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Societies at odds over PCI for left main disease; questions of trial conduct draw response

The European Association for Cardio-Thoracic Surgery has withdrawn its support for the left main disease recommendations of the 2018 European Association for Cardio-Thoracic Surgery/European Society of Cardiology Clinical Guidelines for Myocardial Revascularization, but a portion of the association’s explanation has drawn criticism from the Society for Cardiovascular Angiography and Interventions.

The guidelines stated PCI is a reasonable option for certain patients with left main disease, based in part on evidence from the EXCEL trial, which, as Healio previously reported, found that PCI with fluoropolymer-based cobalt-chromium everolimus-eluting stents (Xience family of products, Abbott) was noninferior to CABG for the primary endpoint of death, stroke and MI at 3 years and at 5 years.

Support withdrawn

The European Association for Cardio-Thoracic Surgery (EACTS) withdrew its support for the left main section of the guidelines after BBC Newsnight alerted the association to its upcoming report on EXCEL stating that the rate of MI in the PCI group was higher than reported based on a different definition of MI and that the PCI group had a 35% increased relative risk for all-cause mortality compared with the CABG group.

The authors of the EXCEL study released a response to the claims of improper conduct in the BBC Newsnight report and to the EACTS decision. It has been posted on Healio in its entirety at the request of the authors.

EXCEL used the SCAI definition of MI as opposed to the third universal definition of MI developed by the ESC, American College of Cardiology, American Heart Association and World Heart Federation.

According to the BBC Newsnight report aired on Dec. 9, the EXCEL investigators had said they would publish results based on the third universal definition of MI in addition to the SCAI definition, but did not, and according to the third universal definition, the rate of MI was 80% higher in the PCI group than in the CABG group.

“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,” Domenico Pagano, MD, FRCS(C-Th), FESC, secretary general of the EACTS and professor of surgery at University Hospital Birmingham–Queen Elizabeth in the United Kingdom, said in a press release. “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 Clinical Guidelines for Myocardial Revascularization. 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.”

Also in the press release, the EACTS stated: “We recognize 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.”

Definitions of MI

In a release issued by SCAI, the society outlined the benefits of its definition of MI and disagreed with the EACTS statements on the EXCEL trial.

“The authors of the EXCEL trial preferred the SCAI definition of MI because it is based on the best available evidence linking biomarker abnormalities to subsequent mortality in large clinical trials, avoids ascertainment bias and uses the same criteria for PCI and bypass surgery,” SCAI wrote in the release. “The SCAI definition has been used in multiple clinical trials because it avoids the pitfall of tabulating MI events that are small enough to have little clinical impact. Instead, the SCAI definition permits assessment of MI events that are likely to be clinically relevant.”

SCAI stated in the release that in EXCEL, all-cause mortality was similar up to 18 months and the curves separated between 18 and 36 months, but not enough to be statistically significant at 3 years or 5 years. At 5 years, all-cause mortality was 13% in the PCI group and 9.9% in the CABG group, but the rates of definite CV death were almost identical (PCI, 5%; CABG, 4.5%), SCAI stated.

“SCAI respectfully disagrees with EACTS regarding EXCEL,” the society wrote in the release. “While all-cause mortality is an important endpoint to follow, the EXCEL trial was neither designed nor powered to assess differences in this endpoint. Lethal differences in treatment effectiveness would be expected to manifest as differences in cardiovascular death rates; while this was also an unpowered observation, the lack of any difference in definite cardiovascular death at 5 years is reassuring. SCAI endorses the guidelines in Europe and the United States that support use of coronary stents for treatment of left main coronary artery disease in appropriately selected patients.”

Healio will continue to follow the story and will provide updates as appropriate. – by Erik Swain

References:

Cohen D, et al. Surgeons withdraw support for heart disease advice. BBC Newsnight. Dec. 9, 2019. Accessed Dec. 11, 2019.

European Association for Cardio-Thoracic Surgery. www.eacts.org/eacts-responds-to-bbc-newsnights-investigation-on-the-excel-trial. Accessed Dec. 11, 2019.

Society for Cardiovascular Angiography and Interventions. www.scai.org/Press/detail/scai-statement-on-eacts-response-to-excel-trial-in#.XfEV8ehKjIU. Accessed Dec. 11, 2019.

Disclosures: EXCEL was sponsored by Abbott. Pagano reports no relevant financial disclosures.

Editor’s Note: This article was updated on Dec. 13, 2019 to note that the EXCEL trial leadership issued a response to claims about conduct of the trial.

The European Association for Cardio-Thoracic Surgery has withdrawn its support for the left main disease recommendations of the 2018 European Association for Cardio-Thoracic Surgery/European Society of Cardiology Clinical Guidelines for Myocardial Revascularization, but a portion of the association’s explanation has drawn criticism from the Society for Cardiovascular Angiography and Interventions.

The guidelines stated PCI is a reasonable option for certain patients with left main disease, based in part on evidence from the EXCEL trial, which, as Healio previously reported, found that PCI with fluoropolymer-based cobalt-chromium everolimus-eluting stents (Xience family of products, Abbott) was noninferior to CABG for the primary endpoint of death, stroke and MI at 3 years and at 5 years.

Support withdrawn

The European Association for Cardio-Thoracic Surgery (EACTS) withdrew its support for the left main section of the guidelines after BBC Newsnight alerted the association to its upcoming report on EXCEL stating that the rate of MI in the PCI group was higher than reported based on a different definition of MI and that the PCI group had a 35% increased relative risk for all-cause mortality compared with the CABG group.

The authors of the EXCEL study released a response to the claims of improper conduct in the BBC Newsnight report and to the EACTS decision. It has been posted on Healio in its entirety at the request of the authors.

EXCEL used the SCAI definition of MI as opposed to the third universal definition of MI developed by the ESC, American College of Cardiology, American Heart Association and World Heart Federation.

According to the BBC Newsnight report aired on Dec. 9, the EXCEL investigators had said they would publish results based on the third universal definition of MI in addition to the SCAI definition, but did not, and according to the third universal definition, the rate of MI was 80% higher in the PCI group than in the CABG group.

“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,” Domenico Pagano, MD, FRCS(C-Th), FESC, secretary general of the EACTS and professor of surgery at University Hospital Birmingham–Queen Elizabeth in the United Kingdom, said in a press release. “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 Clinical Guidelines for Myocardial Revascularization. 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.”

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Also in the press release, the EACTS stated: “We recognize 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.”

Definitions of MI

In a release issued by SCAI, the society outlined the benefits of its definition of MI and disagreed with the EACTS statements on the EXCEL trial.

“The authors of the EXCEL trial preferred the SCAI definition of MI because it is based on the best available evidence linking biomarker abnormalities to subsequent mortality in large clinical trials, avoids ascertainment bias and uses the same criteria for PCI and bypass surgery,” SCAI wrote in the release. “The SCAI definition has been used in multiple clinical trials because it avoids the pitfall of tabulating MI events that are small enough to have little clinical impact. Instead, the SCAI definition permits assessment of MI events that are likely to be clinically relevant.”

SCAI stated in the release that in EXCEL, all-cause mortality was similar up to 18 months and the curves separated between 18 and 36 months, but not enough to be statistically significant at 3 years or 5 years. At 5 years, all-cause mortality was 13% in the PCI group and 9.9% in the CABG group, but the rates of definite CV death were almost identical (PCI, 5%; CABG, 4.5%), SCAI stated.

“SCAI respectfully disagrees with EACTS regarding EXCEL,” the society wrote in the release. “While all-cause mortality is an important endpoint to follow, the EXCEL trial was neither designed nor powered to assess differences in this endpoint. Lethal differences in treatment effectiveness would be expected to manifest as differences in cardiovascular death rates; while this was also an unpowered observation, the lack of any difference in definite cardiovascular death at 5 years is reassuring. SCAI endorses the guidelines in Europe and the United States that support use of coronary stents for treatment of left main coronary artery disease in appropriately selected patients.”

Healio will continue to follow the story and will provide updates as appropriate. – by Erik Swain

References:

Cohen D, et al. Surgeons withdraw support for heart disease advice. BBC Newsnight. Dec. 9, 2019. Accessed Dec. 11, 2019.

European Association for Cardio-Thoracic Surgery. www.eacts.org/eacts-responds-to-bbc-newsnights-investigation-on-the-excel-trial. Accessed Dec. 11, 2019.

Society for Cardiovascular Angiography and Interventions. www.scai.org/Press/detail/scai-statement-on-eacts-response-to-excel-trial-in#.XfEV8ehKjIU. Accessed Dec. 11, 2019.

Disclosures: EXCEL was sponsored by Abbott. Pagano reports no relevant financial disclosures.

Editor’s Note: This article was updated on Dec. 13, 2019 to note that the EXCEL trial leadership issued a response to claims about conduct of the trial.