Maximizing QRS duration reduction in contemporary cardiac resynchronization therapy is feasible and shorter QRS duration is associated with better clinical outcome

Introduction: Cardiac resynchronization therapy (CRT) is an established treatment for heart failure in selected patients [1]. The primary aim of CRT is to resynchronize a dyssynchronous contraction of the left ventricle. Dyssynchrony may be caused by left bundle branch block or other conduction disturbances, and current guidelines emphasize the importance of prolonged QRS duration (QRSd) in the selection criteria for suitable candidates, where a class I indication is given only to patients with LBBB and QRS duration ≥ 150 ms, and patients with non-LBBB have a stronger recommendation if the QRSd is ≥ 150 ms (IIa) compared to < 150ms (IIb) [2]. Similarly, the magnitude of reduction of QRS duration has in several studies been associated with better clinical outcome and higher probability of echocardiographic reverse remodeling [3]. However, there are still a significant number of patients in this group who do not improve after CRT.

It is well-known that individual programming of the device’s timing of atrioventricular (AV) and ventriculo-ventricular (VV) delay can be important in order to maximize the benefit of CRT [4]. The introduction of quadripolar electrodes and device-based algorithms for optimization of AV and VV delays and delivery of LV-only pacing and fusion pacing have greatly increased the programming options in each individual CRT-treated patient. All major vendors of CRT devices now have built-in optimization algorithms in their devices, and most of these algorithms have shown non-inferiority to echocardiography-optimized device settings regarding short-term outcome. Head-to-head comparisons between different vendors’ algorithms have not been performed, and it is not clear which is the best strategy for optimizing device settings. It would be appealing to apply a uniform (validated) optimization strategy to all patients, regardless of device brand. Retrospective studies have consistently indicated that a larger reduction in QRS duration is associated with better outcome, as well as improved reverse remodeling [3]. A recent study has also shown that by combining the built-in algorithm (in this case the Sync AV algorithm) with individually tailored AV delay, it was possible to obtain a greater mean reduction in QRSd, compared to using the algorithm alone [5].

We aimed to evaluate if it is feasible to obtain additional QRS reduction, on top of the built-in algorithms in the device, by adjusting AV and VV delays in a structured way, in an all-comer CRT population. We also aimed to assess whether larger QRS reduction was associated with better clinical outcome.

We aimed to develop and implement a pragmatic vendor-independent strategy for CRT optimization in a tertiary care referral center, and to evaluate if the successful implementation of this optimization scheme resulted in better clinical outcome.

The study was performed in a tertiary care center. Medical records of 254 consecutive patients with left bundle branch block (LBBB) according to the 2018 ACC/AHA/HRS criteria and a class I indication for CRT, during the period 2015-2020, were retrospectively evaluated [6]. The right atrial lead was typically placed in the right appendage, the right ventricular lead in the apex or septum (operator’s preference). The coronary sinus lead was placed in a lateral, posterolateral or posterior position if possible, and anterior position only as a last resort. Left ventricular lead position was retrospectively evaluated in the left anterior oblique and right anterior oblique views by an experienced electrophysiologist (RB), using the 17-segment model, and positions were split into lateral (anterolateral or inferolateral), anterior, inferior, or apical position [7].

Implants performed during the first 3 years (2015-2017) were designated as the control group, and in these patients, the suggested settings from the device-based algorithms were used, if applicable. This included primarily the aCRT algorithm from Medtronic and the QuickOpt algorithm from Abbott [8, 9]. For patients where the algorithms could not be used, typical programming in the control group included a fixed AV time at least 20 ms shorter than the intrinsic conduction time to ensure biventricular capture and simultaneous pacing of the right and left ventricle, or (in the case of permanent atrial fibrillation) synchronous biventricular pacing without trigger mode. Starting in 2018, an active 12-lead electrocardiogram (ECG)-based optimization of QRS duration reduction post-implant was implemented, and these patients were designated as the intervention group. There was a gradual implementation, and the strategy was fully implemented in 2020 and onwards, where all patients routinely went through the optimization process. The method is summarized in Fig. 1. Starting in the year 2018, postoperative QRS duration and morphology were evaluated in a structured stepwise way at various device settings, including the use of specific device algorithms when applicable (AdaptiveCRT, SyncAV, SmartDelay) with manual modifications of AV and VV delays and LV-only pacing when applicable, aiming to maximize the reduction of the QRS duration. A pacing electrode was chosen based on the longest Q-LV or longest RV-LV conduction time (if no intrinsic AV conduction). If the best vector had a threshold at or above the limit of 3.0 V/1.0 ms, then the second-best vector was chosen. If two vectors were similar, the one with the lowest threshold and/or highest impedance was chosen. Vectors with diaphragmatic stimulation were not considered suitable and hence excluded. The suggestion from the device-based algorithm was then tested and evaluated using 12-lead ECG with different AV intervals (as suggested by Varma et al. [5]). If LV-only or fusion pacing was the suggested setting, then a standard BiV setting was also tested. For the BiV setting, a fixed AV delay at least 20 ms shorter than intrinsic conduction was chosen, typically 140/170 ms, or shorter if needed. Finally, LV pre-activation was evaluated with – 20 ms and – 40 ms respectively. The setting with the overall narrowest QRS complex was then chosen. If two settings were similar in QRS duration, a morphology with visible LV pre-activation (i.e., early positive deflection in lead V1 and/or lead I) was favored. Optimization was performed immediately post-operatively or the day after. If the chosen settings resulted in subjective improvement and no objective signs of worsened heart failure, the settings were kept the same at follow-up visits. Follow-up interval was typically at 2 months, then at 6 months (for non-responders) and then every 12 months, plus continuous remote monitoring. Digital ECGs before and after CRT implantation were collected and QRS duration reduction was automatically analyzed, with manual inspection and validation of correct position of the automatic timing calipers.

The primary endpoint was a composite of hospitalization due to heart failure or death from any cause.

A total of 254 patients were included and were followed for up to 6 years (median 2.9 [1.8–4.1] years). The time spent on postoperative optimization was not uniformly recorded, but typically varied between 15 and 45 min.

During follow-up, 82 patients (32%) reached the primary endpoint; in total, there were 53 deaths (21%) and 58 (23%) heart failure hospitalizations. Baseline demographic data is presented in Table 1. Median QRS duration pre-implant during the entire time period was 162 ms [150–174] and post-implant 146 ms [132–160]. Progressively, more patients underwent structural QRSd reduction evaluation for each year, and correspondingly, the mean reduction in QRS duration was progressively larger for each year during the intervention period, changing from − 9.5ms in the control group to − 24 in the year 2020 (p = 0.005) (Fig. 2). The use of LV-only pacing algorithms, AV and VV times are reported in Table 1. LV-only pacing was used more often during the intervention period, compared to the control period, but the reduction in QRS duration was not significantly different between those with LV-only pacing and patients with biventricular pacing from both RV and LV electrodes. Overall, at the group level, the sensed and paced AV times did not differ significantly between the control and intervention period, but LV pre-activation was shorter in the intervention period.

During the intervention period, fewer patients had their LV leads placed in an anterior position. Cox regression analysis was used to determine the hazard ratio for QRS duration reduction with regards to the combined primary endpoint; HR 0.89 [CI 0.80–0.99] per 10-ms QRS reduction, p = 0.037. If QRS duration reduction was dichotomized using the median value (− 14 ms), the corresponding HR for QRS reduction ≥ 14 ms was 0.57 [0.33–0.98] p = 0.038, compared to QRS reduction < 14 ms (Table 2). In a multivariate Cox regression model, variables with p < 0.05 were entered. The final model was thus adjusted for age, gender, NYHA class, ischemic etiology, CRT-P/CRT-D, left ventricular ejection fraction (LVEF), and diabetes, and the adjusted hazard ratio for larger QRS reduction was 0.54 [0.29–0.98] (p = 0.04).

In Kaplan Meier analysis a QRS reduction > 14 ms was associated with a lower risk of death or heart failure hospitalization (see Fig. 3, p = 0.049). When comparing the cohort from 2020 (with the full effect of the optimization procedure, − 24.5ms QRSd reduction on average) with the control cohort, the patients from 2020 had a significantly better survival free of heart failure hospitalization (see Fig. 4, p = 0.01).

We show that it is feasible to obtain a larger QRSd reduction in an all-comer CRT-treated population, by using an individualized optimization strategy on top of, or instead of, the device-based optimization algorithms. Despite similar baseline demography and baseline QRSd, the use of a structured optimization resulted in narrower paced QRS complex, and this was in turn associated with a lower risk of heart failure hospitalization and all-cause mortality. Overall, there were only minor differences in the programmed delays between the intervention and control periods, suggesting that there is no general rule to shorten or prolong the intervals in order to achieve larger QRS reduction, but rather that individualization of the AV and VV intervals is key. There was a trend for longer AV delays in the intervention period, which may have allowed for more fusion with intrinsic conduction in the right bundle branch, thereby narrowing the QRS complex and providing better ventricular synchrony.

Implementing an ECG-based general strategy of CRT device optimization by aiming for shorter QRS duration is feasible in a structured clinical setting, and results in larger reductions in QRS duration post-implant. In patients with larger QRS reduction, compared to those with smaller QRS reduction, there is an association with a lower risk of mortality and heart failure hospitalization. If confirmed in prospective trials, this strategy may become useful for improving clinical outcome for CRT recipients, regardless of device brand and underlying etiology of heart failure.