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

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.

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 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?

DISCUSSION POINTS

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.

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.

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.

DISCUSSION POINTS

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).

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).

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.

DISCUSSION POINTS

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.

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

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.

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.

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.

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.

DISCUSSION POINTS

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.

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.

DISCUSSION POINTS

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).

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.

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.

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.

DISCUSSION POINTS

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.