EuroPCR 2012 Press Release No 2 Friday 18 May 2012

On Friday 18 May, EuroPCR 2012 said farewell to all 11,387 participants from the interventional cardiology community, industry partners and journalists. Their support was hugely appreciated and contributed to another highly successful week in Paris during this special ‘Year of the Textbook’.

The PCR mission to serve the needs of each individual patient, by helping the cardiovascular community share knowledge, experience and practice, continues throughout the year across the globe:

• PCR London Valves: 30 September - 02 October 2012, London, UKGulfPCR-GIM: 12-14 December 2012, Dubai, UAE
• AsiaPCR/SingLIVE: 24-26 January 2013, Singapore
• AfricaPCR: February 2013 (exact dates to be confirmed), Cape Town, Republic of South Africa
• ... and then of course EuroPCR: 21-24 May 2013, Paris, France

The EVOLUTION trial

Junbo Ge presented the 1-year results of the EVOLUTION trial on Thursday 17 May at EuroPCR 2012. This multicentre, open-label, non-inferiority randomised study undertaken in 30 centres in China investigated the safety and efficacy of a sirolimus-eluting stent (SES) with biodegradable polymer (EXCEL) compared to a SES with durable polymer (Cypher Select). Concern still remains regarding the long-term use of durable drug-eluting stents, with debate over the risks of late stent thrombosis due to poor endothelialisation, possibly related to the polymer coating.

A total of 1,923 patients with de novo coronary artery lesions and diagnosis of stable angina, ACS or silent ischemia were randomised for implantation with either a SES with biodegradable polymer (n = 1,239) or a SES with durable polymer (n = 670).

Angiographic inclusion criteria dictated the presence of one or more de novo coronary artery lesions in at least 50% of native coronary arteries, with target lesions greater than 29 mm in length and reference diameter between 2.5 mm and 3.75 mm.

The primary endpoint was ischemia-driven target vessel failure within 12 months, which was a composite of cardiac death, myocardial infarction, and ischemia-driven target vessel revascularisation. Secondary endpoints included total lesion failure at 12 months, rates of stent thrombosis per ARC definition, MACE at 6 and 12 months and 2–5 years, and device and procedural success.

At 1-year follow-up, the SES with biodegradable polymer was comparable to the SES with durable polymer in terms of clinical efficacy and safety; TVF rates were 0.89% and 1.34%, respectively. Longer term follow-up, especially after cessation of antiplatelet therapy, will be necessary to elucidate any potential divergence in outcomes between these two different types of stents. More data will follow as the trial continues.

The SORT OUT V trial

Evald Høj Christiansen presented the 9-month results of the SORT OUT V Trial on Thursday 17 May at EuroPCR 2012. The objective of the trial was to compare the efficacy and safety of the biolimus-eluting Nobori stent and the sirolimus-eluting Cypher Select+ stent in an all-comer population.

After implantation of the sirolimus-eluting non-biodegradeable polymer coated Cypher stent the risk of restenosis is low, but the risk of stent thrombosis is a concern and stent thrombosis may be related to the polymer coating of the Cypher stent. The biolimus-eluting Nobori stent has a biodegradable polymer coating, and initial data indicate a low risk of restenosis and stent thrombosis after implantation. However, there are no large scale randomised comparison studies of Cypher and Nobori stents in all-comer populations.

In the SORT OUT V trial the primary endpoint was major adverse cardiac events (MACE) at nine months (composite of cardiac death, myocardial infarction, definite stent thrombosis and clinically-driven target vessel revascularisation). Secondary endpoints were the individual components of the primary endpoint.

The statistical assumptions used to plan and analyse the data are particularly important to consider. A non-inferiority design was used and it was estimated that the 9-month event rate in the Cypher group would be 0.03, a figure taken from the SORT OUT III trial, which is a very low figure. In some studies the margin for comparison stents has been set at 0.04 but with this low event rate anticipated it was decided to reduce this margin to 0.02. With a one-sided type I error of 0.05 and power of 90%, 2,400 patients would be needed to demonstrate non-inferiority.

In total, 2468 patients were enrolled and randomised with 1229 and 1239 entering the biolimus and sirolimus stent arms, respectively.

After nine months the cumulative incidence of MACE in the biolimus stent group was 4.1%. In the sirolimus stent group the rate was 3.2%, very close to the predicted event rate, which means that non-inferiority was not demonstrated (P = 0.06). Non-inferiority of the Nobori stent compared with the Cypher stent cannot therefore be excluded from these data. At 12 months, a superiority analysis demonstrated no significant difference in MACE - 5.4% and 4.5% in the biolimus and sirolimus stent groups, respectively (HR=1.22, [95% CI: 0.85 - 1.74]).

Whilst the statistics do not demonstrate non-inferiority of the biolimus stent, the event rates are nevertheless very low. Operator experience in the deployment of the older Cypher stent is much greater than with the newer Nobori stent, which may account for one divergence in the curves, which occurs very soon after implantation and is due to definite stent thrombosis. It is also possible that the beneficial effect of the biodegradable polymer will not become apparent until the results of longer term follow-up become available. Evald Høj Christiansen summarised: "We have a very early endpoint here and very low events rate and I cannot exclude that there is non-inferiority of the Nobori stent but these results may change at longer term follow up".

Non-invasive cerebral oxygenation monitoring may help improve outcomes in cardiac arrest patients

At EuroPCR 2012 on Friday 18 May, Cathy De Deyne described the first experiences of using non-invasive cerebral oxygenation monitoring during therapeutic hypothermia (TH) after cardiac arrest (CA) and posed the question as to whether this is a first step to a patient-tailored and goal-directed strategy.

Non-invasive cerebral oxygenation monitoring uses near infrared spectroscopy (NIRS); four wavelengths of laser infrared light penetrate the brain and oxygen saturation is measured at a depth of 3 cm within the cerebral cortex. A mix of arterial and venous oxygen saturations is measured and using the Fick principle, the calculated regional cerebral tissue oxygen saturation (SctO2) is used to reflect the adequacy of cerebral perfusion. The normal SctO2 range is 65-75% with an ischemic threshold of around 50%. Data collected during cardiac and aortic arch surgery has been used to validate this technique and it has been shown that cerebral oxygen saturation is related to neurological outcome. Therapeutic strategies geared towards improving cerebral oxygen saturation are associated with improved post-operative cognitive outcome.

Improved survival rate and neurological outcome after CA are achieved through TH and this neuroprotective effect is in part related to a reduction in overall cerebral metabolism. Within the cardiac surgery literature, there are data demonstrating that, using NIRS technology and saturation monitoring, hypothermic conditions (< 28˚C) are associated with an increase in SctO2. However, to date there have been no studies looking at the adequacy of cerebral perfusion in the early hours after CA, when TH induction to 33˚C has been achieved as early as possible after CA.

A single centre observational study commenced a year ago using non-invasive neuromonitoring in 28 out-of-hospital CA patients. Monitoring commenced immediately on arrival at the emergency department. Patients underwant therapeutic hypothermia, cathlab intervention and transfer to CCU for haemodynamic and multimodality-neuromonitoring. After discharge and at six months, patients underwent extensive neuropsychological testing. Mortality was 28%.

Hypothermia to 33˚C within four hours was achieved in all patients but non-survivors cooled down much earlier. This is probably becasue the thermoregulatory centre in non-survivors has already been damaged, enabling more rapid cooling.
It was surprising that the SctO2 decreased in the first four hours in all patients. Furthermore, there was a significant difference between survivors and non-survivors in that survivors showed a decrease but their SctO2 stabilised much earlier than non-survivors.

These observations were not explained by overall changes in the mean arterial blood pressure (MAP) but MAP values were lower in non-survivors, particularly in the first hour. In both groups, PaCO2 reduced from high levels over the first four hours. There was no change in arterial oxygen saturations in either group.

These data illustrate that in survivors and non-survivors, there is inadequacy of cerebral perfusion during induction of TH and this may be explained by the observed decreases in PaCO2, which cause intense cerebral vasoconstriction.
The observed differences between survivors and non-survivors may be related to the severity of initial brain damage but there may exist a 'window' of opportunity in these 'golden' early hours for therapeutic intervention to improve the cerebral outcome and survival rate.

In Cathy De Deyne's opinion, "The early management after cardiac arrest should not just include the heart but should also include a focus on the brain". She considered it important to achieve a MAP of at least 85-90 mmHg, normocapnia and adequate sedation, which in turn would optimise cerebral perfusion pressure and normalise cerebral vessel diameter and cerebral metabolism.

Emerging interventional technologies for treatment of resistant hypertension

Hypertension is a major public health concern affecting approximately one billion people worldwide, but only a third of these patients are adequately managed by existing medication. Blood pressure is directly associated with cardiovascular mortality: a 20/10 mm Hg increase in blood pressure leads to a doubling of cardiovascular mortality risk. In 2010, the Symplicity HTN-2 trial revealed marked reductions in blood pressure following renal denervation in hypertensive patients, prompting a surge of interest in this approach as a means of treating resistant hypertension.

Recent preclinical and clinical data on six new technologies aimed at reducing blood pressure via renal sympathetic denervation were presented at EuroPCR 2012 in a session entitled ‘Emerging interventional technologies for treatment of resistant hypertension’. Most of the techniques involve selective disruption of renal nerves by localised delivery of energy through an intravascular catheter. The major differences in these techniques are related to the form of energy delivered to the sympathetic nerves; radio-frequency (RF) energy, as delivered by the St Jude Medical EnligHTN catheter and Vessix Vascular catheter; ultrasound, provided by Cardiosonic TIVUS Technology and the ReCor Percutaneous Renal Denervation System; and radiation, as supplied by the Novoste’s Beta-Cath 3.5F System. In addition, Kona Medical is developing a non-invasive system that delivers low-intensity, focused ultrasound from outside the body.

“Devices based on RF energy, as used in the original Symplicity HTN-2 trial, are considered the most established of these techniques as they are already in clinical use for cardiac arrhythmia ablation”, commented the session Chair, Robert Whitbourn, of St Vincent’s Hospital in Australia. Indeed, using this modality in a study of 62 patients, Stephen Worthley of the Royal Adelaide Hospital, Australia found a significant drop in systolic blood pressure at one month after treatment (p<0.0001), with 78% of patients achieving at least a 10 mmHg reduction in systolic blood pressure. Similarly, Vessix Vascular’s renal denervation balloon catheter reduced systolic blood pressure by a mean of 30mm Hg within one month in a small study of seven patients.

Robert Whitbourn also considers ultrasound an energy source with great potential for renal denervation because it is relatively clean, but there remains a question mark regarding its ability to achieve selective injury to renal nerves.

Another question that triggers significant debate is whether renal denervation also has therapeutic potential in other diseases. Several conditions, including congestive heart failure, have been linked to sympathetic hyperactivity, and the potential of renal denervation to reduce sympathetic activity is established. However, most pressing for the development of these techniques is the need for clinical data in large numbers of patients. Currently, results have only been collected for approximately 250 patients. To this end, a global registry has been set up to collect data on renal denervation in 100 countries, which will provide a large body of real-world evidence to guide technology development. Randomised controlled trials are also required to compare technologies and to define the most appropriate energy delivery system to target renal nerves.