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Compliance In Focus
Posted by Michael Marotta on Mon, Apr 21, 2014

Should Sham Procedures Become a More Integral Part of Medical Device Trials?

Currently hypertension affects 30.4% of the American population and is projected to cost the Sham Procedurenation 91.4 billion dollars a year in 2015.  A subset of hypertensive patients have what is referred to as resistant hypertension.  This refers to a patient receiving three or more anti-hypertensive medications without receiving adequate benefit.  Because of this arbitrary definition, the number of people afflicted with resistant hypertension has varied between 5% in general medical practice and 50% in nephrology clinics. As an alternative to additional anti-hypertensive medication, renal denervation has been used as a therapy to combat high blood pressure.

In April of 2013, the European Society of Cardiology (ESC) issued a consensus statement that considered catheter-based renal denervation to be a therapeutic option for patients with resistant hypertension who “cannot get to goal with a combination of lifestyle and pharmacologic therapy”.  At the time of this statement, current thinking in the field stemmed from the results of the Medtronic Symplicity HTN-2 trial that showed renal denervation significantly reduced blood pressure at 6, 30, and 36 month end points. The Medtronic Symplicity system had CE mark approval along with additional renal denervation devices including EnligHTN (St Jude Medical) used in the EnligHTN-1 study, Vessix V2 (Boston Scientific) used in REDUCE-HTN ,OneShot (Covidien) used in the Renal Hypertension Ablation System study, and Paradise (ReCor Medical) used in the REALISE study6.However, recent findings have called into question both the results of these earlier studies as well as the way medical device trials are conducted in general.

On March 29th 2014 at the annual American College of Cardiology (ACC) meeting, pre-published data was presented indicating that renal denervation offered no significant benefit to the recipient.  These findings were later presented in the April 10th edition of the New England Journal of Medicine.  In this article, the authors describe the results of a pivotal trial for the Symplicity HTN-3 (Medtronic).  In this trial, investigators used a randomized, blinded, sham procedure trial to assess the benefit of renal denervation for treatment of those suffering from resistant hypertension.  The results of this study at both the primary (6 month) and secondary (change in mean 24-hour ambulatory systolic blood pressure) efficacy end points showed no significant difference in blood pressure between those that received the treatment procedure (renal denervation) or sham procedure (angiography only).   This pivotal trial was carried out at 88 sites across the United States between October 2011 and May 2013 and enrolled a total of 535 subjects with a 2:1 ratio for treatment of device versus sham (364 vs. 171).

The authors of the article provide a number of reasons for why results in the pivotal trial could have deviated from previous trials including:

  • Prior nonrandomized studies compared the treatment results with base baseline observations rather than with the results in a control group
  • Without a control group, treatment effect may have been a result of trial participation, with the reduction in systolic blood pressure due to good care and a high degree of adherence to antihypertensive therapy as a result of close follow-up
  • Lack of blinding may have introduced a bias with both patients and assessors may be subject to bias in favor of a new treatment that is expected to increase efficacy
  • Limitation in results since medical adherence to medication could not be confirmed
  • Limitation in that the 6-month time point may not have been long enough to remove the placebo effect

Interestingly, the authors also assert that this trial “underscores the importance of conducting blinded trials with sham controls in the evaluation of new medical devices before their clinical adoption”.  This is an assertion that has also been discussed in a previous article.

On the heels of these results, many physicians, including the Cleveland Clinic’s Dr. Steven Nissen, have called for a suspension of all renal denervation products and have thrown into flux the means by which physicians can successfully treat patients suffering from resistant hypertension. While renal denervation is not currently approved for use in the United States, these devices have received approval in more than 80 countries worldwide. Going forward, renal denervation will need to be further evaluated and better understood to determine if this is a viable option for treatment of resistant hypertension.

In the larger picture, should the use of blinded, sham procedure trials be given greater consideration when a company is considering a clinical trial for a medical device?

Photo Credit: Sanofi Pasteur

Drugs & Devices Trial Guideline

Topics: Renal Denervation, Sham Procedures, Clinical Research

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