Author + information
- Wilbur Y.W. Lew, MD⁎ ( and )
- Anthony N. DeMaria, MD
- ↵⁎Reprint requests and correspondence:
Dr. Wilbur Y. W. Lew, Cardiology Section 111A, VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, California 92161
Clinical guidelines are effective vehicles for incorporating evidence-based medicine into clinical practice. Experts in the field review the literature, weigh the strength of the evidence, and develop specific guidelines based on this evidence. This approach to achieving quality care has been championed by cardiovascular subspecialty societies for decades, including the American College of Cardiology (ACC), American Heart Association (AHA), European Society of Cardiology, and others. Writing groups distill and codify a vast amount of information and form recommendations for practice, which often are ultimately disseminated as joint documents representing multiple societies. Most guidelines are widely accepted and frequently are the basis of metrics used to evaluate the performance and quality of clinical care.
If guidelines are accepted as carefully considered consensus opinions from experts, it follows that there should be a high degree of adherence to those recommendations to improve outcomes. When there is a divergence between guideline recommendations and clinical practice, this creates a dissonance that can be troubling and calls for an adequate explanation.
In this issue of the Journal, Rassi et al. (1) examine the use of aldosterone antagonist therapy in patients with acute myocardial infarction (AMI) manifesting moderate to severe heart failure (HF), reduced ejection fraction (EF) (<40%), and no contraindications (hyperkalemia or history of renal insufficiency). The Class I recommendation (general agreement that treatment is beneficial, useful, and effective) to use these agents, based on level of evidence A (multiple randomized clinical trials) is presented in the 2004 ACC/AHA guidelines for managing ST-segment elevation myocardial infarction (STEMI) (2) and in the 2007 ACC/AHA guidelines for managing patients with unstable angina/non-STEMI (3). Long-term aldosterone receptor blockade is recommended in unstable angina/NSTEMI patients without significant renal dysfunction or hyperkalemia who are receiving therapeutic doses of an angiotensin-converting enzyme inhibitor (ACEI), have a left ventricular EF ≤40%, and symptomatic HF or diabetes mellitus (3). Similar Class I recommendations, Level of Evidence: B are in the 2005 European Society of Cardiology guidelines for the diagnosis and treatment of chronic HF (4). The evidence supporting these recommendations was based on 2 large multicenter trials using aldosterone antagonists: eplerenone in the EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) (5) and spironolactone in the RALES (Randomized Aldactone Evaluation Study) (6).
Rasti et al. (1) examine the use of aldosterone receptor blockers for patients admitted with AMI to 219 hospitals between 2006 and 2009 from the Get With the Guidelines–Coronary Artery Disease (GWTG-CAD) registry. They found that 11,255 (13.8%) patients fulfilled guideline criteria for aldosterone antagonist therapy, but only 1,023 (9.1%) of those qualifying received this treatment at the time of hospital discharge. There was a wide variation in use among hospitals, with aldosterone antagonists more likely to be prescribed in larger hospitals. There was only a small increase in the use of therapy between 2006 and 2009 (from 6.0% to 13.4%) (1).
The reasons underlying this wide disparity between a Class IA recommendation and clinical practice are not known. However, the possibilities may be related to barriers to the awareness, acceptance, or implementation of the guideline. A lack of awareness is unlikely because >90% of patients received other guideline-recommended therapies including aspirin, beta-blockers, ACEIs, or angiotensin receptor blockers, and lipid-lowering therapy at discharge (1). Widespread adherence to other guidelines for managing AMI is not surprising because hospitals participating in the GWTG-CAD registry have generally already “bought in” to the concept of evidence-based medicine. This behavior may be reinforced by a hospital culture sensitive to adherence to guidelines because they are included in performance measures used to judge hospitals for accreditation. There may be less focus on recommendations that are not included in performance measures or in standard admission order sets. Finally, the relatively small number of patients with AMI who qualify for aldosterone antagonist therapy, 13% in this study, may decrease awareness and application of this guideline (1).
Another possible explanation is that a general reluctance to use aldosterone antagonists may be prevalent among practicing clinicians. The 2005 ACC/AHA chronic heart failure guidelines, updated in 2009 (7), also include a Class I indication to use aldosterone antagonist therapy in patients with moderately severe to severe HF and reduced left ventricular EF, again with close monitoring for renal function and potassium. This is based on Class B Level of Evidence. Adherence to this guideline has been similarly low as that for post-infarction, with only 32% of patients hospitalized with HF being discharged with an aldosterone antagonist (8). This demonstrates a general resistance to using aldosterone antagonists in either the setting of HF alone or after AMI, even when it is a Class I recommendation.
A major concern with aldosterone antagonists is the risk of hyperkalemia, which is exacerbated by renal dysfunction and may be a life-threatening complication. There was a 5-fold increase in the prescription of spironolactone to treat HF after the publication of the RALES, which was associated with 3-fold increases in hospitalizations for hyperkalemia and in-hospital mortality (9). In a meta-analysis of randomized clinical trials using aldosterone-blocking agents (spironolactone, eplerenone, or canrenoate) in patients with left ventricular dysfunction, the treatment group compared with the control group had a higher incidence of hyperkalemia (5.9% vs. 3.0%) and worsening renal function (8.9% vs. 1.6%) (10). The risk of hyperkalemia increases with higher dose ACEIs, nonsteroidal anti-inflammatory drugs, and cyclo-oxygenase-2 inhibitors. Concerns about interactions between multiple drugs may become both physician and patient barriers to acceptance and decrease medical compliance. The guidelines specifically caution against these risks and recommend careful selection of patients and monitoring to avoid these complications. However, such dramatic risks, whether encountered in the published literature or individual experience, can be a marked deterrent for physicians to embrace such therapy, especially if their assessment is that the benefit is only modest.
If lack of awareness or poor implementation explains the disconnect between a guideline and clinical practice, then the potential exists to improve use by increasing the awareness of the indications and benefits of aldosterone blocker therapy and improving processes to minimize adverse effects. However, if the explanation involves a lack of acceptance by the medical community, there may be a need to re-evaluate the specific guideline. If the overwhelming majority (86%) of practicing physicians choose not to follow the guidelines regarding aldosterone antagonist therapy in AMI, yet the vast majority (>90%) accept other recommendations, the “wisdom of the crowd” of expert clinical practitioners may inform experts in the field as to the need to re-examine the guideline.
It is well recognized that patients enrolled in multicenter randomized clinical trials are often not representative of those encountered in clinical practice (11). It is possible that the patients enrolled in the RALES and EPHESUS yielded different results from those seen in the practice setting. Guidelines are updated to incorporate the most current evidence available. The EPHESUS (5) and RALES (6) were published in 2003 and 1999, respectively. Since that time, focused updates have provided new evidence to support the earlier use of beta-blockers, antiplatelet agents, anticoagulants, and percutaneous coronary interventions. There have been advances in other areas as well, such as electrophysiological approaches to identify the risks of and to prevent sudden cardiac death. The guidelines recommendation for aldosterone blockers was based largely on the decrease in sudden death observed with eplerenone in the EPHESUS (5). As this dynamic and rapidly changing field evolves, the management of current AMI patients may differ significantly from that of patients treated in the EPHESUS and RALES. Recommendations need to reflect contemporary medication and management practices, which may modify (increase or decrease) the benefits derived from aldosterone antagonist therapy.
The mechanisms of the cardioprotective effects of aldosterone antagonists remain to be elucidated. The survival benefits of eplerenone in HF patients post-MI are unrelated to either its diuretic or potassium-sparing effects (12). It has been postulated that these drugs may be protective by increasing intracellular potassium to decrease arrhythmias. Several drugs have cardioprotective mechanisms other than their primary action (e.g., pleiotropic effects of statins). As data emerge regarding mechanisms, the guidelines for aldosterone antagonists may be modified.
In conclusion, clinical guidelines are valuable for applying data-based evidence derived from clinical studies to the direct care of patients. When there is a divergence between clinical practice and recommended guidelines, as exists in the use of aldosterone antagonists, the causes need to be identified. If poor adherence results from a lack of knowledge or means of implementation, corrective measures must be taken to improve outcomes. However, it must be accepted that failure to follow guidelines by the vast majority of physicians may indicate that the evidence base is not predictive of the results that will be obtained in contemporary clinical practice. Recommendations need to be re-evaluated based on how representative trial enrollees are of contemporary patients encountered by practicing physicians, newly emerging evidence, changes in context, and a broad view of why some guidelines are not embraced by physicians and/or patients. Resolving apparent discrepancies is fundamental to the processes by which advances in medicine and science are made.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
↵⁎ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
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