ORBITA: Sham PCI Trial Sends Stents and CardioTwitter Reeling

Tricia Ward

Disclosures

December 12, 2017

On the final day of the Transcatheter Cardiovascular Therapeutics (TCT) meeting in Denver, the first sham-controlled trial of percutaneous coronary intervention (PCI) was presented to a half-empty arena.[1]

Rasha Al-Lamee, MD (Imperial College London, United Kingdom) calmly delivered the findings that improvements in exercise capacity and angina symptoms were not significantly different between patients with stable angina and single-vessel coronary artery disease (CAD) who had real or sham PCI. Panelist and TCT co-chair Martin Leon, MD (Columbia University Medical Center, New York City) cautioned against sensationalizing the results. Meanwhile, CardioTwitter exploded.

Timeline of English-language tweets on the ORBITA trial, November 1-9, 2017. Data provided by Keyhole; a real-time social media data tracker (± hashtag; includes retweets, excludes tweets unrelated to the trial).

There were more than 1700 English-language tweets on the ORBITA trial between November 1 and 9 alone (Figure). These ranged from a thoughtful appraisal of the strengths and weaknesses of the study by interventional cardiologist Robert Yeh, MD (Beth Israel Deaconess Medical Center, Boston, Massachusetts) to ORBITA Limericks.

Controversy Parallels the US Political Divide

The controversy felt familiar to William Boden, MD (Boston University School of Medicine), principal investigator of the COURAGE trial,[2] which also dealt a blow to the utility of stents in stable CAD. Via email he couldn't help but draw a comparison between the ORBITA critics and the current US President's tendency to cite "fake news," "because he disagrees with well-documented facts and chooses to perpetrate a counter-narrative to suit his own belief system."

ORBITA co-investigator Darrel Francis, MD, was warned by his fellows to stay off Twitter. "My office at ORBITA HQ is a temple to rational discussion," he explained in a phone conversation with theheart.org | Medscape Cardiology, but after watching the debate unfold, "I felt obliged to come out and give the most idiotic comments a slapping."

Dr Al-Lamee opened a Twitter account in case there were some comments about ORBITA but did not anticipate the magnitude of response. Speaking by phone, she said that "most of the comments were very constructive, but sometimes the nuanced comments are difficult to make in 280 characters." Dr Boden, who is not on Twitter, lamented that he may have "missed out on much of the fireworks."

When the COURAGE trial was published in 2007, Twitter was in its infancy with nary a physician online. A presentation at ESC 2016[3] cited a much disputed figure of 94 cardiologists on Twitter. A search of about 600,000 Twitter users found nearly 1000 active accounts that list cardiologist, electrophysiologist, or cardiac/cardiothoracic surgeon in their profiles.

Biggest Misperceptions About ORBITA

What are the biggest misperceptions about the ORBITA trial propagated on social media? Prof Francis' pet peeve was reading that "it was too small, because other PCI trials have thousands of patients"—a comment that he could only describe as "stupid."

Dr Al-Lamee's choice was "that these are patients that we would not normally stent," a criticism she anticipated 2 years ago when she made the decision to publish all of the angiograms, to quash any doubts that they enrolled patients with tight lesions in their left anterior descending artery (LAD). If a picture is worth a thousand words, perhaps an angiogram is worth at least 140-280 characters. Cardio tweeps certainly appreciated the chance to peruse the films.

Dr Al- Lamee also challenged the claim that the patients had good exercise capacity pre-randomization, noting that the average exercise time of 8.5 minutes was on a modified Bruce protocol and equates to about 5.5 minutes of a standard Bruce protocol. "They were not athletes; they were just regular patients," she said.

Was ORBITA Buried?, and Other Conspiracy Theories

It has been questioned whether a sham-controlled PCI trial would have received funding in the US. ORBITA investigators were turned down by all of the major UK funding bodies and stent companies they approached. Potential supporters believed the trial to be unnecessary. Prof Francis was confident that the trial would be positive for PCI and cajoled fellow researchers to participate on their own time.

As with any good controversy, there are conspiracy theories, such as why the trial was presented at TCT and not at the American Heart Association (AHA) meeting, the simple explanation being that an interventional cardiology meeting was the logical choice for a PCI trial from the investigators' point of view.

Dr Boden was originally an invited panelist for the late-breaking session but couldn't attend because of work obligations. Still, he charges that the presentation was held for the last day so as not to disrupt the meeting and because most attendees would have already departed.

In a presentation on November 30 at the Cardiovascular Clinical Trialists Forum (CVCT17), Prof Francis said the presentation was moved from the Lancet-co-sponsored late-breaking clinical trials on day 2 of the meeting to the "graveyard session" on the final day.

TCT organizers have refuted accusations of burying the trial, pointing out that they scheduled ORBITA before knowing the results and grouped it with the FAME 2 study on fractional flow reserve (FFR)-guided PCI in stable CAD.

Practice-Changing or Not?

A catalyst for much of the controversy was the accompanying editorial in the Lancet by David L Brown, MD (Washington University School of Medicine, St Louis, Missouri) and Rita Redberg, MD (University of California, San Francisco) that called for the downgrading of PCI in stable CAD.[4] Dr Al-Lamee described it as overreach, and Ajay Kirtane, MD (New York-Presbyterian Hospital/Columbia University Medical Center, New York City) criticized the authors for misstating the risks of PCI.

In an email exchange, Dr Redberg confirmed that she stands by her words: "PCI for stable angina should be Class lll, as the risks clearly outweigh the benefits. One can quibble over the exact rate of MI... but how would we justify even a very small risk of MI and death for a procedure with no proven benefit [her italics]?"

Prof Francis disagrees. "PCI doesn't kill you and people like to have it," he noted. He sees the results of COURAGE and ORBITA as empowering better conversations with patients and is saddened that more interventional cardiologists don't see it that way. "I wouldn't want an 80% craggy lesion in my LAD... But there's no reason why a patient should think the same way as me."

After COURAGE, there was a decline in elective PCI for stable angina in the United States.[5,6] Will ORBITA trigger another downward slope? The National Cardiovascular Data Registry (NCDR) CathPCI registry data show a reduction in the number of PCI procedures deemed inappropriate per the Appropriate Use Criteria (AUC) for revascularization between July 2009 and December 2014.[7] Dr Boden and others suspect that "there has been an increase in 'coding creep' to up-classify patients with 'stable angina' to 'unstable angina.'" There is an interventional cardiology "joke" that if you want to stent a lesion, do intravascular ultrasound, and if you prefer to just use medical therapy, do FFR.

Al-Lamee noted that the NCDR data show that at least 20% of US patients who undergo elective PCI are asymptomatic.[7] And Prof Francis highlighted the fact that current AUC criteria[8] give a green light to PCI in patients with single-vessel disease on at least two antianginals.

Dr Redberg even challenges those who are confident that PCI relieves angina in patients with multivessel disease: "They have no evidence to support this speculation and, in fact, do not even propose a mechanism by which this could happen," she wrote.

ORBITA Controversy an American Phenomenon

For all of the hoopla that ORBITA generated in the lay press stateside, there was barely a murmur on the other side of the Atlantic. Prof Francis speculated that differences in the healthcare system may explain the disparate responses.

UK cardiologists are typically paid the same whether they're an imager, interventionalist, or clinical cardiologist and view each other "as fellow soldiers in the war against disease; we're not in private enterprise against each other," he said. Prof Francis also believes that the UK National Health Service fosters greater patient trust of physicians.

He doesn't believe that American ORBITA deniers are thinking of the dollars-and-cents implications but rather that the incentive structure creates a culture of putting in a lot of stents, making it hard for US interventional cardiologists to accept data that challenge this.

During a session at AHA, when panelists were asked, "How many patients with stable angina should undergo PCI?", European Heart Journal editor Thomas Lüscher, MD (University Hospital Zurich, Zurich, Switzerland) suggested that PCI and FFR be reimbursed at the same rate because the whole field "is still a bit money driven."

More Respect for Sham Control

In all of the debate, there is one point of near universal consensus: ORBITA has raised the bar for procedural clinical trials and data transparency.

Dr Redberg believes that ORBITA shows the importance of doing sham-controlled trials prior to US Food and Drug Administration (FDA) approval. "Having the first blinded RCT come so many years after FDA approval and widespread use makes it hard for people to accept the evidence that actually there is no benefit for PCI [in stable CAD] compared to a fake procedure," she wrote.

When former FDA commissioner Robert Califf (Duke University, Durham, North Carolina) was asked at AHA whether sham controls should be required for device approval, he thought that it was more of a decision for the clinical community: "Do you want to get the truth or not?"

Dr Al-Lamee and Prof Francis also believe that the major lesson from ORBITA is that placebo-controlled and sham-controlled trials are very necessary. Prof Francis recalled being laughed at for predicting that renal denervation for hypertension would underperform in a truly blinded trial[9] and then being hailed a genius when SYMPLICITY HTN-3 was reported.[10]

Finally, Prof Francis objects to the use of the word "sham" for ORBITA because sham also means deception. He proposed this riddle: If Alan volunteers to participate in a placebo-controlled trial while Bob pays to have an ineffective procedure that hasn't been tested in a placebo-controlled trial, who is the victim of sham?

Additional reporting by Liz Neporent.

Disclosures: ORBITA was funded by grants from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, Foundation for Circulatory Health, Imperial College Healthcare Charity, and NIHR Barts Biomedical Research Centre. Philips Volcano supplied the coronary pressure wires. Dr Al-Lamee has received speaker honoraria from Philips Volcano. Drs Francis, Boden, and Redberg disclose no relevant financial relationships.

Follow Tricia Ward on Twitter: @_triciaward

For more Cardiology, follow us on Twitter @theheartorg

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