Scientific Advisory Committee on Medical Devices used in Cardiovascular Systems - Record of Proceedings - June 26, 2015

• Committee Members Present: John Ducas (Chair), Eric Cohen, Marino Labinaz, Alan Menkis, Barry Rubin, Raymond Yee, John Webb(via teleconference/WebEx)
• Invited Guests: Sébastien Bergeron, Vivek Rao, Sanjit Jolly
• Health Canada Representatives:
  • Office of Science: Hripsime Shahbazian
  • Office of Planning, Performance, and Review Services: Caroline Hunt
  • Medical Devices Bureau: Carey Agnew, Kevin Day, Ian Aldous, Patrick Fandja, Ian Glasgow, Ian Grimwood, Jianming Hao, Karen Kennedy, Mark Korchinski, Christine Lefebvre, James McGarrity, Catherine Milley, Michael Rosu-Myles, Philip Neufeld, Jason Pearman, Maurice Sylvain, KokSwang Tan, Lanyi Xu, Brian Wong
• Regrets: Joaquim Miró, Renzo Cecere, Christopher Feindel, Brent Mitchell

Abbreviations used in this record:

AAA:

abdominal aortic aneurysm

AMI:

acute myocardial infarction

ATP:

anti-tachycardia pacing

AVR:

aortic valve replacement

BMC:

bone marrow cell

CABG:

coronary artery bypass grafting

CACs:

circulating angiogenic cells

CADTH:

Canadian Agency for Drugs and Technologies in Health

CPC:

cardiac progenitor cell

CSF:

cerebrospinal fluid

CT:

computed tomography

DEB:

drug eluting balloons

ECC:

extracorporeal circulation

EEC:

endovascular elephant trunk completion

EPC:

endothelial progenitor cell

EVAR:

evolution of endovascular aneurysm repair

HF:

human factors

ICD:

implantable cardioverter-defribrillator

IFU:

instructions for use

LVEF:

left ventricular ejection fraction

MDB:

medical devices bureau

MI:

myocardial infarction

MEP:

motor-evoked potentials

MRI:

magnetic resonance imaging

MSC:

mesenchymal stem cell

OEC:

open elephant trunk completion

OPC:

objective performance criteria

RCT:

randomized clinical trial

SAC-MDUCS:

scientific advisory committee on medical devices used in the cardiovascular system

SAP:

special access program

SCI:

spinal cord fluid

SEP:

somatosensory evoked potentials

SVT:

supraventricular tachycardia

TAA:

thoracic aortic aneurysm

TAVI:

transcatheter aortic valve implantation

VF:

ventricular fibrillation

VT:

ventricular tachycardia

VTA:

ventricular tacky arrhythmia

1. Opening Remarks & Welcome

Dr. John Ducas, Committee Chair
Cindy Evans, A/DG, TPD

Dr. Ducas opened the meeting, welcomed the committee members and guest speakers. Cindy Evans, the Senior Executive Director of the Therapeutic Products Directorate (TPD), thanked the committee members and guest speakers for sharing their time and expertise and acknowledged the efforts all participants had made to attend the meeting. Ms. Evans highlighted the importance of the Scientific Advisory Committee on Medical Devices Used in the Cardiovascular System (SAC-MDUCS) to Health Canada’s regulatory review and decision-making process.  She commended the committee on its continued support and noted that their past recommendations have been helpful in numerous license evaluations.  Ms. Evans concluded by reviewing the topics of the day’s agenda and wished the committee members and guests fruitful deliberations.

2. Review of the Agenda, Affiliations and Interests Declarations, and Confidentiality Agreement

Dr. John Ducas, Committee Chair

The Chair reviewed the agenda items with the committee. The agenda was accepted with minor adjustments to accommodate all speakers. Members were asked to disclose any conflicts that may arise as the meeting proceeds.

Presentations are available upon request.

The responses outlined below are representative of the discussions/recommendations generated by the committee. 

3. Summary of how Health Canada has used information generated from previous SAC-MDUCS meetings

Kevin Day, Medical Devices Bureau (MDB)

Mr. Kevin Day presented a brief summary of how previous advice and recommendations provided by the committee have been considered by Health Canada.

The following topics were noted:

• Absorb Bioresorbable Vascular Scaffold: committee feedback has been helpful in determining additional considerations for evaluating this new technology.
• LAA closure Devices: The MDB has faced challenges regarding the clinical data currently available for these devices and previous discussions and recommendations have been useful in providing some perspective.   
• Sutureless (minimally sutured) Heart Valves: these valves represent another expanding area within the field of medical devices.  The committee’s input and recommendations provided a better understanding of this technology before issuing a license for the Perceval Heart Valve (licensed in Canada on June 15, 2015).
• Drug Coated Balloons: we continue to reference recommendations of this committee in terms of minimal requirements regarding trial sizes and follow-up.  There has been a lot of activity on the drug coated balloons front, both on coronary and peripheral indications where the committee’s input has been helpful.  

He also provided updates on additional SAC-MDUCS engagements where Health Canada solicited expert opinion on two specific issues whereby select SAC-MDUCS members provided recommendations through an email consultation process.

• TAVR/TAVI sub-clinical valve immobility (February 2015):  members were consulted on an issue regarding observations brought forth to Health Canada.  Specifically, observations of ‘sub-clinical’ leaflet motion anomalies, possibly due to thrombus formation on TAVI systems, typically occurring at the base of the valve leaflet on the aortic side adjacent to the valve frame. 
• Pericardial closure patches (April 2015):  members were consulted on an issue regarding pericardial closure devices, specifically, concern associated with the effectiveness of a proposed device made from porcine derived collagen.  Health Canada requested the committee’s clinical recommendations for actions that could be taken to provide appropriate regulatory oversight on the issue and to ensure Canadians continue to have timely access to safe and effective medical devices.

It was noted that the Medical Devices Bureau (MDB) uses the recommendations and advice provided by the SAC-MDUCS when discussing clinical trials or licensing requirements with Industry.  The Committee’s input also ensures that good clinical oversight is continually being applied towards decision making processes.  Mr. Day summarized that since 2012, approximately 25 evaluations have specifically referenced the Committee’s discussions and that the MDB continues to rely on the expertise of the Committee as new technologies and challenges arise.

A question regarding how the SAC-MDUCS agendas are developed was posed by one of the Committee members.  It was explained that several factors drive the topics of the MDUCS’ agendas including, but not limited to:

• Constant surveillance of publications to check on any new developments, signals;
• Pre-submission meetings;
• Monitoring the activity of the Special Access Program;
• A change in work, philosophies, or features surrounding previously-discussed technologies.

Mr. Day thanked members for their ongoing dedication to the committee. 

Before proceeding with the agenda Dr. Ducas acknowledged the passing of Dr. Bilodeau, one of the long serving core members of this committee.

** Dr. John Webb joined the meeting by webex/teleconference.

4. TAVR Valve in Valve Procedures

Dr. John Webb, Committee Member,

Participated by Teleconference

While the three TAVR devices currently licensed in Canada are not indicated for ‘valve-in-valve’ use, this situation is often encountered clinically.  Please discuss the frequency of this clinical situation, the options available to this patient population and the risks and benefits of using a TAVR device within an existing prosthetic valve.

Dr. Webb joined the meeting via webex to address this topic.  After declaring his affiliations, he proceeded with his presentation and addressed the questions posed by Health Canada.

Dr. Webb’s presentation included the following topics in relation to TAVR valve-in-valve procedures:

• Valve durability (transcatheter valves vs. surgical valves);
• Apical access;
• Low profile systems for patients with small femoral arteries;
• Accurate positioning;
• Hemodynamic function;
• Coronary obstruction;
• Mitral and Tricuspid valve-in-valve options;
• Vancouver British Columbia’s valve-in-valve experience.

1. What clinical evidence should Health Canada require to expand the indications of currently licensed TAVR devices to include ‘valve-in-valve’ use?

   Dr. Webb explained that valve-in-valve use is an evolving field and clinicians are still learning.  There is an enormous amount of information available such as the global valve-in-valve registry that includes over 1500 valve-in-valve implants (aortic, mitral, and tricuspid). The registry demonstrates a trend of improving outcomes and can also be useful in highlighting certain valves that may introduce greater concerns such as coronary obstruction. 

   The valves of particular concern are freestyle, unstented valves that introduce higher levels of risk. Despite the increased risk, however, these valves are only refused based on patient screening (e.g., patients at a higher risk of coronary obstruction would be refused). Similarly, in terms of high gradients, some valves have smaller internal diameters than others and appropriate patient screening would therefore play an important role.

   Dr. Webb indicated that it should not necessarily be the role of Health Canada to exclude certain surgical valves but instead be the responsibility of the surgeons and cardiologists to make appropriate decisions on which patients should be deemed good candidates. Furthermore, based on current valve-in-valve outcomes, he thought it reasonable to expect that if a valve is licensable for a TAVR device, follow-through to a valve-in-valve indication would be acceptable. Dr. Webb noted that it is unlikely that there will be a randomized controlled trial in Canada, especially given that this indication has already been approved in Europe and is on its way to being approved in the United States.

2. How does the type of TAVR (i.e., self-expanding, balloon-expandable, repositionable) impact use in ‘valve-in-valve’ procedures?

   Technical advances have led to the development of newer, smaller devices that work well in patients with smaller arteries.  As a result, TAVI procedural approaches have been moving away from the transapical access routes towards less invasive transfemoral approaches (90% of TAVI patients are now treated with the transfemoral approach).

   Low profile systems

   Dr. Webb noted that early generations of the Edwards SAPIEN expandable valves had large sheath diameters (24F, 22F, and 16F) that made less invasive approaches difficult.  Therefore, the third generation valve, the SAPIEN 3, was designed to contain an artery sheath diameter of 14F (comparable to the diameter of a pencil) and an external fabric cuff to improve sealing.  This 40% reduction in cross-sectional area in addition to the anti-leakage fabric cuff dramatically improved outcomes as evidenced by the results of the most recent series of clinical trials run in Europe and the US.  Trial results demonstrated a mortality risk of around 2% in high-risk patients and 1% in intermediate-risk patients.  The SAPIEN 3 has received market approval in both Europe and the US. 

   Other lower profile systems include the EnVeo R delivery catheter and the CENTERA delivery catheter.

   He explained that if a low profile system is unavailable, alternative access points are transapical, aortic, subclavian, transcarotid, transvenous, and translumbar.

   Transapical procedures

   Dr. Webb noted that if a transapical procedure is to be performed, one of the following four devices should be used:

   • SAPIEN
   • Portico
   • Jenavalve (used in valve-in-valve patients)
   • Engager
     • Equipped with arms that can clip to the aortic valve.

   He further explained that most surgical valves that fail in the mitral position will be treated with transapical access. The CoreValve cannot be used in these cases because it would be mounted in the opposite direction which would create disruption of flow. Recently, there has been some experience with the Lotus valve because it can be deployed transapically in the right direction. The Lotus is also removable.

   Mitral valve-in-valve and Tricuspid valve-in-valve procedures

   Dr. Webb noted that the valves that have been used for mitral and tricuspid valve-in-valve procedures have been the Medtronic Melody and the Edwards Sapien XT.  These valves are used because they can be mounted in the correct direction, ensuring no disruption in flow.  In some rare cases, the Lotus valve has also been used in mitral valve-in-valve procedures.

   He explained that performing a mitral valve-in-valve procedure using a transvenous approach introduces potential difficulties including accurate positioning, and correct puncture through the apex.  As a result, the trend has favored transseptal transcatheter mitral valve-in-valve implantation because there is no puncture through the apex required and there is much less morbidity associated with the procedure.

   The Sapien XT presents many advantages that make it a popular choice for transseptal and tricuspid surgical procedures.  Some of its most notable advantages are:

   • Additional suction;
   • Longer length for more accurate and easy positioning;
   • Bendable catheter tip to create a stable, accurate position.

   It was noted that for transfemoral procedures, the CoreValve can be used in most patients.  The CoreValve is designed for first time positioning accuracy and enhanced sealing which makes recapture extremely difficult or impossible. 

   Repositionable Valves

   Dr. Webb reviewed a list of repositionable valves currently being manufactured.

   • The CoreValve
     • Can be used in most patients transfemoral;
     • Manufactured in multiple different sizes. 
     • Repositionable to a very limited extent;
     • Important to implant high with high gradients;
     • Positioning is important to obtain higher durability in valve-in-valve patients.
   • Portico (being used in Canada)
     • Desirable for valve-in-valve procedures;
   • CoreValve Evolut R
     • Similar capturability as the Portico valve;
   • Lotus
     • Increased control;
     • Can be fully recoiled (can be taken out and put back in);
     • Has not been used much in valve-in-valve procedures;
   • Centera;
   • Direct Flow;
   • Edwards Sapien 3
     • Cannot be recaptured, however, has more controlled delivery (accurate positioning controls);
     • Being used routinely in Europe for valve-in-valve implants;
     • Negligible risk of atrioventricular (AV) block because the surgical valve protects it, annular rupture, and paravalvular (PV) leak; 
     • Most Sapien 3 valve-in-valve patients are discharged the next day.

3. Some surgical AVR bioprosthetic valves may be more suited for valve-in-valve procedures.  Should this information be available in the labeling of either the surgical valves or the TAVR valves as a contraindication or warning?  Currently no valves are licensed for this indication in Canada.

   Dr. Webb mentioned that Health Canada should not necessarily assume responsibility for excluding or including certain surgical valves.  This responsibility, according to Dr. Webb, should be left to the surgeons and cardiologists. 

   Dr. Webb also noted that given current outcomes, a valve that is considered licensable for TAVR devices could feasibly follow-through to a valve-in-valve indication without the need for a randomized trial.  Individual programs, according to Dr. Webb, will likely continue to make decisions for individual patients rather than wait for there to be expansion of the indication to include a valve-in-valve approach.

   When asked about the possibility of requiring warnings on some valves to indicate the danger of performing valve-in-valve procedures with specific devices, Dr. Webb did not feel these would be necessarily helpful.  Alternatively, he suggested that these kinds of issues be discussed at surgical meetings and training sessions.

Dr. Webb concluded his presentation and the chair opened the floor to questions. The following questions were discussed:

What are minimum data requirements to approve a valve for valve in valve procedure? Should it be valve specific? How important is the height of the valve itself in assessing the risk of coronary obstruction?

It was noted that the trials are allcomers, and at this time no one is considering to do a randomized trial. There is no feasibility to get a randomized trial in Canada. Valve in valve procedures are safer. It is a question of screening the patients appropriately. It was also noted that the centers do not refuse this procedure based on valve type. Therefore there is no reason to exclude certain valve types.

Assessing the risk of coronary obstruction is extremely complicated; it would be too simplistic to pay attention to the valve height alone.  However, if the coronaries are low, the risk is higher and if the coronary is occluded, mortality rates exceed 50%.  One way to dramatically lower risk is to use a repositionable valve or the SAPIEN 3 that can be positioned accurately.  Valves that are implanted at the appropriate height allow for a better pace maker rate.

Given that screening for valve-in-valve procedures is complex, which centers should be doing it?

Dr. Webb noted that in British Columbia, there is a regional program with a site assigned to carry out low volume procedures (transapical, aortics, etc.) and two additional sites assigned to carry out transfemoral procedures exclusively.  However, meetings are underway to expand the program.  The expanded program will include any centers that currently perform TAVI procedures. 

The access through SAP was discussed. It was noted that HC encourages the users to opt for a licensed product however it is difficult to refuse access through SAP if physician believes it is the best product for their patient.

Some members felt that changing the SAP access may impact on available choices and impact on cost of health care.

Dr. Webb concluded by noting the growing popularity of ‘valve-in-valve’ procedures.  The procedure is being performed more routinely because it is extremely teachable and relatively easy to perform.

Dr. Webb disconnected from the meeting.

5. Thrombectomy in patients with STEMI

Dr. Sanjit Jolly, Guest Speaker

Currently, there are a number of thrombectomy devices licensed for use in Canada.  The evidence for the use of these devices is weaker than in some other areas as there are not a substantial number of well-designed randomized controlled clinical trials.

Dr. Jolly thanked the Committee for inviting him to attend the meeting and speak to this topic.  He began with a brief bio and declared his affiliations before proceeding with his presentation and addressing the questions posed by Health Canada.

Dr. Jolly’s presentation addressed the following topics in relation to thrombectomy in patients with STEMI:

• Review of the rationale for thrombectomy in STEMI;
• Review of the results of the TOTAL trial.

1. What is the current evidence for the mechanical thrombectomy and manual (aspiration) thrombectomy in STEMI patients, typically performed prior to PCI?

   Dr. Jolly recommended that future trials of thrombectomy devices should carefully collect stroke outcomes (safety) to determine safety in addition to efficacy.  He added that manual thrombectomy should be reserved as a bailout procedure in patients with STEMI.

   Dr. Jolly reviewed and discussed the following clinical trials:

   • TAPAS Trial: Thrombectomy (Export) versus PCI alone during PPCI. 
     • Trial results demonstrated a modest improvement in the surrogate outcome in routine thrombectomy. 
     • After the TAPAS trial, Guidelines were revised which marked an increase in thrombectomy use (1 in 5 of all STEMI cases in the United States received manual thrombectomy).
   • TOTAL Trial: randomized trial of manual aspiration thrombectomy and PCI versus PCI alone in STEMI patients.  This was a large sample trial of nearly 11,000 patients.   
     • Trial conclusions: routine thrombectomy compared to PCI alone with only bailout thrombectomy did not reduce Cardio Vascular (CV) death, Myocardial Infarction (MI), shock or heart failure within 180 days.  Also, routine thrombectomy was associated with increased risk of stroke within 30 days. 
   • TOTAL and TASTE trials emphasized the need to conduct large randomized trials of common interventions even when small trials appear positive.
   • Angiographic Sub-study of the TOTAL trial: a randomized trial of manual thrombectomy during PCI for STEMI.
     • Conclusions: routine thrombectomy did not result in an improvement in final myocardial blush or TIMI Flow following PPCI for STEMI.  Also, routine thrombectomy reduced angiographic distal embolization.  Distal embolization was independently associated with mortality in multivariable analysis.
   • Stroke in the TOTAL trial: randomized trial of manual aspiration thrombectomy in STEMI.
     • Conclusions: Routine thrombectomy compared to PCI alone (with only bailout thrombectomy) is associated with increased risk of stroke that is evident within 48 hours.  Also, there is an increase in primarily ischemic strokes as well as hemorrhagic strokes.

2. What key messages should be taken from recent clinical data from the TOTAL Study (NEJM, 2015, 372;15:1389-1398)?  How should Health Canada translate these results to other similar manual thrombectomy devices?  What is the impact on the results from this study on the current clinical practice guidelines for the use of thrombectomy in patients with STEMI?

   Dr. Jolly presented a detailed analysis on stroke using data from the TOTAL trial.  Factors such as timing, stroke severity, stroke subtypes, and independent stroke predictors were analyzed.  In instances where the report was unclear in terms of the stroke subtype, the case was reviewed in a blind fashion to increase the rigor of the analysis.  The following list includes observations generated by the analysis:

   • Slightly longer procedural times;
   • Slightly higher use of 5 French catheters;
   • Smaller diameter catheters were used more frequently;
   • Stroke within 30 days was increased;
   • Stroke and TIA at 90 days and 180 days was increased;
   • There was a significant increase in stroke severity and major or fatal strokes;
   • Most strokes were ischemic strokes (0.7 versus 0.4%);
   • Within the first 48 hours, there was a significant increase in stroke while at all other time points, the difference was not significant;
   • Mortality of stroke within 180 days was nearly 31% versus 3% if no stroke occurred;
   • Independent predictors: thrombectomy, age, sex, peripheral vascular disease, previous stroke, prior diabetes, CABG, etc.

   When all data from all available randomized trials were compiled in a meta-analysis, an increase in stroke was demonstrated.  Furthermore, when the meta-analysis was observed for mortality, there was a trend for reduction in mortality. Dr. Jolly noted that an important caveat for this meta-analysis, is that it was very tenuous in terms of what method was used (fixed model).  A trend did exist; however, it was not definitive; it emphasized the importance of these small reductions (powered for a 20% reduction).

3. In the design of a clinical trial for this type of device, what clinical outcomes should be measured and assessed?  What are the appropriate follow-up durations?

   Routine thrombectomy is associated with an increase in stroke.  Therefore, future trials should carefully collect stroke outcomes in addition to efficacy outcomes. 

4. Should Health Canada require additional post-market studies for any of the existing licensed thrombectomy devices?  Please provide some recommendations if you feel additional studies are required.

   Dr. Jolly suggested that requiring a warning about an increased risk of stroke is not necessary as it would not change how the device is being used.  The strategies for this device continue to be largely physician driven.

5. In some cases, thrombectomy devices targeted CABG thrombosis as these could be very ‘dirty’.  Please comment if further investigation is needed in this area and if this indication continues to be appropriate.

   Not addressed.

Questions posed by Committee Members

1. Was stenting analyzed for benefit in patients with direct stenting?  Would that negate the benefit of thrombectomy?

   It was noted that any analysis done on interaction with direct stenting would be flawed.  When interaction by sight was analyzed, there was no significant interaction for stroke or for the primary outcome. Operator technique can never be ruled out as a contributor.

Dr. Jolly concluded his presentation

6. Interatrial shunting for patients with left ventricular failure

Dr. Sebastien Bergeron, Guest Speaker

As there has been more clinical activity associated with creating interatrial shunts in the treatment of patients with left ventricular failure, Health Canada is requesting clinical insights into this treatment to better understand:

1. The potential benefits and risks of the treatment,
2. The key device design considerations, and
3. The ideal patient population that may be ideally suited for this treatment.

Dr. Bergeron thanked the Committee for inviting him to attend the meeting. He introduced himself, declared his affiliations, and proceeded to address the topics and questions provided by Health Canada.

Dr. Bergeron began by describing how the pathology and CRT treatment of heart failure is well understood.  Despite this understanding coupled with good drugs, CRT treatment and surgery, many patients continue to be diagnosed with Heart Failure in both Canada and the United States.  Most of these patients have a poor quality of life and will be seen in the emergency room monthly.  Dr. Bergeron explained that a structural device within the world of Heart Failure would be beneficial and described a novel intra-atrial shunt called the V-Wave device to the Committee. 

The V-Wave device is indicated for left ventricular failure and was designed to release the elevated filling pressures of the left atrium by shunting blood from the left atrium to the right atrium.  The device is percutaneously implanted and is equipped with a tricuspid valve.

• Preliminary Study (DelRio CL, AHA 2013): The V-Wave device was implanted into sheep with chronic ischemic Heart Failure.  The sheep underwent serial/selective coronary embolizations resulting in chronic left HF.  They were randomized into either a control group or a V-Wave group.  Results demonstrated higher left ventricular ejection fractions (LVEFs) and lowered left-atrial pressures in the V-Wave group. 

• The V-Wave Shunt FIM Safety and Feasibility Study: this is a first in man (FIM) study with intra-patient comparisons expected to be completed by December 2016.  Inclusion criteria for the study was as follows:

  • Patient is ≥ 18 and < 85 year old;
  • Patient has chronic ischemic or non-ischemic cardiomyopathy NYHA Class III or ambulatory Class IV heart failure despite optimal medical therapy;
  • Patient LVEF >15% and ≤ 40%;
  • Patient has elevated Left Atrial Pressure (LAP);
  • Patient has normal Right Atrial Pressure (RAP);
  • BNP or NTproBNP levels are >300 or >1500 pg/mL, respectively.    

  Six patients (mean age of 67) with profound diastolic dysfunction were followed and all six were considered too sick to qualify for heart transplant or LVAD.  The V-Wave device was implanted in all patients with no thrombosis and no embolization.  30 days after V-Wave implantation, flow remained persistent. 

  3 months post implantation, the following observations were made: 

  • Patients could be re-classified from Class III to Class II;
  • proBNP levels decreased for all six patients;
  • Patients were experiencing less shortness of breath. 
  • Echocardiogram results showed no change in LVEF;
  • Diastolic diameters of the patients remained the same;
  • There was no change in the right ventricle function or volume.

1.  What is the rationale for creating left-to-right shunt for the treatment of left ventricular failure?

   Dr. Bergeron noted that left atrial decompression through a left-to-right shunt represents a novel concept for the treatment of patients with left ventricular failure.  The V-Wave device demonstrates the feasibility of applying this new therapy with the successful and uneventful implantation (e.g., no thrombosis or embolization) of the device, which is associated with significant improvement in functional, quality of life and hemodynamic parameters.

   Early studies have shown that management of left atrial pressure is associated with improvement in NYHA functional class and increased LVEF, Dr. Bergeron reported.  He went on to state that decompression of the left atrium with the non-invasive V-Wave catheter can be considered safe.   

2. What are the indications for this treatment?  What hemodynamic parameters are suitable for this treatment?  Under what conditions should shunting not be done?

   This treatment is intended to decrease the left atrium pressure by the shunting of blood from the left atrium to the right atrium. 

   Regarding suitable hemodynamic parameters, Dr. Bergeron suggested the following patient selection criteria:

   • NYHA functional class III or IV;
   • A pulmonary wedge pressure (PWP) of > 15mmHg and < 28mmHg;
   • A pressure gradient less than 16 mmHg between the left and right ventricle.

   According to Dr. Bergeron, shunting should not be done if the patient does not meet all of the above-mentioned selection criteria.

It has been firmly established that CRT results in a reduction of symptoms and a decrease in morbidity and mortality in patients diagnosed with moderate to severe chronic heart failure  (ACC/AHA C, NYHA class III/IV).  This demonstrates the importance of appropriate patient evaluation and determination of NYHA class. 

Patients with class III or IV with a pulmonary wedge of more than 15mmHg but less than 28mmHG and a gradient of less than 16 between the left and right ventricle are ideal candidates to receive the V-Wave device.   
 

7. LV only pacing and LA + LV only pacing - what are the benefits and how should this be studied?

Dr. Raymond Yee, Committee Member

Recently, studies have been proposed to investigate the possibility of having a dual chamber pacemaker work with left heart signals instead of with right heart signals.  In this situation, leads placed through the coronary sinus will both sense and pace the left atrium (LA) and the left ventricle (LV).  This approach may introduce new challenges as typically, sensing has been performed exclusively on the right side of the heart.

Dr. Yee declared his affiliations, and proceeded to address the topic and questions posed to him by Health Canada.

Trends in Pacemaker Therapy

The factors that have been driving the development of devices over the last few decades have been the relentless desire to develop more physiologic pacing.  This push towards increased development is the driving force behind the introduction of left atrial and left ventricular pacing despite the fact that pacing is predominantly a right heart function. 

Current pacing is right-heart based because it is easy to do and safe.  Right ventricular pacing, however, is no longer considered “good enough” since clinical outcomes have been less than optimal.  Inherently, right heart pacing is non-physiologic as pacing does not occur directly on the sinus node (asynchronous), causing “dyssynchronous ventricular activation”, a worsening of the temporal relationship between the right atrium and left atrium.  This suboptimal LV performance leads to an increase in mortality (DAVID Trial, 2002), heart failure (MOST), and atrial fibrillation (CTOPP, DANPACE, 2011). 

Review of Clinical Studies

Dr. Yee provided a brief review of the DAVID Trial and the BLOCK-HF Trial.

LA and LV Systolic Timing

He noted that in right heart pacing, it is assumed that what is being done for the right heart is good for the left heart and, if the only objective is to increase the patient’s heartrate, this assumption would be correct.  However, there are two factors at play: the time taken for interatrial activation, which is critical to left heart function, and AV nodal and LV conduction time, which determines the optimal timing of right ventricle and right atrial pacing.  

In current right heart pacing practice, the left side of the heart is not typically monitored or observed.  On the rare occasion that monitoring of the left heart does occur, it is predominantly because the patient has had a heart failure. 

An important question to be posed, given that the left side of the heart drives performance and outcomes, is whether there is a benefit to trying to pace the left side correctly.

Dr. Yee presented two possible processes to pace the left side of the heart:

• Two separate leads: one lead is implanted into the atrium to cause early activation in the left atrium. 
  • The left atrium lead is placed in the interatrial septum, coronary sinus or atrial branch. 
  • The LV lead would then be placed through the coronary vein, coronary sinus, or a mini thoracotomy. 
• A single lead:  one lead has two sets of electrodes; one set of ventricular electrodes and one set of right atrial electrodes.  The lead tip and ventricular electrodes are placed in the coronary vein and the atrial electrodes in the coronary sinus.  

LV-Only Pacing Benefits

There is limited data pulled from acute studies that looked at the difference between LV echocardial pacing and RV pacing, however, this novel field has still yet to accumulate significant data.

Although LV pacing attempts to be more physiological, it is done through the coronary veins and is still unphysiologic: epicardial to endocardial activation.

Is LV pacing superior to RV pacing?

One acute study focused on the questions of LV pacing’s superiority over RV pacing.  The Kass (Circulation 1999) study involved 18 patients with dilated cardiomyopathy (DCM) and no bradycardia indication.

1. What are the benefits and risks of the LA-LV pacing mode?

   The benefit and risks of LA-LV pacing mode were outlined as follows:

   Benefits

   • Hemodynamic; optimal AV timing
   • Pacing LA to reduce AF episodes

   Risks

   • Ventricular arrhythmias
     • In low LVEF patients only?
     • Nonetheless, low rate of occurrence

   Dr. Yee noted that there is a potential for possibly reducing atrial fibrillation, however, this has yet to be studied.  Thus far, the studies looking at pacing the interatrial septum have not shown any benefit from dual-site atrial pacing.

2. What differences may be anticipated in sensing cardiac signals from the left heart compared to the right heart?

   From the coronary sinus, the LA signal will vary in amplitude and frequency content:

   • Location and course of the cardiac signal (CS);
   • Contact of the LA electrodes with the roof of the CS;
   • Will often contain a far field LV signal also.

   LV amplitude will generally be good to better than RV unless there is myocardial scar.

   There is a larger mass in the myocardium in the left section which creates better left ventricular signals than could be achieved in the RV unless the lead lands in scar tissue.  There is a larger population with endocardial scar pathology, which, consequently translates into better ventricular signals on the right ventricle.

   The left atrium is more variable.

   Atrial signals will be as good as or better than a diseased right atrium.

3. Does this represent an appealing approach for patients requiring dual chamber pacing?

   This potentially does represent an appealing approach for patients requiring dual chamber pacing.  Hemodynamic advantages are significant; however, they’re influenced by the following factors:

   • Ease of implant;
   • Reliability of hardware is obtaining acceptable sensing;
   • Reliability of electrical performance over chronic implant;
   • Extraction for injection.
     • The more robust a mechanism you create to ensure a lead stays put, the harder it is to extract.  

4. Are there additional benefits that might improve a CRT system by allowing pacing and sensing of the left heart to drive resynchronization?

   Yes, some additional benefits that might improve a CRT system by allowing pacing and sensing of the left heart to drive resynchronization are:

   • Hemodynamics advantages accrue from knowing the time of LA activation (to optimize timing of RV/LV pacing output).
   • LV sensing is less important; may be helpful to know relative RV and LV signal to calculate optimal RV/LV output timing, less important.
   • Reduce atrial fibrillation by LA pacing.

   In an ideal world, a lead would be inserted into the left atrium and the procedure would be followed by an epicardiogram that would be performed every 6 months thereafter to maintain optimal function.  In practice, however, only non-responders receive epicardiograms.

   Left ventricular sensing is much less important.

5. In standard CRT devices, is there a likely benefit to sensing and pacing the LV instead of the RV and the primary ventricular signal?

   Probably not, the LV is usually activated late so sensing a late signal is of limited value.  Though, RV sensing may still be valuable to coordinate LV output timing (as per adaptive CRT).

6. What clinical endpoints should be included in clinical trials to determine the safety and effectiveness of systems that are investigating left heart sensing and pacing?

   The same clinical endpoints as for CRT studies should be included in clinical trials to determine the safety and effectiveness of systems that are investigating left heart sensing and pacing.   These endpoints are as follows:

   • Composite of total mortality (or CV mortality),
   • HF events,
   • Ventricular tachyarrhythmias,
   • New AF or progression to persistent AF.

8. LVAD: Issues associated with continuous flow with periodic pulsatility, increased numbers of patients on long-term support - what is best practice regarding anticoagulation?

Dr. Vivek Rao, Guest Speaker

Continuous flow left ventricular assist devices (LVAD) have emerged as the standard therapy option for patients with advanced heart failure.  They offer several advantages over previously used pulsatile-flow LVADs, including improved durability, less surgical trauma, higher energy efficiency and lower thrombogenicity.  These benefits translate into better survival, lower frequency of adverse events, improved quality of life and higher functional capacity of patients.  However, there is mounting evidence showing unanticipated consequences of continuous-flow support such as acquired aortic valve insufficiency and acquired Von Willebrand syndrome.  Recently, there has been an effort to introduce some pulsatility to continuous flow devices to mitigate these unanticipated consequences.

Dr. Rao thanked the Committee for inviting him to present on this topic.  He introduced himself, reviewed his disclosures, and proceeded to address the topic and questions posed to him by Health Canada.

An overview of the current evidence on the difference between continuous and pulsatile mechanical circulatory support focusing on the complications that were unanticipated with the long-term support of patients with continuous flow devices.

Dr. Rao provided a brief overview of objectives for his presentation:

• Describe the need for mechanical circulatory support;
• Briefly review indications for MCS;
• Review adverse events associated with prolonged MCS;
• Discuss the potential benefits of new technology.

Dr. Rao noted that every year, 50,000 patients are diagnosed with Heart Failure in Canada.  The ideal solution for these patients was once considered cardiac transplantation because of its success rates (5 year survival >75%), however, there are limitations to this therapy including a limited supply of donors and, consequently, a growing waiting list mortality rate.  

The number of adult and pediatric heart transplants per year has plateaued at around 1000.  Also, because the median survival (11 years) and conditional survival (13 years) associated with this therapy are so similar, transplantation is associated with constant attrition.

An increase in mechanical devices has led to an increase in cardiac transplantations being carried out on patients with mechanical circulatory support devices (ventricular assist device (VAD) patients).  In 2014, 50% of patients in North America were transplanted with a device.  Results have indicated no change in survival rates with the exception of patients on Extracorporeal Membrane Oxygenation (ECMO). 

Why use VADs to support Cardiac Transplantation?

A ventricular assist device (VAD) provides a bridge to transplant for high-risk candidates and a bridge to recovery for high-risk donors.  Also, VADs are used as backups in advanced cardiac care scenarios (e.g., high-risk surgical intervention, reversible causes of heart failure).  Finally, VADs are used to provide therapy for end-stage heart disease, or “destination therapy”.   An increasingly important indication in the United States is destination therapy for patients who are beyond the limits of transplantation.     

The current standard for ventricular assist devices (VADs)

From an engineering perspective, current devices are designed to last forever.  However, because of the adverse event profile of some devices, transplantation will continue to have a role.

The current standard of VAD, the HeartMate II, was introduced in Canada in 2006.  It is much smaller and has been estimated to have a lifespan of between 7 and 10 years.

Frequency of VAD use

Dr. Rao explained that funding from the Ministry of Health has resulted in an increase in VAD use.  In Canada in 2015, there have already been 18 VAD implants and 21 transplants.  The VAD implants are mostly being performed at transplant centers across the country.

Regarding VAD data, there are sufficiently large amounts of long-term data available.  Over 5000 patients have been supported by VADs for over a year and over 300 patients have been supported for over 5 years.  As follow-up continues, it can be expected that the curves will come down and more patients will be given extended support.
  
Dr. Rao explained that survival is based on the durability of the device.  The Heartmate II demonstrated significantly better survival rates in the older, sicker population than the Heartmate I.

Clinical evidence that supports the incorporation of pulsatility to continuous flow devices may mitigate some of the complications observed. 

The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) data was published in 2012.  The analysis looked at incremental survival associated with transplantation over the last 30 years.  When survival rates of INTERMACS, Rematch (2201) and Transplants were compared, a significant improvement was observed between older generation devices (Rematch) and newer generations (INTERMACS).  Transplant survival rates remained the highest.

Provide an overview of any additional new features or products that could have significant impact on the clinical outcomes of patients who require an LVAD in the near future.   

Dr. Rao provided an overview of some additional new features/products.

It has been hypothesized that a lower rpm could mean higher durability.  The HeartWare device was designed with a lower rpm that provides the same flow; it mimics pulsatility and promotes aortic valve opening.  The device also has a special levitation system that may also increase durability. 

• HeartWare HVAD
  • Designed for infinite durability, no breakable parts;
  • Intrapericardial implant, no preclotting required;
  • Full Mag-Lev technology;
  • Very flexible driveline;
  • 75 patients followed independently at 5 Canadian sites.  All Canadian implants were between May 2010 and September 2012 with 100% complete follow-up by December 2012.
  • 5 site experience across Canada.  Reflected all Canadian implants between 2010 and 2012.  Complete follow-up by end of 2012.
  • Associated with implant mortality of less than 13%.
• Device characteristics for Heartmate II compared to HeartWare
  • Heartmate II: second generation, first implant in 2000, 7800-11000 rpm, abdomen (pre-peritoneal).
  • HeartWare: third generation, first implant in 2006, 2400 - 3200 rpm, pericardial space.

A Canadian study of the HeartWare HVAD followed 75 patients independently at 5 Canadian sites.  Follow-up was completed on all patients by December 2012 (Total of 44.9 years of patient experience) and results demonstrated persistent ‘late’ tamponade thought to be due to heparin bridge.

Key points of 2006 Guidelines (HeartMate II)

• Bridge with heparin until International Normalized Raio (INR) is greater than 2;
• Maintain INR between 2 and 3;
• Maintenance therapy with warfarin, ASA, dipyridamole.

Key points of initial HeartWare HVAD IFU

• Bridge with heparin until INR is greater than 1.7;
• Maintain INR between 1.7 and 2.3;
• Maintenance therapy with warfarin, ASA (81mg).

The data show that HeartMate II patients experience relatively low rates of stroke and pump thrombosis with INRs greater than 1.5.

Dr. Rao reviewed the ADVANCE Trial.  He mentioned that the trial showed a 6% pump thrombus rate; a clinical experience that resulted in establishing revised recommended INR targets of between 1.5 and 2 by HeartWare.

Dr. Rao’s Opinion: pump thrombosis is a recognized complication of any mechanical circulatory support device:

• Axial flow;
• Centrifugal flow;
• Paracorporeal, short term.

While the recent concerns regarding increased pump thrombus rates are valid; it may be iatrogenic in nature, noted Dr. Rao.

Current TGH Protocol

All VADs:

• Complete reversal of heparin in the operating room;
• ASA 325mg PO/PR on POD#1;
• If the patient is extubated, start coumadin POD#2;
• All patients receive heparin to maintain PTT 50-80s.
  • HeartMate II: Target INR 2.5
  • HeartWare: Target INR 2.5
• There are now higher speeds (9000 or 2800 for HVAD) in all devices.

Dr. Rao went on to describe the results of a comprehensive review on the detection and management of aortic insufficiency in patients with a continuous-flow left ventricular assist device.

• Cumulative incidence of  >2+ AI at 2 years ~ 30%
• Balanced management approach:
  • Attempt aortic valve opening if possible;
  • Ensure adequate hemodynamic support;
  • Avoid excess support.

In summary, Dr. Rao noted that heart failure remains an important and growing problem in society.  Transplantation will never meet the need of heart failure patients, therefore, advancements in VAD technology will allow patients to live normal lives with survival matching or exceeding that of heart transplant.

9. Durability of Bioprosthetic Valves

Dr. Eric Cohen, Committee Member

In the past, bioprosthetic valves were recommended for aortic valve replacement (AVR) in older patients and those unable to tolerate anticoagulation therapy. Lately, mechanical valves are being displaced by prosthetic valves as preferred options for aortic valve replacement procedures. The expanding market for these devices includes patients receiving conventional surgical bioprosthetic valves such as Medtronic’s Hancock valve, Sorin’s Mitroflow valve and Edward’s C-E Perimount Magna valve and patients receiving bioprothetic valves as components of the newer sutureless valves such as Sorin’s Perceval S Heart Valve and the increasingly popular transcatheter valves including Edward’s Sapien XT Valve and Medtronic’s Corevalve. This trend is occurring against the backdrop of the proven long term durability of mechanical valves.

One major issue with bioprosthetic valves is structural valve deterioration (SVD). Cusp tears and thickening, calcification, pannus formation, and thrombus formation lead to SVD and unfavourable hemodynamic characteristics resulting in the need for valve explantation and replacement. Recently, in a single center study conducted in France involving 617 consecutive patients (aged 76.1±6.3 years) who underwent aortic valve replacement with a Mitroflow prosthesis (models 12A/LX), it was reported that the cumulative probability of SVD increased significantly from 0.8% at 2 years to 8.4% at 5 years (Sénage et al. Circulation. 2014;130: 2012-2020 and Kaneko et al. Circulation. 2014;130: 1997-1998). Among the 39 patients with SVD, 13 patients (33%) had an accelerated SVD once the mean gradient exceeded 30 mm Hg.  Small-diameter prosthesis (19 and 21 mm) was used in 64.2% of the patients and this was a significant risk factor for SVD in the analyses. In the ISTHMUS study with over 1500 patients (Eur J Cardiothorac Surg 2011;39:18-26), actuarial freedom from SVD was 65.5% at 18 years with patients < 60 years of age with actuarial freedom from SVD at 54.4% at 18 years (2.2 pt/yr).  In a similar study of the Hancock II valve with over 1100 patients in Toronto (Ann Thorac Surg 2010;90:775- 81), freedom from SVD was 63.4% at 20 years but only 29.2% in patients < 60 yoa.  Based on their results Sénage et al. recommended the following:

• Monitoring patients who received older-generation Mitroflow valves with frequent echocardiography should be mandatory to prevent undesired complications, especially in high-risk patients, e.g. patients who have a small prosthesis and gradient >30 mm Hg across the bioprosthesis. Echocardiogram surveillance should be performed at ≤6 months for early detection. SVD and its accelerated pattern is a life-threatening condition, not only in young but also in old people, an incentive to a close follow-up after implantation.
• Aggressive treatment is needed even in asymptomatic patients once the gradient becomes severe. Given the poor outcome of these patients, re-operative aortic valve surgery or a transcatheter procedure for high risk non-small-annulus patients should be offered when the diagnosis of SVD is made, even if the patient is asymptomatic.
• Users should be warned about the possibility of increasing numbers of patients implanted with Mitroflow A12 and LX presenting with early SVD over the next few years.
• Given the poor outcome of these patients, re-operative aortic valve surgery or a transcatheter procedure for high risk non-small-annulus patients should be offered when the diagnosis of SVD is made, even if the patient is asymptomatic.

It should be noted that the Mitroflow Models A12 and LX models have been largely replaced by the Model DL. The Model DL is manufactured using an anti-mineralization process (phospholipid reduction treatment) intended to decrease calcification and subsequent SVD.

Dr. Cohen introduced himself, reviewed his disclosures, and proceeded to address the topics and questions provided by Health Canada.

Dr. Cohen’s presentation began with a brief description to provide the committee with some context.  He explained that there has been a long-term trend of an increasing proportion of bioprosthetic versus mechanical valves and that novel anti-coagulants have not safely extended to mechanical valves.  Also, he noted that there has been use of bioprosthetic valves in young adults even knowing that the durability is less and they will likely face repeat procedures in their lifetime.  There have been concerns regarding durability generally; however, the soran mitroflow in particular has generated heightened concerns of durability.  

There is an attractiveness of trans-catheter valves as a subsequent intervention that perhaps shifts valves even further towards tissue valves in younger people, with caveats:

• It’s an unproven strategy for younger patients over the long-term;
• Uncertain how many times this can be done;
• Technical limitations (annulus size, coronary obstruction, etc.)

Trans-catheter valves arn’t a catch-all solution for all of these issues and do not justify the widespread use of tissue valves in young patients.

Dr. Cohen described the Mitroflow valve.  It is a bovine pericardium mounted external to the stent and it’s positioned surgically supra-annularly which is to allow it to be used in smaller annulus.  Those features together supposedly provide superior hemodynamics.  Because of these features, this valve has been used preferentially in patients with small annulus (e.g., small, elderly females).  This preferential use creates an uneven playing field when comparing the outcomes of this valve.

Dr. Cohen outlined the different iterations and history of the Sorin Mitroflow valve since it was first introduced in 1982 as the Mitroflow A11 in Europe and Canada.  Additionally, he reviewed the following studies/papers:

• Mitroflow aortic pericardial bioprosethesis—clinical performance, Jamieson Eur J Cardiothor Surg, 2009;36:818
  • Used only newer Mitroflow model (A12/LX);
  • 70% women with 19/21 mm valves;
  • Mean time to explant for SVD 7.8 years;
  • Hazard function for SVD increasing over time;
  • Cumulative incidence of SVD - 90% over 10 years.
• Early Structural Valve Deterioration of Mitroflow Aortic Bioprosthesis—Mode, Incidence, and Impact on Outcome in a Large Cohort of patients
  Thomas Sénage, MD, et. Al. Circulation. 2014; 130L2012-2020
  • Just over 600 patients;
  • Mitroflow valves used selectively in patients with small annulus;
  • Small trend over time towards increasing gradient.
• Modes of failure in explanted mitroflow pericardial valves
  Ann Thorac Surg. 2011 Nov; 92(5): 162-7. Doi: 10.1016/j.athoracsur.2011.06.092
• Accelerated Degeneration of a Bovine Pericardial Bioprosthetic Aortic Valve in Children and Young Adults
  Susan F. Saleeb, et.al.
  • Compared magna valve with the mitroflow and showed a striking difference, the mitroflow outperformed.
• Pathological Evaluation of 28 Mitroflow Pericardial Valves: A 12-Year Experience
  Ann Thorac Surg. 99(1)
  • Structural valve deterioration was seen in 18 or 19 explanted valves with implant durations of at least 30 months, and is related to valve design.  It appears that clinical should carefully consider Mitroflow valve implantation in all patients, even in patients older than 65 years old, given the early presence of structural valve deterioration.

Some concerns regarding the Mitroflow valves were outlined:

• Whether it performs similar, better or worse than other tissue valves in large sizes is not the issue because its benefits are purported to be in smaller sizes and that is where it has been selectively used.
• Evidence is reasonable clear that in small sizes (19/21) there is at least a subset of patients with accelerated SVD.
• Also concerning for very early SVD in very young patients.
• There are biologic factors that give reasonable plausibility to these concerns
  • Mechanical design features in earlier model (leaflet abrasion)
  • Absence of anti-calcification treatment.

Dr. Cohen continued his presentation by addressing each of Health Canada’s questions.

1. Are there substantial differences between the different surgical bioprosthetic  valves marketed in Canada that make one or more of these products superior to the others in general or for particular groups of patients?

   Although there are observations about different performance of certain valves, the ability to conclude conclusively if one is better than the other is extremely difficult.  Effectively, there are no randomized trials randomizing one valve to another, especially not with long-term outcomes and large numbers of patients.  Consequently, it is mainly observational work, trying to compare one type of valve to observed results with a different valve.  If there are differences, explained Dr. Cohen, they are subtle. 

2. Have differences in design, valve materials (porcine versus bovine pericardium), anti-mineralization treatments or other changes in the manufacture of bioprosthetic valves substantially changed rates of SVD and long-term durability?

   Yes, differences in design have changed rates of SVD and long-term durability.  First generation bioprosthetic valves were not given any anti-calcification treatment and, consequently, showed high rates of potential calcification.  As a result, second generation valves received calcification treatment and performed better accordingly. 

   There are potentially important differences in design, explained Dr. Cohen.  Some of these differences could include:

   • Whether valve tissue is fastened on the inside or outside of the ring;
   • Whether there are lining sutures around the struts create differential tensions on the valve material;
   • Variables in the actual design.

   Variables in design and features can provide superior hemodynamics, especially for small annulus.  The Sorin Mirtroflow, for example, features bovine pericardium mounted external to the stent and is positioned supra-annularly, features that together are believed to provide superior hemodynamics. 

   One component that has evolved is standardized reporting of what constitutes valve related mortality, valve related morbidity, and what the definition of structural valve deterioration is.  Some thought has gone into the different ways of statistically analyzing these effects, for example, whether actual or actuarial probabilities are used.  Actuarial probability is based on the declining denominator of the people still remaining at risk (e.g., once a patient dies from another cause, in a sense they are no longer at risk for valve deterioration) while the actual probability includes everybody, predicting the probability of failure that is not inevitable, but can be precluded by other events such as death.  There have been attempts to try to find better ways of expressing this, however, currently; it is not consistently reported in the same way.

   One of the basic facts is that at a younger age, patients are more likely to have SVD regardless.  This is primarily because of two factors: living longer and calcification occurs more quickly than in older patients.

   A general concept that cardiologists are familiar with, noted Dr. Cohen, are the competing risks and benefits of mechanical valves which have a price to pay in terms of anticoagulation versus bioprosthetic valves that have a higher risk of re-operation, especially in younger people. 

3. Are more aggressive recommendations on surveillance and prophylactic replacement of bioprosthetic valves warranted?

   Dr. Cohen listed Dr. Thomas Sénage’s recommendations:

   • Monitoring patients who received older-generation Mitroflow valves with frequent echocardiography should be mandatory to prevent undesired complications, especially in high-risk patients, e.g. patients who have a small prosthesis and gradient >30 mm Hg across the bioprosthesis. Echocardiogram surveillance should be performed at ≤6 months for early detection. SVD and its accelerated pattern is a life-threatening condition, not only in young but also in old people, an incentive to a close follow-up after implantation.
   • Aggressive treatment is needed even in asymptomatic patients once the gradient becomes severe. Given the poor outcome of these patients, reoperative aortic valve surgery or a transcatheter procedure for high risk non-small-annulus patients should be offered when the diagnosis of SVD is made, even if the patient is asymptomatic.
   • Users should be warned about the possibility of increasing numbers of patients implanted with Mitroflow A12 and LX presenting with early SVD over the next few years.
   • Given the poor outcome of these patients, reoperative aortic valve surgery or a transcatheter procedure for high risk non-small-annulus patients should be offered when the diagnosis of SVD is made, even if the patient is asymptomatic.

   Current follow-up recommendations:

   • American (2014)
     • initial trans-t-echo (TTE) 6 weeks to 3 months post implant (I-B)
     • repeat TTE if change in signs or symptoms (I-C)
     • TEE if signs/symptoms suggest prosthetic valve dysfunction (I-C)
     • annual TTE for bioprosthetic valve only after 10 years (IIa - C)
     • no routine imaging for mechanical valves
   • European
     • annual TTE after 5 years

   If one were to adopt these recommendations, mentioned Dr. Cohen, it would be a dramatic change in monitoring frequency.  Increased monitoring has been widely accepted; however, the recommendation for re-operation for high gradients is less accepted.

4. Should the minimum standard for durability testing of bioprosthetic valves be extended?

   Three facts have evolved out of a 15 year durability testing experience with accelerated fatigue testing of prosthetic heart valves. First, the component of a prosthetic valve that fails in vitro fails in vivo. Second, the site of fatigue in the component worn in vitro is the same site of wear found on clinical specimens.  Third, those valves with high durability in vitro appear to have similar durability in patients. 

   Parameters of testing:

   • Accelerated wear testing
     • 200 million cycles for tissue valves
     • 400 million for mechanical (ISO)
     • 600 million for mechanical (FDA) 
     • includes specification of closing pressure, interim inspection, etc.
     • Valve stent 600 million cycles
     • CF intravascular stent 400 million
     • NB one year = 40 million cycles

In conclusion Dr. Cohen noted that recent references about the correlation of bench testing and clinical failure are hard to find.

10.  Next Steps, Closing Remarks and Adjournment of Meeting

Dr. John Ducas, Committee Chair

The Chair thanked committee members and Health Canada staff for their participation and valuable input.  He highlighted the importance of attendance to these meetings and asked that members make attending future meetings in their entirety a priority in the future. This will allow full participation to all topics discussed.

Members will be canvassed to select a date for the next meeting.

Meeting adjourned.