Продолжение
Table: Study design, clinical characteristics, major outcomes and rates of hyperkalemia in RALES, EPHESUS and EMPHASIS-HF
RALES6 EPHESUS7 EMPHASIS-HF8
No. of patients 1663 6632 2737
NYHA Class III, IV II-IV, post-MI II
MRA Spironolactone Eplerenone Eplerenone
Mean Dose (mg daily) 26 43 39
Follow-up (months) 24 16 21
Mean Age (years) 65 64 69
Male (%) 73 72 77
Mean EF (%) 26 33 26
All-cause mortality (ARR %) 11.3 2.3 3.0
Cardiac mortality (ARR %) 9.8 2.3 2.7
All-cause hospitalization (ARR%) 8.3 1.1 5.9
Hyperkalemia Definition ≥6 mmol/L ≥6 mmol/L ≥5.5 mmol/L
Hyperkalemia (Risk excess %) 0.5 1.6 4.6
NYHA = New York Heart Association; MRA = mineralocorticoid receptor antagonists; EF = ejection fraction; ARR = absolute risk reduction
Clinicians are hesitant to initiate MRA therapy during hospitalization, as evidenced by the poor rates of discharge prescription. We speculate that this may be primary related to concerns of hyperkalemia and adverse side effect profiles of these agents in the acute setting since a significant number of patients have a hospital course complicated by worsening renal function, many have diabetes (~40%) and the majority are concomitantly taking an ACE-inhibitor or ARB. However, patients may be particularly amenable to change during hospitalization and adding underutilized, but efficacious, agents to their existing regimen may be beneficial. The hospitalization provides a unique opportunity for clinicians to optimize medical therapy and provide assistance extending beyond mere symptomatic relief.(23,24) If MRAs are administered as indicated with close monitoring and surveillance, especially immediately after initiation and at higher therapeutic doses, metabolic derangements can be identified early and successfully managed. There is an enormous unmet need in AHFS with alarmingly high mortality and rehospitalization rates seen within the first 90 days of discharge.(25) The minor risk of metabolic fluctuations may be a small price to pay for these dismal event rates.
Matching the Right Drug with the Right Patient
MRAs have successfully linked our basic science understanding of HF pathophysiology to its direct clinical management. Although MRAs are well-established and provide a consistent mortality benefit (albeit through an unknown mechanism), they remain an underutilized class of agents in the setting of HF. Currently, we are only offering this potentially life-saving therapy to a minority of eligible patients. Treatment should not be provided based solely on structured algorithms, clinical care teams involving physicians, nurses, pharmacists, patients and their families must work together to determine appropriateness of MRA initiation.
It is also important to appropriately adjust and up-titrate dosage to achieve maximal natriuretic and mortality benefit. Initial studies suggest that MRAs may have two distinct beneficial effects in HF. At lower doses (25-50 mg/day), the drug has minimal cardiac penetration, but has a documented mortality benefit. Mean doses utilized in RALES, EPHESUS and EMPHASIS-HF were 26 mg, 43 mg and 39 mg daily, respectively. At higher drug levels (50-75 mg/day), similar to dosing employed by our hepatology colleagues, natriuretic effects are achieved and help to modulate intravascular volume and congestion. At these dosing ranges in the RALES trial, spironolactone significantly decreased sodium retention within days of drug initiation.(6) Starting at trial doses and up-titrating if necessary (and tolerated) to attain diuretic effect may be a plausible treatment strategy.
As our clinical experience and familiarity with this class of agents continue to grow, we will hopefully be able to close this apparent gap between evidence-based guidelines and clinical practice in the setting of HF. As with most agents available for use in the setting of HF, one size certainly does not fit all. Careful selection of patients and vigilant follow-up after initiation of MRAs are imperative for therapeutic success. Despite initial concerns that a treatment-patient mismatch existed for MRAs, contemporary appropriateness guidelines have shown that use of these agents in patients with documented contraindications was only 0.5%.(3)
Further research will be necessary to shed light on whether we can extend the clinical usefulness of MRAs to other important patient populations with HF. Unfortunately, we currently lack substantial clinical evidence regarding the efficacy of aldosterone blockade in the setting of HF with preserved EF and in AHFS. In the near future, hopefully we will be able to better ascertain drug appropriateness in these special populations. We also eagerly await the development of novel MRAs that confer higher receptor specificity that may lessen the metabolic fluctuations and adverse risk profiles associated with current therapies. In this era of heart failure management, clinical trials tend to define the limits of our therapeutic boundaries. However, we must also be mindful of our lack of understanding of MRA effectiveness in “real world”, unselected patients. Tailoring and individualizing therapy to fully balance the benefits and risks of aldosterone antagonism will be necessary for the treatment of each and every patient.
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