a Polymeric Potassium Binder, in a Double-Blind, Placebo-Controlled Study in Patients with Chronic Heart Failure (the PEARL-HF) Trial. Eur Heart J. 2011;32(7):820-8. doi: 10.1093/eurheartj/ehq502. Pitt B Anker SD Bushinsky DA Kitzman DW Zannad F Huang IZ et al Evaluation of the Efficacy and Safety of RLY5016, a Polymeric Potassium Binder, in a Double-Blind, Placebo-Controlled Study in Patients with Chronic Heart Failure (the PEARL-HF) Trial Eur Heart J 2011 32 7 820 828 10.1093/eurheartj/ehq502. 65. Pharithi RB, Ferre-Vallverdu M, Maisel AS, O’Connell E, Walshe M, Sweeney C, et al. Sacubitril-Valsartan in a Routine Community Population: Attention to Volume Status Critical to Achieving Target Dose. ESC Heart Fail. 2020;7(1):158-66. doi: 10.1002/ehf2.12547. Pharithi RB Ferre-Vallverdu M Maisel AS O’Connell E Walshe M Sweeney C et al Sacubitril-Valsartan in a Routine Community Population: Attention to Volume Status Critical to Achieving Target Dose ESC Heart Fail 2020 7 1 158 166 10.1002/ehf2.12547. 66. Kittleson M, Hurwitz S, Shah MR, Nohria A, Lewis E, Givertz M, Fet al. Development of Circulatory-Renal Limitations to Angiotensin-Converting Enzyme Inhibitors Identifies Patients with Severe Heart Failure and Early Mortality. J Am Coll Cardiol. 2003;41(11):2029-35. doi: 10.1016/s0735-1097(03)00417-0. Kittleson M Hurwitz S Shah MR Nohria A Lewis E Givertz M Fet et al Development of Circulatory-Renal Limitations to Angiotensin-Converting Enzyme Inhibitors Identifies Patients with Severe Heart Failure and Early Mortality J Am Coll Cardiol 2003 41 11 2029 2035 10.1016/s0735-1097(03)00417-0. 67. Sackner-Bernstein JD. Use of Carvedilol in Chronic Heart Failure: Challenges in Therapeutic Management. Prog Cardiovasc Dis. 1998;41(1 Suppl 1):53-8. doi: 10.1016/s0033-0620(98)80031-5. Sackner-Bernstein JD Use of Carvedilol in Chronic Heart Failure: Challenges in Therapeutic Management Prog Cardiovasc Dis 1998 41 1 Suppl 1 53 58 10.1016/s0033-0620(98)80031-5. 68. Butler J, Khadim G, Belue R, Chomsky D, Dittus RS, Griffin M, et al. Tolerability to Beta-Blocker Therapy Among Heart Failure Patients in Clinical Practice. J Card Fail. 2003;9(3):203-9. doi: 10.1054/jcaf.2003.34. Butler J Khadim G Belue R Chomsky D Dittus RS Griffin M et al Tolerability to Beta-Blocker Therapy Among Heart Failure Patients in Clinical Practice J Card Fail 2003 9 3 203 209 10.1054/jcaf.2003.34. 69. Lam PH, Packer M, Fonarow GC, Faselis C, Allman RM, Morgan CJ, et al. Early Effects of Starting Doses of Enalapril in Patients with Chronic Heart Failure in the SOLVD Treatment Trial. Am J Med. 2020;133(2):25-31. doi: 10.1016/j.amjmed.2019.06.053. Lam PH Packer M Fonarow GC Faselis C Allman RM Morgan CJ et al Early Effects of Starting Doses of Enalapril in Patients with Chronic Heart Failure in the SOLVD Treatment Trial Am J Med 2020 133 2 25 31 10.1016/j.amjmed.2019.06.053. 70. Krum H, Roecker EB, Mohacsi P, Rouleau JL, Tendera M, Coats AJ, et al. Effects of Initiating Carvedilol in Patients with Severe Chronic Heart Failure: Results from the COPERNICUS Study. JAMA. 2003;289(6):712-8. doi: 10.1001/jama.289.6.712. Krum H Roecker EB Mohacsi P Rouleau JL Tendera M Coats AJ et al Effects of Initiating Carvedilol in Patients with Severe Chronic Heart Failure: Results from the COPERNICUS Study JAMA 2003 289 6 712 718 10.1001/jama.289.6.712. 71. Pitt B, White H, Nicolau J, Martinez F, Gheorghiade M, Aschermann M, et al. Eplerenone Reduces Mortality 30 Days After Randomization Following Acute Myocardial Infarction in Patients with Left Ventricular Systolic Dysfunction and Heart Failure. J Am Coll Cardiol. 2005;46(3):425-31. doi: 10.1016/j.jacc.2005.04.038. Pitt B White H Nicolau J Martinez F Gheorghiade M Aschermann M et al Eplerenone Reduces Mortality 30 Days After Randomization Following Acute Myocardial Infarction in Patients with Left Ventricular Systolic Dysfunction and Heart Failure J Am Coll Cardiol 2005 46 3 425 431 10.1016/j.jacc.2005.04.038. 72. Konstam MA, Neaton JD, Dickstein K, Drexler H, Komajda M, Martinez FA, et al. Effects of High-Dose versus Low-Dose Losartan on Clinical Outcomes in Patients with Heart Failure (HEAAL study): A Randomised, Double-Blind Trial. Lancet. 2009;374(9704):1840-8. doi: 10.1016/S0140-6736(09)61913-9. Konstam MA Neaton JD Dickstein K Drexler H Komajda M Martinez FA et al Effects of High-Dose versus Low-Dose Losartan on Clinical Outcomes in Patients with Heart Failure (HEAAL study): A Randomised, Double-Blind Trial Lancet 2009 374 9704 1840 1848 10.1016/S0140-6736(09)61913-9. 73. Vardeny O, Claggett B, Packer M, Zile MR, Rouleau J, Swedberg K, et al. Efficacy of Sacubitril/Valsartan vs. Enalapril at Lower than Target doses in Heart Failure with Reduced Ejection Fraction: The PARADIGM-HF Trial. Eur J Heart Fail. 2016;18(10):1228-34. doi: 10.1002/ejhf.580. Vardeny O Claggett B Packer M Zile MR Rouleau J Swedberg K et al Efficacy of Sacubitril/Valsartan vs. Enalapril at Lower than Target doses in Heart Failure with Reduced Ejection Fraction: The PARADIGM-HF Trial Eur J Heart Fail 2016 18 10 1228 1234 10.1002/ejhf.580. 74. Packer M, McMurray JJV. Rapid Evidence-Based Sequencing of Foundational Drugs for Heart Failure and a Reduced Ejection Fraction. Eur J Heart Fail. 2021;23(6):882-94. doi: 10.1002/ejhf.2149. Packer M McMurray JJV Rapid Evidence-Based Sequencing of Foundational Drugs for Heart Failure and a Reduced Ejection Fraction Eur J Heart Fail 2021 23 6 882 894 10.1002/ejhf.2149. 75. Bhatt AS, Abraham WT, Lindenfeld J, Bristow M, Carson PE, Felker GM, et al. Treatment of HF in an Era of Multiple Therapies: Statement From the HF Collaboratory. JACC Heart Fail. 2021;9(1):1-12. doi: 10.1016/j.jchf.2020.10.014. Bhatt AS Abraham WT Lindenfeld J Bristow M Carson PE Felker GM et al Treatment of HF in an Era of Multiple Therapies: Statement From the HF Collaboratory JACC Heart Fail 2021 9 1 1 12 10.1016/j.jchf.2020.10.014. 76. Stevenson LW, Perloff JK. The Limited Reliability of Physical Signs for Estimating Hemodynamics in Chronic Heart Failure. JAMA. 1989;261(6):884-8. Stevenson LW Perloff JK The Limited Reliability of Physical Signs for Estimating Hemodynamics in Chronic Heart Failure JAMA 1989 261 6 884 888 77. Stevenson LW. Design of Therapy for Advanced Heart Failure. Eur J Heart Fail. 2005;7(3):323-31. doi: 10.1016/j.ejheart.2005.01.004. Stevenson LW Design of Therapy for Advanced Heart Failure Eur J Heart Fail 2005 7 3 323 331 10.1016/j.ejheart.2005.01.004.

Sources of Funding: There were no external funding sources for this study.

 Artigo de Revisão Tratamento Farmacológico do Paciente com Insuficiência Cardíaca Avançada: Recomendações e Desafios 0000-0002-0265-7474 Scussel Fernanda 1 Brasil Santa Casa de Misericórdia de Curitiba, Curitiba, PR – Brasil Correspondência: Fernanda Scussel • Rua Nunes Machado, 471, apto 1402. CEP 80250-000, Curitiba, PR - Brasil E-mail: ferscussel@gmail.com

Contribuição dos autores

Redação do manuscrito: Scussel F

Potencial conflito de interesse

Não há conflito com o presente artigo

 Resumo

A insuficiência cardíaca é uma condição altamente prevalente, e uma série de novas terapêuticas vêm surgindo nos últimos anos, melhorando a sobrevida e qualidade de vida dos pacientes, concomitante a uma maior complexidade do seu manejo. Em se tratando de pacientes com insuficiência cardíaca avançada, ou seja, com sintomas limitantes persistentes e internações recorrentes, a condução dos casos costuma ser ainda mais desafiadora, pois além de muitas vezes apresentarem características que os excluiriam da maioria dos estudos clínicos, apresentam uma série de dificuldades para a otimização das terapias, principalmente por hipotensão sintomática e disfunção renal, mas também por dificuldade de aderência à crescente lista de medicamentos, custos elevados, e baixa compreensão da sua própria doença. O conceito em voga atualmente é de que a otimização terapêutica, incluindo as 4 drogas fundamentais no tratamento da insuficiência cardíaca com fração de ejeção reduzida (inibidores da enzima conversora da angiotensina/bloqueadores do receptor da angiotensina/inibidores do receptor da angiotensina-neprilisina, betabloqueadores, antagonistas do receptor da aldosterona e inibidores do cotransportador sódio-glicose 2) seja realizado de maneira rápida, em até 4 semanas após o diagnóstico ou internação por descompensação, caso o paciente não estivesse em uso das 4 classes. Este pode ser um objetivo um pouco “ousado” quando se trata de pacientes em estágios mais avançados. Nesses casos algumas estratégias podem ajudar para que se atinja o melhor tratamento possível tolerado, com bom controle de sintomas e melhora da sobrevida. Além disso, a intolerância ao tratamento clínico é também um marcador de doença avançada por si só e deve motivar o referenciamento para centros especializados em insuficiência cardíaca avançada sempre que possível.

 Insuficiência Cardíaca Tratamento Farmacológico Introdução

A insuficiência cardíaca (IC) é uma condição altamente prevalente, para a qual uma série de tratamentos farmacológicos e dispositivos têm sido desenvolvidos, com melhora importante na sobrevida e na qualidade de vida dos pacientes. A despeito disso, uma parcela dos pacientes segue o curso natural da doença, atingindo estágios mais avançados, definido por estágio D.1 E, mesmo os pacientes que inicialmente beneficiam-se das terapias disponíveis podem em algum momento progredir para a forma avançada.

As definições de IC avançada são diversas, de acordo com a fonte analisada, mas todas convergem na questão de sintomas graves persistentes (classe funcional da New York Heart Association [NYHA CF] III a IV) e internações repetidas, a despeito de terapia otimizada máxima tolerada.2 - 5 É necessário ressaltar que o conceito de IC avançada vai além da presença de disfunção ventricular esquerda, uma vez que pacientes com fração de ejeção (FE) preservada também podem ser caracterizados como tal, bem como cardiopatias congênitas, doenças valvares graves sem possibilidade de intervenção e disfunção isolada de ventrículo direito.3 Entretanto, as opções terapêuticas discutidas no texto a seguir aplicam-se aos pacientes com FE reduzida. Outro ponto de convergência na maioria dos documentos que tratam de IC avançada é a questão da intolerância à otimização terapêutica máxima, geralmente por hipotensão sintomática e disfunção renal, com ou sem hipercalemia. Ademais, outras questões frequentemente presentes nesse grupo de pacientes também dificultam a otimização clínica, como sugerem as diretrizes.3 , 6 - 8 como por exemplo idade avançada, comorbidades associadas e polifarmácia, com consequente dificuldade de aderência, além do crescente custo.

O objetivo desta revisão é trazer dados de evidências sobre o tratamento farmacológico nesse grupo específico de pacientes, bem como seus desafios na prática clínica diária.

Tratamento farmacológico clássico

De maneira geral, pacientes com características de doença mais avançada acabam sub-representados na maioria dos estudos clínicos. No estudo PARADIGM-HF, que randomizou mais de 8 mil pacientes com FE < 40% (mudado posteriormente para ≤ 35%) para receberem sacubitril/valsartana (S/V) ou enalapril, e que mostrou redução importante em mortalidade por todas as causas, mortes por causa cardiovascular e hospitalização por IC, além de redução de morte súbita, menos de 1% dos pacientes foram categorizados como NYHA CF IV.9 Aproximadamente 20% dos pacientes triados para o período de run-in (4 a 6 semanas para testar a tolerância ao medicamento) não puderam ser incluídos por intolerância à dose alvo da medicação, por hipotensão ou piora da função renal. No PIONEER, que avaliou o uso de S/V em pacientes com IC descompensada, apenas 9% eram NYHA CF IV.10

O estudo LIFE foi desenvolvido para tentar preencher essa lacuna em relação ao uso de S/V em pacientes com IC avançada (definido por FE ≤ 35%, NYHA CF IV, BNP ≥ 250 pg/mL ou NT-proBNP ≥ 800 pg/mL e ≥ 1 achado(s) objetivo(s) de doença avançada).11 Os pacientes foram randomizados para receberem S/V ou valsartana isoladamente, após um período de run-in de 7 dias para avaliar tolerância à dose inicial de S/V de 24/26 mg duas vezes ao dia. O desfecho primário incluía a mudança proporcional no NT-proBNP em 24 semanas, avaliada pela área sob a curva. Os desfechos secundários incluíam mortalidade cardiovascular, hospitalização por IC, hipotensão e outros marcadores de tolerância ao medicamento. O estudo precisou ser interrompido precocemente por conta da pandemia de COVID-19, e a análise dos resultados foi realizada com os 335 pacientes incluídos até o momento da interrupção (objetivo inicial eram 400 pacientes). Não houve diferença entre os grupos em nenhum dos desfechos avaliados, e a dose atingida da medicação foi < 50% da dose alvo para ambos os grupos. Apesar das limitações do estudo, pode-se começar a entender que esse grupo de pacientes tem de fato suas peculiaridades em relação ao manejo, não devendo ser tratados da mesma maneira que pacientes em estágios mais iniciais. A intolerância ao tratamento clínico deve motivar o referenciamento para centros especializados em IC avançada, para avaliar a indicação de outras terapias (não farmacológicas).

Dentre os estudos avaliando os efeitos dos inibidores do cotransportador sódio-glicose 2 (SGLT2) em pacientes com IC e FE reduzida, com ou sem diabetes tipo 2, menos de 1% dos pacientes no DAPA-HF12 eram em NYHA CF IV. Comparado a este, pacientes incluídos no EMPEROR-REDUCED13 apresentavam menor FE, maiores níveis de NT-proBNP e taxa de filtração glomerular (TFG) menor, refletindo uma população de maior gravidade. Metanálise que incluiu os dois estudos mostrou redução de 13% em mortalidade por todas as causas, de 14% em mortalidade cardiovascular, além de importante redução em hospitalizações por IC, já demonstrada pelos dois estudos individualmente. No entanto, em análise de subgrupos, o efeito mostrou-se atenuado, embora ainda significativo, em pacientes em NYHA CF III a IV.14 Por serem medicações com efeitos modestos na pressão arterial, além de excelente perfil de segurança, costumam ser bem toleradas mesmo por pacientes mais limítrofes. O uso inicial dessas medicações tem sido proposto, juntamente com o betabloqueador, como primeira etapa nos pacientes virgens de tratamento, ou que tiveram o tratamento suspenso por uma descompensação mais grave, pois graças ao seu efeito natriurético, pode ajudar a contrabalancear os sintomas de piora clínica que podem surgir no início da terapia com betabloqueador.15

Para os tratamentos mais antigos para IC, dispomos de alguns estudos que incluíram pacientes ambulatoriais em estágios mais avançados,16 - 20 mostrando resultados consistentes de benefício. O estudo COPERNICUS17 foi o maior estudo que avaliou pacientes com NYHA CF III a IV e FE < 25%, com redução expressiva em mortes e hospitalização por IC, além de boa tolerância dos pacientes ao medicamento. Metanálise de estudos randomizados avaliando efeito dos betabloqueadores em pacientes em NYHA CF IV reiterou esse conceito.21

Apesar disso, ainda existe receio em relação à utilização de betabloqueadores, principalmente nas doses preconizadas, em pacientes com doença mais avançada. Um estudo não randomizado que avaliou o uso de carvedilol em pacientes NYHA CF IV mostrou que, a despeito de serem pacientes mais propensos a apresentarem piora da IC logo após o início da medicação, a maioria consegue seguir com a terapia após período inicial de ajustes, além de apresentarem maior magnitude de melhora sintomática após 3 meses de tratamento.22 , 23 Hipotensão e hiponatremia, condições que refletem pacientes mais graves, e, possivelmente, mais congestos, são preditores de piora da IC após início do carvedilol.22 , 23 A ideia é que pacientes em estágios mais avançados exigem um seguimento mais de perto quando do início de betabloqueadores, muitas vezes com necessidade de aumento temporário na dose dos diuréticos, mas toleram bem e beneficiam-se ainda mais da terapia. Antes do início ou progressão da dose do betabloqueador, os pacientes devem estar minimamente compensados, a fim de tolerar a discreta, porém relevante nesses casos, elevação das pressões de enchimento e redução no débito cardíaco.

Os antagonistas do receptor da aldosterona são uma das classes mais subutilizadas nos pacientes com IC e FE reduzida,24 - 27 apesar da redução de 15% a 30% em mortalidade e de até 40% em reinternação nos principais estudos.19 , 28 , 29 As principais ressalvas são em relação à piora de função renal e hipercalemia e, eventualmente, à hipotensão. Para esta última questão, um interessante estudo analisou retrospectivamente os pacientes incluídos no RALES e EPHESUS (4.396 pacientes no total), subdivididos de acordo com a pressão arterial sistólica inicial (≤ 105, > 105 e ≤ 115, > 115 e ≤ 125, > 125 e ≤ 135, e > 135 mmHg) e mostrou ausência de redução significativa da pressão arterial entre o medicamento e placebo, em contraste com o que ocorre no tratamento de pacientes hipertensos.30 Além disso, o benefício de redução relativa na mortalidade mostrou-se consistente em todos os subgrupos analisados. Levando-se em conta que os pacientes com pressão arterial sistólica ≤ 105 mmHg eram pacientes mais graves por várias características analisadas, são eles que se beneficiam ainda mais com o tratamento proposto. A preocupação com uma possível piora na função renal e hipercalemia é justificada, porém atualmente dispomos de algumas estratégias para minimizar esses efeitos, como será descrito posteriormente.

Em pacientes com sintomas refratários, pode-se considerar também a utilização de digoxina, especialmente como adjuvante no controle de frequência cardíaca nos casos de fibrilação atrial, atentando-se apenas para o risco de toxicidade, principalmente em mulheres, pacientes com baixo peso e na presença de disfunção renal.31 , 32 A terapia deve idealmente ser ajustada conforme dosagem de nível sérico da droga. Dados de coortes mais contemporâneas de pacientes com IC são conflitantes em relação ao benefício e à segurança da utilização de digoxina, especialmente quando em ritmo sinusal.31 , 33 A descontinuação da digoxina em pacientes internados por IC, mesmo sob tratamento otimizado com outras terapias, parece estar associada a maiores taxas de re-hospitalização.34

O estudo que avaliou os efeitos da ivabradina em pacientes com IC e FE reduzida não incluiu pacientes em NYHA CF IV.35 No entanto, a droga parece interessante para o perfil de pacientes mais avançados em determinados contextos, uma vez que reduz a frequência cardíaca, sem efeito inotrópico negativo.36 Uma subanálise do estudo SHIFT utilizando avaliação ecocardiográfica mostrou um aumento no volume sistólico, ao melhorar o acoplamento ventrículo-arterial com a redução de frequência cardíaca.37 Postula-se que a ivabradina possa ser útil em pacientes com taquicardia sinusal induzida pelo uso de inotrópicos, em especial pela dobutamina.38 A taquicardia sinusal costuma ser um mecanismo compensatório, na tentativa de manutenção de um débito cardíaco minimamente adequado. No entanto, a relação fisiológica direta entre o aumento da frequência cardíaca e o aumento da contratilidade miocárdica, observada em corações normais, perde-se quando há disfunção miocárdica, condição em que passa a ocorrer uma redução paradoxal na força de contração com frequências mais elevadas.39 Nesse sentido, a ivabradina poderia contribuir para mitigar uma taquicardia excessiva em um paciente em uso de inotrópico, controlando a frequência cardíaca sem causar inotropismo negativo e potencialmente melhorando a hemodinâmica. Essa hipótese foi testada apenas em estudos animais e pequenos estudos em pacientes com IC, avaliando efeitos hemodinâmicos de curto prazo e os dados não podem ser extrapolados para a prática clínica.40 , 41 Formalmente, a indicação de uso de ivabradina em pacientes com IC avançada é a mesma utilizada para os demais perfis de pacientes com IC e FE reduzida.

Diante das diversas opções terapêuticas com comprovado impacto positivo na IC com FE reduzida, e levando-se em consideração que o benefício de cada uma das drogas é independente da presença das outras e que os mecanismos de atuação são complementares, a melhor estratégia parece ser a individualização.42 Os pacientes apresentam-se com diferentes fenótipos, que refletem diferentes necessidades, e definir a estratégia farmacológica de maneira mais personalizada, mantendo o objetivo de incluir todas as classes fundamentais (inibidores da enzima conversora da angiotensina/bloqueadores do receptor da angiotensina/inibidores do receptor da angiotensina-neprilisina [IECA/BRA/ARNI], betabloqueadores, antagonistas da aldosterona e inibidores SGLT2), parece ser um método adequado.

 Novos tratamentos farmacológicos

O omecamtiv mecarbil é uma medicação mais recente que vem sendo testada na IC. Ele atua como um ligante específico da miosina cardíaca, otimizando a interação actina-miosina no músculo cardíaco, promovendo melhora da contratilidade (chamado efeito “miotrópico”). Ao contrário de outras medicações que aumentam a contratilidade miocárdica, o omecantiv não aumenta o influxo de cálcio para o miócito, reduzindo consideravelmente o risco de arritmias e isquemia miocárdica. Estudos farmacocinéticos iniciais mostraram aumento do tempo de ejeção ventricular e do volume sistólico, além de redução nos volumes sistólico e diastólico finais do ventrículo esquerdo.43

O primeiro estudo avaliando desfechos clínicos do omecantiv mecarbil na IC foi o GALACTIC-HF, que randomizou mais de 8 mil pacientes entre 18 e 85 anos de idade, NYHA CF II a IV (embora apenas 124 pacientes NYHA CF IV em cada grupo), com FE < 35%, internados, ou com hospitalização no último ano, para receberem placebo ou omecantiv, com dose guiada pela dosagem de nível sérico. Foram excluídos pacientes em uso de inotrópico, com pressão arterial sistólica < 85 mmHg e com TFG < 20 mL/min/1,73 m2 . O desfecho primário incluía tempo até o primeiro evento relacionado a IC (internação, visita urgente ao serviço de emergência ou ambulatorial) ou morte por causas cardiovasculares. Houve redução de 8% no desfecho primário (hazard ratio 0,92, intervalo de confiança de 95% 0,86 a 0,99; p = 0,03), sem redução na mortalidade cardiovascular. Não houve diferença no número de eventos adversos entre os grupos. Hipotensão, piora de função renal ou hipercalemia também não ocorreram.44

Foi realizada análise de subgrupos de acordo com a FE (divididos em quartis: FE ≤ 22%, FE de 23% a 28%, FE de 29% a 32%, e FE ≥ 33%), análise esta já pré-especificada no desenho do estudo inicial. A taxa de eventos do desfecho primário foi significativamente maior (até 80% maior) no quartil com a menor FE, comparada com a maior FE, e o benefício da terapia foi significativamente maior em pacientes com FE ≤ 28% ( hazard ratio 0,84; intervalo de confiança de 95%: 0,77 a 0,92; p = 0,0003), quando comparado com FE > 28% ( hazard ratio 1,04; intervalo de confiança de 95%: 0,94 a 1,16; p = 0,45), sendo essa diferença motivada pela redução de hospitalizações e não por mortalidade cardiovascular.45 Apesar da queda observada nos níveis de peptídeos natriuréticos, não houve melhora sintomática (avaliada pelo Kansas City Cardiomyopathy Questionnaire ).

Com esses dados, é possível especular sobre a potencial utilização dessa medicação em pacientes com IC avançada, tendo em vista o racional fisiopatológico sobre o seu funcionamento, as evidências de maior benefício em subgrupos com maior disfunção ventricular e a ausência de efeitos colaterais comuns a esse grupo de pacientes, como hipotensão e disfunção renal, mas mais estudos serão necessários para firmar essas conclusões.

O vericiguat é uma molécula que atua estimulando o monofosfato cíclico de guanosina solúvel através de um mecanismo que independe do óxido nítrico, mas também aumenta a sensibilidade do monofosfato cíclico de guanosina ao óxido nítrico endógeno, estabilizando a ligação do óxido nítrico com o seu receptor, por fim melhorando a função miocárdica e exercendo efeito vasodilatador. A medicação foi aprovada pelo Food and Drug Administration dos Estados Unidos em janeiro de 2021, após resultados favoráveis do estudo VICTORIA,46 que randomizou pacientes com FE < 45%, NYHA CF II a IV e elevação de peptídeos natriuréticos (NT-proBNP > 1000 pg/mL ou > 1600 pg/mL se em ritmo de fibrilação atrial), com piora recente (internação nos últimos 6 meses ou em uso de diureticoterapia parenteral em regime ambulatorial) para receberem placebo ou vericiguat, na dose alvo de 10 mg/dia. Foram excluídos pacientes com pressão arterial sistólica < 100 mmHg ou que estivessem recebendo inotrópicos. Um dado interessante é que o recrutamento de pacientes ocorreu de maneira mais rápida do que o esperado, e o número de eventos do desfecho primário também foi maior do que o inicialmente calculado, representando assim uma população mais grave. Houve redução significativa no desfecho de re-hospitalização por IC no seguimento médio de 10 meses. Hipotensão sintomática foi mais frequente nos pacientes em uso da droga, mas sem diferença significativa com o grupo placebo. Anemia foi um evento adverso mais comum nos pacientes recebendo vericiguat, e o mecanismo dessa alteração ainda não é bem elucidado. Análise de subgrupos de acordo com os níveis de NT-proBNP (divididos em quartis) mostrou ausência de benefício no quartil com dosagens mais elevadas (> 5314 pg/mL), possivelmente refletindo uma população com doença muito avançada, com indicação de outras terapias que não farmacológicas, ou mesmo cuidados paliativos. O vericiguat entrou como indicação IIb na diretriz européia de IC de 2021, para pacientes com IC com FE reduzida, NYHA CF II a IV, com piora da IC a despeito de tratamento com betabloqueador, IECA/BRA ou ARNI e antagonista da aldosterona.7

 Disfunção renal e hipercalemia no paciente com IC avançada

A presença de disfunção renal em um paciente com IC é um marcador de maior morbi-mortalidade, bem como de doença avançada, quando se considera que a perda de função renal é secundária às alterações hemodinâmicas impostas pela IC, e apesar disso, são pacientes que sabidamente recebem com menor frequência as terapias classicamente indicadas para essa condição,47 , 48 principalmente antagonistas do sistema renina-angiotensina-aldosterona.49 Ademais, pacientes com doença renal crônica apresentam risco aumentado de desenvolverem IC, independente da presença de doença arterial coronária.50 Em se tratando de doença renal crônica mais avançada (graus 3 ou 4), também são pacientes extremamente sub-representados nos estudos clínicos. Dados de benefício e segurança na utilização de IECA/BRA nesses casos advém na sua maioria de estudos observacionais. De maneira geral, a utilização de IECA/BRA pode piorar a função renal, especialmente em curto prazo, e isso carrega consigo um pior prognóstico, no entanto o benefício da terapia com IECA/BRA se mantém, podendo ser inclusive ainda maior.51 Em pacientes que inicialmente apresentem doença renal crônica (TFG ≤ 30 mL/min/m2ou creatinina > 2,5 mg/dL), o benefício da utilização dessa classe de medicamentos, quando tolerados, se mantém.52 Assim, a presença de disfunção renal não deve excluir o paciente da tentativa de utilização de IECA/BRA e, mais recentemente ARNIs, uma que vez que, sendo pacientes de maior risco de eventos, tendem a beneficiar-se mais dos tratamentos, mesmo que em baixas doses, aquém daquelas definidas como doses alvo pelos estudos clássicos, com a condição de serem seguidos mais de perto, com reavaliações clínicas e laboratoriais mais frequentes.

Sobre as terapias mais recentes, análise subsequente do estudo PARADIGM mostrou que a redução na TFG foi menor no grupo S/V em comparação aos pacientes que receberam enalapril, independente da função renal inicial e a despeito do aumento na relação albumina/creatinina na urina promovida pelo S/V.53 Esse aumento mostrou-se leve e estabilizou-se após algumas semanas de tratamento. Vale a pena ressaltar que o estudo excluiu pacientes com TFG < 30 mL/min/1,73 m2 .

Os inibidores SGLT2 também se mostraram bastante favoráveis nesse cenário, com resultados de menor progressão da disfunção renal no uso a longo prazo,54 , 55 além de menor risco de hipercalemia quando usado conjuntamente com antagonistas da aldosterona.56

Já para os antagonistas dos receptores da aldosterona, as recomendações quando há disfunção renal costumam ser mais conservadoras, contra-indicando o uso quando a creatinina for > 2 mg/dL em mulheres ou > 2,5 mg/dL em homens, devido ao maior risco de piora na função renal e hipercalemia, sem uma contrapartida de benefício claro.57 Uma vez que o paciente já esteja em uso do antagonista da aldosterona e evolua com disfunção renal mais importante (TFG ≤ 30 mL/min/1,73 m2), a medicação não deve ser suspensa de rotina e cada caso pode ser individualizado.58

A hipercalemia é outro desafio frequente durante o manejo de pacientes com IC, especialmente naqueles com algum grau de comprometimento da função renal, e está associada a piores desfechos, principalmente pela menor utilização de terapias que bloqueiam o sistema renina angiotensina aldosterona.59 - 61 A não suspensão de rotina dessas terapias quando há hipercalemia leve é proposta por Ferreira et al.62 em uma revisão recente, onde um algoritmo para o manejo desses pacientes foi proposto, a fim de minimizar a subutilização de terapias que comprovadamente melhoram o prognóstico. O risco de hipercalemia associada à utilização concomitante de antagonistas da aldosterona é menor quando com S/V quando comparada ao enalapril,63 sendo essa uma das estratégias propostas, caso o paciente ainda não esteja em uso de ARNI. O risco de hipercalemia também é menor quando um inibidor de SGLT2 é associado ao tratamento.56

Outra possibilidade é a utilização de quelantes de potássio. O uso do patiromer (ligante de potássio) foi testado em pacientes com IC, mostrando ser efetivo para esse objetivo,64 e está aprovado para manejo de hipercalemia secundária ao uso de bloqueadores do sistema renina angiotensina aldosterona nos Estados Unidos e Europa, mas ainda indisponível no Brasil. Não há dados de eficácia e segurança com o poliestirenossulfonato de cálcio nesse contexto. Estudos estão em andamento com o objetivo de avaliar se a utilização de quelantes, com consequente aumento na utilização de bloqueadores do sistema renina angiotensina aldosterona, melhoram desfechos em pacientes com IC.

 Hipotensão e dificuldade de progressão das doses

A otimização da terapia e o manejo de sintomas em pacientes com doença mais avançada podem ser bastante desafiadores. Uma das questões mais limitantes nesse sentido é a hipotensão sintomática. Quando isso ocorre, é importante avaliar a possibilidade de hipovolemia, com eventual necessidade de redução no uso de diuréticos65 e revisar com cuidado todas as medicações em uso para checar se há alguma não relacionada ao tratamento da IC que possa estar contribuindo para a hipotensão, como bloqueadores dos canais de cálcio e medicações para hiperplasia prostática benigna, entre outras. O fracionamento da administração das medicações ao longo do dia, evitando a ingesta simultânea de IECA/BRA/ARNI com betabloqueadores também pode ser útil. Pode-se priorizar betabloqueadores sem efeito alfa adrenérgico (metoprolol e bisoprolol) e, portanto, com menor potencial de causar hipotensão.

A intolerância ao uso de IECA/BRA por limitação circulatória (hipotensão sintomática) ou renal (piora significativa da função renal) é um importante marcador de gravidade e de elevado risco de morte, necessidade de suporte circulatório mecânico ou transplante cardíaco em 6 meses.66 Desse modo, são pacientes que devem idealmente ser referenciados para avaliação especializada.

O início da terapia com betabloqueador em pacientes mais avançados, apesar de seguro, quando a doença está minimamente compensada, pode ser mais difícil de tolerar para o paciente, pois é frequente que ele experimente uma sensação de “piora clínica”, com fadiga, cansaço e sonolência. Nesses casos, é interessante que o paciente seja advertido dessa possível sensação de piora e que, com a persistência do uso, tende a melhorar. Enquanto pacientes mais estáveis podem ter a medicação titulada a cada 7 dias, em pacientes com IC avançada pode ser prudente um intervalo maior entre os incrementos na dose do betabloqueador.67

A intolerância ao betabloqueador não é um efeito de classe, logo, é válido tentar mais de uma opção antes de definir o paciente como intolerante à droga.68

Os benefícios das terapias farmacológicas fundamentais (IECA/BRA/ARNI, betabloqueadores e antagonistas da aldosterona) são evidentes e significativos, mesmo quando em baixas doses, e são vistos a curto prazo – em média 30 dias.69 - 73 Assim, a associação das terapias, mesmo em doses abaixo das tidas como doses alvo, é uma estratégia superior para redução de desfechos no paciente com IC,74 e frequentemente acaba sendo utilizada em pacientes com doença mais grave. O conceito de que a utilização de baixa dose é melhor do que a não utilização do medicamento deve sempre ser levada em conta quando estamos frente a um paciente mais grave, que não tolera progressão.75

 Reconsiderando objetivos terapêuticos na insuficiência cardíaca avançada

Tendo em vista a escassez de dados de qualidade em relação ao real benefício das terapias classicamente recomendadas para IC com FE reduzida no subgrupo de pacientes com doença avançada, muito da prática diária acaba sendo baseada na experiência pessoal de profissionais que habitualmente tratam desses pacientes.

Via de regra, os tratamentos instituídos têm o objetivo de reduzir a progressão da doença e aumentar a sobrevida, mas em se tratando de pacientes em estágios mais avançados, muitas vezes a melhora dos sintomas e de qualidade de vida deve passar a ser um dos objetivos perseguidos, uma vez que a grande maioria acabará não sendo elegível ou não terá acesso a terapias avançadas, como o transplante cardíaco ou dispositivos de assistência circulatória.

Na maioria das vezes a alteração hemodinâmica que gera sintomas limitantes é o aumento nas pressões de enchimento em repouso, causada por hipervolemia. Quando há congestão sistêmica, sintomas gastrointestinais como inapetência, desconforto abdominal e sensação de saciedade precoce podem predominar. Uma boa parte dos pacientes referenciados com sintomas refratários pode melhorar com um adequado ajuste da volemia, que pode ser difícil de avaliar, especialmente nos pacientes crônicos.76 Em alguns casos, além da otimização na dose e eventual associação de diuréticos, o uso de nitratos pode ser tanto benéfico como sintomático.77

A congestão refratária, com resistência aos diuréticos, é um cenário comumente encontrado em pacientes com doença avançada, e necessita de uma abordagem direcionada e específica para esse fim, que não faz parte do escopo desta revisão.

Por fim, é importante que pacientes com IC avançada sejam abordados a respeito das expectativas em relação ao tratamento. Em alguns casos o controle de sintomas passa a ser prioridade, em detrimento de prolongamento da sobrevida, e o tratamento farmacológico deve ser guiado priorizando esse objetivo.

 Conclusão

Pacientes com IC avançada apresentam diversas particularidades no manejo e otimização farmacológica, com crescente complexidade. É um grupo de pacientes que deve crescer progressivamente, com o aumento da sobrevida proporcionado pelas terapias disponíveis atuais. Sendo assim, é providencial que haja mais estudos voltados para esse perfil de pacientes, bem como uma maior representatividade nos ensaios clínicos. A dificuldade de manejo farmacológico deve motivar o referenciamento para centros especializados, pois é um marcador de pior prognóstico.

Fontes de financiamento: O presente estudo não teve fontes de financiamento externas.