“History has time and again shown that unlimited power in the hands of one person or group in most cases means that others are suppressed or their powers curtailed. The separation of powers in a democracy is to prevent abuse of power and to safeguard freedom for all.” (https://www.parlament.gv.at/ENGL/PERK/PARL/POL/ParluGewaltenteilung/index.shtml) The legislative power is in charge of making laws, the executive power implements these laws and the judicial power administers justice. When the 3 powers merge into one, we have an autocratic regime. How can we correlate the democratic regime with medicine and specifically cardiology. The executive power is integrated by cardiologists, interventional cardiologists and surgeons who perform their daily practice on its “citizens” (patients). The legislative power are the societies in charge of drafting the guidelines and recommendations on how to act in case of our citizens present with specific ailments. Finally, the judicial power is who defines what should be taken into account when assessing the effect of the treatment of our citizens and how should we interpret these findings. When the same group of people are the ones who make definitions, state relevant outcomes in trials, write the guidelines, run the trials and practice cardiology, we are in an autocratic regime.

The Valve Academic Research Consortium (VARC) has been founded in 2010 with the objective of standardizing definitions related to clinical research. In its original version, a diverse group of stakeholders were represented. Interventional cardiologists, surgeons, Food and Drug Agency (FDA), cardiac imaging, industry, clinicians. Definitions proposed by VARC were rapidly accepted and taken into consideration in major trials of transcatheter aortic valve replacement (TAVR). If we use our previous analogy, VARC represents the judicial power of cardiology.

The third version of VARC has been recently published by the European Heart Journal (1). In its authorship it is not surprising to see experienced and prestigious cardiologists who represent key opinion leaders on our community. In contrast to previous versions of VARC, in which members of the FDA were mentioned at some point in their manuscript or supplementary material, in this case the FDA is not present anywhere in the main manuscript nor supplemental. Absolutely all authors have either received personal fees or research grants to their institution by industry. This, along with the fact that 91% of the authors are related to one of the big TAVI vs SAVR trials (PARTNER, SURTAVI and Portico), suggest that fusion of powers has been taken to the highest level. Of these, 76% belong to PARTNER trial. One of its authors, J. Popma has recently joined Medtronic as Vice President and Chief Medical Officer for Coronary, Renal Denervation, and Structural Heart Businesses. Rebecca T Hahn is Chief Scientific Officer for the Echocardiography Core Laboratory at the Cardiovascular Research Foundation. David J Cohen is current Director of Clinical and Outcomes Research at Cardiovascular Research Foundation. In the VARC-2 document, the funding statement mentioned that grants have been provided to the ARC Board including representatives of Cardialysis, the Cardiovascular Research Foundation and others, by Abbott Vascular, Boston Scientific, Direct Flow Medical, Edwards Lifesciences, Heart Leaflet Technologies, Medtronic Corporation, and St. Jude Medical. Let’s not forget that Cardialysis and Cardiovascular Research Foundation were the trial units involved in EXCEL trial and Cardiovascular Research Foundation in PARTNER. No information regarding funding is declared in the VARC-3 article.

According to data from https://openpaymentsdata.cms.gov, mean general payments US physicians receive per year from industry is US$ 3,500. Payments received by some authors of VARC-3 are 3 to 350 times the mean US.

Can one ever even mitigate for these COI, even if declared ?

I believe no one will doubt the level of expertise of each of the co-authors involved in VARC-3. But my question is, is it not possible to find key opinion leaders without COI to be part of this important task?

The relationship of each author as investigator of trials, guidelines committee and VARC is presented in Table 2. As shown, 4 authors of VARC-3 are simultaneously investigators of PARTNER (except Jeroen Bax) and members of the ACC/AHA or ESC/EACTS guidelines committee. When you have authors under the payroll of industry with key positions in the 3 powers of government, industry is who directs the course of practice.  

 

Table 1. Authors of VARC-3 and their relationship with TAVI trials, guidelines committees and VARC.

Author	Investigator	Guidelines	VARC
Philippe Genereux	PARTNER	No	Yes
Nicolo Piazza	SURTAVI	No	Yes
Maria C Alu	PARTNER	No	Yes
Tamin Nazif	PARTNER	No	Yes
Rebecca T. Hahn	PARTNER	2020 Content Reviewer ACC	Yes
Philippe Pibarot	PARTNER	2020 Content Reviewer ACC/AHA	Yes
Jeroen J. Bax	None	2020 ESC/EACTS Guideline	Yes
Johnathon A. Leipsic	PARTNER	No	Yes
Philipp Blanke	PARTNER	No	Yes
Eugene H. Blackstone	PARTNER	No	Yes
Matthew T. Finn	PARTNER	No	Yes
Samir Kapadia	PARTNER	No	Yes
Axel Linke	PORTICO	No	Yes
Michael J. Mack	PARTNER	2020 Committee ACC/AHA	Yes
Raj Makkar	PARTNER	No	Yes
Roxana Mehran	None	No	Yes
Jeffrey J. Popma	SURTAVI	No	Yes
Michael Reardon	SURTAVI	No	Yes
Josep Rodes-Cabau	PARTNER	No	Yes
Nicolas M. Van Mieghem	SURTAVI	No	Yes
John G. Webb	PARTNER	No	Yes
David J. Cohen	PARTNER	No	Yes
Martin B. Leon	PARTNER	No	Yes

 

Several new definitions have been added, some have been removed and others have been modified. One of the best new additions of VARC-3 which merited its inclusion as the graphical abstract of the manuscript, is the inclusion of a classification for structural valve deterioration. Previously, structural valve deterioration has been related to need for reoperation. Although this definition is very specific and has very low false positives, it surely misses several cases which are associated with structural valve deterioration and do not get a re-intervention. On the other hand, having such a sensible new definition for structural valve deterioration, has the potential of including several false positive cases.  

Hospitalization or re-hospitalization may represent the most controversial definition included in the new VARC-3. This outcome has been part of the primary composite outcome of PARTNER 3 and the main driver for non-inferiority and superiority at one year of TAVR vs SAVR. Having as co-authors the same principal investigators of PARTNER 3, puts into question the opportunity in including this definition into VARC-3. The authors propose dividing hospitalization into cardiovascular hospitalizations related to the index procedure and cardiovascular hospitalizations not related to the index procedure.  In cardiovascular hospitalizations not related to the index procedure, they include acute myocardial infarction (AMI). This means that if a patient after TAVR, is discharged and then gets an AMI and is hospitalized, this is not considered related to the procedure. I personally believe this is an important omission which affects surgical and TAVR patients. The decision to undergo SAVR or TAVR has an implicit therapeutic approach (incomplete revascularization in TAVR patients compared to SAVR) in case the patient has associated coronary artery disease. Not acknowledging that future ischemic events might be a direct result of an unsatisfactory revascularization approach during the index procedure is controversial.

Valve thrombosis in VARC-2 has been defined as the presence of a thrombus in the prosthesis with partial obstruction to the flow. The use of this definition explains the significantly higher incidence of valve thrombosis at 2 years in PARTNER 3. VARC-3 instead of adding a new definition of clinically significant valve thrombosis decided to update this definition, in other words to replace it with clinical significant thrombosis and bury valve thrombosis as part of Stage 1: Morphological valve deterioration. The significance of valve thrombosis is downgraded without sufficient justification and without any evidence that a thrombus without hemodynamic obstruction in the prosthesis has no long-term effects. There is no solid evidence in the role of anticoagulation in presence of HALT, but what would you do in presence of a thrombus in the prosthesis? What would a cardiologist do in presence of a thrombus in the left atrium? Therefore, in future trials, a patient with a thrombus in the prosthesis will not be considered as having valve thrombosis unless additional criteria are present (clinically evident or hemodynamic obstruction). Removing such a definition without any evidence at the moment that long-term outcome of these patients (with a thrombus in the prosthesis) is the same as those without a thrombus is again, controversial.

Significant bleeding as a composite endpoint of early safety has been considered differently for surgery and TAVI. In the words of the authors, “As a result of the frequency and relative benign nature of VARC-3 type 2 bleeding in the setting of surgery and its significant impact on prognosis after TAVR, early safety should include VARC-3 type 3–4 bleeding in the setting of surgery but VARC-3 type 2–4 bleeding in the setting of TAVR.” This is a completely sound argument. Now, why not hold this same argument of myocardial infarction ?

Definition for myocardial infarction has also been updated in this new version of VARC-3. One might recall months of controversy around the EXCEL trial and its questionable periprocedural myocardial infarction definition. Besides the issue around the best unit of measurement (CK or TnT), the main point of discussion was based on the use of biochemical ONLY criteria to define with the same threshold a MI after PCI or CABG. The authors in VARC-3, which some of them hold key positions at Cardiovascular Research Foundation (entity in charge of conducting PARTNER and EXCEL), decided to modify their VARC-2 definition (which was aligned to the Universal Definition of MI) and adopted the modified SCAI definition. In it, patients after TAVI and SAVR are considered under the same biochemical ONLY criteria in order to define procedural related MI. The same threshold is used for a procedure in which the heart is arrested (biochemical released is inevitable) for a procedure in which TAVI is placed on a beating heart. We concur with the need to remove ascertainment bias and that using different cut-off values might affect it, therefore, the best way is to include additional criteria besides biochemical markers. In total disrespect to the surgical community (which goes in hand with the low % of practicing surgeons as co-authors), VARC-3 embraces a controversial definition.

The need for a new permanent pace-maker has been added to the composite early safety which is something for which the authors should be congratulated. Nonetheless, although clinical evidence has been growing regarding the negative impact of new left branch bundle branch block (LBBB), the authors state that “new LBBB was not included in the safety composite, but VARC-3 recognizes that this may become an important endpoint to consider in the future”. Furthermore, one of the authors of VARC-3 (JRC), was senior author of a meta-analysis in which its conclusion was that new onset LBBB was a marker of an increased risk of cardiac death and need for PPI at 1 year follow-up (2).

Finally, NYHA class has been removed as part of the clinical efficacy composite outcomes under the justification that is a subjective measure of functional status. On the contrary, the use health related QOL questionnaires (such as Kansas City Cardiomyopathy Questionnaire) is promoted. Aren’t these questionnaires subjective as well? Cardiovascular Inc is the sole provider for these questionnaires (for which a fee is paid to use them) and is part of Cardiovascular Outcomes Research Consortium in which several investigators from the following institutions are part of it:

The Mid America Heart Institute and the University of Missouri at Kansas City

Yale University

Harvard University

Duke University

Emory University

Case-Western Reserve University

Stanford University

University of Colorado

University of Alberta

Northwestern University

University of Iowa

Washington University .

Do these questionnaires provide an objective reality as opposed to the subjective nature of NYHA class ? Let’s not forget that the PARTNER 2 trial has shown that the percentage of patients in NYHA III-IV class was higher for TAVR at 2 (p=0.04) and 5 years (p=0.08). On the contrary, no differences were seen when using the KCCQ-OS. These results make one wonder why VARC-3 decided to abandon NYHA class and embrace KCCQ.

Industry is a great ally of the medical practice, but medical practice should not be a great ally of industry. Great trials will still be sponsored by industry, in order to circumvent these and future controversies:

• Industry should strive to include in their trials surgeons and cardiologists with no COI
• Guidelines committees should be made up by authors with no COI nor participation in trials by industry
• Consortiums such as VARC, need to be integrated by authors with no COI nor participation in trials by industry

History has taught us that autocracy benefits a selected group of people (the establishment or oligarchy) and in the medical arena it is prone to medical reversal. Although sooner or later evidence will show its true nature, in the meantime patients loose.

Take-home message

• The recently released VARC-3 guidelines has introduced several new definitions and composite outcomes to aid in advancing towards having an universal language among trials. Structural valve deterioration definition and classification has been one of the main positive introductions. Nonetheless, the simultaneous participation of co-authors in trials, the introduction of re-hospitalization as primary outcome, modification in the definition of AMI and removal of valve thrombosis is controversial. 
• Las directrices VARC-3 publicadas recientemente han introducido varias definiciones nuevas y resultados compuestos para ayudar a avanzar hacia un lenguaje universal entre los ensayos. La definición y clasificación del deterioro de las válvulas estructurales ha sido una de las principales introducciones positivas. No obstante, la participación simultánea de los coautores en los ensayos clínicos, la introducción de la rehospitalización como resultado primario, la modificación de la definición de IAM y la eliminación de la trombosis valvular son controvertidas.
• As diretrizes VARC-3 lançadas recentemente introduziram várias novas definições e resultados compostos para ajudar no avanço no sentido de ter uma linguagem universal entre os ensaios. A definição e classificação da deterioração da válvula estrutural tem sido uma das principais introduções positivas. No entanto, a participação simultânea de coautores nos ensaios, a introdução da re-hospitalização como desfecho primário, a modificação na definição de IAM e a remoção da trombose valvar é controversa.