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Research
August 2013
Real-world data confirm safety of renal denervation system
Medtronic has revealed the first results from its global SYMPLICITY registry. It reported that the results affirm the safety of the Symplicity renal denervation system in a real-world patient population
A
mong the 617 registry patients with follow-up information avail- able for this first analysis, no ma- jor complications or serious adverse events related to delivery of radio frequency energy to the renal artery were reported. Of these patients, two experienced access site vascular complications immediately post procedure. There was a 9% incidence of renal vessel irregularity on angiography due to the application of radiofrequency energy to the vessel wall following the procedure; none interfered with brisk renal blood flow and all are believed to have resolved shortly after the procedure. While the primary endpoint of the global SYMPLICITY registry is to verify procedure safety with the Symplicity system, available data for the secondary efficacy analysis at six months showed renal denervation also has a significant reduction in both office and ambulatory blood pressure compared with baseline. Patients with systolic blood pressure of 180mmHg and diastolic blood pressure of 100mmHg had an average office blood pressure reduction of -30/-16mmHg (n=17) [systolic blood pressure p<0.0002; diastolic blood pressure p<0.0008] from baseline at six months. Patients with a sys- tolic blood pressure 160mmHg (or 150mm Hg in patients with diabetes) (n=114) had an average office blood pressure reduc- tion of -18/-9mmHg) [p<.0001]; average
blood pressure reduction for these patients who also had ambulatory blood pressure measurement (n=29) was -11/-4mmHg [p<.0001] from baseline. These data were presented at EuroPCR in Paris, France (21–24 May).
“These data speak strongly to the safety and efficacy of the renal denervation procedure with the Symplicity system; it is encouraging to see these positive results in a real-world setting,” said Felix Mahfoud, interventional cardiologist at the University Hospital Homburg/Saar, Germany. “The significant reductions in blood pressure seen in these patients could substantially reduce cardiovascular risk, as we know that in middle age even a 2mmHg decrease in systolic blood pressure can lead to a decrease risk of death from stroke by 10% and lower risk of death from ischaemic heart disease or other vascular cause by 7%.” Medtronic has also announced that it
has finished the randomisation process for Symplicity HTN-3, which is its pivotal US clinical trial of the Symplicity system. According to the company, the Symplic- ity renal denervation system is also one of the first medical devices to participate in the FDA and the Centers for Medicare & Medicaid Services (CMS) parallel review programme, which will allow the CMS to begin national coverage determination while the FDA completes its review of
Symplicity
safety and efficacy. Data from the Symplic- ity HTN-3 clinical trial will be a significant component of the parallel review. “The results of this study will provide the medical community with data that will not only further our understanding of the impact of renal denervation on treatment- resistant hypertension, but also potentially help bring a new treatment option to people in the US affected by this condition,” said George Bakris, professor of medicine and director of the ASH Comprehensive Hypertension Center at the University of Chicago Medicine and past-president of the American Society of Hypertension, and co-principal investigator of Symplicity HTN-3.
Symplicity HTN-3 is Medtronic’s first blinded, randomised, controlled trial designed to evaluate the safety and ef- fectiveness of renal denervation with the Symplicity renal denervation system in patients with treatment-resistant hyperten-
sion in the USA. The trial randomised 530 patients across nearly 90 medical centres in the USA to receive either renal denervation and treatment with antihypertensive medi- cations or treatment with antihypertensive medications alone.
“Because patients had to meet the most strict inclusion criteria of any renal denervation clinical trial to date, enrol- ment in Symplicity HTN-3 was at first challenging,” said Deepak L Bhatt, chief of cardiology, VA Boston Healthcare System, director, Integrated Interven- tional Cardiovascular Program, Brigham and Women’s Hospital and VA Boston Healthcare System, professor of medicine, Harvard Medical School, and co-principal investigator of Symplicity HTN-3. “The Symplicity HTN-3 study investigators and research coordinators should be recognised for their leadership in addressing initial recruiting challenges to complete this seminal clinical trial.”
Surrogate endpoints do not eliminate need for large-scale trials
ANDREAS BAUMBACH
COMMENT & ANALYSIS
Large-scale trials are required to show actual clinical benefit—ie. reductions in target lesion revascularisation and major adverse cardiac events (MACE)—of novels stents compared with drug- eluting stents. Therefore to allow moderate-sized trials to be performed, surrogate endpoints (such as late lumen loss) are often used instead. Andreas Baumbach states why he believes large-scale trials are still needed
W
ith the advent of drug-eluting stents for the treatment of symptomatic coronary artery disease, clinical efficiency endpoints have decreased to single digit figures. For example, in the most recent all- comers trials, the rate of target lesion revascularisation (defined as ischemia driven revascularisation of the stented vessel) was around 6% and the rate of MACE (including acute sent thrombosis
and death) was also very low. This development means that for any new stent platform, which has to have clinical safety and efficacy if it is to be introduced into the market, large patient numbers would be required to prove its non-inferiority or even superiority with regard to target lesion revascularisation or MACE. Hence, it has become com- mon practice to introduce new stents with moderately sized clinical trials
using proxy or surrogate endpoints—late lumen loss, stent strut malapposition and endothelial coverage of stent struts are frequently described at six, nine or 12 months’ time points.
In the context of drug-eluting stents, late lumen loss has been extensively validated and is the best surrogate of tar- get lesion revascularisation. Late lumen loss was seen to be lower in drug-eluting stents compared with bare metal stents and in comparisons, the large difference correlated well with significant differ- ences in target lesion revascularisation. However, when drug eluting stents are compared to each other, the smaller differences in late lumen loss do not always reflect clinically relevant differ- ences in target lesion revascularisation. While the absolute late loss is important in drug-eluting stents evaluation, the standard deviation or distribution of late lumen loss is equally important with narrower standard deviations reflect- ing more consistent results and wider standard deviations with rightward skew reflecting less consistent and possibly a signal of less effective effectiveness results. An additional limitation of this
surrogate endpoint is the lack of correla- tion between late loss and stent throm- bosis or other safety parameters. Post-procedural stent strut malappo- sition as documented by intravascular ultrasound and optical coherence tomog- raphy, has not been shown to directly translate into clinical events. The extent to which endothelial strut coverage at various time points after stent implanta- tion correlates to the risk of stent throm- bosis remains equally unclear.
Conclusion
Therefore while surrogate endpoints can give us an idea about efficacy and safety, and reports of low malapposition rates and high strut coverage might be reassuring, these parameters will not eliminate the need for larger scale trials that document the true clinical efficacy and safety of any novel drug-eluting stent. Only with adequately powered studies, in broader patient populations with longer term follow-up, will we be able to detect smaller but potentially relevant differences in target lesion revascularisation and adverse clinical safety events.
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