The TRILUMINATE trial of transcatheter edge-to-edge repair (TEER) vs medical therapy in patients with symptomatic tricuspid valve regurgitation (TR) provides an excellent canvas for thinking about not only valvular heart disease but also the entire medical-science endeavor.
Let's start with some facts. None of this is nefarious. It just is.
TR is extremely common in older patients, and it is hard to quantify.
Given the high prevalence of TR, regulatory approval of a device and procedure to fix it would have major financial implications.
Patients with TR can feel terrible, yet it's hard to know if the TR is the problem or the result of other problems.
Surgical repair of severe TR is high risk and difficult for patients not because of the complexity of valve repair or replacement but because of those "other" problems, such as right ventricular dysfunction.
Even when surgical repair of TR is done during the time of mitral surgery, harm may be greater than benefit.
Industry-physician collaboration has resulted in great innovations, but the incentive of Industry is profit.
A common form of bias in research comes before the first patient is enrolled.
Now to the specifics of TRILUMINATE.
Exactly 350 patients with severe and symptomatic TR were randomly assigned to TEER or medical therapy. Enrolled patients had a mean age of 78 years; 55% were women.
Investigators chose a hierarchical composite primary endpoint of death, need for tricuspid surgery, hospitalization for heart failure, or quality of life as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ). The trial duration was 12 months. Multiple other secondary endpoints were measured; one that I will come back to is the 6-minute walk test.
TRILUMINATE delivered positive results.
Investigators chose an atypical analytic method for the primary endpoint, called a win ratio. A standard analysis considers all components of a primary endpoint equally. A win ratio analysis estimates the likelihood that one or the other treatment is "better," but the more serious events are given higher priority and are analyzed first.
The win ratio for the primary endpoint favored the TEER group (1.48; 95% CI, 1.06 - 2.13; P = .02).
The problem comes when we look at the components of the primary endpoint. There were no significant differences in death, need for tricuspid valve surgery, or even hospitalizations for heart failure.
Improvements in quality of life drove the positive results. Yet the 6-minute walk test did not reveal any significant differences.
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We can keep this simple: Patients who had an invasive procedure reported better well-being than patients who did not receive the procedure.
Even a cursory look at placebo-controlled trials expose this design as fatally flawed. The history of medicine is replete with interventions disproven with proper placebo controls: transmyocardial revascularization and internal mammary ligation for angina and pacing for hypertrophic cardiomyopathy, to name just three.
An invasive procedure puts out a huge caring signal. The investigators address this flaw by citing the possibility of a Hawthorne effect.
But this doesn't seem correct. The Hawthorne effect occurs when people change their behavior because they know they are being observed. The KCCQ questionnaire asks people how they feel about their own well-being.
TRILUMINATE is a premarket approval study. FDA regulators will use these data to determine approval. The stakes are massive.
The company and the investigators surely know the history of placebo controls in medicine. If blinding of patients could be accomplished for percutaneous coronary intervention for severe coronary stenoses in the ORBITA trial, surely it could have been done for clipping tricuspid valve leaflets.
You don't believe me. I'm just an electrophysiologist. Here is first author of the ORBITA trial, Rasha Al-Lamee:
TRILUMINATE found no differences in clinical outcomes or objective measures of function (6-minute walk test). You simply cannot rely on quality-of-life measures when one arm gets an invasive procedure and the other arm does not. Proponents might point to the reduction in TR. I would discount this endpoint on two grounds: grading of TR is difficult in the best-case scenario and a clip prevents blinded adjudication.
To not include a sham-procedure placebo control and use a subjective quality-of-life endpoint biased the trial before the first patient was enrolled. It nearly guaranteed the positive outcome. Quality-of-life endpoints are perhaps the most important of all outcomes, but you cannot judge subjective endpoints without blinding.
The lack of any signal of benefit in harder clinical endpoints, especially no difference in hospitalizations, must lead us to conclude that TEER with this device in these patients did not deliver any benefit over medical therapy.
Some might say FDA should approve the device because there are surely a handful of patients who may benefit. My answer is always the same: when it comes to expensive invasive interventions, the burden of proof is on the proponents to show us who these patients are in a proper trial.
If TEER is approved, an expensive procedure will be widely done without a shred of evidence that it helps anyone besides industry's, hospitals', and doctors' bottom line.
John Mandrola, MD, practices cardiac electrophysiology in Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence.
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Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
Cite this: John M. Mandrola. The TRILUMINATE Transcatheter Tricuspid Repair Trial: Positive but No Benefit? - Medscape - Mar 05, 2023.
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