left ventricle (the lower chamber). The valve prevents blood regurgitating backwards into the upper heart chambers during cardiac contractions.

Transcription

1 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 valve 1 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 1 The 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

2 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 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

3 00-04 Years Years Years Years Years Years Years Years Years Years Years Years Years Years Years Years Years 85+ Years The capture-recapture method 2 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 % 4.5% 4.0% 3.5% 3.0% 2.5% 2.0% Prevalence Prevalence (CRC) 1.5% 1.0% 0.5% 0.0% Source: NHC analysis of NMDS 2 See Appendix two for explanation. Percutaneous Interventions for Mitral Regurgitation 3

4 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 In Australia the Therapeutic Goods Administration (TGA) approved the device in November 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 to 28 February 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 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 3 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

5 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) N=130 Potentially relevant citations identified through HTA agency search (excluding duplicates) N=3 Additional citations identified through Google Scholar, HealthPACT, contact with researchers, and manufacturer websites 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 3 Reviews 11 other Percutaneous Interventions for Mitral Regurgitation 5

6 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. Embase 4, 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 The Indirect Annuloplasty approach involves positioning a device within the coronary sinus 5 to reduce the mitral annulus area 6. 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 Embase has 25 million records including all MEDLINE records produced by the National Library of Medicine. 5 The coronary sinus is a short vein located along the heart's posterior surface between the left ventricle and left atrium. 6 The mitral annulus is a ring that is attached to the mitral valve leaflets. Percutaneous Interventions for Mitral Regurgitation 6

7 Table 2: Alternative Percutaneous Devices for MR Percutaneous Mitral Valve Repair Site of Action Mechanism of Action Device (Developer) Status Embrase Publication Count Leaflets Edge-to-edge (leaflet plication) Space occupier (leaflet coaptation) Mitra Clip (Abbott Laboratories PLC, USA) MitraFlex (TransCardiac Therapeutics, USA) Percu-Pro (Cardiosolutions, USA) Phase l and ll Randomised Control Trials CE Mark (2008) 251 Pre-clinical development 3 Phase I trial in progress 3 Leaftlet ablation Thermocool (Biosense Webster J&J PLC subsidiary, USA) Animal models 3 Indirect annuloplasty Monarc (Edwards Lifesciences PLC, USA) Phase I in progress 52 Coronary sinus approach Carillon (Cardiac Dimensions, USA) Phase I complete CE Mark (2011) 64 Viacor (Viacor Incorporated, USA) Phase l in progress 31 Asymmetrical approach Direct annuloplasty Unnamed device (St Jude Medical PLC, USA) NIH Cerclage technology (Nat. Institutes of Health, USA) Animal models 8 Animal models 5 Annulus Mitralign (Mitralign, USA) First-in-human (Phase 0) results 0 Percutaneous mechanical cinching Accuicinch GDS (Guided Delivery Systems, USA) Millipede ring system (Millipede) SP USA First-in-human results 15 Preclinical development 0 Percutaneous energy medical QuantumCor (QuantumCor, USA) Unnamed device (ReCor Medical, France) Animal models 25 Preclinical development 7 Hybrid Unnamed device (Mitral Solutions Inc, USA) Unnamed device (MiCardia, USA) Preclinical development Surgically implanted may go percutaneous Preclinical development Surgically implanted may go percutaneous 3 5 Percutaneous Interventions for Mitral Regurgitation 7

8 Transpical Chordal Implants Artificial chord Transapical-Transseptal Neochord (Neochord Inc, USA) Mitraflex (Neochord Inc, USA) Preclinical development 12 Preclinical development 3 Artificial chord Left Ventricle Babic (Unknown developer) Pre-clinical development 1 LV (and mitral annulus) remodelling Mardil-BACE (Mardil Inc, USA) First-in-human results 2 Percutaneous Mitral Valve Replacement Right minithoracotomy Endovalve-Herrmann prosthesis (Micro Interventional Devices, USA) Animal models 6 Valve Implants Transapical Transseptal Lutter prosthesis (Unknown developer) CardiaQ Prosthesis (CardiaQ Valva Technologies, USA) Animal models 5 First-in-human results 0 Transapical- Transseptal valvein-ring Melody Transcatheter Pulmonary Valve (Medtronic PLC USA) Primary Sources:[13, 14], and Embase for publication count Animal models for MR, in clinical use for other indications 0 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 fluoroscopy 7 and transesophageal echocardiography 8. 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 A common imaging device based around x-ray. 8 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

9 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 studies 9. 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 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 9 Percutaneous Interventions for Mitral Regurgitation 9

10 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

11 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 measure 12 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

12 Table 3 Subgroup Analysis of effectiveness at 12 months Subgroup Percutaneous Repair % Surgery % P-value 13 FMR DMR Age Age < LVEF < LVEF 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

13 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 surgery 16 [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 NYHA class measures the stages of heart failure according to patient symptoms on an increasing severity scale of one to four: 15 Clinical events committees review outcomes (endpoints) reported by trial investigators to determine whether the outcomes meet protocol-specified criteria. 16 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%. 17 Pacing of both right and left ventricles independently and simultaneously to improve heart function Percutaneous Interventions for Mitral Regurgitation 13

14 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 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< ). 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

15 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

16 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 Purpose Type and size Patient group Start finish dates Clinical Outcomes Assessment of the MitraClip Therapy Percutaneous Therapy for High Surgical Risk Patients (COAPT) United States 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 Sponsor: Evalve - subsidiary of Abbott Abrogation of Mitral Regurgitation Using the MitraClip System in High-Risk Patients Unsuitable for Surgery (ISAR- CLIP) Germany Sponsor: German Heart Centre Munich 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 [Logistic EuroScore 15 or STS-Score 15] Sept 2011 Sept 2014 ACCESS-Europe Sponsor: Evalve 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. 800 patients All-comers Oct Dec 2013 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 All-comers Nov 2011 Dec 2014 Percutaneous Interventions for Mitral Regurgitation 16

17 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) 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. RCT 800 Participants New York Heart Association Functional Class III or IV chronic heart failure patients Feb Aug 2016 Pivotal Study of a Percutaneous Mitral Valve Repair System (EVEREST II) Sponsor: Evalve EVEREST II Randomized Controlled Trial (RCT), including the EVEREST II High Risk Registry (HRR) RCT 957 Patients Patients with Grade 3 (moderate to severe) or Grade 4 (severe) mitral regurgitation (MR) based on American Society of Echocardiography guidelines May Dec 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

18 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

19 Cases (n) 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 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 private or public hospital or post mortem Source: NMDS, Mortality Register Age group No surgery or drugs Post mortem Surgery and Drugs Surgery only Drugs only Percutaneous Interventions for Mitral Regurgitation 19

20 Treatment (%) 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 private or public hospital or post mortem 100% 90% 80% 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

21 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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