3 Clinical evidence

3 Clinical evidence

Summary of clinical evidence

3.1 The key clinical outcomes for ENDURALIFE‑powered cardiac resynchronisation therapy-defibrillator (CRT‑D) devices in the decision problem were:

  • device survival

  • battery survival (or time to battery depletion)

  • CRT‑D component failure

  • number of invasive procedures including CRT‑D replacements

  • incidence of complications after replacement procedures for battery depletion or CRT‑D component failure (as per definitions in the REPLACE registry)

  • inpatient admissions and bed days (related to interventions)

  • death

  • patient satisfaction

  • quality of life

  • device-related adverse events.

3.2 The company did 2 searches for published literature on studies of device lifespan, the incidence of complications associated with device replacement, and outcomes relating to patient quality of life or satisfaction associated with device replacement. Its submission included: 6 case series studies of CRT‑D lifespan reported in 7 sources; 5 product performance reviews (see section 3.9); and 20 studies (17 observational studies and 3 systematic reviews) that highlight the complications associated with implantable cardioverter defibrillators or CRT‑D replacement, as well as patient preference for device size or lifespan. The external assessment centre (EAC) excluded 14 of the 17 observational studies because data from these studies were also used in the submitted systematic reviews. It judged that 1 further study on complications (Kirkfeldt et al. 2014), identified by clinical experts, was relevant. In total, the EAC assessed 6 observational studies on ENDURALIFE‑powered CRT‑D battery life (Alam et al. 2016, Ellis et al. 2016, Landolina et al. 2015, Von Gunten et al. 2015, Lau et al. 2015 and Williams and Stevenson 2014), 5 product performance reviews (Boston Scientific, Biotronik, Medtronic, Sorin and St Jude Medical) and 6 studies on adverse events arising from cardiac device replacement (Lewis et al. 2016, Polyzos et al. 2015, Zeitler et al. 2015, Nichols et al. 2016, Lovelock et al. 2014 and Kirkfeldt et al. 2014).

Battery life

3.3 Alam et al. (2016) and Alam et al. (2014) are retrospective observational studies, both reporting on the same cohort, evaluating the time from device implantation to battery depletion. The most recent publication included 621 patients, of which 122 had ENDURALIFE‑powered CRT‑Ds, 51 had a non‑ENDURALIFE-powered Boston Scientific device and 448 had a device from another company (Medtronic n=391, St Jude Medical n=57). The devices were implanted between January 2008 and December 2010, with a maximum possible follow-up of 8 years and mean follow-up was 3.4 years. Rates of CRT‑D replacement because of battery depletion were 16% (Boston Scientific) compared with 51% to 53% for devices from other companies. When comparing time to battery depletion, Boston Scientific devices lasted longer than either Medtronic (hazard ratio [HR] 0.15, 95% confidence interval [CI] 0.10 to 0.22, p<0.001) or St Jude Medical devices (HR 0.28, 95% CI 0.16 to 0.48, p<0.001). The hazard ratios for battery depletion (adjusted for unbalanced electrical pacing parameters) were:

  • Boston Scientific compared with Medtronic: 0.11 (95% CI 0.07 to 0.16, p<0.001)

  • Boston Scientific compared with St Jude Medical: 0.25 (95% CI 0.13 to 0.47, p<0.001).

    Of the 67 patients still alive 6 years after implantation, battery survival rates were 77% (Boston Scientific), 44% (St Jude Medical) and 10% (Medtronic).

3.4 Ellis et al. (2016) is a retrospective observational study designed to assess how the battery capacity of a CRT‑D affects the time until the elective replacement indicator (ERI) is reached. A total of 1,302 CRT‑Ds (Boston Scientific n=322 (97.0% ENDURALIFE‑powered CRT‑Ds), Medtronic n=794 and St Jude Medical n=186) were implanted between August 2008 and December 2010. Over a mean follow-up of 3 years, the proportions of devices reaching ERI were: 0.3% (Boston Scientific, battery capacity=2.0 Ah), 13.5% (Medtronic, 1.0 Ah) and 3.8% (St Jude Medical, 1.4 Ah). The odds ratio (OR) for reaching ERI with a Medtronic device (1.0 Ah) compared with a St Jude Medical (1.4 Ah) or Boston Scientific (2.0 Ah) device was 9.73 (p<0.0001). Univariate predictors for ERI included 1.0 Ah device and an LV pacing output of over 3 V at 1 ms (OR: 3.74, p<0.001). Mortality rates with each device were 28.0% (Boston Scientific), 16.7% (St Jude Medical) and 21.8% (Medtronic). No CRT‑D failures were observed. High left ventricle lead impedance was protective of reaching ERI: OR (>1,000 versus 500 Ohms) 0.38, 95% CI 0.20 to 0.71, p=0.0025.

3.5 Landolina et al. (2015) is a retrospective observational study examining the rate of replacement for battery depletion and to identify reasons for early depletion. A total of 1,726 CRT‑Ds (Boston Scientific n=608 [291 (47.9%) ENDURALIFE‑powered CRT‑Ds], Biotronik n=49, Sorin n=99, St Jude Medical n=172 and Medtronic n=798) were implanted from January 2008 to March 2010. The CRT‑Ds were commercially released between 2003 and 2010 and had different battery types; 708 were early-generation (released before 2007) and 1,018 were recent-generation families (since 2007). The median follow-up was 3.6 years. Among the recent-generation CRT‑Ds (excluding those from Sorin and Biotronik, because there were fewer than 100 of these implants included in the study), rates of devices still working after 5 years were 88% (Boston Scientific), 75% (St Jude Medical) and 52% (Medtronic). Table 1 shows multivariate analysis factors associated with CRT‑D replacement because of battery depletion.

Table 1 Factors associated with CRT‑D replacement because of battery depletion

Hazard ratio

95% confidence interval

P value

Boston Scientific vs Medtronic

0.64

0.47–0.89

0.008

Recent-generation device

0.57

0.45–0.72

<0.001

Battery chemistry:

Li/MnO2 vs Li/SVO

Li/CFx-SVO vs Li/SVO

0.37

0.28

0.22–0.64

0.16–0.50

<0.001

<0.001

High left ventricle lead output (pulse amplitude >2.5 V, duration >0.5 ms)

1.96

1.57–2.46

<0.001

Unipolar left ventricular lead

1.58

1.25–2.01

<0.001

3.6 Von Gunten et al. (2015) report findings from a retrospective observational study looking at device lifespan. Only 26.3% (n=1,284) of devices included in the study were CRT‑Ds, but the results are presented separately for this subgroup. ENDURALIFE‑powered CRT‑Ds comprised 39% of Boston Scientific devices. Median follow-up was 4.4 years. For devices implanted after 2006, the proportions of devices still working after 6 years were 97.6% (Boston Scientific), 26.5% (St Jude Medical), 46.3% (Medtronic) and 44.9% (Biotronik).

3.7 Lau et al. (2015) is a published abstract based on a conference poster presentation reporting the findings from a UK hospital. The study compared battery life after 6 years of use in Boston Scientific ENDURALIFE‑powered CRT‑Ds, and Medtronic and St Jude Medical CRT‑Ds. At 6-year follow-up, none of the Boston Scientific devices needed replacement because of battery depletion. St Jude Medical CRT‑Ds first began to reach ERI after 2.8 years, and Medtronic CRT‑Ds after 2.5 years. Pairwise comparisons showed a significant difference between Boston Scientific and St Jude Medical (p=0.0018) and between Boston Scientific and Medtronic (p<0.0001).

3.8 Williams and Stevenson (2014) is a published abstract from a conference poster presentation reporting battery life of CRT‑Ds. The primary end point was device replacement after reaching ERI. A total of 91 CRT‑Ds were implanted from July 2008 to July 2010 (final device follow-up: October 2013): Boston Scientific n=53 (company's submission states that 51 [96.2%] were ENDURALIFE‑powered), St Jude Medical n=10 and Medtronic n=28. At 4-year follow-up, the ERI rates were 1.9% (Boston Scientific), 10.0% (St Jude Medical) and 50.0% (Medtronic). Multivariate analysis showed that CRT‑Ds reaching ERI had higher right ventricle lead output, left ventricle lead output and right ventricle pulse width (no values reported).

PPRs reporting on device malfunction and survival probability

3.9 Product performance reviews (PPRs) are based on devices that have been replaced and returned to the manufacturer, as well as additional information provided to the manufacturer from various sources about out-of-service devices that have not been returned. They aim to report device malfunctions in a standard format. PPRs report survival probability in 2 ways (based on real, observed data): survival free from both malfunction and normal battery depletion, and survival free of malfunction alone leading to device removal (cases of normal battery depletion are excluded from the analysis). In both cases the definition of 'normal battery depletion' is a function of the manufacturer's predicted device lifespan (based on bench testing, which differs by manufacturer and may not accurately reflect clinical performance). The company presented PPRs from 5 manufacturers of CRT‑Ds in its submission. The EAC accepted that the PPRs showed that normal battery depletion, rather than CRT‑D malfunction, is the main reason for CRT‑D replacement. However, it judged that data in the PPRs could not be used to reliably compare the lifespan of ENDURALIFE‑powered devices with that of other devices.

Adverse events associated with CRT‑D replacement

3.10 Lewis et al. (2016) is a systematic review assessing the risks and benefits of replacing implantable cardioverter defibrillators, which included 17 studies (n≥167,000 patients). The median rate for major complications was 4.05% (range: 0.55% to 7.37%), of which the most frequent was infection needing antibiotic therapy and/or device removal (median rate 1.70% [range: 0 to 5.23%]). Other reported major complications included haematoma needing evacuation (median 0.57%; range: 0 to 1.55%), stroke (median 0.45%, range 0.01% to 0.82%) and reoperation for any other reason (such as pocket erosion or device repositioning because of pain; median 1.56%; range: 0.07% to 3.24%). The median rate for minor complications was 3.5% (range: 0.36% to 7.37%), with the most frequent being pocket haematoma (median 0.93%; range: 0.35% to 3.49%). Other reported minor outcomes include: incisional infection (median 0.9%; range: 0.01% to 1.77%) and discomfort or pain at the site (median 0.44%; range: 0.39% to 0.45%).

3.11 Polyzos et al. (2015) conducted a systematic review and meta-analysis on risk factors associated with cardiac implantable electronic device infection, including 60 studies with a total of 233,184 patients. The average reported device infection rates were 1.6 for prospective studies (n=21 studies), 1.0% for case-control studies (n=9 studies) and 1.2% for retrospective cohort studies (n=30 studies). The pooled OR for the risk of infection associated with generator change (20 studies; 33,322 patients) was 1.74 (95% CI 1.22 to 2.49). Device replacement or revision was associated with a pooled OR of 1.98 (95% CI 1.46 to 2.70) for infection. The authors concluded that a 'decision to replace a device should be made on a risk/benefit approach weighting the risk for death because of device failure, the rate of device failure, and the risk for procedure-related death'.

3.12 Zeitler et al. (2015) present a systematic review and meta-analysis of the complications associated with the replacement of cardiac implantable electronic device generators, following US Food & Drug Administration (FDA) recall. The review included 7 studies (1,435 patients) with a primary end point of major complications and mortality; other end points included reoperation and pocket revision. Device replacement following FDA recall was associated with a combined major complication rate of 2.60% (95% CI 0.9% to 4.8%). Five of the 7 included studies reported mortality, which showed an overall mortality of 0.4% (95% CI 0.1% to 1.1%). The rate of reoperation/pocket revision (5 studies) was 2.7% (95% CI 0.8% to 5.1%). The authors conclude that generator replacement in response to an FDA recall has a similar rate of major complications as elective generator replacement. The authors also conclude that patient and device characteristics, patient preference and remaining battery life should all be considered when replacing devices, elective or otherwise.

3.13 Nichols et al. (2016) investigated the incidence of lead damage following cardiac implantable electronic device replacement procedures and its economic impact. The study included 45,252 patients: 22,557 (50%) pacemaker generator replacements, 20,632 (46%) implantable cardioverter defibrillator replacements, and 2,063 (5%) CRT‑D device replacements. Lead damage was observed in 406 patients (0.90%) at a median of 107 days following device replacement. Lead damage incidence was 1.94% for patients with CRT‑Ds. In a Cox proportional hazards model, controlling for patient demographic and clinical characteristics, CRT‑D replacement showed >2.5 times (HR 2.58, 95% CI 1.73 to 3.83) the risk of lead damage compared with pacemaker replacement. Of the 406 patients with lead damage, 368 (91%) were inpatients with a median length of stay for lead damage of 3 days; this did not significantly differ based on device type. The mean cost of lead damage management across all device types in the first year was $25,797. Average lead damage hospitalisation costs were significantly different across device types: $19,959 for pacemaker replacement; $24,885 for implantable cardioverter defibrillator replacement; and $46,229 for CRT‑D replacement (p=0.048). The authors conclude that the higher rates of lead damage observed in implantable cardioverter defibrillator and CRT‑D replacement are likely to be attributable to the greater number of and complexity of leads in these procedures.

3.14 Lovelock et al. (2014) investigated the risk of lead alerts after replacing implantable cardioverter defibrillators. This study utilised patients enrolled on the ALTITUDE project, an initiative to prospectively analyse data obtained from implanted Boston Scientific devices through its LATITUDE home monitoring system. A total of 60,219 patients were eligible for inclusion in the study, of which 7,458 patients (12.4%) had implantable cardioverter defibrillator replacement. A time-dependent Cox proportional hazards model (adjusted for age, gender and device type) was used to evaluate potential associations between lead failure and device replacement. Lead performance in the 7,458 patients having device replacement was compared with leads of similar age (68 months) in patients who did not have device replacement. Patients who had device replacement showed a 5-times higher lead alert rate (HR 5.20, 95% CI 3.45 to 7.84) compared with those who did not; this was significantly different even when covariates were adjusted for (p<0.001). Younger age and single-lead implantable cardioverter defibrillators were also associated with an increase in lead alerts: HR 1.02, 95% CI 0.98 to 0.99, p<0.001; HR 2.49, 95% CI 1.96 to 3.17, p<0.001 respectively. However, both age and system type were associated with lead alerts to a lesser degree than device replacement. The authors suggest that surveillance is needed after device replacement in addition to technique development and lead modifications to minimise the risk of lead damage during surgery. In another study, Lovelock et al. (2012) reported that the rate of failure in Medtronic Fidelis leads was 20.8% following device replacement and 2.5% in lead age-matched controls (p<0.001).

3.15 Kirkfeldt et al. (2014) was a retrospective multicentre (14 hospitals) cohort study in Denmark which analysed complications occurring within 6 months of cardiac electronic devices implanted between May 2010 and April 2011. The analysis included 5,918 patients: 74% (n=4,355) had new implants, 19% (n=1,136) had device replacements and 7% (n=427) had system upgrades or lead revisions. The complication rate was 5.9% following a device replacement. Infection rates for new implants and generator replacements were 0.6% and 1.5% respectively. When complications were categorised, 3.5% of patients experienced a major complication within 6 months of a device replacement.

EAC's critique of the clinical evidence

3.16 The EAC felt that although the studies of battery life were done under similar conditions to normal clinical practice, they were retrospective and it was not possible to determine the rationale for choice of CRT‑D. It concluded that the published studies demonstrate that ENDURALIFE‑powered CRT‑Ds implanted between 2008 and 2010 lasted longer than other CRT‑Ds implanted during the same period. However, some of the CRT‑Ds in these studies, particularly the comparator devices, are no longer marketed.

3.17 The EAC accepted the company's submission of evidence on the rate of complications following CRT‑D replacements. The EAC acknowledged that the PPRs submitted by the company demonstrated that most CRT‑Ds are replaced because of normal battery depletion, and not device malfunctions.

Committee considerations

3.18 The committee concluded that ENDURALIFE‑powered CRT‑Ds have a greater battery capacity and longer battery life compared with other CRT‑Ds available at the time of the published studies. It noted that, because of the follow-up time needed to study battery life, the retrospective, observational studies presented included CRT‑Ds no longer marketed. Clinical experts advised the committee that the company's claims relating to battery life and the ENDURALIFE battery technology have been borne out in their own subsequent clinical experience, as well as in the published literature.

3.19 The committee heard that other technologies claim to offer similar advantages to ENDURALIFE‑powered CRT‑Ds, but these have not been reviewed in this assessment.

3.20 The committee was advised by clinical experts that in terms of determining the lifespans of different CRT‑Ds, published, peer-reviewed clinical studies are a more reliable source of information than unpublished, extrapolated and predicted lifespan data. The committee considered that the updating and publication of further clinical outcome studies in patients with CRT‑Ds from all manufacturers would be helpful. In this regard, the committee was made aware of the existence of a large volume of data possessed by the National Institute for Cardiovascular Outcomes Research (NICOR) relating to CRT‑Ds implanted in the NHS since 2008 (when ENDURALIFE‑powered CRT‑Ds entered the market). These data include lifespan outcomes for almost all CRT‑Ds implanted in the UK since 2008. The committee was advised that further analyses of these data may provide valuable insights into how long different CRT‑Ds last in real-world clinical practice. The committee encouraged the publication of these lifespan outcomes.

3.21 The committee heard from clinical experts that battery depletion depends on a number of factors including the needs of the patient, lead technology, battery design and the algorithms used in the CRT‑D. However, it was advised that a central factor in determining device lifespan is the ampere hours a battery can carry. The experts stated that accepting recent developments in battery technology by all CRT‑D manufacturers, ENDURALIFE‑powered batteries still have one of the largest ampere hours ratings.

3.22 The experts acknowledged that advances in CRT‑D technology continue to be made by all manufacturers, particularly in minimising battery drain. However, the experts advised that these developments applied to all manufactured devices including ENDURALIFE‑powered CRT‑D devices.

3.23 The committee was advised that replacement procedures are associated with a risk of serious complications and that complications are more common in replacement than primary implants. Infection can have major consequences in terms of patient morbidity and resource use, including the need for hospital admission that may last days or weeks. The committee heard from a patient expert that replacement procedures have a detrimental impact on quality of life. The clinical experts also advised that patients see replacement procedures as a significant life event.

3.24 The committee heard from the clinical experts that predicting a patient's individual life expectancy after device implantation is difficult. Nonetheless, experts advised that given the prognostic benefit of CRT‑D implantation in patients with heart failure, the choice of a CRT‑D with a greater lifespan is logical.

3.25 The committee was advised that CRT‑Ds differ in size and shape between manufacturers and that Boston Scientific devices are slightly thinner than others. Experts stated that the shape of the CRT‑D is sometimes more important than the size, and that the choice of device needs to be personalised to the patient's individual needs. This usually involves shared decision-making between the patient and the clinician.

  • National Institute for Health and Care Excellence (NICE)