ORBITA-2 Saves Interventional Cardiology, Questions Guidance

When Christopher Rajkumar, MD, presented the positive results of ORBITA-2, the second placebo-controlled trial of percutaneous coronary intervention (PCI) in stable angina, you could almost feel the relief of cardiologists at the American Heart Association meeting.

All is right again. Thank goodness.

The first ORBITA trial stunned our community when it showed that PCI compared with a placebo procedure had little to no effect on exercise time or symptoms in patients with severe single-vessel coronary artery disease. It didn't make sense because we had all seen patients feel better after a major obstruction was relieved.

ORBITA-2 also tested the placebo-resistant ability of PCI to improve symptoms, but its design led to different results.

ORBITA-2 found that among patients with stable angina and confirmed evidence of ischemia due to a severe narrowing, PCI significantly reduced angina symptoms and improved exercise time vs a placebo procedure.

The key difference between the two trials is that patients in ORBITA-2 had their antianginal medicines held for 2 weeks before randomization.

The ORBITA-1 and ORBITA-2 Trials

Here are 10 points to remember from the two ORBITA trials.

ORBITA allowed only patients with single-vessel disease; ORBITA-2 allowed multivessel disease, but 80% of enrolled patients had single-vessel disease.
ORBITA-2 required the lesion in question to be objectively significant by either a noninvasive stress test or hemodynamic test in the lab. As in the first ORBITA trial, the authors published angiograms from all 300 patients. The pictures show lesions that few operators leave untreated.
The first ORBITA trial required maximal medical therapy and then tested PCI as an add-on procedure. ORBITA-2 did the opposite. By stopping antianginal drugs, the authors could isolate the effect of PCI alone. Recall that antianginals have no disease-modifying effects. Drugs like statins and antiplatelets were continued.
ORBITA-2 used a unique endpoint of a daily symptom score. Patients had a smartphone app in which they recorded whether and how many episodes of angina they had each day. The ordinal score accounted for the presence of antianginal medications. For instance, one episode of daily angina on no meds scored a 2; but one episode of angina while taking two antianginals scored a 16. The highest daily scores occurred if there was a clinical event such as myocardial infarction.
Numerous centers around London referred patients to the trial, but the pre- and posttesting, as well as the PCI or placebo procedure, was done at a single center, Imperial College.
Patients in the placebo arm underwent angiogram and pressure wire studies, and then were sedated and left on the table. Both the postprocedure management team and patients were blinded. Tests for blinding confirmed that it was successful.
The ORBITA-2 results were clearly positive for PCI. Compared with the placebo procedure, PCI improved the angina symptom score. The odds ratio was 2.21 (95% CI, 1.41-3.47; P < .0010). Angina frequency was three times less in the PCI arm. Canadian Cardiovascular Society (CCS) angina severity was also significantly reduced by PCI. Numerous patient- and physician-reported angina scales were also better in the PCI arm.
Treadmill exercise time increased by 59 seconds in the PCI arm vs placebo. This was statistically significant and equivalent to the increase seen with a placebo-controlled trial of an anginal medication.
There were no differences in clinical outcomes nor safety issues.
The authors concluded that the benefits of PCI occurred immediately, were sustained over 12 weeks, and were consistent across multiple endpoints.

Ethics Questions and Comments

This is remarkable science. PCI has been used for nearly a half-century, and if not for the Imperial College investigators, we would not truly know its effects. They were bold and rigorous, and now we understand much more about this procedure.

One criticism I heard was the ethics of stopping meds and doing a placebo procedure. I asked senior author, Rasha Al-Lamee, MBBS, PhD, about this, and she countered with three lines of argument. She said stopping antianginals is akin to stopping acetaminophen in arthritis. No disease-modifying drugs were held. Her second counter to the ethics critique was that patients had stable angina, and unblinding would occur in 12 weeks in which they could choose therapy with their own physicians. Her third and most important argument is relevant to all procedural fields: namely, one has to balance the ethics of a placebo procedure against the ethics of exposing patients to an invasive procedure without knowing whether there is a placebo-resistant effect.

Another criticism of the trial concerned the external validity (generalizability) of stopping meds before randomization. The authors countered that this was the only way to isolate the effect of PCI. Some of the online comments suggest that this decision makes ORBITA-2 less clinically relevant. I disagree.

What the first ORBITA trial showed is that medications relieve angina quite well, and in that setting, PCI adds little. ORBITA-2, however, shows that PCI alone also relieves angina.

That is super-provocative because many patients would rather have a procedural fix than taking numerous (additional) medications. Guidelines now suggest that we should initiate antianginal medications first. ORBITA-2 strongly challenges that recommendation.

These results should lead to even more nuanced discussion between patient and doctor. (I, for one, would want to avoid the downsides of having a metal cage in my coronary — and the long-term dependence on antiplatelet therapy.)

Finally, ORBITA-2 did not answer all the questions regarding symptoms and coronary disease.

Substantial numbers of patients remained symptomatic despite clear resolution of ischemia. There were also patients who had resolution of angina despite having a placebo procedure. There remains more to learn, and the ORBITA authors have already planned numerous future studies exploring these mysteries.

What a pleasure it has been to read and explore this experiment. Interventional electrophysiologists could learn a lot from these studies. If only we were that bold.

John Mandrola practices cardiac electrophysiology in Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence.

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