January 30, 2018
25 min read
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ORBITA: Lessons Learned and Lingering Questions

Results spurred debate about appropriateness of PCI and clinical trial design.

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Although the benefits of PCI are indisputable in certain patient populations, the ORBITA trial has raised questions about the advantages of the procedure in patients with stable angina.

The trial, presented at TCT 2017 and simultaneously published in The Lancet, showed that PCI, compared with a sham procedure, did not improve exercise time in patients with medically managed angina and a single severe coronary stenosis. Despite the findings, experts contend that certain aspects of the trial, such as its design, size and subjective endpoints, should give clinicians pause when interpreting the data.

Cardiology Today’s Intervention spoke with eight experts — William E. Boden, MD, Emmanouil S. Brilakis, MD, PhD, David P. Faxon, MD, Kirk N. Garratt, MD, MSc, Ajay J. Kirtane, MD, SM, Sunil V. Rao, MD, Arnold H. Seto, MD, MPA, and Gregg W. Stone, MD — to gain insight into ORBITA’s clinical implications.

In light of the ORBITA findings, is PCI unnecessary in stable CAD?

William E. Boden, MD

The ORBITA findings are incredible when one considers that stenting a coronary artery with a mean 84% stenosis should impart an immediate clinical and physiologic benefit — yet there was none observed across the board between the PCI and sham PCI groups: Canadian Cardiovascular Society (CCS) angina class, Seattle Angina Questionnaire scores, the EQ-5D quality of life score, all exercise indices, and Duke Treadmill scores were neutral, though the peak stress wall motion score index did improve in the PCI group as one would expect — meaning that the PCI was technically successful.

William E. Boden

A 2014 editorial in JACC: Cardiovascular Interventions after FAME-2 was published addressed the need for a sham control trial in stable CAD, and cites how this was accomplished in the late 1950s with internal mammary artery ligations to improve angina, so this paper highlighted many of the shortcomings of more recent unblinded trials in the PCI era like COURAGE, BARI-2D and FAME-2, in which preconceived treatment biases led to assumptions of procedural treatment superiority and clinical benefit and which likely introduced bias into the less rigorous/soft endpoints like “unplanned revascularization” in FAME-2 that drove the composite primary endpoint in favor of fractional flow reserve-guided PCI, and angina relief in all of these trials. This same limitation will apply to the large, ongoing ISCHEMIA trial, which is also unblinded, but won’t end until 2019. Both the JACC: Cardiovascular Interventions editorial and ORBITA underscore the powerful placebo/nocebo effect on both physicians and patients who undergo a procedure that is supposed to impart significant symptomatic improvement — yet remarkably, ORBITA found no between-group differences.

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The narrative in the aftermath of COURAGE was a glib dismissal of the trial findings by many in the interventional community who stated simply: “COURAGE taught us nothing new,” which were the talking points for months/years as many tried to downplay the COURAGE trial results. What we were told repeatedly was: “We’ve known for decades that PCI doesn’t reduce death or MI in stable CAD, but that’s not why we do PCI in these patients — we do it to improve symptoms and quality of life, and PCI is better than optimal medical therapy for angina relief. Plus, many patients don’t like to take medications or don’t want to wait for medications to work, so PCI is a more effective treatment for angina, and that’s what we can offer to our patients.” Moreover, this prevailing view has been firmly espoused by cardiology professional society guidelines internationally for the past 8 to 10 years.

So now, along comes ORBITA, which confronted this “angina superiority with PCI hypothesis” head-on with a sham-controlled trial, the results of which emphatically underscored the powerful placebo/nocebo effect of a PCI procedure that both physicians and patients assumed — and have for 40 years — would be of unquestioned benefit. These results are a “Back to the Future” requiem in an earlier era some 60 years ago when the sham-controlled internal mammary artery ligation studies of the late 1950s showed the unexpected findings of a lack of benefit of this procedure.

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 optimal medical therapy, combined with the use of well-validated quality of life metrics before and after randomization. Overall, the results were stunningly negative, which ORBITA supporters have cited. By contrast, many in the interventional community have been quick 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 last remaining sacred cow of PCI benefit for angina relief as the sole basis to justify PCI in patients with stable CAD. Many in the interventional community will likely cite the limitations of small numbers, only 200 patients; that the study was woefully underpowered; the potential ethical conundrum of subjecting patients with significant flow-limiting CAD to a sham procedure (or deferred PCI for clinical need); that 28% to 32% of randomly assigned patients had either normal FFR or instantaneous wave-free ratio, and therefore didn’t have a “physiologically significant” or flow-limiting stenosis that PCI would otherwise benefit; that the study was undertaken only in stable patients with single-vessel CAD; that the short duration of follow-up, only 6 weeks, was too brief to assess potential benefit (though this actually favored the PCI group); and, of course, who would have the time or patience to call patients three times per week to assess their response to intensifying medical therapy — it is deemed “not real-world,” just like the optimal medical therapy used in COURAGE was said to be unachievable in the real world.

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Will ORBITA change practice? Likely not, because the narrative will likely be that rates of PCI for stable ischemic heart disease are declining, while more recent data from American College of Cardiology’s National Cardiovascular Data Registry show that, based on appropriate use criteria, the percentage of patients undergoing inappropriate PCI — or the more recently sanitized term “rarely appropriate PCI” — is likewise declining. But, what isn’t entirely clear at present is whether, in the post-appropriate use criteria era, there has been an increase in “coding creep” to up-classify or re-classify patients with “stable angina” to “unstable angina” so as to blur these distinctions — is it CCS Class 2 angina or CCS Class 3 angina? So, by re-classifying stable angina as “unstable angina,” such up-coding then flies under the radar of public reporting requirements. Recall also that the large ACC NCDR registry is voluntary and represents self-reported information. It is not an objectively validated data set.

We thought that COURAGE was an appropriate acronym for a large, almost 2,300-patient study where patients were followed up to 7 years after randomization with no clinical benefit on any hard endpoints. ORBITA required even more “courage” than our trial did, and the results are very important to advancing our understanding of how procedures may elicit powerful effects, but not necessarily the effect of angina relief most have long-assumed to be a benefit of PCI. It is — or should be — a wake-up call that we always need to challenge long-held assumptions, unless they have been subjected to rigorous, prospective, blinded study.

There is another very important aspect of ORBITA that fundamentally addresses the patient perspective on what undergoing PCI means, and what message patients take away. Most importantly, we need to be honest that our biases and pre-existing beliefs about the benefits of PCI color the way we approach this discussion with patients. When even a patient with stable CAD is found to have a flow-limiting coronary stenosis during angiography, what is conveyed to the patient in real time in the cath lab (along with the frightening appearance of an angiographic obstruction) is an impending catastrophic event: If we don’t intervene and “fix this blockage” right here and now, something very bad could happen. In this context, who could blame a patient for acquiescing to PCI? But, I suspect there is little discussion about the lack of PCI benefit on improved survival or reduced MI in this setting — though well there should be. And, in this context, when an interventional cardiologist says to a patient: “I can fix that blockage,” what the patient may hear and take away is: “He can cure that coronary disease.” Inflated expectations and misperceptions of clinical benefit are critically important at this physician-patient interface.

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Lastly, the looming question post-ORBITA is: Will we need to start informing our patients that PCI may not necessarily improve their angina either? Only time will tell.

Emmanouil S. Brilakis, MD, PhD

The ORBITA trial hit home several important points.

First, PCI for stable coronary disease has, in addition to other effects, a significant placebo effect. Second, despite the lack of significant difference in exercise time between the PCI and sham-procedure groups in the study, medical therapy does improve symptoms, including quality-of-life symptoms. Third, we need to perform more studies like ORBITA. The investigators designed a very robust, albeit small, study and worked through the difficulties involved with conducting a placebo-controlled trial.

However, we must be cautious in our interpretation of these findings with regard to clinical practice. The ORBITA trial enrolled only patients with single-vessel CAD who already had fairly good exercise capacity at baseline. Therefore, the results may not be applicable to patients with more complex disease, such as multivessel CAD or chronic total occlusions. Additionally, some patients did not experience severe symptoms during the pre-randomization period, so the results may be different for severely symptomatic patients.

Emmanouil S. Brilakis

Another criticism of ORBITA is that some patients who underwent PCI in the trial had normal FFR. In general practice, we would not normally recommend PCI for those patients, as there is no benefit of intervention in patients with stable coronary disease who have FFR or iFR above the cut points of 0.80 and 0.89, respectively. However, judgement should be used in interpreting those cutoffs. Patients who have an FFR of 0.81 or an iFR of 0.90, for example, are likely not that different from those who have an FFR or an iFR of 0.80 and 0.89, respectively. In those cases, for the FFR/iFR measurement should be taken into consideration in addition to the patient’s symptoms and clinical condition.

One explanation for the lack of difference between the two study groups relates to the level of angina that patients were experiencing in the trial. At pre-randomization, the Seattle Angina Questionnaire scores were above 70 in both the PCI and the sham procedure groups, which did not indicate severe angina. We would expect to see more improvement after the procedure in patients with scores less than 70. Moreover, in addition to coronary lesions, there are many other factors that can influence exercise capacity, such as obesity, orthopedic disease and exercise habits, which was the primary endpoint of ORBITA.

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ORBITA was a very well-conducted study for which the researchers are to be congratulated. Aside from the discussion surrounding the trial itself, ORBITA highlights the need for more similar studies, for example in patients with CTOs or multivessel coronary disease.

David P. Faxon, MD

ORBITA has generated significant discussion about the management of stable angina beyond the strengths and limitations of this study.

Importantly, the trial reaffirms the effectiveness of medical therapy. This is not a new concept, and the trial design allowed a good look at how intensifying medical therapy can effectively relieve angina in patients with stable angina and single-vessel disease. However, these are patients whom we would not normally send for revascularization unless they had refractory or severe angina that could not be managed medically. What this study shows is that a very large percentage of this patient group can achieve angina relief with one, two or three drugs. This is important because, despite previous trials such as COURAGE and others that emphasize the value of optimal medical therapy, many physicians toss in the towel early. They give up on medical therapy after one drug, believing it did not work and subsequently send their patients to PCI. The ORBITA findings re-inform what we have already learned in a more contemporary study.

Unfortunately, the clinical implications of ORBITA are limited. The trial included a very select group of stable patients with single-vessel disease, thus excluding many of the patients we typically see in practice. So, the principal question is: How generalizable is this study to the usual patient population whom we currently see? The answer is not very.

At present, we see many more patients with unstable angina vs. stable angina. According to national registries, the number of patients with stable angina is decreasing, whereas the number of patients with unstable angina or non-STEMI is increasing. Furthermore, within the group of patients with stable angina, not many have single-vessel disease. The vast majority of patients with stable angina have multivessel disease, often with left ventricular dysfunction, pulmonary hypertension, chronic total occlusions and other comorbiites. Whether the results of ORBITA apply to these patients is not known.

David P. Faxon

As others have mentioned, a number of patients with normal FFR underwent PCI in the trial, which can be interpreted in two different ways. On the one hand, we could consider it a protocol violation, as they should not have undergone PCI in accordance with guidelines. On the other hand, we could argue, from a trial design perspective, that stenting these patients is consistent with clinical practice. Under certain circumstances or in certain situations, PCI may be appropriate with a negative FFR. For instance, if FFR is borderline, and angiographic IVUS or OCT features related to the lesion reflect a bad outcome, this could nudge us toward intervention. Even so, I would say that stenting patients with normal FFR is not optimal for a trial, in which criteria must be fairly strict so as to achieve cleaner results that are easier to interpret.

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Aside from those limitations, a major weakness of ORBITA is the size of the trial. A better design would have been to focus on the patients who still had unacceptable angina after maximum medical therapy. These patients should have been randomly assigned to PCI to determine if the procedure conferred any additional benefit. That is what the guidelines state and that is our standard of practice. Given that only 105 patients were randomly assigned to PCI and 95 were randomly assigned to sham procedure, and only about 15% of these patients had unacceptable angina after medical therapy, not only is the overall trial too small, but the subgroup of interest is tiny. For this reason, it is difficult to draw any conclusions about the data with so few patients.

The second major weakness is the 6-week duration of follow-up, because it prevented the researchers from excluding a placebo effect. There were trends in each measurement toward a better outcome with PCI, but they did not show significance because there were too few patients. All of this is further complicated by the difficulty involved in the evaluation of subjective endpoints. Even objective evidence, including stress testing and nuclear imaging, is impacted by the brain-heart interaction, which can have a prolonged effect if someone believes they received an effective therapy. To overcome this hurdle in a clinical trial, a large number of patients should be included and very long-term follow-up is necessary. Unfortunately, ORBITA had neither.

The best part about ORBITA, though, is that it once again shines a light on this topic. We do need to think about PCI in patients with stable CAD, so we can design a rigorous trial that will help us to more definitively answer these questions. For now, we should bear in mind that the evidence, including data from large, randomized trials like BARI, is overwhelming that PCI is effective for relieving angina in those who do not respond to optimal medical therapy.

Therefore, ORBITA does not spell the end for PCI in this patient population. Rather, it reaffirms our guideline recommendations and what we have learned from prior clinical trials, including the fact that intensive medical therapy is effective and should be tried first. If that fails, PCI has an important role in relieving angina and improving quality of life in patients with stable angina.

Kirk N. Garratt, MD, MSc

This new study has sparked a controversial dialogue within the cardiology community about the effectiveness of PCI for specific patient populations. While new research and the exchange of ideas drive innovation and, ultimately, improve patient outcomes, we need to be careful in the way we interpret study results. Discussions among colleagues are certainly encouraged, especially within the medical community, but it is our collective responsibility to guard against snap judgments or shortsighted conclusions.

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During the last 40 years, clinical studies and evidence-based research have defined the benefits of PCI. This procedure is the foundation of interventional cardiology and has been widely embraced. PCI has been proven to save lives when patients have unstable heart trouble such as MI. It’s also the preferred treatment for patients with stable ischemic heart disease who have limiting symptoms despite good medical therapy. Today, more than 13 million people in the United States have ischemic heart disease (or CAD), and nearly 9 million have angina. PCI typically involves placement of a stent to relieve a heart artery blockage, improve blood flow and relieve angina. In routine practice, PCI has been reliably effective for this purpose and has improved the quality of life of millions of people.

The benefits of PCI have come into question most recently with the first-of-its-kind, multicenter, masked, randomized ORBITA study. This study compared the efficacy of PCI plus optimal medical therapy against sham PCI plus optimal medical therapy in patients with stable ischemic heart disease.

ORBITA studied 200 patients who had stable but limiting anginal symptoms. Each patient had a stress test, then underwent intensive, supervised medical therapy optimization for 6 weeks prior to invasive treatment. After 6 weeks, patients underwent heart catheterization that included fractional flow reserve measurements of targeted blockages, to assure these blockages were causing ischemia. The blockages were then treated with PCI or a sham PCI, in which equipment was inserted into the patient, but no actual angioplasty was performed. Neither patients nor physicians were aware of their treatment assignment. The objective of ORBITA was to test whether differences in exercise tolerance, quality of life and symptom relief after invasive treatment were real or simply a placebo effect. Six weeks after the procedure, patients were questioned about symptoms and underwent a second exercise stress test. Exercise duration at 6 weeks was compared with exercise duration at baseline for each patient, and the average change in exercise tolerance for the PCI group was compared with the average change in the sham-treated group. Both groups had better exercise tolerance after treatment. The difference in average improvement between the two groups was not statistically significant. PCI-treated patients improved by 28.4 seconds while sham-treated patients improved by 11.8 seconds.

As a clinician-scientist, I admire the use of a sham procedure. The placebo effect is a consistent phenomenon, observed to some degree in nearly all placebo-controlled trials. Furthermore, there is evidence that sham procedures trigger a stronger placebo effect than sham pills or noninvasive treatments. ORBITA seems to confirm that PCI is not immune to the placebo effect. But that doesn’t mean PCI is a sham.

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The primary endpoint in ORBITA, change in exercise tolerance, is relatively imprecise and subjective. Patient tolerance normally varies from week to week. As a result, differences of just a few seconds of exercise tolerance are difficult to interpret. Patients were given three times as many heart pills than they usually took during the 6 weeks before PCI or sham procedure. Consequently, one of nine patients did not have any symptoms. Such patients would not be offered PCI in clinical practice because we don’t expect PCI to provide any additional benefit. Roughly one-quarter of patients who underwent randomization had class 0 or I angina, that is, so little symptoms that even highly effective treatments would have minimal impact.

Other concerns are more typical of these studies: Patients with stable angina are abundant, yet it took five hospitals 3.5 years to find just 368 eligible patients, raising questions of selection bias and generalizability of findings. Exercise time was, in fact, greater for patients assigned PCI, and the same final findings in a larger study could easily have been positive for PCI. There’s also the interesting question of nicorandil, a vasodilator with potassium-ATP channel blocking properties. This medication, which is not available for clinical use in the United States, works like a nitrate but has been proven to reduce symptoms when nitrates are not effective. Nicorandil use at randomization was significantly greater in the sham group, the impact of which is uncertain.

Studies like ORBITA fuel debate and are imperative for the advancement of medicine. We need, though, to couch new findings in the context of earlier works. In the case of ORBITA, the findings are not sufficiently compelling to change convictions or practices. Rather, ORBITA shows us that sham-controlled studies are possible for PCI and suggests that their use may be helpful in further defining the full benefits of invasive therapies.

We should and will continue to work together to push boundaries, advance medicine and improve the lives of our patients. Through that process, we can be confident that we’ll define the best ways to use invasive therapies in the care of our patients.

Ajay Kirtane, MD, SM

The “big picture” takeaway from ORBITA is that we must be patient-centered in our approach to care. We have to understand the relative benefits of all therapies, including medical therapy as well as revascularization.

Ajay Kirtane

In terms of how the findings relate to clinical practice, we can say the results directly pertain to patients with single-vessel disease who are well managed medically over the short term. That is the purest way of assessing the results of the clinical trial. That said, the results can likely be more generalized to clinical practice on a patient-specific basis for those who do not have prognostically important disease and respond quite well to medical therapy. Notably, the findings are not applicable to patients who have more significant disease than those studied, patients with symptoms refractory to medical therapy or, perhaps more importantly, those who do not want to take lifelong anti-anginal therapy.

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As has been mentioned, in contrast to idealized practice, some patients with normal physiologic indices assessing flow abnormalities attributable a coronary stenosis did undergo PCI in the ORBITA trial. To maximize the benefits of PCI, a physician typically wants to observe a flow disturbance in the artery that is being treated, which is important to note. Even so, the current clinical challenge is that many patients do not have physiology assessed, and we as physicians need to recognize the limitations of coronary angiography, which ORBITA emphasizes.

Some criticism has also centered around the trial’s size, questioning whether it was adequately powered to detect a difference in exercise duration or angina after medical therapy. The absolute improvement in either exercise duration or angina, in my opinion, with PCI or sham procedure really depends on the patient. It is not necessarily an issue of a small trial. For me, the telling data points from ORBITA are the Seattle Angina Questionnaire scores. After 6 weeks of medical therapy, these patients generally appeared to have angina that was quite well controlled with the medication. In those patients, we would likely not see dramatic changes from a revascularization procedure. On the other hand, in clinical practice, there are many patients who have angina that is refractory to medical therapy. In those patients, we would expect more measurable changes.

Overall, the ORBITA findings do not characterize PCI as unwarranted. Obviously, the procedure is life-saving in patients with ACS and improves symptoms immediately. Moreover, other trials such as COURAGE show PCI is associated with a more rapid improvement in symptoms over medical therapy (and with less anti-anginal medication). We also know that PCI is an excellent option for many patients in whom medical therapy has failed. Therefore, although the ORBITA study is interesting, it should not be overgeneralized and does not suggest that PCI is useless or unnecessary, as that conclusion has unfortunate ramifications for patients.

In discussing this trial, it is also critical to recognize that potentially overemphasizing the overuse of PCI comes at the price of not mentioning underuse of PCI for appropriate patients. In my own practice, I am seeing more patients who are referred to me after they have failed medical therapy and other physicians have told them that further treatment does not make sense or is not possible. Usually, we have the skills and thoughtfulness necessary to treat those patients successfully. And when they do very well (and with down-titration of medication), which is not only gratifying for them as patients but also for us as treating physicians.

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Despite the debate surrounding the findings, ORBITA serves as a reminder to continue considering how to improve our treatment approach. During the past 10 years, we have made efforts to ensure that PCI is being performed appropriately, but there remains significant room for improvement. This trial can help amplify that conversation. In that respect, ORBITA is a very important trial because it prevents us from remaining overly dogmatic in our current practices.

Sunil V. Rao, MD

The ORBITA findings show that, after contemporary medical therapy, patients with a low level of angina and good exercise tolerance should not undergo PCI because the procedure confers no greater benefit than medical therapy for increasing exercise tolerance. This is a general recommendation based on the trial and this patient population should be made aware that PCI will likely not be more beneficial than medical therapy. The decision-making process, though, would be individualized to that specific patient and ORBITA informs that conversation.

However, because certain types of patients were excluded from the trial, such as those who underwent prior CABG, those with left main disease and those with low exercise tolerance and severe angina, the results clearly do not apply to all patients.

PCI is obviously most beneficial in the patient who presents with ACS, with or without ST-segment elevation, and then in the patient who has failed medical therapy. Nevertheless, it is important to note that certain challenges accompany medical therapy, including the tendency for physicians to use low doses of anti-anginal medications and a lack of patient adherence to treatment. Before we declare medical therapy a failure, particularly in low-risk patients such as those included in ORBITA, we must do our best to ensure that patients are adherent and that they understand that their symptomatology can usually be very well controlled with a combination of anti-anginal medications.

Sunil V. Rao

Although people have commented on the fact that some patients with normal FFR underwent PCI in ORBITA, I don’t necessarily believe the decision to perform PCI in these patients warrants criticism. In clinical practice, of course, I don’t believe we should be performing PCI in patients who have normal FFR, but it is important to remember that ORBITA is a strategy trial, not an FFR-based trial. One interesting point of discussion, though, is whether an FFR less than 0.8 actually predicts angina. We know that FFR less than 0.8 is a reflection of ischemia, but as of now, we do not know if it actually correlates with angina.

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ORBITA has also been criticized for its size and lack of power, but I’m not sure that is an accurate criticism either. If patients underwent medical therapy and the researchers only randomized patients who continued to have angina, that is a different trial designed to answer a different question. In this case, the trial was adequately powered for the primary endpoint of exercise tolerance. The discussion around angina relief and failed medical therapy would require a different sort of trial with a different design.

One of the most valuable implications of ORBITA has less to do with the actual findings. The basic lesson that we should take away from all of the discussion about the trial is that it is important to still be able to question new trials and debate the findings while still being respectful. Unfortunately, the commentary around ORBITA has devolved, particularly on social media, giving the impression that we should not be questioning any clinical trial that comes out. But it is important to remember that is not the point of scientific debate.

Arnold H. Seto, MD, MPA

The ORBITA trial is a milestone in the study of the placebo effect in cardiology. In this first-ever sham-controlled study of angioplasty, 200 patients with stable angina with low-risk clinical features (single-vessel disease, normal ejection fraction, normal exercise tolerance) were treated during run-in phase of optimal medical therapy, then randomly assigned to either PCI or a sham-controlled procedure. Despite a very high-risk lesion profile (average 85% angiographic stenosis, FFR of 0.69, and iFR of 0.76), the trial showed no statistically significant differences in exercise time, angina or quality of life between PCI and placebo.

Arnold H. Seto

Although the headline results of the study might appear to be negative for PCI in stable angina, a closer look suggests several reasons why PCI should remain an option, even with optimal medical therapy. Ischemia was clearly relieved with PCI as measured by dobutamine stress echo and FFR/iFR, and from the FAME-2 study, we know that the outcomes for ischemic patients are unfavorable, especially due to unplanned urgent revascularization. In ORBITA, over only a 6-week observation period, unplanned revascularization occurred in five patients assigned placebo compared with zero patients assigned PCI. Although the trial was underpowered for clinical endpoints, this represents a significant difference, with a P value of .02.

The primary endpoint of exercise time was significantly different for patients before and after PCI (28.4 seconds improvement after PCI, P = .001), whereas this was not significantly different before and after sham PCI (11.8 seconds, P = .235). Only the between-group comparison proved to be nonsignificant (16.6 seconds, P = .2), indicating that while PCI reduces symptoms, this trial was unable to show that it did so more than a sham-PCI control.

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Similarly, there are reasons to believe that the trial was underpowered to assess a clinical difference between PCI and placebo. The patients at baseline were relatively fit, with an average exercise tolerance of 8.8 minutes, indicating a lower-risk population that would have less to gain from PCI. Although the mean FFR and iFR values were low, 29% of patients had an FFR > 0.8 and 32% had an iFR > 0.89, indicating that in almost a third of patients there was no significant ischemia that could be relieved with PCI. In ORBITA, unplanned revascularization occurred in five placebo patients compared with zero PCI patients. Four of these were pressure-wire dissection requiring urgent PCI, creating a crossover of what were likely the most severe lesions, further diluting any potential benefit to PCI.

This trial demonstrates both the effectiveness of medical therapy and the power of the placebo, as reductions in angina occurred after both interventions. The effectiveness of PCI on a background of aggressive medical therapy would naturally be more difficult to demonstrate with a small number of low-risk stable angina patients. Symptom relief and exercise tolerance may be less-sensitive markers of the effect of an intervention than ischemia. The durability of the placebo effect is also of concern. A larger, longer-term trial of higher-risk patients would have a greater potential of showing a difference between PCI and placebo.

Gregg W. Stone, MD

ORBITA reinforces the well-known fact that not all lesions require a stent simply because atherosclerosis is present in the coronary artery. The findings will re-emphasize to referring and treating physicians that we need to be circumspect in understanding that patient symptoms truly are due to CAD and that the coronary lesion is producing ischemia, which is indeed leading to symptoms or sufficient LV dysfunction to cause exercise limitations, dyspnea on exertion or other symptoms.

Gregg W. Stone

As has been stated, though, the ORBITA findings are not very generalizable. For example, in patients with ACS, large-scale randomized trials have shown that angioplasty and stenting reduce death, MI and recurrent ACS. Furthermore, the results are not applicable to patients with more extensive disease, such as multivessel or left main disease, patients who have refractory symptoms that are not being well controlled on medical therapy and patients who cannot tolerate multiple medications. Indeed, most of the patients in ORBITA, even in the control group, ultimately required angioplasty because most patients cannot tolerate three to four anti-anginal and antiplatelet medications every day. Consequently, the therapy applied in ORBITA was not realistic, and I actually expect the trial to have relatively little impact in the community if the results are interpreted appropriately.

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Another limitation that warrants mentioning is the fact that about 27% to 29% of patients with normal FFR underwent PCI. In most patients, that is inappropriate and guidelines call that a class III indication. If the patient has ischemia on the basis of another test, however, the choice may be less clear because no one test is perfect. If a patient clearly has angina and anterior wall ischemia but has an FFR of 0.84 in the left anterior descending, it would be reasonable to treat that lesion. Conversely, if a patient had no other evidence of ischemia and clearly has a negative FFR, the patient should not undergo PCI, as they have an excellent prognosis, as shown in FAME-2 and other studies.

ORBITA was also very small and involved a very heterogeneous group of patients. Additionally, even though there was not much ischemia, PCI did reduce ischemia and nearly improved exercise duration, despite the fact that patients basically had normal exercise duration at baseline. In a study of this size, it is impossible to perform a meaningful subgroup analysis, but there is no doubt that PCI is effective in relieving ischemia of hemodynamically significant atherosclerotic lesions. It’s a matter of finding the right patient with stable ischemic heart disease who will benefit from PCI.

In terms of trial size, ORBITA was powered for the primary endpoint of exercise duration. However, one limitation of the study is that not only was exercise duration nearly normal — about 9 minutes — in the PCI and sham procedure groups, but by chance was 38 seconds greater in the angioplasty group vs. the sham procedure group. The trial was only powered to detect a 30-second difference. Therefore, by chance, the groups were more different than the potential treatment benefit, which generates a regression to the mean phenomenon and it is impossible to have a positive result in that setting.

Moreover, angina as an outcome has a major limitation. In the trial, the Seattle Angina Questionnaire scores were greater than 70, which correlates with monthly angina. It is impossible to demonstrate a difference with such infrequent angina. Essentially, one cannot treat normal patients with normal exercise duration and almost no angina and make them walk longer and feel better. It is not mandated or recommended that PCI should be performed in such patients. We should instead reserve PCI for patients who have had symptoms in stable coronary disease, patients who have symptoms that are truly attributable to their epicardial atherosclerotic lesions and patients who are not otherwise managed well on medication. We have known this for many years.

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In light of the study limitations, ORBITA does not render PCI unnecessary. Rather, ORBITA reaffirms that PCI is unnecessary in lesions for which it is unnecessary. Wise cardiologists and interventionalists will work diligently to identify those lesions and those patients in whom stenting will be of benefit, and they will equally strive to avoid angioplasty and stenting in lesions and patients in whom it will not improve quality of life.

Even though we applaud the fact that ORBITA was sham-controlled, this one small, randomized trial is not nearly sufficient to overcome 40 years of experience and thousands of other trials demonstrating the value of PCI in stable CAD. It hopefully will, however, help us ensure that PCI is performed in appropriate patients with stable ischemic heart disease. - by Melissa Foster

Disclosure: Brilakis reports he receives consulting or speaker honoraria from Abbott Vascular, ACIST, Amgen, Asahi, CSI, Elsevier, GE Healthcare, Medicure and Nitiloop; receives research support from Boston Scientific and Osprey; and is on the board of directors for the Cardiovascular Innovations Foundation; and is on the board of trustees for the Society of Cardiovascular Angiography and Interventions. Faxon reports no relevant financial disclosures. Kirtane reports he receives institutional research grants from Abbott Vascular, Abiomed, Boston Scientific Cardiovascular Systems Inc., CathWorks, Medtronic and Siemens. Rao reports he is an advisor for Medtronic, CSI, Corindus and Phillips. Seto reports he receives research grants and honoraria from Acist Corp. and Volcano Philips and is on the speakers bureau for Janssen. Stone reports he has financial ties with Abbott Vascular, Ablative Solutions, Aria, Backbeat Medical, Biostar family of funds, Cagent, Caliber, Claret Medical, Guided Delivery Systems, Lupin Pharmaceuticals, Matrizyme, MedFocus family of funds, Medical Development Technologies, Micardia, Miracor, Neovasc, Qool Therapeutics, Reva, Sirtex, St. Jude Medical, TherOx, Topay, Valfix, Vascular Dynamics and V-wave. Boden, Faxon and Garratt report no relevant financial disclosures.