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Sutureless Aortic Valve Replacement –

Tier 3 Assessment

Sutureless Aortic Valve Replacement – Tier 3 Assessment 1

National Health Committee (NHC)

The National Health Committee (NHC) is an independent statutory body charged with prioritising new and existing health technologies and making recommendations to the Minister of Health.

It was re-formed in 2011 to establish evaluation systems that would provide the New Zealand people and the health sector with greater value for money invested in health.

The NHC executive is the secretariat that supports the committee. The NHC executive’s primary objective is to provide the committee with sufficient information for it to make decisions regarding prioritisation and reprioritisation of interventions and services. They do this through a range of evidence-based products chosen according to the nature of the decision required and timeframe within which decisions need to be made.

The New Zealand Government has asked that all new diagnostic and treatment (non-pharmaceutical) services, and significant expansions of existing services, are to be referred to the NHC.

In August 2011 the NHC was appointed with new terms of reference and a mandate to establish the capacity to assess new and existing health technologies. Its objectives (under Section 4.2 of its terms of reference – www.nhc.health.govt.nz) include contributing to improved value for money and fiscal sustainability in the health and disability sector by:

providing timely advice and recommendations about relative cost-effectiveness based on the best available evidence;

providing advice and recommendations which influence the behaviour of decision-makers, including clinicians and other health professionals;

providing advice and recommendations which are reflected in resource allocation at national, regional and local levels; and

contributing to tangible reductions in the use of ineffective interventions and improved targeting to those most likely to benefit.

In order to achieve its objectives under Section 4.2 and to achieve ‘value for money’, the NHC has adopted a framework of four assessment domains – clinical safety and effectiveness; economic; societal and ethical; and feasibility of adoption – in order that assessments cover the range of potential considerations and that the recommendations made are reasonable.

It is intended that the research questions asked will fall across these domains to ensure that when the committee comes to apply its decision-making criteria, it has a balanced range of information available to it. When the NHC is setting those questions, they will have the decision-making criteria in mind.

The 11 decision-making criteria will assist in the determination of the NHC work programme and in the appraisal and prioritisation of assessments.


Executive summary1. Aortic stenosis (AS) is a pathological narrowing of the aortic valve that obstructs blood flow out of

the heart. In adults, AS is most commonly caused by age-related calcification of the aortic valves, although it can also be the result of a congenital heart defect or rheumatic heart disease.(1, 2) Patients with asymptomatic AS mostly do not require treatment. For patients with severe symptomatic AS, or severe AS with significant left ventricular dysfunction, aortic valve replacement (AVR) is the standard of care.(2) In the absence of valve replacement, patients die on average within two to three years of the emergence of symptoms.(3)

2. Sutureless AVR is a relatively new procedure which employs a bioprosthetic (tissue) valve requiring no (or very few) sutures to stay in place. Sutureless valves stay in place using either a self-expanding or balloon-expandable frame. By removing the need for sutures, operative and cardiopulmonary bypass times may be reduced compared with conventional AVR. Reduced operative time is particularly advantageous for patients requiring multiple procedures. Sutureless AVR may be undertaken using conventional open heart surgery or minimally invasive techniques. In New Zealand about 80 sutureless AVR procedures have been undertaken since 2011, all of which have used open heart surgery.(4) Sutureless valves have now been approved for use in Australia and Europe, but not yet in the United States outside clinical trials.

3. The current evidence base is limited. Randomised controlled trials with short follow-up time suggest that sutureless AVR is safe with low incidence of complications and comparable mortality, compared with conventional surgical AVR. This is supported by observational studies. Compared with TAVI, sutureless AVR may have lower rates of paravalvular leak.

4. Current evidence suggests sutureless AVR may have similar cost-effectiveness to conventional surgical AVR, with sutureless AVR having comparable outcomes and the possibility of lower costs. The price differential between sutureless valves and conventional bioprosthetic valves is small and declining. There is currently no evidence of additional procedural or downstream costs associated with sutureless AVR compared with conventional surgical AVR, but there is some evidence of potential savings from reduced hospital and ICU length of stay.(5-7) Sutureless AVR is a substitute procedure for conventional surgical AVR in high-risk patients; as such it is not expected to significantly expand the population pool receiving surgical AVR.

5. Given that the safety and efficacy of sutureless AVR seems comparable, varying access to sutureless valves does not give cause for concern. However, this view may change as the evidence for sutureless AVR evolves.

6. There may be between five and ten percent of AVR patients that could benefit from sutureless AVR; potential beneficiaries of the procedure include patients with anatomical features that make suturing difficult or risky such as a heavily calcified aortic annulus or a very small aortic root. There are no workforce or infrastructure considerations identified that would impede the increase


use of sutureless AVR; although, like with all new treatments, appropriate training and oversight would need to be put in place if the use of sutureless AVR increased.

7. Sutureless AVR should not replace conventional surgical AVR as the standard of care for severe symptomatic AS. If clinicians would prefer to use sutureless valves, there seems to be sufficient justification in them doing so; providing the sutureless valve is a similar price to conventional bioprosthetic valves.


ContentsExecutive summary 3

1. Introduction 6

2. Background 7

3. Clinical safety and effectiveness 12

4. Economic 26

5. Societal and ethical 31

6. Feasibility of adoption 33

7. Conclusion 35

Appendix 1: Methods 36

Appendix 2. Description of clinical trials of sutureless AVR 39

Appendix 3 Summary of clinical findings for sutureless AVR 45

8. References 51


1. IntroductionThe purpose of this report is to evaluate the latest evidence around sutureless aortic valve replacement in order to assist the NHC in formulating recommendations regarding how the diffusion of the technology into New Zealand clinical practice for treatment of aortic stenosis should be best managed in terms of public funding and the target population.

The National Health Committee (NHC) prepared a brief Technology Note on sutureless aortic valve replacement (AVR) in May 2012. At this time it was concluded that there was insufficient evidence available for a full assessment to be made, and that sutureless AVR should be conducted only under clinical trial conditions.

In March 2013, representatives from the Australian and New Zealand Society of Cardiac and Thoracic Surgeons and the Waikato Cardiothoracic and Vascular Surgery Unit requested that the NHC carry out further assessment of sutureless AVR. It was decided that further assessment of sutureless AVR would be appropriate at this time, given that in the time since the previous NHC report, additional clinical data had been published, NICE (National Institute for Health and Care Excellence) had issued guidance,(8) and HealthPACT had assessed the procedure.(1, 9)

Our work on sutureless AVR has been developed in tandem with the NHC's transcatheter aortic valve implantation (TAVI) assessment and fits within an overall assessment of the model of care for aortic stenosis (AS). This paper reviews the evidence for sutureless AVR against the NHC's four domains of assessment: clinical safety and effectiveness; societal and ethical; economic; and feasibility of adoption.


2. Background

Condition description

Aortic stenosis (AS) is a pathological narrowing of the aortic valve that obstructs blood flow out of the heart. In adults, AS is most commonly caused by age-related calcification of the aortic valves, although it can also be the result of a congenital heart defect or rheumatic heart disease.(1, 2). Age-related calcification of the normal aortic valve typically presents in those aged ≥70 years. AS usually presents as an asymptomatic disease and progresses slowly over many years. In the absence of valve replacement, patients die on average within two to three years of emergence of symptoms.(3)

Prevalence and incidence

In the absence of published data, the NHC used the New Zealand National Minimum Dataset (NMDS)i to estimate the prevalence and incidence of hospital diagnosed AS. In 2012/13, the prevalence of any hospital diagnoses of AS was 103 per 100,000 population or approximately 4,700 patients. Patients were recorded as having AS if they were still living in 20012/13 and had received any hospital diagnosis of AS since 2005/06 but not an aortic valve replacement3. Detail on our methodology is contained within National Health Committee Aortic Stenosis Overview Tier 2 (2015). Incidence was 36 cases per 100,000 population, counting any patient who received a new hospital diagnosis of AS in 2012/13 not previously present.

Just over a third of all patients with a hospital diagnosis of AS in 2012/13 had AS recorded as a primary diagnosis. A primary hospital diagnosis is assumed to represent a more severe and symptomatic population as it is more likely to represent symptomatic admission rather than as a secondary condition. The prevalence of a severe hospital diagnoses of AS is estimated at 38 per 100,000 population or approximately 1,703 patients. Of these patients, 23 were recorded as having rheumatic AS. Incidence of AS was 19 cases per 100,000 population, ranging from one patient per 100,000 population for those aged under 50 to 145 per 100,000 population for those aged over 70. There were 860 new cases of severe AS in 2012/13. As prevalence and incidence of AS are greatest in older age groups, population ageing can be expected to increase the incidence of AS.

Mortality

In 2011 there were 295 deaths attributed to AS in New Zealand.(10) The age standardised mortality rate was three per 100,000 population, with only four deaths recorded for Māori. Eighty-two percent of all deaths occurred in patients aged over 80.

Current treatment

Patients with asymptomatic AS mostly do not require treatment. For patients with severe symptomatic AS, or severe AS with significant left ventricular dysfunction, surgical aortic valve replacement is the standard of care.(2) Surgical AVR can considerably improve patient survival and quality of life. Long-term survival following surgical AVR is commonly reported as being close to that observed in the general population of a similar age.(11) A single centre retrospective Swedish study of 2,359 patients found a relative 15-year survival rate of 75% after surgical AVR compared to that expected in the general Swedish population.(12) A systematic review of clinical studies found health-related quality of life equivalent or superior for surgical AVR patients aged over 70

i The NMDS records all publically funded inpatient events.


compared with an age-matched general population. Follow-up time extended to five years in some of the included studies. But significant heterogeneity among study designs, methods, and follow-up times prohibited pooling of the results.(13)

AS mainly affects older people and for many patients, AVR will be futile due to frailty, significant comorbidities, dementia or poor life expectancy. Where the risks from AVR outweigh the potential benefits, patients are treated with palliative care. New Zealand and international studies estimate that between a third and a half of all patients with severe symptomatic AS are considered ineligible for surgical AVR.(14-16) For these patients, mortality rates are very high, with approximately half of all patients dead within two years.(14)

Today there exist three major technologies for AVR: conventional surgical AVR, transcatheter aortic valve implantation (TAVI), and sutureless AVR. Other treatment options, including pharmaceutical treatment and balloon aortic valvuloplasty, have a very limited role in adults with AS and are primarily used to control symptoms or as part of palliative care. Balloon aortic valvuloplasty may occasionally be used as a bridge to surgical AVR or to test if AVR is likely to be beneficial.

Conventional surgical AVR remains the primary avenue of treatment. Surgical care has traditionally involved open heart surgery with a full sternotomy (separation of the sternum to allow access the chest cavity) and requires the aortic valve to be sutured into place. TAVI is a potential alternative treatment for patients who are at very high surgical risk or may otherwise be considered inoperable.(17, 18) TAVI is a percutaneous intervention (delivered through a small incision in the skin) that avoids major surgery and does not require cardiopulmonary bypass. TAVI requires specialised catheterisation laboratory facilities and doesn’t allow the stenosed natural valve to be removed or decalcification to be carried out. The role of this technology in the treatment of AS in New Zealand is discussed in the NHC’s report: Transcatheter Aortic Valve Implantation: Assessment Report Tier 3 (2015).

Sutureless AVR is potentially less invasive than traditional open-heart surgical valve replacement and, unlike TAVI, it allows the stenosed valve to be replaced and decalcification of the annulus to be carried out. Sutureless valves allow the valves to stay in place without suturing by use of either a self-expanding or balloon-expandable frame. By removing the need for sutures, operative and cardiopulmonary bypass times may be reduced compared with conventional surgery. Sutureless aortic valves may also facilitate minimally invasive procedures, through reducing operative time, though comparative evidence is required to confirm this.(19) Internationally, sutureless AVR is often undertaken using minimally invasive surgery.(19, 20) However, in New Zealand, sutureless AVR is not currently undertaken using minimally invasive surgery.

Technology status

This report is limited to bioprosthetic sutureless aortic valves that have undergone clinical testing: Perceval S (Sorin Group), 3f Enable (Medtronic) and Intuity (Edwards Lifesciences LLC). The sutureless aortic valve Trilogy (Arbor) is not included because only one small clinical trial has been reported,(21) and there is no evidence that the valve is being further developed. Bioprosthetic valves are partly comprised of an animal heart valve or contain animal tissue. Sutureless mechanical aortic valves (eg the Magovern-Cromie device) have been available since the 1960s,(22) but are no longer widely in clinical use because of the technical difficulties of implantation and risk for paravalvular leak and thromboembolic complications. These valves are not considered in this report.


The available sutureless aortic valves are described in Table 1. The bioprosthetic valves have metallic frames that can be compressed to allow insertion through a smaller incision than conventional surgery. Guiding sutures aid the correct positioning of the valve. When deployed (with or without balloon expansion), the valve expands and anchors in the annulus.

Table 1. Overview of sutureless aortic valve devices(23-25)

Valve characteristics Perceval S 3f Enable model 6000 IntuityAppearance

Mounted on delivery system

Deployed

Undeployed

Deployed

Manufacturer Sorin(Saluggia, Italy)

Medtronic – devloped by ATS Medical(Minneapolis, USA)

Edwards Lifesciences(California, USA)

Valve design Trileaflet bovine pericardial valve Three equal sections of equine pericardial leaflets interlocked in a tubular structure. Polyester flange at the inflow aspect.Based on 3f Aortic Bioprosthesis stentless valve (model 1000).

Three independent, symmetrical bovine pericardialleaflets matched for thickness and elasticity.Based on Perimount valve.

Frame Self-expanding nitinol frame with two ring segments (outflow and inflow rings)

Self-expanding Nitinol frame Polyester cloth-covered stainless steel frame with broad sealing cuff

Positioning and deployment Three guiding sutures aid correct positioning, and are removed after valve deliveryValve is deployed with balloon expansion

A single guiding suture aids orientation, and is removed after valve deliveryThermal-controlled expansion

Three guiding sutures aid correct positioning, and are removed after valve deliveryValve is deployed with balloon expansion

Notification - NZ NZ WAND database 2012 NZ WAND database 2012 NZ WAND database 2012

Registration - Europe CE Mark Approval 2011 CE Mark Approval 2009 CE Mark Approval 2012

Registration – Australia Austrlian Registry of Therapeutic Goods (ARTG) number : 232485 (09/01/2015)

Avialable under TGA Special Access Scheme

ARTG: 226932 (14/08/2014)

Registration – USA Food and Drug Administration (FDA) approval for investigational use only 2013

FDA approval for investigational use only was pending.

FDA approval for investigational use only 2012

Key trials CAVALIER(26, 27) Enable Multicentre European Trial(28)

TRITON(29)

WAND = Web-Assisted Notification of Devices

Source: Shrestha 2013; Meuris 2010; Carrel 2013(23-25), Medsafe WAND database, ARTG database. Manufacturers were contacted to confirm the regulatory status of their respective sutureless valves in January 2015.

There is currently no approval process for medical devices in New Zealand. For medical devices to be legally supplied in New Zealand, however, they must be notified to Medsafe’s WAND database. All three sutureless valves were notified on the database in 2012. All three sutureless valves have


been approved for use in Europe; where the CE (European Conformity) Mark indicates that the product complies with the essential requirements of the relevant European health, safety and environmental protection legislation and can be legally marketed. In Australia, the Intuity and Perceval S valves have been approved for use by the Therapeutics Goods Administration, while the 3f Enable valve is available only under a Special Access Scheme for clinical trials or by an authorised prescriber. Medtronic announced the discontinuation of its Sutureless valve in May 2015, discussed below.(30) In the United States no sutureless valve has been approved for routine use, but the Intuity and Perceval valves are approved for investigational purposes, meaning the valves can be used in clinical trials.

Sorin Group advertises that more than 12,000 patients have received a Perceval S sutureless valve replacement worldwide since 2007.ii

Use in New Zealand

Sutureless AVR, using conventional open heart surgery, have been undertaken in Waikato, Canterbury and Auckland DHBs, and is provided privately in one institution (St George’s Hospital Christchurch). Minimally invasive sutureless AVR has not been undertaken in New Zealand. Canterbury and Waikato DHBs have, however, expressed interest in the minimally invasive approach.

The current status of sutureless AVR is summarised in Table 2. Volumes remain very low, with just 19 publicly funded sutureless AVRs undertaken in 2013/14. Twelve of these operations were funded by Canterbury DHB and five were funded by Auckland DHB. Canterbury DHB has been the largest funder of sutureless AVR nationally with 66 operations between August 2011 and September 2014.(31)

Sutureless valves have declined significantly in price over the past four years as a result of competition. When the NHC first assessed sutureless AVR in 2012, the valve was nearly twice the price it is today. A sutureless valve purchased by Auckland DHB is now roughly the same cost as a regular tissue valve purchased by Canterbury DHB. However, whilst the Sorin Perceval S valve and Medtronic 3f Enable model 6000 valve have become price competitive, the Edwards Lifesciences Intuity valve is reportedly about twice the price of its competitors; with no head-to-head trials available to justify the premium.(32) However, Medtronic announced its intention to discontinue production of the Medtronic 3f Enable valve in May 2015. There remains variation in price of sutureless valves across the country, which indicates there could be savings. The savings could be obtained from all the DHBs receiving the lowest cost, the lowest costs could be obtained through DHB sharing pricing information or from national collective purchasing.

ii Sorin Company marketing forwarded to National Health Committee, 20/08/2015, title: Sorin Cardiac Surgery

Perceval Sutureless Valve”.


Table 2: Sutureless aortic valve status in New ZealandDHB Valve type Volume

(2013/14Cost per valve (2014)

Change in cost Minimally invasive sutureless AVR

Auckland Sutureless 5 $5,500 Not currently used and would require Clinical Practice Committee agreement

Canterbury Sutureless 14 $6,500 Sorin Valve: $15,000(2011) $9,900 (2012) $6,500 (2014) Price equivalent to Medtronic Valve

Not currently used but interest expressed in the approach

Surgical tissue $5,700Surgical mechanical

$4,800

Waikato Sutureless 2 (2012/13) $18,000 (2011) $9,900 (2013)

Expressed interest in minimally invasive SU-AVR

Capital and coast

Do not use Sutureless and have no plans to use them

Southern No record of Sutureless useNew Zealand (2013/14)

Sutureless 19

Source: Information collected by NHC from DHBs, the NMDS, and valve manufacturers. It is difficult to get exact volumes

as there is currently no specific ICD-10 procedure code for sutureless AVR and the type of device is recorded only in free

text fields within the NMDS. Hence the NHC had DHBs confirm or amend records as a check.


3. Clinical safety and effectivenessSutureless AVR was developed principally for high-risk surgical patients that may be under-served by conventional AVR through enabling less invasive and more rapid surgery.(4) The current evidence base is limited. Randomised controlled trials with short follow-up time suggest that sutureless AVR is safe with low incidence of complications and comparable mortality, compared with conventional AVR. This is supported by observational studies with a control group. Results of observational studies without a control group are broadly reflective of comparative studies regarding complications and mortality.

Whilst several hundred studies of sutureless AVR have been published, many are earlier reports of the same studies, or subgroups of larger studies. More than 1,000 patients have been treated within observational studies but nearly all these studies are small single arm observational trials. There have been just two small randomised controlled clinical trials of a sutureless aortic valve.(33,

34) Only four comparative studies have reported patient outcomes for 12 months or longer.(6, 35-37) The methods for the literature search upon which this section is based is contained in Appendix 1.

In comparative studies of sutureless AVR to date, patients receiving a sutureless valve have most often undergone minimally invasive surgery; whereas patients receiving a conventional valve have most often undergone open heart surgery. This makes it difficult to distinguish the direct effect of the sutureless valve from the effect of minimally invasive surgery.

Randomised controlled trials of sutureless AVR

Two randomised controlled trials (RCTs) have compared sutureless AVR with conventional AVR. The results are limited to very short follow-up times, ie up to a month. Both studies report comparable outcomes between treatment groups. The RCTs are further summarised below.

CADENCE-MIS randomised controlled trial

The CADENCE-MIS randomised controlled trial compared Edwards Lifesciences Intuity sutureless valve performed with the minimally invasive technique (MIS-RDAVR, 46 patients analysed) with conventional AVR performed with full sternotomy (FS AVR, 48 patients analysed). Baseline characteristics were similar between groups, where patients had low preoperative risk; mean STS scores were 1.6% and 1.7% in the sutureless and surgical AVR groups, respectively.(38)

Sutureless AVR was associated with reduced aortic cross-clamp times compared with conventional AVR, 41.3 minutes compared with 54.0 minutes (p < 0.001). There were no statistically significant or clinically significant differences in cardiopulmonary bypass time, operative time or implanted valve size (Table 3).


Table 3: Procedural outcomes of CADENCE-MIS randomised controlled trial

Source Borger et al 2015

Early clinical outcomes were similar between the two groups. Early mortality was 4.3% (2 deaths) for sutureless AVR, compared with 2.1% (1 death) for conventional AVR; this difference was not statistically significant (p=0.5) (Table 4). The initial abstract for the study reported mortality on an intention to treat basis, where the corresponding 30-day mortality rates were 6.1% vs 2.1%, p=0.32, for sutureless AVR and conventional surgical AVR, respectively.(33) In the final analysis the authors excluded three patients because of difficulty seating the valve from coronary anatomy; one of these patients died.

Table 4 Early (<30 day) clinical outcomes of CADENCE-MIS randomised controlled trial

Source Borger et al 2015

The sutureless group had better postoperative hemodynamic function with sutureless AVR patients having a significantly lower transvalvular gradient of 8.5 vs 10.3 mm Hg (p = 0.044). There was no report of paravalvular leak in either arm and quality of life was relatively unchanged at three months compared with baseline for both groups.

Small German RCT including sutureless AVR

A small randomised controlled trial of 54 elderly (>75 years) high surgical risk patients with symptomatic AS and EuroSCORE >10 were randomly assigned to three treatment groups:


standard AVR using a Sorin flow bioprosthesis (n= 19), sutureless AVR using Medtronic 3f Enable (Enable group, n= 18), and transapical aortic valve implantation using the Edwards Sapien valve (TAVI group, n=17).(34) The groups were comparable regarding age, gender, EuroSCORE, and transvalvular gradient. Few details are available on patient characteristics or methodology as only an abstract was available.

Early outcomes were reported to be comparable between groups. The study reported CPB time and aortic cross-clamp time were reduced by 15 minutes for sutureless AVR, compared with conventional AVR. Mortality rates were not reported. There was no difference in ICU or hospital length of stay between groups.

Observational studies of sutureless AVR with a control group

Four observational studies of sutureless AVR with a retrospective control group were identified that reported clinical outcomes for 12 months or longer.(6, 35-37) Of these studies, three compared propensity matched patient groups to reduce the risk of selection bias.(6, 35, 37) Propensity score matching is a statistical technique that attempts to control for observed or unobserved confounding factors, such as preoperative risk, that may affect the outcomes of a treatment. These four studies inform the mortality and hospital length of stay sections below. Further comparative studies were identified that have shorter follow-up times. Some of these studies compare sutureless AVR to conventional AVR and are used to inform comparisons of cross-clamp time, cardiopulmonary bypass time, haemodynamic outcomes, and complications.

The characteristics of the patients included in the comparative trials are shown in Table 11, Appendix 2. Patients in the trials had severe AS; most reports did not clearly state whether patients were symptomatic. Most patients had a moderate to high surgical risk based on log-EuroSCORE (European System for Cardiac Operative Risk Evaluation). Two studies focused on patients with low to moderate surgical risk (5, 35) (mean Logistic EuroSCORE <10). The average age of patients was greater than 70 years in all studies, and greater than 80 years among sutureless AVR recipients in two studies. A detailed summary of procedural outcomes from comparative studies is contained in Appendix 3; the main findings are summarised below.

Mortality

Broadly comparative studies with follow-up of 12 months or more found no increased risk of death from sutureless AVR in moderate to high-risk patients compared with conventional surgery at 30 days or up to 12 months (Table 5).

Comparative studies with shorter term follow-up are contained in Table 13, Appendix 3. These studies report no statistically significant difference in 30-day mortality: for minimally invasive sutureless AVR compared with minimally invasive AVR with a conventional valve (4% vs 6% respectively);(5) and for sutureless AVR compared with TAVI (0% vs 1% respectively).(39) Across all comparative studies the average 30-day, or within hospital, mortality rate is about 3% for sutureless AVR. This is comparable with conventional surgical AVR. (40)

There is very limited longer-term data. Mortality rates at three years were similar for sutureless AVR and standard surgical AVR in Shrestha et al (39% v.s 34% respectively).(36) The study comprised patients in both arms with small aortic roots, an anatomical feature associated with high operative risk. Mortality at 20 months was better for minimally invasive sutureless AVR compared with minimally invasive conventional AVR in Gilanov et al, but the result was not statistically significant (9% v.s 4% respectively, p = 0.33).(35) Compared with TAVI, Santarpino et al reported significantly lower mortality at 19 months for sutureless (2.7% v.s 13.5%, p=0.015).(37) The difference in mortality was attributed to paravalvular leak, where 25% of TAVI patients experienced


paravalvular leak but sutureless patients did not. When comparing survival in the absence of paravalvular leak, no statistically significant difference in mortality was observed (2.7% vs 0%).

Hospital length of stay

Four comparative studies reported on hospital and intensive care (ICU) length of stay. Two of these studies report statistically significant reductions in length of stay; none report increased length of stay for sutureless AVR (Table 5). Pollari et al found a statistically significant reduction in ICU and hospital length of stay for sutureless AVR compared with conventional AVR.(6) ICU length of stay was reduced by 0.8 days (2.0 vs 2.8 days, p<0.001) and hospital length of stay was reduced by 1.5 days (10.9 vs 12.4 days, p=0.001). Santarpino et al found a statistically significant reduction in ICU length of stay of 0.9 days for patients undergoing sutureless AVR compared with standard surgical AVR (1.9 vs. 2.8 days, p=0.002).(5) They also reported a small reduction in hospital length of stay but the result was not statistically significant (10.5 vs. 10.9 days, p=0.3). Gilmanov et al found no difference in hospital or ICU length of stay for sutureless AVR compared with standard AVR. (35) Preoperative risk in both studies (Gilmanov et al and Santarpino et al) was low to moderate (mean logistic EuroSCORE <10). Arguably there was less potential in these studies for a length of stay reduction compared with studies with high risk patients, as lower risk patients tend to have a lower length of stay.(41) Shrestha et al reported a 1.8 day reduction in hospital length of stay for sutureless AVR compared with standard AVR, but the result was not statistically significant.(36) It is possible that time in ICU and overall hospital stay will reduce once clinicians are more confident with the outcomes of sutureless procedures; stakeholders have reported that this is the case for TAVI in New Zealand.


Table 5: Primary outcomes from four observational studies with a control group with at least 12 months follow-up

Author Device (no. patients)

Logistic euroSCORE %

Propensity matched method

% minimally invasive

All-cause mortality (n; %) Length of stay (mean/ median days)

In-hospital or 30-day

1-year ICU Hospital

Gilmanov et al (2014)(35)

Perceval S (n = 133)

5.46 (3.53–8.17)

36 risk factors matched

100% 1 (0.8%) Median 10mo:4%

1 6

Standard AVR(n = 133)

5.83 (3.74–8.77)

0% 2 (1.5%) 5% 1 6

Pollari et al (2014)(6)

Perceval S(n = 82)

12.1 ± 4.9 14 risk factors matched

51% 2 (2.4%) Median 13mo:2.5%

2.0* 10.9*


10.9 ± 4.2 40% 3 (3.7%) 3.8% 2.8 12.4

Santarpino et al (2013)(37)

Perceval S(n = 37)

18.1 ±1.9 13 risk factors matched

60% 0 Mean 19mo: 2.7%*

NR NR

TAVI(n = 37)

20.6 ± 2.2 3 (8.1%) Mean 19mo: 13.5%*

NR NR

Shrestha et al (2013)(36)

Perceval S (n = 50)

20.4 ± 10.7 No matching

72% 0 5(13%)

1.8 14.1


16.7 ± 10.4 4.3% 3(4.3%)

10(16%)

2.0 15.9

* Significant to the 95% confidence level

Cross-clamp and cardiopulmonary bypass time

Sutureless AVR was reported to have lower cross-clamp times between 12 and 32 minutes.(5, 6, 35, 36) Sutureless AVR was reported to have lower cardiopulmonary bypass times between 16 and 30 minutes.

Haemodynamic outcomes

Non-statistically significant differences were reported in haemodynamic outcomes, in four studies that compared sutureless AVR and conventional AVR. Three of the four studies reported a reduction in mean transvalvular gradient (5, 35, 39), the other study reported an increase(36)


Complications

Sutureless AVR was not associated with a higher rate of complications compared with conventional surgical AVR in comparative trials, with the possible exception of paravalvular leak. The severity of paravalvular leak was graded in a variety of ways in the comparative studies, making it difficult to interpret the data. In D’Onofrio et al’s propensity matched study postoperative aortic regurgitation (mild grade 1 or greater) was 19.4% in sutureless AVR compared with 1.8% in conventional AVR (statistical significance not reported).(39) Shrestha et al’s non-propensity matched study recorded mild (grade 1) perioperative paravalvular leak in 2.5% of conventional AVR patients and 8.2% of sutureless patients, though the difference was not statistically significant.(36) Santarpino et al’s propensity matched study reported no post-operative cases of paravalvular leak in sutureless AVR compared with 13.5% (grade 1+) in TAVI patients (p=0.027).(37)

Regulatory warning for the 3f Enable aortic valve

Medsafe and the Australian Therapeutic Goods Administration released a warning for the 3f Enable Aortic Bioprosthesis (model 6000) in late 2014, noting that there is the potential for the valve to move after implantation, including partial or complete displacement or tilting from its original implant location.(42, 43) The likelihood of this problem occurring is rare, with an occurrence rate of less than 0.55% globally (as of 31 October 2014). Medtronic subsequently announced in May 2015 the discontinuation of the 3f Enable Aortic Bioprosthesis due to lack of commercial adoption, ceasing enrolment of all patients in all clinical studies. (30)

Meta analysis of observational studies

A recent meta analysis identified 12 studies that assessed AVR using a sutureless valve and reporting mortality and complications.iii (19) The studies were predominantly single arm studies, also included were studies comparing sutureless AVR to TAVI and one study comparing two different sutureless valves. Pooled 30-day and 1-year mortality rates were 2.1%, and 4.9% respectively.(19) The mean log EuroSCORE was 11.7 indicating moderate preoperative surgical risk. The total patient population was 1,037 with a mean age of 77 years. The mortality rates were described by the authors as low and acceptable, and similar to other recently reported rates for standard surgical AVR.

The authors concluded that the evidence suggests sutureless AVR is a safe procedure associated with shorter cross-clamp and cardiopulmonary bypass (CPB) duration, and comparable complication rates to the conventional approach in the short-term.

Table 6 summarises key outcomes from the meta analysis. Mean postoperative paravalvular leak rate was 3%, less than reported in earlier reports, suggesting a possible learning curve improvement. The mean rate of stroke, with up to one year of follow-up, was 1.5%, comparable with conventional surgical AVR (44). The mean rate of permanent pacemaker implantation was 5.6%, greater than for conventional AVR (around 3%).(19)

iii Studies were included to January 2014 but excluded abstracts and conference presentations, case reports,

editorials, reviews and expert opinion papers were excluded.


Table 6. Summary of outcomes from meta analysis No. of trials 12

No. of patients 1,037

Outcomes (weighted mean - incidence of complication at latest available follow-up)

30-day mortality 2.1%

1-year mortality 4.9%

Paravalvular leak 3.0%

Stroke 1.5%

Permanent new pacemaker 5.6%

Valve degeneration/dislocation 0.4%

Renal failure 1.2%

Endocarditis 2.2%

Source: Phan et al.(19)

Included trials: Gilmanov et al. 2013(45); Kocher et al. 2013(29); Martens et al. 2011(28); Eichstaedt et al. 2013(46); : Folliguet

et al. 2012(27); Shrestha et al. 2013(36); D’Onofrio et al. 2012(47); Breitenbach et al. 2010(21); Flameng et al. 2011(48);

Santarpino et al. 2014(37); Doss et al. 2005(49); Concistre et al. 2013(50)

The meta analysis found a mean CPB of 73 minutes and aortic cross-clamp time of 45 minutes. These times were even shorter for isolated minimally invasive sutureless AVR procedures, with CPB and cross-clamp time being 57 and 33 minutes respectively. The authors of the meta analysis note that this data compares favourably with recent data for isolated conventional AVR with full sternotomy from the STS database showing CPB and cross-clamp times of 106 and 78 minutes, respectively.(19) This is suggestive of a halving of CPB and cross-clamp time with sutureless AVR compared with standard full sternotomy.(19)

Efficacy in terms of haemodynamics was demonstrated in the sutureless AVR trials, with the mean and peak transvalvular gradients (indication of aortic stenosis) decreasing from 11.1 and 19.6, respectively, at discharge, to 9−10 and 17−18mmHg, respectively, at 6 and 12 months. Mean effective orifice area (measure of valve quality) was maintained at 1.7−1.8 cm from discharge to 1 year. (19)

Facilitation of minimally invasive surgery

The authors conclude that sutureless AVR appears to facilitate minimally invasive surgery. This is apparently due to the sutureless valve making minimally invasive surgery (which is technically challenging) easier and reducing cross-clamp, CPB and operative duration.(51) Minimally invasive aortic valve surgery involves smaller incisions allowing patients to recover more rapidly, and is associated with reduced hospital and intensive care length of stay without elevated risk of death.(52-

56) The Canadian Agency for Drugs and Technologies in Health note, however, that the use of minimally approaches increases technical difficulty, leading to longer CPB and cross-clamp times, potentially offsetting one of the main advantages of sutureless AVR over surgical AVR.(57) In support, they cite a pooled analysis of 731 consecutive patients who underwent sutureless AVR using the Perceval S valve in Europe between 2007 and 2012. (58) The study found that cross-clamp and cardiopulmonary bypass times were greater using the minimally invasive sutureless


AVR compared with sutureless AVR with conventional full sternotomy. In isolated AVR, mean cross-clamp and cardiopulmonary bypass times were 30.8 and 50.8 minutes in full sternotomy, and 37.6 and 64.4 minutes in the minimally invasive approach, respectively. What the study shows is not that sutureless valves cannot simplify minimally invasive surgery, but that a comparative study is needed to test the value of sutureless valves compared with conventional valves in minimally invasive surgery.

Limitations

Reported statistical heterogeneity was moderate to high in the meta analysis of one-year mortality (I2=59%), stroke (I2=43%), endocarditis (I2=58%), and paravalvular leak (I2=72%). This indicates that the combined studies had significant underlying clinical diversity in their populations, interventions, and outcomes and/or methodological diversity with variation in the intervention effects being evaluated.(59) Studies included in the meta analyses mixed comparative and single arm trials; mixed minimally invasive and conventional surgical sutureless AVR; and used different sutureless valves. All studies included in the meta analysis were observational; ten were prospective and two retrospective. Two studies included propensity matching. The number of patients was more than 50 in only seven of the 12 studies, and follow-up was 12 months or more in only five studies.

The strength of observational studies is in determining incidence, prevalence, and prognosis of a condition. When studying the effect of an intervention, an association may be found between intervention and effect because there actually is a causal link, or due to bias, confounding, or chance. Study results are more reliable if the study is designed to minimise or eliminate the effects of bias, confounding and chance. Observational studies ‘observe’ differences in outcomes, but do not address bias, confounding, and chance. There can be more confidence in the findings of studies designed to identify unbiased causal associations between exposure and outcome; that is, they are more reliable. Randomised controlled trials (RCTs) are considered the best way of proving causality. However, observational studies are frequently the best or only available evidence. When this is the case they need to be evaluated for quality and their findings interpreted with caution.(60, 61)

New Zealand data

New Zealand data have been reported for the first 68 patients who underwent sutureless AVR (91% with the Perceval sutureless valve) between 2011 and 2014 in Canterbury.(31) At the time of writing, the results have not been published and limited information is available to report. Ninety-one percent of patients had a diagnosis of AS. The mean follow-up duration was four months (range: 0-31months), and the median age was 78 years.

Thirty-day mortality was 6.1 percent, for a patient population with a predicated operative mortality (logistic EuroSCORE) risk of 13.1 percent. Mean hospital stay was eight days (range: 4-45 days). Mean aortic gradient improved from 45.4 mmHg to 12.3 mmHg postoperatively. Complications included: neurological events in 9.0% of patients, including stroke in three patients, bleeding/ tamponade, acute renal failure, leg ischaemia, prolonged ICU stay, deep vein thrombosis, and pneumonia in one patient each respectively. No patients developed a paravalvular leak. The study did not address durability of performance.

The study compared isolated sutureless and isolated conventional AVR surgery, ie not including concomitant procedures, for aortic cross-clamp time and cardiopulmonary bypass time. Baseline characteristics have not yet been reported, making the comparison tenuous. Nevertheless, cross clamp time and cardiopulmonary bypass time were lower in the sutureless group compared with


the conventional AVR group, at 55 vs 110 minutes and 38 vs 78 minutes for sutureless and conventional surgery, respectively.

Observational studies without a control group

The observational studies without a control group include data for more than 1,000 patients in total. However, it is likely that some patient groups have been reported more than once and have been included in both comparative and non-comparative analyses (see Table 12 and Table 14, Appendix 2). Observational studies without a control group have some value in demonstrating the feasibility and safety of an intervention; but have limited value in demonstrating the marginal value of a new intervention compared with standard care.

Mortality

The overall average early mortality rates (in-hospital or within 30 days) was 3% (Table 14, Appendix 3,), with mean follow-up periods of eight months to one year, mortality rates were 5% to 13%.(26-29, 45, 46, 62, 63) A pooled analysis of 731 consecutive patients who underwent sutureless AVR in 25 European centres using the Perceval S valve between 2007 and 2012, reported overall survival rates at one and five years of 92.1 and 74.7%, respectively.(58) The mean age of patients was 78.5 years, with moderate preoperative risk (mean logistic EuroSCORE 10.9%).

Complications

Consistent with the comparative studies discussed above, overall complications appear relatively low. Folliguet et al (n=208) found a relatively high rate of paravalvular leak and bleeding complications requiring blood transfusion in moderate to high risk patients at 8% and 6% respectively.(27) Paravalvular leak was 3% or less in seven other studies.(26, 28, 29, 45, 46, 62, 63) Gilmanov et al (n=137) found 5% of patients had bleeding complications requiring revision surgery(45), and Eichstaedt et al (n=120) reported bleeding complications in 3% of patients(46); bleeding complications were 2% or less in two further studies. (26, 29) In the aforementioned pooled analysis of 731 Perceval S patient’s - major paravalvular leak occurred in 1.4% and 1% at early and late follow-up, respectively.(58) There were no valve migrations, structural valve degeneration or valve thrombosis in the follow-up to five years.

Sutureless AVR versus TAVI

Sutureless AVR has been positioned in what some researchers have termed the ‘grey zone’ – essentially asserting sutureless AVR as an alternative to TAVI in moderate to high-risk but operable patients. (37, 39, 47, 64, 65) TAVI is discussed in detail in our Tier 3 Assessment report on the technology: Transcatheter Aortic Valve Implantation: Assessment Report Tier 3 2015. Briefly, in one randomised controlled trial, TAVI demonstrated non-inferiority (regarding all-cause mortality) to surgical AVR in high-risk patients with five years of follow-up;(66) in another RCT with two years of follow-up TAVI was superior.(67) For sutureless AVR, just one small RCT has reported non-inferior all-cause mortality compared with surgical AVR at 30 days in low-risk patients (discussed above).(33) Although sutureless AVR is a surgical procedure, just with a modified bioprosthetic valve, non-inferiority between TAVI and sutureless AVR cannot be inferred as the study populations of the TAVI and sutureless RCTs are different. There has been no RCT for sutureless AVR compared with surgical AVR in high-risk patients. No RCTs have compared TAVI with sutureless AVR, and none are known to be in the pipeline. Accordingly, we discuss below the observational data comparing TAVI with sutureless AVR. Overall, sutureless has similar clinical outcomes to TAVI, but may be associated with lower rates of paravalvular leak, consistent with the randomised controlled


trials showing higher rates of paravalvular leak in TAVI compared with conventional surgical AVR. (67-69)

Biancari et al propensity matched 144 pairs of TAVI and sutureless AVR patients using the Perceval S prosthesis.(65) Matched patients had low to moderate preoperative risk with mean EuroSCORE II < 5% in both groups. For matched pairs, in-hospital mortality was greater for TAVI patients compared with sutureless AVR (6.9% vs 1.4%, p=0.035). Moderate or severe paravalvular leak was evident in 14.8% of TAVI patients and 0.7% of sutureless AVR patients, p<0.001. TAVI access was performed mostly using the transfemoral approach (97.7%), and using the Medtronic CoreValve (72.6%). Fifty-four percent of sutureless AVR cases underwent minimally invasive surgery. In the propensity matched groups 26.4% of sutureless patients underwent concomitant coronary artery bypass surgery; while just one patient (0.7%) in the TAVI group underwent concomitant percutaneous coronary intervention. Concomitant coronary artery bypass surgery is a known operative mortality risk factor.(70) Hence in this observational study short-term survival appears to be favourable in the sutureless group.

D’Onofrio et al (2013) undertook a propensity matched study comparing transapical TAVI with sutureless AVR and conventional surgery. (39) Patients were matched across ten variables including heart failure class (New York Heart Association Class ≥3) and preoperative risk (logistic EuroSCORE). TAVI patients remained slightly older post-matching compared with open heart surgery (conventional and sutureless) (mean 77.6 vs 73.5, p=0.003). All other baseline characteristics were similar, with mean logistic EuroSCOREs of 18.3% and 20.2%, p=0.22, for open heart surgery and TAVI, respectively. Post-matching baseline characteristics of the sutureless group were not individually reported. Post-matching groups comprised 143 TAVI patients, 31 sutureless AVR patients and 112 conventional surgical AVR patients. 30 day mortality was lower for conventional AVR compared with TAVI (7% vs 1.8%, p=0.26), but no significant difference in mortality was observed between sutureless and TAVI (1.8% vs 0%, p=0.21). Lower rates of postoperative aortic regurgitation, pacemaker implantation, and renal replacement therapy were observed in the sutureless group compared with the TAVI group, but did not reach statistical significance. Postoperative aortic regurgitation (mild or greater) was 28.7%, 19.4% and 1.8% in the TAVI, sutureless and conventional AVR groups, respectively. For TAVI versus conventional surgical AVR the difference was significant, p<0.001.

In an earlier analysis D’Onofrio et al (2012) propensity matched 38 pairs of sutureless AVR and TAVI patients, and reported hospital mortality of 5.3% and 0% in TAVI and sutureless groups, respectively ( p=0.49). (47) Patients were moderate risk, with a mean logistic EuroSCORE of 14.8% and 13.7 % in the TAVI and sutureless AVR groups, respectively (p=0.47). Again TAVI was performed using the transapical approach.

Santarpino et al propensity matched 37 pairs of sutureless AVR and TAVI patients, reporting in-hospital mortality of 0% and 8.1% in the sutureless and TAVI groups, respectively (p=0.24). (37) Patients were moderate to high-risk with a mean logistic EuroSCORE of 18.1% and 20.6% in the sutureless and TAVI groups, respectively (p=0.81). Pre-hospital discharge paravalvular leak (at least mild) was higher in the TAVI group (13.5% vs 0%, p=0.027). Results are difficult to interpret as the TAVI arm comprised a mix of approaches, (transapical and transfemoral) while some sutureless patients also underwent concomitant heart surgery.

Muneretto et al compared TAVI (n=55), conventional surgery (n=55) and sutureless AVR (n=53) in a prospective non-propensity matched observational study.(64) Baseline characteristics showed patient groups had similar preoperative (moderate STS ≤6%) risk, but chronic obstructive pulmonary disease was more frequent in TAVI patients (47%) compared with sutureless AVR (15.1%) and surgical AVR (27.2%); while pulmonary hypertension was lower in the TAVI group


compared with the other groups. The study compared transfemoral TAVI with a mix of minimally invasive or conventional surgery (using either standard or sutureless valves). Post -procedure pacemaker implantation using the Medtronic CoreValve was high (25.5%) compared with conventional surgery (1.8%) and sutureless AVR (2%). The TAVI result is consistent with high rates of pacemaker implantation observed in randomised controlled trial for the Corevalve.(71) Peripheral vascular complications were more frequent in the TAVI group (14.5% vs 0%, 0%), as would be expected from a percutaneous procedure which enters through the groin rather than the chest. All-cause mortality was similar between groups at 24 months, being 14.5%, 9.4% and 12.7% in the conventional AVR, sutureless AVR, and TAVI groups, respectively, p=0.46.


Health technology assessments of sutureless AVR

HealthPACT has reviewed sutureless AVR in patients with severe AS in 2014. (9) They concluded ‘Short-term results are comparable to standard aortic valve replacement and benefits of using these valves may include a shorter duration of surgery, however appropriate patient selection is important. It would be prudent to await the results of a number of trials currently underway, therefore HealthPACT recommends that this technology be monitored for further information in 24-months’.

The National Institute for Health and Care Excellence (NICE) reviewed sutureless AVR in 2013, finding evidence of limited quality supporting the efficacy of sutureless AVR for AS in the short-term.(8) The evidence on safety was not considered to raise any major concerns apart from paravalvular leak and central leaks. NICE supports sutureless AVR in high-risk surgical AVR patients with special arrangements for clinical governance, consent and data collection. Clinicians are to ensure patients understand the uncertainty around the intervention's safety and efficacy, and communicate the alternative options to patients. Sutureless AVR was not supported for non-high-risk surgical patients outside the context of research.

The Canadian Agency for Drugs and Technologies in Health reviewed sutureless valves for the treatment of aortic stenosis in 2015. They noted that:

Initial evidence suggested sutureless had comparable outcomes to surgical AVR, but results in higher rates of paravalvular leakage and pacemaker implantation.

Sutureless AVR has lower rates of paravalvular leakage and pacemaker implantation than TAVI.

There was potential savings due to lower procedure costs compared with surgical AVR, citing a small McGill University study discussed below.

It is unclear which patients are the best candidates for sutureless valves, or if any sutureless valve type was superior.(57)


Current and future trials

The Australian and New Zealand Clinical Trials Registry, and United States Institute of Health’s clinical trial registry, ClinicalTrials.gov, were utilised to identify ongoing and planned trials relating to sutureless AVR. Two small randomised trials are underway looking at the short-term efficacy of minimally invasive surgery, with or without a sutureless valve, compared with conventional surgical AVR. The trials are run by the same Swedish research team based in a single centre (Table 7). The largest ongoing trial is the CAVALIER trial, with estimated enrolment of 658 patients. Its primary completion date (final data for collection of primary outcome measure) was October 2014, but the trial is ongoing with an estimated completion date of September 2018. The trial is for the Sorin Perceval S valve as are the other two large single arm observational studies, all sponsored by Sorin – the Perceval Pivotal Trial and the Perceval S Aortic Heart Valve Study – North North America. Compared with TAVI, where there are more than 100 trials underway, including 24 RCTs, there is relatively little ongoing research for the sutureless valve. Adding to this is Medtronic’s recent exit from the market, stopping enrolment of new patients in all clinical studies, including:

3f Enable long-term follow-up study

3f Enable EASE post-market study.

Countering this, the International Valvular Surgery Study Group (IVSSG) was recently formulated representing a global collaboration of 30 valvular surgeons from ten countries.iv The collaboration aims to conduct sutureless research projects, with a particular aim to establish a multi-national sutureless AVR registry to collect long-term outcomes data. New Zealand is not currently a member of the collaboration, though two centres contribute from Australia. The IVSSG appears to be actively looking for participants.

iv http://suturelessprojects.com/


http://suturelessprojects.com/

Table 7: Current and planned trialsStudy Primary end point Comparator N Primary

completion date

Phase Sponsor Valve Clinical trial ID

Pilot Trial: Comparison of Flow Patterns

Comparison of maximum and minimum velocity, effective orifice area, percentage of turbulent flow, pressure drop between 6 months and 4 years after AVR

Regular valve 20 July2015

Medical University of Vienna

Edwards Intuity valve

NCT02288871

Perceval S Aortic Heart Valve Study- North America

All-cause mortality 12 months NA 300 January 2016

Sorin Group USA

PERCEVAL S NCT01810679

Perceval Pivotal Trial Incidence of mortality and morbidity at 3-6 months after implant

NA 150 October 2009

2 and 3 Sorin Group USA

PERCEVAL S NCT00860730

CAVALIER Incindence of Incidence of mortality and morbidity at 12 months

NA 658 October 2014

2 and 3 Sorin Group PERCEVAL S NCT01368666

Surgical Trauma After Partial Upper Hemisternotomy Versus Full Sternotomy Aortic Valve Replacement (RCT)

Surgical Trauma up to 3 days post operaively

Minimially invasive AVR vs conventional surgery AVR

20 December2015

2 Karolinska University Hospital

Mechanical and bioprosthetic (stented or sutureless) aortic valves

NCT02272621

Cardiac Function After Minimally Invasive Aortic Valve Implantation (CMILE) (RCT)

Cardiac function upto 40 days post procedure

Minimially invasive AVR vs conventional surgery AVR

40 July2015

2 Karolinska University Hospital

Mechanical and bioprosthetic (stented or sutureless) aortic valves

NCT01972555


4. EconomicCurrent evidence suggests sutureless AVR may have similar cost-effectiveness to conventional AVR, with sutureless AVR having comparable outcomes and the possibility of lower procedural costs. The methods for the economic literature search are contained in Appendix 1.

The cost of sutureless valve has been falling in recent years, which has led to the costs of sutureless and conventional valves being similar (Figure 1). The Edwards Intuity valve may be an exception to falling costs of sutureless valves, where a recent report from Germany suggests the valve costs about twice that of the Sorin and Medtronic valves.(32) There are no head to head trials of the Edwards Intuity valve with the Sorin or Medtronic valves to justify any price differential.v

Figure 1: Cost of a sutureless valve 2011 to 2014

Source: Cost of sutureless valve provided to NHC by the manufacturer. Cost of conventional bioprosthetic valve provided

by Auckland DHB for 2014

The evidence for reduced procedure and admission costs from sutureless AVR is mixed. One study reported savings due to reduced hospital stay,(6) and there are indirect comparisons that report reduced hospital stay and reduced operation time.(7, 19, 34, 72) Other studies report no differences in length of stay.(35, 36) Costing studies that assume a reduction in hospital length of stay and a reduction in hospital related costs, estimate sutureless AVR to cost 10% – 47% less than conventional AVR.(6, 7, 72)

New Zealand cost data – cost of admission

The average cost of an admission with a sutureless AVR procedure in 2012/13 was $51,500 (range $43,000 to $73,000), with an average length of stay of 13 days (Table 8). Accounting for the recent $3,500 price decline in two sutureless AVR valves, we estimate that the average cost of

v Edwards were contacted for cost and comparative head-to-head studies with competing valves. Cost information

was not provided. No head-to-head studies or RCTs have been undertaken using the valve.


sutureless AVR is now approximately $48,000. There were, however, just 12 records for sutureless in 2012/13 for which cost information was available. 2012/13 data was used as it is the most recent year for which data is available in the National Costing Collection and Pricing Programme.

Table 8: New Zealand cost data sutureless AVR 2012/13

RecordAverage length of stay (days)

Total CS-7 cost for sutureless AVR

Additional procedures recorded

1 11 $72,678 Reopening of the chest2 16 $40,8233 8 $65,2784 8 $45,272 CABG5 6 $41,568 CABG6 6 $41,7097 36 $73,3998 16 $52,6369 14 $45,535

10 13 $59,018 CABG11 11 $41,318 CABG12 6 $38,817

Average 13 $51,504

Source: NHC analysis of NCCP data 2015, using cost schedule seven.

Four of the 12 identified sutureless AVR operations included concomitant coronary artery bypass grafts (CABG) and one recorded a reopening of the chest. In our small dataset, the average cost of sutureless AVR with concomitant CABG is $4,700 less than the total average cost of sutureless AVR – probably due to the lower length of stay for these patients (9.5 days vs 13 days).

Incremental cost of sutureless AVR

National data collections do not record sufficient patient information to reliably estimate the incremental cost of sutureless AVR compared with standard surgical AVR. In particular, there is no record of surgical risk, where greater surgical risk is associated with greater cost.(73) In New Zealand, sutureless AVR is being targeted at moderate to high-risk patients,(31) so we would expect its average cost to be greater than the average cost of conventional bioprosthetic surgical AVR. Our data, though limited to just 12 sutureless AVR records, shows a modest cost increase of $2,000 with similar length of stay compared with conventional bioprosthetic surgical AVR (Table 9).


Table 9: Cost of sutureless AVR compared with conventional bioprosthetic AVRSutureless AVR

All bioprosthetic valves

Average cost $48,000 $46,000Average length of stay (days)

13 12

Valve cost $6,500 $5,700Number of records 12 331

Source: NHC analysis of NCCP data accessed in 2015, using cost schedule seven.

International cost data

No cost-effectiveness evaluations of sutureless AVR have been identified, but three studies have reported on cost. All three studies suggest cost savings for sutureless AVR compared with conventional surgical AVR. Two studies report the costs associated with undertaking sutureless AVR with the Perceval S valve (6, 72) while a Canadian health technology assessment included a cost analysis of the 3f Enable valve.(7) One study is of reasonable quality as it is based on the results of propensity matched study. The other two studies are of relatively low quality and are based on indirect comparisons.

Cost-saving estimate from propensity matched study

Pollari et al (2014) undertook a propensity matched analysis of the short term outcomes of sutureless valves; the study included 82 matched pairs(6) using the Perceval S valve. They reported cost savings of approximately 25% using minimally invasive sutureless AVR, compared with minimally invasive surgical AVR using a conventional valve. Savings were driven by a 1.5 day reduction in hospital length of stay and a 0.8 day reduction in ICU length of stay. Patients were moderate risk with a mean Logistic EuroSCORE of 12.1 in the sutureless arm and 10.9 in the conventional surgical arm.

Further results of the study have been summarised in Table 4 and Table 13.

Simulation cost model based on indirect comparisons

Pradelli and Zaniolo (2012) examined the non-device costs associated with the procedure in four European countries.(72) The study aimed to predict the costs and outcomes of AVR procedures associated with Perceval S sutureless aortic valves compared to standard surgical AVR for medium to high surgical risk patients. The researchers used probabilistic patient level simulation to estimate the cost of sutureless AVR using conventional surgery (full sternotomy) and minimally invasive surgery compared with standard surgical AVR. Simulations were conducted using cost schedules from Italy, France, Germany and the United Kingdom. The methods used included a number of indirect comparisons which leads to uncertainty in the results.


An indirect comparison of health care utilisation was undertaken to estimate the differences between sutureless AVR and conventional surgical AVR. The comparison was made by:

indirectly comparing cross-clamp time for sutureless AVR and conventional surgical AVR.

estimating cost outcomes by cross-clamp time based on three matched case-control studies of conventional surgical AVR. Only direct health costs for the AVR surgery were included – the cost of the operation, hospitalisation, and any complications.

applying costs for each of the outcomes based on country specific costs for each of the four countries.

The cross-clamp time for sutureless AVR (Perceval S valve) was taken from the non-comparative CAVALIER trial as reported by Folliguet et al (n = 208).(27) The cross-clamp time for conventional AVR were taken from an adhoc study. Both sources included full sternotomy and minimally invasive procedures.

Sutureless AVR done either as minimally invasive or conventional surgery were found to be cost-saving compared with conventional surgical AVR. Perceval S was associated with fewer complications and reduced costs in both approaches, with the minimally invasive approach associated with the least complications and costs. The savings ranged from NZ $5,766 to NZ $7,754 for conventional surgery (full sternotomy) and NZ $9,483 to NZ $13,139 for mini-invasive sternotomyvi; these savings equate to a 19% to 47% reduction in costs.

Cost analysis from a Canadian university

McGill University Health Centre undertook a technology assessment of sutureless AVR, which was published in 2013.(7) They noted that the 3f Enable valve had an additional cost of $3,750 Canadian dollars (NZ$4456); but potentially shorter operating room (OR) time, intensive care unit (ICU) time, and hospital stay could result in lower procedure costs.

They speculated possible savings from sutureless AVR by assuming:

the minimally invasive technique employed with sutureless AVR would result in less hospital costs than conventional surgery (full sternotomy) employed with conventional surgical AVR;

hospital stay would be 1.5 days shorter, based on a doctors opinion;

operation time would be reduced by two hours, based on a doctor's opinion; and

ICU time would be reduced by 2.4 days, based on a comparison of 19 sutureless AVRs and 853 conventional surgical AVRs done at the university. This was supported somewhat by a meta analysis of four studies reporting reduced ICU time of 0.57 days due to minimally invasive surgery.

They reported an incremental cost of $1,665 (CAD$1,401) if savings in ICU time were excluded. When reduced ICU time was included, the reported savings were $2,055 (CAD $1,728), ie 10% less.

vi All costs were in 2011 or 2012 values, and were in either Euros or Pounds. Costs were converted to New Zealand

dollars using the average exchange rate for 2012.


Budget impact

There does not appear to be a material cost impact from sutureless AVR in New Zealand. Procedure volumes remain low, and there is no evidence of a significant incremental cost over conventional surgical AVR. In total we have identified less than 80 sutureless AVR procedures undertaken since the first report in 2011, most of which have been undertaken in Christchurch.(31)

There is unlikely to be a significant cost impact on DHBs from increased use of sutureless AVR as it is a substitute technology for conventional AVR, rather than a procedure for currently inoperable patients. While international estimates suggest savings from sutureless AVR, they are of limited quality and it is questionable if the estimated savings would eventuate in the New Zealand setting.

Clinical advice to the NHC's executive suggests that between five and ten percent of AVR patients may benefit from sutureless AVR.vii In 2012/13, 511 patients with a primary diagnosis of aortic stenosis underwent publicly funded aortic valve replacement (including TAVI and sutureless AVR). Taking the higher end of this estimate suggests that about 50 patients per annum could possibly benefit from sutureless AVR. Assuming an incremental cost/saving range of +$2,000 per procedure to a 25% saving per procedure implies a budgetary impact of +$102,000 to a saving of $586,500 per annum nationally.

vii Email correspondence from a cardiac surgeon at Waikato DHB to the NHC executive dated 26/11/2014.


5. Societal and ethicalGiven that the safety and efficacy of sutureless AVR seems comparable, varying access to sutureless valves does not give cause for concern. However, this view may change as the evidence for sutureless AVR evolves. Sutureless has been suggested in patients with difficult anatomies, including porcelain aorta or small aortic root; or where re-do surgery is required. These are traditionally risky operations when using standard valve implantation. It is possible that sutureless AVR may prove to have a comparative advantage compared with standard AVR in these population subsets. Shrestha et al (discussed above) found similar mid-term mortality between conventional AVR and sutureless AVR in a non-propensity matched single centre study of patients with a small aortic root.(36) Data on other anatomical features appears limited to case studies. Thus whilst sutureless AVR appears to have a similar safety and effectiveness profile to conventional AVR in general, its potential comparative advantage in specific population subsets requires further investigation. Any questions of inequality in access is premised upon clear evidence of clinical advantage.

As with TAVI and any other implantable device, it is important that sutureless valves are appropriately tracked for patient safety in the event of unforeseen issues with the valve. Registries can be of significant benefit in tracking patients where there is a device recall for safety or any other issue. The use of registries for tracking implantable devices is not yet systematic in New Zealand. An example of the relevance of a registry is the recall of a hip implant in April 2012. The NZ Joint Registry was set up in 1997 by the New Zealand Orthopaedic Association to keep track of all implantsviii. When a faulty hip implant was recalled in April 2012, the distributor contacted all surgeons who implanted the devices with the request to contact their patients. The distributor also worked with the New Zealand Orthopaedic Association and the New Zealand Joint Registry to ensure that patients were notified.ix

Regional variation

The majority of sutureless AVR procedures in New Zealand are done at one hospital (Christchurch Hospital), creating regional disparities in access. Regional variance in access is to be expected with very low procedure volumes. Diffusion rates can vary for a host of reasons, including divergent clinical opinion about an interventions value; resource constraint (including scarce clinical expertise); variation in underlying population need. With greater certainty around patient selection, regional variation may become an issue to consider if sutureless AVR is introduced into business as usual.

Ethnic inequality

There is historic evidence of ethnic inequality in the provision of cardiovascular interventions in New Zealand.(74) Data from the mid-2000s show that while ischaemic heart disease mortality rates were more than two times higher for Māori than non-Māori, cardiac revascularisation procedures were provided at similar rates for the two groups. It is important to ensure equity of access to health services, however, Māori have low incidence and prevalence of AS, and low associated mortality (Table 10).

viii http://www.nzoa.org.nz/nz-joint-registry

ix http://www.medsafe.govt.nz/hot/media/2012/RecallHipImplantDevice.asp


Table 10 Māori/non-Māori prevalence, incidence and mortality for aortic stenosis – 2011Age-standardised prevalence per 100,000

Age standardised incidence per 100,000

Mortality Age standardised mortality per 100,000

Māori 49 7 4 1.3Non-Māori 63 12 291 3.1Total 62 12 295 3.0

Source: NHC analysis of NMDS and mortality records. Prevalence, Incidence and mortality are age standardised to the

WHO population. Incidence is for the 2012/13 financial year while mortality is for the 2011 calendar year, the most recent

year for which data was available at the time of analysis.

Rheumatic fever is a cause of AS, and Māori and Pacifica have high rates of rheumatic fever. This, however, does not translate through to high rates of AS, as the disease mostly affects the mitral valve, not the aortic valve. Incidence of rheumatic heart disease is respectively 20- and 40-times higher for Māori and Pacific children than for non-Māori/non-Pacific children.(75) Pathological evaluation of terminally ill patients with rheumatic heart disease indicates that mitral valve disease is present in 90-95% of cases; with up to a quarter of these patients having aortic valve disease.(76) Isolated aortic valve disease was reported in less than eight percent of cases. In 2012/13, less than two percent of patients diagnosed in a New Zealand hospital with AS had rheumatic AS. During this time, five patients with rheumatic heart disease underwent (publicly funded) AVR.x In 2011 there were two deaths from rheumatic AS, neither person was Māori.xi

Other issues

Though not specifically identified in the sutureless AVR literature, there is significant crossover with the societal and ethical issues facing TAVI. These include the need to ensure informed consent, and mitigate unnecessary harm through avoidance of futile interventions. These issues are discussed in more depth in Transcatheter Aortic Valve Implantation: Assessment Report Tier 3 2015. Briefly, informed consent is a right enshrined in the Code of Health and Disability Services Consumers’ Rights (right seven). No health or disability service can be provided to a consumer without his or her informed consent.(77, 78) Corresponding rights include right five, the right to effective communication, and right six, the right to be fully informed – implying that patients should be fully informed of the potential harms and benefits of an intervention. This is particularly important in the case of emerging technologies such as sutureless AVR where there is uncertainty in mid and long-term outcomes.

An intervention may be considered medically futile if it fails to improve survival with an acceptable quality of life, or in the case that there is no survival benefit, fails to improve quality of life. United States and European professional guidelines note the need for clinicians to consider expected life expectancy and patient quality of life post aortic valve replacement; where a life expectancy of less than one year is considered a contraindication for intervention. (79, 80)

x NHC analysis of national minimum dataset.

xi MoH analysis of mortality records.


6. Feasibility of adoptionThere may be between five and ten percent of AVR patients that could benefit from sutureless AVR. There are no workforce or infrastructure considerations identified that would impede the increased use of sutureless AVR; although, like with all new treatments, appropriate training and oversight would need to be put in place if the use of sutureless AVR increased. Sorin Group informed the NHC that it funds training and support for the use of its Perceval sutureless valve. This includes onsite clinical specialist support for surgical and nursing staff. Sorin Group informed the NHC that the learning curve for the technology is short, with proficiency typically achieved after five cases. They also noted that there were no additional capital requirements for sutureless AVR. In the case of minimally invasive surgery, hemi-sternotomy (involving a smaller chest incision than traditional full-sternotomy) can be performed with standard surgical equipment. Right anteriormini-thoracotomy (entry through the rib cage) would require standard specialist minimally invasive instruments used in minimally invasive cardiac surgery.

Patient selection

Outcomes for sutureless AVR and conventional surgical AVR are expected to be similar, based on evidence to date. Given the lack of long-term safety and efficacy evidence for sutureless AVR, sutureless AVR should not be adopted as the standard of care. However, there may be a small subset of patients for whom sutureless AVR is beneficial. Concise selection criteria for sutureless AVR have not been identified in literature. Clinical advice to the NHC's executive suggests that between five and ten percent of AVR patients may benefit from sutureless AVR, equating to roughly 25 to 50 patients per annum.xii Potential beneficiaries of the procedure include patients with anatomical features that make suturing difficult or risky, such as a heavily calcified aortic annulus or a very small aortic root.(36, 81) Conventional valves may not be suitable for some patients with small aortic roots, resulting in a patient-prosthesis size mismatch. There are alternative surgical techniques for addressing this issue, including the use of homografts. Sutureless AVR is proposed as an additional option due to the large effective orifice of the valve.(36) Patients with an anticipated prolonged bypass and cross-clamp time, including patients undergoing concomitant cardiac surgery, may also benefit.(19) Two non-comparative feasibility studies have also looked at the role of sutureless AVR in targeting patients with significant left ventricular hypertrophy in AS.(82, 83) While the studies suggest that LV mass may be significantly reduced, well-designed comparative studies are required to determine if sutureless AVR confers any advantage over conventional surgical AVR. The learning curve for sutureless AVR is expected to be small as most surgeons are acquainted with the valve insertion techniques required. xiii Figure 2 presents a draft patient selection criteria for sutureless AVR. The criteria are presented purely to promote discussion.

xii Email correspondence from a cardiac surgeon at Waikato DHB to the NHC executive dated 26/11/2014.

xiii Email correspondence from a cardiac surgeon at Canterbury DHB to the NHC executive dated 04/11/2013


Figure 2: Draft patient selection criteria for sutureless AVR

Patient selection criteria

1. Severe symptomatic AS or equivalent indication for AVR, and

2. Anticipated good prognosis without severe impairment from any combination of frailty, cognitive impairment and/or multiple significant comorbidities, and

3. Patient has been accepted by the cardiac surgical conference as suitable for surgery, and one of the following

a. Patient has one or more of the following that make standard surgical AVR unattractive:

i. Heavily calcified aortic annulus

ii. Previous AVR with a homograft

iii. Very small aortic root, or

b. Patient for whom reduced aortic cross-clamp time would be extremely desirable to improve perioperative survival, including high surgical risk patients undergoing multiple valve replacements and/or concomitant coronary artery bypass grafting, or

c. Patient has chest anatomy such that partial sternotomy is greatly preferred over full sternotomy.

Source: Draft clinical criteria provided to NHC during clinical engagement

Workforce and infrastructure considerations

Sutureless AVR is currently being undertaken in three DHBs including, Auckland, Waikato, and Canterbury. It has been estimated that surgeons need to undertake sutureless AVR on 10 to 20 patients to achieve a satisfactory level of experience.(5) The procedure does not involve a significant learning curve,(31) and there is no additional workforce requirement suggested in the literature. The findings of Pollari et al suggest that sutureless AVR may in fact require slightly less medical labour, primarily due to reduced length of stay.(6) If patients were able to be discharged from hospital earlier, this may allow waiting lists to be reduced.


7. ConclusionSutureless AVR is a new valve procedure for patients with severe symptomatic AS. Evidence to date suggests comparable outcomes with sutureless AVR and conventional surgical AVR. However, evidence of long-term safety and efficacy is currently lacking.

Sutureless valves are now approved for use in Europe and Australia. There is unlikely to be a significant cost impact on DHBs from sutureless AVR as it is a substitute technology for conventional surgical AVR, rather than a procedure for currently inoperable patients. The cost of sutureless valves is now close to the cost of conventional bioprosthetic valves. The admission costs of sutureless AVR may be less than conventional surgical AVR.

No significant social or ethical issues have been identified. The main issue regarding the feasibility of adoption involves identifying the patients who are most likely to benefit. The procedure is associated with a small learning curve, where the training overhead is expected to be met by industry. It is hypothesised that the technology may have a comparative advantage for patients with anatomical features that make conventional surgery risky and in patients requiring a repeat aortic valve replacement. Data is currently lacking here to establish a comparative advantage relative to conventional AVR. If such an advantage were established, then equity of access would become an issue the health system would need to address.

Sutureless AVR should not replace conventional surgical AVR as the standard of care for severe symptomatic AS. If clinicians would prefer to use sutureless valves, there seems to be sufficient justification in them doing so; particularly in a small number of high-risk patients.


Appendix 1: MethodsA number of different methods were used to answer the research questions across the NHC’s four domains: clinical safety and effectiveness; economic; feasibility of adoption, and; societal and ethical.

Methods for clinical safety and effectiveness

The questions in the clinical safety and effectiveness domain were addressed primarily by a systematic review of existing literature.

The following databases were searched up to end September 2014: MEDLINE, Embase, CENTRAL (Cochrane Central Database of Controlled Trials), Cochrane Database of Systematic Reviews, and DARE (Database of Abstracts of Reviews of Effect). Further trials were identified by scanning the reference lists of relevant papers. Additionally, international health technology assessment sites were searched for relevant reports.

The search terms used were: ((sutureless OR suture-less OR stitchless OR stitch-less) adj3 aortic adj3 valve).mp OR 3f-enable.mp OR ATS 3F.mp OR perceval s.mp OR (perceval AND (sutureless OR suture-less OR stitchless OR stitch-less)).mp OR intuity valve system.mp OR trilogy aortic valve system.mp.

The following inclusion and exclusion criteria were applied to the retrieved citations. Clinical trials of AVR using a sutureless bioprosthetic device in adults were included; trials in children and AVR using mechanical valves were excluded. To be included the trial must report clinical outcomes of patients, including one or more of: haemodynamic results; procedural outcomes (aortic clamp time, cardiopulmonary bypass time and/or procedural success); mortality and/or safety. Pre-clinical studies and those that reported solely on valve implantation technique were excluded.

Where a series of patients appeared to have been reported more than once, the most recent and/or complete report was included. Case reports were excluded because of the high risk of bias, ie there tends to be a bias towards publishing the most successful or complex cases. Due to the lack of good quality evidence for sutureless aortic valves, case series were included where it seemed likely that the outcomes of all patients treated sequentially were reported, rather than only outcomes for selected patients within the treated group being reported. The latter approach has a high risk of bias because patients for whom results are reported may have different characteristics or outcomes than those who for whom results are not reported.

Methods for economic evaluation

A literature search was conducted to identify cost and cost-effectiveness analyses of sutureless AVR that could provide information relevant to inputs for economic modelling. The same databases and search terms as described above, in combination with a range of cost and economic terms, were used.

Volume estimates were obtained by searching free text fields in the National Minimum Dataset and asking DHBs to confirm or amend our estimates from their records. There is not yet a unique identifier for sutureless AVR in the NMDS. Costs for sutureless AVR


procedures were obtained from National Costing Collection and Pricing Protocol (NCCP) data cube for all years for which data was available; more recent data than 2012/13 was not available because of reporting lags. Several New Zealand DHBs take part in the NCCP, which aims to create an annual national price book for hospital services. As a part of this, DHBs are asked to provide unit record estimates of expenditure for each intervention across several cost schedules, which represent different cost centres. Cost schedule seven was used to estimate cost as it is considered more inclusive and reflective of cost than cost schedule two.

Sutureless AVR cost data 2013 financial year

Sutureless AVR events were identified using the information recorded in the free text field of the NMDS. The events were then sent to the DHBs which performed the procedures for confirmation and amendment where necessary. The information supplied by the DHBs was used to ensure that the records used in the analysis were correct and there was no duplication of records.

Cost data from the National Cost Collection Project (NCCP) was used to estimate the costs of sutureless AVR events. Data collected in the NCCP project is sourced from the costing systems employed by DHBs to allocate the cost of care across events occurring in their hospitals. Costs are allocated on the basis of the length of stay in hospital and the procedures included in the care of the patient. Costs were identified by linking the unique patient identification code recorded in the verified NMDS data and the NCCP data.

Cost data sutureless AVR compared to bioprosethetic valves 2013 financial year

Sutureless AVR events were identified using the information recorded in the free text field of the NMDS. The events were then sent to the DHBs which performed the procedures for confirmation and amendment where necessary. The information supplied by the DHBs was used to ensure that the records used in the analysis were correct and there was no duplication of records.

Bioprosethetic valve events were found by identifying records in the NMDS where the implantation of a bioprosethetic valve was an element of the care provided during the episode of care.

Cost data from the National Cost Collection Project (NCCP) was used to estimate the cost of the TAVI and bioprosethetic valve events.

Data collected in the NCCP project is sourced from the costing systems employed by DHBs to allocate the cost of care across events occurring in their hospitals. Costs are allocated on the basis of the length of stay in hospital and the procedures included in the care of the patient.

Costs for the TAVI and bioprosethetic valve events were identified by linking the unique patient identification code recorded in the verified NMDS data and the NCCP data.


Māori/non-Māori prevalence, incidence and mortality for aortic stenosis – 2011

Mortality data for the 2012 calendar year was sourced from mortality statistic data sets maintained by the Ministry of Health. Mortality events were selected where the cause of death was coded as one of the following:

I350 Aortic (valve) stenosis

I352 Aortic (valve) stenosis with insufficiency

I060 Rheumatic aortic stenosis

I062 Rheumatic aortic stenosis with insufficiency

The data was aggregated into the following:

a) Ethnicityb) Age groupc) Aortic stenosisd) Rheumatic aortic stenosis.

Age group population data was obtained from the World Health Organisation (WHO) website, aggregated and proportions calculated. Statistics New Zealand population estimates for the 2012 calendar were aggregated using:

a) Ethnicity Māori and non-Māorib) Age group.

The age adjusted rate was found by dividing the aggregated mortality data by the Statistics New Zealand population estimates, which were then weighted by the proportions derived from the WHO population statistics.


Appendix 2. Description of clinical trials of sutureless AVRTable 11: Patient characteristics and description of comparative trials of sutureless AVR; including comparisons with conventional AVR, TAVI and different sutureless valves.Author Device Patient group Log Euro

SCORE (mean/ median%)

Mean/ median Age (y)

Surgical technique

Comments

Concistre et al (2013)(50)

Perceval S(n = 97)

SSASAge >75y

11.4 NR Mini 65%Concomitant or redo procedures 35%

Reports initial experience with the technologies at the study centres; choice of valve at physician discretion. Some or all patients in the Perceval S group may be part of CAVALIER trial.The authors declared no conflicts of interest; financial relationship with Sorin for two of the authors disclosed in another paper (Pfeiffer and Fischlein)Design: retrospective. Baseline characteristics similar between groups other than body surface area

3f Enable(n = 32)

13.8

D’Onofrio et al (2012)(47)

Perceval S(n = 38)

SSASAge >75y

13.7 81 Mini 29%Plus CABG 32%

Patients represent the entire experience with Perceval S at the study centresTAVI data from Italian Registry of Transapical Aortic Valve Implantation, representing the majority of such procedures undertaken in ItalyDecision re choice of technology made by cardiac surgeon based on patient characteristicsDisclosure: No commercial supportDesign: prospective, propensity-matched. Baseline patient characteristics similar after propensity matching.Excluded inoperable patients treated with TAVI

TAVI(n = 38)

14.8 81 Transapical TAVI


Perceval S(n = 31)

SSASAge ≥75y for Perceval S

18.3a 74a Mini 39% Extension of above studyPerceval S and TAVI are drawn from the same patient groups as aboveStandard AVR from a consecutive series of patients, using the same dataset and definitions as for the other groups

TAVI(n = 143)

20.2 78 Transapical TAVI


Author Device Patient group Log Euro SCORE (mean/ median%)


Surgical technique

Comments

The propensity matched cohort included 143 TAVI recipients and 143 surgical AVR recipients. Amongst the latter group, 31 underwent sutureless AVR and 112 underwent standard surgical AVR.The primary comparisons were: (1) TAVI vs Perceval S, and; (2) TAVI vs standard AVR. Perceval S and standard AVR were not directly compared.Disclosure: No commercial supportDesign: Prospective for Perceval S and TAVI; retrospective for standard surgical AVR. Propensity-matched. TAVI group significantly older than the surgical AVR group (Perceval S or Standard AVR)


18.3a 74a Full sternotomyIsolated AVR


Sutureless(n = 133)

Eligible for isolated AVR by right anterior minithoracotomy

5.8 75 Mini all patientsIsolated AVR

Sutureless cohort is likely to include some patients from Gilmanov et al noncomparative study(45)

Design: Retrospective, propensity matched. Baseline patient characteristics similar after propensity matching.


5.5 74

Pollari et al.(6) Perceval S(n = 82)

Severe ASAge >65y

12.1 76 Mini when possibleIsolated AVR

Some patients in the Perceval S group part of CAVALIER multicentre trialControl group ineligible for Perceval SThe patient cohort is likely to include some patients also reported in Santarpino et al. 2013(5) but the latter wasn’t propensity matched.Disclosure: Financial relationship with Sorin disclosed by two of the authors (Pfeiffer and Fischlein)Design: Propensity matched. Baseline patient characteristics similar after propensity matching.


10.9 75


Perceval S(n = 50)

SSAS Age ≥65y for Perceval S

9.9 78 Mini all patientsIsolated AVR

Some patients in the Perceval S group part of CAVALIER multicentre trialControl group ineligible for Perceval SDisclosure: Financial relationship with Sorin disclosed by two of the authors (Pfeiffer and Fischlein)


4.3 72




Surgical technique

Comments

Design: Prospective. Significant differences between groups in age and surgical risk because the control group comprised patients for whom sutureless AVR was not indicated.


Perceval S (n = 37)

SSASAge ≥65y

18.1 81.5 Mini all sutureless AVR

First enrolled Perceval S patients were part of the CAVALIER multicentre trial; later patients received Perceval S under routine useDisclosure: Financial relationship with Sorin disclosed by two of the authors (Pfeiffer and Fischlein)Design: retrospective. Propensity matched.

TAVI(n = 37)

20.6 84.5


Perceval S (n = 50)

Age ≥75ySmall aortic roots (<22mm)

20.4 80 Mini 72%Isolated AVR

Perceval group may be part of Perceval Pivotal trial and/or CAVALIERUnclear whether control group were ineligible for Perceval S or were treated prior to Perceval S being in useUnclear whether data on control patients were collected prospectivelyDisclosure: Institute received an unrestricted research grant from Sorin to conduct the studyDesign: Prospective. Baseline characteristics did not differ significantly between groups other than a marginally higher surgical risk in the Perceval S group (20.4 vs 16.7; p = 0.05)


16.7 77 Mini 4%Isolated AVR

Doss et al (2012)(84)

3f Enable(n = 27)

Severe AS 13.7 78 Full sternotomy and concomitant procedures 37%Partial sternotomy for isolated AVRs

Unclear how patients were selected for treatment group3f Enable patients may be part of larger study as reported in Martens et al. 2011(28)

Reports initial experience with the technologies at the study centreNo information provided regarding funding and conflicts of interestDesign: Prospective, nonrandomised cohorts. Surgical risk significantly higher in the TAVI groupTAVI

(n = 29)35.3 85 Transapical TAVI

Muneretto et al (2014)(64)

Perceval S(n=53)

Severe AS 16 79 18.9% ministernotomy

Design: Prospective, nonrandomised cohorts

CoreValve 20.4 81 Transfemoral




Surgical technique

Comments

TAVI (n=55)

Standard AVR ( 55)

21.3 79 49.1% ministernotomy

Biancari et al (2015)(65)

Perceval S(n=142)

Severe AS 4.1 (ESII) 79.4 54% mini Design: Retrospective propensity matched study. Sutureless AVR with concomitant CABG in 26% of patients compared with Isolated TAVI.

TAVI (n=142)

3.6 79 98% Transfemoral

a Data for surgical AVR group as a whole (n= 143), including both sutureless and standard AVR.AS = aortic stenosis; AVR = aortic valve replacement; CABG = coronary artery bypass grafting; NR = not reported; EuroSCORE = European System for Cardiac Operative Risk Evaluation score; mini = minimally invasive; SSAS = severe, symptomatic AS or equivalent indication; TAVI = transcatheter aortic valve implantation


Table 12: Patient characteristics and description of non-comparative trials of sutureless AVRAuthor Device No. pts Patient group Log

Euro SCORE (mean/ median%)

Mean/ median age

Comments

Eichstaedt et al. (46)

3f Enable 120 SSAS 20.7% 77y Retrospective single centre experience

Disclosure: two authors have a financial relationship with Medtronic as proctors

Folliguet et al (2012) (27)

Perceval S 208 AS or steno-insufficiency

>5% (mean 8.7%)

79y Part of CAVALIER trialNo information provided regarding funding and conflicts of interest


Perceval S 137 Eligible for isolated AVR by right anterior minithoracotomy

10% 77y Retrospective initial single centre experienceUpdate with 175 patients later presented at a conference(81)

No information provided regarding funding and conflicts of interest

Kocher et al (2013)(29)

Intuity 152 AS or steno-insufficiency

7.9% 76y Part of TRITON trialDisclosure: Edwards Lifesciences funded the study and managed collection and monitoring of data

Martens et al (2011)(28)

3f Enable 140 AS, steno-insufficiency or insufficiency

NR 76y European Multicentre Enable trialDisclosure: Financial support provided by ATS Medical

Mazine et al (2013)(85)

Perceval S 123 SSAS NR 79y


Author Device No. pts Patient group Log Euro SCORE (mean/ median%)

Mean/ median age

Comments


Perceval S 83 Severe calcified AS

10.7% 77y Part of CAVALIER trialNo information provided regarding funding and conflicts of interest; financial relationship with Sorin for two of the authors disclosed in another paper (Pfeiffer and Fischlein)


Perceval S 180 SSAS 13% 81y Perceval Pivotal trialPublication in Abstract formNo information provided regarding funding and conflicts of interest

Zannis et al (2012)(63)

Perceval S 140 9.7% 79y Single centre experience likely part of the Perceval Pivotal trial and/or CAVALIER, with at least some patients included in other reportsPublication in Abstract formNo information provided regarding funding and conflicts of interest

AVR = aortic valve replacement; ; EuroSCORE = European System for Cardiac Operative Risk Evaluation score; SSAS = severe, symptomatic aortic stenosis


Appendix 3 Summary of clinical findings for sutureless AVRTable 13: Summary of clinical findings from comparative trials of sutureless AVRAuthor Device

(no. patients)

Mean TV gradient(mm Hg)

Complications All-cause mortality (n; %)

PV leak (severity)

Permanent pacemaker implant

Stroke MI Renal failure/ dialysis

Bleeding complications


1-year

Concistre et al (2013) (50)

Perceval S(n = 97)

9.1* 1%*(moderate)

2 (6%) 2 (2%) NR RI: 3 (3%) NR 2(2.1%)

3(3.2%)c

3f Enable(n = 32)

11.2 16%(moderate)

2 (6%) 1 (3%) NR RI: 1 (3%) NR 1(3.1%)

1(3.1%)c


Perceval S(n = 38)

10.95 0a

(moderate AR 2+/3+)

2(5.3%)

0 0 2 (5.3%) 1 major bleed

(2.6%)

0 NR

TAVI(n = 38)

10.25 8%(moderate AR 2+/3+)

2(5.3%)

0 0 1 (2.6%) 1 major bleed; 1 fatal bleed(5.3%)

2(5.3%)

NR


Perceval S(n = 31)

11.1 19.4%(all at least mild; AR ≥1+/3)

1(3.2%)

0 0 1 (3.2%) NR 0 NR

TAVI(n = 143)


7(4.9%)

4 (2.8%) 5(3.5%)

7 (4.9%) NR 10(7%)†

NR



1(0.9%)

0 1(0.9%)

0 NR 1(0.9%)

NR

Gilmanov et al Sutureless 11 NR 6 (4.5%) 2 (1.5%) 2 (1.5%) 1 (0.8%) 7% requiring 1 (0.8%) Median





PV leak (severity)





1-year

(2014)(35) (n = 133) reexploration 10mo:d

4%


12 NR 3 (2%) 0 0 0 4% requiring reexploration

2 (1.5%) 5%


Perceval S(n = 82)

NR NR 5 (6%) 3 (4%) (including TIA)

NR NR 2% requiring reexplorationMean blood tx1.2U*

2 (2.4%) Median 13mo:d

2.5%


NR NR 7 (8.5%) 6 (7%) (including TIA)

NR NR 6% requiring reexplorationMean blood tx2.5U

3 (3.7%) 3.8%


Perceval S(n = 50)

8.4 2%(PV leak 1/4)

3 (6%) NR 0 RI 2 (4%) Mean blood tx

1.1U*

2(4%)

NR


10 4%(PV leak 1/4)

4 (8%) NR 1(2%)

RI 3 (6%) 2.3U 3(6%)

NR


Perceval S(n = 37)

13.3 0(at least mild AR)

4 (10.8%) 2 (5.4%) NR 0 NR 0 Mean 19mo:d

2.7%*

TAVI(n = 37)

14.2 13.5%(at least mild AR)

1 (2.7%) 2 (5.4%) NR 2 (5.4%) NR 3 (8.1%) Mean 19mo:d

13.5%*

Shrestha et al Perceval 8% NR NR NR NR 2 major bleedb 0 5





PV leak (severity)





1-year

(2013)(36) S (n = 50) 15.9 (Minor; grade 1) (4%) (13%)


12.7 2%(Minor: grade 1)

NR NR NR NR 2 major bleedb

(2.9%)3(4.3%)

10(16%)

Doss et al (2012)(84)

3f Enable(n = 27)

9 0(Mod/major)

0 0 NR NR NR 3(11%)

NR

TAVI(n = 29) 7

17%(Mod/major)

1 (3.5%) 0 NR NR NR 5(17%)

NR

a Significant difference for all paravalvular leak of at least mild severity (16% with Perceval S versus 45% with TAVI).

b Postoperative bleeding necessitating rethoracotomy.

c Mean follow-up 8 months.

d Based on Kaplan-Meier survival analysis

* Significant difference for sutureless AVR versus comparator (p < 0.05)

† Significant different for TAVI versus standard surgical AVR

AF = atrial fibrillation; AI = aortic insufficiency; AR = aortic regurgitation; AS = aortic stenosis; AVR = aortic valve replacement; CABG = coronary artery bypass grafting; MI = myocardial infarction; NR = not reported; PV = paravalvular leak; RI = renal insufficiency; TAVI = transcatheter aortic valve implantation; TIA = transient ischaemic attack; TV = transvalvular; tx = transfusion.

Two late additions to this report: Biancari et al (2015)(65) and Muneretto et al (2014)(64) are discussed in the report but not summarised in the above table.


Table 14: Summary of clinical findings from non-comparative trials of sutureless AVR

Author Device ICU stay (mean/ median days)

Hospital stay (mean/ median days)

Implant successa

Complications All-cause mortalityPV leak (severity)


Stroke Renal failure/ dialysis


In-hospital Follow-up (period)

Folliguet et al (2012) (27)


NR NR 96% 8% (majorc) NR 1%

(other TE 4%)

6% requiring tx 2.4% 9.6%

(mean 10mo)

Gilmanov et al (2013)(45)e


1.5 7 100% 1.5%

(mild)

4% 2% (mild dysfunction 4%)

5% requiring revision

0 0.7% noncardiac

(median 6mo)


Perceval S (n = 83)

NR 11 99% 1%

(major 3/4+)

4% 2% 1% major bleedb

1% fatal GI bleed

2.4% 4.8%

(mean 8mo)


Perceval S 9 n = 180)

NR NR 96% 2%

(>2+ mod/major)

7% 1% NR 3%

(30 day)

11%

(median 1y)

Zannis et al (2012)(63)


NR NR 99% 3% (majord) 5% 1% NR 4.3% 10%

(1y)


Author Device ICU stay (mean/ median days)

Hospital stay (mean/ median days)

Implant successa

Complications All-cause mortality

Kocher et al (2013)(29)

Intuity (n = 152)

NR NR 96% 2%

(mod/major)

8% (other TE 4%) 1% major bleedb 2.1%

(30-day)

7.5%

(mean 10mo)

Martens et al (2011)(28)

3f Enable (n = 140)

NR NR 100% 3%

(major)

NR 1% NR 3.6%

(30-day)

12.9%

(≈1y)

Eichstaedt et al.(46)

3f Enable (n = 120)

NR 9 100% 2%

(major; ≥grade 2)

7% 1%

(other TE 1%)

3% major bleedb 6.7%

(30-day)

9%

(mean 9mo)

a Study valve successfully implanted and functioning.

b Reoperation required due to significant bleeding.

c 4% during implantation and affecting successful valve implantation; 4% necessitating reoperation.

d Necessitating reoperation.

e An update including 175 patients was later presented at a conference.(81) Outcomes were very similar. At a median follow-up of 10 months the noncardiac mortality rate was 1.7%.

ICU = intensive care unit; GI = gastrointestinal; TE = thromboembolism; tx = blood transfusion.


Table 15: Summary of procedural outcomes from comparative trials of sutureless AVR


ACC time (mins)

CPB time (mins)

Valve implant successb

ICU stay (mean/median days)

Hospital stay (mean/median days)

Concistre et al (2013)(50)

Perceval S(n = 97)

Isolated AVR

36*Isolated AVR

66*NR NR NR

3f Enable(n = 32)

66 103 NR NR NR


Perceval S(n = 38)

Isolated AVR

44

Isolated AVR

69

100% NR NR

TAVI(n = 38)

NA NA 97% NR NR

Gilmanov et al (2014) (35)

Sutureless(n = 133)

56* 90* NR 1 6

Standard AVR (n = 133)

88 120 NR 1 6


Sutureless(n = 82)

47* 71* NR 2.0* 10.9*

Standard AVR (n = 82)

59 92 NR 2.8 12.4


Perceval S(n = 50)

Isolated AVR

40*Isolated AVR

69*98% 1.9* 10.5


66 105 100% 2.8 10.9


Perceval S(n = 37)

39 69 95% NR NR

TAVI(n = 37)

NA NA 95% NR NR


Perceval S(n = 50)

Isolated AVR

30*Isolated AVR

59*100% 1.8 14.1


50 75 NR 2.0 15.9

Doss et al (2012)(84)

3f Enable(n = 27)

Isolated AVR

52Isolated AVR

7593% NR NR

TAVI(n = 29)

NA NA 93% NR NR

a D’Onofrio et al. (2013) is not included because the paper didn’t report the outcomes of interest for this table.b Study valve successfully implanted and functioning.* Significant difference versus comparator (p < 0.05)ACC = aortic cross-clamp; AVR = aortic valve replacement; CPB = cardiopulmonary bypass; ICU = intensive care unit; NA = not applicable; NR = not reported; TAVI = transcatheter aortic valve implantation.


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Citation: National Health Committee. 2015. Sutureless Aortic Valve Replacement: Assessment Report Tier 3. Wellington: National Health Committee

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