A Brief Overview of Cardiac Resynchronization Therapy and its Current Use in Clinical Practice

This article refers to ‘Association between demographic, organizational, clinical, and socio-economic characteristics and underutilization of cardiac resynchronization therapy: results from the Swedish Heart Failure Registry’, by L.H. Lund et al. published in this issue on pages 1270–1279. The pharmacological treatment of chronic heart failure (HF) is now an established part of clinical practice across the western world, with 80-90% of patients taking at least some of the recommended drugs.1 In approximately three-quarters of prescribed patients the doses are lower than the targets set by placebo-controlled trials in the now-remote past, which were subsequently systematically confirmed in the guidelines as ‘optimal medical therapy’.2 However, drug dosing in practice is typically an individual process, not easy to standardize. The recommendations dealing with the use of implantable cardiac devices, in particular cardioverter-defibrillators (ICD) and cardiac resynchronization therapy (CRT), are still less adhered to in practice. The robustness of current clinical indications and their interpretability/applicability by the physicians can play a substantial role in the decision-making regarding CRT. First, clinical indications, inspired by the latest evidence emerging from trials, are not always crystal-clear or consistent with previous recommendations. For instance, the European Society of Cardiology (ESC) recommendations on CRT released in 2012, 2015 and 2016 are based on four elements: symptoms, left ventricular ejection fraction (LVEF), and both QRS morphology and duration. The recommendations reported in Table 1 include several changes in QRS duration and morphology and in LVEF cut-offs not always consistent over time even in trend. These changes may look marginal, however both QRS duration and LVEF are approximate estimates while the threshold values for CRT candidacy are categorical, and small numerical changes can be determinant for decision-making on device implantation. A further example lies in the application of the American College of Cardiology/American Heart Association guidelines in clinical practice. In the guidelines released in 2009,3 the criteria for CRT were: QRS duration ≥120 ms, New York Heart Association (NYHA) class III or IV, and LVEF ≤35%. In the 2013 guidelines—the current version4—the recommendations were: left bundle branch block (LBBB) with a QRS duration of ≥120 ms or non-LBBB (right bundle branch block or interventricular conduction delay) with a QRS duration of ≥150 ms, NYHA class III or IV, and LVEF ≤35%. An analysis of 25 102 patients hospitalized for HF from 2012 to 2015 and enrolled in the Get With The Guidelines HF registry has recently been reported.5 Patients with a medical, system-related, or patient-related reason for not undergoing CRT were excluded. The basic inclusion criterion was a LVEF ≤35%, then the indication criteria for the previous and the current guideline recommendations were applied. The results showed that 49% of patients were eligible for CRT on the basis of historical guidelines, and 33% of patients were eligible for CRT on the basis of current guidelines, a 16% absolute reduction in eligibility (P < 0.0001). This apparent volatility of the appropriateness of such a technically and clinically demanding treatment (besides the cost) charges of heavy responsibility the physicians taking the ultimate clinical decision. Of course, the art of medicine implies flexibility in using the academic recommendations, which are sometimes forced to sacrifice interpretability and practical usability for the sake of evidence-based precision. However, the case of CRT can be felt specifically challenging. The dilemma may be further complicated by the dynamic nature of HF, which can evolve with quite different individual courses due to a multitude of factors that can also be reversible, which implies that the phenotype classification of the patient may change over time with an indication for device implantation that may appear and disappear. For instance, in a longitudinal community study—conducted in the Olmsted County, Minnesota, cohort—LVEF changed over 5 years by crossing the 50% threshold, transitioning 38.5% of patients from HF with preserved ejection fraction (HFpEF) to HF with reduced ejection fraction (HFrEF) and 38.8% of patients from HFrEF to HFpEF.6 Moreover, defining the CRT response is complex, and numerous endpoints have been used, including remodelling measures, functional measures, hard or composite endpoints, generating inconsistent or non-comparable data.7 Several other non-clinical reasons can impact on practice adherence, including the discouraging invasiveness of the procedures, the need for recognized specific skills of the operators, local availability of facilities, costs, and the need for regular physical visits of implanted patients. Finally, the enormous global disparity in national economies and healthcare structures can undermine the availability of costly and technology demanding medical procedures.5 Even among European countries (supposedly relatively homogeneous), the implantation rate of cardiac devices is quite heterogeneous, as evidenced in a recent observational ESC survey conducted across European and Mediterranean countries8 (Figure 1). Analyses carried out on the implementation of CRT in clinical practice have led to the conclusion that CRT is largely underused.9 A survey by the ESC, involving 2438 implantations from 13 countries, performed in 2008–2009 showed that clinicians were exploring indications broader than those recommended in the ESC guidelines.10 Substantial numbers of patients with mild symptoms, atrial fibrillation, a narrow QRS complex, a previous device, or advanced age received CRT devices. Subsequent contributions have been made by the ESC through the EURObservational Research Programme. Overall, approximately 10 000 ambulatory patients with HF were enrolled. A pilot survey in 12 European countries showed that only 22% of the patients with a device indication were implanted. In the following ESC HF Long-Term Registry, conducted in 21 European countries from May 2011 to April 2013, 7401 patients were enrolled.1 In 77%, CRT was not indicated, for 4.5% there were insufficient data to establish the indication, whereas 13% were already implanted; leaving 6% (450 patients) who had an indication for CRT but who were not implanted. The implantation was claimed as planned in about 60% of them. The reported reasons for not implanting a CRT device were medical uncertainty about the indication, patient refusal, or logistic/cost issues. Similar figures have been described in the same registry for ICD implantation: of 731 patients with an indication for ICD, the implantation was planned in 408, but the procedure was not performed or planned in 323 (44%). Recently, the experience recorded in the Swedish HF registry on CRT has been reported.11 This registry included 12 807 chronic HF patients enrolled in 2000–2012. Again, the main conclusion was that CRT was still remarkably underused. The overall prevalence of CRT use was 7% in this nationwide representative HF population, whereas 24% candidates to CRT according to current guidelines were not implanted. Interestingly, non-use was associated mostly with demographic and organizational, rather than clinical or socioeconomic, factors. Contemporary data have also come from the US Get With The Guidelines HF registry, a recent reported analysis mainly focusing on device implantation rates with respect to renal function, which included 310 468 patients with HF hospitalized from 2008 to 2014.12 After exclusion of patients with no indication for a device or lack of all the data necessary to establish an indication, logistic or other reasons for not implanting, 26 286 patients were eligible for an ICD or CRT, but only 30% of the CRT candidates were prescribed for CRT device implantation. Overall, the findings reported above and others suggest that only about one-third of CRT candidates are actually implanted with a CRT device. Accordingly, it seems that physicians and/or their patients are reluctant to put into practice the guideline recommendations on cardiac devices; alternatively, current indications to CRT do not take into due account the real-life clinical context, including co-morbidities, age, etc., and/or there are strong barriers within healthcare systems opposing the recommendations based on clinical science. On the other hand, new individual meta-analytic data and new observational research do not encourage to extend the indication criteria to CRT by confirming that the larger the QRS and the lower the LVEF, the greater the CRT effectiveness.13-15 However, contemporary data coming from the USA are in sharp contrast with those reported above. Out of a cohort of 63 506 patients eligible for CRT defibrillator (CRT-D) at the time of device implantation included in the National Cardiovascular Data Registry ICD Registry,16 nearly 90% received a CRT-D device. Although the use of CRT-D differed by race (black patients were exposed to lower use of CRT-D), type of hospital and implanting operator characteristics, overall these apparently representative data would document a high incorporation of CRT in clinical practice in the USA. An encouraging experience has also been reported in the USA.17 A prospective multidimensional practice-specific performance improvement intervention involving 34 810 outpatients with reduced LVEF enrolled in the IMPROVE-HF registry showed that at baseline 49% of patients eligible for ICD and 38% of those eligible for CRT had received the indicated therapy. However, 2 years after the implementation of the programme aimed at facilitating CRT use, 77% and 66% of patients with an ICD or CRT indication, respectively, had been treated, with a significant reduction in mortality and a significant improvement in the quality of life measures. Such findings strongly suggest that benefits can be gained from the adoption of an accurate, individual professional approach to the care of patients at risk. A further issue concerning the appropriateness of CRT use remains open, namely whether the aetiology of the cardiac disease underlying the HF syndrome—in essence, ischaemic vs. non-ischaemic—does matter in the clinical decision regarding the use of CRT-D. A propensity-score analysis carried out on the French-UK-Sweden CRT Network database including 5307 consecutive HF patients with dilated cardiomyopathy or ischaemic cardiac disease and no history of sustained ventricular arrhythmias, who underwent CRT implantation with (n = 4037) or without (n = 1270) a defibrillator, showed that after a mean follow-up of approximately 3.5 years patients with ischaemic disease who received a CRT-D device had a better survival compared to those who received CRT without a defibrillator (hazard ratio 0.76, 95% confidence interval 0.62–0.92), whereas in patients with dilated cardiomyopathy no such difference was observed. Moreover, excess mortality in patients who did not receive defibrillators was related to sudden cardiac death in 8% of those with ischaemic disease but in only 0.4% of those with dilated cardiomyopathy.18 As perspicaciously Wayne Levy pointed out in a recent editorial,19 we still lack good criteria for candidacy of a patient for ICD, namely we lack the ability to grade the individual arrhythmic risk (not the risk of all-cause mortality).20 While looking for more sensitive and specific criteria, the aetiology may be of some help, as well as age and gender.14 It is also evident that data are needed on outcomes (including procedural complications, quality-adjusted life-years gained, and healthcare costs) of ICD and CRT implantation in a broad spectrum of patients, particularly older and multi-morbid patients. The US 21st Century Cures Act mandates the Food and Drug Administration to develop rules for the use of “real-world evidence (defined as ‘derived from sources other than randomized clinical trials’), most urgently in the device domain where randomized clinical trials are most difficult and costly, and the inconsistency among the rules applied for approval by regulatory bodies across the world are more different and sometimes apparently erratic”.21 Of course, implicitly, this also mandates the public health networks to collect high quality data!