QRS Duration Criteria to Select Patients for Cardiac Resynchronization Therapy
2013; Lippincott Williams & Wilkins; Volume: 6; Issue: 2 Linguagem: Inglês
10.1161/circep.112.970939
ISSN1941-3149
Autores Tópico(s)Neurological disorders and treatments
ResumoHomeCirculation: Arrhythmia and ElectrophysiologyVol. 6, No. 2QRS Duration Criteria to Select Patients for Cardiac Resynchronization Therapy Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBQRS Duration Criteria to Select Patients for Cardiac Resynchronization TherapyCardiac Resynchronization Therapy: 150 Is Not A Magic Number! Maya Guglin, MD, PhD and Anne B. Curtis, MD Maya GuglinMaya Guglin From the Department of Cardiovascular Sciences, University of South Florida, Tampa, FL (M.G.); and Department of Medicine, University at Buffalo, Buffalo, NY (A.B.C.). and Anne B. CurtisAnne B. Curtis From the Department of Cardiovascular Sciences, University of South Florida, Tampa, FL (M.G.); and Department of Medicine, University at Buffalo, Buffalo, NY (A.B.C.). Originally published1 Apr 2013https://doi.org/10.1161/CIRCEP.112.970939Circulation: Arrhythmia and Electrophysiology. 2013;6:429–435Scope of the ProblemCurrent American College of Cardiology/American Heart Association/Heart Rhythm Society as well as European Society of Cardiology guidelines recommend the use of cardiac resynchronization therapy (CRT) in patients with symptomatic heart failure (HF) and QRS durations >120 ms1,2 (Table 1). However, 2 recent meta-analyses by Sipahi et al6 and Stavrakis et al7 challenged these recommendations. Both studies found that patients with QRS durations between 120 and 150 ms do not benefit from CRT.Table 1. Indications for Cardiac Resynchronization TherapyGuidelines, YearIndicationNYHA ClassStrength of RecommendationAllLVEF ≤35%QRS ≥120 msACC/AHA/HRS 20081III-IVIndicatedACC/AHA HF, 20093 (on optimal medical therapy)III-IVIndicatedHFSA, 20104 (on optimal medical therapy)II-IVMay be consideredESC2 (on optimal medical therapy)III-IVIndicatedACC/AHA/HRS 20081: consider when internal defibrillator is implantedReduced LVEFIITo be consideredESC2 (on optimal medical therapy)LVEF ≤35%IIIndicatedCRTQRS ≥150 msHFSA, 20125LVEF ≤35%II-IIIIndicatedQRS ≥150 msACC indicates American College of Cardiology; AHA, American Heart Association; ESC, European Society of Cardiology; HFSA, Heart Failure Society of America; HRS, Heart Rhythm Society; LVEF, left ventricular ejection fraction; and NYHA, New York Heart Association.Response by Sipahi and Fang on p 435This is a very important conclusion, from both the clinical and financial standpoints. If the conclusions of these meta-analyses are correct, the guidelines should be revised, and the cutoff for QRS duration indicating the need for CRT should be changed from 120 to 150 ms. From the reimbursement standpoint, these analyses would suggest that the cost of CRT devices implanted in patients with QRS durations shorter than 150 ms should not be covered by insurers. Indeed, the authors of the second meta-analysis state that "the decision to routinely recommend CRT for patients with QRS 150 ms (and not because of right bundle-branch block), with severe left ventricular (LV) systolic dysfunction and persistent New York Heart Association (NYHA) functional class II-III symptoms, despite optimal medical therapy. According to the same update, CRT may still be considered for patients with QRS intervals between 120 and 150 ms and severe left ventricular dysfunction who have persistent symptoms on medical treatment.5 However, the wording "may be considered" reflects the lowest possible strength of recommendation. Despite the high quality of both meta-analyses, as well as of the individual trials included in them, we doubt that such a conclusion is justified.CRT is a unique therapy for patients with HF and prolonged QRS duration. Not only does it induce reverse LV remodeling, it also improves functional status and increases longevity in these patients.8,9 Unlike any other therapy with the exception of ventricular assist devices, CRT interrupts the progression of the disease and reverses the natural course of HF,9 even in minimally symptomatic or asymptomatic patients with complete left bundle-branch block (LBBB) and systolic dysfunction. In just 1 year of therapy, LV end-systolic and end-diastolic volume decreases and ejection fraction increases in most patients, especially those with nonischemic cardiomyopathy. There is also a subset of super-responders in whom biventricular pacing leads to restoration of cardiac geometry and function to a normal or nearly normal state. Although the proportion of super-responders is modest (10% to 22%),10–14 the large total volume of CRT procedures means that a significant number of patients receive this benefit of almost complete recovery of ventricular function.Because of the uniqueness of this therapy, indications for CRT should be worded very carefully, with full consideration of the entire pool of data accumulated to date.Evidence for the 150 ms CutoffA summary of the CRT clinical trials is presented in Table2. Almost all of them performed a subanalysis of clinical outcomes in patients with severely prolonged QRS (>150 ms, with some interstudy variability) and moderately prolonged QRS ( 150None+NoMIRACLE22III, IV≤35≥130Benefit is independent of QRS duration, which was analyzed as a continuous variable+YesPATH CHF8III, IV≤35≥120NoneNoCOMPANION15III, IV≤35≥120≤147−No148–168+>168++CARE HF16III, IV≤35≥120 160++Effects on reverse remodelingREVERSE20 (European cohort)I, II≤40<152−No≥152+MADIT CRT21I, II≤30≥130<150−No≥150+RAFT19II, III≤30≥120<150−No≥150+CARE-HF indicates The Cardiac Resynchronization -Heart Failure; COMPANION, The Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure; LVEF, left ventricular ejection fraction; MADIT-CRT, The Multicenter Automatic Defibrillator Implantation Trial—Cardiac Resynchronization Therapy; MIRACLE, the Multicenter InSync Randomized Clinical Evaluation; MUSTIC, The MUltisite STimulation In Cardiomyopathy; NYHA, New York Heart Association; PATH-CHF, the Pacing Therapies for Congestive Heart Failure; RAFT, The Resynchronization–Defibrillation for Ambulatory Heart Failure; and REVERSE, The REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction.The Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial15 demonstrated that CRT decreased the combined risk of death from any cause or first hospitalization, but provided no benefit if the QRS was 120 ms qualified for the study, there were additional requirements of dyssynchrony by echocardiographic criteria for QRS durations between 120 and 149 ms. Patients were categorized into QRS durations above and below 160 ms, and only the latter subgroup did better with CRT. However, during a 3-year extended follow-up, there was benefit for both subsets.17The MUltisite STimulation In Cardiomyopathy (MUSTIC) Study18 included only patients with QRS durations >150 ms. The Resynchronization–Defibrillation for Ambulatory Heart Failure (RAFT) trial19 demonstrated that the addition of CRT to an implantable cardioverter defibrillator (ICD) reduced the rates of death and hospitalization for symptomatic HF. CRT was effective in patients with QRS durations >150 ms and ineffective in patients with QRS durations <150 ms.The REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction (REVERSE) trial9 demonstrated that CRT in asymptomatic LV dysfunction and in minimally symptomatic HF resulted in major structural and functional reverse remodeling, especially in nonischemic cardiomyopathy. There was no benefit in patients with QRS durations 160 ms. In the European cohort of the REVERSE trial, no benefit was demonstrated in patients with QRS durations 150 ms, whereas no benefit was derived in the subset with QRS between 120 and 149 ms.21In summary, almost all of the CRT trials reported no effect in patients with moderately prolonged QRS durations. Indeed, every 1 of the 5 trials included in both of the aforementioned meta-analyses (COMPANION, CARE-HF, MADIT-CRT, REVERSE, and RAFT) demonstrated a beneficial effect of CRT in severely prolonged QRS and no effect in moderately prolonged QRS. Examining this point in greater detail, in both the REVERSE (European cohort)20 and the RAFT19 studies, the investigators stated that their cohorts with longer QRS durations derived more benefit than those with shorter QRS durations, implying that patients with shorter QRS durations also benefit, at least somewhat, from CRT. However, the odds ratios with corresponding confidence intervals overlapping one indicate that, in terms of clinical outcomes, CRT, in fact, made no difference in patients with shorter QRS durations.19,20Flaws in the Evidence for the 150 ms CutoffIndeed, there is no need to do a meta-analysis to demonstrate that there is no benefit from CRT in patients with moderately prolonged QRS if each of the included trials already reached the same conclusion individually. However, there is an important problem with this seemingly obvious conclusion. All the above studies share the same feature: the duration of the QRS interval was categorized.In clinical trials, many continuous variables are categorized for analysis purposes. For instance, LV ejection fraction is a continuous variable. It can theoretically be anywhere between 0% and 100%. But, for the purpose of this analysis, let us say that it is either normal, above 50%, or reduced, below 50%. Now, instead of a continuous set of values, we have 2 categories: normal and reduced. If we use these categories for analysis, all ejection fractions below 50%, whether, for example, 10% or 45%, will be analyzed together, as if there is no difference between them.Likewise, QRS duration is a continuous variable. But, for the subgroup analyses, the investigators categorized QRS durations into those above 150 ms and below 150 ms (120–150), and thus they obscured all the differences that can exist between 121 and 149 ms. The authors of both meta-analyses reproduced the same strategy. Lo and behold! They found exactly what each of the trials already proved individually.In other words, outcomes in patients with QRS durations 120 to 149 ms were analyzed as a single group. Meanwhile, better outcomes in patients with QRS durations >160 ms compared with 150 ms virtually always experienced acute hemodynamic improvement, some patients with QRS durations between 120 and 150 ms also showed improvement. In the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trial, the only study in which QRS duration was analyzed as a continuous variable, the magnitude of favorable effects was not influenced by baseline QRS duration.22QRS Duration and DyssynchronyThese results are not surprising, because there is plenty of evidence that the severity and prognosis of HF is dependent on QRS duration.23 Intraventricular conduction delay resulting in electric and mechanical dyssynchrony occurs commonly in HF. According to different sources, the prevalence of prolonged intraventricular conduction ranges from 20% to 30% in HF with systolic dysfunction.22,24,25 It is well established that a QRS duration above 120 ms is a significant predictor of LV systolic dysfunction, and moreover, prolonged QRS is associated with a poor prognosis.2,3,15 For the purpose of this discussion, studies examining outcomes in HF based on graded duration of QRS are of particular interest. It is important to realize that patients with QRS durations exceeding 120 ms are almost equally distributed between moderately and severely prolonged QRS.26 This means that if the cutoff 150 ms is accepted, about half of all patients who currently qualify for CRT would be found ineligible for this therapy.In a study of nearly 3500 patients with HF, Shenkman et al24 found a stepwise increase in the prevalence of systolic LV dysfunction as QRS duration increased progressively above 120 ms. Reduced LV ejection fraction was present in 42.5% of patients with a QRS duration 150 ms (P=0.01). Sandhu and Bahler26 reported a progressive decrease in LV ejection fraction and an increase in LV diameter and the severity of mitral regurgitation with incremental prolongation of the QRS from 150 ms (Figure 1). In other words, a moderate degree of QRS prolongation, which, according to the new proposals, should not be corrected with CRT, was associated with significant deterioration of LV systolic dysfunction.Download figureDownload PowerPointFigure 1. Prevalence of left ventricular systolic dysfunction (ejection fraction <45%) in relation to QRS duration.26In terms of prognosis, a prolonged QRS duration of 120 to 149 ms was associated with an increased mortality at 60 months (P=0.001), even after adjustment for age, sex, and race (P=0.001).24 In another study, the 3-year mortality rate was 20% for an intraventricular conduction delay of 160 ms27 (Figure 2).Download figureDownload PowerPointFigure 2. Graded increase in mortality with increasing intraventricular conduction delay (IVCD).27Stratifying patients according to 2-year event free survival, Kalra et al28 found that the optimal QRS duration providing the best demarcation between benign and poor prognosis was 120 ms. Moderate prolongation of QRS duration (120–149 ms) was associated with worse NYHA class, lower peak oxygen consumption, and poorer LV ejection fraction compared with patients with normal QRS durations (all P 150 ms.Studying the predictors of response to CRT in patients with non-LBBB morphology, Rickard et al29 found that QRS duration (>120 ms) was the only variable significantly associated with response (odds ratio per each 10 ms increase in QRS, 1.23; 95% confidence interval, 1.01–1.52; P=0.048). During follow-up, QRS duration was inversely related to poor long-term outcomes (hazard ratio per 10 ms increase in QRS duration, 0.79; 95% confidence interval, 0.66–0.94; P=0.005). When the authors categorized QRS duration into 150 ms, there was a clear-cut survival benefit in patients with QRS 130 to 150 ms in comparison with those with narrower QRS.When patients with symptomatic end-stage HF were grouped according to QRS duration (QRS <120 ms, QRS ≥120 ms but <150 ms, and QRS ≥150 ms), conventional (posterolateral LV and right ventricular apex) CRT did not lead to improvement in stroke work and contractility in the narrow QRS group, but there was a significant increase in the intermediate (+27%, P=0.020; and +5%, P=0.044) and wide (+48%, P=0.002; and +18%, P<0.001) QRS groups. In contrast, 15% of patients had deterioration by conventional CRT in the intermediate and wide QRS groups. Apparently, some patients could be improved by lead placement in the anterolateral rather than the posterolateral region, which may be of particular importance with patients with moderately prolonged QRS.30Thus, it is clear that many patients with QRS durations <150 ms do respond to CRT, but it may be even more important in these patients compared with those with severe QRS prolongation to select the location of the LV lead carefully, and to program the device optimally. In other words, almost any posterolateral or lateral lead location could potentially lead to at least some improvement in LV structure and functional status in patients with marked QRS prolongation, provided that the lead is not placed in a location of scar. In contrast, in patients with milder degrees of QRS prolongation, improvement over native conduction may require more targeted lead placement and more careful selection of atrioventricular (AV) and ventricular-ventricular (VV) timing.LBBB and HFIn particular, LBBB has been found to have a detrimental effect in HF. In 1 study, mean ejection fraction in patients with HF was 40% in those with normal QRS (<120 ms), 36.3% in those with right bundle-branch block, and 29.6% in those with LBBB. Short-term mortality rates were 46.1%, 56.8%, and 57.7%, respectively (P<0.0001).31The normal sequence of electric activation is reversed in LBBB, with the direction of septal depolarization proceeding from right to left and the impulse spreading first to the right ventricle and then to the LV. The resulting delay in the inward motion of the lateral wall of the LV depends on the duration of the QRS, with greater duration of the QRS producing more dyssynchronous contraction.32 When patients with LBBB have been compared with control subjects, striking delays were observed in both LV systolic and diastolic events in the LBBB group. The delay was associated with shortening of LV diastole with a resultant increase in the ratio of right to LV diastolic time. Also, the abnormal interventricular septal motion in LBBB corresponded to periods of asynchrony in contraction, ejection, end systole, and end diastole between the right and left ventricles. This loss of septal contribution resulted in a reduction in global ejection fraction in LBBB compared with normals (54 + 7% compared with 62+5%; P<0.005).33In the Framingham study, QRS duration was modeled as a continuous and as a categorical variable (<100, 100–119, and ≥120 ms). QRS duration was positively related to LV dimensions but inversely related to fractional shortening (a surrogate of ejection fraction). Importantly, LBBB was associated with greater LV mass and dimensions, and with lower fractional shortening than other types of QRS prolongation.34 In another study, LBBB was an independent predictor of long-term mortality in patients with acute HF.35In the MADIT-CRT trial, patients with LBBB treated with CRT experienced a 53% reduction (hazard ratio, 0.47; P 15%, was evident in 46% of the moderately prolonged QRS group and in 68% of those with severely prolonged QRS. Similarly, improvement in LV systolic function and in functional status (NYHA class) occurred in all patients with QRS >120 ms. Specifically, LV ejection fraction increased from a baseline value of 28.4±7.3% to 33.9±9.7% (P<0.001) in 3 months in patients with QRS between 120 and 150 ms, and from 26.0±12.9% to 37.0±12.5% (P 150 ms, creating a gain of 5.5±7.3% versus 11.0±12.1% (P=0.04), respectively.39The origin of the currently recommended cutoff for CRT of 120 ms is clear. It is an upper range for normal intraventricular conduction. Beyond that, longer QRS durations mean a higher degree of dyssynchrony (because of greater delay between the arrival of the electric signal at the ventricular septum and the LV free wall), which translates into poorer clinical outcomes. Therefore, the response to CRT will be better in patients with longer QRS durations. However, there is no reason to limit CRT only to patients with QRS durations above 150 ms. There is nothing magical about this number! It is simply an arbitrary cutoff chosen by clinical trial investigators for categorization of QRS into moderately and severely prolonged.If we really want to know the appropriate cutoff for QRS duration below which the risks of CRT implantation outweigh the benefits, we would need to reanalyze existing data sets from the clinical trials studying QRS as a continuous variable or subdivide QRS durations between 120 and 150 ms into smaller increments. This should be a topic of a separate meta-analysis. But eliminating all the gradations between 120 and 150 ms, and only recommending CRT for patients with very prolonged QRS (>150 ms) will deny a very effective treatment to a substantial number of patients with HF.DisclosuresDr Curtis is a consultant with Medtronic, Inc. and has received honoraria and research grants, and is a member of the advisory board of St. Jude Medical and has received honoraria from the same. The other author has no conflicts to report.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Anne B. Curtis, MD, Charles and Mary Bauer Professor and Chair, Department of Medicine, University at Buffalo, 100 High St, D2-76, Buffalo, NY 14203. E-mail [email protected]References1. 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