COMMENTARY

When Guideline Authors Dismiss Important Studies

John M. Mandrola, MD

Disclosures

September 03, 2019

The European Society of Cardiology released five new guideline documents at this year's congress. This hardly seemed like controversial news.

But then I read the guidelines on management of chronic coronary syndromes.[1]

Pollution and noise reduction garnered top billing. Then the usual nods to lifestyle, avoidance of smoking, and adherence to medication. Even mood and anxiety disorders and the potential benefits of cognitive-behavioral therapy gained a mention.  

All reasonable, but what about one of the most important trials in modern-day cardiology, the ORBITA trial?[2] In the 68-page document with 529 references, the authors mentioned it only once:

"The study highlights a significant placebo component to the clinical effects, and alerts us to the pitfalls of interpreting end-points subject to bias in the absence of sham control and blinding. However, the ORBITA results cannot inform Guidelines due to the limited trial size, short-term observation time until crossover, and insufficient power to assess clinical endpoints."

Clogged Pipes

When new people join our cath lab, I always ask if they have heard the stent story. Young learners are fun to teach because they harbor no entrenched biases, such as the clogged-pipe frame of coronary artery disease (CAD).

Here is the short story on stents:

Acute coronary syndromes are different from chronic CAD. An acute closure of a coronary artery should be opened quickly. Chronic stenoses, however, are a manifestation of the diffuse disease of atherosclerosis. Clinicians treat atherosclerosis with a combination of lifestyle interventions and optimal medical therapy (OMT).  

We learned from the COURAGE trial and others that adding percutaneous coronary intervention (PCI) to OMT did not reduce the chance of heart attack or death.[3,4,5] It took time, but most now agree that PCI in COURAGE-like patients does not reduce hard outcomes.

The neutral young learner is perplexed. Why do we do it then? Proponents note that COURAGE showed a reduction in angina symptoms in the PCI arm, though this advantage disappeared at 36 months.[3,6] The ACME trial also showed that plain old balloon angioplasty improved exercise time by 96 seconds.[7]

The problem with both of those trials is that patients knew which treatment they got. Angina is a subjective symptom, susceptible to both the placebo and nocebo effect.

A patient with a stenosis is told she has a blockage and the doctor will fix it. The post-PCI pictures confirm the fix. The patient has faith in the fix. The caring signal is immense; you can see it in the face of the patient, her family, and even the staff.

Now imagine the patients assigned to the OMT arm in trials. They have a stenosis but know there is no stent, no fix. The next time they feel a twinge in the chest, they worry the blockage is progressing. Hospitalizations for unstable angina may rise, as in the FAME-2 trial.[8]

Rajkumar and colleagues call this placebo and nocebo effect "faith healing" and "subtraction anxiety."[9]

This is why the ORBITA trial earns its landmark status. Patients with single-vessel disease who had angina and were on medical therapy underwent PCI or a placebo procedure. The investigators went to great lengths to blind patients and treating clinicians. In the end, PCI improved exercise time, but the difference did not reach statistical significance.[10] 

The guideline authors' reasons for not incorporating ORBITA have all been debunked.

Short follow-up is not relevant because ORBITA did not study hard outcomes; it studied the ability of PCI vs placebo to improve exercise time. If flow limitation is the cause of angina, PCI should immediately improve exercise time. Indeed, in the trial, PCI nearly resolved ischemic wall-motion abnormalities on stress echo.

Citing ORBITA's "limited" size and "insufficient" power belies an understanding of the purpose of the study. As ORBITA principal investigators explained, the trial did not study binary outcomes, such as death or MI. It studied a continuous variable—change in exercise time.[10,11] The authors powered their study to find a 30-second improvement, which is conservative given that drugs improve exercise time by at least 45 seconds[12,13] and balloon angioplasty improved it by 96 seconds.[7] Had they set a higher bar for PCI, of a greater improvement in exercise time, even fewer patients would have been needed. Thus, you could argue that ORBITA was overpowered.

Comments

As a believer in science, I am disappointed with the guideline writers.

Disappointed because science is supposed to be objective. No matter the implications for the field, interpretation of the evidence should be impartial. A neutral observer sees it clearly: PCI in patients with stable CAD does not improve outcomes and, in patients with single-vessel disease, it does not add much angina relief on top of the caring signal of a physician.

Guidelines have many upsides, but for these documents (and authors) to have influence, trust is crucial. Dismissing a landmark trial reduces trust in the medical field when it is needed most.

The choice to dismiss ORBITA fosters cynicism. It gives fodder to those who see the darker side of medicine. This is because the writers have vested interests in the fixing of chronic stenoses. Beyond the cath lab, the search for ischemic heart disease, with biomarkers, stress tests, coronary CT, and coronary artery calcium scores, is the engine that powers cardiology. If the clogged-pipe thesis is flawed, a bunch of modern-day cardiology looks to be of dubious benefit.

This dismissal also demeans the value of a caring clinician. The quick take of ORBITA is to say PCI is no better than placebo. That is the negative frame.

The positive frame of ORBITA is how strongly it highlights the healing power of caring. I often see patients who say they feel better hours after a PCI for a nonacute lesion. I don't doubt that they do, but ORBITA shows that it isn't due to improved flow across a stenotic lesion.

All practicing clinicians know that words and actions can heal, or harm. Our effort matters. The observation that stenting open a proximal left anterior descending artery lesion does not relieve angina more than a placebo supports the notion that placebo effects—caring signals—are not inert. This deserves more than one sentence in a long guideline document.

In an eloquent review of the history of CAD, David Brown, MD, from Washington University, wrote that the scientific arc bends toward truth.[14] In the treatment of patients with chronic CAD, this arc bends slowly.

I wonder: how will history view this resistance to paradigm-changing evidence?

Comments

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