Cardiac disease is the leading cause of death in Canada (1). The increasing age of
the population along with the use of resource-intensive therapies have serious
implications for the sustainability of Canada’s universally funded Medicare system. The
direct cost of cardiovascular disease in Canada has been estimated to be 6.8 billion
dollars (1998), representing the largest proportion of Canadian hospital care expenditures
(2). The significant burden of cardiovascular disease demands treatments that are not
only clinically effective, but also cost-effective.
Cardiac transplantation is the leading therapy for patients under 65 with cardiac
failure when all other treatments have been unsuccessful. However, there is insufficient
quantity of donor hearts to meet the current (and expected future) demand. Innovative
mechanical assist devices have been developed and introduced in many industrialized
nations to help address this shortage. However, mechanical circulatory support poses a
concern to hospitals, and the health care system in general, due to its high cost and
consumption of limited resources (3).
This review focuses on ventricular assist devices (VAD) and total artificial hearts
(TAH) used for patients with terminal cardiac failure as bridge-to-transplant (BTT),
bridge-to-recovery (BTR), and alternative/destination therapy (DT). We review the recent
cost-effectiveness literature on mechanical assist devices, and anticipate the implications
for Canada.
Need for an alternative
Congestive heart failure (CHF) is the most rapidly growing cardiovascular
condition in Canada (1). Tsuyuki et al. 2003 (11), using CIHI data calculated 85,679
patients with CHF in Canada, with a total of 106,130 hospital discharges in 2000/2001.
1
Incidence of heart failure is on the rise and prevalence increases with age (12). In Canada
the average age of patients hospitalized for congestive heart failure in 2000/2001 was 76
(11). As the population in Canada ages CHF is expected to become an even more serious
population health concern.
Cardiac transplant is the most effective therapy for advanced heart failure patients
under 65 for whom optimal medical management (OMM) has not been successful.
Transplant wait-time depends on a patient’s medical condition at the time they are listed,
presence of mechanical assistance, time spent on the wait list, and their blood type (3).
Canadian patients in the ICU between 2000 and 2002 at the time of listing had a median
wait-time of 19 days, compared to 97 days for non-ICU patients (3). Between 1996 and
2001, the average one-year survival rate for heart transplantation was 85.9%. For 3 years,
it was 82.3%, and for 5 years, it was 78.3% (3). However, the number of available donor
hearts creates an upper limit to the benefit of this treatment. Of the 294 patients on the
Canadian heart transplantation wait-list in 2004 (3):
-
8.8% died on the waitlist (26 deaths).
-
42.5% remained on the wait-list for a heart at year-end (125 patients).
-
48.6% received heart transplants (143 patients).
Although international heart-transplant wait-list mortality rates are reported to be as high
as 30% (14,15), such high mortality has not been seen in Canada. Between 1993-2004
this rate was ~11% (~33 deaths per year), with the minimum being ~9% and the
maximum being ~15% (3). While there has been an expansion in the population
qualifying for heart transplantation (4), there has not been a dramatic effect on the overall
2
wait-listed population in Canada. Figure 1 shows that the wait-listed population has
remained within a fairly stable band, with no obvious upward tend over the past decade.
The main purpose of elective bridge-to-transplantation is to reduce mortality on
the transplantation wait-list. In Canada this rate is relatively low (~33 potential lives
saved per year). Emergent BTT VAD placement increases the number of patients on the
transplant wait-list and demand for donor hearts; if the number of donor hearts stays
constant this procedure would not save additional lives (13). BTR could save lives and
reduce demand for heart transplantation, but there is not enough evidence to show that
this therapy is largely effective. Current listing criteria for a heart transplant is fairly strict
and many patients do not qualify, such patients could benefit from an alternative to
transplant. It is estimated that as many as 5000 patients <65 could benefit from such an
alternative (14). McGregor (13) has suggested that requirement for VADs as destination
therapy could be 20 times the number of patients currently on the transplant list.
According to McGregor’s estimation technique a total of approximately 6000 patients in
2004 could benefit from such an alternative.
Methods
A systematic literature search was preformed to locate all relevant effectiveness
and cost-effectiveness literature on VADs. PubMed (MEDLINE) and the International
Network of Agencies for Health Technology Assessment (INAHTA) Health Technology
Assessment (HTA) database were searched using the search terms: “left ventricular assist
device,” or “LVAD,” or “ventricular assist device,” or “VAD,” or “artificial heart,” or
“assisted circulation,” or “mechanical circulatory support.” In addition, key HTA
websites were visited to search for any additional recent VAD assessments. Reports were
3
selected if they provided an assessment of the efficacy, effectiveness, or efficiency of
VADs, in terms of clinical efficacy/effectiveness or/and cost-effectiveness. The
references of relevant publications were also consulted to search for additional relevant
literature. The final identification of studies was completed by a review of the abstracts.
Only English or French reports published between January 2000 and December 2005
were included. Selected HTAs and studies met the following criteria:
-
Limited to humans (i.e. no animal, simulation, or in-vitro studies were
considered).
-
Randomized controlled trials, comparative clinical studies and quality of life
studies (with 10 or more subjects), economic studies, systematic reviews, or
health technology assessments that addressed -the efficaciousness, effectiveness,
or efficiency of LVADs.
Role of mechanical assist devices
The shortage of donor hearts, and growing pool of qualifying patients has led to
the exploration of alternatives to biological heart transplantation, such as: left ventricular
reconstruction procedures; mitral valve repair; cardiomyoplasty; and ventricular assisting
devices (4). In 2004, six of the twelve Canadian transplant programs were using VADs
(3).
Mechanical assistance is mainly used for three purposes: bridge-to-transplant
(BTT), bridge-to-recovery (BTR), and destination therapy (DT). These categories can be
broken into two implantation strategies: 1) emergency support and 2) elective support.
The emergency group includes post-cardiogenic shock myocardial infractions, and other
acute causes where a patient is deteriorating quickly, thus a VAD is inserted as an attempt
4
to save the patient. This group often receives mechanical support for a short period of
time, until statilitation or urgent heart transplantation. The second group includes patients
deemed suitable for transplantation but whose condition deteriorates before a heart is
available (5). Most centres implant VADs in the elective setting. This is the most
common implantation strategy, and thus the main focus of this review.
Currently, Health Canada has approved seven VADs: Novacor Left Ventricular
Assist System (LVAS), the Heartmate Implantable Pneumatic (IP) LVAS, the Heartmate
XVE, the Abiomed BVS5000 BiVAD and AB5000, and the Thoratec VAD and IVAD.
There is also a recently approved total artificial heart (TAH), the Cardiowest C 70 TAHT; designed to replace the bottom portion of the heart thus assuming the task of
circulation. There are currently four device-manufactures on the Canadian market, but at
least 10 device-manufactures internationally (notably the US, Germany, and Japan);
many of these devices are approved in other countries, others are still in clinical trials.
The growing size of the market indicates that manufactures feel the demand for such
devices will increase.
General consensus based on non-randomised observational evidence is that BTT
with a VAD is an effective treatment. The mortality rate for BTT VAD support in the 19
observational studies we reviewed (post-2000, n>10, excluding subset analyses) is
presented in Table 1. Mortality rate while on VAD support is observed to be between 10
and 52% (average support time ranged from 40.7 to 542 days). There is insufficient
evidence to draw conclusions about the efficacy of BTR, but overall it seems that bridgeto-recovery is not possible in most cases. The only randomised study showed no
advantage to VAD compared to IABP in cardiogenic shock post myocardial infraction
5
(6). One large randomised trial (REMATCH) demonstrates a survival gain for VADs as
destination therapy when compared to optimal medical management (OMM) (7). KaplanMeier survival estimates for the VAD group was 52% compared to 25% for the OMM
group (P=0.002), two-year survival was 23% versus 8% respectively (P=0.09).
Safety of the devices also needs to be considered. Yet, it is difficult to synthesize
device safety in the observational literature because complications are defined differently
across studies/centers, rates are often calculated differently, and there is often no
comparison group. However, reported complications include hemorrhaging, right
ventricular failure, infection, thromboembolism, hemolysis, abdominal complications,
liver failure, and device failure.
The randomized studies available suggest that VADs are less safe than their
comparison. REMATCH demonstrated that the HeartMate XVE as destination therapy
was associated with a 2.35 (95% CI: 1.86-2.95) times higher complication rate than
optimal medical management (7). 67 of the 68 DT VAD patients (99%) experienced a
serious adverse event (8). Thiele et al. (6) found that the Tandem Heart VAD as a bridgeto-recovery was associated with more overall bleeding events than intra aortic balloon
pumps (IABP) (VAD=19, IABP=8, p=0.002), but specifically more disseminated
intravascular coagulation (DIC) (VAD=13, IABP=3, p=n/a), and a higher probability of
limb ischaemia than IABP (VAD=7, IABP=0, p=0.009). Such increase risk of adverse
events not only increases mortality and morbitity, but it also has a significant impact on
hospital costs.
The long-term effects of VAD implantation are not well known. Long-term
outcomes of destination therapy VAD may not be a major concern due to the high
6
mortality rate associated with this therapy. No studies have evaluated the long-term
effects of bridging-to-recovery due to the limited application of BTR. Data on the longterm effect of VADs used as bridge-to-transplantation is limited. There is however, some
evidence to suggest that neurological events while on VAD support may lead to some
cognitive impairment after transplantation (9). Radovancevic et al. (10) retrospectively
analysed whether bridging patients to transplant with a VAD increased the risk of
coronary artery disease. Their results showed no statistical association between VAD as a
bridge-to-transplant and transplant coronary artery disease.
The developments in VAD technology are steadily progressing. Such progress is
expected to lead to increased survival and reduction in adverse events. Manufacture
interest likely arises from a societal demand for alternatives to cardiac transplantation,
however, it remains unclear what price society is willing to pay to meet this demand.
Cost-effectiveness
Concern regarding the economic aspects of cardiovascular therapy is increasing.
Approval of devices by Health Canada, and use in the hospital setting are often based
solely on effectiveness; despite increasing health care costs, efficiency remains a
secondary issue.
Our review found only one economic evaluation of mechanical assistance in
Canada. The results for elective implantation of VADs are outlined in Table 2. Although
this estimation does not use data from randomised studies, it documents assumptions in a
clear manner for the reader to evaluate the applicability of the results to their
setting/experience. The cost effectiveness of bridging a patient to transplant with a VAD,
when compared with current survival is estimated to be $126,300 or $186,000 ($138,900
7
and $204,6001 (2004CDN)) (0% or 5% discount rate respectively) per life year gained.
The cost effectiveness of DT is found to be $71,000 or $68,000 ($78,100 and $74,800
(2004CDN)) (0% or 5% discount rate respectively) per life year gained. These estimated
are not adjusted for quality of life. The survival data used for the DT was estimated
before the results of the REMATCH trial and over estimate current expectation of
survival by approximately 1.3 (70% survival versus 52%) in the first year and almost 3fold (66% versus 23%) in the 2nd year. Therefore the actual cost-effectiveness ratio of
VADs compared to OMM for destination therapy is expected to be much higher than this
study suggests.
Although there have been several simple cost-analyses of VADs (37, 38, 39, 40,
41). Our review found only two international cost-utility studies since McGregor’s
evaluation was published. The results of these studies are outlined in Table 3. A recent
British study by Clegg et al. (15) evaluated the cost-effectiveness of BTT and DT. The
cost-effectiveness of BTT using observational data with an expected increase in survival
post-heart transplant (as found by Aaronson et al. (16)) of VADs compared to OMM was
estimated to be £65,242/ QALY (~$153,3002 (2004CDN)). When no post transplant
survival is expected (as found by Massad et al. (17)) the cost effectiveness of VADs
compared to OMM is found to be £497,708/ QALY (~$1,169,6001 (2004CDN)). The
authors estimate the cost-effectiveness of DT VAD compared to OMM for patients not
qualifying for transplantation (survival results from REMATCH). They estimate the cost-
1
Bank of Canada CPI of 112 (Jan 2000) to 123.2 (Jan 2004) (base year: 1992).
2
Using the December 2004 exchange rate of 2.35 CDN = 1 GBP.
8
effectiveness ratio to be £170,616/ QALY (~$400,9001 (2004CDN)). Finally, a study by
the Blue Cross Blue Shield (18) in the United States used REMATCH survival data to
calculate the cost effectiveness of VAD compared to OMM for destination therapy. They
estimate the cost-effectiveness ratio to be $802,700US/ QALY (~$1,324,4003
(2004CDN)).
Although the generalisability of international cost-effectiveness studies is limited.
International findings suggest that VADs as BTT and DT may not be cost-effective.
However, there has been no on-going Canadian discussion about this issue or recent
evidenced based evaluation of these devices, within the Canadian context. From the
viewpoint of cost-effectiveness VADs as BTT or as destination do not appear to be cost
effective. However, rigorous economic evidence has not been presented in Canada. A
discussion of the use of VADs taking cost-effectiveness into account is necessary.
Discussion
Devices are approved by Health Canada and are being offered in half the
transplant clinics in Canada as BTT and BTR. VADs were initially developed for the
purpose of providing an alternative to transplantation, their use as bridge-totransplantation was a derived use that has proven beneficial in terms of prolonging some
lives that may have been lost, and providing information on the efficacy and safety of
these devices, but does not increase the number of donor hearts, or decrease the demand
for donor hearts. Thus the benefit of BTT remains limited.
3
Using December 2002 exchange rate of 1.56 and Bank of Canada CPI of 116.2 (Jan 2002) to 122.9 (Jan
2004) (base year: 1992).
9
VAD technology produces a conundrum for the current Canadian Medicare
system: how to properly balance population and individual health. From an individual
health standpoint it is difficult to deny access to a currently available Health Canada
approved life extending technology. However, from a population standpoint it is difficult
to justify the use of BTT VADs, as the benefit is short term and available to a very small
proportion of the population. In this case, giving each individual patient the optimal care
is likely to lead to decreased resources for others, thus less optimal overall population
care. Although DT VADs appear to produce a greater increase in life-years saved, they
remain a resource intensive therapy, and may lead to a similar dilemma, although
conclusions should not be drawn until a cost-effectiveness evaluation is completed within
the Canadian context.
Evidence regarding the cost-effectiveness of these devices in Canada is very
limited. Cost-effectiveness studies in the UK and US suggest that VADs as BTT or DT
are likely not cost-effective. The increasing age of the population along with the
proliferation of cardiac technology have grave implications for the sustainability of
Canada’s universally funded Medicare system (19). Thus treatments should be not only
effective, but also efficient. Efficiency, through the use of cost-effective therapies, is
essential in order to maintain universally provided Medicare.
Initially cardiac transplantation had disappointing results, but it has since emerged
as the gold standard for terminal heart failure. VAD research and device improvement
could ultimately lead to future VADs being more promising, notably the axial flow
pumps, which do not require valves or venting. Investing in research in this area is
10
worthwhile, however as it stands, it does not appear that investing in VADs for
widespread use is as valuable.
Figure 1: Cardiac Transplant Wait-list Canada: 1993-2004
350
300
Number of patients
250
200
Deaths on Wait-list
Patients Waiting for Transplant at Year-End
Heart Transplants
150
100
50
0
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
Year
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Table 1: Observational bridge-to-transplant VAD studies 2000-05 (excluding subset
analyses, with n>10)
Study
Device
Period
Patients Support Time
Mortality on
(average days)
VAD (%)
Bank, 2000 (20) HeartMate
1995-1998 20
N/A
10%
Korfer, 2000
Thoratec
1992-1998 84
44.9
30%
(21)
El-Banayosy,
Novacor
1996-1998 20
235.3
20%
2000 (22)
Deng, 2000 (23) Novacor
1993-1996 39
98
36%
HeartMate
Medos
Di, 2000 (24)
Novacor
N/A
36
203
30.5%
Noon, 2001
DeBakey
2000-2001 21
47
31%
(25)
Frazier, 2001
HeartMate
1996-1998 280
112
29%
(26)
Frazier, 2002
Jarvik 2000 2000-2001 10
84
30%
(27)
Aaronson, 2002 HeartMate
1996-2001 104
N/A
18%
(16)
Narvia, 2002
HeartMate
1991-2001 264
N/A
29%
(28)
Novacor
(at 1year)
MicroMed
Meyns, 2002
Novacor
1998-2000 47
N/A
36%
(29)
Abiomed
Medos
Holman, 2002
HeartMate
1997-2001 46
138
33%
(30)
Thoratec
Granfeldt, 2003 HeartMate
1993-2002 59
99.5
18.6%
(31)
Goldstein, 2003 DeBakey
1998-2002 150
75
45%
(32)
Vitali, 2003 (4) DeBakey
2000-2001 11
51
18.2%
Vitali, 2004
Thoratec
1988-2003 80
77
25%
(33)
Abiomed
Novacor
Medos
DeBakey
Impella
12
Copeland, 2004
(34)
El-Banayosy,
2005 (35)
Baran, 2005
(36)
CardioWest
(TAH)
CardioWest
(TAH)
HeatMate
Novacor
1993-2002
130
79.1
2001-2003
42
86
21% (per
protocol)
52%
1989-2002
39
78.3
33.3%
Table 2: Cost-effectiveness of VADs in Canada (McGregor 2000 (13))
Bridge-to-transplant Destination
Device evaluated
Novacor
Novacor
Comparator
Current survival
Live one year in
absence of VAD
Method
Estimated additional Estimated additional
survival divided by
survival divided by
estimated cost
estimated cost
Perspective
Payer
Payer
Time period
13 years
12 years
Costs included
Device, 100 days of Device, device
support, transplant
replacement
Discount rate
0 or 5%
0 or 5%
Baseline ICER
$126,304 or
$71,000 or 68,000/
186,000/ LYG
LYG
Sensitivity
N/A
N/A
Source of survival
Systematic review
Transplant data,
data
of observational
expert opinion‡
studies, expert
opinion
‡
Hypothesized mortality rate of 30% for the first year and an additional 4% for each
subsequent year.
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Table 3: International cost-utility studies on VADs
Clegg et al. (15)
Clegg et al. (15)
Country
Device evaluated
Indication
Comparator
Method
UK
HeartMate*
Bridge-to-transplant
OMM
5-year decision
analytic model
Payer
UK
HeartMate
Destination
OMM
Pseudo-Markov
model
Payer
5-years
Assessment, device,
operation, medical
management
Baseline ICER
5-years
Assessment, device,
operation,
transplant, medical
management
Costs 6%, benefits
1.5%
£65,242/ QALY
Sensitivity
£52,125 to £84,152
£136,597 to
£190,283
REMATCH (7)
Perspective
Time period
Costs included
Discount rate
Costs 6%, benefits
1.5%
£170,616/ QALY
Blue Cross/ Blue
Shield (18)
US
HeartMate
Destination
OMM
Decision and
Markov model
Societal (excluding
indirect costs)
3 years
Device, implant, rehospitalizations, and
outpatient
3%
$802,700US/
QALY
$447,600 to
$1,350,700
REMATCH (7)
Source of survival
Aaronson et al.
data
(16)†
*
Also used Novacor, MicroMed DeBakey and Jarvik in the sensitivity analysis.
†
If other survival data source used (i.e. no post-transplant increase in survival) cost/
QALY changes considerably: ex. Massad et al. (17) yields £497,708/ QALY or Noon et
al. (25) yields £59,642 to £366,270/ QALY.
14