The background here is important. The tricuspid valve, which separates right atrium and right ventricle is often called the forgotten valve because the two left-sided valves (mitral and aortic) get most of the attention.
When the tricuspid valve leaks, so called tricuspid regurgitation or TR, the patient feels full in the abdomen and has severe peripheral edema. It’s a difficult problem to treat, mainly because the main cause of the leakage is pressure overload from the left side of the heart. Though sometimes pacemaker leads can tether a leaflet and create TR. One huge problem with TR is that when a patient comes in with severe TR, they are given diuretic therapy, and days later, when the pressure is reduced, the TR has decreased a lot. TR we say is highly dynamic.
The prevalence of TR increases rapidly with age. Millions of people in the US are affected. In days of old, there were only two options: careful titration of diuretic therapy and/or surgery. The problem with surgery when done only on the tricuspid valve is that complications were super high.
Enter percutaneous solutions. The idea here is that if you could snake a tool up to the valve, which is a straight shot from the femoral venous access site, you might be able to clip the valve leaflets to stop the leakage or even replace the valve, much like what is done with transcatheter aortic valve implantation (TAVI).
Two devices for tricuspid valve have passed FDA clearance. One is called a transcatheter-edge-to edge repair (TEER), which is, basically, a clip device. The other is a complete valve called the EVOQUE valve.
I have previously discussed the TRILUMINATE trial, which was one of the most biased trials in all of cardiology, because one group got the procedure, the other group got tablets, and the primary endpoint was driven only by quality of life changes. In TRILUMINATE, there was no reduction in death or hospitalizations for heart failure. The bias was obviously the lack of placebo control; you can’t compare quality of life when one group gets a procedure, and the other gets no procedure.
The TRIC-I-HF trial
TRIC-I-HF was a German investigator-initiated trial at 29 sites. It was also open-label with no placebo procedure. There was a 2:1 randomization of 360 patients. The authors used two primary endpoints: one was a hierarchical composite of death from any cause, hospitalization for heart failure, and quality-of-life improvement at 1 year, assessed by the win ratio. If the between-group difference was significant, a second primary end point would be tested: a composite of death from any cause or hospitalization for heart failure through 3 years.
The patients were quite old (80) and sick: 55% had a HF hospitalization in the prior year, 82% had cardiorenal syndrome, and 92–98% had AF. While multiple types of intervention were allowed, 98% of patients had TEER.
Notably, it was sicker group than TRILUMINATE, with roughly 17.5% 1-year mortality in the control arm versus 5–8% in prior trials.
Results
The trial posted quite positive results. The win ratio for the first primary endpoint was 2.42 (95% CI, 1.76 to 3.33; P<0.001), favoring tricuspid-valve repair.
For the second primary endpoint, freedom from death from any cause or hospitalization for heart failure through 3 years was 52.4% in the tricuspid-repair group and 21.0% in the medical-therapy group (hazard ratio 0.40; 95% CI, 0.29 to 0.55; P<0.001).
Unlike TRILUMINATE there was a marked reduction in hospitalizations for heart failure 19.4% vs 43.9% HR 0.35 (95% CI 0.25-0.50).
Much was made in the discussion about death rates. In the primary analysis at one year, the death rate was lower in the repair arm: 13.1% vs 16.3% (HR 0.74, 95% CI 0.42-1.29). At three years, the difference was 19.0% vs 27.6% with a HR 0.62 and 95%n CI that now stayed below 1.0 at 0.40-0.96. (More on this in the discussion).
Major adverse events within 30 days occurred in 14 patients (6%) in the tricuspid valve intervention arm.
Comments
The authors declared victory. The accompanying editorialist was highly positive. My friends in structural cardiology were clearly happy, as millions of people have TR.
The thing is that there are indeed people with really bad tricuspid valve disease who I have referred for something interventional. Most often, my colleagues say there is not much to do because of anatomic hurdles. But if this procedure worked as reported in the trial, it would be a real win for lots of people.
But I worry about the trial results. While they look positive, there are at least six nuances that I see. Maybe you see more.
The endpoint that drove the results were open to bias in this open label trial. In the win ratio, the HF hospitalization endpoint did the work: 9,280 vs 2,871 wins. Death rates were close (4,366 vs 3,166), and 74% of pairs were tied on death. Hospitalization, of course, is a clinician decision. Since everyone knows the treatment assignment, it’s easy to give an increase in oral diuretics to a patient with a device while admitting a patient without one.
The second issue also relates to HF hospitalization. That is the crossover rule allowed a patient in the medical arm to get crossed over only after a hospitalization for heart failure. Tricuspid repair is reimbursed and available in Germany. For a control patient (or their doctor) who wants the valve fixed, a qualifying hospitalization is required. The data are consistent with this concern: 48 of 123 control patients (39%) crossed over. In 28 of those 48 cases (58%), the procedure was done during the index hospitalization itself.
The third issue is that congestion markers don’t support a 65% reduction in hospitalizations. For instance, if the repair was so great at reducing congestion, you’d expect more improvements in body weight, edema and 6-minute walk distance. None of these measures were that impressive. In fact, the improvement in KCCQ, a questionnaire regarding quality of life was only 6.9 points better in the device arm, which was less than in TRILUMINATE. In the past trials, there was a big quality of life benefit and no effect on hospitalization, but in this trial there was little effect on quality of life and a big effect on hospitalization. This makes you wonder about a bias-driven effect as both should track similarly.
The fourth issue was that the amount of TR reduction was modest. Only 70% of repair patients had moderate or less TR at 30 days, versus 30% of controls. That is less complete than reported in TRILUMINATE. How do you explain the outsized effect on hospitalization with such a modest reduction in TR? Maybe there is a threshold effect? Maybe not.
The fifth issue comes in the death numbers at three years. Multiple proponents have emailed me that I should not ignore the lower death rate at 3 years. Death, they rightly argue, is an unbiased endpoint. The problem is that only 20% of patients had completed the three-year follow-up. At one year, when follow-up was complete, there was no statistical difference in death rates.
The sixth issue was baseline imbalances which favored the device arm. The control arm had slightly more patients with a higher TRI score, AF, CAD, previous MI and stroke.
The bottom-line is that we need trials to guide our advice to patients.
But trials have to minimize bias. Device trials are always going to be harder than drug trials where a placebo does the work of masking.
I don’t suspect any nefarious intent in this trial, but the biases noted above preclude making strong conclusions about the value of this device.
A proper test of tricuspid valve intervention would at minimum include a sham-control arm, where patients would be blinded to the treatment arm. If we can blind coronary stenting, surely we could blind tricuspid valve interventions. Blinding would not fix everything in this case because the clip is obvious on an x-ray, but at least it would blind patients.
We would also want to know about the difference between cardiovascular death and all-cause death, because when you recruit 80-year-olds, there are many non-valvular causes of death.
Before embracing the tricuspid valve repair approach, I feel we need more compelling data.
Let me know what you think.
John- Most of your concerns about the trial (which have been raised by many in the last 6 weeks since its publication) are reasonable. There are no perfect trials and TRIC-I-HF is no exception.
However, it's quite naive to say that "if we can blind a PCI procedure, we can blind a tricuspid valve intervention". The challenges with blinding a TR intervention are much greater than with PCI given the size of the devices (they show up on any imaging procedure including chest x-rays, CT scans, and echocardiograms) and the risk of large bore access vs. 6F transradial access (which raises the stakes substantially).
Nonetheless, I agree with you that a placebo-controlled trial of TTVI would be ideal, and we are very close to starting to enroll patients in that trial in the UK-- hopefully, in the next few weeks.
Excellent article. It's always a good idea to be prepared to tap the brakes on highly reimbursed interventional procedures, especially in 80 year olds.