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.
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.
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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