EDITORIAL COMMENT
Cardiac Resynchronization TherapyAre Modern Myths Preventing Appropriate Use?*
John G.F. Cleland, MD, FRCP, FACC ,*,
Luigi Tavazzi, MD, FESC ,
Jean-Claude Daubert, MD, FESC ,
Ahmed Tageldien, MBBS and
Nick Freemantle, PhD||
Department of Cardiology, Castle Hill Hospital, Kingston upon Hull, United Kingdom
IRCCS Policlinico S. Matteo, Pavia, Italy
Département de Cardiologie, Hôpital Pontchaillou, Rennes, France
|| University of Birmingham, Edgbaston, United Kingdom
* Reprint requests and correspondence: Dr. John G. F. Cleland, Department of Cardiology, Castle Hill Hospital, Hull York Medical School, University of Hull, Kingston-upon-Hull, United Kingdom (Email: j.g.cleland{at}hull.ac.uk).
Key Words: heart failure • hemodynamics • cardiac resynchronization therapy • remodeling
Observational studies can help describe patient outcome, but only randomized controlled trials can assess the response to treatment. All too often, doctors confuse outcome with response, and nowhere is this better illustrated than with cardiac resynchronization therapy (CRT). If someone with little evidence of cardiac disease is implanted with a CRT device, he or she will almost certainly have an excellent outcome, but it would be wrong to attribute this to the device. A patient who was otherwise destined to die soon, who survived because he or she received CRT, but who had little improvement in symptoms may be considered to have had a poor outcome but, nevertheless, has responded to treatment. Differentiation between outcome and response is rendered even more difficult because most patients with heart failure experience episodes of acute deterioration and many experience a gradual decline in underlying cardiac function that may confound assessment of the benefits of treatment. Any patient with heart failure who has not deteriorated might be considered to have benefited from intervention. Indeed, this was a definition of treatment response used in the CARE-HF (Cardiac Resynchronisation in Heart Failure) trial (Table 1) (1–3). Prevention of sudden death in a patient who enjoys a reasonable quality of life is also generally regarded as a benefit even if the treatment does not improve symptoms and has some side effects. Observational studies are not very good at assessing the importance of the absence of such events.
However, observational studies can be useful. In this issue of the Journal, Mullens et al. (4) show, in an observational study, that patients who do not appear to have benefited from CRT often deteriorate when it is withdrawn (4). This suggests that in some patients, the benefit from CRT is "trumped" by deterioration in the underlying cardiac disease. This casts further doubt on the validity of observational trials that have attempted to predict who needs CRT using imaging or the electrocardiogram, as their results are highly dependent on the definition of response (5). Paradoxically, the observations made by Mullens et al. (4) undermine the notion that treatment response can be assessed reliably in an observational trial.
The mythological patron of medicine was Hermes (Greek) or Mercury (Roman), and many institutions use his wand (the caduceus) as a symbol. He was also the god of merchants, thieves, and gamblers. Maybe, as a profession, we are at risk of being as much doctors of "spin" as doctors of medicine. Doctors are very good at creating myths. Chronic aspirin therapy for coronary artery disease (6), antiarrhythmic drugs for ventricular arrhythmias (7,8), revascularization to improve the prognosis of patients with stable coronary disease (9) or for heart failure (10), and tight glucose regulation for diabetes (11) are but a few examples of recent or current management concepts, based on belief rather than on strong evidence, that have been challenged. Such beliefs, if wrong, may not be considered a large problem by a practicing physician, but from the point of view of generations of patients who may suffer the consequences of myth-based treatment this may be a disaster. The CAST (Cardiac Arrhythmia Suppression Trial) study saved millions of lives by exposing the delusion that suppressing ventricular arrhythmias with class I antiarrhythmic agents was an essential part of cardiology practice (7,8). We need more studies like it. Hopefully, some will show that the mythology was correct and the treatment really does work. However, treating people on the basis of inadequately tested hypotheses should be abhorrent to all good physicians, even if they are forced to practice this way until freed by science.
About 8 years ago, several groups of experts gathered to discuss the design of trials for CRT. No one had a strong rationale for which patients to select. Pioneers had developed the concept that QRS duration was a guide to ventricular dyssynchrony and used it as the basis to select patients for CRT (12,13). The sponsors of large trials have to balance innovation and wise investment. When the COMPANION (Comparison of Medical Therapy, Resynchronization, and Defibrillation Therapies in Heart Failure) (14) and CARE-HF trials (2,3,15,16) were conceived, there were only the results of the MUSTIC (Multisite Stimulation in Cardiomyopathies Study) trial to guide selection criteria (17). There was a healthy discussion between scientific groups, each anxious to provide a high-quality trial but each hoping for a positive result. These committees had to identify patients at substantial risk of cardiac events to justify implanting, at some risk, a device of unknown value. A best-guess set of entry criteria was evolved. Unfortunately, once clinical trial entry criteria are used to formulate recommendations, they can become a barrier to progress because the concepts of an absence of evidence of an effect and evidence of absence of an effect are often confused. Despite considerable efforts, analyses of the CARE-HF study has failed, as yet, to identify a particular set of patient characteristics that lead to clinically important differences in treatment effect (18,19). The effect of CRT in CARE-HF was large, suggesting that, by chance, the precise criteria for response had been chosen or, more likely, that the entry criteria had excluded many patients who would have responded. We need further randomized trials to find out which of the inclusion and exclusion criteria applied in trials should be adopted into clinical practice. It is important to know who CRT does and does not help, but only randomized trials can deliver a secure answer in most cases.
For potentially curable diseases, such as infections, it is sensible to talk about response rates. Heart failure is not generally curable—yet (20). It is naïve to think that patients with heart failure neatly divide into responders and nonresponders. There will be a spectrum of response. Some patients will be harmed by CRT, for instance those that get an infected system. Others may derive no benefit because they are too sick or too well and others will have a good response, which in some cases can appear miraculous. As with most interventions in clinical practice, there will also be a placebo response. Intercurrent events further complicate attempts to predict the course of the disease. However, response is also time dependent. Some patients do not appear to respond initially but may respond later, at a time when ventricular function and symptoms would have deteriorated had they not had the device. Cardiac dyssynchrony is unlikely to be a fixed entity and probably varies, either in response to stress or as a function of disease progression (5,21–23). The benefit of CRT may not be predictable before implantation because the substrate on which it will act in the future is not yet present (23). Perhaps it is best to abandon attempts to define narrowly who will or will not benefit from CRT and focus instead on optimizing outcomes (and response) after implantation in all those that might benefit.
There is, as yet, no evidence that QRS duration, dyssynchrony, or left ventricular ejection fraction is relevant for selecting patients for CRT. The appropriate trials to find out have not been done. We can identify patients who have good outcomes without CRT and, therefore, do not need it and perhaps a group of patients (e.g., cardiogenic shock) who will do badly despite CRT. Everything else is guess work, which should not be good enough for us or our patients.
Analyses of CARE-HF, which is much larger than any observational trial, have struggled to identify anything that predicts the effects of CRT on morbidity, mortality, or quality of life. Indeed, dyssynchrony predicted a better prognosis regardless of assigned treatment possibly because such patients are more likely to have dilated cardiomyopathy and more viable myocardium, both of which are associated with a better prognosis (18,19). In observational studies of CRT implantation, patients with dyssynchrony will have a better outcome because they have a better intrinsic prognosis. Whether CRT has an additional benefit remains uncertain. Improvement in cardiac function 3 months after implantation of a CRT device is a good sign associated with a better outcome but explains very little of the long-term response to CRT (19). Patients with ischemic heart disease had less improvement in ventricular function than patients with dilated cardiomyopathy with CRT and they had a worse prognosis, but the change in prognosis caused by CRT was similar in patients with or without ischemic heart disease (24,25).
Of all the variables studied so far in CARE-HF, amino-terminal pro-brain natriuretic peptide (NT-proBNP) was the best baseline predictor of outcome (19), bettered only by NT-proBNP measured 3 months after randomization, but neither value predicted the long-term response to CRT. The absolute improvement in prognosis with CRT was similar in patients with values above and below the median NT-proBNP (26). Patients with relatively normal values of NT-proBNP have an excellent prognosis, and treatment with CRT may be deferred. On the other hand, patients who have extreme elevations of NT-proBNP have a poor prognosis. Although they may have a large response to CRT, the outcome is likely still to be poor, unless they are suitable for a heart transplant. The optimal response to treatment, that is, change in outcome, is to be expected among patients at intermediate risk with moderately elevated increases in NT-proBNP. Clinical trialists should restrain their instinct to enroll populations with high event rates in whom treatment response is often small. Far better to design trials that exclude patients at either extreme of risk who cannot benefit and find the "sweet-spot" associated with large treatment effects (Fig. 1).
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Figure 1 The Goldilocks Effect
When considering treatment for many diseases there will be some patients who are too well to benefit and will thrive without treatment and others who are too sick who will die despite intensive management. In between, there will be a group that obtains the maximum benefit from treatment. This may be likened to the story of Goldilocks, who found that 1 bowl of porridge was too hot, 1 was too cold, but another was just right. In more scientific terms, it might be called the risk–benefit parabola or optimal treatment window.
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In conclusion, the report of Mullens et al. (4) indicates that we should be very wary indeed in asserting whether or not a patient has responded to CRT. Observational data are usually hard to interpret and translate into clinical practice. For the time being, stick to the guidelines when selecting patients for CRT and optimize programming, particularly atrioventricular delay, for those patients who remain symptomatic after implantation. We must also ensure that we do not confuse outcome with treatment and response to treatment.
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Footnotes
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* 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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References
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