By Krishna Rocha Singh
I, like many others, am keen to understand why the US pivotal randomised sham controlled SYMPLICITY HTN-3 trial failed to meet its primary effectiveness endpoint. Given the established treatment effect from the SYMPLICITY HTN-1 and HTN-2 trials, I want to know if the failure was due to differences in trial design, patient cohort selection, the catheters used, operator experience or the introduction of a sham arm.
If the introduction of a sham arm resulted in the failure of SYMPLICITY HTN-3, I would like to know more about the veracity of the maintenance of the sham through the entirety of six months prior to and including the primary endpoint analysis. It would also be interesting to understand the duration of the sham effect beyond the six-month primary endpoint assessment.
Is there a class effect?
I would like to know, regardless of the issues of trial design and potential differences in cohorts enrolled in renal denervation trials, whether there is a “class effect” between use of mono-polar radiofrequency, bipolar radiofrequency and ultrasound thermal energy sources. Translational medicine models using pigs and human cadaver renal arteries would suggest that a depth of thermal penetration up to 4mm from the renal intima should ablate a sufficient number of renal efferent and afferent nerves, which should translate into a clinical benefit. However, given the ongoing concern of “non-responders” to the mono-polar radiofrequency therapy, it has to be considered whether another energy source (ie, bipolar radiofrequency or ultrasound) may provide deeper or more homogeneous penetration of ablative thermal energy and thereby ablate a larger number of renal nerves which may result in a blood pressure effect. Of course, this issue must be balanced by safety as thermal energy which reaches deeper into the renal vessel wall may also be associated with intimal damage as well.
From my experience…
I know the identification of pre-procedure predictors, beyond simply severe treatment resistant hypertension (>180 mmHg on ≥ 3 anti-hypertensive medication, one being a diuretic) will be critical to the continued growth of the clinical science. This is because there are an apparently growing number of patients deemed “non-responders” (patients who experience
Pre-procedure predictors are especially important because there is no intra-procedural feedback that signals to the operator that a successful and complete anatomic denervation has been performed. This means we must look to potential biomarkers or other surrogates.
Patient referral patterns
Having enrolled patients in both SYMPLICITY HTN-1 and HTN-3, it is my suspicion that the differences in patient referral patterns between the two trials may have resulted in different patient populations selected to undergo renal denervation. In speaking with my European colleagues, I understand that the vast majority of patients referred for renal denervation in both HTN-1 and HTN-2 came from European Society of Hypertension Centres of Excellence that employed a team approach to patient hypertension education and treatment. These patients were essentially “no option” patients in that they had exhausted all pharmacological therapies in treatment of their resistant hypertension and were, importantly, likely on stable and consistent therapy prior to trial enrolment. Importantly, in both HTN-1 and HTN-2, patients were required to be on minimally six weeks of stable therapy ensuring a consistent and stable medication regimen. This is different from the HTN-3 trial where, theoretically, patients could have their medications “up-titrated” in an attempt to “optimise” their medical therapy. Theoretically, this could have selected a very different patient cohort. Importantly, waiting two weeks prior to trial enrolment and subsequent randomisation, as required in SYMPLICITY HTN-3, may have been an insufficient time to fully realise the full pharmacological effect of medication up-titration. This may represent an important variable between these trial designs and has potentially impacted their results.
The role of catheters
Given my experience using the Flex catheter and Arch catheter, I perceive them to be very different in their feel and ability to manipulate in the renal artery. From simple observation, the mono-polar electrode appears to be larger on the Arch catheter than the Flex catheter. Additionally, the contact pressure applied by the Arch catheter to the renal intima, in my experience, seemed to be greater and required more facility and caution to avoid potential dissection and spasm. While Medtronic likely performed all appropriate preclinical testing with the two catheters to ensure similar histologic results in a pig model, this may have introduced a potential confounding variable between the SYMPLICITY trials. The impact of the use of these two different catheters may not be resolved unless appropriately powered observational data in similar patient cohorts are examined.
Krishna Rocha Singh is with the Prarie Heart Institute at St John’s Hospital, Springfield, Illinois, USA. He is a consultant for Medtronic