Small Trial Raises Big Concerns That PCI In Stable Angina Is Just A Placebo

ORBITA trial may spark a heated debate in the cardiology community.

It is only a small trial but it may have an enormous impact as it raises major questions about one of the core beliefs of clinical cardiology as it suggests that PCI for stable coronary disease has no more effect than a sham procedure. Although there are a number of necessary caveats and cautions, the trial will likely force the cardiology community to consider and debate the possibility that throughout its 40 year history many of the benefits of PCI, at least in the population with stable disease, have been the result of a placebo effect both in patients and in their cardiologists.

Background

Coronary angioplasty was developed 40 years ago as a less invasive alternative to bypass surgery for patients with stable ischemic disease. Over the past generation PCI for acute coronary syndromes has grown to predominate; the new study, ORBITA, has no direct bearing on this indication, but it does pose troubling questions about the true effects of many of the half million or so PCI procedures performed each year on stable patients.

In the early years of PCI it was widely believed that PCI to open a severely blocked artery would have long term cardiovascular benefits, even in stable patients. Angina patients, the thinking went, were at higher risk for CV events and death, and PCI or CABG lowered that risk by restoring flow through the blocked vessel and preventing a future MI. But over time doubts grew, as it became increasingly clear that MIs were more likely to occur at other, less obvious blockages. Coronary artery disease began to be seen more as a systemic condition and less as a focal plumbing problem. The positive role of medical therapy, including statins and aspirin, became increasingly recognized. Finally, a decade ago the COURAGE trial, despite widespread and fierce initial resistance in the interventional cardiology community, led to widespread agreement that in fact PCI in stable lesions did not produce long term improvements in outcome when compared to optimal medical therapy (OMT). But PCI for stable angina maintained a strong clinical presence as a new consensus emerged in the cardiology community that PCI was superior to OMT in the relief of symptoms. The mantra was that patients would need a stent eventually so they might as well get it upfront. It is this reduction in symptoms that the ORBITA trial sought to test.

It appears likely that ORBITA, like COURAGE a decade ago, will provoke an emotional response and lead to a heated debate. As with COURAGE, the interventional cardiology community will probably attack the trial with fierce intensity, but in the end I suspect they will be forced to yield most of the intellectual ground, just as they did, quietly and eventually in the long wake of COURAGE.

Trial Details

The Objective Randomised Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina (ORBITA), presented today at the TCT meeting in Denver and published simultaneously in the Lancet, is a small, investigator initiated study. It is the first randomized controlled trial of PCI to employ a sham procedure in the control group. In previous trials a “placebo effect” could not be ruled out since both patients and healthcare workers were aware of treatment assignment.

Rasha Al-Lamee (Imperial College London)

The ORBITA investigators randomized 200 patients with severe single-vessel stenosis to PCI or sham PCI. In the first phase of the study all patients received intensive OMT for 6 weeks. Patients were then randomized to either PCI or a sham procedure and followed for another 6 weeks.

There was no significant difference in the primary endpoint, which was exercise tolerance the change in exercise time between the two groups at 6 weeks. Exercise time increased by 28.4 seconds in the PCI group and by 11.8 seconds in the sham control group (p=0.20). The investigators said that the trial was “conservatively designed to be able to detect an effect size of 30 seconds,” which is smaller than the effect shown in studies with antianginal agents. There were no other differences in the exercise test, including the time to 1 mm ST depression and the peak oxygen uptake.

There were also no significant differences in a battery of other tests, including Seattle angina questionnaire (SAQ) assessments of the effects of angina, quality of life assessments, or the Duke treadmill score. In the PCI group there was a small statistically significant difference in the peak stress wall motion index score on dobutamine stress echocardiography, but this difference was not thought to be clinically significant.

There were no deaths or significant differences in outcomes. 4 patients in the placebo group received PCI for a pressure-wire related complication. During the follow-up phase 1 patient in the placebo group had an ACS and two patients had major bleeding while taking DAPT.

The authors, led by Rasha Al-Lamee (Imperial College London), concluded:

“In ORBITA, the first blinded, placebo-controlled trial of PCI for stable angina, PCI did not improve exercise time beyond the effect of the placebo. This was despite the patients having ischaemic symptoms, severe coronary stenosis both anatomically (84·4% area 20 reduction) and haemodynamically (on-treatment FFR 0·69 and iFR 0·76), and objective relief of anatomical stenosis, invasive pressure, and non-invasive perfusion indices (FFR p<0·0001, iFR p<0·0001, stress wall motion score index p=0·0011). There was also no improvement beyond placebo in the other exercise and patient-centred endpoints, including Canadian Cardiovascular Society class and the metrics of the Seattle Angina Questionnaire and EQ-5D-5L questionnaire.”

Clinical Implications

The authors write that the trial does “not mean that patients should never undergo PCI for stable angina,” though undoubtedly some observers— even more skeptical or disillusioned than myself— may reach that conclusion. “Not all patients would be satisfied with taking multiple antianginal agents forever. They might prefer an invasive procedure with a small procedural risk for the potential to need fewer medications.”

The authors also emphasize that the trial does not apply to PCI for patients with ACS: “the results have no implications for patients undergoing PCI for acute coronary syndrome, including ST-elevation myocardial infarction for which morbidity and mortality advantages from PCI have been proven.”

The results also should not be applied automatically to patients with multivessel disease: “Patients with more extensive territories of coronary disease might receive a larger physiological benefit from PCI and have no obvious reason for a larger placebo effect.”

Another important point is that the investigators went to extraordinary length to deliver intensive medical therapy. Achieving similar real world results might well require a degree of effort equal to that used in the trial.”The medical optimisation phase was designed to be more intensive than routine clinical practice. Patients were up-titrated to an average of three antianginal agents during the initial 6 weeks before randomisation. Achieving this required several consultations per week with a consultant cardiologist.”

Weaknesses or Strengths?

The investigators preemptively addressed several objections likely to be raised about the trial, including its small size and short duration, or that it was underpowered. The key point is that, in the post-COURAGE era, the investigators believed there was no need to design a trial long enough and big enough to assess long term clinical outcomes. Instead, the trial was designed only to assess the early effect of PCI on exercise capacity, in a patient population typical of those seen in many clinical practices. For this endpoint, they assert, the trial was more than adequately designed.

The most important and innovative aspect of the trial is the use of sham controls, which have been rarely used in cardiovascular trials. Sham controls gained a big boost with the Symplicity HTN-3 trial in which the early hype and hope linked to renal denervation was definitively deflated only because the trial used a sham control. All previous studies of renal denervation had relied on assessments by patients and physicians who were aware of treatment assignment. ORBITA now reemphasizes that it is simply impossible to eliminate this bias through more conventional means. As the authors write:

“The necessity for placebo-controlled trials has been rediscovered several times in cardiology, typically to considerable surprise. Often a therapy is thought to be so beneficial that a placebo-controlled trial is deemed unnecessary and perhaps unethical. However, 40 years after the first PCI, ORBITA’s findings show that placebo-controlled randomised trials remain necessary.”

Response to ORBITA

I asked a wide variety of cardiologists and clinical trial experts for their thoughts about the trial. All agreed that the trial was well performed and exceptionally interesting and important, though many, interventional cardiologists in particular, sought to diminish the practical implications of the trial.

(Please see accompanying post for detailed responses to ORBITA by William Boden, Ajay Kirtane, and Dan Mark.)

Many pointed out that despite its unexpected and controversial nature, the clinical consequences are largely already supported by guidelines. Sanjay Kaul (Cedars Sinai) said that “if one has stable one vessel CAD, maximizing antianginal therapy is a reasonable treatment option as PCI doesn’t offer a material advantage in the short-term. This is exactly what the current guidelines recommend.”

James Stein (University of Wisconsin) agreed that “yes, the guidelines already say that OMT is fine for low risk CAD (single vessel, small area of ischemia, mild or no angina, etc).” But he offered this important qualification: “that is not how many physicians practice (even if they say they do). Many cardiologists say, to paraphrase them – ‘you have ischemia, you need a cath, and we’ll open up a blockage if you have one, and that will reduce your chest pain’. And cardiologists still say or imply that opening the blockage will reduce their risk of having a heart attack or dying. I still hear ‘the vessel was hanging by a thread’, ‘it’s a good thing we opened it up’, and, worse of all, ‘I fixed him’.”

Stein acknowledged, however, that “patients in general prefer fewer meds (though 1-2 more antianginals is counterbalanced by 1 more antiplatelet drug). A bigger issue is that all the incentives are aligned to intervene percutaneously – docs make money, hospitals make money, there are less phone calls and office visits dealing with medication titration and side effects, and the psychology of ‘we intervened’ (said with chutzpah, as if medications are not interventions) is strong.”

Ethan Weiss (UCSF) made a similar point. He thinks that the reaction to the trial will be “spectacular. I hope ORBITA leads to more placebo-controlled trials, especially for things like CTO. ORBITA shows it can can be done.” But Weiss thinks it’s unlikely that ORBITA will change clinical practice. “It should change practice but may well fail to do so. There is a reflex to ‘fix’ these lesions and I seriously doubt this will change based on this small trial.” “Interventional cardiology,” Weiss notes, “is a big business.”

Dan Mark (Duke University) praised the conduct of the trial but said that the results were “predictable” given the trial design and patient population: “The ORBITA main results are a predictable function of two main factors: a small estimated incremental effect size of PCI (about half of the postulated benefit), likely due to the relatively low angina burden study population enrolled (little opportunity for PCI to do anything measurable in the QOL space), and a lack of precision in estimating the effect sizes (as reflected in the CIs) due to a small sample size.”(See accompanying story for Mark’s full statement.)

William Boden (VA Boston) predicted that ORBITA will receive a reception similar to that of COURAGE, which he presented the COURAGE trial results almost exactly a decade ago. “How will the results of ORBITA be viewed? It will be a combination of love and hate. ORBITA was rigorously designed and undertaken with great care and painstaking attention to detail using objective exercise and physiologic outcome measures before and after stabilization on OMT, combined with the use of well-validated quality of life metrics before and after randomization. Overall, the results were stunningly negative, which ORBITA supporters will cite. By contrast, it is very likely that many in the interventional community will be ready to pounce on and discredit this study—there certainly hasn’t been an opportunity since COURAGE was published 10 years ago in 2007 to potentially discredit a trial that now confronts the sacred cow of PCI benefit for angina relief as the sole basis to justify PCI in stable CAD patients. “ (See accompanying story for Boden’s full statement.)

Robert Yeh (Beth Israel Deaconess) said that ORBITA “is certainly very provocative and appears to be very well executed.” But for Yeh the take home message of the trial is less about the lack of effect of PCI and more about the power of optimal medical therapy. “In many ways, the results are not particularly surprising. We already know that for many patients with significant coronary disease, medical therapy is very effective at reducing angina. That was evident here again with a large fraction of patients seeing improvement in symptoms during the run-in period. The majority had class II or less angina at the time of randomization and angina frequency scores around near 80, and some had no angina at randomization. So those patients make an already very small trial even more likely to show a null result…This is still a really important point to emphasize to our community though (even if it should really be known): medical therapy for stable angina is very effective and really should be first line. I’d note that medical therapy delivered in this study is really very intensive and I’m not sure how many patients get this type of careful med titration in routine practice, maybe none.”

Sripal Bangalore (NYU) said ORBITA “is an important trial given that it is the first trial to compare PCI with a sham procedure. The findings are clear in that despite greater ischemia reduction with PCI, there were no significant difference for other short-term endpoints including angina relief. The trial once again shows how angina related endpoints can be problematic and subjective… While this certainly bursts the bubble that PCI is better at relieving symptoms, it is not clear if the ‘placebo effect’ is sustainable long term.”