Introduction

The heart failure pandemic

Acute heart failure (AHF) is the most common cardiovascular reason for hospital admission of patients over the age of 60.1 Over 20% of patients who develop AHF die before they ever reach a hospital. Within 6 months after discharge from a HF admission, the mortality rate is 20% while the readmission rate is over 30%. Despite the prevalence and dire outcome of AHF, little progress in its treatment has been made in the last 2–3 decades, with many therapeutic innovations that have failed the test of clinical trials.2

Hospitalization for HF still accounts for two-thirds of the costs associated with management of affected patients. So far, the best possible option is to optimize the management of patients with chronic HF with reduced ejection fraction (HFrEF), with the aim of preventing hospital admissions. Optimization of chronic HF therapy prior to discharge needs improvement, especially in the outpatient setting.

 

Numerous registries have indeed emphasized the large and persistent gap between real-life clinical practice and international guidelines regarding the use of mortality-reducing, evidence-based therapies. Both medical inertia as well as discontinuous and widely spaced patient visits play important roles in this gap, but it is also amplified by under-prescribing and suboptimal dosing. These are due to frequent episodes of worsening renal function (WRF) and potassium-related adverse events that are inherently associated with the pharmacological effects of diuretics and renin-angiotensin-aldosterone system inhibitors (RAASis), the main basis of HFrEF therapy.

Evidence-based guidelines vs. clinical utilization of HF therapy

AHF is associated with dramatically high morbidity and mortality. Guidelines for HFrEF management include the use of RAASis.3,4 Allen and colleagues used the Get With The Guidelines–HF US registry data from 2008 to 2013 to characterize prescribing, indications, and contraindications for angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs), beta-blockers, mineralocorticoid receptor antagonists (MRAs), hydralazine/isosorbide dinitrate, and anticoagulants.


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The difference between a patient’s medication regimen at hospital admission and that recommended by HF quality measures at discharge was calculated. Among 158,922 patients from 271 hospitals with a primary discharge diagnosis of HF, compared with the number of new medications indicated (mean, 1.45 ± 1.23), the number of new prescriptions at discharge was actually lower (mean, 1.16 ± 1.00). ACEis/ARBs were prescribed in 91.2% of patients eligible, but not receiving these agents before admission; MRAs in 27.2% only.5

In a consecutive series of 500 patients hospitalized with a diagnosis of AHF, only 21% of patients who were eligible for MRAs on admission received them. Importantly, preadmission and newly started MRAs were discontinued in 36% of patients during the period of hospitalization, with WRF being the most common identifiable reason. After a median follow-up of 57 days, an additional 6% of patients discontinued their MRA.6

Critical importance of improving post-discharge management and outcomes

The post-discharge phase is the most vulnerable period, with high mortality and high readmission rates (10–15% and 25–35%, respectively, in the 6 months after discharge). International guidelines recognize the urgent need for improvement in management and outcome in this “vulnerable” phase, particularly because most patients after discharge from the hospital either have limited and late follow-up or are not followed by a clinician with expertise in HF.3,4

There is increasing evidence that lack of adherence to guidelines is associated with worse outcome.7 The reason that physicians are reluctant to start a post-discharge optimization program is unclear and might be related to safety. Increasing the doses of diuretics or other long-lasting cardiovascular agents may induce alterations in potassium or renal function that cannot be predicted on an individual basis. Opportunities to better monitor and manage WRF and potassium-related events

Increased mortality associated with under-utilization of RAASis

In a large meta-analysis from 57 HF trials and registries (1,076,104 HF patients), chronic kidney disease (CKD), as assessed by the estimated glomerular filtration rate, was highly prevalent, being present in 32% of HF patients. Both CKD and WRF during hospitalization or thereafter were found to be associated with increased mortality rates.8 Registry data consistently demonstrate that impaired kidney function and hyperkalemia are associated with the non-prescribing9–11 and under-dosing of RAASis.10,12 Data also suggest that the non-prescribing of RAASis at discharge is associated with a two-fold increase in the 30-day mortality or readmission rate and associated days-alive-out-of-hospital in 1520 Italian patients discharged alive after admission for AHF.13

Percent of Patients Who Experienced Adverse Outcomes or Mortality by Prior RAASi Dose

In a large US database of electronic health records, Epstein and associates recently observed that nearly 60% of 20,529 patients with HF who discontinued RAASis after a hyperkalemic episode experienced an adverse outcome or mortality, compared with 52.3% of patients on submaximum doses and 44.3% of patients on maximum doses (all comparisons P <.05; see Figure 1). HF patients on submaximum dose or who discontinued RAASis died twice as frequently as patients on maximum dose (see Figure 2).14

Implementation of guideline recommendations to improve outcomes

The guideline-recommended increased use of ACEis, ARBs, and/or MRAs has resulted in an increased awareness and risk of serious WRF and/or hyperkalemia. The fear of inducing WRF or hyperkalemia has limited the initiation or escalation in dose of these mortality-reducing drugs in patients with HF, and especially when associated with CKD.15

Percent Mortality by Prior RAASi Dose

Recent publications have shown that episodes of both WRF and hyperkalemia are common, recur frequently, and may pose a therapeutic dilemma in daily practice, since the patients at highest risk for these complications are the very patients who derive the greatest cardiovascular benefit from RAASis.16–18 Notwithstanding the latter, HF patients who received an ACEi vs placebo,19 or the MRAs spironolactone20 or eplerenone 17,21 vs placebo, or high-dose vs low-dose ARB,18 all in conjunction with the best medical care, displayed better outcomes. It is therefore of paramount importance to maintain patients on adequate RAASi treatment, albeit with a readiness to manage any WRF or dyskalemic episode.

Utilizing a novel potassium binder to reduce the incidence of hyperkalemia

Should WRF or hyperkalemia occur, a temporary down-titration or discontinuation of RAASi should be considered, together with the use of potassium chelating agents if hyperkalemia is present.19 For instance, in the PEARL study,22 the potassium binder patiromer (Veltassa™; Relypsa; Redwood City, CA) was studied in patients with congestive heart failure with normal serum potassium levels who had a history of discontinuing either RAASis or beta-adrenergic blocking agents due to hyperkalemia. In this study, spironolactone was administered at a dose of 25–50 mg/day and patients were randomized to placebo or patiromer. Patiromer reduced the incidence of hyperkalemia and increased the percentage of patients who could achieve the 50 mg dose of spironolactone.

The significant gap between evidence-based guidelines and daily practice in monitoring for WRF and hyperkalemia

The development of WRF and/or hyperkalemia should trigger a careful clinical assessment, taking into consideration the patient’s present condition and medical history.15 Registry data consistently suggest that the guideline-recommended potassium and creatinine monitoring is non-optimal in patients receiving RAASis. In a large (n = 52,906, 15.5% with HF) retrospective cohort study designed to assess the rates and correlates of serum potassium and creatinine monitoring among individuals dispensed ACEi or ARB in an ambulatory setting within 10 geographically diverse organizations in the United States, it was observed that only two-thirds of the patients dispensed with ACEi or ARB also received serum potassium and serum creatinine monitoring in a 1-year period; and, of those patients, one-half had a second evaluation of their serum potassium and serum creatinine. Although patients at increased risk of hyperkalemia were more likely to be monitored, many remained unmonitored.23

In a recent report by Cooper and associates describing the data related to 10,443 Medicare beneficiaries with HF who were initiated on an MRA, it was found that measurement of serum potassium was common (91.6%) in the several months prior to initiation of the MRA. However, only 13.3% and 29.9% of patients underwent appropriate testing in early and extended follow-up, respectively, after initiation of an MRA.24 Close monitoring of serum potassium and renal function is essential during these periods of RAASi adjustments; the monitoring should be continued until the patient is stable, and then take place at regular intervals. This dynamic management of RAASi dosing as implemented in the landmark MRA randomized trials such as RALES,25 EPHESUS,26 and EMPHASIS-HF27 was associated with a reduction in total mortality; and although hyperkalemia and WRF occurred, there was not a single death attributed to these conditions.15 The reason that most physicians are reluctant to start a post-discharge potassium and kidney function monitoring program is unclear and might be related to the lack of validated therapeutic algorithms to manage RAASis and diuretics. In addition, patients are reluctant to undergo repeat venous sampling for laboratory testing.

Conclusion

Although the use of multiple RAASis is frequently associated with the development of WRF and hyperkalemia in patients with HF and reduced ejection fraction, increased efforts—including appropriate clinical and laboratory monitoring—should be expended to initiate and maintain target doses of these lifesaving agents, albeit with a readiness to manage any serious episode of
hyperkalemia or WRF.

References

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  1. Shirazian S, Grant CD, Mujeeb S, et al. Underprescription of renin-angiotensin system blockers in moderate to severe chronic kidney disease. Am J Med Sci. 2015; 349: 510–515.
  2. Gheorghiade M, Albert NM, Curtis AB, et al. Medication dos- ing in outpatients with heart failure after implementation of a practice-based performance improvement intervention: find- ings from IMPROVE Congest Heart Fail. 2012; 18: 9–17.
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Disclosure: Dr. Rossignol is a consultant to AstraZeneca, Novartis, Relypsa, Inc., and Stealth BioTherapeutics Inc. He is a co-founder of CardioRenal