Scientific Advisory Committee on Medical Devices used in Cardiovascular Systems - Record of Proceedings – June 15, 2018

Committee Members Present: John Ducas (Chair), Eric Cohen, Marino Labinaz, Renzo Cecere, Brent Mitchell
Regrets: Alan Menkis, Christopher Feindel, Barry Rubin, John Webb, Raymond Yee
Invited Guests: Anita Asgar, Kevin R. Bainey, John Granton, Ashish Shah
Health Canada Representatives:
Office of Science:
Hripsime Shahbazian
Medical Devices Bureau (MDB): Patrick Stuart, David Boudreau, Kevin Day, Ian Aldous, Marianne Ariganello, Ben Elliot, Monica Forero, Jianming Hao, Amanda Jones, Karen Kennedy, Mark Korchinski, Roy Masters, James McGarrity, Catherine Milley, Chris Schmidt, Maurice Sylvain, Lanyi Xu
Bureau of Cardiology, Allergy and Neurological Sciences (BCANS):Timao Li
Marketed Health Products Directorate (MHPD):
Patrick Fandja
Regulatory Operations and Regions Branch (RORB): Barbara Harrison

Abbreviations used in this record:

Acetylsalicylic acid
American College of Cardiology
Acute Coronary Syndrome
Activated Clotting Time
American Heart Association
Aortic Insufficiency
Twice daily
Coronary artery bypass grafting
Congestive Heart Failure
Computed Tomography
Computed Tomography Angiography
Cardiac resynchronization therapy
Dual Antiplatelet Therapy+
Everolimus-Eluting Stent
Endovascular aortic aneurysm repair
Health Canada
Implantable pulse generator
Left atrium
Left Main
Medical Devices Bureau
Magnetic Resonance Angiography
Magnetic Resonance Imaging
Non-ST-segment elevation acute coronary syndrome
Once daily
Pulmonary Arterial Hypertension
Pacing Capture Threshold
Percutaneous Coronary Intervention
Patent Foramen Ovale
Plain old balloon angioplasty
Permanent Pacemaker
Percutaneous transluminal coronary angioplasty
Right atrium
Randomized Controlled Trial
Scientific Advisory Committee on Medical Devices Used in the Cardiovascular System
Special Access Program
Transcatheter aortic valve implantation
Transcatheter aortic valve replacement
Transthoracic echocardiogram
Therapeutic Products Directorate
Transesophageal echocardiogram
Ventricular Assist Device
Valve Academic Research Consortium-2
Vascular Closure Device

1. Opening Remarks & Welcome

Dr. J. Patrick Stewart, Director General, Therapeutic Products Directorate

Dr. J. Patrick Stewart opened the meeting and welcomed all committee members and guest speakers. Dr. Stewart identified and described current and ongoing efforts related to Stakeholder engagement including the creation of a new digital health unit with a focus on cyber security, which touches the cardiovascular space. Dr. Stewart highlighted the value of the input provided by the SAC-MDUCS.

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

David Boudreau, Executive Director, MDB

Dr. John Ducas, Committee Chair

David Boudreau reviewed the agenda items with the committee and presented the guest speakers.

3. Summary of How Health Canada has used Information Generated from Previous SAC-MDUCS Meetings

Kevin Day, MDB

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

The following topics were noted:

Mr. Day offered that the SAC-MDUCS discussions significantly influence how HC regulates medical devices, and on how HC understands the risks associated with these regulations. The discussions further provide HC with some very meaningful basis to challenge some of the manufacturers and also help position the technology in an appropriate space in the Canadian medical system.

4. PFO Closure Devices

Dr. Ashish Shah, Guest Speaker

In Canada, about 345 PFO closure procedures were performed in 2016 Footnote 1. This is an estimate of the number of devices used in Canada, based on the sale numbers of Amplatzer and Gore devices.

Three major trials were published in 2017 that compared PFO closure with medical therapy. All three trials showed the rate of stroke/cryptogenic stroke was significantly lower with PFO closure as compared to medical therapy, and patients with: a substantial shunt, persistent shunting, atrial septal aneurysm, and those on antiplatelet, but not anticoagulant medical therapy, benefitted most.

Question Response/Discussion
Question 1 a) Is PFO closure use limited to the reduction of stroke risk or is the use broader given the licensed indication is more general?

PFO closure is predominantly used to address cryptogenic stroke, but may also be used for paradoxical systemic embolization in the presence of risk factors from the venous system or right heart (e.g. pacemaker leads, permanent venous line).

Patients with shunting severe enough to cause hypoxia and dyspnea should also be treated with PFO closure, including rare cases of platypnea orthodeoxia syndrome.

b) Has the more recent clinical data changed how the device is used in Canada? Has use increased or decreased over time? Recently published clinical data supports trans-catheter closure of PFO in highly selective group of patients with cryptogenic stroke thought to be secondary to paradoxical embolization through PFO. Although there has been some increase in trans-catheter PFO closure over last few years, the difference does not appear to be significant.
Question 2 (a) What indications are supported by the currently available clinical data? 1.Cryptogenic stroke;
2. Paradoxical systemic embolization with venous or right heart risk factors (pacemaker lead/permanent venous line);
3. Severe shunting causing hypoxia and dyspnea, including Platypnea – orthodeoxia syndrome.
(b) Are there specific patient populations that have been demonstrated to benefit more than others?

Patients that would benefit most are those under 60 years. Dr. Shah indicated that younger patients may benefit for a long period of time.

Dr. Shah added that the decision to close a PFO should not be a single person decision, but for a multidisciplinary team that should consider:

  • neurology review – confirming a cryptogenic stroke, and identifying other causes;
  • CT, MRI, MRA or CTA – head & neck arteries;
  • Holter monitor data for at least 4 weeks; and, long-term monitoring (4 weeks vs 24 hours) can increase the diagnosis of atrial fibrillation, which would not benefit from PFO closure due to increased risks of stroke and left side events and thus give a false sense of protection to the patient;
  • TTE & TEE;
  • thrombophilia screen (not part of guideline), patients might be more likely to have a clot (particularly in the presence of thromboembolic disease or those at high risk of venous thrombosis).

Patients with pacemaker/defibrillator leads and severe shunting are at increased risk and may benefit more from PFO closure. Risk of stroke in patients with pacemaker/defibrillator leads and PFO is increased (8.2 % vs 2%) as compared to patients without a PFO over 3.5 years (Circulation, 2013;128:1433-1441).

Question 3 Recommendations in the clinical guidelines are conflicting. The 2017 Canadian Stroke Best Practice Recommendations do provide support for PFO closure while other clinical guidelines do not. Given there are different recommendations, how do Canadian users interpret what the appropriate use should be? The conflicting guidelines result from guideline publication timing. There is currently compelling evidence that PFO closure is beneficial for cryptogenic stroke, and guideline changes can take time. However, the current recommendations from the Canadian Stroke Best Practices (2017 update) are satisfactory. An evidenced-based algorithm for PFO closure is available.
Question 4 (a) Given that Canada's licensed indications are not as specific as those recently approved by the FDA, do the currently licensed indications remain acceptable? Yes, given that increasing the stringency criteria might be more limiting for clinicians, and case based management should be used to determine if patient has had a cryptogenic stroke, and thereby provide evidence that the PFO is responsible for the patient presentation.
(b) If manufacturers wanted to update the indications of currently licensed devices, what level of data should be required? Randomized trails would be required for anything other than cryptogenic stroke and paradoxical embolization, as sufficient evidence currently exists.
Question 5 Discuss the possible safety concerns with these devices. (a) What are the safety risks based on current clinical data? Based on the findings from the RESPECT, REDUCE and CLOSE trials, atrial fibrillation was consistently reported mostly within 1 month of the procedure, but not thereafter. Two procedure-related ischemic strokes were observed, which emphasizes that PFO closure is not a benign procedure. There was an increase in venous thromboembolic (VTE) events, mostly due to previous VTE history. There were also reports of device dislocation, device-related thrombosis and aortic dissection.
(b) Are there different risks if the device is used in the licensed broader indication for "PFO closure" (i.e. uses other than the reduction of stroke in a specific population)? No, overall the complication rate and the procedure challenges are not different.
(c) Are there specific risks that the labelling should warn users about? Atrial fibrillation; the user should be aware and look for the development of AF. As it is difficult to predict who will develop AF, perhaps patients should wear a Holter monitor for 4 weeks to identify susceptible patients.
(d) Is there evidence of device thrombus with PFO occluders? How is this managed or prevented given the device's intended purpose is to be an alternative to long term anticoagulation. There is currently very limited information describing device thrombus formation. Common practice is to give patients dual antiplatelet therapy for 3 to 6 months post PFO closure procedure. No thrombus formation was observed on the Amplatzer device, as compared to older devices, in two studies. However, thrombus formation has been observed on CardioSeal devices.
(e) Is there a need for more post-market studies of these devices? Long term follow-up data are very limited (average of 5.5 years) to assess safety including AF risk, anticoagulants and/or DAPT therapy.

Question 6 Provide overall recommendations for the level of clinical evidence required to support the safety and effectiveness of transcatheter PFO closure devices for the following scenarios:

(a) A new device that has not been previously licensed. What indications?

The current indications appear to be adequate. Safety and effectiveness of devices previously marketed in Asia or Europe and that have the CE mark, can be demonstrated through registry data that demonstrates similarity to other licenced devices.
(b) A change in indications for a currently licensed device to be specific to reduction in stroke following cryptogenic stroke. No change in the indications is warranted; PFO closure has been shown to be beneficial.


A participant highlighted the improved efficacy with newer anticoagulants, and using medical therapy as a comparator in future trials should consider anticoagulation regimen.

Dr. Shah indicated that patients who have a clot and PFO closure for paradoxical embolization, also have a very low rate of recurrence, but the cause of the second stroke and whether it will be AF, is unknown.

A participant suggested that approximately 20 or 25 patients is the number needed to treat over 5 years against medical therapy.

Dr. Shah indicated that there is little evidence to suggest that anticoagulants are on par with anti-platelets; patients are more likely to benefit from anticoagulants if they are at risk for a stroke (pre-PFO closure).

Dr. Shah further added that patients should be on dual anti-platelet therapy for up to 6 months post-PFO closure. After that the device is endothelialized, and the likelihood of thrombus formation on the device is reduced.

Dr. Shah indicated that in all the 3 trials, the bubble test showed that 7% of patients had incomplete closure and residual shunting after 6 and 12 months (attributed to incomplete endothelialisation, which can take up to 2 years). Dr. Shah's group published a paper two weeks ago in JACC Intervention looking at 600 pts in which PFO devices were deployed, and showed that of those with moderate to strong positive bubble test at 12 months or more, 1.3% have additional sources of left to right shunting. But in patients that had stroke after the procedure, the cause was not determined. Dr. Shah was not sure whether a positive bubble test indicated there is a path for a thrombus to move through. Dr. Shah found nearly 3% of patients have mildly positive bubble tests, but do not have AVM, and don't see shunting. Therefore, a positive bubble test has not been shown yet to equate to a risk of thrombus and stroke.

A participant asked if the committee was comfortable with HC relying on a registry/post-market data from Europe for licensing these technologies.

A participant suggested that there is a low probability of seeing a randomized trial with these devices, based on cost and long term follow-up requirement (10 years). They also suggested that if HC does not make it moderately easy for them to come to Canada; they won't.

Key Messages / Evaluator Summary
Indications for PFO closure: - Cryptogenic stroke (risk reduction)
- Paradoxical systemic embolization with venous or right heart risk factors
- Patients with severe shunting causing hypoxia and dyspnea, including rare cases of platypnea orthodeoxia syndrome
Clinical data references supporting indications: RESPECT trial (N Engl J Med 2017; 377:1022-1032)
REDUCE trial (N Engl J Med 2017; 377:1033-1042)
CLOSE trial (N Engl J Med 2017; 377:1011-1021)
Data limitations: - There is no long term follow-up past 5.5 years
Target patient population characteristics: - Patients under 60 years, patients with cardiac leads or permanent venous lines
Recommended data requirements for expanded indications: - Randomized trials for anything other than cryptogenic stroke and paradoxical embolization.
- For new devices with similar indications that have the CE mark, safety and effectiveness can be demonstrated through registry data that demonstrates similarity to other licenced devices.
Identified risks: - Atrial fibrillation (mostly within 1 month of procedure)
- Procedure-related ischemic strokes
- Venous thromboembolic (VTE) events (may be due to previous VTE history)
- Device dislocation
- Device-related thrombosis
- Aortic dissection
Specific warnings that must be addressed in IFU: - Atrial fibrillation (patients should wear a Holter monitor for ~4 weeks to identify susceptible patients).

5. Large Bore Femoral Artery Closure Devices

Dr. Marino Labinaz, Committee Member

Dr. Labinaz introduced himself and declared he had no disclosures and no financial interests in catheters or closure devices.

There are no consistent definitions in the literature; however, large bore vascular access sheaths are generally defined as those larger than 10 Fr. He indicated that this value refers to the internal diameter of the catheter, while the external diameter impacts the patient and is what the artery 'sees'; he also offered that the external diameter is also not generally published. E.g. the 14 Fr Edwards e-sheath has an external diameter of 23 Fr, which further expands when the valve goes through it.

First device by Abbott was a suture-based technology, the Prostar XL. Dr. Labinaz described a 2011 meta-analysis (Eur J Vasc Endovasc Surg (2011) 41, 201-213). Across 692 patients, Prostar XL had a 90% success rate (defined as adequate hemostasis without the need to convert to surgical repair), was 1 hour shorter, and has a complication rate 10% less than that of the surgical arm. The Prostar XL became the gold standard for large bore device closure.

Furthermore, the effectiveness of the Prostar XL and the Proglide devices for vascular closure following TAVI procedures were compared by Barbash et al. (Eur Heart J. 2015 Dec 14; 36(47):3370-9). Major vascular complication rate (VARC) was significantly higher in the Prostar XL vs. the Proglide group (9.5% vs. 5%) and included major bleeding, and acute injury (transfusion, and hypotension). However, mortality rate was not increased. Also, stenosis rate was higher with the Proglide due to the "pinch" that the sutures create on the artery, which is normally left alone. Based on the subgroup analysis, with sheath sizes larger than 18 Fr, it appears that the Prostar XL could be better for closing large arteriotomies.

A systematic review of the safety and efficacy of the ProstarXL vs. Proglide after TAVR and EVAR, Maniotis et al. (2017) showed all vascular complications (VARC) were numerically higher with the Prostar XL, and while mortality was not greater, acute kidney injury was higher with ProstarXL. Dr. Labinaz indicated his own experience was similar, and based on these data his center uses the Proglide for large bore device closure.

The Japanese OCEAN-TAVI study compared single versus double Proglide in 16Fr to 20Fr TAVI (Kodama A et al Catheter Cardiovasc Interv 2017: 90 E55-62), and found a single Proglide in transfemoral TAVI could achieve equivalent, acceptable rates of technical success and procedural complications compared with the double Proglide technique. Dr. Labinaz indicated he uses a single Proglide technique in 2/3 of patients, especially if they are 14 Fr eSheaths, and observes less "pinching", stenosis with a single Proglide.

The safety and efficacy of the MANTA plug-style system, as compared to the Proglide (two device technique) was demonstrated in patients undergoing TAVI (Int J Cardiol. 2018 Jul 15; 263:29-31). Device failure rates were not significant different, but were greater in the Proglide group.

Question Response/Discussion
Identify new closure devices used to close large access sites in femoral arteries created during interventional procedures. Describe their operating principles, highlighting strengths and weaknesses of the designs.

Four devices were discussed: Prostar XL, Proglide (1 or 2), MANTA, and PerQseal. Prostar XL is 10 Fr, with 4 needles and 2 sutures. Proglide is 6 Fr, with 2 needles and 2 sutures and it uses a similar suture based technology than the Prostar. Two Proglides are used to imitate how the Prostar works. The advantage of using two Proglides is that if some sutures fail, another Proglide suture can be added, while if the Prostar XL fails, all 4 sutures are lost. MANTA is a plug device that is used in 6-8 Fr arteriotomy sites. The MANTA components dissolve over 6 months (except for the lock marker and suture line). The disadvantage is that re-accessment of the femoral artery cannot be done within 6 months with a large bore catheter and the puncture should be at least an inch away from the steal marker. The PerQseal closure device uses a bioabsorbable patch that is curved for the femoral artery. The device is completely degradable. This device has been used in Europe in 120 patients. There were no VARC II vascular complications and no adverse events following 1 year.

Proglide is currently the gold standard, and has a failure rate of approximately 5-10%, which is usually due to calcium (needles won't deploy well and won't suture) and patient obesity (knots will be caught in subcutaneous or adipose tissue). The advantages of the Proglide are that the access to the artery is maintained and additional devices may be deployed. In addition, the artery can be reused immediately. The "plug/patched" based devices appear to have a similar failure rates than the suture-based devices. However, if the device fails, bailout is more difficult, and the artery can't be reused for several months.

Compare the benefits and risks of these devices to each other and to conventional methods for femoral artery larger bore closure.

These devices are generally used femorally, but there are reports of subclavian use for: endovascular procedures (e.g. TEVAR, EVAR, TAVI, ECMO, and peripheral ventricular assist devices). Surgical repair was once the standard of care. It allowed for direct artery visualization of the artery, so that challenging anatomy could be addressed. As a result was associated with low failure rates. Complication rates ranged from 14-22% (nerve injury and infection). However, large incisions meant slower healing, and because of a lack of vascular surgeons, there was a need to close holes without vascular surgeons.

Conversely, percutaneous hold closure involves small incisions and shorter procedure times, but is limited by arterial wall calcification. Patient obesity is also a challenge, as sliding knots can get caught in subcutaneous adipose tissue; tying the knot above the arterial plane results in bleeding. Other risks include: device failure, device stenosis and late pseudoaneurysm due to incomplete closure. In some cases two devices may be needed to close. Also, percutaneous closure requires imaging for a good puncture technique which is usually assisted by: CT scan artery assessment, and intraprocedure angiograpy to target and direct ultrasound to puncture. Progressive dilatation may also be used to create a large enough puncture hole to accommodate the large bore. Also, stiff guidewires are used for large bore devices.

Are there contraindications for these devices based upon anticoagulation/antiplatelet therapy or vessel characteristics such as size, tortuosity or degree of calcification? Dr. Labinaz indicated that there are no contraindications with respect to anti-platelet or anti-coagulants; all patients are pre-treated with DAPT, so they are given aspirin and clopidogrel before the procedure, and most clinicians use heparin. He also indicated that differences in bleeding are related to the device and not DAPT.
What constitutes a reasonable amount of clinical data? Dr. Labinaz suggested that a non-inferiority trial (based on his calculations) with 650 patients would be sufficient to prove that a new device is not inferior to Proglide by more than 5% (conservative value). However, as with most non-inferiority trials with a larger margin (20-30%), fewer patients would be needed. Endpoints shall include VARC-2: failure of closure device to achieve hemostasis at the arteriotomy site (which leads to alternative treatments). Dr. Labinaz also suggested consideration of VARC-2 vascular complications, and not just access site success.


Dr. Labinaz emphasized that no matter how good a closure device might be, if the hole is done poorly, the closure device won't be able to fix the situation. He also indicated that proper imaging is imperative for visualization (CT scan and/or angiography, ultrasound guidance) the femoral artery in order to make a good puncture.

A participant raised the following question: given that the Proglide and MANTA are different technologies, is one better suited for a particular niche of patients than the other?

Dr. Labinaz suggested that the Proglide and MANTA are limited by the same factors, such as calcified arteries. However, obese patients might do better with MANTA because there isn't the reliance of the suture slipping down into position. He also suggested that price may ultimately be an important consideration; the MANTA is priced at approximately $800, while the Proglide is $160. If prices are competitive most clinicians will likely try it. He added that it would be viable to do a RCT; VARC definitions could help set the trial.

A participant added that it is important to consider usage circumstances. Most studies include TAVI patients, where the access to the artery is controlled, while that is not the case with ECMO patients in which the circumstances are not good. He suggested that these devices may not be indicated in these circumstances, and that their use in other circumstances should also be studied and considered in the context of indications.

A participant indicated that that the US FDA is focusing on real world data and prospective registries and less RCT data. He indicated that HC may be progressing in a similar direction.

Dr. Labinaz suggested that the more biased the endpoint, the more important RCT data become,

A participant noted that the registry question is an important one. Manufacturers will want to include the best patient cases as part of registries to make the device appear "good." In reality, clinicians will likely choose to use a device like the MANTA on patients with bad, calcified vessels, where a good result may not be achieved with the Proglide. But companies should be required to demonstrate the performance in those patients, who are the most likely to receive the device. Since you can't re-access the vessel with the MANTA, registry data would be needed for these particular patients because when you use the MANTA you want and need it to work. Another important consideration is longer term vascular complications. It is important to note that complication rates might be different depending on the size of the vessel. Device performance should be stratified by vessel size (i.e. 6 mm vessel vs. a 10 mm vessel).

Dr. Labinaz indicated to patients undergoing TAVI that they can expect a 5 to 10% major vascular complication rate (i.e. major life-threatening bleed).

Key Messages / Evaluator Summary
Large Bore Femoral Artery Closure Devices: Prostar XL, Proglide (*Gold Standard), MANTA, PerQseal
Clinical data: Barbash et al. (Eur Heart J. 2015 Dec 14; 36(47):3370-9)
Maniotis et al. (2017)
Contraindications based on anticoagulation/anti-platelet regimens: No. All patients are pre-treated with DAPT, so they are given aspirin and clopidogrel before the procedure, and most clinicians use heparin.
Recommended data requirements for new devices: - A non-inferiority trial (based on his calculations) with 650 patients would be sufficient to prove that a new device is not inferior to Proglide by more than 5% (conservative value). However, as with most non-inferiority trials with a larger margin (20-30%), fewer patients would be needed.
- Endpoints to include: VARC-2 - failure of closure device to achieve hemostasis at the arteriotomy site (which leads to alternative treatments), VARC-2 vascular complications.
Identified limitations/risks: - Limited by arterial wall calcification, and obesity.
- Device failure.
- Device stenosis.
- Late pseudoaneurysm due to incomplete closure.
In some cases, two devices may be needed to close. Also, percutaneous closure requires imaging for a good puncture technique which is usually assisted by: CT scan artery assessment, and intra-procedural angiography to target and direct ultrasound to puncture. Progressive dilatation may also be used to create a large enough puncture hole to accommodate the large bore. Also, stiff guidewires are used for large bore devices.
Specific information to be included in the IFU: - Proper imaging is imperative for visualization (CT scan and/or angiography, ultrasound guidance) the femoral artery in order to make a good puncture.

6. Evolving Clinical Use of TAVR and Increasing Clinical Data Stratification

Dr. Anita Asgar, Guest Speaker

Dr. Asgar introduced herself as an Interventional Cardiologist at the Montreal Heart Institute, and declared that she is a consultant for Medtronic, Edwards LifeSciences and Abbot Vascular.

She indicated it is important to realize that TAVI technologies have undergone multiple design iterations, and despite the multiple differences in design, they are intended to do the same thing.

What's been learned is how to better evaluate and classify patients, as outlined in the ACC/AHA 2014 guideline risk assessment. In addition, clinicians have learned which patients they should not treat, such as those with important co-morbidities and those who are frail and considered to be at prohibitive risk (medically futile).

Current indications for TAVI are approved for high-risk patients and there is a pending approval for intermediate-risk patients (data is currently available). The question remains if the indications should be expanded to low-risk patients.

Intermediate-risk Patients

The PARTNER 2A RCT showed no difference in primary endpoint for all-cause mortality or disabling stroke for TAVR vs SAVR at 2 years, in intermediate-risk patients. Of note, in the transfemoral-access cohort, TAVR resulted in a lower rate of death or disabling stroke than surgery, whereas in the alternative access cohort, the outcomes were similar to or worse than those with surgery and appear to be inferior to those with transfemoral TAVR. Take home message for surgeons: intermediate-risk patients who can achieve transfemoral access, TAVI is better. If you have to use alternative access, SAVR is better. SURTAVI trial Footnote 2 also showed no differences in the primary endpoints between TAVR and SAVR in intermediate-risk patients, which led the ACC to change the indications in 2017 and recommend TAVI as a Class II indication for patients at intermediate surgical risk. For high and prohibitive risk, TAVI is now a Class I indication. The FDA approved TAVI for intermediate-risk patients in August 2016. However, only SAVR has a Class I indication for low risk patients.

There has been a movement for a TAVI-specific risk assessment that includes imaging, and TAVI approaches are now being done under minimal sedation, in which patients are conscious. So, in terms of the next frontier: low risk, patients with asymptomatic AS, moderate AS and HF, and TAVI valve in valve.

Low-risk Patients

Two new trials are underway, have completed enrollment, and are now in the follow-up phase. The PARTNER 3 trial compares TAVR (transfemoral access only) to SAVR in low-risk patients (STS<4). An alternative access registry will be included. Recall that the results in the alternative access arm were quite poor in the PARTNER 2 trial. The primary endpoint will be all-cause mortality, all strokes or re-hospitalization at 1-year post-procedure.

Dr. Asgar suggested that special considerations related to low-risk patients were raised in the NOTION trial (Europe), 2009, which compared TAVI to SAVR in lower-risk patients over 70 years of age. The primary outcome was composite of all-cause mortality, stroke or MI, safety outcomes at one year. It took them 4 years to randomize. The trial was designed to show superiority of COREVALVE (1st gen), but their primary outcome estimates were very inaccurate: 5% event rate in the TAVI arm and 15% in the SAVR arm. These are older patients with low STS, and low rates of co-morbidities. The study was underpowered, so one should not expect to see differences. Five-year outcomes of this trial show, no sig difference in all-cause mortality or stroke, or MI. Messages from this: the low risk population was comprised of older individuals with few/low burden comorbidities. We expect their improvement in QoL would be better. TAVI access route should be an important consideration – transfemoral approach is better. In a healthier or low-risk population, their tolerance for risk is much lower. Important for this population is valve durability; because they represent a healthier population, their life expectancy is also expected to be greater and with this the need for long-term valve durability, as well as future coronary access (valve leaflets may obstruct coronary ostia) is important as they may need an intervention in the future. As the TAVI outcomes had fewer bleeding complications, more vascular complications, less acute kidney injury, but very high PPM implantation (~1/3) vs. 2% for surgery.

With respect to valve durability, there are some data that describe bioprosthetic failure out to 72 months that is not different between TAVI vs. SAVR arms.

Comparing these two options in low-risk patients, PPM implantation is a risk and cost issue, as patients are "condemned" to continual follow-up. Pts that become pacemaker dependent after TAVI, and are RV paced, are more likely to be readmitted with HF. This is becoming an issue.

It's important to recognize that all valves are not created equally, and because each one has different complications, each valve must be evaluated differently. In Quebec, Dr. Asgar indicated she has seen pacemaker rates from 10 to 50% depending on the valve that's used.

Question Response/Discussion
To what extent is TAVR currently used in these populations? n/a
Are there any specific valve performance issues or clinical outcome measures that are unique or critically important for any of these indications that are different from what HC would have reviewed as part of a high risk or intermediate risk patient population? Dr. Asgar indicated (based on data from NOTION trial) that valve durability is important, particularly in low-risk patients that are expected to have greater longevity; durability may need to be greater in a younger individual and can be less an in older one. Leaflet thrombosis is another issue that needs consideration. She added that access route was important to consider in low-risk patients (outcomes in alternative access arm are not as good), because of the known inherent risks with alternative access, and their limited tolerance for severe complications (major bleeding and stroke). Future coronary access is important given that these patients might need an intervention in the future. Also, future coronary access and permanent pacemaker implantation are two additional issues. However, Dr. Asgar reiterated that not all valves are created equal and should not be approved in the same way, as some may have different complication rates. For examples, in Québec, there has been a range of 10% to 50% pacemaker implantation rate depending on the type of valve used.
Are there clinical outcome measures we should require for these clinical trials? (see above) Long term follow up; specifically need registry data for these patients (real world data). Perhaps mandatory follow-up should be required for both TAVI and SAVR given that leaflet thrombosis is not unique to TAVI.
Can some studies be pooled together for a common data-set, including by risk classification, delivery system route, etc. Dr. Asgar indicated that not all devices are created equal, and she was not sure if that's possible. However, with respect to access route, she indicated that a trans-apical approach is very different than a trans-carotid or a trans-auxiliary. She suggested that one could pool vascular access, but that for trans-apical, the results seem to be quite different. There doesn't seem to be significant differences between trans-auxillary and trans-femoral.
When could a TAVR system be compared head to head with a surgical valve with a more generic indication for use, similar to a surgical bioprosthetic valve? Dr. Asgar: emphasized that not all valves are created equal. The Accurate Neo has no RCT data, and the data are limited, but is approved. She is using this valve at their site (cost based decision), and have seen a lot of AI and aortic dissections. Clinically, she thinks we need more evidence for a new valve. Dr. Asgar suggested that RCT data are needed. And the comparator could be a performance goal, for higher risk patients, but should be much more stringent as we move into lower risk patients. Eg. PPM at 80% for one valve and 15% in others.
Are there any of these indications where you would not require an RCT where the TAVR system was compared to current gold standard treatment? n/a
In the treatment of asymptomatic patients, when should intervention be allowed and what type of evidence would you want to see to be confident of the safe and effective use of TAVR in this patient population?

Dr. Asgar highlighted that Guideline recommendations (2017) have recently changed to recommend a valve replacement in these patients, three Class I indications, level of evidence B, without randomized data. She stressed that asymptomatic doesn't mean low-risk, and it's difficult to convince an asymptomatic patient to have open heart surgery, particularly in the elderly.

The literature indicates that as a consequence of severe AS, the mortality rate is 1-3% per year, even if asymptomatic. Perioperative mortality (SAVR) is 1-5%. For this reason, early surgery is not elected; however, the 30-day mortality associated with TAVR is lower (2.2% for Core Valve in SURTAVI and 1.1% for Sapien 3 in PARTNER trial). A 2016 meta-analysis demonstrated that there is a 3.5 fold increase in all-cause mortality if the patient is left on medical therapy vs early intervention with AV replacement. Therefore, there may be no benefit to keep the patient on medical therapy, when they're asymptomatic.

Dr. Asgar suggested that before a decision can be made about what to do with asymptomatic patients, trial data are needed (Early TAVR Trial for truly asymptomatic patients by Généreux currently ongoing but until we see the evidence that early intervention is NOT associated with significant complications out of proportion of what would be expected on the basis of patient risk).

Given the less invasive nature of TAVR, are there indications where TAVR might be feasible and where SAVR would not be appropriate in low risk patients? It is already being used in bicuspid aortic valve disease and in aortic insufficiency (Medtronic, CoreValve and Evolute in AI). Dr. Asgar suggested that TAVR would be appropriate for individuals requiring emergent surgery, low-risk patients, and to address patient preference.
Are there other potential indications that you foresee TAVR expanding into?

Dr. Asgar described the available evidence for TAVR to treat moderate AS in the presence of CHF. She indicated aortic stenosis is a physical obstruction which increases afterload, and the concept of reducing afterload by addressing the stenosis might confer a potential benefit. She indicated this application is being studied as part of the TAVR-UNLOAD trial, run in the US and Europe. Dr. Asgar believed this has the potential to alter practice but is less enthusiastic as, it's difficult to know whether death, AVR or HF hospitalization would be reduced with TAVR. They saw in this cohort that previous HF hospitalization was associated with an increased likelihood of subsequent hospitalization, so the message is that endpoint was driven by HF hospitalization. She suggested that we need RCT data before clinicians adopt TAVR in patients with moderate AS.

Dr. Asgar also discussed TAVI for low-risk patients for treating a failed surgical bioprosthesis. Dr. Asgar reiterated that all surgical bioprostheses are not equivalent, and some may not support a TAVI for valve-in-valve (VIV). She highlighted that this area has exploded with many different TAVI devices, without randomized trial support for the practice (Sapien XT, CoreValve, Sapien 3, Evolut R). Registry data show that VIV procedures accounted for 1.7% of all TAVRs in 2012, and for 5.6% in 2015. In addition, TAVRs are being used for failed sutureless surgical valves (e.g. Perceval). The questions are whether this should be happening and what we need to watch for. Dr. Asgar indicated that the approach could be effective in reducing a gradient and improving functional class, whether stenosis or insufficiency is the mechanism of failure. She added that there are US data to indicate the mean STS score of patients being treated with VIV is decreasing. There seems to be a link between why the valve is failing and the risk of death so that patients with stenosed valves have a higher risk of mortality. A similar trend is found with valve size, the smaller the valve size, the higher the risk of mortality.

Of particular concern with VIV is coronary artery occlusion, and the CAs being affected after long term follow-up. She described these concerns in the context of lower-risk patients where there's a price to be paid for VIV, as compared to redo surgery. In addition, prognosis with coronary obstruction is poor (47.8% survival after one year vs. 88% without coronary obstruction). She reiterated that not all valves are created equal, and the risk of CA occlusion could be much higher with some valves (e.g. Mitroflow). Dr. Asgar's center performs multiple CT assessments to determine whether a patient can have this procedure; if the distance between the coronary ostia and virtual valve is < 4 mm then the risk of obstruction is exceptionally high.

The other concern is restenosis of the TAVI VIV; there is evidence from registries that the smaller the valve the higher risk for a higher gradient that will lead to structural deterioration. The available data suggest that mortality risk is increased with gradients > 20mmHg after a VIV.

The other issue is leaflet thrombosis, as you have two layers of metal. A similar trend for patients on dual anti-platelet therapy, there is still a risk of thrombosis. If one considers structural valve deterioration and gradients the smaller the surgical valve the greater the gradient. The Medtronic CoreValve, because it is supra-annular position has a lower gradient than the Edwards which is trans-annular, and may suggest the use of a supra-annular valve to maintain lower gradient, over a trans-annular valve.

A new practice is using a balloon to "break the ring".

The enthusiasm for doing this ("fracking the valve") is increasing because there are few options for some patients. However, the fracturing is uncontrolled and therefore represents a significant risk. Therefore, Dr. Asgar suggests that low-risk patients may not be ideal candidates. Also, there is some evidence that surgical valves with titanium sewing rings cannot be fractured. This has led some manufacturers to design surgical valves to be expanded (e.g. Edwards valve designed to expand when a balloon is placed inside of it).

A participant asked whether there are any anecdotal adverse events associated with "fracking". Dr. Asgar indicated there have been annular ruptures (reported to be less than 10%, but the numbers are small) and deaths, and suggested that patients should be advised that the risks are significant. Dr. Asgar did not see the logic in choosing VIV with fracturing the failed surgical valve (and risk of mortal complication) in low-risk patients, over a redo procedure. Conversely, a high-risk patient may not have other options.

A participant asked for recommendations how HC might access that information from within the clinical community.

Dr. Asgar suggested that some of the clinical registry data sharing has helped with the choice of THV for specific circumstances. The data show the outcomes are good, but there are no RCT data, and she is not sure if there will be. They are used with a minimal approach in low-risk patients. Another important point was that patients that receive a VinV almost never require pacemakers. However, severe patient prosthesis mismatch is a problem, and a VinV may not improve a surgical valve that has patient prosthesis mismatch. Higher device implantation to help mitigate higher gradients. Thrombosis appears to be more common with VIV than TAVI. Although anticoagulation therapy is not generally prescribed with VinV, this should be considered.


Dr. Asgar indicated that leaflet thrombosis was identified serendipitously, originally identified by 4D CT in the PORTICO trial (abnormal leaflet motion), and saw it with several TAVI and SAVR valves. However, anticoagulation with Coumadin, but not the NOACs, the thrombus is resolved. A low-risk trial, single arm TAVI study LRT (Medstar in Washington) is evaluating patients for sub-clinical leaflet thrombosis (aka leaflet motion abnormality) assessed with 4D CT or TEE. In 12.5% of cases, hypo-attenuating leaflet thickening was observed; reduced leaflet motion in 11%; and 9.3% had hypo-attenuation affecting motion. Administration of antiplatelet medication did not appear to impact it, but anticoagulation seemed to have improved it. The question that remains is when to stop administering Coumadin.

A participant reiterated a comment that was previously made that the "first 5 years are free" with a bioprosthetic valve, but after that we tend to see the true performance of the valve.

Dr. Asgar commented that the statement is not necessarily true. She has seen (as have other interventionalists in Canada and the US) that new device iterations exhibit gradients in as short as 30 days. SAPIEN 3 has low rates of perivalvular AI but that the gradients are jumping fast at 30 days post-implantation (from 9 mm Hg to 20 or more). She has elected to anticoagulate these patients and the gradients go back down. There was no indication of thrombosis and the patients seemed to be doing better with anticoagulation.

A participant indicated that they implant many SAPIEN 3 valves, but have not observed this. Dr. Asgar indicated that centers in Morristown and Pittsburgh have seen similar trends, but it may be the problem with the smaller size (as she generally implants 23 mm SAPIEN 3).

Dr. Asgar described the use of cerebral protection against stroke during TAVI, and indicated it was approved in the US. Although she indicated that the evidence is weak, there appears to be a lot of enthusiasm.

A participant asked what the users are doing, as several years ago, several devices came through special access, but they're not seeing that enthusiasm.

A participant indicated that they are cumbersome, but the technology is not there yet.

Dr. Asgar commented that there is enthusiasm for using the sutureless Perceval valve, with little evidence. In the GARY (German Aortic Valve Registry), they showed the highest pacemaker rate and AI, and yet many are using them because of reduced pump time and no need to put in sutures. Quebec is also limited with the number of cases that are funded. Dr. Asgar expressed that TAVI provides known benefits to high-risk patients, but are not funded to even meet that need, let alone to meet the need for low-risk patients.

A participant suggested that the clinical community should comment on the ISO standard that describes the bar at which a heart valve needs to perform, and the Perceval valve met that standard. They indicated that it would be helpful to engage the clinical community to identify elements of clinical performance not reflected in that standard (SAVR), as that is HC's bar for bioprosthetic valves – this would help us setup expectations for how those valves should perform. The participant would like to facilitate input from the clinical community. The struggle with the Perceval was that early data were not good, but as adverse events are front-weighted, if patient follow-up is done for a few extra years, the adverse event rates per year decreases and eventually the valve meets the standard. Most recently, the 1-year outcomes have been removed from the standard, so it only relies on adverse events on a per year basis.

A participant shared the clinical endpoints outlined in the ISO standard. It assumes that early structural failure will not occur.

A participant asked whether there should there be an absolute requirement for robust registry data in the absence of a randomized clinical trial, and whether regulators should be imposing that.

Dr. Asgar thought that if there is approval for a new device, the manufacturer should be mandated to have a clinical registry for every patient implanted with that device, at the manufacturer's expense. Otherwise, it won't be feasible if it were at the investigator's expense. Where the data is collected and reviewed, the argument shouldn't be, "well it was approved by HC, so we can use it" but rather "are the clinical results good enough to justify its use?". She thought it was peculiar that the burden of proof required for a TAVI valve was the same [and higher] as that for a sutureless valve.

A participant indicated that a balance may be needed; implementing a firm requirement like approval being contingent on a clinical registry, the manufacturer may decide that they do not need to sell their device in Canada as it is only 2% of the global market and Canadians would not have access to the device entirely.

A participant commented that the Accurate Neo was an interesting case. An argument can be made that a RCT should not be conducted for high-risk patients against surgery. The committee was asked when choosing a valve for a patient, whether they consider that Sapien should be indicated for intermediate-risk patients, and whether Accurate Neo should only be indicated for high-risk patients. The challenging question is how to approach the regulation of valves approved for different indications and based on different levels of confidence/evidence.

Dr. Asgar highlighted that indication creep is moving towards lower-risk.

Key Messages / Evaluator Summary
Current populations targeted for TAVI: High-risk patients. Approval is pending for intermediate-risk patients (data is currently available). More data is required for low-risk patients.
Clinical data: PARTNER 2A RCT (intermediate-risk - in the transfem cohort, rate of death was lower with TAVR)
PARTNER 3 (low-risk)
NOTION trial (Europe), 2009 (low risk)
Potential indications for TAVR: - Asymptomatic patients
- Low surgical risk patients
- AS in the presence of heart failure
- emergency surgery
Recommended data requirements for expanded indications: - RCT data
Important risks/safety endpoints: (General)
- Durability
- Leaflet thrombosis
- Access route (major bleeding and stroke)
- Future coronary access
- Permanent pacemaker implantation

- Restenosis (reduced valve area)
- "Fracking" the failed bioprosthesis

7. Treatment of Unprotected Left Main Coronary Disease

Dr. Eric Cohen, Committee Member

The motivation for the talk is that there are recent and important RCT trial results that inform LM revascularization, NOBEL and EXCEL findings are not completely concordant with existing guidelines for the treatment of Left Main Disease. In addition, Dr. Cohen acknowledged that HC may be anticipating broadened indications for DES that include LM use.

Treatments of Left Main Disease (LMD) are much broader than just the indications for use for a particular device, as there is uncertainly within the medical community about the role of stenting in left main disease and when it should be done. An interventionalist's hierarchy of decision-making considerations when treating left main disease includes: define anatomy, determine whether revascularization required (there's a big spectrum of mild to moderate LM disease), identify burden of ischemia, consider symptoms, medical therapy appropriateness or treatment in the presence of other CA disease, and the options available for LM treatment (stent vs bypass). Dr. Cohen indicated that there is often no choice, so it becomes a question of whether the LM anatomy suitable for intervention. The choice of stent and whether the stent is indicated for LM are often the last and least important considerations.

Context and background: paper from 1981 CAS study registry (CA patients). The findings showed that patients treated medically didn't do well for LM, and surgery was superior, and this was clear across all subsets. One may even extrapolate from these data that LM lesions that are not hemodynamically important, may become just as stable with aggressive medical treatment, but RCT data are needed. Today, everyone is treated with statins/ASA, so we don't know the natural history of moderate LM patients.

One of the very first angiography reports, emergency POBA for LM was attempted and shown to be the appropriate treatment. In another study of 20 patients, POBA trial (1985) concluded that bypass is best for stable elective LM patients, but emergency PTCA is better for unstable high risk patients when surgical risk is too high. Dr. Cohen stated that although this study is more than 30 years old, this approach is still used today.

What limited the development of LM PCI was the unpredictability of the acute result with POBA, and late restenosis risk, as well as the uncertainty in treating bifurcations. Generally, the thinking was the surgery was preferable to PCI and that pervaded clinical decision making.

Historically, most RCT trials suggested there was some equipoise between PCI and surgery, and surgery was largely favoured. The trials were relatively small, and occurred prior to 2011, so PCI did not include 2nd generation stents.

Contemporary studies, meta-analysis - EXCEL and NOBLE trials.

At a time when approaches to bifurcations were established, as well as the ability to support patients hemodynamically (maturity of PCI of the left main), the EXCEL trial included 2,000 randomized patients (+ 1,000 in a registry). Patients with a high burden of ischemia were included (50-70%), and those with intermediate to high complexity lesions. Primary endpoint was death, stroke or MI at 3 years, and was designed as a NI trial with a provision to test for superiority between CABG and PCI (Xience V). Average age was 66 years; however, LM stenting is generally done on much older patients. Approx. 30% were diabetic. 5-7% had a prior MI/TIA which impacts surgical risk. Based on syntax scores, lesion complexity was a bit higher than mild/moderate. No significant difference at 3 years. But, adverse events are higher with CABG. Five-year data is pending. Therefore, the non-inferiority hypothesis was met. When you add in ischemia-driven revascularization – the event rate is higher with PCI, but it's not clear whether the re-interventions were for LM or other segments.

The NOBLE trial included patients, in whom the vast majority had stable LM disease. There were similar inclusion criteria; NOBLE excluded CTO or bifurcation disease. Primary endpoint included: death, stroke, MI and primary TLR. Stent used was mostly the Biolimus. Event rates were lower than expected, and recruitment needed to be extended. The challenge is that too many eras of technology were covered. Only 15% diabetics (half of N.American level) and Syntax score was intermediate. It was structured as a non-inferiority trial, but failed. CABG was superior on the primary endpoint. Non-procedural MI is higher in the PCI group. The findings seem to indicate that bypassing the troubled coronary vasculature is associated with fewer adverse events. TLR is higher with PCI, but rate is ~10% with CABG.

The guidelines have not been revised. Surgery gets Class II (B level evidence) and PCI gets a IIa for low complexity, and IIb for moderate complexity, and III for high complexity. It's hard to imagine the data to support PCI would become more convincing over time. In Canada, there is a 2014 position statement on multi-vessel revascularization that references LM. Dr. Cohen's position is that an individualized approach is warranted, which should consider: coronary complexity, technical feasibility, co-morbidities, local expertise, and patient preference. Patients should be made aware of a historical preference for CABG, but that more recent data has demonstrated some equipoise.

He presented several "Indications for Use" documents and highlighted that the indications only mention increasing the lumen diameter, and don't reflect any barriers to doing LM. He believed that the precautions for LM are in the same category as complex acute MI.

Question Response/Discussion

To assist with the interpretation of the EXCEL and NOBLE trial findings, compare trial designs, summarize findings, and discuss any limitations and data gaps that may influence future studies.

Also, describe the type of clinical studies that could be practically run to answer any remaining important clinical questions.

The EXCEL trial compared the performance of a second generation stent (EES) with CABG. This is considered to be a relatively large trial, and included an accompanying registry. Results at 3 years showed no statistical difference in the primary endpoint (composite of Death, stroke and MI) between the two treatments but there are clearly differences earlier on in the time course, with CABG having higher rates of these events. For secondary outcomes, PCI is associated with higher rates of ischemia driven revascularisation. Dr. Cohen added that there is no information on whether revascularization is a result of treatment of the LM or elsewhere, new lesions, or existing ones. Dr. Cohen considered the conclusions published in NEJM to be a clearer representation of the data, that PCI was non-inferior to CABG.

In terms of inclusion and exclusion criteria, as well as endpoints, the NOBEL and EXCEL trials were equivalent. However, the NOBEL trial included repeat revascularisation as part of the composite primary endpoint. There were lower event rates than predicted, and a slower rate of recruitment. As a result, the data collection period has been extended out to 2020, and the time point for the assessment of the primary endpoint has been scaled back to a median of 3 years (rather than 5 years). Dr. Cohen noted that this study started in 2008. One result of this extended time period is that the data will now be collected across more "eras of technology". In addition, baseline characteristics were similar, although Dr. Cohen noted that, as is typical in a European study, the diabetes rates are lower than in a North American study (15% vs 30%). The NOBEL study showed at 5 years, the PCI arm did not meet the primary endpoint of non-inferiority to CABG. Also PCI patients had higher rates of non-procedural MI. Dr. Cohen described these data as "sobering" for interventional cardiologists, as the higher rates of MI would be a measure of progression of CAD; these may not occur in the surgery patients, as more diseased vessels would be bypassed. He states that these events would not be MI in the left main (as these would be fatal), but elsewhere in the vasculature. The findings support the superiority of CABG to stenting, while all cause mortality was similar between the two groups.

Dr. Cohen highlighed some issues with the EXCEL trial: trial took place in Scandinavia, which typically has lower rates of stenting; the first 10% of patients received first generation stents, with the remaining population receiving the Biomatrix biolimus stent (uncertainty around its performance); and, IVUS might not have been used as well as it could have been to optimise stent performance.

Dr. Cohen provided a summary showing the current treatment recommendations, comparing European and American guidelines. He highlighted that the Europeans provide a "1B" recommendation for PCI in low complexity cases (Syntax score <22), and the US guidelines provide "IIB" support for the same. He stated that it remains unclear whether the European guidelines will change as a result of the available NOBLE results; this decision may have to wait until the 5-year results are available. However, it would be reasonable for the PCI-Intermediate score recommendation to be upgraded from a IIB to a IIA. He noted that a Class I recommendation usually requires multiple concordant trials, which is not the case here.

Dr. Cohen reiterated that the existing 2014 Canadian statement on multi-vessel revascularisation is still valid, as it highlights that an individualised approach is appropriate, depending on patient specific factors, and that patients should be made aware of both historic and more recent evidence regarding the selection of treatment modality. He further re-emphasized that guidelines do not tell the clinician what to do in the vast majority of patients, as they will only be suited to one or the other treatment.

Discuss the EXCEL and NOBLE studies in the context of the DES used, and how the use of newer generation DESs may affect the decision between PCI and CABG. NOBLE used mostly a biolimus stent and EXCEL using Xience V, an everolimus stent. Registry data showed that although there is a difference between 1st and 2nd generation stents in treatment of LM (with the latter being more effective), both the stents in these trials were essentially 2nd generation, and Dr. Cohen did not expect there to be a difference.
Discuss the role of patient preference in the LM revascularization approach.
Is the need for DAPT expected to impact patient preference?

Dr. Cohen emphasized that for most patients, the choice between PCI and bypass is clear (inputs to this decision include anatomic, comorbidities, diabetes, disease diffusion). If stenting is appropriate, the last consideration is whether the stent is indicated for use in the left main coronary artery.

The ability to shorten DAPT is not a consideration in choosing PCI or surgery, unless the patient must have PCI and also has other comorbidities that require a shortened DAPT period. Patient preference, specifically around stopping DAPT sooner, is not typically used to determine the appropriate treatment choice between CABG and PCI, but instead, patient necessity is an important factor. DAPT should not be stopped earlier; if it needs to be stopped, it is stopped due to medical necessity. Patient preference between surgery and PCI can be considered, and is part of the overall discussion, depending on the situation.

What should HC accept as reasonable indications for use, contraindications, warnings and precautions for PCI devices indicated for revascularization of Left Main disease and unprotected LM disease?

Dr. Cohen presented an example of stent indications from its IFU, which state that the stent is intended to improve luminal diameter. Further, he stated that the precautionary statement ("safety and effectiveness...have not been established…for the following coronary disease patient populations…) applies to numerous patient subgroups that clinicians stent every day. Left main patients represent one of these subgroups. Dr. Cohen pointed out that clinicians may be more cautious about treating LM patients than some of the other conditions, not because data has not been collected on a particular stent model, but because the data that has been collected on PCI versus surgery for these patients is still equivocal.

Dr. Cohen recommended that manufacturers could include LM in the indications and/or remove the precautionary statement caution on LM, if the manufacturer is able to provide RCT or registry data which shows the stent thrombosis and TVF at 1 year is non-inferior (using the same or similar non-inferiority margin as in the EXCEL trial) to other stents in the same location, or to the same stent in another location. He also recommended that a warning be retained in the labelling regarding the use of ancillary techniques. He added that reasonably low rates of stent thrombosis and TVF in LM registry data at 1 year could also be evidence of acceptable performance, especially in the case of a stent that is already licensed and used in locations other than the LM.

Dr. Cohen stated that, notwithstanding the above recommendations, he did not think that changes in labelling or indications would directly affect clinical practice.

Is longer, high-quality follow up data required?

Dr. Cohen stated that 5 years, and even 10 year data, would be ideal. His standard of care: patients that are young enough, with good targets and no significant comorbidities and a "10 year horizon" opt for surgery. If the outcome curves continue to separate (i.e. PCI demonstrates higher rates of revascularisation (NOBLE) or death/stroke/MI (EXCEL)) he expects the standard of care to remain unchanged, arresting any momentum towards increasing the use of PCI in LM patients. However, if the curves do not continue to separate, then there may be a change in practice. Regarding stent sizes and a LM application, there are already stents available large enough to accommodate the LM location.

Dr. Cohen also highlighted the importance of operator experience in the outcomes in LM PCI, and presented data which showed that patients with high volume operators had much better outcomes than those with lower volume operators. This difference was maintained even when the high volume operators had higher complexity patients.


The committee discussed EXCEL and NOBLE, in particular the observation that the trials are actually showing the same outcomes, rather than conflicting, but that this is masked due to the use of different endpoints. Surgery can be seen as having a more stable outcome overall. On the other hand, if the only target is LM, a stent will keep it open. What stenting doesn't address the issue, this is an indication that the disease progression is elsewhere. Other factors discussed included the observation of strong patient preference for less invasive treatment, especially when absolute outcome endpoints (rather than relative) are compared.

Key Messages / Evaluator Summary
Recommended indications for PCI devices used for LM revascularization, and clinical data requirements to support: [Based on evidence available from EXCEL and NOBEL trials – 5-year data pending]
- Reasonable to include LM in the indications and/or remove the precautionary statement caution on LM, if the manufacturer is able to provide RCT or registry data which shows the stent thrombosis and TVF at 1 year is non-inferior (using the same or similar non-inferiority margin as in the EXCEL trial) to other stents in the same location, or to the same stent in another location. Also, reasonably low rates of stent thrombosis and TVF in LM registry data at one year would also be evidence of acceptable performance, especially in the case of a stent that is already licensed and used in locations other than the LM.

8. Antiplatelet Regimen for Drug-Eluting Stents

Dr. Kevin R. Bainey, Guest Speaker

In 2018 the CCS/CAIC published the Focused Update of the Guidelines for the Use of Anti-Platelet Therapy. The original Guidelines were published in 2007 with three updates since. This document discussed the recommendation for the duration and type of anti-platelet therapy for patient having PCI in the setting of Acute Coronary Syndrome (ACS and NSTEACS) and non-ACS. The Summary recommendations can be found on the Canadian Cardiovascular Society websiteFootnote 3.

IFUs reference CCS clinical guidelines, and refer to DAPT for stents. Three updates have occurred since 2007. Patients that received a DES should receive DAPT for at least 12 months. Dr. Bainey highlighted the recommendations from the focused update, and described the following two supportive studies:

A meta-analysis of studies that included more than 33,000 patients with prior MI, DAPT reduced major adverse events, myocardial infraction, and stroke and cardiovascular death with an increased incidence of bleeding, but not fatal bleeding. The new recommendations in the guideline document are evidence based, and include patient factors associated with a benefit in extending DAPT: previous MI; diabetics; CKD; prior stent thrombosis; and, angiographic features (e.g. multiple stents, multiple lesions lengths, "CTOs", LM and proximal stenting). Also, demographic and clinical features that can be used to identify higher bleeding risks are identified.


It was therefore recommended that for PCI in the setting of ACS that DAPT be used with ASA and ticagrelor or pasugrel (preferred over clopidogrel) for 1 year. At 1 year with a patient not at high-risk of bleeding DAPT should be continued for up to 3 years with ASA and ticagrelor 60mg BID. In patients at high-risk of bleeding, single anti-platelet therapy was recommended with ASA or clopidogrel. Dr. Bainey stated to treat the ACS and the burden of disease, and not to just save the stent.

For patients undergoing (elective) PCI with stable ischemic heart disease (non-ACS) with a 2nd generation DES, the recommendation minimum is 3 to 6 months of DAPT with ASA and clopidogrel. In patients who have additional high-risk clinical or angiographic features, and are at low-risk of bleeding, it is considered reasonable to extend DAPT to 1 year or greater. For those at high risk of bleeding, DAPT should be used for a minimum of 1 month with BMS and 3 months minimum with DES.

Question Response/Discussion
Should the 2018 CCS Guidelines be adopted and incorporated into the Directions for Use for future stent products (Warnings)?

Dr. Bainey indicated there is good evidence to support the DAPT recommendations of the CCS/CAIC. Dr. Bainey added that Scar registry data is ideal for after the fact (after RCT) data, with 100,000 people that received stents showed a reduction in CV death and thrombosis.

PCI in the non-ACS patients. Randomized studies/meta-analysis that tested shortened vs. regular DAPT, and the majority of these patients have 2nd generation DES. No difference in mortality between shortened and regular DAPT duration, reduction in bleeding, but no difference in MI, or no difference in ST. This is the primary reason why 6 months of aspirin + clopidogrel is supported. 1 month of DAPT for BMS, is based on scant evidence.

Should the comment, "need to carefully consider the benefits and risks on an individual patient when choosing between DES and BMS" now be removed? Dr. Bainey indicated that those comments should now be removed, and suggested they be replaced with "need to carefully consider the risk and benefits in an individual patient when choosing the duration of DAPT with current/second generation DES." Dr. Bainey reiterated that meta-analyses indicate the BMS should not be used. With cardiac death as the clinical endpoint. DES is superior to BMS, as is the case for MI/fatal MI, and ST. EXAMINATION trial (STEMI) BMS vs. Xience showed dramatic reduction in ST with DES, and TLV also improved. Also, Network meta-analyses (Morini) shows that in definite ST, DES was superior to BMS. Death was lowest with DES, which also showed superiority of 2nd generation.
What information would be required to support a change in duration / type of antiplatelet therapy for a given licensed device? Dr. Bainey suggested that to support a change in type / duration of anti-platelet therapy a large scale RCT with hard clinical endpoints is required, because treatment of ACS is so good that event rates are low; therefore, a large number of patients is needed for comparison, with robust clinical endpoints. Clinical endpoints that are appropriate for studying DAPT duration should be included.


A participant indicated that the DES are so good, it's the biology/disease that's being treated not the stent. They asked what happens with patients that come in with stable disease and have a stent. Are these patients upgraded at 1 year?

Dr. Bainey indicated that based on the current evidence, a tricagrelor based strategy is not recommended; it is still an aspirin + clopidogrel is supported for those patients. In an ACS setting - treatment is of the ACS not the stent. For new stents with shorter durations, 6 months of usage may be possible.

There was some discussion about the evidence available to support 1 month DAPT with BMS.

Dr. Bainey described two trials that LEADERS FREE RCT trial – used the Biolimus A9 stent, and assessed the feasibility of 1 month DAPT vs. BMS. Primary endpoints: death, MI, or ST; clinically driven TLR (surrogate endpoint). 1 month was good. The Biolimus A9 was superior. (only 1000 patients in each arm). Dr. Bainey also described the GLOBAL LEADERS trial – 16000 patients (acs+stable) using the Biolimus A9, that studied 1 month of DAPT with aspirin and ticagrelor, and following one month with ticagrelor alone vs. std care of aspirin + ticagrelor/clopdogrel for 12 months, and then to aspirin alone. Primary endpoint: all-cause death, non-fatal MI. Bleeding as a secondary endpoint. Results are not in yet.

A participant indicated the likelihood of obtaining RCT data to support a new license application is low, and that the information provided by the GLOBAL LEADERS trial is difficult to extrapolate to the gold standard DES.

Dr. Bainey responded by saying that GLOBAL LEADERS study should answer the question whether 1 month DAPT is feasible. He also suggested that he expects to see much more future RCT data for 3rd vs. 2nd generation DES.

A participant indicated that ¾ of patients are ACS and will get a year of DAPT. Bleeding is largely seen in the first month, so there's not much concern following the one-year guidance if there aren't any concerns of bleeding.

A participant suggested that there might be a challenge in addressing special labelling of a stent (e.g. stent approved for 1 month of DAPT).

Key Messages / Evaluator Summary
2018 CCS Guidelines be adopted and incorporated into the Directions for Use for stents: - There is supportive evidence (DAPT and Pegasus trials)
- For ACS:

DAPT be used with ASA and ticagrelor or pasugrel (preferred over clopidogrel) for 1 year. At 1 year:

  • with a patient that are not at high-risk of bleeding, DAPT should be continued for up to 3 years with ASA and ticagrelor 60mg BID.
  • with patients that are at high-risk of bleeding, single anti-platelet therapy was recommended with ASA or clopidogrel.

- For Stable Ischemic Disease:

For patients undergoing (elective) PCI with stable ischemic heart disease (non-ACS) with a 2nd gen DES, the recommendation minimum is 3 to 6 months of DAPT with ASA and clopidogrel. In patients who have additional high-risk clinical or angiographic features and are at low-risk of bleeding it is considered reasonable to extend DAPT to 1 year or greater. For those at high-risk of bleeding, DAPT should be used for a minimum of 1 month with BMS and 3 months minimum with DES.

Recommended labelling changes: - Removed references to choice between BMS and DES
- Include the statement, "need to carefully consider the risk and benefits in an individual patient when choosing the duration of DAPT with current/second generation DES."
Clinical data required to support different DAPT recommendations: - Large scale RCT with hard clinical endpoints.

9. Interatrial Shunting for Pulmonary Arterial Hypertension (PAH)

Dr. John Granton, Guest Speaker

Dr. Granton joined the meeting via teleconference to give his presentation titled "Atrial Septostomy for PAH". Specifically, Dr. Granton's talk covered 1) physiological rationale for atrial septostomy, 2) hemodynamic benefits (atrial septostomy), 3) candidate selection, and 4) endpoints (for clinical studies on interatrial shunting devices/procedure).

PAH is a clinical condition characterized by pre-capillary pulmonary hypertension (mean pulmonary artery pressure ≥ 25 mmHg and pulmonary artery wedge pressure ≤ 15 mmHg). According to World Symposium on Pulmonary Hypertension (JACC 2013;62:D34), PAH can be classified into five categories as shown below:

  1. Pulmonary arterial hypertension
  2. Pulmonary hypertension due to left heart disease
  3. Pulmonary hypertension due to lung diseases and/or hypoxia
  4. Chronic thromboembolic pulmonary hypertension (CTEPH)
  5. Pulmonary hypertension with unclear multifactorial mechanisms

It is of note that the definition and classification of pulmonary hypertension has evolved in recent years.

Dr. Granton provided a brief overview of the pathophysiology of PAH and reviewed the standards of care for patients with PAH and the treatment goals. The pathological basis of PAH are lesions that generally affect the distal pulmonary arteries, which are characterized by medial hypertrophy, intimal proliferative and fibrotic changes, adventitial thickening with perivascular inflammatory infiltrates, complex lesions, (plexiform, distal lesion), and thrombotic lesions. Standard-of-Care of PAH includes drug therapy, lung and heart-lung transplantation, and balloon atrial septostomy (BAS). There has been progress in recent years in the drug therapy owing to better understanding of the pathophysiology and signaling pathway in PAH.

Currently approved treatment options for PAH have good correlation to the pathophysiology of PAH. Survival by change in different risk group is also summarized. The prognosis of patients with PAH is generally very poor. Studies have shown that a combination therapy has resulted in improved clinical benefits compared to monotherapy. The outcomes of the treatment of PAH are directly correlated to the performance of the right ventricle (RV). This is measured as the functional capacity, BNP, 6MWT, etc. These measurements can show improvement of patient condition. Pressures are not as an important measure as the ventricle fails. In recent pharmaceutical trials, composite endpoints have been used, including mortality, hospitalization, etc. There is limited mortality benefit with interventions in PAH patients. Some reduction in hospitalization and some improvement in quality of life have been observed.

Question Response/Discussion
Please discuss the rationale for creating a right to left shunt for treatment of PAH. Specifically, considering the differences in hemodynamics between pulmonary arterial hypertension and chronic congestive heart failure, discuss how a right to left shunt could affect the pulmonary artery pressure and pulmonary vascular resistance (PVR), thus resulting in clinical benefits.

Theoretically, by creating a right to left shunt (atrial septostomy), desaturated blood flows to the left side, decreasing right atrium (RA) volume, which has an effect on the right ventricle (RV) afterload. This gives a net improvement in cardiac output and oxygenation, and net improvement in stroke volume from left ventricle (LV). However, too big of a hole/shunt causes severe blood oxygen desaturation. This improves systemic blood flow.

Shunt size (hole) can determine the level of oxygen desaturation, and too large of a hole is associated with increased morbidity. As shunt flow increases cardiac output is increased, but is lost again if there is too much shunting – this highlights an 'ideal' size, which is associated with saturation at ~88%. During the procedure of atrial septostomy, the hole is slowly opened step-by-step to the "optimal size", by checking the hypoxic level after 24-48 hours.

Studies of the chronic effects for atrial septostomy have shown improvement in hemodynamics, RV function, RA volumes, and BNP. There have been no RCTs on atrial septostomy and the studies have been of highly selected patients. There are no long-term (3 year) outcomes, but survival data in these patients (although biased) was reported to be successful.

2. Please discuss how the hemodynamics, and the associated atrial and pulmonary pressures, are likely to change over time, both acutely and chronically.
3. How should the range of the pressure differences between the left and right atriums be considered for this procedure for a clinical trial design? How is the ratio of right-to-left interatrial flow measured post-procedure?
4. What are the risks related to interatrial shunting for PAH, e.g., decreased blood oxygen saturation, and thrombosis formation, worsening left ventricular function? n/a
5. How can the risk/benefit profile be assessed? What clinical endpoints should be chosen to assess the clinical benefits? How does survival weigh over the quality of life? Are there additional concerns for pediatric patients?

Dr. Granton recommended that during design of clinical studies on PAH, the following aspects should be considered: feasibility of the study should be supported by proof-of-concept; patients on transplant list and high mortality should be considered for enrollment; exercise capacity should be examined in addition to rest capacity; and, objective measurement of improvement in RV, e.g., function by volume, should be included.

Dr. Granton added that endpoints for possible future studies for this treatment should include: longer term data, survival, NYHA class, walk distance, BNP, RV function/RV volumes, quality of life, hospitalization, time to clinical worsening, death/transplant/hospitalization/escalation of therapy, hemodynamics, and quality of life.

Dr. Granton added that the size of the hole has to be known before implant. Not the same as septostomy where step-by-step dilation can be done. Therefore, a conservative approach may be to undersize so as not to generate too big of hole, but this may lose effectiveness. It was noted that fenestrated devices may have a small capacity to be dilated. There are differences between rest and exercise in shunt flow. None of the studies have been done with measurement during exercise. All studies were at rest, but this shows an improvement in functional capacity.

6. Can any conclusions be drawn as to whether right to left shunting, by any device or procedure, is feasible for the treatment of PAH? Is there a known population that will benefit? n/a


A participant asked why excessive diuresis does not achieve the same effect.

Dr. Granton indicated that up to a point, there are limits from cardio-renal syndrome, and the difficulty in mobilizing fluid, and these patients would be candidates for septoscopy.

A participant asked whether RV enlargement and RV interdependence are the primary criteria.

Dr. Granton suggested to only do this if RV dilation were demonstrable, and not with minor. This is country-dependent; most centers that have access to pharmacotherapies, unlike S. American countries where other intravenous therapies are unavailable (i.e. septoscopy may be their only available option). They had less severe patients, and did well with the procedure.

A participant asked when a shunt is created over time, whether RV stroke volume and output increase and what that does to pulmonary pressure.

Dr. Granton indicated the flow is balanced, and pressures are not concerning, as shunting leads to improved RV function; however, no long term – 3-year data are available. It may be true that higher pressure exacerbates pulmonary injury, but the improvement in RV function is thought to outweigh that.

A participant asked about the life expectancy of these patients.

Dr. Granton indicated these patients are NYHA functional III/IV patients. PAH patients have historically had a median survival of 3 years. Functional class is the strongest predictor. Risk/benefit is not there for Class I/II patients. The devices are attractive because they could prevent closure, but one doesn't know how big of a hole is needed. It would be advantageous to be able to modulate the size of the hole to meet the patients' needs.

A participant indicated that atrial holes are created in mitral interventions, in patients with PAH. They asked what the impact is of TR on shunting.

Dr. Granton said that leaving the ASD alone, the left to right shunting is helpful, in the presence of MR.

A participant asked about devices with a given diameter, and how sensitive specific sizing /patient size is to the effectiveness of a given diameter shunt/hole.

Dr. Granton was mostly concerned about undersized holes that would not be effective. He suggested that fenestrated devices are nice because they are somewhat adjustable, but negates the fenestrations. We're not confident in determining the correct size. Acutely you can cause severe hypoxemia if too large of a hole is made.

A participant asked what clinical endpoints should be chosen for effectiveness, and effects on survival.

Dr. Granton indicated that it was difficult to use transplant as an endpoint, but investigators can use symptoms, or exercise testing looking at VO2. Hemodynamic endpoints seem to be important: objective improvements in markers of RV function.

A participant asked if this is a bridging or palliative procedure.

Dr. Granton indicated it was both, for symptom relief and as a bridging procedure to transplant. If septostomy resulted in improved RV function, there may be a better result after transplantation.

A participant asked about paraodoxical emboli associated with shunting.

Dr. Granton indicated there is not much data on stroke or thromboembolic complications. There have been no reports of paradoxical emboli as adverse events in long term, but that doesn't mean it doesn't occur. Anticoagulation can be used to mitigate.

A participant asked about treatment strategies for patients with large holes and significant oxygen desaturation.

Dr. Granton indicated those patients have a high mortality rate, and that closure devices could be used.

Key Messages / Evaluator Summary
Potential indications: - Patients with PAH that are not hemodynamically unstable, not hypoxic, and whose right atrial pressure is between 10 to 20 mmHg (moderate RHF).
- Moderate to severe RV dilation and demonstrable RV dysfunction with RV-LV interplay.
- Class IV might be excluded due to high mortality risk (patients in NYHA Class III/IV have a median survival of 3.5-4 years.)
- Bridge to treatment, or palliative
Target patient population:
Comparator: - Atrial septostomy
Endpoints: - Symptoms, or exercise testing looking at VO2. Hemodynamic endpoints seem to be important: objective improvements in markers of RV function.
Footnote 1

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Footnote 2

N Engl J Med 2017; 376:1321-1331

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Footnote 3

(Canadian Journal of Cardiology 33 (2017) 1201-1205)

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