Upgrading right ventricular pacemakers to biventricular pacing or conduction system pacing: a systematic review and meta-analysis

Abstract

Guidelines recommend patients undergoing a first pacemaker implant who have even mild left ventricular (LV) impairment should receive biventricular or conduction system pacing (CSP). There is no corresponding recommendation for patients who already have a pacemaker. We conducted a meta-analysis of randomized controlled trials (RCTs) and observational studies assessing device upgrades. The primary outcome was the echocardiographic change in LV ejection fraction (LVEF). Six RCTs (randomizing 161 patients) and 47 observational studies (2644 patients) assessing the efficacy of upgrade to biventricular pacing were eligible for analysis. Eight observational studies recruiting 217 patients of CSP upgrade were also eligible. Fourteen additional studies contributed data on complications (25 412 patients). Randomized controlled trials of biventricular pacing upgrade showed LVEF improvement of +8.4% from 35.5% and observational studies: +8.4% from 25.7%. Observational studies of left bundle branch area pacing upgrade showed +11.1% improvement from 39.0% and observational studies of His bundle pacing upgrade showed +12.7% improvement from 36.0%. New York Heart Association class decreased by −0.4, −0.8, −1.0, and −1.2, respectively. Randomized controlled trials of biventricular upgrade found improvement in Minnesota Heart Failure Score (−6.9 points) and peak oxygen uptake (+1.1 mL/kg/min). This was also seen in observational studies of biventricular upgrades (−19.67 points and +2.63 mL/kg/min, respectively). In studies of the biventricular upgrade, complication rates averaged 2% for pneumothorax, 1.4% for tamponade, and 3.7% for infection over 24 months of mean follow-up. Lead-related complications occurred in 3.3% of biventricular upgrades and 1.8% of CSP upgrades. Randomized controlled trials show significant physiological and symptomatic benefits of upgrading pacemakers to biventricular pacing. Observational studies show similar effects between biventricular pacing upgrade and CSP upgrade.

Introduction

Nearly 1 000 000 people a year worldwide develop cardiac conduction system disease and require cardiac pacing therapy to prevent life-threatening or symptomatic bradycardia.¹ The standard approach has remained the same for 60 years, namely pacing from the right ventricle, as this is frequently technically straightforward.

In recent years, however, chronic right ventricular (RV) pacing has been recognized as harmful to left ventricular (LV) function with two distinct effects.² First, the altered ventricular activation pattern immediately produces dyssynchrony that impairs cardiac function. Secondly, there is chronic progressive damage to the myocardium through adverse ventricular modelling.^3–5

So clear and powerful are these effects that society guidelines recommend that if a patient requiring a new pacemaker has LV impairment, even if it is only mild, and there is expected to be a high proportion of ventricular pacing, the device should be a biventricular or conduction system pacing (CSP) device to provide physiological ventricular activation.^6,7

In contrast, patients who already have an RV pacemaker and are discovered to have LV impairment are not routinely recommended to have an upgrade to a biventricular or CSP device, until the impairment becomes severe [left ventricular ejection fraction (LVEF) < 35%]. Even the recommendation for the upgrade for those with severe LV impairment has been downgraded from Class I to Class IIA in 2021.^6,7

This meta-analysis assesses the data on upgrading from RV pacing to either biventricular pacing or CSP approaches. [Conduction system pacing includes both His bundle pacing (HBP) and left bundle branch area pacing (LBBAP).]

Methods

Search strategy

We performed a systematic search of the MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, OVID, and PubMed databases from inception to 17 July 2022 for all studies in humans. No language restrictions were applied; studies published in other languages were included if English abstracts were available with data relevant to extraction. The literature search strategy was designed by M.J.S.-S., D.K., and N.K. The study protocol was registered on PROSPERO on 21 April 2022 (registration number CRD42022315610).

The search included the search strings (‘pacemaker’ or ‘crt’ or ‘cardiac resynchronisation’ or ‘cardiac resynchronization’ ‘right ventricular’ or ‘biventricular’ or ‘coronary sinus’ or ‘His bundle’ or ‘left bundle’ AND ‘upgrade’). N.K. and V.H. additionally manually searched the bibliographies of relevant selected studies, reviews, and meta-analyses to identify further eligible studies.

Inclusion and exclusion criteria

We included all randomized trials^8–13 and observational reports^14–68 which prospectively or retrospectively measured clinical and/or echocardiographic outcomes before and after upgrading to a cardiac resynchronization therapy device (using the addition of either a lead placed in the coronary sinus, at the His bundle, or at the left bundle) from an RV pacemaker or implantable cardioverter defibrillator. Studies reporting procedural complications of upgrades were also eligible for inclusion.^69–80

We excluded studies that reported outcomes of LV endocardial pacing, leadless pacing, or multi-site pacing mixed with coronary sinus upgrades. Studies reporting outcomes for upgraded patients combined with outcomes for de novo cardiac resynchronization therapy (CRT) patients were also excluded. In studies reporting procedural complications, those reporting outcomes mixed with lead revision procedures were also excluded.⁸¹ Finally, studies in paediatric populations were also excluded.

The prespecified primary outcome was the echocardiographic assessment of LVEF. Left ventricular end-systolic volume (LVESV) was also assessed. Clinical outcomes reported included change in New York Heart Association (NYHA) functional class, serum brain natriuretic peptide (BNP/nt-pro-BNP), QRS duration, peak oxygen uptake (peak VO₂), and quality of life (QoL). Data from studies reporting complication rates following upgrade were also extracted (focusing on rates of device infection, pneumothorax, cardiac perforation, and lead-related complications). Relevant abstracts were reviewed for suitability, and full-text versions of studies were retrieved accordingly.

Two authors performed the search and literature screening (N.K. and V.H.) with any disputes resolved through discussion with a third author (D.K.). Two authors, N.K. and V.H. independently extracted all data, verified by a third author (M.J.S.-S.). If studies had overlapping first or senior authors, the published methods were evaluated to look for evidence of overlapping patient cohorts (dates, disease group, modality of CRT upgrade).

Endpoints

The primary efficacy outcome was a change in LVEF. The primary safety outcome was the complication rate.

Data abstraction and statistical analysis

N.K., D.K., and M.J.S.-S. formulated the analysis plan and N.K., V.H., and A.M. undertook the analysis.

We extracted outcome parameters including (where available) LVEF, LVESV, NYHA class, QoL, peak exercise oxygen capacity, and BNP, as well as rates of infection, pneumothorax, tamponade, and lead-related complications. For studies reporting at multiple follow-up times, the final report was used. Data are presented as mean difference (±SD).

Two authors (N.K. and V.H.) assessed the included studies for risk of bias using the Cochrane Collaboration’s risk of bias tool for quality assessment of randomized controlled studies (RCTs) and observational studies.^81,82

Results are reported in accordance with the PRISMA guideline (see Supplementary material online, Appendix S1).⁸³

Results

Eligible studies

The search strategy initially identified 1149 studies of which 129 studies were eligible for full-text review (Figure 1).

A total of 6 RCTs (randomizing 161 patients) and 47 observational studies (including 2644 patients) of biventricular pacing upgrades were eligible for analysis of efficacy outcomes. Eight observational studies of CSP upgrades (including 217 patients) were also eligible for analysis.

Fourteen studies additionally were eligible to provide data on safety. The total number of patients for safety analysis was 25 412.

Of the six RCTs, all were of upgrade to biventricular pacing, two included patients upgraded at the time of routine generator replacement whilst the remaining four studies enrolled patients at any time point. Of the RCT trials, five had a crossover design, between biventricular pacing and RV pacing modes after upgrade to a biventricular pacing device. One had a parallel-arm design, randomizing between generator replacement of the RV pacemaker and upgrade to biventricular pacing.

Observational studies of CSP upgrade included three studies of HBP upgrade and four studies of LBBAP upgrade. One study reported outcomes for both HBP and LBBAP upgrades separately.

The follow-up duration after the upgrade ranged from 2 to 69.6 months. Five out of six RCTs recruited patients with >80% RV pacing burden. In the observational studies of biventricular pacing upgrade, the ventricular pacing burden was not always reported; however, the overwhelming majority had a >40% pacing burden at the time of upgrade. In two biventricular upgrade observational studies, the RV pacing burden was low (<15%). The mean RV pacing burden in patients in CSP studies was 85%. Each study’s inclusion criteria and patient characteristics of included studies are summarized in Supplementary material online, Appendix S2.

A risk of bias table is presented in Supplementary material online, Appendix S3.

Overall findings of the effect of upgrade are summarized in Figure 2.

Effect of upgrade on left ventricular function

Left ventricular ejection fraction was reported in 5 RCTs of biventricular pacing upgrades, including 151 patients (Figure 3). In these studies, the baseline EF was 35.5 ± 10.2%. Ejection fraction was significantly higher with biventricular pacing when compared with RV pacing [+8.4%, 95% confidence interval (CI) 5.6–11.1, P = 0.001, I² = 65%].

The 46 observational studies of biventricular pacing upgrades reporting EF included 2580 patients. In these studies, the baseline EF was 25.7 ± 8.1%. Ejection fraction was similarly significantly higher with the biventricular pacing upgrade when compared with RV pacing (+8.4%, 95% CI 7.0–9.6, P < 0.001, I² = 84%).

The 8 observational studies of CSP upgrades included 217 patients. The baseline EF was 38.4% ± 8.8, this was higher than in the biventricular RCTs (P = 0.004) and biventricular observational studies (P < 0.0001). (His bundle pacing studies had a mean baseline EF of 36% and LBBAP studies had a mean baseline of 39%.)

Ejection fraction was significantly higher with HBP upgrade in 136 patients (+12.74%, 95% CI 9.72–15.76, P < 0.0001, I² = 38%) and also with LBBAP upgrade in 81 patients (+11.12%, 95% CI 6.16–16.09, P = 0.0004, I² = 78.5%) when compared with RV pacing.

Overall, EF was significantly higher with CSP upgrade when compared with RV pacing (+11.59, 95% CI 8.30–14.88, P < 0.001, I² = 75%).

A larger effect size was noted in the studies where follow-up assessment was performed more than 12 months after the upgrade. The effect of endpoint assessment timing on EF stratified by <12 or ≥12 months is shown in Supplementary material online, Appendices.

Effect of upgrade on left ventricular end-systolic volume

Left ventricular end-systolic volume was reported in 3 of the RCTs of biventricular pacing, which included 96 patients. Left ventricular end-systolic volume was significantly decreased with the biventricular pacing upgrade (−25.7 mL, 95% CI −37.4 to −14.0, P < 0.001, I² = 0%) from a mean weighted baseline of 98 mL during RV pacing.

Left ventricular end-systolic volume was reported in 15 observational studies of biventricular pacing upgrades including 861 patients. Left ventricular end-systolic volume was significantly decreased with biventricular pacing upgrade (−23.7 mL, 95% CI −30.5 to −16.9, P < 0.001, I² = 74%) from a mean weighted baseline of 148 mL with RV pacing.

Left ventricular end-systolic volume was reported in 3 observational studies of CSP including 118 patients. One study of HBP upgrade in 74 patients showed LVESV decreased by −31.5 mL (95% CI −57.7 to −5.4) from a baseline of 97 mL with RV pacing. Two studies of LBBAP upgrade in 36 patients showed LVESV decreased by −43.66 mL (95% CI −62.18 to −25.14) from a mean weighted baseline of 146 mL with RV pacing. Overall, LVESV decreased significantly with CSP upgrade (−32.39 mL, 95% CI −54.01 to −10.78, P = 0.003, I² = 7%), from a mean weighted baseline of 110 mL during RV pacing (see Supplementary material online, Appendix S4).

Effect of upgrade on New York Heart Association class

New York Heart Association class was reported in 3 RCTs of biventricular pacing upgrades including 106 patients. New York Heart Association class improved significantly with biventricular pacing upgrade when compared with RV pacing (−0.4, 95% CI −0.62 to −0.18, P = 0.0003, I² = 41%).

New York Heart Association was reported in 24 observational studies of biventricular pacing upgrades including 1226 patients. New York Heart Association class also improved significantly with biventricular pacing upgrade when compared with RV pacing (−0.8, 95% CI −0.90 to −0.66, P < 0.001, I² = 90%).

New York Heart Association was reported in 6 studies of CSP upgrades including 128 patients. In 3 studies of HBP upgrade including 57 patients, NYHA improved significantly (−1.2, 95% CI −1.8 to −0.6, P = 0.0002, I² = 85%) when compared with RV pacing. In 4 studies of LBBAP upgrade including 71 patients, NYHA class also improved significantly (−0.98, 95% CI −1.36 to −0.60, P < 0.0001, I² = 70%) when compared with RV pacing. Overall, NYHA class improved significantly with CSP upgrade when compared with RV pacing (−1.06, 95% CI −1.38 to −0.74, P < 0.001, I² = 76%) (Figure 4).

Effect of upgrade on QRS duration

Change in QRS duration was reported in 4 of the RCTs of biventricular pacing, which included 128 patients. QRS duration significantly decreased with biventricular pacing upgrade (−40.72 ms, 95% CI −48.7 to −32.7, P < 0.001, I² = 32%) from a mean baseline of 193.5 ms with RV pacing.

Change in QRS duration was reported in 14 observational studies of biventricular pacing upgrades including 2943 patients. QRS duration significantly decreased with biventricular pacing upgrade (−32.3 ms, 95% CI −40.3 to −24.4, P < 0.001, I² = 9%) from a mean baseline of 180.2 ms with RV pacing.

Change in QRS duration was reported in 6 observational studies of CSP including 165 patients. Four studies of HBP upgrade in 114 patients showed QRS duration decreased by −53.6 ms (95% CI −66.4 to −40.9, P < 0.001, I² = 82%) from a mean baseline of 173.8 ms with RV pacing. Three studies of LBBAP upgrade in 51 patients showed QRS duration decreased by −56.6 ms (95% CI −62.9 to −50.3, P < 0.001, I² = 0%) from a mean baseline of 175.8 ms with RV pacing. Overall, QRS duration decreased significantly with CSP upgrade (−55.5 ms, 95% CI −62.4 to −47.9, P < 0.001, I² = 68%) (see Supplementary material online, Appendix S8).

Effect of upgrade on quality of life

Quality of life was reported in 3 RCTs of biventricular pacing including 104 patients. Quality of life as measured by the MLWHF tool showed a significant improvement with biventricular pacing upgrade when compared with RV pacing (−6.89, 95% CI −13.02 to −0.75, P = 0.027, I² = 11.8%).

Quality of life was reported in 6 observational control studies of biventricular pacing upgrade including 261 patients. Quality of life as measured by the MLWHF tool showed a significant improvement following the biventricular pacing upgrade when compared with RV pacing (−20.96, 95% CI −29.48 to −12.43, P < 0.001, I² = 87%).

Quality of life was reported in one observational study of LBBAP upgrade including 10 patients. Quality of life as measured by the MLWHF tool showed a significant improvement following LBBAP upgrade when compared with RV pacing (−11.7, 95% CI −19.1 to 4.3, P = 0.002, I² = 0.0%) (see Supplementary material online, Appendix S5). There were no studies of HBP upgrade reporting an effect on QoL.

Effect of upgrade on VO₂ max

VO₂ max was reported in 3 RCTs of biventricular pacing upgrade including 94 patients. The peak exercise oxygen capacity as measured by VO₂ was significantly improved by biventricular pacing upgrade when compared with RV pacing (+1.1 mL/kg/min, 95% CI 0.0–2.19, P = 0.049, I² = 0.0%).

VO₂ max was reported in 3 observational studies of biventricular pacing upgrade including 76 patients. Peak exercise oxygen capacity as measured by VO₂, also showed a significant improvement following biventricular pacing upgrade when compared with RV pacing (+2.63 mL/kg/min, 95% CI 0.45–4.81, P = 0.018, I² = 95%).

There were no studies of CSP upgrade that reported an effect on VO₂ max (see Supplementary material online, Appendix S6).

Effect of upgrade on brain natriuretic peptide

Brain natriuretic peptide was reported in 4 RCTs of biventricular pacing upgrades including 85 patients. They revealed a trend towards improved BNP levels (−177 pg/L, 95% CI −413 to +59, P = 0.239, I² = 1.4%).

Brain natriuretic peptide was reported in 4 observational studies of upgrade to biventricular pacing including 92 patients. They reported a significant change in BNP (−271 pg/L, 95% CI −313 to −230, P < 0.001, I² = 0.0%).

Brain natriuretic peptide was reported in 3 observational studies of CSP including 33 patients. One study of HBP upgrade in 16 patients showed improved BNP levels (−420 pg/L, 95% CI −776 to −65). Two studies of LBBAP upgrade in 37 patients showed improved BNP levels (−1727 pg/L, 95% CI −1727 to 772, P = 0.45, I² = 71%). Overall, the three studies of CSP upgrade reported a trend towards improved BNP levels (−293, 95% CI −768 to 180, P = 0.2, I² = 78.5%) (see Supplementary material online, Appendix S7).

Complication rates associated with device upgrade

Amongst the randomized and observational studies of biventricular pacing upgrade, infection rates averaged 3.7% over a follow-up averaging 24 months. Pneumothorax rates averaged 2.0%. Cardiac perforation or tamponade occurred in ∼1.4% of patients and lead-related complications (micro- or macro-dislodgement, phrenic nerve stimulation, and lead revision) occurred in 3.3% of patients. In studies of CSP upgrade, lead-related complications occurred in 1.8% of patients (see Supplementary material online, Appendix S10).

Discussion

This meta-analysis found that RCTs of biventricular upgrade showed improvements in LVEF, LVESV, BNP, QRS duration, QoL, and cardiopulmonary exercise capacity. The corresponding observational studies of upgrade to biventricular pacing also report better outcomes in the patients who underwent upgrade.

There are no RCTs of upgrade to a CSP strategy. However, the observational studies of this question suggest similar significant improvements in LVEF, LVESV, QRS duration, and NYHA class.^61–68

Our primary endpoint, change in LVEF, showed almost identical effects between the biventricular upgrade RCTs (+8% LVEF units), the observational studies of biventricular upgrade (+8%), and CSP upgrade (+11%). Whilst the physiological promise of device upgrade is shown in this meta-analysis, it is important to acknowledge the paucity of data on its effect on heart failure hospitalizations and mortality.

Appropriate guidance for right ventricular paced patients with impaired left ventricular function

These findings suggest that patients with impaired LV function benefit from upgrade from RV pacing to biventricular or CSP. Randomized controlled trial evidence is only available for biventricular pacing. However, the similarity of the effect size reported between the observational and randomized studies of biventricular pacing may be an indication that the randomized effect size of CSP may be similar to the favourable effect size seen in observational studies.

Guideline writers may have had two reasons to hold back from recommending more routine upgrade. First, observational reports suggest that long-term outcomes are worse in patients having upgrades than de novo pacing strategies (biventricular pacing or CSP).^69,71,74,84 However, this is an inappropriate comparison, since no patient has the choice between de novo and upgrade: the choice is between upgrade and no upgrade. Patients reaching the decision point for an upgrade are almost certainly inherently at higher long-term risk than patients undergoing de novo implants as they are generally older, frequently have had heart disease for several years longer, and have likely accumulated more comorbidities in the interim.⁸⁵

Secondly, of the six RCTs that do exist, five are crossover.^8–11,13 This enabled them to make a precise assessment of the difference of pacing strategy on physiological markers, but unfortunately prevent these trials from directly measuring the trade-off between excess procedural risk and potential long-term benefit (since all the patients had the upgrade procedure).

To date, there is only one completed parallel-group RCT focusing on the correct comparison.¹² However, its small size of only 50 patients may have led to its positive results being overshadowed by the less relevant but much more numerous data points from de novo vs. upgrade comparisons.

Is the physiological benefit worth the procedural risk?

The reported procedural complication rates appear low (mostly infection, ∼4%), but are higher than those receiving de novo implants. While the risk of procedural complications may be spread evenly across all patients, the net risk against the net benefit may be affected by the patients’ baseline state, for example, mild vs. severe LV impairment or low vs. high pacing burden. Whether a small additional procedural risk is offset by the physiological and symptomatic improvement that an upgrade can deliver needs to be assessed in a formal manner. The existing data sets do not adequately address this question as there is no adequately powered non-crossover RCT. Furthermore, many studies included in this meta-analysis of complication risk were conducted prior to clear antimicrobial recommendations and the availability of antibiotic pouches which may further lessen infection risk without reducing the benefit. For example, the more recent Centurion and Citadel registries included significant numbers of patients undergoing device upgrades with antibiotic envelopes and report remarkable infection rates of <1%.⁸⁶

The rationale for recommending biventricular or CSP strategies for de novo implants is that, even though at the time of implant, it is not known whether that patient would suffer LV impairment from conventional pacing, there is sufficient likelihood of this to make biventricular or CSP worthwhile. This was seen even in patients with just mild LV impairment in the BLOCK HF study.⁵ We suggest that amongst patients who have already demonstrated impairment from conventional pacing, one should expect an even bigger benefit from switching to biventricular or CSP strategies.

In fact, several series have shown a higher tendency to super response in upgrades compared with de novo implantation. Moreover, pacing-induced LV dysfunction is likely to be related to dysynchrony, while de novo CRT candidates form a mixed population of various conduction system diseases with variable responses to CRT.

Study limitations

This meta-analysis examined physiological and symptomatic endpoints because all but one RCT was crossover (i.e. no survival data), and the 1 parallel-group RCT only had 50 patients in total (2.2 years follow-up during which there were 17 events, 6 in the upgrade arm and 11 in the RV pacing arm). The question of mortality impact is important but cannot be answered with the existing RCT data. Observational data are not reliable for judging treatment effects. The best assessment we can make of probable mortality impact is from the consistent favourable changes reported in the RCTs for symptoms, LVESV, and cardiopulmonary exercise capacity, each of which have previously been found to predict better outcomes.^5,87

The individual studies measuring the efficacy had a follow-up of range of 2–70 months which may not be long enough to manifest the full extent of the treatment effect. Nevertheless, the effect size at this time was statistically significant for the benefit of upgrade.

The RCTs had heterogenous entrance criteria and protocols. While this can be seen as a weakness, it also increases the generalizability of the results. The observational studies had an even wider range of characteristics, which is common in observational data sets.

The timing of echocardiographic endpoint assessment across all included studies varied widely. With prolonged time, reverse remodelling may result in even greater observed responses. The studies that report LV function after 12-month follow-up had a greater observed increase in LV function than those studies reporting at earlier time points. However, it is likely that even the smaller but earlier observed effects are clinically relevant.

In only 1 out of 6 RCTs and 4 out of 47 observational studies, was it specified that a blinded core lab was used for the assessment of EF. Blinding is important in reducing bias.⁸⁸ Core lab assessment can reduce the variability of the measure and improve the precision of the estimate of the effect size. Future studies should use a blinded core lab for echocardiographic endpoints.

There is heterogeneity in the clinical scenarios under which upgrade was performed. This is associated with statistical heterogeneity in the size of the effect (e.g. LVEF BiV RCT I² 84%). However, both the majority of the observational and RCT studies are positive, and the studies themselves are significant. Therefore, whilst there may be uncertainty in the exact magnitude of the effect size, we can be confident that the effect is positive.

Included studies varied in the timing of when patients received device upgrade. Patients who undergo early device upgrade due to clinical deterioration with accompanying symptoms, LV impairment, and a high pacing burden might be protected from further clinically important deterioration. Conversely, deferring upgrade procedures to the time of elective generator replacement may offset some of the additional procedural risks but with a similar expected effect size. Future studies should be designed to stratify patients by these two indications.

This meta-analysis provides limited data on a threshold of RV pacing at which upgrade may be beneficial. Most studies only included patients with high pacing burdens and just two observational studies report data from patients with <20% pacing burden. In these studies of patients with low pacing percentages whilst clear improvements were reported, there are confounding factors at play. The effect in one¹⁷ is confounded by subsequent uptitration of prognostic heart failure therapy such as beta-blockers, and in the other,⁵⁹ the patients’ intrinsic non-paced QRS duration fulfilling conventional CRT implant criteria. It is possible that one might extrapolate upgrade pacing percentage criteria from de novo implant guidelines (ESC >20%, ACC/AHA >40%), but it should be acknowledged there is limited evidence for this.

Need for randomized controlled trial data

What is needed now is sizeable randomized controlled data designed to assess the clinically relevant question, namely the decision to upgrade or not in a patient with existing RV pacing and LV impairment. Those with severe LV impairment may show the greatest relative risk reduction, but there are two reasons why patients with less severe LV impairment may also be an important target. First, even if the relative risk reduction is slightly smaller, because the absolute risk is much lower, the extension in the life span provided could easily be larger. Secondly, patients with less severe LV impairment are far more frequent, which, therefore, makes intervention on that group have a larger effect on the population on a whole.

In principle, future trials could address two classes of questions: (i) patient symptoms and (ii) event outcomes. A trial design addressing patient symptoms can be much more cost-effective because each patient can report multiple data points, and effects might manifest early. However, an event endpoint trial would likely be needed before upgrading features more strongly in guidelines.

A future trial design might utilize an adaptive Bayesian approach, with an early assessment based on symptoms which manifest more quickly and if positive, would allow the trial to continue to heart failure hospitalization and mortality endpoints. Patients would be included with both evidence of early clinical deterioration and at elective generator replacement with a reduction in EF (results would be stratified between these two groups). Patients would be included with any significant reduction (>5–10%) in EF from baseline.

Until such trials are conducted, guidelines may continue to recommend waiting until LV impairment is severe before upgrading.

Appropriately designed future studies may also enable clinicians to decide the optimal timing for the system upgrade, for example, whether these procedures should be performed prior to progression to severe LV function. Future decision criterion may include not only a particular threshold of LVEF but also change in symptoms or change in LVEF.

While the results of the Budapest-CRT Upgrade trial (NCT02270840) are eagerly awaited, these will not resolve many of the questions that remain. In this trial, almost all patients will receive an upgrade procedure, either from a pacemaker to an ICD or from a pacemaker or an ICD to a biventricular defibrillator (CRT-D). Only very few patients (those with an existing ICD, randomized to the ICD arm) did not receive an upgrade procedure and therefore in post hoc analysis, this small group could potentially be utilized as a control group to consider the direct result of the net benefit of the upgrade procedure (namely physiological benefit minus upgrade complications).⁸⁸ Furthermore, this study focused only on patients with high RV pacing burden, severe LV dysfunction (baseline LVEF 25 ± 7), and frequent heart failure hospitalizations. The Budapest-CRT trial does not therefore address the clinical question of how to manage patients with a high pacing burden within a broader range of LV dysfunction nor delineate whether upgrading from RV pacing at an earlier stage in the disease trajectory of cardiomyopathy may be indicated.

Conclusions

Upgrading a patient with LV impairment to biventricular pacing or CSP improves multiple physiological and symptom endpoints. The RCTs show this clearly for biventricular pacing, but there have been no RCTs for CSP. Observational studies (available for both biventricular and CSP) suggest similar-sized effects to those seen in RCTs of biventricular pacing. Complication rates are around 4% for infection and 2% for pneumothorax for upgrade procedures. Whether the physiological benefits of upgrade in patients with LV impairment of any degree outweighs this risk should now be assessed in an appropriately designed RCT.

Supplementary material

Supplementary material is available at Europace online.

Funding

No funding sources contributed to this work.

References

Author notes