Interventional cardiology

Controversy as ISCHEMIA softens its endpoints

Changing the primary end points on the quiet and just as recruitment drew to a close hasn’t gone down well for the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA).

While the apparent last-minute amendment to the study protocol may well be legitimate, it drew some criticism across the Twittersphere, cardiology and clinical trials community.

A Perspective piece in Circulation: Cardiovascular Quality and Outcomes kicked off the debate saying the amendments would ‘undermine the value of this well-designed study’.

ISCHEMIA will compare optimal medical therapy versus optimal medical therapy plus cardiac catheterisation and revascularisation in patients with stable ischaemic heart disease.

The end points, initially cardiovascular death and non-fatal MI, now also include resuscitated cardiac arrest and hospitalisation for unstable angina or heart failure.

“With such clear emphasis on bias-resistant end points throughout the many years of recruitment, it is disappointing to learn, just days before closure, of the intention to insert into the primary end point events which are vulnerable to bias in an unblinded trial,” the UK critics said.

They said hospitalisation for unstable angina and heart failure in particular was an event that could ‘rely heavily on perceptions of both the patient and their healthcare provider’.

In a right of reply to the journal, the ISCHEMIA leadership have rejected any criticism and said their trial has been conducted in accordance with the most rigorous clinical trials standards.

They plan to follow-up with full details of the rationale for changing the endpoints.

Columbia University’s Dr Gregg Stone, a co-principal investigator on ISCHEMIA, told the limbic the changes related to under-recruitment. About 5,000 people have been enrolled into the trial.

“ISCHEMIA, like all trials, requires a certain number of accrued events to have adequate power for analysis. The approved protocol pre-specified converting from the original endpoint of cardiovascular death or MI to the 5-component endpoint if a sufficient number of events was not accrued (which might occur, for example, if fewer than the originally planned 8000 patients were recruited).”

“This plan was approved by the NIH, and the change was effected in accordance with the protocol with the entire study leadership blinded to the outcomes in the study groups,” he said.

Professor Paul Glasziou, director of the Centre for Research in Evidence-Based Practice at Bond University, told the limbic people will still be able to examine the data on the original endpoints ‘provided it is presented to allow that’.

He said the UK Perspective piece was a ‘thoughtful discussion of the issues’.

“The resuscitated cardiac arrest probably doesn’t matter but the hospitalisations do – they are softer endpoints. That will weaken the conclusions,” he said.

Cardiologist Associate Professor Sanjay Patel, from Royal Prince Alfred Hospital and the Heart Research Institute, told the limbic the study would still be of value despite the changes.

“I think that generally now it’s pretty difficult to get really hard clinical end points in studies – deaths, MI – simply because medical therapy has become so good and that basically requires you to recruit 15,000-20,000 patients to see hard medical end points.”

“There is no way you are going to see enough deaths or MI in a stable population. You need to enrich it with people with diabetes or COPD or post-ACS.”

He added that despite criticism of FAME 2 – that it was driven only by urgent revascularisation – it was still used every day in the cath lab to guide decision making.

ISCHEMIA is expected to report results in early 2020.

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