Summary of Lectures at ECC Lousanne Switzerland 17-19 June

Summary of lectures and presentation at the Endovascular Cardiac Complication Conference in Lousanne, Switzerland 17-19 June 2011.

Pondering on antiplatelet business
One of the much talked about issue these days is stent thrombosis. The risk of Stent Thrombosis is known to be highest with STEMI – 3%, 1.5% with UA/NSTEMI, 0.5% with stable angina patients undergoing PCI. In short there are three independent factors namely lesion, procedure and patient factors.
Lesion – lesion length, vessel diam, complex lesion, calcifications. PCI/procedure related factors are – mechanical, dissection, final MLD, hence procedure (eg stent) optimisation. Patient factors such as DM, RF, impaired LV, compliance, antiplatelet non-responders etc. Of note there had been marked reduction in the incidence since the introduction of clopidogrel, still 1.5-2% stent thrombosis in ACS/PCI (20% mortality).
It has long been known on the unreliable platelet inhibition with clopidogrel. Genetically, polymorphism of gene CYP2C19*2 was implicated with worse response to clopidogrel.
Clinical factors related to also have their influence– noncompliance, underdosing, drug-drug interaction, ACS, DM, HIGH BMI, RF, elderly
Some patients with mutation – have good response! Other factors present eg BMI, DM (genetic mutation only explains 10-15% of non-responders!).
Clinically phenotyping is better than genotyping for Stent Thrombosis prediction (ie non-responders vs responders).

Platelet testing (phenotyping)
Who should be subjected to platelet testing?
Good candidates:
STEMI
High risk NSTEMI
DM (prasugrel)
Prior stent thrombosis
Recurrent event on clopidogrel
Patient with CKD (Ticagrelor)

Poor candidates:
Elderly
Lower body weight
Prior stroke/TIA
Chronic OAC

Buonamici JACC – non-responders were shown to have higher event rate.
However, higher clopidogrel response (the very good responders) tend to have higher rate of bleeding complications!
ARCTIC – randomisation to no test vs test and open label dosing – awaited.
Someone asked about aspirin allergy. Very low incidence of true aspirin allergy, and in the case it is suspected, ‘aspirin desensitisation’ can be attempted, by giving small incremental doses
Question about resistance to prasugrel – Yes, some expert suggested 4% incidence. However, in the ‘switch’ study and from the data, when patients with high platelet reactivity switched to prasugrel, they consistently showed good platelet suppression.
Question about which platelet analysers to use – stick to the major ones that have been used in trials eg Verify Now, Multiplate

 
On the subject of thienopyridine
They are P2Y12 inhib. Clopidogrel is a prodrug. Subjected to :
Genetic polymorphism
Drug interactions, PPI
Slow onset
Variable inter-individual response
25% non-responders
Irreversible receptor binding

In PCI-CURE – 31% RR reduction in patients treated with clopidogrel.

Prasugrel
Irreversible binding.
Metabolism more efficient
Faster onset of action
No clinically relevant drug interaction or CYP genetic variants

Based on TRITON-TIMI 38 NNT – 46 to reduce primary endpoints (CV Death, MI, stroke) (Mainly non-fatal MI). Increased incidence of TIMI major bleed, NNT 167 to cause one serious bleed.
KM curve showed early separation after loading dose, consistent effect of maintenance dose in favour of prasugrel vs clopidogrel in TRITON TIMI.
In DES only, 64% RR (relative reduction) reduction in Stent Thrombosis (even very early).
In BMS patients, lower, 48% RR reduction in ST
Diabetic (absolute 4.8%) – benefit more, with no difference in bleeding complication
STEMI cohort also benefited most compared to the rest of cohort
Caution with Increased fatal bleeding
One group not to be given – prior TIA/stroke – no benefit!
>75 years or 75 y.o)
In NSTEMI prasugrel still better than clopidogrel, but more bleeding
Future trials: ACCOAST trial – optimal dosing of antiplatelets, MULTIPRAC

Endovascular cooling during primary PCI
Concept: endovascular cooling improves myocardial viability/reduces infarct size.
COOL MI trial & ICE-IT trial. Both negative – ?Only 1/3 reached <35C at time of reperfusion. In patients reached <35C before reperfusion, trend for reduction in infarct size seen
In animal studies hypothermia protects during ischaemia and against reperfusion injury – no effect when initiated after reperfusion, but it improves survival in cardiogenic shock
Combination hypothermia: cold saline, 1 Litre saline. Rapid cooling – core body cooling – can reach target within 5 mins.
RAPID MI-ICE trial – 20 patients presenting with anterior or large inferior STEMI. Used Philips innercooll endovascular system. Buspirone plus meperidine (avoid shivering) plus cold saline 1-2L. Place endovascular catheter in IVC. Then primary PCI done.
Control of shivering is essential – don’t let shiver – external warming, internal cooling – buspirone PO, pethidine/meperidine boluses
Result – 38% reduction in infarct size, 43% reduction in Troponin. No APO, HF, but trend for pneumonia
CHILL-MI trial – Shorter post reperfusion cooling to one hour. Primary efficacy – CMR & 6m outcome. Still ongoing.

A Referesher on Drug Eluting Balloon
Acetone as solvent plus iopromide as additive – low dose paclitaxel
PACCOCATH was the first trial on DEB – in Instent restenosis patients. Late Loss of 0.13mm. Higher Minimum Luminal Diameter (MLD) at 6m.
PEPCAD II – Used DES in ISR in BMS – Taxus vs DEB. DEB had better outcome, TLR 3 vs 20%
PEPCAD I – DEB in small vessel CAD, 72% DEB only, 28% DEB + BMS. Better LL with DEB alone (0.18 vs 0.67), better restenosis with DEB (5.5% vs 39.3%).
We should know about PEPCAD III and IV too.
PEPCAD III was rather an ambitious trial that had extended the usage of DEB beyond conventional. In fact you may consider PEPCAD III not a DEB trial, since it compared a Coroflex Deblue stent (which is a drug coated balloon with BMS mounted on it) to Sirolimus (Cypher). Therefore, it was no surprise that the result favoured that of Cypher – there was double late lumen loss and TLR in the Deblue group.
Then came the PEPCAD IV (comparison of DEB vs Taxus in diabetic patients – the methodology was in DEB group was DEB then BMS with no overlap). This study was carried out in Malaysia and Thailand, recruiting 84 patients. The result showed similar outcome between DEB group and Taxus, with a rather high LLL at 9 months, TLR (9 vs 10%), though a higher rate of cardiac death in DEB group (statistically non-significant).
The two latest trials are PERFECT STENT and PEPCAD-CTO. PERFECT study – combination of DEB and Endothelial Progenitor Capture stents vs EPC stents alone (n = 120). The result showed a better primary endpoint namely LLL in DEB group (0.34 vs 0.88), better binary restenosis (5.1% vs 23.2%) and TLR (4.8% vs 15.5%) favouring DEB/EPC combination. However, one serious question is: why compared DEB/EPC with EPC stent (instead of a DES), and second is the issue of cost – since combining a DEB and EPC stent easily double the cost of procedure comparing to a DES alone.
As for PEPCAD CTO study, it examined the role of DEB (plus BMS) versus Taxus DES in the treatment of CTO. Total MACE and TLR were identical, though lower LLL in Taxus group, and higher ISR in the DEB/BMS group. Again, a methodology question here is the way DEB/BMS combo applied – where they have done it the opposite of usual recommendation – the vessels were treated with a BMS first then DEB.
In conclusion – usage of DEB – undoubtedly in BMS ISR – has become a class IIa recommendation now, so there is no doubt about its value as proven by the data. In DES ISR, it is a question (there was a data comparing DEB vs limus). In small vessel disease, it’s interesting, as, if you can successfully treat the vessel with a DEB alone, then be assured that the long term result should be good. Lastly, bifurcation lesion is another interesting area. The German group recommendation has it that, to treat a bifurcation lesion with a DEB, the aim is to try avoid stenting completely – DEB applied to the branch first, followed by DEB to the main vessel.

SCIENCE BEHIND TRIALS
FEATURES OF PCI TRIALS
As with other interventions, there are unique features in trials involving PCI. One of these, we frequently unable to blind eg stent vs CABG – therefore loss of control
Caution is advised in interpreting trials that use surrogate endpoints. At least we have to carefully weigh the value of these surrogate to real clinical practice.
Composite endpoints: should be very clear. Some objective endpoints may be mixed up with subjective ones and then put together as composite. E.g – survival, MI, test results (eg LVEF) or subjective? Eg TVR,QOL. …decrease TVR – not necessarily better! Therefore use of hierarchical endpoints is recommended.
Example of Differing interpretations of the SYNTAX trial very dependent on who interpret the trial!
Cardiologist – though failed to achieve endpoint, offering optimistic outcome, hence, up to patient to asses diff risk. As for the Surgeons – CABG is superior!

REVEAL – erythropoietin in STEMI – unclear basis – 5 previous failed trials. Negative results – outcome based on infarct size on CMR.
Comment – negative result predictable– probably should not have been performed!
• Insufficient preclinical evidence!
• EPO at >3hrs after PCI ineffective – too late
• Excess of serius adverse events
• Excess composite of death, MI, CVA or ST – harm to patients
R Bolli – clinical trials not based on rigorous preclinical evidence, thus premature
Suboptimal methodology in preclinical trials – discordant and not reproducible

GRAVITAS
Variability in plt inhib – at start mechanism unclear. It’s known that high on treatment plt reactivity linked with increase in CV events after PCI. However, in designing this trial, best cut off values of platelet reactivity unclear. There was no preclinical studies with similar design. Furthermore, no dose adjustment to reach PRU target.
It is already anticipated, based on other clinical data that platelet reactivity changes over time – this fact was ignored (no test during study). There was no data to support increased efficacy with high dose clopidogrel.Why not enrol only highest risk patients? ACS, DM

Antiplatelet & Anticoagulation in STEMI
Focused on HORIZONS AMI & ACUITY. Carefully controlled trials?
Non inferiority, open label, multiple randomisations, inconsistent ancillary drug use
Are they pragmatic trials?

Ultimate research goal should be to improve quality of care
10000 clinical trials published yearly in 2000 compared to 100 in 1970
We need clinical decision support systems – diagnosis and management of disease

Endothelial Function
(Amir Lerman, Mayo Clinic)
This brings us to the concept of ‘Vulnerable patients’ – it’s an established fact that coronary artery stenosis predicts the development of AMI, however the severity does not. For instance, >60% of patients have <50% stenosis.

Endothelium vs smooth muscle – Endothelial releases NO. Multifunction of NO
Platelet
Vascular smooth muscle relaxation
Smc proliferation
Leukocyte etc
In disease – endothelium lose ability to relax…
1989 endo function with exercise and mental stress – cor blood flow increase in response to exercise
L-arg – NO – GTP-cGMP - relaxation
1992 – reactive hyperaemia – endothelium dependent
1995 Anderson – FMD has correlation with coronary disease
Inject Ach in coro – vasoconstriction if endo dysfunction present
With DES – endo dysfunction (in segment)

Low risk FRS – microcirculation dysfunction – make them at risk
1995-97 Cor endo dysfunction in huma assoc with myo perfusion defect.

Coronary endothelial dysfunction and hyperlipidaemia assoc with diastolic dysfunction

ED – predictive of Stroke and TIA
ED markers of atherosclerosis progression and vulnerable plaque
Endothelial Progenitor cells

2000-04 ED and CV events (meta of 15 studies) – finding ED, whether coronary or peripheral – strong predictor of future events
Leads to understanding of systemic manifestation of ED

Assesment of ED to identify vulnerable patients – and predicting future events – even in patients who have disease already.

Endo-PAT test (Mayo Clinic – finger based assessment of ED)
Correlate with coronary circulation
Higher event is predicted in patients with ED by EndoPAT

CAD with ED – if ED persistent with therapy – predict more future event
May reclassify FRS from intermediate to high score

Conclusion: What I learned from this lecture is that endothelial dysfunction is a predictor of future CV events, in patients who have established disease (CVD). Finger based ED test as practised by Mayo Clinic has been shown to effectively correlate with event prediction. http://www.cardiorisk.us/endopat.php This may have some similarity with what we are doing here with PPG (Photoplethysmography).