A flow chart describing the process of identifying relevant literature on the clinical effectiveness of VADs can be found in . Following the removal of duplicates, our searches identified 4325 potentially relevant articles. We removed 2794 articles which did not meet our inclusion criteria at title sift, leaving 1531 articles to be screened at abstract sifting stage. A total of 1196 articles were removed at abstract sift because they did not meet inclusion criteria, leaving 335 articles to be sifted at full-paper stage. A total of 40 publications42,52,53,56–92 met the current inclusion criteria and reported findings on the following devices: HMII (n = 29);52,53,56–82 HW (n = 1);83 Berlin Heart INCOR (n = 1);86 DuraHeart (n = 2);42,85 MicroMed DeBakey (n = 1);84 and mixed devices (n = 6).87–92 Included papers were published between 2003 and 2012.
Seven systematic reviews were identified. After full investigation it was concluded for each one that the majority of their included studies and patients did not meet the inclusion criteria and these reviews were therefore rejected.
A list of the 288 articles that were excluded at full paper sift with reasons for exclusion is provided in Appendix 5.
Delineating multiple overlapping populations between publications
Many of the identified publications investigated overlapping populations; this was especially true for studies of HMII, most of which were conducted in the USA. Also, in some studies the patient group received different devices and authors did not report results separately for each of the several devices investigated. There were many studies in which different patients were given bridge or destination therapies; however, in most of these outcomes were not reported according to indication.
The US HMII publications can be classified as (a) from single centres (n = 14); (b) deriving from the multicentre FDA approval study and its extension (n = 12); and (c) multicentre registry studies.
Starling et al.52 and John et al.65 reported on HMII, while Nativi et al.89 indicated the number of HMII recipients but reported data for a mix of different VADs. In 12 of the single-centre studies53,56,59,60,62,72,76–81 both DT and BTT patients were included, or indication was not clearly defined; none of these analysed results separately for BTT patients. The other two single-centre publications (Petrucci et al.74 and John et al.64) reported results for BTT patients, but these single centres appear to have contributed participants to the FDA approval group of multicentre publications. The FDA approval study publications reflect the gradual accrual of more patients and multiple publications have been produced for overlapping groups of patients. Five of these publications58,59,65,67,82 report on the same 469–486 participants by either dichotomising the population by various criteria,67,82 focusing on a particular outcome,58 combining BTT patients with HMII DT patients,59 or not separating the outcome data according to therapy received. Registry studies, including John et al.65 and Starling et al.,52 reported on post-approval HMII BTT patients who were not participants in the FDA extension study. We consider it likely that the 169 patients reported in Starling et al.52 are participants in the analysis by John et al.65 The International Society for Heart & Lung Transplantation (ISHLT) registry report by Nativi et al.89 included 417 patients who received later generation LVADs for BTT. Of these, 291 were implanted with the HMII device and some were likely to also be participants in the FDA approval study or its extension although outcome results for HMII were not reported.
attempts to summarise the ‘family tree’ of the large number of US HMII VAD publications. As publications lacked sufficient detail, these relationships between publications cannot be stated with total certainty and it would be valuable to confirm this diagram with the authors. A similar situation of overlapping patient populations applies to the other included publications. These reported on a single device other than HMII, or reported results from studies conducted at European centres employing a mix of LVADs or the HMII device. There were two publications about HMII use with European patients;68,78 these included both BTT and DT patients. In Lahpor et al.68 outcomes were not stratified by therapy and in Strueber et al.78 the only outcome reported according to therapy was survival. The relationship between these is summarised in . The European multicentre study of patients implanted with the HMII device for BTT, DT or BTR, by Lahpor et al.68 (n = 184), included the patients (n = 101) reported separately by Strueber et al.,78 and possibly some of the patients in the mixed VAD studies by Drews et al.87 and Oswald et al.90 The two BTT publications by Sandner et al.91,92 examined the same 86 patient population (who received an amalgam of several devices which did not include HMII and results were not stratified according to device). The source of patients for the multiple device studies by Klotz et al.88 and Drews et al.87 were single German centres. Two publications of the DuraHeart (Morshuis et al.42,85) investigated almost identical patient populations differing slightly in size (n = 6885 and n = 8242). A single-centre publication describing 79 HMII patients (BTT n = 64, BTT and DT n = 15) did not identify the centre and it was uncertain if this was a French or US study.81
Summary of relationships between the included US HMII publications. All US multicentre BTT HMII FDA protocol publications shared patients with each other; the John 2010 publication reported on 250 patients who received a HT out of 486 BTT participants. (more...)
Summary publication relationships: non-HMII single-device publications and European centre studies. One single-device publication was included for each of the INCOR, HW (centres in Europe and Australia) and MicroMed DeBakey devices. The INCOR study included (more...)
The overlapping inter-relationship of populations described above, especially notable for HMII studies, renders any summary of baseline characteristics or of outcome results problematic if double counting is to be avoided. Therefore, where duplication of patients was judged to occur we have included the largest and/or most recent study of the cohort, conditional on availability of data. However, because of the multicentre nature of many of the HMII studies and authors' contention that experience with LVADs over time has influenced study results for some outcomes, we have occasionally also discussed earlier and smaller studies. We have organised baseline characteristics and outcome results according to device; in the main text we have not considered results for DT patients, or where results combine DT and BTT patients, or where this distinction was unclear. For full data on all baseline characteristics, and on outcome results irrespective of therapy, please consult Appendix 3.
Overall quality assessment
The 40 primary included publications42,52,53,56–92 were each quality assessed using an adapted set of criteria developed by Thomas et al.55 For completeness, see Appendix 4 for copies of the quality assessment sheets for each publication.
Selection of participants
The methodological strength of the studies in terms of population representativeness and selection bias varied: 38 studies42,52,53,56–58,60–89,91,92 were rated moderate and two studies59,90 were rated weak. Individuals selected to participate in the studies were considered to be ‘somewhat likely’ to be representative of the target population in just under half of the studies (n = 17).52,53,56,59,64–67,70,71,73–75,82–84,87 Two studies69,88 were not likely to be representative, and in 21 studies42,57,58,60–63,68,72,76–81,85,86,89–92 it was not possible to tell.
Study design
There were no RCTs included in the 40 publications.42,51,52,56–92 No publications reported on a comparison group who received MM or best supportive care. Likewise, no publications reported on direct comparisons between VADs and HT. Some publications reported outcomes (e.g. on clinical functioning or functional assessment/QoL) using patients as their own controls (before–after designs) or within-study comparison on the basis of baseline characteristics such as age > 70 years.
Fourteen publications42,52,53,63,64,70,71,73–75,83–85,90 used a prospective design; mostly these were single-arm studies either using routine-collected data in registry studies or collecting de novo data. Some of these prospective studies reported used a mixture of data collection methods including both prospective and retrospective data.
Twenty-five publications42,52,53,63,64,70,71,73,74,75,83–85,90 reported a retrospective design (e.g. based on retrospective case note review).
Confounders
Two publications73,80 were rated as strong in relation to dealing with confounding factors and 3342,52,53,56–67,69–71,75–79,82–88,91,92 of the 40 publications were rated as moderate overall. Problems related to important differences between groups prior to the intervention and the percentage of relevant confounders that were adjusted for in analysis. Five publications68,72,81,89,90 were rated weak on this quality criterion.
Blinding
It was considered that 3742,52,53,56–73,76–81,83–92 of the 40 publications had weak overall blinding, one publication82 was rated moderate and two publications74,75 as strong. In the 37 publications42,52,53,56–73,76–81,83–92 the outcome assessor was aware of the intervention or exposure status of participants. Interestingly, only 12 publications42,57,61,63,65,70,71,73,74,83–85 reported that participants were aware of the research question.
Data collection methods
Overall, the data collection methods of eight42,73,75,76,85,89,91,92 of the studies were rated strong, of 2352,53,56,57,59–65,67,70–72,74,79,82–84,86,87,90 as moderate and of nine as weak.58,66,68,69,77,78,80,81,88 In 24 publications42,52,53,56,59,62–64,67,69–76,83–85,89–92 the data collection tools were shown to be valid; in the other 16 publications57,58,60,61,65,66,68,77–82,86–88 it was not possible to tell. Eighteen publications42,52,63,64,70,71,73–76,79,83–86,89,91,92 reported that the data collection tools were shown to be reliable, three were not reliable,58,60,80 and in the remaining 19 publications53,56,57,59,61,62,65–69,72,77,78,81,82,87,88,90 it was not clear.
Withdrawal and dropout
Thirty-seven publications42,52,56–81,83–86,88–92 reported an 80–100% completion rate for study participants. Of these, 15 studies57–60,62–65,70–74,83,90 detailed numbers of dropouts and reasons. Overall, the methodological considerations relating to dropouts were considered strong in 17 publications,57–65,70,71,73,74,83,84,87,90 moderate in 21 publications42,52,66–69,72,75–82,85,86,88,89,91,92 and the remaining two weak.53,56
Integrity
In all but one study 80–100% of participants received the intervention of interest.42,52,53,56–82,84–92 Two publications62,89 measured the consistency of intervention, five56,65,69,85,87 did not and in 33 publications42,52,53,57–61,63,64,66–68,70–84,86,88,90–92 it was not possible to tell either way. Eighteen publications42,56,66,68,69,72,76–81,85,86,88,89,91,92 reported that participants were likely to have received an unintended intervention that may have influenced the results. In the remainder it was not possible to tell.52,53,57–65,67,70,71,73–75,82–84,87,90
Analysis
This section of quality assessment included unit of allocation, unit of analysis, use of appropriate statistical method and whether the analysis was performed by intervention allocation status rather than the actual intervention received. In all 40 publications,42,52,53,56–92 the unit of allocation and analysis was the patient. Twenty-eight publications42,52,53,56,57,59,61,62,64–67,69–76,80,83–85,87,89,91,92 reported statistical methods that were deemed appropriate, in four60,63,68,88 statistical methods were not appropriate and in eight58,77–79,81,82,86,90 it was not possible to tell. In 30 publications42,57–71,73,76–81,85–87,89–92 it was not possible to tell how the analysis was performed.
Summary
For the 40 included publications, overall quality ratings were as follows: one study was rated strong,75 15 studies as strong to moderate,42,52,53,64,70,71,73,76,80,83–85,89,91,92 13 studies as moderate,56,57,59,62,63,65–67,74,79,82,86,87 10 studies as moderate to weak58,60,61,68,69,72,77,78,88,90 and one study as weak.81
Overall, the study designs were not strong: studies were likely to be only moderately representative of underlying populations, there were no randomised trials and blinding of outcomes assessors was weak. Most patients received the intervention they were anticipated to receive although this criterion is not relevant for the 25 retrospective designs. Data collection methods and recording of withdrawal and dropout were moderate. Analysis was deemed appropriate for the majority of studies and most studies attempted to deal with confounding. Detailed quality assessment reports for each study are presented in Appendix 4.
Baseline characteristics
An apparent 19,161 participants were described in the 40 included publications; however, please see Delineating multiple overlapping populations between publications, which explains the issue of multiple reporting of patients by publications. The majority of the studies took place in the USA (n = 27); others were listed as taking place in Germany (n = 3), Europe specifically (n = 2), Austria (n = 2), unclear (n = 1) and multiple counties (n = 5).
All included studies reported some baseline characteristic values for the population investigated, one study reported five84 baseline characteristics while two others reported 43.79,80 Method of reporting varied; for example, age was reported as a mean (standard deviation; SD), a median with range, a proportion or percentage within each of several defined age bands or as a combination of these methods. Some authors reported data for subgroups only but, where possible, subgroups have been combined to provide a value for the whole study population. Authors frequently used baseline characteristics in regression analyses attempting to identify factors that influence outcomes of particular interest in their study (e.g. aortic insufficiency,60,72 renal function62 and stroke58,81).
The baseline characteristics of BTT patients are presented in –. To avoid double counting caused by overlapping populations, the largest or most recent publication from each known cohort, conditional on the availability of data, has been included. Pooled estimates are provided. If the two large registry studies by Nativi et al.89 and John et al.65 were to be included in pooling then pooled estimates would merely reflect their input; therefore, these have been omitted from pooling but where possible have been compared with the pooled estimate. A further difficulty concerns whether or not mixed-device studies should be included. We have included data from Sandner et al.91,92 when reported, as overlap with other studies is likely to be minimal. Pooled estimates should be treated with extreme caution as they:
Mean age at baseline for individual studies. (Note: studies with minimal population overlap with other studies; only BTT patients included.) There was statistical heterogeneity between studies (I2 = 64%). lCI, lower CI; uCI, upper CI. (more...)
Baseline systolic BP (mmHg). (Note: Studies with minimal population overlap with other studies; only BTT patients included.) lCI, lower CI; uCI, upper CI.
may miss studies that should be included
may not be representative either of all included studies or of all patients within a particular VAD study (most studies defined sampling frames and patient selection methods poorly)
may include clinical heterogeneity and missing information (not all studies provided analysable information and we excluded studies with fewer than 50 patients).
Nevertheless, pooled estimates provide a picture of baseline characteristics of relevant populations receiving VADs.
Age
Where mean age was reported it varied between 45 years (Klotz et al.88) and 65 years (Adamson et al.56). Two large studies involving 115782 and 855789 participants reported comparable mean ages of 51 years. The distribution of mean age in the included non-overlapping studies of BTT patients is summarised in . The pooled estimate was 50.8 years, and this is similar to the large registry study by Nativi et al.89 of 8557 BTT LVAD patients, which found mean ages of 50.1, 50.2, 50.8, 51.4 and 51.8 years, respectively, in patients who received pulsatile first-generation LVADs, pulsatile second-generation LVADs, continuous second-generation LVADs and for second-generation patients (no LVADs) on inotropes and second-generation patients (no LVADs) not on inotropes.
Gender
The percentage of males in all these studies ranged from 68.5% (Lahpor et al.68) to 91.5% (Morshuis et al.85) (summarised in ).
Baseline number (%) of patients reported to be male. (Note: studies with minimal population overlap with other studies; only BTT patients included.) lCI, lower CI; uCI, upper CI.
The pooled estimate was 84% with moderate heterogeneity (I2 = 40%). Again, the combined result is similar to the large registry study of 8557 LVAD BTT patients reported by Nativi et al.89 which found percentages of males to be 85.5%, 86.1%, 82.3%, 75.0% and 74.9% for pulsatile first-generation LVADs, pulsatile second-generation LVADs, continuous second-generation LVADs, second-generation patients on inotropes and second-generation patients not on inotropes respectively.
Race
White or Caucasian patients constituted 44.2% (Schaffer et al.77) to 95.1% (Oswald et al.90) of patient populations. The proportion of African American or black patients ranged between 6.6% (Topilsky et al.79) and 22.6% (Miller et al.70). All studies reporting race were undertaken in the USA. Studies were overlapping in terms of population and most reported a mix of destination and bridged therapies. Overall, there was limited reporting of race across all devices. The large registry studies (Nativi et al.89 and John et al.65) (n = 1496) did not report race of patients.
Body mass index
Fourteen studies59,62–65,71,72,77,81,83,86,88,89,91 reported baseline BMI (kg/m2) of patients. All but one of the studies reported BMIs suggestive that patients were overweight.59,62–65,71,72,77,81,83,86,89,91 The results reported in non-overlapping studies of BTT patients are shown in .
Baseline BMI (kg/m2). (Note: studies with minimal population overlap with other studies; only BTT patients included.) lCI, lower CI; uCI, upper CI.
The pooled estimate of 26.5 kg/m2 is similar to the value in the large registry study of 8557 LVAD patients reported by Nativi et al.,89 which found values of 26.7, 27.4, 26.8, 26.2 and 26.3 kg/m2, respectively, for BTT patients who received pulsatile first-generation LVADs, pulsatile second-generation LVADs, continuous second-generation LVADs, and for second-generation patients on inotropes and second-generation patients not on inotropes. A somewhat larger value of 28.8 kg/m2 was reported by John et al.65 for 1496 registry patients. It should be noted that in HF BMI may be misleading, owing to the underlying fluid retention of HF.
New York Heart Association functional classification of the extent of heart failure
A minority of studies (n = 16) reported baseline information on the NYHA functional classification of patients and where this was reported, the majority of patients were reported as having NYHA class IV. Overall, there was limited reporting of NHYA classification across all devices. Four-fifths (83.5%) of BTT patients had a rating of NYHA class IV assessed from non-overlapping studies ().
Baseline number (%) of patients with NYHA IV classification. (Note: studies with minimal population overlap with other studies; only BTT patients included.) lCI, lower CI; uCI, upper CI.
There was some heterogeneity among studies (I2 = 38%). Neither large registry study65,89 included usable NYHA class information.
Diabetes mellitus
A total of 12 studies reported the number of patients with diabetes mellitus at baseline (HMII, n = 8; HW, n = 1; mixed devices, n = 3). The percentage of patients with diabetes mellitus at baseline in these studies ranged from 14% (Strueber et al.83) to 38.5% (Pak et al.72). In some studies, subgroups with different rates of diabetes mellitus were reported at baseline [e.g. Sandner et al.91 reported 17.9% compared with 53.3% (group 1 aged < 60 years vs. group 2 aged > 60 years respectively)]. summarises results reported in non-overlapping studies of BTT patients.
Baseline number (%) of patients with diabetes mellitus. (Note: studies with minimal population overlap with other studies; only BTT patients included.) lCI, lower CI; uCI, upper CI.
The pooled value of 25.2% is similar to reported values, ranging between 20.5% and 28.3%, for patients who received pulsatile first-generation LVADs, pulsatile second-generation LVADs or continuous second-generation LVADs, and for second-generation patients taking inotropes and second-generation patients not taking inotropes, in the large registry study of 8557 LVAD patients (Nativi et al.89).
Inotropes
The baseline numbers (and percentages) of patients receiving inotropes in non-overlapping studies of BTT patients are shown in .
Baseline number (%) of patients using inotropes in non-overlapping studies of BTT patients. lCI, lower CI; uCI, upper CI.
There was heterogeneity between studies (I2 = 49%) and percentage values ranged widely, from 40% to 100% of patients receiving inotropes; the pooled estimate of 81% is similar to the value of 80.4% reported for 1496 HMII patients in the large registry study by John et al.65
Systolic blood pressure
Baseline systolic blood pressure (BP) was reported in 15 studies.42,52,53,56,59,63,65,70,71,74,75,79,80,83,85
summarises the results reported in non-overlapping studies of BTT patients. Systolic BP can be seen to be low compared with normal physiological levels, reflecting the severity of HF in these patients, with a pooled estimate of 97.3 mmHg.
Heterogeneity (I2 = 83%) between studies arose mainly from the study by Morshuis et al.85 The pooled estimate is similar to the value of 100.9 mmHg reported for 1496 HMII patients in the large registry study by John et al.65 Nativi et al.89 did not report this characteristic for registry patients.
Outcomes by device
In this section we describe outcomes including adverse events, survival, causes of death and QoL for each device.
Outcomes for HeartMate II
A total of 29 studies52,53,56–82 met the current inclusion criteria concerning HMII (see ).
Adverse events
Twenty-three studies52,56–61,64–73,75,76,78,79,82 reported adverse events or complications during the follow-up of HMII implantation. Given the problems of reporting on overlapping populations within studies (see Delineating multiple overlapping populations between publications), adverse events for HMII are best described by John et al.65 ().
Adverse events. Adapted from John et al.
Adverse events with HMII affect high proportions of patients. Twenty-one per cent of patients had bleeding requiring re-exploration; 20% had percutaneous lead infection and 3% pump pocket infection. Stroke is a very serious adverse event affecting approximately 10% of patients (it is assumed the ischaemic and haemorrhagic stroke did not occur in the same patient). Event rates per year should be treated with caution as follow-up rates are variable and events are highest in the first year after surgery.
Survival
summarises the K–M survival results as reported in the HMII studies (see ).
Summary of K–M survival results reported in HMII studies
The most recent and largest study of survival in the HMII BTT programme for HF appears to be that of John et al.,65 who included 486 patients from the extension of the HMII FDA approval study and 1496 post-approval patients in the INTERMACS registry. This analysis indicated superior survival for the latter patients (p < 0.0001 for log-rank test comparison). These results led the authors to propose that increasing experience with the HMII device has led to a gradual improvement in survival ().
Kaplan–Meier survival results reported by John et al. for patients who received an HMII LVAD.
Earlier publications in the HMII FDA approval series included those of Miller et al.,70 with 133 patients, and Pagani et al.,71 with 281 patients; they represent samples from John et al.,65 a growing cohort of the HMII approval study patients which accumulated 486 patients. The survival results reported are shown in together with those for the first 169 post-approval patients analysed in Starling et al.52 The results tend to support the proposition that a so-called learning curve leads to improving survival as the cohort grows. Survival at 1 year was 68.5% in Miller et al.,70 73% in Pagani et al.,71 75.6% in John et al.65 and 85% in Starling et al.52 as well as for the 1496 registry post-approval patients in John et al.65
Kaplan–Meier survival results for the HMII FDA approval trial and registry patients.
Greater experience with the device offers one explanation for the apparently improving survival; however, the similarity of these populations at baseline is difficult to gauge.
Three publications reported survival for subgroups of patients in the extension of the HMII FDA approval study (Bogaev et al.,57 Kormos et al.67 and Pal et al.73). In each of these studies participants were dichotomised according to a single variable. The results are summarised in . No significant difference was observed between genders, although early RV failure was associated with poorer survival (p = 0.026), as were concurrent cardiac procedures undertaken (p = 0.048).
Kaplan–Meier results reported for subgroups of patients receiving HMII LVAD.
In summary, publications suggest that survival at 1 year is approximately 75% but may improve with gain in surgical experience. These K–M analyses censor patients when they receive a HT. The problem here is that if the chance of receiving a donor heart depends on a patient's prognosis, for example if more seriously ill patients are selectively removed from follow-up and receive priority for transplantation, then survival estimates are susceptible to informative censoring and may thereby represent overestimates.
Causes of death
Twelve of the included HMII papers reported causes of death.56,57,64,68,70–73,78–80,82 Of these, the most recent and largest publication reporting this outcome in the HMII BTT programme for HF appears to be that of Bogaev et al.57 This publication dichotomised participants according to gender. The reported leading causes of death in men were sepsis (3.9%), right HF (2.8%) and multisystem organ failure (2.2%). The leading causes of death in women were multisystem organ failure (3.8%), haemorrhagic stroke (2.9%), ischaemic stroke (1.9%), right HF (1.9%) and external component device malfunction (1.9%; percutaneous lead trauma in one patient and pump disconnection in another).57
provides a summary of the causes of death reported in the 12 HMII studies.
Causes of death reported in included HMII papers
Common causes of death included (a) multiorgan failure (n = 12 studies), (b) right heart (ventricular) failure (n = 8 studies), (c) bleeding (n = 7 studies) and (d) stroke and cerebrovascular accident (CVAs) (n = 9 studies).
Quality of life
The HMII studies used several instruments for monitoring QoL and functional status of HF patients. provides a summary of HMII studies indicating which QoL measures were used.
Quality of life and functional status outcome measures reported for HMII
For this variety of QoL measures, data were presented as group means at various time points, change in group mean from baseline, or as change in mean or median for paired measures for individual patients. The number of patients investigated during individual studies gradually diminished as a result of death, transplantation with a donor heart and loss to follow-up or withdrawal. Baseline values were not always complete because some patients may not have been sufficiently well to participate. Full QoL results can be found in Appendix 3.
Five of the nine studies (Rogers et al.,53 Bogaev et al.,57 John et al.,65 Miller et al.70 and Pagani et al.71) contribute to the multicentre HMII BTT FDA approval programme with overlapping populations. By far the fullest QoL information was provided in Rogers et al.53 (n = 281). Although the largest BTT patient groups were investigated in Bogaev et al.57 (n = 465) and John et al.65 (n = 486), relatively limited results were presented and neither report paired measures; therefore, here we focus on the data presented in Rogers et al.53 (for this study information in Pagani et al.71 can be used to gauge the completeness of the reported data). Rogers et al.53 presented results separately for 281 BTT and 374 DT patients; the DT results were similar to those for BTT patients. (They are not considered further here but can be found in Appendix 3.) In the following section, the QoL results presented by Rogers et al.53 are summarised and considered separately according to the investigatory instrument. Comments on the results from Bogaev et al.57 and John et al.65 should be viewed in the knowledge that the populations in these studies included participants from Rogers et al.53
Minnesota Living With Heart Failure Questionnaire
Scores on the MLWHF questionnaire ranged from 0 to 105, with lower values signifying improved QoL. Scores reported by Rogers et al.53 decreased over time relative to baseline scores (–10 points at 1 month and –29 points at 6 months; median per cent improvement at 6 months of 38%), indicating an improvement in QoL (p < 0.05). These results for MLWHF scores at 1, 3 and 6 months for BTT patients are summarised in .
Changes in MLWHF for the BTT group over time (Rogers et al.). Bars indicate 25th, 50th and 75th percentiles, and the whiskers indicate fifth and 95th percentiles.
Reading from the graph in Pagani et al.71 the number of patients supported on HMII at 6 months was about 132, so that the return of 115 questionnaires at 6 months represents a data set approximately 87% complete.
Rogers et al.53 also reported paired change (i.e. mean change from baseline for patients with measures at both time points) ().
Paired changes in MLWHF scores reported in Rogers et al.
Borgaev et al.,57 who subdivided the population by gender, reported similar results: a significant improvement (both genders group) between baseline and 6 months (female: 73 ± 22 to 35 ± 22; male: 71 ± 22 to 40 ± 23). There was no significant difference between the sexes (p = 0.661).
The Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score (OSS) and clinical summary score (CSS) improved during HMII support. The median KCCQ OSS showed improvements at 1, 3 and 6 months compared with baseline and (p < 0.05 at each time point). KCCQ group OSS also showed similar improvements (p < 0.05 at each time point) ().
Kansas City Cardiomyopathy Questionnaire scores (Rogers et al.). Bars indicate 25th, 50th and 75th percentiles, and the whiskers indicate fifth and 95th percentiles. (a) OSS; and (b) CSS.
Rogers et al.53 reported paired KCCQ score changes (i.e. mean of change from baseline for patients with measures at both time points). These results are summarised in .
Paired changes in KCCQ OSS and CSS
Again, paired measures support the evidence for an improvement in QoL for patients surviving after implant of the HMII VAD (p-value and statistical significance were not reported).
Borgaev et al.,57 who subdivided the population by gender, reported significant improvements for both men and women in mean values on the KCCQ OSS and CSS between baseline and 6 months (there was no significant difference between the sexes).
Metabolic equivalent task score
The metabolic equivalent task score (METs) measures patient-reported exercise ability. Rogers et al.53 presented serial assessments of METs following HMII (). At baseline, > 90% of patients described their level of function as low or very low. At 6 months, about two-thirds of patients described their level of function as moderate to very high (p < 0.001 vs. baseline).
Summary of METs. BTT FDA study: data from Rogers et al.
Borgaev et al.57 found no significant difference between males and females in METs improvements (p = 0.348).
Quality of life visual analogue scale
Rogers et al.53 did not report on this outcome. For purposes of completeness, results from other studies are reported here. The data presented by Starling et al.52 for the first 169 post-FDA-approval HMII patients are summarised in . Visual analogue scale (VAS) scores (scale 0–100; best QoL = 100) improved at 3, 6 and 12 months relative to baseline. Changes were large, but p-value and statistical significance were not reported. Results were based on 253 tests (50%) completed in 508 potential test sessions.
Visual analogue scale for HMII and comparator VADs at different time points (Starling et al.). Note: the comparator group consisted of patients who received other LVADs than HMII approved for BTT.
John et al.65 presented METs QoL data for a sample from the INTERMACS registry BTT post-approval HMII patients (). Improvements of 32 points at 3 months were sustained at 12 months. The authors provided limited discussion of these findings. The overlapping underlying populations preclude development of a summary estimate combining results with those of Starling et al.52
Visual analogue scale results for the post-trial cohort. Adapted from John et al.
Functional status
New York Heart Association
Rogers et al.53 reported that at baseline patients were classified as NYHA class IV, by 1 month 59% had improved to NYHA class I or II, and at 6 months 82% were NYHA classified as class I or II (). Relative to baseline scores, highly significant improvements in NYHA functional class were observed at all study intervals (p < 0.001).
Summary of NYHA classification at each time point reported (Rogers et al.). Ratings were determined by an independent clinician.
Bogaev et al.57 reported significant improvements from baseline in the proportion of patients classified as NYHA functional class I/II for both women [0–49 (83%)] and men [0–147 (85%)] (p < 0.001). No significant differences were observed between men and women (p = 0.55).
6-minute walk test
At baseline, Rogers et al.53 reported that of 281 BTT patients 38 (14%) were able to perform the 6-minute walk test. Baseline distance walked for was 214 ± 125 metres. At 6 months the distance walked was 372 ± 199 metres although only 97 patients completed the test. There was a statistically significant improvement over time.
Bogaev et al.57 reported that before LVAD implantation, many patients were unable to walk and could not provide baseline values. Group means exhibited significant change for both women and men at 1, 3, and 6 months. Distance walked at all times was further for men (p = 0.037). Registry data for the 6-minute walk test results reported by John et al.65 similarly indicated improvement from baseline. No statistical analysis was reported.
Summary of quality-of-life results
The results presented by Rogers et al.53 provide a persuasive indication that those patients who survive implantation of the HMII device as BTT experience an improvement in QoL by 3 months sustained at 6 months. Some of the changes are substantial and statistically significant (e.g. improvements in MLWHF, KCCQ, NYHA and METs in Rogers et al.53), but data sets were not complete and this may have skewed results.
These results were supported in other publications with somewhat larger populations and where measures are extended to 12 months.
Summary of outcomes for HeartMate II
The relatively modest quality and diversity of reporting of outcomes and the occurrence of overlapping populations in the 29 publications of HMII have precluded numerical synthesis of results. Outcomes for HMII overall show a profile of substantial adverse events. One in five patients had bleeding requiring re-exploration and almost one in three patients had infection. Stroke is a very serious adverse event affecting 1 in 10 patients. The K–M estimates of survival post implant of the HMII device suggest improvement with growing experience. The best 1-year survival estimate for this device was 85%. It should be borne in mind that in estimating survival of BTT patients during VAD support using K–M analyses, those patients who receive a HT are censored at the time of transplant; if these patients have poorer prognosis than uncensored patients then survival may be overestimated (or vice versa). Furthermore, any comparison between device types for any outcome may be confounded by differences in underlying populations (e.g. owing to geography, time period, eligibility criteria).
Set against this, however, is reported improvements in QoL and functional status reported using a number of different measures in a number of different studies.
Outcomes for HeartWare
One study reporting on 50 patients implanted with a HW VAD as a BTT fulfilled our inclusion criteria (Strueber et al.83).
Adverse events
Adverse events were reported in detail and are shown in . Overall, 22 infections occurred among 50 patients; 20% of patients required repeat surgery for bleeding. Six of the 50 patients suffered from stroke and seven device replacements were required. Other important adverse events suffered by smaller numbers of patients included renal and hepatic dysfunction, haemolysis and right HF. Some patients may have experienced multiple events; therefore, summing percentages within categories may be misleading.
Adverse events for patients with a HW device. Adapted from Strueber et al.
Survival
provides a summary of the K–M survival results for patients who received the HW VAD in the study by Strueber et al.83
Kaplan–Meier survival results for patients who received the HW VAD
Strueber et al.83 reported K–M survival results for HW BTT patients (n = 50; ). Relative to HMII studies (shown in and ), survival with HW appears to be at least comparable, with 85% of patients alive at 1 year after implant. When compared with the earlier HMII publications, survival appears superior for HW. Strueber et al.83 also provided a survival curve for a ‘virtual control’ group; this was based on the application of the Seattle Heart Failure Model (SHFM) to the baseline characteristics of the intervention group. This virtual control data fits well when a SHFM score of 2.416 is applied. These results are summarised in .
Survival of BTT patients implanted with the HW. Reported by Strueber et al.
Causes of death
Reports on nine deaths from the 50 eligible patients in the HW study78 suggested that three were caused by sepsis, three by multiorgan failure and three were thought to be caused by haemorrhagic stroke.
Quality of life
Strueber et al.83 reported KCCQ data for stated sample sizes of 38, 37, 36 and 21 presurgery and 1, 3 and 6 months post surgery for the 50 patients in their study. Results are summarised in . It was unclear if these were paired data.
Group mean scores for the KCCQ (Strueber et al.). Bars indicate means with 95% CIs and asterisks indicate 90th percentiles. *Statistically significant improvement reported in KCCQ score at p < 0.05.
Health-related quality of life (HRQoL) improved significantly by 1 month for all subscales of the KCCQ. The authors found statistically significant (p = 0.05) improvement in physical limitations, QoL, symptom burden, and overall functional status across all time points. Greater improvements were found during the first 30 days following the HW implant.
Summary of outcomes for HeartWare
Only one small publication reported on the HW VAD; there is a profile of substantial adverse events and mortality due to infection, bleeding and stroke, and one in seven patients with a HW device was reported as requiring the device to be replaced. Although it is possible that mortality within the first year is slightly less than as reported in HMII analyses published during earlier years of experience with that device (e.g. Miller et al.70 and Pagani et al.71), it should be borne in mind that the K–M estimates are subject to censoring for receipt of a HT. Significantly improved QoL and functional status were reported over the first 6 months after a HW implant.
Outcomes for the Berlin Heart INCOR
One study by Schmid et al.86 of the Berlin Heart INCOR fulfilled our inclusion criteria. This study reported on 138 patients who received a short cannula device and 78 patients who received a long cannula device.
Adverse events
shows adverse events for the Berlin Heart INCOR. Nearly one in four patients (23.2%) with a short cannula suffered a thromboembolic stroke. This rate appeared to be significantly lower in the smaller group of patients with a long cannula (3.8%). The authors distinguished stroke from intracerebral bleeding, again finding higher rates in the short cannula group – although not significantly so.
Adverse events. Adapted from Schmid et al.
Survival
Kaplan–Meier analysis of survival was performed for 78 patients with a short cannula device and 138 who received a long cannula device in this study.86 Survival reported at 12 and 24 months for each device type is summarised in , showing that even in the improved survival (long cannula) group, 39% of the patients had died by 12 months.
Kaplan–Meier survival analysis for patients who received a Berlin Heart INCOR VAD
Causes of death
In this study there were 92 deaths including 48 from multiorgan failure; 13 due to a cerebrovascular event; eight from right ventricular artery failure; two owing to cancer; two to trauma; and one each from pulmonary artery embolism and bleeding. Seventeen additional deaths were reported with ‘other’ or ‘unknown’ cause.
Quality of life and functional status
No data were reported on QoL or functional status.
Summary of outcomes for the Berlin Heart INCOR ventricular assist device
Only one relatively small study reported on the Berlin Heart INCOR VAD with a profile of substantial adverse events caused by intracerebral bleeding and stroke. Mortality within the first year was high. No data were reported on QoL and functional status.
Outcomes for the DuraHeart ventricular assist device
Two publications fulfilled our inclusion criteria.42,85 These reported on overlapping populations.
Adverse events
The 2010 study (Morshuis et al.42) reported adverse events in more detail and these are shown in . Almost all patients (31/33; 94%) suffered at least one serious adverse event. There were 114 serious adverse events in all, equivalent to each patient suffering nearly four events. Infections, cardiovascular complications and bleeding were the most commonly reported.
Incidence of serious adverse events. Adapted from Morshuis et al.
Survival
Both publications reported K–M survival results for BTT patients who received the DuraHeart VAD.42,85 Populations in the studies overlapped. The 2009 study85 provided survival results for the greater number of patients (n = 68) as follows: 87% (95% CI 77% to 94%) at 3 months, 81% (95% CI 67% to 89%) at 6 months and 77% (95% CI 34% to 78%) at 1 year.
These figures are comparable with studies reporting early experience with the HMII VAD.
Causes of death
Morshuis et al.86 reported on 20 deaths from 82 eligible patients, 13 of which were adjudicated by the Clinical Event Committee. The causes of death in the 13 patients were as follows: CVA, six patients (four haemorrhagic; two ischaemic); sepsis, three patients; non-traumatic subdural haematoma, one patient; accidental fall, one patient; acute myocardial infarction, one patient; and one patient was unknown.
Quality of life and functional status
No data were reported on QoL or functional status.
Summary of outcomes for the DuraHeart ventricular assist device
Two relatively small publications with overlapping populations reported on the DuraHeart VAD with a profile of substantial serious adverse events. Major causes of adverse events and death were CVA bleeding and infection, as with the other devices. Mortality within the first year was apparently similar to that reported in the publications describing earlier experience with the HMII device. No data were reported on QoL and functional status.
Outcomes for the MicroMed DeBakey ventricular assist device
One relatively small international study of 150 patients in 14 centres (of which 11 centres were European) by Goldstein84 reported on the MicroMed DeBakey VAD.
Adverse events
shows adverse events in this study. One-third of patients required reoperation for surgery and one-third suffered a thromboembolic event. Adverse event reporting in this study was mainly restricted to those related to the device. Complications not directly related to the device were not reported.
Adverse events. Adapted from Goldstein
Survival
This study84 did not provide K–M survival data.
Quality of life and functional status
No data were reported.
Summary of outcomes for the MicroMed DeBakey ventricular assist device
Only one study reported on this device with a profile of substantial adverse events. No data were reported on survival or on QoL or functional status. Little can be concluded on outcomes from this device as yet.
Outcomes for the publications reporting on mixed devices
This section reports findings from six studies88–93 of different VADs (where > 80% of patients received a VAD type which met the inclusion criteria and where results are not reported separately by VAD type).
Adverse events
provides a list of the adverse events and complications reported in the six studies88–93 concerning a mixture of devices. All six studies reported adverse events or complications. The most common adverse events reported were death (n = 4 studies), bleeding (n = 2 studies), stroke (n = 3 studies), renal failure (n = 2 studies), and right heart (RV) failure (n = 2 studies).
List of adverse events and complications in included papers reporting a mixture of devices (n = 6)
Drews et al.87 reported details of device malfunction. Pump thrombosis occurred in five patients (four patients fitted with the MicroMed DeBakey LVAD; one patient who received the Jarvik 2000 device) and three patients had pump-stop due to technical failure (MicroMed DeBakey, Berlin Heart INCOR) or due to pannus on inflow cannula (DuraHeart). Two patients had bearing problems (Berlin Heart INCOR), one patient had a broken driveline and in five patients pump exchange was performed. Two patients died and four patients underwent successful HT.
Among 86 patients common to both Sandner et al. publications,91,92 22 episodes of bleeding requiring surgery, 19 strokes, 30 instances of renal failure requiring continuous venovenous haemofiltration, and five cases of right HF requiring a RVAD were reported; these outcomes were reported by risk groups according to baseline age and glomerular filtration rate (GFR) status (see ). The studies by Oswald et al.90 and by Nativi et al.89 reported adverse events post HT; these are listed in .
Survival
Of the six studies,88–93 two studies88,90 did not provide survival results. The population in Drews et al.87 mostly received the VAD as DT patients and results could not be separated for BTT patients; post-HT survival only was reported. Likewise, Nativi et al.89 reported post-HT survival only. Results for the remaining two studies, Sandner et al.91,92 are summarised in . The two studies91,92 appear to have analysed the same populations which were dichotomised according to age in one study and according to renal function status in the other. It was unclear if patients were censored on receipt of a donor heart. Survival appears to be worse for younger patients,91 but these findings are not adjusted for severity or case mix and these studies lack power; numbers are too small to provide definitive information.
Kaplan–Meier survival results for populations who received more than one type of VAD
Causes of death
All six of the included papers83–93 reporting on a mixture of devices provided information on the causes of death. summarises the causes of death. Common causes of death included (a) multiorgan failure; (b) right heart (ventricular) failure; (c) bleeding; and (d) stroke/CVA. Because the proportion of different devices varied from study to study, or was not reported, events rates could not be attributed to a particular device.
List of causes of death reported in included papers reporting a mixture of devices
Quality of life and functional status
None of the included studies with mixed devices reported QoL or functional status measures.
Summary of outcomes for studies reporting on more than one ventricular assist device
Among these studies, outcomes were not reported by device and the mixture of devices varied from study to study. Therefore it was difficult to derive meaningful conclusions. Overall rates of survival and adverse events are in line with findings reported earlier in this chapter. None of the studies reported on QoL or functional status.
Summary of clinical effectiveness findings
We have reported outcomes for the 40 included publications (for full details see Appendix 3). The lack of prospective comparative study design, modest study quality, diversity of reporting of outcomes, and overlap between populations investigated, render it difficult to draw firm overall conclusions. The only comparisons between devices reported were between early generation VADs and second-/third-generation devices. (See also Appendix 3.)
For all the devices there was a profile of substantial serious adverse events caused by infection, thrombosis, bleeding and stroke, and of mortality from various causes in this already frail population. By 12 months patients had suffered a variety of serious complications. Studies reported the following ranges for adverse events: 4–27% bleeding requiring transfusion; 1.5–40% stroke; 3.3–48% infection (sepsis); 1–14% device failure; 3–30% HF; 11–32% reoperation; and 3–53% renal failure. gives a summary of the range of rates of the main adverse events by device type per patient-year demonstrating these high rates of adverse events.
Range of main adverse events by device type (% of patients with event)
The wide range of rates for stroke, with a very high upper end, represents data from a variety of studies. Higher rates of stroke emanate from shorter studies, as stroke is more likely to occur in the first 3 months after an implant ().
Hazard analysis depicting varying incidence over time of four major adverse events: stroke, reoperation for bleeding, pump thrombus and haemolysis (redrawn from Goldstein 2003).
Early follow-up data (e.g. at 1–3 months) cannot reliably be extrapolated to longer time periods (e.g. over 6 months) owing to the changing adverse event profile over time. Also, as few of the papers reported outcomes beyond 12 months, numbers and percentages in represent the best estimate of adverse events likely in the first year after the VAD intervention, but cannot reliably be extrapolated to later years after the intervention.
Kaplan–Meier estimates of survival post implant of the HMII device suggest improvement with growing experience. The best 1-year survival estimate for this device was 85%. A similar estimate of 85% survival at 1 year was reported for 50 HW patients (investigated at centres in Europe and Australia). While preparing this report, Aaronson et al.94 published a larger study of 140 US HW patients and estimated survival at 1 year to be 86%. Estimates of survival at 1 year for other devices as reported in the included publications were less impressive (INCOR 61% and DuraHeart 76%). It should be borne in mind that in estimating survival of BTT patients during VAD support using K–M analyses, those patients who receive a HT are censored at the time of transplant; if these patients are unrepresentative of the overall population studied (e.g. have a poorer prognosis than uncensored patients) then survival may be overestimated (and vice versa). Furthermore, any comparison across device types for any outcome may be confounded by differences in underlying populations (e.g. geography, time period, eligibility criteria, case mix, etc.)
Quality of life and functional status, where these were measured for patients who were still alive, showed a trajectory of improvement in the first year after implant for all groups of patients especially over the first 3 months. Improvements at 6 months were statistically significant in studies of HW and HMII.
In the next chapter we describe the individual patient data (IPD) set provided by the NHS Blood and Transplant National Registry (BTNR) from the UK Blood and Transplant Database (BTDB) maintained on behalf of the UK transplant community and explain derivation of parameters for the Warwick Evidence cost-effectiveness model.
