Definition Of Left Bundle Branch Block Research Articles

Comparison of the relation of the ESC 2021 and ESC 2013 definitions of left bundle branch block with clinical and echocardiographic outcome in cardiac resynchronization therapy.

We aimed to investigate the impact of the 2021 European Society of Cardiology(ESC) guideline changes in left bundle branch block (LBBB) definition on cardiac resynchronization therapy (CRT) patient selection and outcomes. The MUG (Maastricht, Utrecht, Groningen)registry, consisting of consecutive patients implanted with a CRT device between 2001 and 2015 was studied. For this study, patients with baseline sinus rhythm and QRS duration ≥ 130ms were eligible. Patients were classified according to ESC 2013 and 2021 guideline LBBB definitions and QRS duration. Endpoints were heart transplantation, LVAD implantation or mortality (HTx/LVAD/mortality) and echocardiographic response (LVESV reduction ≥15%). The analyses included 1.202, typical CRT patients. The ESC 2021 definition resulted in considerably less LBBB diagnoses compared to the 2013 definition (31.6% vs. 80.9%, respectively). Applying the 2013 definition resulted in significant separation of the Kaplan-Meier curves of HTx/LVAD/mortality (p < .0001). A significantly higher echocardiographic response rate was found in the LBBB compared to the non-LBBB group using the 2013 definition. These differences in HTx/LVAD/mortality and echocardiographic response were not found when applying the 2021 definition. The ESC 2021 LBBB definition leads to a considerably lower percentage of patients with baseline LBBB then the ESC 2013 definition. This does not lead to better differentiation of CRT responders, nor does this lead to a stronger association with clinical outcomes after CRT. In fact, stratification according to the 2021 definition is not associated with a difference in clinical or echocardiographic outcome, implying that the guideline changes may negatively influence CRT implantation practice with a weakened recommendation in patients that will benefit from CRT.

Aortic valve implantation-induced conduction block as aframework towards auniform electrocardiographic definition of left bundle branch block.

IntroductionNew-onset left bundle branch block (LBBB) following transcatheter or surgical aortic valve replacement (LBBBAVI) implies a proximal pathogenesis of LBBB. This study compares electrocardiographic characteristics and concordance with LBBB definitions between LBBBAVI and non-procedure-induced LBBB controls (LBBBcontrol).MethodsAll LBBBAVI patients at Ghent University Hospital between 2013 and 2019 were enrolled in the study. LBBBAVI patients were matched for age, sex, ischaemic heart disease and ejection fraction to LBBBcontrol patients in a 1:2 ratio. For inclusion, a non-strict LBBB definition was used (QRS duration ≥ 120 ms, QS or rS in V1, absence of Q waves in V5-6). Electrocardiograms were digitally analysed and classified according to three LBBB definitions: European Society of Cardiology (ESC), Strauss and American Heart Association (AHA).ResultsA total of 177 patients (59 LBBBAVI and 118 LBBBcontrol) were enrolled in the study. LBBBAVI patients had more lateral QRS notching/slurring (100% vs 85%, p = 0.001), included a higher percentage with a QRS duration ≥ 130 ms (98% vs 86%, p = 0.007) and had a less leftward oriented QRS axis (−15° vs −30°, p = 0.013) compared to the LBBBcontrol group. ESC and Strauss criteria were fulfilled in 100% and 95% of LBBBAVI patients, respectively, but only 18% met the AHA criteria. In LBBBcontrol patients, concordance with LBBB definitions was lower than in the LBBBAVI group: ESC 85% (p = 0.001), Strauss 68% (p < 0.001) and AHA 7% (p = 0.035). No differences in electrocardiographic characterisation or concordance with LBBB definitions were observed between LBBBAVI and LBBBcontrol patients with lateral QRS notching/slurring.ConclusionNon-uniformity exists among current LBBB definitions concerning the detection of proximal LBBB. LBBBAVI may provide a framework for more consensus on defining proximal LBBB.Supplementary InformationThe online version of this article (10.1007/s12471-021-01565-8) contains supplementary material, which is available to authorized users.

Long-term outcome of intraventricular conduction delays in the general population.

BackgroundPrevious population studies have presented conflicting results regarding the prognostic impact of intraventricular conduction delays (IVCD).MethodsWe studied long‐term prognostic impact and the association with comorbidities of eight IVCDs in a random sample of 6,299 Finnish subjects (2,857 men and 3,442 women, mean age 52.8, SD 14.9 years) aged 30 or over who participated in the health examination including 12‐lead ECG. For left bundle branch block (LBBB) and non‐specific IVCD (NSIVCD), two different definitions were used.ResultsDuring 16.5 years’ follow‐up, 1,309 of the 6,299 subjects (20.8%) died and of these 655 (10.4%) were cardiovascular (CV) deaths. After controlling for known clinical risk factors, the hazard ratio for CV death, compared with individuals without IVCD, was 1.55 for the Minnesota definition of LBBB (95% confidence interval 1.04–2.31, p = .032) and 1.27 (95% confidence interval 0.80–2.02, p = .308) for the Strauss’ definition of LBBB. Subjects with NSIVCD were associated with twofold to threefold increase in CV mortality depending on the definition. While right bundle branch block, left anterior fascicular block and incomplete bundle branch blocks were associated with seemingly higher mortality, this was no longer the case after adjustment for age and sex. The presence of R‐R’ pattern was not associated with any adverse outcome.ConclusionsIn a population study with long‐term follow‐up, NSIVCD and Minnesota definition of LBBB were independently associated with CV mortality. Other IVCDs had no significant impact on prognosis. The prognostic impact of LBBB and NSIVCD was affected by the definition of the conduction disorder.

Association of left bundle branch block definitions with response to cardiac resynchronisation therapy in patients with congestive heart failure

Aim To compare diagnostic significance of different criteria for complete left bundle branch block (cLBBB) in prediction of reverse left ventricular (LV) remodeling associated with cardiac resynchronization therapy (CRT).Materials and methods This study included 93 patients (men, 81.7 %; mean age at the time of implantation, 56.6±9.3 years). Achievement of a maximum decrease in LV end-systolic volume (ESV) was recorded during the entire follow-up period for evaluation of LV reversibility by CRT. Based on the dynamics of LV ESV, patients were divided into two groups, non-responders (n=27) and responders (n=66). cLBBB was determined by 9 criteria (ESC 2006 and 2013, AHA 2009, Strauss, and MIRACLE, CARE-HF, MADIT-CRT, REVERSE, and RAFT used in large multicenter studies).Results Incidence of cLBBB was significantly higher in the group of responders as demonstrated by the AHA (p=0.001), ESC 2013 (p=0.014), Strauss (p=0.002), MADIT-CRT (p=0.014), REVERSE (p=0.013), and RAFT (p&lt;0.001) criteria. The highest specificity was shown for the AHA and RAFT (92.6 %) criteria, and the highest sensitivity and overall accuracy were shown for the Strauss (80.3 % and 72.04 %, respectively) criterium. The criteria proposed in actual clinical guidelines (AHA and ESC 2013) demonstrated a strong consistency in detecting cLBBB (κ=0.818, 95 % CI, 0.7-0.936; p&lt;0.001). However, the Strauss and ESC 2006 / AHA / ESC 2013 showed the least consistency in identifying cLBBB. For the criteria described in large multicenter studies, consistency in detecting cLBBB was minimal in most cases. However, criteria with moderate or strong consistency were used in the studies, which results have substantiated the use of cLBBB as a selection criterium (MADIT-CRT, REVERSE, and RAFT).Conclusion The reversibility of LV remodeling associated with CRT was different in patients with cLBBB determined by different criteria. All actual cLBBB criteria (AHA, ESC 2013, and Strauss) were significantly more frequently observed in the responder group. Nevertheless, these criteria differed in their sensitivity and specificity. A number of large multicenter studies have used criteria with minimal consistency in detecting cLBBB, which should be taken into account in interpreting results of these studies.

P309Aortic valve implantation-induced bundle branch block as a framework towards a more uniform electrocardiographic definition of left bundle branch block

Abstract INTRODUCTION The electrocardiographic (ECG) pattern of true left bundle branch block (LBBB) has not been fully clarified and various definitions of LBBB exist. New-onset LBBB after transcatheter (TAVR) or surgical (SAVR) aortic valve replacement implies a proximal pathogenesis of LBBB and thus may provide a reference to characterize and define true LBBB. PURPOSE This study compares ECG characteristics in aortic valve implantation-induced LBBB (AVI-LBBB) to a non-procedural-induced LBBB control group (co-LBBB) in order to set a more homogenous definition for true LBBB. METHODS The study enrolled all patients with new-onset TAVR- and SAVR-induced LBBB between 2013 and 2019. AVI-LBBB was defined as new-onset persistent LBBB occurring within 24h after TAVR or SAVR. Patients were matched for age, sex, ischemic heart disease and left ventricular systolic function to randomly selected co-LBBB patients in a 1:2 ratio. For inclusion in both groups, a non-strict LBBB definition was used (QRSD ≥120ms, QS or rS in lead V1, absence of Q wave in leads V5-6). ECG characteristics were digitally analysed by the MUSE algorithm and confirmed by two experts. All ECG recordings were classified according to 4 different LBBB definitions: MADIT, European Society of Cardiology (ESC), Strauss and American Heart Association (AHA). RESULTS 59 patients with AVI-LBBB (34 TAVR, 25 SAVR, median age 82 years, 42% male) were compared to 118 matched co-LBBB patients. All patients with AVI-LBBB presented with QRS notching/slurring in the lateral leads, whereas this was present in only 85% of the co-LBBB group (p = 0.001). QRS duration (148ms vs 145ms, p = 0.074) and R wave peak time (58ms vs 62ms, p = 0.065) were not significantly different among both groups. AVI-LBBB was characterized by a more rightward QRS axis (-15° vs -30°, p = 0.013). When comparing AVI-LBBB to LBBB controls with QRS notching/slurring, a comparable QRS axis was observed. Almost all AVI-LBBB patients met the MADIT (98%), ESC (100%) and Strauss (95%) definition. Only 18% of patients met the AHA definition, because of the low combined presence of QRS notching/slurring in all 4 lateral leads (54%) and because only 27% of patients had an R wave peak time &amp;gt;60ms in both leads V5-6. In the co-LBBB group, adherence to the different definitions was significantly lower compared to the AVI-LBBB group: MADIT 86% (p = 0.007), ESC 85% (p = 0.001), Strauss 68% (p &amp;lt; 0.001) and AHA 7% (p = 0.035). Lower presence of lateral notching/slurring and more patients with smaller QRS duration (QRS duration ≥130ms, 86% vs 98%, p = 0.007) in the co-LBBB group explain these results. CONCLUSIONS Discordance exists between various definitions in scoring AVI-LBBB. Our data show that presence of QRS notching/slurring in the lateral leads is a crucial feature of proximal LBBB, rather than QRS duration and R wave peak time. The AVI-LBBB population provides a framework towards a more uniform definition and criteria for assessing true, proximal LBBB.

Evaluating Electrocardiography-Based Identification of Cardiac Resynchronization Therapy Responders Beyond Current LeftBundle Branch Block Definitions.

This study aimed to evaluate the association of 4 left bundle branch block (LBBB) definitions and their individual ECG characteristics with clinical outcome. Furthermore, it aimed to combine relevant outcome-associated electrocardiographic (ECG) characteristics into a novel outcome-based definition. LBBB morphology is associated with positive response to cardiac resynchronization therapy. However, there are multiple LBBB definitions. Associations with outcomes may differ between definitions and depend on varying contributions of the individual ECG characteristics that these LBBB definitions are composed of. A retrospective multicenter study was conducted in 1,492 cardiac resynchronization therapy patients. Patients were classified as LBBB or non-LBBB according to definitions provided by the European Society of Cardiology, American Heart Association, MADIT-CRT (Multicenter Automatic Defibrillator Implantation with Cardiac Resynchronization Therapy) trial, and according to Strauss et al., the primary endpoint was left ventricular assist device implantation, cardiac transplantation, and all-cause mortality. LBBB classification differed significantly between the 4 definitions (kappa coefficients ranging from 0.09 to 0.92). The American Heart Association definition correlated the least (0.09 to 0.12) with the other definitions. Only 13.8% of patients were classified as LBBB by all definitions. During a follow-up period of 3.4 ± 2.4 years, 472 (32%) patients experienced the primary endpoint. For each LBBB definition survival analysis showed a significant association of LBBB with outcome, with relative risk reduction ranging from 39% to 43%. Each LBBB definition included characteristics that were not associated with outcome. Combining outcome-associated ECG characteristics into a novel prediction model did not significantly improve diagnostic performance (relative risk reduction 43%). The classification of LBBB is highly dependent on the LBBB definition used. However, each LBBB definition provides a comparable difference in risk of adverse clinical events between LBBB and non-LBBB patients. Combining individual outcome-associated ECG-characteristics into a novel prediction model does not improve association with outcome.

A new electrocardiographic definition of left bundle branch block (LBBB) in patients after transcatheter aortic valve replacement (TAVR)

BackgroundCurrent LBBB definitions cannot always distinguish LBBB from left ventricular conduction delay. Only patients with LBBB are expected to normalize with His bundle pacing. Patients who develop new LBBB immediately post transcatheter aortic valve replacement (TAVR) provide an excellent model to define electrocardiogram (ECG) features of LBBB. We sought to describe their ECG features and develop a new ECG definition of LBBB. MethodsWe screened ECGs from 264 consecutive patients who underwent TAVR at the University of Ottawa Heart Institute. Patients with a baseline QRS of ≤100 ms who developed QRS ≥120 ms immediately after TAVR were included. Two electrocardiologists reviewed all ECG independently. Baseline demographics and echocardiographic data were retrospectively collected. Results36 patients were included in the analysis. The median age was 85.5 years (IQR, 81.8–89 years) and 52.8% were males. The minimum QRS duration was 126 ms. The median QRS axis was −18° (IQR, −40–4.5°), which is 18.5° leftward compared to the median QRS axis before TAVR. Fourteen patients (38.9%) had left axis deviation. All patients had a notched/slurred R wave in at least one lateral lead and an R wave duration of ≤20 ms in V1 when present. ConclusionWe developed a new ECG definition of LBBB that includes 2 novel findings: notching/slurring of the R wave in at least one lateral lead and an R wave ≤20 ms in V1. Further larger studies are warranted to confirm these findings.

P5429Mechanical dyssynchrony has a higher predictive value for CRT response than different ECG-based definitions of LBBB

Abstract Background/Aim To investigate the value of baseline assessment of mechanical dyssynchrony (Dyss) in predicting response to cardiac resynchronization therapy (CRT) in comparison to the classic ECG definition of left bundle branch block (LBBB) (Classic-def) as well as the recently proposed Sex- based definition (Sex-def.). Methods The baseline ECGs of 194 patients (31% females, 39% with ischemic cardiomyopathy, mean QRS width 159±25 ms and mean LVEF 29±8%) were investigated for identifying the criteria of LBBB before CRT implantation. Classic-def., defined as notched or slurred QRS complex in at least two of the leads I, aVL, V1, V2, V5 and V6 with a total width of at least 120 ms in addition to the absence of Q wave in lead I, V5 and V6 was identified in 74% of the study population. Sex-def. was identified in 69%, which is a QRS duration of at least 140 and 130 ms for men and women respectively with otherwise the same criteria of the Classic definition. Dyss was defined as the presence of either apical rocking and/or septal flash in 2D echocardiography prior to implantation. Volumetric response to CRT was defined as a reduction of at least 15% of the LV-end systolic volume (ESV) at follow up echocardiography (12±6 months after device implantation). Results Patient with baseline Dyss showed the highest response rates (76%) with a sensitivity of 88%, a specificity of 63% and an area under the curve (AUC) of 0.76 (P&lt;0.001) compared to 70% (sensitivity 82%, specificity 47%, AUC 0.65, P&lt;0.01) in patients with Sex-def. and 65% (sensitivity 84%, specificity 40%, AUC 0.62, P=0.01) in patients with Classic-def. (Figure A). Pairwise comparisons showed that the accuracy of the Sex-def. did not differ significantly from the Classic-def. in response prediction (AUC=0.65 vs. 0.62 for Sex-def. vs. Classic-def. respectively, P=0.27). Alternatively, Dyss showed a significantly higher accuracy in predicting response to therapy (AUC=0.76) as compared to Sex-def. and Classic-def. (P=0.02 and &lt;0.01 respectively, Figure B). Mech. dyssynchrony vs. ECG-based LBBB Conclusion The presence of Apical rocking and/or septal flash before CRT is associated with better response to CRT as compared to various ECG definitions of LBBB. Although a Sex-based definition of LBBB showed a trend of better response to CRT as compared to the Classic definition, it was not statistically significant.

True left bundle branch block and long-term mortality in cardiac resynchronisation therapy patients.

Left bundle branch block (LBBB) is an important qualification criterion and determinant of prognosis in cardiac resynchronisation therapy (CRT) patients. Our goal was to investigate the long-term mortality and morbidity in a sizable cohort of patients with CRT with regard to the new strict LBBB definition proposed by Perrin. We performed a longitudinal cohort study that included consecutive CRT patients. Primary endpoint (all-cause death) and secondary endpoint (all-cause death and hospitalisation for heart failure) were analysed. All preimplantation elec- trocardiograms were categorised as LBBB or non-LBBB according to the new definitions/criteria analysed. The survival analysis comprised 552 patients with CRT. The Perrin criteria, CRT guidelines class I indication criteria, and Strauss criteria were fulfilled in 38.9%, 79.4%, and 62.3% of all LBBB patients, respectively. During the nine-year study period, 232 patients died and the combined endpoint was met by 292 patients. The Perrin "true LBBB" definition criteria were inferior to the Strauss "complete" LBBB definition criteria in predicting survival as reflected by Kaplan-Meier survival curves (C-statistics). Multivariate Cox regression models showed that both LBBB definitions predicted mortality, however, the Perrin definition had a higher hazard ratio (HR 0.67) compared to the Strauss definition (HR 0.51). It seems that the Perrin "true LBBB" criteria are not well-suited for the selection of CRT candidates. Perhaps they do not reflect the presence of a true/complete LBBB or exclude too many patients who, despite some residual conduction in the left bundle branch, responded well to CRT.

Stricter criteria for left bundle branch block diagnosis do not improve response to CRT.

Cardiac resynchronization therapy (CRT) has proved to be effective in patients with heart failure and left bundle branch block (LBBB). Recently, new electrocardiography criteria have been proposed for the diagnosis of LBBB. These criteria are stricter than the current American Heart Association (AHA) criteria. We assessed the rate of echocardiographic response to CRT in patients with traditional LBBB versus patients who met the new criteria (strict LBBB). Consecutive patients undergoing CRT were enrolled in the CRT MORE registry. Patients with no-LBBB QRS morphology according to AHA criteria, atrial fibrillation, right bundle branch block, and right ventricular pacing were excluded. Strict LBBB was defined as: QRS ≥ 140ms for men and ≥130 ms for women, QS or rS in V1-V2, mid-QRS notching or slurring in ≥2 contiguous leads. Patients showing a relative decrease of ≥15% in left ventricular end-systolic volume (LVESV) at 12 months were defined as responders. Among 335 patients with LBBB, 131 (39%) had strict LBBB. Patients with and without strict LBBB showed comparable baseline characteristics, except for QRS duration (166 ± 20 ms vs 152 ± 25 ms, P < 0.001). On 12-month evaluation, 205 patients (61%) were responders; 85 of 131 (65%) had strict LBBB and 120 of 204 (59%) had traditional LBBB (P = 0.267). On multivariate analysis, a history of atrial fibrillation, larger LVESV, and the presence of mid-QRS notching in ≥1 lead (odds ratio 2.099; 95% confidence interval 1.061-4.152, P = 0.033) were independently associated with echocardiographic response. Stricter definition of LBBB did not improve response to CRT in comparison to the current AHA definition.

New or presumed new left bundle branch block in patients with suspected ST-elevation myocardial infarction.

Using a comprehensive large prospective regional ST-elevation myocardial infarction (STEMI) system database, we evaluated the prevalence, clinical and angiographic characteristics, and outcomes in patients with ischemic symptoms and new or presumed new left bundle branch block (LBBB). We then tested a new hierarchical diagnosis and triage algorithm to identify more accurately new LBBB patients with an acute culprit lesion. From March 2003 to June 2013, 3903 consecutive STEMI patients were treated using the Minneapolis Heart Institute regional STEMI protocol including 131 patients (3.3%) with new LBBB. These patients had fewer culprit arteries (54.2% vs. 86.4%; P<0.001), were older, more commonly women, with a lower ejection fraction, and more frequently presented with cardiac arrest or heart failure than those without new LBBB. At 1 year follow-up, all-cause mortality accounting for baseline differences was higher in patients with new LBBB (hazard ratio 1.73, 95% confidence interval 1.17-2.58; P=0.007). The new algorithm yielded high sensitivity (97%) and negative predictive value (94%) for identification of a culprit lesion. Using the definition of new LBBB with either hemodynamically unstable features or Sgarbossa concordance criteria on electrocardiogram (ECG), 45% of new LBBB patients would have been treated as 'STEMI equivalent'. Patients with acute ischemic symptoms and new LBBB represent a high-risk population with unique clinical challenges. If validated in an independent dataset, the new algorithm may improve the diagnostic accuracy regarding reperfusion therapy for new LBBB patients.

Vectorcardiographic QRS area as a novel predictor of response to cardiac resynchronization therapy

BackgroundQRS duration and left bundle branch block (LBBB) morphology are used to select patients for cardiac resynchronization therapy (CRT). We investigated whether the area of the QRS complex (QRSAREA) on the 3-dimensional vectorcardiogram (VCG) can improve patient selection. MethodsVCG (Frank orthogonal lead system) was recorded prior to CRT device implantation in 81 consecutive patients. VCG parameters, including QRSAREA, were assessed, and compared to QRS duration and morphology. Three LBBB definitions were used, differing in requirement of mid-QRS notching. Responders to CRT (CRT-R) were defined as patients with ≥15% reduction in left ventricular end systolic volume after 6months of CRT. ResultsFifty-seven patients (70%) were CRT-R. QRSAREA was larger in CRT-R than in CRT non-responders (140±42 vs 100±40 μVs, p<0.001) and predicted CRT response better than QRS duration (AUC 0.78 vs 0.62, p=0.030). With a 98μVs cutoff value, QRSAREA identified CRT-R with an odds ratio (OR) of 10.2 and a 95% confidence interval (CI) of 3.4 to 31.1. This OR was higher than that for QRS duration >156ms (OR=2.5; 95% CI 0.9 to 6.6), conventional LBBB classification (OR=5.5; 95% CI 0.9 to 32.4) or LBBB classification according to American guidelines (OR=4.5; 95% CI 1.6 to 12.6) or Strauss (OR=10.0; 95% CI 3.2 to 31.1). ConclusionQRSAREA is an objective electrophysiological predictor of CRT response that performs at least as good as the most refined definition of LBBB. Condensed abstractIn 81 candidates for cardiac resynchronization therapy (CRT) we measured the area of the QRS complex (QRSAREA) using 3-dimensional vectorcardiography. QRSAREA was larger in echocardiographic responders than in non-responders and predicted CRT response better than QRS duration and than simple LBBB criteria. QRSAREA is a promising electrophysiological predictor of CRT response.

Simpler Is Better

“It has long been an axiom of mine that the little things are infinitely the most important” — —Sherlock Holmes in “A Case of Identity” by Arthur Conan Doyle Cardiac resynchronization therapy (CRT) can have a profound therapeutic impact on appropriately selected patients. However, even when the current clinical guidelines for CRT1 are rigorously applied, the response rate is ≈70%. Nearly a third of patients who undergo implantation of a CRT device are clinical nonresponders and more may be “remodeling nonresponders.” An extensive body of literature reports on a wide variety of methods that can be better used to identify potential responders by measurement of mechanical dyssynchrony. Factors responsible for nonresponse include comorbid conditions, cardiac substrate, left ventricular (LV) lead location, and device programming. Comorbid conditions such as obstructive sleep apnea, right-sided heart failure, and type of intraventricular conduction delay should be considered at the preprocedural stage. Device programming may help minimize the number of nonresponders. Prediction of responders by invasive hemodynamic assessment is impractical for daily clinical practice. Cardiac magnetic resonance imaging is too expensive for routine use and is not an option for many patients who already have devices and need upgrades. The appeal of echocardiography for predicting responders by identifying mechanical dyssynchrony has been dampened by its limited reproducibility and poor predictive value.2 It is also impractical to perform echocardiography during implantations. The prolonged QRS duration (QRSd; electric dyssynchrony), as measured on a standard 12-lead ECG, remains the best method for identifying candidates for CRT. In an elegant and important study reported in this issue of Circulation , Sweeney and colleagues3 use the 12-lead ECG and show that, despite its apparent simplicity, analysis of the standard 12-lead ECG can yield both pitfalls and impressive rewards. Article see p 626 Current clinical guidelines specify a …