Department of Cardiovascular Sciences, University of Leicester, Leicester LE 1 7LX, UK
* E-mail address: is11{at}le.ac.uk
This editorial refers to Under-utilization of evidence-based drug treatment in patients with heart failure is only partially explained by dissimilarity to patients enrolled in landmark trials: a report from the Euro Heart Survey on Heart Failure
by M.J. Lenzen et al., on page 2706
The medical community should, by now, be well aware of the importance of chronic heart failure (CHF), an increasingly common condition with high morbidity and mortality. We know that for patients with CHF in clinical trials, meaningful mortality and morbidity benefits are obtained with angiotensin-converting enzyme (ACE) inhibitors (or alternatively angiotensin receptor blockers), ß-blockers, and aldosterone antagonists. The accumulated body of evidence for the efficacy of these treatments in CHF is powerful. Guideline documents from national and international societies1 endorse the evidence, guide and encourage physicians to prescribe evidence-based therapies, and, to a large extent, define the expected standards of care.
These guidelines have for some years recommended that the routine management of patients with CHF with left ventricular systolic dysfunction (LVSD) should include both ACE-inhibitor and ß-blocker, unless contraindicated. However, observational studies consistently indicate that large proportions of patients with CHF do not receive these therapies.2 It is often cited that this shortfall is explained in large part by the limited generalizability of the results of clinical trials, because of the highly selected nature of the patients included.
Lenzen et al.3 show that failure to prescribe in CHF is due to more than the patient's failure to meet clinical trials criteria. The authors report the extent of eligibility for three landmark CHF trials: SOLVD (ACE-inhibitor),4 MERIT HF (ß-blocker),5 and RALES (aldosterone antagonist)6 in the Euro Heart Survey Heart Failure (EHS HF). Patients were categorized as trial eligible (objective evidence of LVSD and eligible for at least one of the above trials), trial ineligible (objective evidence of LVSD but not eligible for any of the above trials), and other patients (no documentation of LV function but otherwise eligible for at least one of the above trials).
Among the 10 701 patients hospitalized with confirmed or suspected heart failure, remarkably few would have been eligible for the trials: 9% for SOLVD, 5% for MERIT HF, and 7% for RALES. Only 13% of the population would have been eligible for at least one of the trials, 6.5% for two, and 2.4% for all the three. Moreover, even among trial-eligible patients, prescription of evidence-based therapies was limited. This was particularly so for ß-blocker and aldosterone therapy: only over half (54 %) of MERIT-HF eligible patients were prescribed a ß-blocker and only 43% of RALES-eligible patients received aldosterone antagonist.
A few caveats apply to these data. First, many of the trial-ineligible cohorts in this study (objective evidence of LVSD but ineligible for SOLVD, MERIT HF, or RALES) may have met inclusion criteria for other relevant trials. This will apply particularly to many of the 2505/6595 (38%) ineligible patients, on the basis of a recent acute coronary syndrome. Many of these are likely to be eligible for AIRE (ACE-inhibitor),7 CAPRICORN (ß-blocker),8 or EPHESUS (aldosterone antagonist).9 Secondly, eligibility for MERIT HF or RALES required pre-existing ACE-inhibitor treatment, perhaps slightly reducing eligible numbers. Thirdly, it is important to consider the current report in conjunction with previous observations from this survey.10,11
That such a tiny minority of patients with CHF meet the criteria for inclusion in clinical trials will surprise most of us. Perhaps of greater concern is that of those who do, many are denied evidence-based therapies. Many of the institutions participating in the EHS HF have particular interest and expertise in heart failure. This survey may over-estimate the application of evidence-based therapy in standard practice. Indeed, this may be inferred from the wide variation in this survey in the use of ACE-inhibitors (4085%) and ß-blockers (1070%) among countries.11 However, as the title of this report suggests, there is much more to managing patients with CHF than whether they meet eligibility criteria for previous trials. The EHS HF tells us much more about the reality of managing heart failure than simply about our prescribing habits.
Let us first look at the other survey patients, those eligible for at least one of the identified clinical trials other than for the lack of documentation of LV function. In the current report and in the whole EHS HF population, 26 and 33%, respectively, of patients were without documentation of LV function.10 If the EHS HF is representative, then in Europe, one in every three to four patients hospitalized with suspected heart failure does not have quantification of LV function. As noted previously by the EHS HF10 authors, this represents a major deficiency when compared with the ESC guidelines. Who are these patients and why might they not undergo assessment of LV function?
A complex mixture of patient-related and physician-related factors is likely to contribute. When compared with both trial-eligible and trial-ineligible cohorts, patients without assessment of LV function were less likely to have CHD, much more likely to have pulmonary disease, and slightly more likely to have hypertension, diabetes, atrial fibrillation, or prior CVA. Importantly, when compared with trial-eligible patients, they were older and twice as likely to be female. In addition to being less likely to have assessment of LV function, they were also 50% less likely to receive ACE-inhibitor or ß-blocker,11 factors which appear to go hand-in-hand.
Importantly, in EHS HF (and other studies), these patients were more likely to be admitted to general medicine or geriatric care than to a cardiology ward. Looking in more detail at EHS HF, female gender and the presence of pulmonary disease each predicated against the finding of moderate-to-severe LVSD in those patients who did have LV function assessed.10 As we have seen, these are the features of the other patients in EHS HF. Physicians place much emphasis on guidelines and also on experience. Perhaps, it is the expectation of finding preserved LV systolic function, which leads some clinicians to omit the assessment of LV function from the management of these patients. The prevalence of airways disease among patients without assessment of LV function may be similarly relevant. In this regard, the author notes with interest the lack of any significant impact of renal impairment and asthma upon ACE-inhibitor or ß-blocker prescription among patients who did have assessment of LV function. It appears that for the physicians whose patients have assessment of LV function (cardiologists), co-morbidity is relatively less important.
The current report tells us that even among trial-eligible patients, prescription of evidence-based therapies is sub-optimal and that even where prescribed, target doses are often not reached. Numerous factors will influence the physician to prescribe, or not, in an individual patient. Many of the factors relevant to these points will not be readily identifiable in a survey such as EHS HF. Once again, physician factors are doubtless important and the increased concordance with guidelines in cardiology units is of direct relevance.
The current report suggests that irrespective of trial eligibility, survival is better for patients prescribed 50% of the target dose. An earlier report from this survey showed better survival associated with either ACE-inhibitor or ß-blocker treatment, irrespective of the presence of LVSD.11 These data should be treated cautiously. Higher drug doses may, in reality, be associated with greater survival but, equally, patients able to tolerate higher doses may be intrinsically more likely to survive, because of less advanced disease and less co-morbidity. It would be of great interest to show from the current report the impact on mortality (and morbidity) of prescription/non-prescription of ACE-inhibitor in SOLVD-eligible patients and similarly for ß-blocker in MERIT-HF-eligible patients. Further to this, this survey highlights the need for robust assessment of the magnitude of benefit of pharmacological treatments in CHF in clinical practice.
The current report from EHS HF3 and those preceding it 10,11 highlight the complexity of managing heart failure in the real world. We have already seen that one in every three to four patients with suspected heart failure does not have assessment of LV function and that the features of the patients, and the environment in which they are managed, are important. The diagnosis itself is often problematic; in over 3000 survivors of the index admission in EHS HF, physicians considered the diagnosis of heart failure definitely present in 44% and definitely absent in 10%.10 In other words, in the remaining 46% of patients, diagnostic uncertainty (related to less intensive investigation)10 remained. Patient factors influence not only eligibility for pharmacological treatments but also physicians propensity to investigate and to prescribe. Our apparent failure to investigate appropriately denies potentially beneficial treatments to some and exposes others to inappropriate therapy.
In this context, institutional factors are relevant and important. EHS HF demonstrates, not for the first time,12 that the management of patients with heart failure, proven or suspected, is more thorough in the hands of cardiologists. Currently, relatively few hospitals in Europe have physicians with specific interest and expertise in heart failure management: only 63 of the 115 hospitals in EHS HF (55%) had a heart failure service.10 As suggested in a previous report from EHS HF Given the ... opportunity that hospitalisation provides to complete key investigations and institute a long term management plan, it would seem appropriate for most hospitals to reorientate some existing space and resources to the care of patients with heart failure.10 Most health care professionals concerned with the management of this important, chronic condition would not disagree.
Conflict of interest: none declared.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
References
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