Welcome back to the Medical Technology Blog. Apologies for the lack of posts lately, busy times at Espicom, thanks for your patience. Today we have a detailed post taken from Espicom’s business publication, Cardiovascular Device Business, please read on…

Medtronic caps busy period for R&D with trial data from DES, pacemakers, heart valves and renal denervation study programmes

RESOLUTE US trial

According to two-year follow-up data from the RESOLUTE US trial, Medtronic’s Resolute drug-eluting stent (DES) maintains a powerful and persistent treatment option for a wide variety of patients with coronary artery disease, including those with diabetes mellitus.  The Resolute DES was approved by the FDA in February 2012, with a specific indication for the treatment of coronary artery disease in patients with diabetes mellitus.

The RESOLUTE US trial enrolled 1,402 patients across 128 US-based clinical trial sites. The two-year results among 1,359 patients include low rates of TLF (7.3 per cent), clinically-driven TLR (4.3 per cent), and def/prob ST (0.2 per cent). These results were achieved despite 34 per cent of the patients having diabetes mellitus, which typically drives higher event rates. Among the 474 patients with diabetes in RESOLUTE US, the Resolute DES showed low two-year rates of TLF (8.9 per cent) and clinically-driven TLR (5.7 per cent) and no def/prob ST (0.0 per cent).

Pooled analyses, provided by the worldwide RESOLUTE clinical programme, consisted of a large randomised controlled trial and a series of confirmatory single-arm studies involving nearly 250 sites in 32 countries. In total, the programme enrolled 5,130 patients who received a Resolute DES; about one third (n=1,535) of these patients had diabetes, a proportion that mirrors the US patient mix for percutaneous coronary intervention (PCI). For the pooled analyses related to safety and diabetes, two-year data on more than 5,000 patients from the RESOLUTE programme who received a Resolute DES were included. Individual trials, while designed for many composite endpoints, are often underpowered to show real differences for low-frequency, but clinically important adverse events such as ST.

The two-year update to RESOLUTE Pooled Safety showed very low rates of clinically-driven TLR (4.7 per cent) and def/prob ST (0.9 per cent), despite 46 per cent of the patients in the RESOLUTE programme being considered complex. Additionally, the two-year update to RESOLUTE Pooled Diabetes, which presents clinical outcomes in patients with and without diabetes who received a Resolute DES, shows consistently low event rates out to two years despite the higher-risk nature of the diabetes patient population.

In a separate development, two clinical trials relating to Medtronic’s Symplicity renal denervation system show that the treatment provides safe, significant and sustained blood pressure reduction for up to three years in patients with treatment-resistant hypertension. The system is not yet cleared for the US market, but has been available since April 2010 in certain parts of Europe, Asia, Africa, Australia and the Americas. The FDA granted Medtronic approval for the protocol for SYMPLICITY HTN-3, the company’s US trial of the Symplicity system, for treatment-resistant hypertension, in August 2011.

SYMPLICITY HTN-1 trial

Results from the SYMPLICITY HTN-1 trial showed sustained safety and effectiveness of renal denervation with the Symplicity system for up to three years, and results from the SYMPLICITY HTN-2 trial showed safe, sustained and significant blood pressure reduction one year following the procedure. Renal denervation therapy is a minimally invasive, catheter-based procedure that modulates the output of nerves that lie within the renal artery wall and lead into and out of the kidneys. These nerves are part of the sympathetic nervous system, which affects the major organs that are responsible for regulating blood pressure: the brain, the heart, the kidneys and the blood vessels.

SYMPLICITY HTN-1 is a series of pilot studies involving 153 patients at 19 centres in Australia, Europe and the US. Subjects in the trial maintained an average blood pressure reduction of -33/-19 mm Hg at 36 months (n=24) from baseline (p<.001) following treatment with the Symplicity system. An increasing proportion of patients who completed follow-up had at least a 10 mm Hg reduction in systolic blood pressure. At six months 71 per cent of patients were classified as responders, which increased to 100 per cent among the patients who completed three year follow-up. There was no evidence of renal impairment, no patients were hospitalized due to hypotension, and no procedure-related serious adverse events were seen.

The SYMPLICITY HTN-2 trial is an international, multi-centre, prospective, randomised, controlled study of the safety and effectiveness of renal denervation in patients with treatment-resistant hypertension. In total, 106 patients were randomly allocated in a one-to-one ratio to undergo renal denervation with previous treatment or to maintain previous treatment alone (control group) at 24 participating centres. At baseline, the randomised treatment and control patients had similar high blood pressures: 178/97 mm Hg and 178/98 mm Hg, respectively, despite both receiving an average daily regimen of five antihypertensive medications.

The one-year follow-up analysis included data from 47 patients initially treated, who at 12 month follow-up sustained their significant drop in blood pressure (-28/-10 mm Hg [p<0.001] from baseline) with no significant difference from the previously disclosed six month follow-up (-32/-12 mm Hg [p=0.16]). In addition, 35 qualified patients in the control group who received renal denervation six month post randomisation also showed a similar drop in blood pressure to the treatment arm at 6 months post procedure (-24/-8 mm Hg [p= 0.15] from 6 month treatment arm). Safety results were sustained with no significant decline in kidney function and no late vascular complications.

The Symplicity system consists of a flexible catheter and generator. In an endovascular procedure, similar to an angioplasty, the physician inserts the small, flexible Symplicity catheter into the femoral artery in the upper thigh and threads it into the renal artery. Once the catheter tip is in place within the renal artery, the generator is activated to deliver a controlled, low-power radiofrequency energy routine according to an algorithm that aims to deactivate the surrounding renal nerves. This, in turn, reduces hyper-activation of the sympathetic nervous system, which is an established contributor to chronic hypertension. The procedure does not involve a permanent implant.

ISSUE-3 study

In the area of pacemakers, Medtronic has released data from a double-blind, randomised study, ISSUE-3, which found that patients who suffered from fainting due to neurocardiogenic syncope had fewer fainting occurrences when treated with a Medtronic pacemaker. The data showed a statistically and clinically significant 57 per cent relative reduction of fainting recurrence in patients at two years. In the study, patients at high risk for syncope recurrence (asystolic neurally-mediated syncop) were identified through the use of Medtronic’s Reveal range insertable cardiac monitors (ICM), thereby allowing physicians to determine which patients could benefit from a pacemaker implant.

While a previous observational study, ISSUE-2 (International Study on Syncope of Uncertain Etiology-2), showed that the use of an ICM effectively diagnosed asystolic syncope, thereby leading to effective treatment outcomes, the ISSUE-3 study was needed to confirm these results through a more rigorous, randomised controlled trial. The ISSUE-3 study was conducted at 51 centres in Western Europe and Canada in two phases: a screening phase, followed by a treatment phase. From September 2006 to November 2011, 511 patients met the inclusion criteria and received a Reveal device to assist with the diagnosis of each patient’s syncope.

Results of the ISSUE-3 trial showed that fainting re-occurred in 185 of the 511 study patients (36 per cent) and was documented by the ICM in 141 (76 per cent) of these patients. The Reveal ICM diagnosed 51 per cent) of patients with reoccurring fainting as an asystolic event, indicating them for a pacemaker and making them eligible for the treatment phase of the study. These patients received a dual-chamber Medtronic pacemaker and were randomised 1:1 (pacemaker on and pacemaker off). The treatment phase showed significant reduction in recurrence of fainting in patients who received Medtronic pacemaker therapy. For patients receiving pacemaker implants, the fainting recurrence rate was 25 per cent when the pacemaker was turned on and the fainting recurrence rate was 57 per cent when the pacemaker was turned off.

Medtronic pacemakers are currently indicated for use in patients who have experienced one or more of the following conditions: symptomatic paroxysmal or permanent second- or third-degree AV block, symptomatic bilateral bundle branch block, symptomatic paroxysmal or transient sinus node dysfunctions with or without associated AV conduction disorders and bradycardia-tachycardia syndrome.

Meanwhile, the largest international, prospective, single-arm clinical trial evaluating Medtronic’s CoreValve system in patients with severe aortic stenosis who are at high-risk for surgical aortic valve replacement (SAVR) showed that, in a real-world setting, patients experienced high procedural success combined with positive clinical outcomes. The CoreValve system is currently limited to investigational use in the US, but has been CE marked since 2007 for treatment of patients deemed at high or extreme risk for SAVR.

ADVANCE study

The CoreValve ADVANCE study displayed survival rates of 95.5 per cent at 30 days and 87.2 per cent at six months, which are consistent with previously disclosed data from national registries in Europe. The procedural success rate was 97.8 per cent, and overall complication rates were low with stroke rates of 2.9 per cent and MACCE rates of 8.3 per cent at 30 days. Patients in the study experienced significant improvement in valve function (mean gradient decreased from 45.6 mmHg at baseline to 9.3 mmHg at 30 days).

According to Medtronic, the study is one of the largest multicentre transcatheter valve trials to date, with 1,015 patients (mean age of 81 years) consecutively treated at 44 transcatheter aortic valve implantation (TAVI) centres across 12 countries. Clinical endpoints in the trial were calculated according to Valve Academic Research Consortium (VARC) standardised definitions. All data were independently monitored, all adverse events related to the primary endpoints were adjudicated by an independent Clinical Events Committee (CEC) consisting of experienced cardiac surgeons and interventional cardiologists, and all cerebrovascular events (including stroke and other events) were adjudicated by an independent neurologist using neuroimaging and systematic NIH Stroke Scale assessments.

This article was taken from Cardiovascular Device Business, edited by Lawrence Miller, Espicom’s medical newsletters team leader.

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Medical Industry Week News

It’s good news this week for some of the biggest medical imaging companies

GE Healthcare, Siemens Healthcare, Philips Healthcare and Toshiba Medical Systems – with all four receiving tentative backing for their respective next-generation cardiac CT scanners in draft guidance drawn up by the National Institute for Health and Clinical Excellence (NICE) in its latest draft guidance on the subject.

Now available for a period of public consultation, the draft guidance specifically applies to the use of the Somatom Definition Flash CT scanner (Siemens), Aquilion One (Toshiba), Brilliance iCT (Philips) and Discovery CT750 (GE) in the NHS in England for people with suspected or known coronary artery disease (CAD) in whom imaging is difficult with earlier generation CT scanners. A review team looked at 24 studies, with the vast majority (20) using Siemens’ Somatom Definition Flash (1) or an earlier model, Somatom Definition (19). Interestingly, despite its glowing endorsement only two of the studies referenced actually used the cutting edge CT scanner technology. In 2007, CAD was estimated to have claimed 91,000 deaths in the UK.

CT scans are performed to evaluate the arteries of the heart, and can also be used to assess the function of the heart, the anatomy of the heart, and the degree of coronary calcification in the heart. The technology survived a review of five recognised models for assessing the cost effectiveness of next-generation cardiac CT scanners, including the Europa model, for the prognosis of people with CAD, and the York Radiation Model, which estimates the impact of imaging in terms of radiation dose on cancer mobidity and mortality.

The recent NICE clinical guideline on chest pain recommends CT coronary angiography and invasive coronary angiography to assess the state of arteries and identify significant narrowing in people with an estimated probability of coronary artery disease of 10 to 29 per cent and a calcium score of <400 or less. People with a calcium score >400 are considered difficult to image using earlier generation CT technologies. Other reasons that make CT imaging difficult are obesity, arrhythmias (irregular heart beat), high heart rates (above 70 beats per minute) or previous coronary stents or bypass grafts.

The latest generation cardiac CT scanners have technical features that aim to overcome these difficulties, including the ability to acquire images much faster than earlier generation CT scanners, better image quality and reduced radiation doses. The NICE guidance recommends the use of these scanners for first line imaging of the coronary arteries in people with suspected stable coronary artery disease who are difficult to image with earlier generation CT scanners and whose estimated probability of having CAD is 10 to 29 per cent. In addition, the draft guidance recommends their use in people with known CAD for first line evaluation of disease progression to establish the need for revascularisation where imaging with earlier generation CT scanners is difficult.

Imaging companies will not quite be celebrating at the moment as final guidance on this topic is not expected until the new year, but they will be quietly confident that there is now a recognised need for the technology within the National Health Service in the UK.

In today’s post from The Medical Technology Blog, I’m covering a couple of articles from my home country, the UK. The first article concerns the coronary stent market, which has had its fair share of difficulties over the years.

Bare Metal Stents were first developed in the mid 1980s and gained wide clinical use throughout the 1990s, but while they were successful in the treatment of coronary artery disease, they also had problems of their own, and were found to cause the growth of scar tissue within a stent.

By the turn of the new century, manufacturers began to develop stents that also included a polymer from which pharmaceuticals could be released called drug-eluting stents, to reduce the inflammatory response of the body to the stent. Again, safety fears arose when long-term clinical data indicated a small risk of late stent-thrombosis. Questions have also been raised on the cost-effectiveness of drug-eluting stents, with bare metal stents still being advocated for certain cases on cost grounds. Please read on to find out how the stent business is moving on…..

Arterius, a UK-based medical device company, is seeking a £3 million investment to fulfill its plans to bring the first biodegradable coronary stent to the worldwide market. Arterius is one of only a handful of companies developing this technology, which is set to significantly cut the cost of heart disease treatment in the UK and worldwide.

Coronary stent technology has been developed over the years from the bare-metal stent, which has a 30 per cent failure rate, to the most recent invention, the drug-eluting stent. However, this latest technology is claimed by some to be flawed as blood clotting can still occur. A fully biodegradable stent is now being considered to be the answer to these problems and Arterius’ work could have a major impact on patient well-being, as well as the overall cost of treatment.

The development work is being led by Kadem Al-Lamee and Alistair Taylor, with support from three UK universities. Prototypes will be developed by Professor Phil Coates and his team at the University of Bradford, IRC in Polymer Engineering. The company is hopeful that the patented technology will enter Phase I trials by 2014.

Founders of Arterius, Kadem Al-Lamee and Alistair Taylor joined forces in 2009 to combine their experience in the stent industry to design a new product. Taylor was co-founder and chairman of Lombard Medical, which bought Al-Lamee’s company, Polymed, in 2001. Taylor was also the CEO of Schneider, which developed the first ever stent.

Elsewhere…

A new study conducted by researchers at the Wake Forest University Baptist Medical Center indicates that chest pain may no longer have to mean a hospital stay, meaning there could be another option for diagnosing heart-related chest pain that costs less and, in some cases, allows the patient to return home the same day. The study is featured online and is scheduled to appear in a future issue of the Annals of Emergency Medicine.

Dr Chadwick D Miller, an assistant professor of emergency medicine and lead author on the study, explained that nearly half of the approximately six million people in the country each year who visit the emergency department (ED) with possible cardiac-related chest pain are categorised as “non-low risk” upon initial consult, and are therefore admitted to the hospital for further testing and evaluation. This tendency to admit immediately, however, leads to an over triaging of patients as only a small fraction of those admitted patients ultimately experience a serious cardiac event.

Current treatment guidelines provide the infrequently-used option of placing these patients with ‘non-low risk’ chest pain in an observation unit, where symptoms are monitored closely and care is delivered based on predetermined care pathways, while more invasive diagnostic testing is postponed until needed and there is an intense focus on efficiency.

For the current study, researchers randomly assigned 110 ED patients with chest pain to either “usual care,” involving admittance to the hospital, or care in an observation unit. Patients in the “usual care” group received a variety of tests typically used for diagnosing chest pain, including stress echocardiograms, cardiac MRI and cardiac catheterisations. For the patients in the observation unit arm, researchers brought in the use of cardiac MRI to provide diagnostics to an area that typically relies mostly on subjective decision-making by care providers.

I included that last article as a couple of years ago I was rushed by ambulance to A & E for a suspected heart attack, I felt foolish, and that I was wasting the time of all these busy people. I was in for 2 days and they wouldn’t let me leave until all tests proved beyond doubt that I hadn’t had an attack, god knows what it cost the NHS, any study that can eventually cut down on these ‘false alarms’ should be followed up.

That’s all from me for now, come back soon. Paul.

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