Technology Note
Percutaneous Interventions for Mitral Regurgitation
March 2013
Introduction
This Technology Note follows from a referral to the National Health Committee (NHC) proposing a
pilot study of Abbott Laboratory’s MitraClip® procedure at Waikato DHB. The MitraClip®
procedure is a percutaneous intervention for mitral valve1 repair to treat mitral regurgitation (MR).
As new health technologies often face competing technologies, alternative percutaneous
interventions for the repair or replacement of the mitral valve have been reviewed. The evidence
base for the emerging procedures is still fairly limited with only MitraClip® having a published
randomised controlled trial to its name. Furthermore, although many such interventions are in
development, only two are currently available on the market internationally; these are MitraClip®
and Cardiac Dimension’s Carillon® procedure. Accordingly, the paper is largely focused on
MitraClip® as it has the most developed evidence base. The paper summarises available
evidence on the population burden of disease for MR, and evaluates the safety, efficacy,
effectiveness and cost-effectiveness evidence for percutaneous interventions.
Mitral Regurgitation
MR, also known as mitral insufficiency or mitral incompetence, occurs when the heart's mitral valve
does not close tightly; allowing blood to flow backward into the upper heart chamber (atrium),
causing the heart to work harder to maintain circulation. MR is the most common type of heart
valve insufficiency [1], with population estimates of significant (moderate or worse) MR ranging from
2-12% [2-4].
It is useful to distinguish between degenerative (primary) MR (DMR) and functional (secondary)
MR (FMR). FMR is caused by ischaemic (coronary artery disease) and non-ischaemic heart
diseases (e.g., idiopathic dilated cardiomyopathy) via multiple different mechanisms, including
impaired Left Ventricular (LV) wall motion, LV dilatation, and papillary muscle displacement and
1The mitral valve
sits between the two chambers on the left side of the heart – the left atrium (the upper chamber) and the
left ventricle (the lower chamber). The valve prevents blood regurgitating backwards into the upper heart chambers during
cardiac contractions.
Percutaneous Interventions for Mitral Regurgitation
1
dysfunction [5]. The mitral valve in FMR is structurally normal [6]. By contrast DMR, sometimes
referred to as organic MR, is caused by structural abnormalities of one or more of the components
of the mitral valve, causing it to leak, and imparting a volume overload on the LV [7]. As discussed
below, there is emerging evidence that the use of MitraClip® may better treat patients with FMR
than DMR.
MR severity is graded on a scale of 1 to 4, where 1 is mild, 2 is moderate, 3 is moderately severe,
and 4 is severe. The MitraClip® has been targeted at patients with significant (moderate or worse)
MR. MR is typically a long-term condition evolving over many years as the heart compensates for
the regurgitant volume by left atrial enlargement, LV volume overload, and progressive LV
dilatation [5]. If untreated the prognosis for patients with severe MR is poor; symptomatic patients
have an annual death rate of 5% or more [7-9].
Burden of Disease
There are few available studies on the prevalence of MR internationally and none for New Zealand.
A commonly cited study of 3,500 Native Americans, the Strong Heart Study, estimates significant
(≥2+) MR occurring in about 2% of the population with a similar prevalence in men and women [3].
The Framingham Study of nearly 3,600 individuals derived a similar finding with both studies
reporting increasing prevalence with age [2]. The grade of severity in these studies, however, was
based on the spatial distribution of the regurgitate jet, a rapid and simple but inaccurate method
[4]
.
A retrospective echocardiographic study of 6851 Americans without suspected valve disease found
the overall prevalence of significant MR was 11.7% in men and 12.5% in women with prevalence
increasing significantly with age [4]. Prevalence of significant MR increased from 5% for men
younger than 31 to 17.1% for men over 80 years of age. Similarly, the figures for women were 3%
(age <31) and 21.4% (age >80). The authors attribute the larger estimates of significant MR in this
study compared with the Framingham and Strong Heart studies, to more accurate testing of
severity but concede selection bias in their study. Patients with MR are more likely to have
echocardiograms ordered; hence they may have overestimated MR prevalence.
Following the Framingham and Strong Heart studies, a 2% prevalence of significant (≥2+)MR
equates to approximately 89,500 New Zealanders with significant MR (census population 2006).
An alternative method was undertaken to count the number of patients, still resident, and
diagnosed with MR in public and private hospitals since 1988. Doing so gives a count of 10,276
patients in 2011, which equates with 0.23% of the population - roughly equivalent to the Strong
Heart’s 0.2% estimate for severe MR(4).
Percutaneous Interventions for Mitral Regurgitation
2
The capture-recapture method2 was used to estimate the number of patients with a similar severity
of MR but not diagnosed in hospital. Using this technique an additional 16,056 patients not
diagnosed in hospital were identified. That equates to 0.36% of the population which is roughly
equivalent with the Strong Heart’s 0.3% estimate of patients with moderately severe MR. Figure 1
presents two estimates of MR prevalence in 2011 by age. The lower estimate is the count
(discussed above) of patients diagnosed in hospital with MR since 1988 who are still resident. The
greater estimate employs the capture-recapture technique, to adjust for under-reporting of the
disease. Consistent with the literature, MR prevalence is shown to increase significantly with age.
Figure 1: Estimated Prevalence of MR in New Zealand 2011
5.0%
4.5%
4.0%
3.5%
3.0%
2.5%
Prevalence
2.0%
Prevalence (CRC)
1.5%
1.0%
0.5%
00-04 Years
05-09 Years
10-14 Years
15-19 Years
20-24 Years
25-29 Years
30-34 Years
35-39 Years
40-44 Years
45-49 Years
50-54 Years
55-59 Years
60-64 Years
65-69 Years
70-74 Years
75-79 Years
80-84 Years
85+ Years
0.0%
Source: NHC analysis of NMDS
2
See Appendix two for explanation.
Percutaneous Interventions for Mitral Regurgitation
3
Regulatory status
Under current New Zealand legislation there is no pre-market scrutiny of devices and no approval
is required before a device can be supplied. However, for medical devices to be legally supplied in
New Zealand they must be notified to MedSafe’s Web Assisted Notification of Devices (WAND)
Database.3 The MitraClip® device was notified to the WAND database in July 2010, but Abbott
has confirmed the device has yet to be used in New Zealand. In Europe the device received
regulatory approval (CE Marking) in 2008. In Australia the Therapeutic Goods Administration
(TGA) approved the device in November 2010. On 20 March 2013 the United States Food and
Drug Administration (FDA) approved the MitraClip® device [10]. The decision required the tiebreaking vote from the FDA Circulatory System Devices advisory panel chair. The decision
followed a largely unfavorable review of the technology for the advisory panel by the FDA Division
of Cardiovascular Devices which found that the evidence presented did not “constitute valid
scientific evidence of safety and effectiveness for the MitraClip® … for use in an inoperable MR
population [11].”
Literature Review Methodology
The NHC undertook to review available published evidence for percutaneous mitral valve repair
and replacement. A systematic literature search was conducted on mitral valve repair to find
available safety, efficacy, and effectiveness evidence adapting an early search strategy developed
by the National Institute for Health and Clinical Excellence (NICE) [12] (Appendix 1). MEDLINE,
Embase, and Cochrane databases were searched from January 1 2005 to 28 February 2013.
Coupled with this was a search of available literature from international health technology
assessment agencies websites using the keyword “mitral valve” and “MitraClip”. The appended
search strategy was refined to identify additional cost-effectiveness literature, but did not yield any
new literature beyond that obtained in the original search. Abstracts were independently screened
by two NHC analysts according to pre-specified PICO question and inclusion/exclusion criteria
(Table 1). Studies that met the inclusion criteria were retrieved and reviewed for study eligibility.
Table 1: PICO question and inclusion and exclusion criteria
Question
3
Inclusion Criteria
Exclusion Criteria
Population
Patients with MR
Non-human/animal trials
Intervention
Percutaneous mitral valve repair
Outcome
Safety, efficacy, effectiveness, cost-effectiveness
other outcomes
Study Type
HTAs, systematic reviews and meta-analyses,
RCTs, and observational studies
case reports, single centre studies,
opinion pieces (other than editorials
to studies), abstracts only (authors
Devices must be notified to the WAND database within 30 calendar days of a person or organisation becoming the
sponsor of the device. A sponsor is a person or organisation that imports or exports a device or that manufactures or
arranges the manufacture of a device in New Zealand.
Percutaneous Interventions for Mitral Regurgitation
4
contacted for full articles)
For procedures other than MitraClip®, a quality filter was not used in the literature retrieval stage
as there were very few such articles identified; instead the focus was on topical relevance. Two
cost-effectiveness analyses for MitraClip® were sourced external to the literature search, through
contact with researchers and Abbott Laboratories.
A separate systematic search building on the NICE search strategy did not yield relevant literature
for percutaneous mitral valve replacement (as opposed to repair). A non-systematic search of
Google Scholar found two recent summaries for the treatment of mitral regurgitation [13, 14]; which in
combination with a current health technology assessment on cardiac technologies prepared for
HealthPACT [15], confirmed that there are relatively few percutaneous mitral valve replacement
procedures in development, and only one first-in-human trial conducted to date. See Figure Two
below.
Figure 2: Flow diagram showing study identification process
Potentially relevant
citations identified through
MEDLINE, Embase and
Cochrane databases
(excluding duplicates)
Potentially relevant
citations identified
through HTA agency
search (excluding
duplicates)
Additional citations
identified through Google
Scholar, HealthPACT,
contact with researchers,
and manufacturer websites
N=130
N=3
N=7
Citations excluded
Retrieval of potentially relevant
articles
N= 35
Studies excluded after
assessment of full text
Studies included in the review
N=21
2 CEA
1 RCT
4 HTAs
Percutaneous Interventions for Mitral Regurgitation
3 Reviews
11 other
5
Alternative Treatments
United States and European clinical practice guidelines recommend mitral valve surgery for
degenerative disease, with surgical repair recommended over replacement where possible due to
better post-operative left ventricular function, improved survival, and lower long-term morbidity [16,
17]
. Surgical treatment, which aims to be curative, is not an option for many patients at high risk of
surgical mortality. For FMR medical therapy is the preferred treatment as there is significant
uncertainty about the long term prognosis of FMR surgical patients [16]. Medical treatment is poorly
defined for some patient groups, and is often purely focused on relieving symptoms
[7,16, 17]
.
At least 25 other percutaneous devices are in development for the treatment of MR (Table 2). Only
a subset of these devices can be expected to come to market. Embase4, a large medical literature
database, was used to count the number of articles each device had been mentioned in (where the
device may or may not be the focus of the article). The count of publication citations is used as a
rough proxy for the development of a technology, or at least the seriousness with which
researchers regard the technology. By this measure the MitraClip® is the clear leading technology
with five times as many citations as any other device. The leading alternative technology appears
to be Indirect Annuloplasty via coronary sinus reshaping. The next three highest scoring devices
all adopt this approach, including the only other technology in clinical use – the Carillon device
which received a CE Mark in 2011.
The Indirect Annuloplasty approach involves positioning a device within the coronary sinus5 to
reduce the mitral annulus area6. The approach has been shown to improve closure of the valve
and decrease MR [13]. Despite receiving CE Mark the Carillon device has yet to be subjected to a
randomised control trial. Evidence to date is limited to three small non-randomised case series: an
initial trial of 9 patients [18], the AMADEUS trial (n=48) [19], and the TITAN trial (n=53) [20]. NICE
reviewed the technology in 2010 finding the evidence base on safety and efficacy “inadequate in
quality and quantity” [21]. The Australia New Zealand Horizon Scanning Network review in the
same year also found a lack of high quality evidence supporting the device [22] - a finding which
was reiterated by HealthPACT’s 2012 assessment [23]. What evidence there is suggests the
approach risks coronary artery compression, mitral annulus calcification, and has a relatively high
device insertion failure rate [13].
4
5
6
Embase has 25 million records including all MEDLINE records produced by the National Library of Medicine.
The coronary sinus is a short vein located along the heart's posterior surface between the left ventricle and left atrium.
The mitral annulus is a ring that is attached to the mitral valve leaflets.
Percutaneous Interventions for Mitral Regurgitation
6
Table 2: Alternative Percutaneous Devices for MR
Percutaneous Mitral Valve Repair
Site of Action
Mechanism of
Action
Edge-to-edge
(leaflet plication)
Status
Embrase
Publication Count
Mitra Clip®
(Abbott Laboratories PLC, USA)
Phase l and ll Randomised
Control Trials CE Mark (2008)
251
MitraFlex
(TransCardiac Therapeutics, USA)
Pre-clinical development
3
Phase I trial in progress
3
Thermocool (Biosense Webster –
J&J PLC subsidiary, USA)
Animal models
3
Monarc
(Edwards Lifesciences PLC, USA)
Phase I in progress
52
Carillon
(Cardiac Dimensions, USA)
Phase I complete
CE Mark (2011)
64
Viacor
(Viacor Incorporated, USA)
Phase l in progress
31
Unnamed device
(St Jude Medical PLC, USA)
Animal models
8
NIH – Cerclage technology
(Nat. Institutes of Health, USA)
Animal models
5
Mitralign
(Mitralign, USA)
First-in-human (Phase 0)
results
0
Accuicinch GDS
(Guided Delivery Systems, USA)
First-in-human results
15
Millipede ring system
(Millipede) SP USA
Preclinical development
0
QuantumCor
(QuantumCor, USA)
Animal models
25
Unnamed device
(ReCor Medical, France)
Preclinical development
7
Unnamed device
(Mitral Solutions Inc, USA)
Preclinical development
Surgically implanted – may go
percutaneous
3
Unnamed device
(MiCardia, USA)
Preclinical development
Surgically implanted – may go
percutaneous
5
Device (Developer)
Leaflets
Space occupier
(leaflet coaptation)
Leaftlet ablation
Percu-Pro
(Cardiosolutions, USA)
Indirect annuloplasty
Coronary sinus
approach
Asymmetrical
approach
Direct annuloplasty
Annulus
Percutaneous
mechanical cinching
Percutaneous
energy medical
Hybrid
Percutaneous Interventions for Mitral Regurgitation
7
Transpical
Neochord
(Neochord Inc, USA)
Preclinical development
12
Mitraflex
(Neochord Inc, USA)
Preclinical development
3
Babic
(Unknown developer)
Pre-clinical development
1
Mardil-BACE
(Mardil Inc, USA)
First-in-human results
2
Artificial chord
Chordal
Implants
Transapical-Transseptal
Artificial chord
Left Ventricle
LV (and mitral
annulus)
remodelling
Percutaneous Mitral Valve Replacement
Right minithoracotomy
Endovalve-Herrmann prosthesis
(Micro Interventional Devices,
USA)
Animal models
6
Transapical
Lutter prosthesis
(Unknown developer)
Animal models
5
Transseptal
CardiaQ Prosthesis
(CardiaQ Valva Technologies,
USA)
First-in-human results
0
TransapicalTransseptal valvein-ring
Melody Transcatheter Pulmonary
Valve
(Medtronic PLC USA)
Animal models for MR, in
clinical use for other
indications
0
Valve
Implants
Primary Sources:[13, 14], and Embase for publication count
Safety, Efficacy, and Effectiveness of MitraClip®
The MitraClip® procedure mimics the Alfieri edge-to-edge surgical technique. A catheter (long thin
flexible tube) is guided through the femoral (inner thigh) vein to reach the heart
[24]
. The clip is
delivered through the catheter to the heart where the mitral valve is clipped at the site of the
regurgitant jet allowing the mitral valve to close more effectively. The procedure is performed under
general anesthesia guided using fluoroscopy7 and transesophageal echocardiography8.
Echocardiography is used to assess the reduction of mitral regurgitation, where the device may be
removed if seen to be ineffective or an additional clip attached. This section reviews the results
from the major trials of MitraClip®.
7
8
A common imaging device based around x-ray.
A specialized probe with an ultrasound transducer at its tip which is passed into a patient's oesophagus to take internal
echocardiograms.
Percutaneous Interventions for Mitral Regurgitation
8
The EVEREST Trials
Evidence suggests the MitraClip® device is safe but less effective at reducing MR than
conventional surgery. The landmark trial for the device is the Endovascular Valve Edge-to-Edge
Repair Study (EVEREST) II. EVEREST II follows on from the phase one EVEREST I trial.
EVEREST II is a five year randomized controlled trial comparing the MitraClip® device to surgery
in 279 patients with moderately severe (3+) or severe (4+) MR [25]. The patient group was split
2:1 with 184 patients in the percutaneous-repair group and 95 in the surgery group. Baseline
characteristics of each group were similar with the exception that a history of congestive heart
failure was more common in the percutaneous-repair group (91%) compared with 78% in the
surgery group [P=0.005].
The trial was critically appraised by three NHC reviewers independently using the GATE critical
appraisal checklist for intervention studies9. The quality of the evidence was then evaluated
against the U.S. Preventive Services Task Force (USPSTF) assessment criteria. The reviewers
agreed that the quality of the evidence presented in the RCT was ‘fair’ (see box below).
Appraisal of EVEREST II
The USPSTF grades the quality of the overall evidence for a service or intervention on a 3-point scale
(good, fair, poor):
Good: Evidence includes consistent results from well-designed, well-conducted studies in representative
populations that directly assess effects on health outcomes.
Fair: Evidence is sufficient to determine effects on health outcomes, but the strength of the evidence is
limited by the number, quality, or consistency of the individual studies, generalizability to routine practice, or
indirect nature of the evidence on health outcomes.
Poor: Evidence is insufficient to assess the effects on health outcomes because of limited number or power
of studies, important flaws in their design or conduct, gaps in the chain of evidence, or lack of information on
important health outcomes.
Main features
9

The trial was conducted across 37 sites across the United States and Canada. All sites were
required to have experience with percutaneous interventions, transseptal punctures, and mitralvalve surgery, along with a strong multidisciplinary team. This may limit the study’s
generalizability to real world settings, particularly in countries where this level of expertise is not
as strong.

The mean age of patients was 67.3 for the percutaneous group and 65.7 in the surgical group.
Other then there being more patients in the percutaneous group with congestive heart failure,
there were no other significant differences between the two groups.

Allocation was randomised through random blocks of 4 to 6. Sites used an interactive voice
response system to complete the randomization assignment for each patient enrolled.

Neither patients nor clinicians were blinded to the allocation of the patients. However, this is
unlikely to introduce an important source of bias as the underlying comorbidities were comparable
http://www.fmhs.auckland.ac.nz/soph/depts/epi/epiq/ebp.aspx
Percutaneous Interventions for Mitral Regurgitation
9
between the two groups. It is also unclear whether the researchers were blinded. If they were
not blinded, this will have introduced the potential for bias. The potential bias is more important
for softer measures of effectiveness such as patient reported quality of life improvements rather
than hard measures like mortality.

More of the surgical group were lost to follow up or dropped out than the percutaneous group.
However, participation rates were still high at 24 months being 93% for the percutaneous-repair
group and 87% for the surgery group. The 21 patients who discontinued particpation were
considered to maintain the same grade of mitral regurgitation as the grade at baseline for the
efficacy analysis, hence it is unlikely dropout rate is a major source of bias.

The study said that groups were analysed according to ‘intention to treat’.

It is unclear whether the repair and surgical group were treated equally or not in terms of the
receipt of additional interventions or the provision of services in a different manner. This may be
an important source of bias.

The surgical group involved multiple techniques and results were not stratified by surgical type.
Mitral-valve replacement was performed in 14% of surgical patients and repair in the remaining
86%. Of the repair patients 55% underwent leaflet resection and annuloplasty, 23% underwent
annuloplasty alone, 20% underwent complex leaflet or chordal repair with annuloplasty, and 1%
underwent an unspecified method of leaflet repair. The MitraClip® may perform better or worse
against different surgical techniques than is suggested by the undifferentiated results of the
surgical group.

Sub-group analyses were not determined apriori. This could heavily influence the results since
they were reported opportunistically.

The follow-up period for complications was only 30 days, as opposed to 12 and 24 months for
efficacy – this may omit any late complication difference (especially as most surgical
complications occur peri-operatively)
All reviewers agreed that the quality of the evidence was ‘fair’. It was sufficient to determine effects on
health outcomes, but the strength of the evidence is limited as there is only one trial investigating the
intervention’s effectiveness, and similar results may be unable to be achieved in real world clinical settings.
Given that the intervention appears most useful in high-risk patients (discussed below), and the study only
looked at candidates suitable for surgery, the results cannot be generalised to this patient group.
Safety
Feldman et al measured the rate of major adverse events at 30 days, a composite of 12 measures
including death, myocardial infarction, reoperation for failed mitral valve surgery and blood
transfusion (2 units or more).10 The rates of major adverse events at 30 days were 15% for the
percutaneous-repair group and 48% in the surgery group [P<0.001]. However, just over 90% of
reported adverse events were for blood transfusions. Adverse events excluding transfusions were
5% for the percutaneous-repair group and 10% in the surgery group, but the difference is
statistically insignificant [P=0.23]. Transfusion is important in cardiac surgery but it dominates the
adverse event rate in the surgical group and is likely to introduce a degree of confounding. Aside
from blood transfusion the only statistically significant difference in adverse events was for the use
of mechanical ventilation (for greater than 48 hours) which was required by 4% of surgical patients
but no percutaneous-repair patients [P = 0.02] .
10
Other measures included non-elective cardiovascular surgery for adverse events, stroke, renal failure, deep wound
infection, and mechanical ventilation for more than 48 hours, gastrointestinal complication requiring surgery, new-onset
permanent atrial fibrillation, and septicaemia.
Percutaneous Interventions for Mitral Regurgitation
10
In May 2011 the device was voluntarily recalled by Abbot for minor modification to the delivery
catheter [26]. Abbot has confirmed to the NHC that the issue has been resolved.
Efficacy
Feldman et al found surgery more effective than the MitraClip® device in addressing mitral
regurgitation [25]. Their primary endpoint for effectiveness was a composite measure combining
freedom from death, freedom from surgery for mitral-valve dysfunction, and freedom from grade 3
or 4 mitral regurgitation. At 12 months 55% of patients in the percutaneous-repair group met the
criteria compared with 73% in the surgery group [P=0.007]. At 24 months the figures were 52%
and 66% respectively. Decoupling the measure, mortality and persistence of severe regurgitation
(grade 3 or 4) were similar between the groups at 12 and 24 months. At 24 months 11% of patients
in both groups had died. At 24 months, 20% in the percutaneous-repair group and 22% in the
surgery group had grade 3 and 4 mitral regurgitation.
The difference in effectiveness between the groups was driven by the third measure – follow-up
surgery for mitral-valve dysfunction. At 12 months the rate of surgery for mitral-valve dysfunction
was 20% (37 patients) in the percutaneous-repair group compared with 2.2% in the surgery group
[P<0.001]. That is, one in five patients who underwent percutaneous repair subsequently required
surgery. Of these patients 17, or just under half, had no implantation of the device. At 24 months
22% of MitraClip® patients had undergone corrective surgery compared with 4% of the surgical
arm.
Feldman et al’s study of 109 patients from the EVEREST I and II trials estimated that Kaplan-Meier
11
freedom from surgery was 88.5%, 83.2%, and 76.3% at 1, 2, and 3 years, respectively [27]. There
is some concern the device might damage the valve and limit secondary surgery if required.
Argenziano et al found that surgical options are preserved in the great majority of patients
receiving MitraClip® [28]. Some evidence suggests, however, the procedure may increase the
probability of valve replacement rather than repair if secondary surgery is required
[29]
. This is an
issue as replacement is associated with worse health outcomes, including reduced survival,
compared with repair [16, 17].
Feldman et al conducted a subgroup analysis of the EVEREST II results. They found patients
older than 70, patients with FMR and patients with a left ventricular ejection fraction (LVEF) of less
than 60% appeared to benefit most from the device. Table three summarizes the main findings of
the subgroup analysis by the composite effectiveness measure12 at 12 months.
11 The Kaplan-Meier is a statistical estimator for survival.
12
combining freedom from death, freedom from surgery for mitral-valve dysfunction, and freedom from grade 3+ or 4+
mitral regurgitation
Percutaneous Interventions for Mitral Regurgitation
11
Table 3 Subgroup Analysis of effectiveness at 12 months
Subgroup
Percutaneous Repair %
Surgery %
FMR
54
50
DMR
56
82
Age ≥70
60
61
Age <70
51
82
LVEF <60
51
54
LVEF ≥60
58
82
P-value13
0.02
0.009
0.06
Source: [25]
As is illustrated in Table three, at 12 months the MitraClip® was still effective for 54% of patients
in the percutaneous repair group (not dead, no corrective surgery, no significant MR). Conversely,
patients with DMR benefited significantly more from surgery. For patients 70-years or older the
scores are similar between the two groups, but patients aged under 70-years appear to benefit
more from surgery. For patients with an LVEF less than 60 the group difference in effectiveness is
small, while patients with an LVEF greater than 60 appear to benefit more from surgery. The LVEF
group comparison, however, is just outside the threshold for statistical significance (P=0.06). It
also appears from these results that surgery gets less effective with age declining from 82%
effectiveness (age <70) to 61% (age ≥70), while the MitraClip® gets more effective with age,
improving from 51% effectiveness (age <70) to 60% (age ≥70). This isn’t a result drawn out by the
authors and there is no measure of statistical confidence for it. The authors note the subgroup
analysis should be considered exploratory as the analysis was not pre-specified.
13
The p-value is a measure of statistical significance, typically, a p-value of 0.05 or less is considered statistically significant,
and a p-value greater than 0.05 statistically insignificant. The p-value here measures the significance of the difference
between the two groups.
Percutaneous Interventions for Mitral Regurgitation
12
EVEREST II High Risk Study
The EVEREST II High Risk Study (HRS) assessed the safety and effectiveness of the MitraClip®
device in high risk patients [30]. The authors concluded the device was safe and effective reducing
MR in the majority of patients. The study included 114 patients (mean age 77) with 78 patients
undergoing the procedure and a retrospective control group of 36 patients. Of the patients
undergoing the procedure 46 had FMR and 32 DMR as their primary diagnosis.
The 30-day procedure-related mortality rate was 7.7% in the study group and 8.3% in the control
group, the difference being statistically insignificant. New York Heart Association (NYHA)
functional class improved with 90% of patients having functional class III / IV at baseline reducing
to 26% at 12 months.14 The 12 month survival rate was 76% in the study group and 55% in the
control group (p=0.047).
The editorial to the publication notes a series of shortcomings
[31]
. There was insufficient scrutiny
of patient eligibility for the comparator group; no adjudication of events by the clinical events
committee;15 a relatively small sample size; and no information of patient management or
outcomes other than mortality. The population sample is high risk, but high risk due to age and
comorbidities, not decreased heart function: the mean left ventricular ejection fraction was 55%, a
little lower than the 60% in EVEREST II. An LVEF of between 55% and 70% is considered normal
[32]. Additionally, more than a third of patients did not meet the Society of Thoracic Surgeons
score (>12) for high risk. The procedure-related mortality risk was relatively high for a
percutaneous procedure (7.7%). MR grade 2+ was 69% at year one which is relatively high. One
in five patients had no reduction in MR, or experienced deterioration in MR after the procedure.
Some of the improvement in NYHA class may be attributable to attrition, as one in four patients
died in the first year, therefore the improvements illustrated should be viewed with caution as they
may overstate the efficacy for high risk patients.
The PERMIT-CARE Trial
A small non-controlled observational study of 51 patients (mean age 70) found the MitraClip® was
safe and significantly reduced FMR for patients ineligible for surgery16 [33]. Prior to treatment
patients had significant FMR, a recent history of heart failure (92% with New York Heart
Association class 3 or 4) and had not responded to cardiac resynchronization therapy.17 Twelve
months after treatment approximately 10% of patients had MR of grade two or worse. NHYA
functional class showed improvement for 73% of patients post discharge and the proportion of
14
15
16
17
NYHA class measures the stages of heart failure according to patient symptoms on an increasing severity scale of one to
four: http://www.abouthf.org/questions_stages.htm
Clinical events committees review outcomes (endpoints) reported by trial investigators to determine whether the
outcomes meet protocol-specified criteria.
Defined by either a EuroSCORE >20 or the Society of Thoracic Surgeons score >12. The average preoperative mortality
risk for patients was estimated at approximately 30%.
Pacing of both right and left ventricles independently and simultaneously to improve heart function
Percutaneous Interventions for Mitral Regurgitation
13
patients with more severe heart failure, NHYA class III and IV, significantly reduced over 12
months. The mortality rate was 4.2% at 30-days and 18% at 12 months.
Again while these results point to a positive role for MitraClip® in high-risk patients, the study did
not have a control group so it is difficult to quantify the benefit. In particular, variation in patient
management over the study period might explain some of the improvement.
The TRAMI Registry
Data from the German TRAMI registry, the largest cohort of patients studied to date, suggests that
MitraClip® is safe and effective for high surgical risk patients with significant MR [34]. 486 patients
were enrolled in the industry independent registry between January 2009 and August 2011. 309
patients were retrospectively enrolled and 177 prospectively enrolled. Compared with EVEREST II
patients, patients in the TRAMI registry were on average nearly 8 years older; a larger subset had
a prior myocardial infarction (28% vs 22%) or coronary-artery bypass graft (30% vs 21%); and the
majority (71%) had an impaired left ventricular ejection fraction (<50%) whereas the mean LVF in
EVEREST II was normal (60%). New York heart Association functional class at baseline also
demonstrated greater severity with 93% of patients having NYHA grade III or IV, compared with
52% in EVEREST II. Furthermore the majority of patients had FMR (67%) rather than DMR,
compared with 27% in EVEREST II. 92% of patients had severe systemic MR (grade III) at
baseline, as defined by the American Society of Anesthesiologists.
Safety
No patients died during the operation and in-hospital mortality was relatively low (2.5%). As with
EVEREST II the main in-hospital adverse event was a need for blood transfusion (10.4%), surgery
for failed percutaneous interventions was 3.5%, and major vascular complication (requiring surgery
or transfusion) was 2.8%. Post-discharge mortality, assessed at a median of about 3 months, was
high at 12.5%, reflecting the high-risk status of the patients. Two of the patients followed up (1.8%)
required surgery for failed percutaneous intervention. The rate of corrective surgery appears much
lower than EVERST II (20% at 12 months), though the studies are not exactly comparable, and this
may signal an important learning curve effect.
Effectiveness
Data from the German TRAMI registry shows the procedure was effective for high-risk patients in
reducing MR from baseline measures [34]. Overall follow-up was at a median duration of 85 days.
92% of patients had severe systemic MR (grade III) at baseline. Post intervention 5% of patients
had no MR and 89% had mild (grade I) or moderate MR (grade II), while 6% of patients still had
severe MR (P< 0.0001). NYHA functional class significantly improved, with 125 of the followed up
patients (64%) in NYHA functional class I or II. The investigators note that the results are
Percutaneous Interventions for Mitral Regurgitation
14
consistent with previous findings that, compared with surgery, less MR reduction is achieved with
percutaneous therapy.
Three limitations are noteworthy:
1. Data is derived from a registry rather than a randomized controlled trial. Whilst this gives
insight into the procedures effectiveness in practice it also introduces a number of potential
biases, including selection bias (enrollment of non-typical patients), and does not enable
researches to derive the marginal benefit of the intervention relative to other forms of
treatment (surgery or medication), as there is no control.
2. Follow-up was not consistent across patients: being approximately 1.5 months for
prospective patients, with 78% of patients followed-up, and 6 months for retrospective
patients with just 47% of patients followed-up.
3. Data accuracy and reliability can be an issue with registries where sites and individuals do
not have training in research methods [35]. In this study echocardiographic analysis was not
performed by a core lab, and grading of MR severity did not adhere to the
recommendations of the American Society of Echocardiography.
HTA Reviews
NICE reviewed MitraClip® in 2009 and found the evidence of safety and effectiveness inadequate
in quality and quantity, concluding it should only be used under special arrangements for patients
well enough, or in the context of research for patients not well enough for surgery [36]. Australia’s
Medical Service Advisory Committee (MSAC) recently released findings from its review noting
there was no evidence of MitraClip’s® safety over surgery, and that the procedure was inferior to
surgery in terms of effectiveness [37, 38]. They noted that although MitraClip® has a place amongst
high risk patients, there needs to be a high level study performed to address the lack of data on
safety and effectiveness. MSAC concluded the procedure was very expensive, cost-ineffective,
and recommended against public funding.
Percutaneous Interventions for Mitral Regurgitation
15
Further Clinical Trials for MitraClip®
Besides EVEREST II we are aware of five recruiting or ongoing clinical trials, three randomized
controlled trials and two observational studies, that may help clarify the optimal use of the
MitraClip® device (4).
Table 4 - MitraClip® Clinical Trials
Name, location,
sponsor
Clinical Outcomes
Assessment of the
MitraClip® Therapy
Percutaneous
Therapy for High
Surgical Risk
Patients (COAPT)
United States
Purpose
Type and size
Patient group
Start –
finish
dates
To confirm the safety and
effectiveness of the
MitraClip® System for the
treatment of moderate-tosevere or severe
functional mitral
regurgitation (FMR) in
high surgical risk subjects.
Randomised
Controlled
Trial. 500
patients
FMR patients with
co-morbidities such
that a patient is
judged to have a
high probability of
death from surgery
Aug 2012 –
Aug 2015
To evaluate the safety
and efficacy of the
MitraClip® System in
symptomatic patients with
severe mitral regurgitation
in comparison to the
previous default medical
treatment - in a study
population that is not
amenable to surgery.
Randomised
Controlled
Trial. 100
patients
High risk MR patients
Sept 2011–
Sept 2014
To observe the outcomes
of patients treated with
the MitraClip® system
throughout 12-months as
compared to the
outcomes of patients
treated with surgery or
medical therapy.
Observational
prospective.
All-comers
Oct 2008Dec 2013
All-comers
Nov 2011 –
Dec 2014
Sponsor: Evalve subsidiary of Abbott
Abrogation of Mitral
Regurgitation Using
the MitraClip®
System in High-Risk
Patients Unsuitable
for Surgery (ISARCLIP)
Germany
Sponsor: German
Heart Centre Munich
ACCESS-Europe
Sponsor: Evalve
[Logistic EuroScore ≥
15 or STS-Score ≥
15]
800 patients
Clinical and health
economic data
(unspecified) gathered.
MitraClip® System
in Australia and New
Zealand (MitraClip®
ANZ)
Sponsor: Evalve
To gathering real world
clinical and health
economic data to support
the long-term safety,
efficacy, and economic
value of the MitrClip
System.
Clinical and health
Observational
prospective.
150 patients
Percutaneous Interventions for Mitral Regurgitation
16
economic data gathered.
See appendix three
A Randomized Study
of the MitraClip®
Device in Heart
Failure Patients With
Clinically Significant
Functional Mitral
Regurgitation
(RESHAPE-HF)
RCT
Sponsor: Evalve
MitraClip® device in heart
failure patients with
clinically significant
functional mitral
regurgitation. A composite
measure of all-cause
mortality and recurrent
heart failure
hospitalizations is
hypothesized to occur at a
lower rate with the use of
the MitraClip® device in
addition to optimal
standard medical therapy
compared to optimal
standard of care therapy
alone.
Pivotal Study of a
Percutaneous Mitral
Valve Repair System
(EVEREST II)
EVEREST II Randomized
Controlled Trial (RCT),
including the EVEREST II
High Risk Registry (HRR)
RCT
800
Participants
957 Patients
Sponsor: Evalve
New York Heart
Association
Functional Class III
or IV chronic heart
failure patients
Feb 2013Aug 2016
Patients with Grade
3 (moderate to
severe) or Grade 4
(severe) mitral
regurgitation (MR)
based on American
Society of
Echocardiography
guidelines
May 2005Dec 2017
Abbott has confirmed that Waikato DHB’s desired MitraClip® pilot is intended to be part of the
Australian-New Zealand trial (above). The trial is aimed at gathering real world clinical and health
economic data to support the long-term safety, efficacy, and economic value of the MitraClip®
System [39]. The observational study (non-randomized and uncontrolled) commenced in Australia
in November last year and seeks to recruit 150 patients.
Compared with the other trials in progress, the value added from this relatively small and
untargeted observational study is unclear. That said, locally derived health economic data is
essential for reliable cost-effectiveness analysis. Nevertheless, unlike the ACCESS-Europe study
there is no comparator group to compare costs and benefits against. As indicated below, evidence
suggests the device will not be cost-effective for an all-comers population. Careful targeting is
required, since current evidence may suggest the procedure is likely to be most cost-effective for
older patients, high-risk patients and patients with FMR. This suggests the comparator groups
should be patients restricted to medical therapy (for inoperable patients). Accordingly, the current
trial set up does not look like it will produce meaningful results from a cost-effectiveness
perspective. Further details of the Australian-New Zealand trial are specified in Appendix Three.
Percutaneous Interventions for Mitral Regurgitation
17
Cost-effectiveness
As noted above, MSAC’s assessment is that the MitraClip® is cost-ineffective due to its high cost
and inferior effectiveness profile compared with surgery [38]. The NHC were provided two cost
effectiveness analyses in confidence, hence their analysis is not presented here. Nevertheless our
assessment is consistent with MSAC’s.
Percutaneous Interventions for Mitral Regurgitation
18
Current Treatment of MR in New Zealand
Figure Three illustrates the treatment of patients first diagnosed with mitral regurgitation in New
Zealand in public or private hospitals in 2006. 1128 patients were identified in this cohort. Hospital
diagnosis is likely to capture more severe and symptomatic MR. Surgery was defined as patients
diagnosed with MR in 2006 that had surgery in the following five years. Drugs were defined as any
prescription of 63 medicines in the following 12 months for patients identified as having MR
including nitroprussides, intropic agents, vasodilators, ACE inhibitors, beta blockers, calcium
channel blockers, digoxin, amiodarone, anticoagulants, spironolactone, endocarditis prophylaxis
nitrates, and diuretics. Follow-up was restricted to 12-months on the basis that patients with severe
MR requiring treatment should have received pharmaceuticals within that time. The
pharmaceuticals selected were not solely indicated for treatment of MR but as the cohort was
recently diagnosed with, likely severe MR, the pharmaceuticals selected would be indicative of
appropriate treatment in the context. The small group with surgery only were likely to be due to a
combination of death in hospital and the fact that hospital dispensing in 2006 was not available in
the PHARMHOUSE dispensing records used in this analysis. Post mortem identified MR was
estimated from the mortality data set counting deaths in 2006 due to MR not identified elsewhere.
The graph shows newly hospital diagnosed cases of MR increasing with age, surgery becoming a
less prominent treatment option after 75, and medicine the primary intervention option for MR.
Figure 3: Mitral Regurgitation Diagnosis 2006 - private or public hospital or post mortem
160
140
Cases (n)
120
100
80
60
40
20
0
Age group
No surgery or drugs
Post mortem
Surgery and Drugs
Surgery only
Drugs only
Source: NMDS, Mortality Register
Percutaneous Interventions for Mitral Regurgitation
19
Figure four presents the same findings as figure two but more clearly illustrates the treatment, or
lack thereof, patients get by age group. In the younger age groups the proportion of patients
without treatment appears high, but the number of patients with MR is low. Furthermore while we
tried to capture as many medicines prescribed for MR as possible we might have missed
treatments for these younger age groups. As such our analysis shouldn’t necessarily be seen as
indicative of an unmet need in these younger age groups.
Figure 4: Mitral Regurgitation Diagnosis 2006 - private or public hospital or post mortem
100%
90%
80%
Treatment (%)
70%
60%
50%
40%
30%
20%
10%
0%
Age group
No surgery or drugs
Post mortem
Surgery and Drugs
Surgery only
Drugs only
Source: NMDS, Mortality Register
Affordability and unmet demand
Technology is a major cost driver in health contributing around 25-50% of increased health service
spending growth [44]. Health technologies have both cost and volume effects. Some technologies
reduce the unit cost of diagnosis and treatment (the cost effect of technology). Cost savings can
also occur if new technologies reduce costs in other parts of the health sector; for example, new
drugs and percutaneous interventions can reduce the need for surgery and hospitalisation. Overall,
however, new technology tends to increase health care spending because it enables more people
to be treated and for longer periods of time (the volume effect of technology).
The likely cost effect of the MitraClip® device is unclear. On balance however, it would most likely
be cost increasing due to the volume effect of addressing unmet demand – those patients not
currently amenable to surgery. The NHCs affordability model is subject to change; however, our
Percutaneous Interventions for Mitral Regurgitation
20
current estimate is that the technology could cost the public health sector an additional (the cost
above standard treatment) $2.5 million in the first year rising to $5 million over five years.
Conclusion
The quality of research currently underway on the device’s effectiveness and cost effectiveness is
encouraging. However, it is unclear, beyond familiarising local clinicians with the device, as to what
value would be added by the proposed Australian-New Zealand trial which Waikato DHB intends to
join. Given the trial is predominantly Australian based and already underway it is unclear what
influence the NHC could exert in changing the trial’s design. Accordingly, we cannot support the
proposal as it stands.
Current evidence suggests the procedure is safe, but less effective than surgery, cost-ineffective,
and potentially significantly cost increasing. Accordingly, it is recommended that the procedure is
not publicly funded in New Zealand. This is consistent with MSAC’s recent decision in Australia.
Percutaneous Interventions for Mitral Regurgitation
21
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Stefano, G., et al., Prevalence of unsuspected and significant mitral and aortic regurgitation. Journal
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Pedrazzini, G.B., et al., Mitral regurgitation. Swiss Med Wkly, 2010. 140(3-4): p. 36-43.
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Schmitto, J.D., et al., Functional mitral regurgitation. Cardiol Rev, 2010. 18(6): p. 285-91.
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Carabello, B.A., The current therapy for mitral regurgitation. Journal of the American College of
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Trichon, B.H., et al., Relation of frequency and severity of mitral regurgitation to survival among
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Carabello, B.A., Mitral valve repair in the treatment of mitral regurgitation. Current treatment options
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NICE, Interventional procedure overview of percutaneous mitral valve leaflet repair for mitral
regurgitation. 2008.
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Chiam, P.T.L. and C.E. Ruiz, Percutaneous transcatheter mitral valve repair: a classification of the
technology. JACC Interventions, 2011. 4(1): p. 1.
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DLA-PIPER, New and Emerging Cardiac Technologies in Australian and New Zealand Public Health
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Vahanian, A., et al., Guidelines on the management of valvular heart disease The Task Force on the
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Bonow, R.O., et al., ACC/AHA 2006 guidelines for the management of patients with valvular heart
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Jerzykowska, O., et al., Echocardiographic evaluation of percutaneous valve repair in patients with
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Schofer, J., et al., Percutaneous mitral annuloplasty for functional mitral regurgitation. Circulation,
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Siminiak, T., et al., Treatment of functional mitral regurgitation by percutaneous annuloplasty: results
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Feldman, T., et al., Percutaneous repair or surgery for mitral regurgitation. New England Journal of
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Feldman, T., et al., Percutaneous Mitral Repair With the MitraClip System:: Safety and Midterm
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MSAC, Application 1192: Percutaneous reconstruction of an insufficient mitral valve through tissue
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Reynolds, M., et al., TCT-786 Cost Effectiveness of the MitraClip® Compared with Mitral Valve
Surgery: 12-month Results from the EVEREST II Randomized Controlled Trial. Journal of the
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Percutaneous Interventions for Mitral Regurgitation
23
Appendix one: Search Strategy
The following search strategy was adopted from NICE [12].
Percutaneous interventions for Mitral Valve repair safety and effectiveness literature
Database searched 1 January 2005 to 28 February 2013: Ovid MEDLINE(R) In-Process & Other
Non-Indexed Citations and Ovid MEDLINE(R), adapted for Cochrane Library, Embase.

Mitral Valve Insufficiency/

(mitral adj3 insufficien*).mp. [mp=title, abstract, original title, name of substance word,
subject heading word, keyword heading word, protocol supplementary concept, rare
disease supplementary concept, unique identifier]

(mitral adj3 regurgitat*).mp. [mp=title, abstract, original title, name of substance word,
subject heading word, keyword heading word, protocol supplementary concept, rare
disease supplementary concept, unique identifier]

(mitral adj3 incomplet*).mp. [mp=title, abstract, original title, name of substance word,
subject heading word, keyword heading word, protocol supplementary concept, rare
disease supplementary concept, unique identifier]

1 or 2 or 3 or 4

(repair or reconstruc* or clos* or OR mitraclip OR mobius OR mitraflex OR percu-pro OR
thermocool OR monarc OR carillon OR viacor OR mitralign OR accuicinch gds OR
millipede ring OR quantumcor OR neochord OR mitraflex OR babic OR mardil-bace).mp.
[mp=title, abstract, original title, name of substance word, subject heading word, keyword
heading word, protocol supplementary concept, rare disease supplementary concept,
unique identifier]

5 and 6

(percutan* or transven*).tw.

7 and 8

mitral valve/

(mitral adj3 valve*).mp. [mp=title, abstract, original title, name of substance word, subject
heading word, keyword heading word, protocol supplementary concept, rare disease
supplementary concept, unique identifier]

9 and (10 or 11)

meta-analysis as topic/

meta analy*.tw.

metaanaly*.tw.
Percutaneous Interventions for Mitral Regurgitation
24

(systematic adj (review*1 or overview*1)).tw.

limit 12 to systematic reviews

randomized controlled trials as topic/

randomized controlled trial/

random allocation/

double blind method/

single blind method/

clinical trial/

clinical trial, phase i.pt.

clinical trial, phase ii.pt.

clinical trial, phase iii.pt.

clinical trial, phase iv.pt.

controlled clinical trial.pt.

randomized controlled trial.pt.

multicenter study.pt.

clinical trial.pt.

exp clinical trials as topic/

epidemiologic studies/

exp case control studies/

exp cohort studies/

case control.tw.

(cohort adj (study or studies)).mp. [mp=title, abstract, original title, name of substance
word, subject heading word, keyword heading word, protocol supplementary concept,
rare disease supplementary concept, unique identifier]

cohort analy*.tw.

(follow up adj (study or studies)).tw.

(observational adj (study or studies)).tw.

longitudinal.tw.

retrospective.tw.

cross sectional.tw.

cross-sectional studies/
Percutaneous Interventions for Mitral Regurgitation
25

or/13-44

12 and 45

limit 46 to humans

limit 47 to (editorial or letter)

47 not 48
Percutaneous interventions for Mitral Valve repair cost-effectiveness literature

Mitral Valve Insufficiency/

(mitral adj3 insufficien*).mp. [mp=title, abstract, original title, name of substance word,
subject heading word, keyword heading word, protocol supplementary concept, rare
disease supplementary concept, unique identifier]

(mitral adj3 regurgitat*).mp. [mp=title, abstract, original title, name of substance word,
subject heading word, keyword heading word, protocol supplementary concept, rare
disease supplementary concept, unique identifier]

(mitral adj3 incomplet*).mp. [mp=title, abstract, original title, name of substance word,
subject heading word, keyword heading word, protocol supplementary concept, rare
disease supplementary concept, unique identifier]

1 or 2 or 3 or 4

(repair or reconstruc* or clos* or OR mitraclip OR mobius OR mitraflex OR percu-pro OR
thermocool OR monarc OR carillon OR viacor OR mitralign OR accuicinch gds OR
millipede ring OR quantumcor OR neochord OR mitraflex OR babic OR mardil-bace).mp

5 and 6

(percutan* or transven*).tw.

7 and 8

mitral valve/

(mitral adj3 valve*).mp. [mp=title, abstract, original title, name of substance word, subject
heading word, keyword heading word, protocol supplementary concept, rare disease
supplementary concept, unique identifier]

9 and (10 or 11)

economics/

"costs and cost analysis"/

cost allocation/

cost-benefit analysis/
Percutaneous Interventions for Mitral Regurgitation
26

cost control/

cost savings/

cost of illness/

cost sharing/

value of life/

cost effective*.tw.

cost utility.tw.

cost minimi*.tw.

Quality-Adjusted Life Years/

(QALY or DALY or ICER).tw.

decision analys*.tw.

Models, Economic/

"Costs and Cost Analysis"/

(cost or costs or economic*).tw.

or/13-30

12 and 31
HTA agencies searched: Agency for Healthcare Research and Quality, AHTA - Adelaide Health
Technology Assessment, Australia and New Zealand Horizon Scanning Network - Technologies
Assessed, MSAC, CADTH, DACEHTA - Danish Centre for Evaluation and Health Technology
Assessment, HSAC (New Zealand), Belgian Health Care Knowledge Centre, Institute of Health
Economics (Canada), Ontario Health Technology Advisory Committee (Canada), NCCHTA National Coordinating Centre for Health Technology Assessment, Quality Improvement Scotland,
NHSC (relationship to Euroscan) (University of Birmingham), VA Technology Assessment,
California Technology Assessment Forum, Health Technology Assessment – Washington, Ludwig
Boltzmann Institut für Health Technology Assessment, Haute Authorité de Santé (primarily
French, but some English content), Norwegian Knowledge Centre for the Health Services,
Swedish Council on Technology Assessment in Health Care, Catalan Agency for Health
Technology Assessment and Research, Blue Cross Technology Evaluation Center, AETMIS,
Ontario Health Technology Advisory Committee, McGill Technology Assessment Unit, and the
Monash – Center for Clinical Effectiveness, NICE.
Percutaneous Interventions for Mitral Regurgitation
27
Appendix two: capture – recapture method
The capture-recapture method can be used to statistically estimate the true population prevalence
of a health condition. Statistical modelling of the overlap between separate data sets is used to
estimate the number of people with a condition not represented in any of the data-sets.
In its simplest form, taking two data sets, the total number of individuals with a particular condition
can be estimated as follows:
𝑁=
MC
R
Where:
N is the ‘Petersen estimator’ of the true total of individuals.
M is the number of individuals with a particular condition identified in one source
C is the number of individuals with the same condition identified in another source
R is the number of people common in both sources
Hence, if 1000 people are identified with MR in after elective admission to hospital, 2000 people
are identified with MR after acute admission to hospital, and 500 people are common between both
data sets, then the number of people with a similar severity of MR can be estimated as follows:
4000 =
1000 × 2000
500
Key assumptions are:
The population is closed (a significant number of individuals are not entering and exiting the
population – people with severe MR are not likely to be travelling)
Individuals can be accurately matched across datasets to get an indication of overlap (i.e. done
through the NHI number – high probability of linking the same individual)
The data sources are independent of each other (being captured in one data source does not
affect the probability of being captured in another – unlikely to be true but have used age-genderdeprivation-gender to adjust for dependence in data source selection probabilities)
People not captured by any data source are similar to those who are captured (for each data
source, each person has an equal chance of being captured – people with mild MR are not likely to
be capture and consequently the CRC estimate for more severe MR)
Percutaneous Interventions for Mitral Regurgitation
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Appendix three - Australian New Zealand Trial of Mitraclip (Information provided by Abbott to the
NHC)
Estimated Enrollment:
150
Study Start Date:
November 2011
Estimated Study Completion Date:
December 2014
Estimated Primary Completion Date:
December 2014 (Final data collection date for primary
outcome measure)
The primary objective of the MitraClip System ANZ Clinical Trial is to gather real-world clinical and
health-economic outcome data to support the long-term safety, efficacy and economic value of the
MitraClip System in the continuum of therapies for treating MR.Specifically, the following clinical
and economic data will be collected: New York Heart Association (NYHA) Functional Class, SixMinute Walk Test (6MWT) distance, quality of life (QOL) information, echocardiographic measures
of left ventricular size and function, and data associated with the index hospitalization,
rehospitalizations, concomitant medications and discharge facility to support the MitraClip System
economic analysis.
The MitraClip System ANZ Clinical Trial is a prospective, observational, single arm, multicenter trial
to evaluate the MitraClip device for the treatment of mitral regurgitation (MR). Patients will be
enrolled at up to 15 investigational sites throughout Australia and New Zealand. At this time, up to
150 patients will be enrolled. Patients will be considered enrolled when local or general anesthesia
is administered for the MitraClip procedure. Patients will be followed at discharge, 30 days, 6
months, 12 months and 24 months. Investigational sites will recruit patients who meet trial
enrollment criteria. Until enrollment in the MitraClip System ANZ Clinical Trial is closed, all patients
who undergo a procedure for placement of a MitraClip device at an investigational site should be
enrolled in the MitraClip System ANZ Clinical Trial.
Patients should be selected for inclusion in the MitraClip System ANZ Clinical Trial by a
multidisciplinary team involving interventional cardiology, echocardiology, and cardiac surgery. It is
designed as an all-comers trial, meaning they need to have significant Mitral Regurgitation (of
Functional, Degenerative, or mixed etiology), where MitraClip is considered as the most
appropriate therapy by the "Heart Team". Experience in Australia, and world wide, is that MitraClip
is prescribed mostly in patients considered at unacceptably high risk of surgery.
Percutaneous Interventions for Mitral Regurgitation
29
Candidates must meet all of the following inclusion criteria for inclusion in the trial:

Age 18 years or older.

Significant, chronic MR (≥ 3+) by echocardiography.

In the judgment of the Investigator, transseptal catheterization and femoral vein access
are feasible.

In the judgment of the Investigator, placement of the MitraClip device on the mitral
leaflets is feasible.

Mitral valve orifice area ≥ 4.0 cm2.

The patient or the patient’s legal representative has been informed of the nature of the
trial and agrees to its provisions and has provided written informed consent as approved
by the institution’s Human Research Ethics Committee (HREC) of the respective clinical
site.

The patient agrees to return for all required post-procedure follow-up visits.
Candidates will be excluded if they meet any of the following:

Have need for emergency surgery for any reason or need for any other cardiac surgery
including surgery for coronary artery disease, atrial fibrillation, pulmonic, aortic or
tricuspid disease.

Have undergone prior mitral valve repair surgery or have any currently implanted
mechanical prosthetic valve or currently implanted ventricular assist device (VAD).

Have active endocarditis or active rheumatic heart disease or leaflets degenerated from
either endocarditis or rheumatic disease (i.e., noncompliant, perforated).

Transesophageal echocardiography (TEE) is contraindicated.

Has a known hypersensitivity or contraindication to trial or procedure medications which
cannot be adequately managed medically.

Currently participating in an investigational drug trial or another device trial that has not
yet completed the primary endpoint or that otherwise clinically interferes with the
MitraClip System ANZ Clinical Trial data collection.

Pregnant or planning pregnancy within next 12 months.
Device and Procedure-Related Endpoints
The following device and procedure-related acute endpoints will be reported:
Percutaneous Interventions for Mitral Regurgitation
30

Implant Rate: defined as the rate of successful delivery and deployment of MitraClip device
implant(s) with echocardiographic evidence of leaflet approximation and retrieval of the delivery
catheter

Acute Procedural Success Rate: defined as successful implantation of the MitraClip device(s)
with resulting MR severity of 2+ or less as determined by the assessment of the discharge
echocardiogram

Procedure Time: defined as the time elapsed from the start of the transseptal procedure to the
time the Steerable Guide Catheter is removed

Device Time: defined as the time the Steerable Guide Catheter is placed in the intra-atrial
septum until the time the MitraClip Delivery System (CDS) is retracted into the Steerable Guide
Catheter. Device Time is shorter in duration than Procedure Time because it does not include
the time required to perform transseptal access into the left atrium.
Echocardiographic Endpoints
The following echocardiographic endpoints will be reported:

• MR Severity Grade

• Regurgitant Volume

• Regurgitant Fraction

• Left Ventricle End Diastolic Volume (LVEDV)

• Left Ventricular End Systolic Volume (LVESV)

• Left Ventricular End Diastolic Dimension (LVIDd)

• Left Ventricular End Systolic Dimension (LVIDs)

• LV Ejection Fraction (LVEF)

• Mitral Valve Area

• Mitral Valve Gradient

• Left Atrial Volumes
Clinical Endpoints
The following clinical endpoints will be reported:

Mortality

NYHA Functional Class

6MWT distance

QOL Assessment (Minnesota Living with Heart Failure Questionnaire)
Percutaneous Interventions for Mitral Regurgitation
31

Mitral valve surgery, including reason for and type of surgery

Second MitraClip device intervention, including reason for intervention

Rehospitalizations
-
Reason for rehospitalization (i.e., heart failure, other cardiac, non-cardiac)
-
Number of rehospitalizations
-
Number of days rehospitalized
Economic Data
Economic data associated with the following will be reported to support the MitraClip System
economic analysis:

Index hospitalization

Rehospitalizations

Concomitant medications

Discharge facility (e.g., home, home with home health care, skilled nursing, long-term acute
care)

Length of stay in ICU and non-ICU following the procedure during index hospitalization
Percutaneous Interventions for Mitral Regurgitation
32
National Health Committee (NHC) and Executive
The National Health Committee (NHC) is an independent statutory body which provides advice
to the New Zealand Minister of Health. It was reformed in 2011 to establish evaluation systems
that would provide the New Zealand people and health sector with greater value for the money
invested in health. The NHC Executive are the secretariat that supports the Committee. The
NHC Executive’s primary objective is to provide the Committee with sufficient information for
them to prioritise interventions and make investment and disinvestment decisions. They do this
through a variety of products including Prioritising Summaries, Technology Notes, EpiNotes,
CostNotes, Rapid Reviews, and Health Technology Assessments which are chosen according
to the nature of the decision required and time-frame within which decisions need to be made.
Citation: National Health Committee 2013. Technology Note: Percutaneous Interventions for
Mitral Regurgitation. Wellington: National Health Committee.
Published in March 2013 by the National Health Committee
PO Box 5013, Wellington, New Zealand
This document is available on the National Health Committee’s website:
http://www.nhc.health.govt.nz/
Disclaimer
The information provided in this report is intended to provide general information to clinicians,
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circumstances of any particular individual or entity. All reasonable measures have been taken to
ensure the quality and accuracy of the information provided.
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Percutaneous Interventions for Mitral Regurgitation
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