VEITHSymposium: Clinical Trial Evidence Changes Practice: A Surgeon Looks Back at an Early Career Reevaluation

Fifteen years after beginning his surgical practice in 1976, Dr. Roger M. Greenhalgh reflects, “I wasn’t aware that clinical trials had any impact on my patients at all.” In 1991, his perception dramatically changed after the publication of NASCET (North American Sympomatic Carotid Endarterectomy Trial) in the New England Journal of Medicine.¹

Why was the publication of NASCET a turning point for you?

The publication of NASCET had a huge impact on the practice of carotid endarterectomy to prevent stroke. Up until that time, I had performed a lot of procedures; in my country, I was performing probably more than many, and I always had a sense that there were more patients that might benefit and were not being referred. NASCET made it clear that any patient who had symptoms of stroke with a stenosis in the carotid artery of 70% to 99% should have an intervention. The consequence of that publication was that the referral for endarterectomy increased enormously. It had a big impact on me personally, as I realized that high-quality evidence, published in a journal like the New England Journal of Medicine, would affect practice. I decided at that moment that I must learn how clinical trials worked.

Imagine, I was a staff member from 1976, professor in 1981, so in 1991, it was 15 years into my practice that this publication had a big impact. The effect of the trial publication was the implementation of a clinical alert in favor of surgery. The trial was stopped, and neurologists, who saw many patients with stroke, started to refer many more patients. I realized that high-quality, randomized, controlled trials, with high levels of evidence, affected referral patterns. As a result of NASCET, patients were directed more appropriately, into the right hands, and surgeons were able to save more patients from stroke. 

You became very supportive of randomized, controlled trials.

Yes. I wasn’t, prior to 1991. At the time in the story I just told you, I wasn’t aware that clinical trials had any impact on my patients at all. This particular event in 1991 demonstrated to me that publication in a very high-impact journal affected the referral to my practice. At that point, I realized I needed to learn the techniques of performing randomized, controlled trials, and not leave it to other physicians to do it, or other disciplines. As a surgeon, I felt I needed a group where clinical trials could be performed to evaluate surgical needs.

How did you begin?

I learned from others that had performed more clinical trials. I had to learn the techniques, and of course, as a busy surgeon, operating all day, the only way I could do it was to assemble around me those who had the necessary skills: a statistician, trial expert, health economist, and so on. I would go and operate all day, and one of my colleagues would talk to me when I had coffee. During this time, we would first pose the clinical questions related to the disease of the patient upon whom I was operating, and second, we would set up trials to see the outcomes. 

What has been the impact of your clinical trial work?

I am from the United Kingdom, so the research I have done has been funded by taxpayers’ money; it is not from any commercial source. We performed a trial for the Medical Research Council called the U.K. Small Aneurysm trial, which was published in the Lancet in 1998.² The ADAM trial, done in the United States, found similar results³, and when two randomized controlled trials agree, it is considered a high level of evidence. The results of these trials directly affected practice for aortic aneurysm: now there was a threshold of 5.5 cm to operate, and when it was less than that, no operation was required. These trials saved lives and stopped patients from having an operation for too small an aneurysm. A few years later, my colleague Alan Scott led the MASS trial⁴, which proved the value of population screening for patients with an abdominal aortic aneurysm of a diameter > 5.5 cm. MASS showed that population screening could save lives. As a result of the U.K. Small Aneurysm trial and then the MASS trial, population screening programs for aortic aneurysm were developed and implemented. These were directly attributable to initiatives from surgeons, who were busy surgeons, but surrounded themselves with trialists. 

How quickly can the trial data publication impact overall practice?

Until endovascular aneurysm repair (EVAR) began in 1991, open repair had been the only possibility. We looked at data for both procedures from the European Vascular and Endovascular Monitor (EVEM) between 2003-2012, which show a decline in open repair and a rise in endovascular repair to the point that they cross over. We compared this against the publication of EVAR trials with randomized data. Thirty-day mortality data, published in 2004⁵, created a steep rise in the year-on-year rate of growth of EVAR: it went from 9% to 39% growth in 1 year. Publication of 5-year trial results a year later in the Lancet⁶ coincided with an 18% growth. After that, the growth of EVAR dropped to low single-digit adoption. Then, in 2010, 10-year results were published in the New England Journal of Medicine⁷, which caused a spike in EVAR adoption, up to 14%, and 15% in 2011. Growth dropped to 8% in 2012. The impact was clear: the release of high-quality data reassured surgeons and patients that this new form of treatment was safe to perform.

Dr. Greenhalgh can be contacted at r.greenhalgh@imperial.ac.uk.

References

1. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med. 1991 Aug 15; 325(7): 445-453.
2. Greenhalgh RM, Forbes JF, Fowkes FG, Powel JT, Ruckley CV, Brady AR, Brown LC, Thompson SG. Early elective open surgical repair of small abdominal aortic aneurysms is not recommended: results of the UK Small Aneurysm Trial. Steering Committee. Eur J Vasc Endovasc Surg. 1998 Dec; 16(6): 462-464.
3. Lederle FA, Johnson GR, Wilson SE, Chute EP, Littooy FN, Bandyk D, Krupski WC, Barone GW, Acher CW, Ballard DJ. Prevalence and associations of abdominal aortic aneurysm detected through screening. Aneurysm Detection and Management (ADAM) Veterans Affairs Cooperative Study Group. Ann Intern Med. 1997 Mar 15; 126(6): 441-449. Thompson S, Kim L, Scott A.
4. Ashton HA, Buxton MJ, Day NE, Kim LG, Marteau TM, Scott RA, Thompson SG, Walker NM; Multicentre Aneurysm Screening Study Group. The Multicentre Aneurysm Screening Study (MASS) into the effect of abdominal aortic aneurysm screening on mortality in men: a randomised controlled trial. Lancet. 2002 Nov 16; 360(9345): 1531-1539.
5. Greenhalgh RM, Brown LC, Kwong GP, Powell JT, Thompson SG; EVAR trial participants. Comparison of endovascular aneurysm repair with open repair in patients with abdominal aortic aneurysm (EVAR trial 1), 30-day operative mortality results: randomised controlled trial. Lancet. 2004 Sep 4-10; 364(9437): 843-848.
6. EVAR trial participants. Endovascular aneurysm repair versus open repair in patients with abdominal aortic aneurysm (EVAR trial 1): randomised controlled trial. Lancet. 2005 Jun 25-Jul 1; 365(9478): 2179-2186.  
7. United Kingdom EVAR Trial Investigators, Greenhalgh RM, Brown LC, Powell JT, Thompson SG, Epstein D, Sculpher MJ. Endovascular versus open repair of abdominal aortic aneurysm. N Engl J Med. 2010 May 20; 362(20): 1863-1871. doi: 10.1056/NEJMoa0909305.