The PICSO system (Miracor Medical Systems, Vienna, Austria) attempts to improve myocardial perfusion by redistributing blood flow into the damaged microcirculation immediately following percutaneous coronary intervention for acute myocardial infarction. Using femoral access, the PICSO Impulse catheter is inserted on the venous site of the heart and intermittently inflated to increase perfusion pressure in the myocardium.
Prof. Piek is the principal investigator of the first-in-human pilot study, Prepare PISCO, which affirmed the diminishment of ischemia with PICSO (data are to be presented at the upcoming TCT meeting). Prof. Piek discusses use of the PICSO system and plans for upcoming clinical trials.
Why doesn’t primary percutaneous coronary intervention (PCI) solve all the problems caused by a ST-elevation myocardial infarction (STEMI)?
Primary PCI can restore epicardial reperfusion, but we do not know whether it provides adequate reperfusion at the myocardial tissue level. We are not informed about the improvement in the coronary microcirculation, although there is some ability to make a rough estimate in the cath lab to evaluate it. Three major parameters can be assessed directly after an intervention: ST-segment resolution, TIMI flow, and myocardial blush grade. At present, it is most likely we have inadequate myocardial reperfusion in about 25–30% of STEMI patients.
In the 25–30% of patients where these parameters are not optimal, what is typically done?
Most patients are pretreated with heparin, aspirin and clopidogrel. In some centers they use prasugrel, and in some centers, based upon the HORIZONS-AMI study, they use bivalirudin as an alternative, which is actually just as adequate as a combination of heparin in combination with a IIb/IIIa receptor blocker. So, in patients treated with primary PCI yet showing inadequate myocardial perfusion, most centers will just give a IIb/IIIa receptor blocker in addition to the present medication.
The PICSO system offers an alternative for these patients. Can you describe it?
The concept of pressure-controlled intermittent coronary sinus occlusion (PICSO) is actually based upon experimental data from about 20 years ago. Until now, a catheter that could be used in a clinical setting was not available, so PICSO has primarily been used in the setting of coronary bypass surgery, in order to augment cardioplegia for myocardial preservation. It also has a history of testing in experimental work to see if there is any additional value in the setting of myocardial ischemia and reperfusion in experimental models. Based upon these models, PICSO has a beneficial effect when treatment is installed for close to 90 minutes after reperfusion. It has hardly been tested in the setting of a coronary angioplasty model during cardiac catheterization. We actually began the Prepare PISCO trial a year ago, after Miracor developed the catheter-based PICSO system. The system was used during elective PCI in stable angina patients. Prepare PICSO concerned a safety and feasibility study to determine whether the catheter can be used safely and if it can be inserted within a certain timeframe. The goal was also to find out if this technique can be used in the setting of primary PCI.
The idea behind PICSO is that when the coronary sinus is occluded, it brings a marked increase in the coronary sinus pressure. We have demonstrated this in the elective PCI patients done in Prepare PICSO. The increase in the coronary sinus pressure is intermittent, because the circulation cannot completely be blocked; otherwise, you don’t have any flow. So, the coronary sinus occlusion is done intermittently. The perfusion at the venous site is increased, which translates into a mild increase in the coronary wedge pressure. Interestingly, the coronary wedge pressure increase was less than what I anticipated. I thought that the increase in perfusion pressure at the venous site would translate to a higher increase in coronary wedge pressure, but this was in the setting of stable angina, so it may be completely different in the setting of acute MI. We hope that flow redistribution may have a beneficial effect on border zones of the infarction area in the setting of primary PCI.
How is the catheter inserted?
Initially, it was thought that the catheter could be inserted through the subclavian vein or maybe through the jugular vein, which is always more easy for cannulation of the coronary sinus. However, electrophysiologists are now using guiding catheters that facilitate the use and insertion of catheters into the coronary sinus from the femoral approach. Most operators will use the femoral vein for the PICSO system, because the catheter is relatively large (9 French) in size. You cannot use the catheter from a jugular vein or a subclavian vein in primary PCI because it is too complex. In order to insert it in a rapid fashion, we tested catheter insertion using the femoral vein, because in the long run, this will be the easiest way to do it in primary PCI. The catheter needs to stay in place for at least 90 minutes, which is what we are now anticipating as the treatment timeframe. Of course, you cannot have the patient wait on the table for 90 minutes, so the patient will transfer from the cath lab to the coronary care unit. He or she has to stay in a supine position, comparable to what is done with an intra-aortic balloon pump, and we would like to keep the catheter in place for at least 1½ hours. We are still considering whether to expand the treatment to 3 hours, but that is something we have to figure out in the upcoming Prepare RAMSES trial, in order to see if that is possible.
There is an algorithm that is propriety to the device to adjust the pressure to the individual patient.
Venous pressure is most likely not very different between the different patients. Maybe there is a variation in the pressure buildup. That depends upon the catheter position. The pressure buildup may be different if you have the catheter occluding the exit of the coronary sinus or perhaps if you occlude more proximally, into the great cardiac vein or in the proximity of the great cardiac vein.
The PICSO system does include an algorithm guaranteeing that within certain pressure limits, the machine will shut off when you exceed the pressure buildup for, let’s say, beyond 60mm of mercury. There are certainly some additional measurements to do it in a safe fashion. We had some problems in the first patient because the system was so sensitive that as soon as the pressure increased, it shut off, and we had to repeat the whole procedure a few times. There were technical problems we had to face in the first couple of patients, but after some adjustment, I think we have equipment that is rather easy to use.
How long does actual insertion of the system take?
The mean value in the first patients was 12 minutes. We have had some variation; sometimes the anatomy is a little bit different such as the offset of the coronary sinus from the right atrium.
Are there any potential complications?
In elective PCI, insertion of the catheter has not been difficult. For an experienced operator, it is not a problem. The major challenge in the Prepare RAMSES trial will be to stabilize the catheter once the patient moves from the cath lab to the bed and is transferred to a coronary care unit. We will need to keep the catheter in a good position for at least 1½ hours. It is, of course, very easy to do with an intra-aortic balloon pump, but because there is a guiding catheter situated into the right atrium, there is certainly will be a learning curve. With PICSO, there is a continuous increase of the coronary sinus pressure due to the negativism of the intermittent balloon inflations. It is not completely certain if the catheter will hold a stable position in the coronary sinus. That is certainly something we have to demonstrate. When the pressure is increased, we can anticipate a gradient from the coronary sinus towards the right atrium, and as a result, there will always be a natural movement of the catheter into the direction of the right atrium. That is something we would like to avoid. I think the technical aspects of positioning will be a major aspect of the Prepare-RAMSES trial.
Where do things stand with the clinical trials?
We have done the first 15 patients (in the first-in-human Prepare PICSO trial) and hope to present the data at the TCT meeting in San Francisco this year. We are now very busy with the preparation of the Prepare RAMSES trial, which we hope to start in September. This trial will be done in multicenter setting that will include 3-4 centers (Amsterdam and a few centers in Germany). We hope to include close to 40 patients in the Prepare RAMSES trial. It depends upon what kinds of technical problems we encounter. Once that is successful, we would like to start somewhere next year (2012) with the RAMSES trial.
Are there other patient populations where you could theorize that this technology might be useful?
No, I think that the major indication will be STEMI. I do not see an indication that patients with unstable angina/non-STEMI coronary syndromes would benefit. If you look at coronary bypass surgery, that is something different. It is possible that for cardioplegia during coronary bypass surgery, PICSO could be an adjunct. It is relatively simple to insert into the coronary sinus and it may facilitate effective cardioplegia for myocardial preservation. Either by cardioplegia using retroperfusion or by a coronary sinus catheter in place that is providing retroperfusion in combination with antegrade cardioplegia through the aortic root. That is, I think, the near future. These would be the two initial indications.
Are you able to share any information about how PICSO may compare to the standard of care, i.e., the use of heparin and IIb/IIIa inhibitors or bivalirudin?
No, it is much too early. Of course, we hope, at least in the Prepare RAMSES trial, that we have some indication of its effectiveness. We hope to gain an idea of how the ST-segment resolution may be improved once we install the coronary sinus catheter. The Prepare RAMSES trial will give us further information on these aspects that will be tested in a randomized trial, RAMSES. In the Prepare RAMSES trial, we are going to look at the ST-segment resolution, TIMI flow, myocardial blush grade, etc., but also have an MRI measurement that will be a better endpoint. Nevertheless, if PICSO demonstrates benefit in the randomized RAMSES trial, it will be a major step forward in reperfusion therapy of acute MI.
How would pharmacotherapeutics be utilized with PICSO?
We would like to have the most optimal pharmacological approach. At the moment, patients are pretreated with a combination of heparin, aspirin and clopidogrel. Most likely it will switch to prasugrel or ticagrelor, but there are some centers using bivalirudin, based upon the results of the HORIZON-AMI trial. At the moment, there is a good argument that the most optimal pharmacological regimen would include bivalirudin during the acute phase, and then followed by prasugrel or ticagrelor during follow up.
Is there any data about the window of time for the system to provide benefit?
We would expect that the most beneficial effect would be within the first 6 hours after the onset of symptoms. In The Netherlands, the mean time from the onset of symptoms to reperfusion is, let’s say, between 2-3 hours. But there are other countries in Europe, such as Germany, where they are frequently confronted with patients who are relative latecomers, and who arrive between 6-12 hours after symptom onset. It could very well be that these patients may benefit from preservation of myocardial tissue, although to a lesser extent, because you have gone beyond 6 hours, which is considered the “golden” time period. Nevertheless, it could very well be that between 6-12 hours, PICSO is still beneficial. Therefore, in the Prepare RAMSES trial, patient inclusion will be up to 12 hours from the onset of symptoms.
Prof Jan J. Piek can be contacted at AMC Heart Center, Academic Medical Center, room B2-250, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands, or by email at firstname.lastname@example.org.