Changing Evidence, Changing Practice

In December 2019 the EACTS Council withdrew its support for the recommendations on left main coronary artery disease of the 2018 joint ESC-EACTS Myocardial Revascularization Guidelines. Here we explain why.  

19 December 2019

Introduction

The pursuit of new innovations and techniques to provide optimal care to patients is both welcome and vital. Without advances in practice, we would not improve quality of life and save as many lives as we do. However patient safety is paramount and that is why there are well established practices to assess the results of clinical trials that support the preparation of clinical guidelines which provide the advice on which clinicians depend to identify optimal treatment. Withdrawing support from guidelines in this fashion is unprecedented for our Association. It was a decision taken by the whole Council with considerable care. This article explains what we did and why.

The guideline in question was prepared in 2018 by representatives from both the European Society of Cardiology (ESC) and the European Association for Cardiothoracic Surgery (EACTS), who had considered a range of evidence including the reported outcomes from the EXCEL trial to develop the recommendations for the treatment of patients with left main coronary artery disease (LMCAD) and stable angina which form part of the joint 2018 ESC-EACTS Myocardial Revascularization Guidelines.

 

EACTS Council made three important decisions

At our Council meeting on 7 December 2019 three important decisions were taken regarding the guidelines.

  1. Council withdrew its support from the current recommendations on treatment of left main disease in the 2018 joint ESC-EACTS Myocardial Revascularization Guidelines. This decision was based on a range of scientific, statistical and professional issues that had been raised.
  2. Council wanted to ensure members were notified and it was agreed to publicise the decision widely.
  3. Council also requested that the ESC was invited immediately to participate in a new joint taskforce to review the LMCAD recommendations in the guidelines.

 

All the decisions were agreed unanimously.

Prior to the Council meeting, the BBC’s Newsnight programme contacted both EACTS and the ESC with revelations about the EXCEL trial. The BBC asked Professor Nick Freemantle, from the Institute of Clinical Trials and Methodology at University College London, to examine their findings. Professor Freemantle shared his analysis of the current evidence and the new findings with the EACTS Council. To help inform their decisions, the EACTS Council was able to consider Professor Freemantle’s comprehensive statistical analysis alongside several matters of scientific and professional propriety, including those raised by the BBC, which questioned the robustness of both the content and the guideline process.

Following the Council meeting, we proactively issued a statement so that members and clinicians knew the Council had removed its support for the LMCAD recommendations in the 2018 ESC-EACTS Myocardial Revascularization Guidelines.

So what evidence underpinned the 2018 Guideline recommendations?

The recommendations in the 2018 ESC-EACTS Myocardial Revascularization Guidelines for the treatment of LMCAD were based on SYNTAX score terciles and the conclusions were:

  1. There was class IA evidence to support CABG in all groups, the highest level of recommendation.
  2. In patients with SYNTAX score <22, PCI was equivalent to CABG. Class IA recommendation.
  3. In patients with SYNTAX 23-32, the evidence for PCI was less clear. Class IIaA recommendation.
  4. In patients with SYNTAX scores >33, PCI was not recommended. Class IIIA.

These recommendations are the same as those published in 2014, which were derived from short-term outcome data and an underpowered subgroup analysis of the SYNTAX trial.

The scientific evidence underpinning the 2018 decisions was based mostly on 3 studies (see references 1-3).

  1. The patient level meta-analysis of randomised trials of CABG versus PCI (3) using up to 5-year all-cause death as the primary endpoint showed that for the overall cohort PCI was associated with a significant survival disadvantage (Hazard Ratio [HR] 1.20, 95% confidence intervals [CI] 1.06-1.37; P=0.0038). A subgroup analysis for patients with LMCAD was reported to have similar outcomes for PCI and CABG. However, this conclusion is scientifically questionable given the non-significant interaction (P=0.12) for the LMCAD subgroups. Thus, the correct scientific interpretation is that the result for the overall cohort applies also for the LMCAD subgroup (4, 5). The patient level meta-analysis was evaluated by the task force in its pre-publication status and shared with the reviewers a short time before the publication of the guidelines; this questions whether sufficient time for scrutiny had been allowed.
  2. The NOBLE trial (2) showed a more frequent occurrence of the primary composite endpoint (all-cause death, non-procedural myocardial infarction (MI), stroke and repeat revascularisation in the PCI than in the CABG group (HR 1.48, 95% CI 1.11-1.96; P=0.007). There was no difference in all cause mortality.
  3. The EXCEL trial which studied patient with SYNTAX Score <32 (1), reported that at 3-year follow up the primary composite endpoint (all-cause death, stroke, or MI) occurred with similar frequency in the CABG and the PCI groups (HR 1.00, 95% CI 0.79-1.26; P=0.98). This was interpreted as showing that PCI was not inferior to CABG.

 

But the evidence available has changed

Our primary concern is patient safety and given there is new emerging evidence, there are multiple reasons for adapting to these different circumstances and reviewing the LMCAD recommendations of the guideline:

  1. More complete understanding of the 3-year data from EXCEL (1) using the standard definition of a myocardial infarction (UDMI) has reversed the perceived advantage/non-inferiority of PCI compared with CABG for LMCAD disease. These data were presented by the BBC but have not been published.
  2. The 5-year data from EXCEL (10) have now demonstrated a significant survival advantage for CABG over PCI for this group of patients.

 

And the BBC has also highlighted the following issues

The recent BBC Newsnight investigation has raised several additional concerns with regards to the EXCEL trial and the guideline process:

  1. To date, the trial authors have not published the trial outcome data using the universal definition of myocardial infarction (UDMI) despite stating they would report the findings.

 EXCEL has attracted controversy since its inception (6), particularly around the definition of MI. There is a standard Universal Definition of MI (UDMI) (7), which was included in the EXCEL protocol as a prespecified secondary endpoint. This definition has the advantage of being endorsed by most cardiovascular organizations, including the ESC, ACC, AHA and regulators. The BBC reported that the EXCEL investigators adopted a new definition for this complication (MI) which would increase the apparent occurrence of peri-operative MI after CABG, leading to results appearing to favor the PCI option. This could only be acceptable if its findings proved to be consistent with those using the UDMI, hence the importance of the secondary endpoint. The protocol of the study was not amended to reflect the decision not to publish – to date, this represents a breach of the CONSORT and Good Clinical Practice Guidelines (ICH E9) (8, 9).

  1. 35% increased risk of death in the PCI group

The BBC received data for the 3-year outcomes, including the hitherto unpublished secondary outcome using the UDMI, which provided a qualitatively different outcome. In an analysis shared by the BBC, when UDMI is used PCI is associated with substantially worse outcomes at 3 years with a significantly higher risk of MI than CABG (HR 1.79, 95% CI 1.25-2.57; P=0.002). When UDMI is used in the composite primary end-point with all-cause death and stroke, PCI is associated with a 40% increased risk for this (HR 1.40, 95% CI 1.09-1.81; P=0.009). This analysis is predictive of the published 5-year EXCEL results (10) which show a 35% increased risk of death in the PCI group, (Odds Ratio 1.38, 95% CI 1.03-1.85).

  1. Emerging mortality data have not been shared

The BBC revealed there were emerging data available to the EXCEL data safety monitoring board (DSMB) indicating an increased mortality for the PCI group. In its news coverage, the BBC considered why these data were not made available to those on the guideline task force. Had all the information described above been available to the task force, the conversation around the choice of guideline recommendation would probably have been different. It is of note that some of the EXCEL investigators were also members of the guidelines task forces.

  1. Alleged conflicts of interest

 Public concerns have arisen over commercial conflicts of interests among both the authors and some members of the guideline committees. The BBC identified that one third of the authors of the guidelines had significant relevant commercial conflicts of interests, including at least one holding a patent for drug-eluting stents. These potential conflicts were not available to the guideline task force members during the writing of the recommendations or to the reviewers (although they had been seen by the guideline chairs) and were published at the same time as the guidelines.

Restoring confidence in our recommendations

Producing clinical guidelines provides an important opportunity for scrutinizing the available clinical evidence. For this reason, the guideline process must take care to minimize bias and the potential influence of conflict of interests. The methodology for developing “Guidelines we can Trust” is well described by The Institute of Medicine (IOM)(11) which recommends steps to minimize bias by using systematic literature search around predefined clinical questions, a transparent management of COIs, the use of statistical methodologists to prepare evidence tables and guide the interpretation of data, and more recently the use of the GRADE collaboration system (12).

The 2018 joint ESC-EACTS guideline task force did not use this methodology as it was not adopted at the time.

The way forward is clear. If vested interests add complexity to the resolution, these must be swept aside by professional, scientific and analytical integrity in the interests of our patients.

Therefore, we have taken the following action to restore confidence in the guidelines.

  1. We have written to the ESC inviting our colleagues to work with us jointly to consider the evidence available and develop updated recommendations as a matter of urgency.
  2. In order to ensure the trustworthiness of the guidelines, we propose to adhere to the Institute of Medicine gold standard principles for developing clinical recommendations.
  3. We have invited Professor Schuenemann, Director of the DeGroote Cochrane Canada Centre and Mc Master Grade Centre, to oversee the process.

The guidelines for myocardial revascularization must be reviewed urgently. By working together collaboratively and transparently, we can restore confidence in our clinical recommendations and send a strong signal to the public that patients’ interests are at the centre of all we do and say.

D. Pagano.

Secretary General of EACTS, on behalf of the EACTS Council

-ENDS-

REFERENCES

  1. Stone GW, Sabik JF, Serruys PW, Simonton CA, Généreux P, Puskas J, et al. Everolimus-Eluting Stents or Bypass Surgery for Left Main Coronary Artery Disease. N Engl J Med. 2016;375(23):2223-35.
  2. Makikallio T, Holm NR, Lindsay M, Spence MS, Erglis A, Menown IB, et al. Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE): a prospective, randomised, open-label, non-inferiority trial. Lancet. 2016;388(10061):2743-52.
  3. Head SJ, Milojevic M, Daemen J, Ahn JM, Boersma E, Christiansen EH, et al. Mortality after coronary artery bypass grafting versus percutaneous coronary intervention with stenting for coronary artery disease: a pooled analysis of individual patient data. Lancet. 2018;391(10124):939-48.
  4. Freemantle N, Ruel M, Gaudino MFL, Pagano D. On the pooling and subgrouping of data from percutaneous coronary intervention versus coronary artery bypass grafting trials: a call to circumspection. Eur J Cardiothorac Surg. 2018;53(5):915-8.
  5. Yusuf S, Wittes J, Probstfield J, Tyroler HA. Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. JAMA. 1991;266(1):93-8.
  6. Ruel M, Falk V, Farkouh ME, Freemantle N, Gaudino MF, Glineur D, et al. Myocardial Revascularization Trials. Circulation. 2018;138(25):2943-51.
  7. Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. Eur Heart J. 2007;28(20):2525-38.
  8. Rennie D. CONSORT revised–improving the reporting of randomized trials. JAMA. 2001;285(15):2006-7.
  9. European Medicines Agency. ICH E9 statistical principles for clinical trials. https://www.ema.europa.eu/en/ich-e9-statistical-principles-clinical-trials. (15 December 2019, data last accessed).
  10. Stone GW, Kappetein AP, Sabik JF, Pocock SJ, Morice M-C, Puskas J, et al. Five-Year Outcomes after PCI or CABG for Left Main Coronary Disease. N Engl J Med. 2019;381(19):1820-30.
  11. Institute of Medicine Committee on Data Standards for Patient S. In: Aspden P, Corrigan JM, Wolcott J, Erickson SM, editors. Patient Safety: Achieving a New Standard for Care. Washington (DC): National Academies Press (US)

Copyright 2004 by the National Academy of Sciences. All rights reserved.; 2004.

  1. Balshem H, Helfand M, Schunemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64(4):401-6.

EACTS-STS new strategic collaboration

We are very excited to announce a new strategic collaboration between STS and the European Association for Cardio-Thoracic Surgery (EACTS).

Both of our organizations share a commitment to professional excellence and improving the lives of patients with cardiothoracic diseases. In addition, STS and EACTS have a long history of collaboration. As a result, we thought it was time to establish a 5-year strategic partnership focused on expanding our collaborative educational offerings and leveraging the power of our respective clinical data registries for quality improvement and research.

STS and EACTS recently offered an extremely well-received 3rd Annual Latin America Cardiovascular Surgery Conference, which brought together 300 people from 35 countries to participate in innovative educational sessions, lively discussions, and hands-on activities in Cancun, Mexico.

Next year, we are planning additional joint conferences in Latin America (Santiago, Chile and Rio de Janeiro, Brazil), as well as other collaborative programs.

As we move into 2020, we will keep you informed about this exciting partnership and hope that you share our enthusiasm about our two organizations working together even more closely.

EACTS responds to BBC Newsnight’s investigation on the EXCEL trial

Following BBC Newsnight’s investigation, Professor Domenico Pagano, Secretary General of EACTS, says:

“The Council of the European Association for Cardiothoracic Surgery (EACTS) has considered the analysis of the data that BBC Newsnight has shown us. It is a matter of serious concern to us that some results in the EXCEL trial appear to have been concealed and that some patients may therefore have received the wrong clinical advice.

“Following the information presented to us by Newsnight, the EACTS Council has unanimously decided, with immediate effect, to withdraw our support for the Left Main Chapter of the joint 2018 EACTS-ESC (European Association for Cardiothoracic Surgery and European Society of Cardiology) Clinical Guidelines for Myocardial Revascularisation. If the information on the trial is proven to be correct, the recommendation is unsafe. On behalf of the EACTS Council I have written to the ESC to invite them to work with us to develop a new joint section of the guidelines as a matter of urgency.

“We deeply regret the obvious concern that this will raise for some patients and their families. We recommend that patients seek the advice of the multidisciplinary heart team at their hospital before deciding which treatment option is most appropriate for them.”

-ENDS-

Additional background

The EXCEL trial

Clinical trials are very important for our profession: advances in medicine can help save patients’ lives that only a few years ago would have been lost.

The EXCEL trial compared conventional open heart surgery (coronary artery bypass graft surgery) with stents (PCI) in patients with the disease of the main coronary artery vessel (left main stem) and concluded that there was no significant difference for patient outcomes, regardless of which treatment option was used.

We welcome Newsnight’s scrutiny of the EXCEL trial and the findings.  These show patients with left main coronary artery disease treated with stents are 35% more likely to die than those treated with conventional open heart surgery.

Guidelines

New clinical trial data help inform the clinical guidelines that we rely on to advise our patients effectively on the best treatment options available. The reported outcomes of the EXCEL  trial were one of the major clinical trial results used to inform the joint 2018 EACTS-ESC (European Association for Cardiothoracic Surgery and European Society of Cardiology) Clinical Guidelines for Myocardial Revascularisation. We recognise that if the data and the analysis Newsnight has carried out are correct, as they appear to us to be, patients have been subjected to an increased risk of death. That’s why the EACTS Council voted unanimously to withdraw our support for the guidelines on Left Main disease with immediate effect. We urge our members to disregard the guidelines relating to left main disease for the time being.

Further information

James Ford, james.ford@barleycommunications.co.uk, 07974 565425

James McCollum, james.mccollum@barleycommunications.co.uk, 07903 741829

Notes to editors

  1. At our annual conference this year, we invited leading international experts to debate the findings from the latest clinical trials, including EXCEL. In the interests of transparency we live streamed the discussion and you can watch it here (from 01:59:00).
  2. University College London’s Institute of Clinical Trials and Methodology will provide its expert advice to EACTS as the new guidelines are developed.

Longer term outcomes for heart surgery significantly better than other procedures, new evidence finds

EACTS facilitates an important debate about the most effective treatment options

Patients with heart disease who have surgery have significantly better longer-term outcomes than patients opting for heart stents or transcatheter aortic valve implantation (TAVI), according to new evidence presented today (Saturday 5th) at the 33rd European Association for Cardio-Thoracic Surgery (EACTS) Annual Meeting in Lisbon.

The new findings from several international studies raise questions about whether the innovations have been adopted too quickly in some instances leading to worse five year survival rates for patients. Leading international experts gathering in Lisbon will facilitate an important debate about the most effective treatment options for heart patients as EACTS highlights the importance of introducing new innovation safely and ensuring patients are able to discuss their individual risks and benefits with a multi-disciplinary heart team before having a procedure.

The findings, to be presented at the EACTS conference, the largest cardiothoracic conference in the world, include:

  • For several decades bypass surgery (CABG) has been known to offer better survival and a much reduced risk of subsequent myocardial infarction (heart attack) and need for further interventions compared to stents. It was also thought that patients with less severe disease could do as well with stents. However, a new study (Excel: Everolimus-Eluting Stent of Bypass Surgery for Left Main Artery Disease) now suggests that even patients with less severe forms of this disease who have bypass surgery have a significantly better chance of surviving for five or more years if they choose surgery. The Excel study not only shows that surgery gives patients around a one-third improved survival rate in comparison to stents but that at 5 years that survival benefit appears to be accelerating.
  • The results of the Partner 2 Trial, to be presented for the first time in Europe, found that the five year outcomes for patients with ‘intermediate’ operative risk having surgical aortic valve replacement (SAVR) were significantly better than for those having the TAVI procedure. This means that for every 100 patients dying within 5 years of having the TAVI procedure, 75 people would have died having had surgery.
  • An analysis in Italy of the long-term outcomes of TAVI vs SAVR led by Dr Barili, Cuneo, Italy, found that while early results are promising for TAVI, from 40 months onwards TAVI has significantly worse outcomes than conventional surgery. TAVI procedures are undertaken by both cardiologists and surgeons.
  • The latest update from the North American TAVI registry reveals that the “real world” outcomes for patients are worse than those of the randomised trials. Data also shows that complication rates are not decreasing with time even though the numbers of TAVI procedures are growing.

 

Discussing the findings of the Excel study, Professor David Taggart, Professor of Cardiovascular Surgery at the University of Oxford, said:

“The EXCEL study looked at the best treatment for a potentially particularly lethal form of coronary artery disease called ‘Left main disease’ as it affects the most important blood vessel supplying blood to the heart muscle. While it is widely accepted that for severe patterns of disease that bypass surgery is best it was also previously thought that for less severe forms of disease the same result could be obtained with stents. However, the EXCEL study, the most definitive study of its kind for this type of disease, now shows that, assuming a patient is relatively fit, their chances of being alive after five years are dramatically better – by almost one-third – if they have heart bypass surgery rather than stent treatment.

“This confirms the importance of doing randomised clinical trials to ensure that potentially innovative techniques are actually as safe as the tried and tested standard techniques and that newer techniques must be implemented with caution. If a patient has blockages in the main heart artery or in more than two arteries and especially if the patient is diabetic, I strongly recommend that they get the opinion of a surgeon. Thankfully, in the UK, we have strong ‘Heart Teams’ consisting of cardiologists, surgeons and other experts who working closely together can recommend the best treatment to the individual patient. However, in most parts of the world the decision to recommend treatment is made by a cardiologist and, regrettably, the patient does not get any opinion from a surgeon.”

 Professor Nick Freemantle, Director Institute Clinical Trials and Methodology, University College London UK, said:

“The Partner 2 findings should be considered very carefully in clinical practice. They serve as a wake up call for the profession. It appears that some people may have adopted TAVI for too broad a range of patients. We know that for patients in need of aortic valve replacement – and who are not well enough for surgery – the TAVI procedure can be a lifeline. But now we have clear evidence – even for those patients with an intermediate level of risk – that the longer-term survival rates for patients who have surgical aortic valve replacement are significantly better than for those who have the TAVI procedure.”

Dr Rita Redberg, Cardiologist at University of California San Francisco, who will co-chair the debate on Saturday 5 October, said:

“These new findings highlight that some patients are living longer if they opt for surgery over some other techniques. This should focus minds: when advising on the right procedure for a patient, we need to know and share the data on risks and benefits. While avoiding surgery seems attractive in the short run, this short term benefit pales if it is at the price of longer survival with surgery. Patients will benefit from having their risks and benefits explained by a multi-disciplinary heart team to ensure they are able to access the best and personalized treatment. Innovation is vital and it’s how practice evolves but we must ensure innovation is introduced safely and is best for patients. We should avoid a race to widely adopt new techniques until such innovations can demonstrate equivalent sustainable results to established surgical techniques.”

To follow the session live at the 33rd EACTS Annual Meeting, visit the EACTS live stream here: www.eacts.org/annual-meeting/eactslive/

The session will also be available to watch again at:

ENDS

Further details on the Annual Meeting are available at the EACTS website: www.eacts.org

Notes to Editors

Experts contributing to the EACTS Annual Meeting discussion include:

  • Dr Rita Redberg(Chair of the Trial Update and Evidence Review session)

Cardiologist at University California San Francisco and Editor in Chief of JAMA Internal Medicine

  • Professor David Taggart, University Oxford

Professor of Cardiovascular Surgery at the University of Oxford

  • Professor Friedhelm Beyersdorf

University Heart Center Freiburg and Editor In Chief of EACTS Journals

  • Professor H. Schünemann

Department of Health Research Methods, Evidence & Impact (HEI), Hamilton, Canada and chair of GRADE collaboration

  • Dr S. Fremes, Toronto

Sunnybrook Health Sciences Centre, Toronto

  • Professor Nick Freemantle, Director Institute Clinical Trials and Methodology, University College London UK

The Excel Extended Survival study

September 2019

STATEMENT – UPDATE ON UNACCEPTABLE SPEAKER SLIDES

19 September 2019

From the Secretary General

On behalf of the Association I would like to state that we are deeply sorry for the sexist, unprofessional and unauthorised slide used by an external speaker at an event in Homburg (Saar), Germany yesterday. This is an issue we are taking extremely seriously and this has been discussed with the Officers of the EACTS Council. I would like to thank Rebecca Dobson (on Twitter @theharveys) for bringing this to our attention. I’m also grateful that another speaker on the course subsequently raised the issue in front of the audience and a full apology was made to the audience at the time. There is no place for sexism or other forms of discrimination in our Association.

We understand that the offensive slide was part of a presentation by an external speaker. We have initiated an investigation to understand the full circumstances. Our investigation continues.

We have reviewed and updated our guidance to speakers. It’s disappointing that we need to state explicitly in writing that slides of this nature will not be tolerated, but we have updated our guidance in any case to make it abundantly clear. It’s vital that EACTS speakers and trainers – as well as our members and staff – uphold the highest professional standards at all times.

EACTS has a long history of inclusiveness and this individual’s slide does not reflect the values and standards that our global members represent.  We are committed to accelerating diversity and openness across the organisation – and the cardio-thoracic specialty more broadly. That’s why we have been working over the summer to establish a new Women in Cardio-Thoracic Surgery Committee. We’re in the final stages of recruitment and the Chair will be appointed and announced in the coming weeks.