The growing and enthusiastic adoption of transcatheter aortic valve implantation (TAVI) in Europe has no justification, according to three researchers who performed a health technology assessment for the Belgian government. In a paper published in BMJ, the authors from the Belgian Health Care Knowledge Centre conclude that TAVI should only be used in patients “who are deemed inoperable for technical reasons,” which is about 10% of patients “of those currently considered for treatment.”
In their paper the writers do not identify any new concerns about TAVI, but they weave together the various threads of criticism that have been directed at the dissemination of TAVI. Hans Van Brabandt, Mattias Neyt, and Frank Hulstaert also charge that the evidence base for TAVI is deeply flawed as a result of an unpublished negative trial, serious baseline imbalances between controls and TAVI patients in the PARTNER trial, and unreported conflicts of interest by the principal investigator of PARTNER.
By the end of 2011 approximately 40,000 TAVI procedures had been performed, they write. Nearly all of the procedures were performed in Europe, where devices do not undergo the same regulatory scrutiny as drugs, needing only a CE mark to go on the market, “putting them on the same footing as domestic appliances such as toasters.” They note that TAVI was used in Europe for four years before the FDA approved its use in the US, but only for patients who were not surgical candidates and only when the transfemoral approach was used.
Despite the greater rigor of the US regulatory process, the authors write that after their careful review of all the available evidence “we remain far from convinced that it is adequate” and that “the arguments supporting the widespread use of TAVI do not stand up to scrutiny.”
Although in the PARTNER A trial TAVI met the predefined criteria for non-inferiority when compared to surgery, the authors write that strokes, TIAs, and major vascular complications occurred more often with TAVI. TAVI performed better in the PARTNER B trial, which studied patients who were not eligible for surgery, but TAVI was still associated with a higher rate of stroke and vascular events. Results of the two trials “suggest that TAVI can be justified for inoperable patients on clinical grounds,” but, write the authors, this conclusion is weakened because the FDA, Edwards (manufacturer of the Sapien TAVI device), and trial investigators have failed to provide data to the authors, despite repeated requests, about a follow-up study comparing TAVI to standard therapy in 90 patients. The failure to share the data, they write, “is both ethically and scientifically unacceptable and should be legally regulated in future.”
The authors also maintain that the principal investigator of the PARTNER trial, Martin Leon, did not fully disclose his financial interest in TAVI. Although it was disclosed in the NEJM papers that Leon had received $6.9 million from Edwards when it purchased Percutaneous Valve Technologies, which Leon had co-founded, the articles did not mention that Leon ”was to receive three further payments on the achievement of three milestones: successful treatment of 50 patients, regulatory approval in Europe, and limited approval in the US.”
The biggest concern about TAVI, write the authors, is widespread use of the transapical appraoch in TAVI patients in Europe, despite what they term a “dearth of evidence.” Overall, there is an absence of evidence to support usage patterns in Europe, they write. They note that the British Cardiovascular Intervention Society and the Society of Cardiothoracic Surgeons have called for randomized trials of TAVI, but “only when centres in the UK have got ‘beyond their learning curve.’” They go on to write: “Patients may be surprised to hear that trials are being delayed to allow cardiologists and surgeons time to learn the technique.”
Sanjay Kaul sent the following comment to CardioBrief:
The FDA and CMS had access to this HTA report as part of their due diligence last year. While the authors raise several interesting points which are hard to completely disagree with, they overlook the fact that the device passed the FDA’s regulatory muster (at least for “inoperable” indication) which they themselves acknowledge is robust enough for European device approval process to emulate. Although randomization attempts to minimize imbalance amongst the treatment groups, it does not always ensure a “random” sample! Overall, none of the issues raised by the authors rise to the level of invalidating the results of PARTNER trial, in my mind. While the benefit-risk balance in inoperable patients clearly favors TAVI over routine medical care, it is arguably questionable for high-risk patients who are otherwise suitable candidates for surgery. This, then becomes more of an issue of patient preference and value judgments regarding what constitutes an acceptable benefit-risk tradeoff. I agree that “indication creep” can potentially become a major issue. It is the collective responsibility of all the stakeholders to ensure appropriate, judicious and evidence-based use of this technology. The lack of access to detailed data regarding Continuous access registry is vexing and raises the challenge of reconciling proprietary information with timely and transparent public disclosure. The FDA does not have legal authority to force the sponsor to make these data publicly available. However, perhaps the payors can help “concentrate” the sponsors mind!
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Here is the press release from BMJ:
Concerns over minimally invasive heart valve surgery
- Practice has gone beyond the evidence, say experts
- Analysis: Transcatheter aortic valve implantation (TAVI): risky and costly
A new type of heart valve surgery known as transcatheter aortic valve
implantation (TAVI) “cannot be justified on medical or cost effectiveness
grounds” warn experts in a paper published on bmj.com today.
Hans Van Brabandt from the Belgian Health Care Knowledge Centre and
colleagues describe the procedure as “risky and costly” and call for better
regulation and transparency around the use of such high risk medical
TAVI is a minimally invasive surgical procedure for patients with aortic
valve disease who are too old or too ill for conventional open heart
surgery. In patients who are suitable for conventional surgery, survival
after TAVI is equivalent to conventional surgery, but the risk of stroke is
higher. TAVI is also much more expensive than conventional surgery.
Since its introduction 10 years ago, around 40,000 procedures have been
carried out worldwide.
TAVI is classed as a medical device. In Europe this means it needs only a
simple quality certificate (CE mark) to gain access to the market, putting
TAVI on the same footing as domestic appliances such as toasters. In
contrast, the US Food and Drug Administration (FDA) demands trial evidence
before it can license any innovative device. Thus TAVI was in use in Europe
four years before the US.
However, guidance from the UK National Institute for Health and Clinical
Excellence (NICE) says that the evidence for TAVI in patients who are
suitable for conventional surgery is “inadequate.”
The authors agree. After rigorous analysis of all the available data,
combined with a study of real world TAVI practice in Europe, they conclude
that “the arguments supporting the widespread use of TAVI do not stand up
They also raise concerns about access to full trial data on TAVI and a lack
of disclosure of financial interests among trial investigators.
They believe that Europe’s regulatory system “should require high quality
randomised trials to show clinical efficacy and safety before granting
marketing approval to innovative, high risk medical devices.”
They also call for a major improvement in transparency of information “to
allow clinicians to practise evidence based medicine, patients to make
informed decisions, and health technology assessment agencies to make the