The highly positive PREVENT trial of percutaneous coronary intervention (PCI) on vulnerable plaques surprised attendees at the American College of Cardiology meeting.
The surprise came because many thousands of patients have been randomized in trials of PCI as an add-on to medical therapy and the results have been clear: PCI improves outcomes in acute coronary syndromes but adds no benefit over meds in stable patients. More than 80% of patients enrolled in PREVENT had stable coronary disease.
The difference between PREVENT and the previous trials of PCI is the targeting of vulnerable plaques. That idea makes sense. One of the tenets of cardiology is that acute coronary syndromes tend to arise from non–flow-limiting vulnerable plaques rather than highly stenotic chronic lesions. The latter are more likely to cause angina; the former are more likely to rupture and cause acute thrombotic vessel closure.
The PREVENT Trial
PREVENT had strict entry criteria. Investigators screened over 5600 patients who underwent coronary angiography to enroll just over 1600 patients. The trialists identified vulnerable plaques in a two-step process. First the lesion had to be greater than 50% on angiography but non–flow-limiting by fractional flow reserve (FFR = 0.80). Those criteria excluded about 2000 patients.
The second step involved intracardiac imaging — by a variety of methods, at the discretion of the operator. For a plaque to be considered vulnerable, it had to meet two of four intracardiac imaging criteria. The two most common qualifying criteria were minimal luminal diameter < 4 mm2and plaque burden = 70% by standard ultrasound.
The primary endpoint was a composite of cardiovascular death, target-vessel myocardial infarction, ischemia-driven target-vessel revascularization, or hospitalization for unstable or progressive angina. The trial had up to 7.9 years of follow-up (median, 4.3 years), but the primary endpoint was assessed at 2 years.
Patients were 65 years of age on average, 73% were men, and approximately one third of them also had PCI of a non-target lesion. In the PCI arm, 9% of patients crossed over to medical therapy alone and 1% of those in the medical arm received preventive PCI.
Preventive Stenting Results
At 2 years, a primary outcome event occurred in three patients (0.4%) in the PCI arm and 27 patients (3.4%) in the control arm.
The authors reported this as an absolute risk difference of –3.0% (95% CI, -4.4 to -1.8; P =·.0003). Converting to relative risk yields a hazard ratio of 0.11 (95% CI, 0.03-0.36). Each component of the primary endpoint favored the PCI arm. A secondary composite endpoint of death, any myocardial infarction, and any revascularization also favored PCI (risk difference, -2.2%; 95% CI, -4.1 to -0.2).
There was very early separation of the Kaplan-Meier curves. All the benefit occurred within months, and then the curves remained parallel. By 7 years, the risk difference in the primary outcome was -2.9%, but this no longer met statistical significance.
There were four procedure-related adverse events in the PCI arm vs one in the control arm.
Vulnerable Plaque: The Holy Grail
I like the idea of this study. It is bold. It dares to find the holy grail of cardiology: to both identify and treat the vulnerable plaque.
But it's going to take more robust data to accomplish these lofty goals. The authors conclude that their findings "support consideration to expand indications for PCI to include non–flow-limiting high-risk vulnerable plaques."
I strongly disagree.
The first and perhaps most important issue is the small number of events in the 2-year analysis. In a trial of more than 1600 patients, there were only 24 fewer (mostly nonfatal) primary outcome events in the PCI arm.
Longer follow-up exposes the fragility of that result. As the number of events accrued, the difference in events lessened. At 4 and 7 years, the lower rates of the primary outcome in the PCI arm no longer met statistical significance. If the treatment was as good as an 89% lower hazard rate would suggest, you'd expect more events to strengthen, not weaken, confidence in the treatment effect.
Adding to the surprise in this large effect size was the fact that the first third of patients who received PCI for a vulnerable plaque had an absorbable stent; these are now discontinued due to higher event rates. This should have blunted any positive effect of PCI.
The small number of events occurred because the authors substantially overestimated the rate of outcome events. They expected a 12% rate of events in the control arm, but the actual rate was 3.4%. That is not even close and leads to less confidence in the estimate of treatment effect.
Another issue is the open-label design. Two of the four components of the primary endpoint require judgement decisions. Knowing whether the patient has a stent could influence the decision to admit them for chest pain or perform target-vessel revascularization.
Another factor favoring the lower rate of cardiac events in the PCI arm was that far more of these patients were taking P2Y12 inhibitors at 2 years: 79% vs 42% of the medical therapy group.
There were also missing data in 50 patients (3%). That's not terrible, but, as the authors write, given the low event rates, they could not exclude the chance that this affected the primary outcome.
Clinical translation of these results would be difficult. Most intracoronary imaging in the trial was done with ultrasonography, but newer methods such as near-infrared spectroscopy to assess lipid-rich plaque were also used. The trial was done in South Korea, Japan, Taiwan, and New Zealand, where intracoronary imaging is more widely used. Uptake of any imaging in the US community is low and not uniform; multiple experts in PCI messaged me that many doctors have little experience with some of the newer imaging techniques used in this trial.
Attention Must Be Paid, But...
Any therapy that reduces major cardiac outcomes by 89% deserves attention. Attention, however, is not the same as acceptance.
While I wish the journal editors and reviewers disallowed the enthusiastic conclusion of the authors, trials like PREVENT should be published.
The value in this study is not in changing practice in the cath lab; it's way too early for that. The value of this trial is that it provides a signal of hope in conquering the mystery of the vulnerable plaque.
It's a beginning, a signal curious enough to warrant further studies — which are ongoing in multiple countries.
Finally, I worry that the enthusiasm from the ACC meeting could induce expanding use of PCI. It should not.
You can celebrate the boldness (and potential) of PREVENT without overinterpreting the results. I urge leadership in interventional cardiology to speak plainly that this study should not influence current PCI decisions.
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.
COMMENTARY
Preventive Coronary Stents: Not There Yet
John M. Mandrola, MD
DISCLOSURES
| April 11, 2024The highly positive PREVENT trial of percutaneous coronary intervention (PCI) on vulnerable plaques surprised attendees at the American College of Cardiology meeting.
The surprise came because many thousands of patients have been randomized in trials of PCI as an add-on to medical therapy and the results have been clear: PCI improves outcomes in acute coronary syndromes but adds no benefit over meds in stable patients. More than 80% of patients enrolled in PREVENT had stable coronary disease.
The difference between PREVENT and the previous trials of PCI is the targeting of vulnerable plaques. That idea makes sense. One of the tenets of cardiology is that acute coronary syndromes tend to arise from non–flow-limiting vulnerable plaques rather than highly stenotic chronic lesions. The latter are more likely to cause angina; the former are more likely to rupture and cause acute thrombotic vessel closure.
The PREVENT Trial
PREVENT had strict entry criteria. Investigators screened over 5600 patients who underwent coronary angiography to enroll just over 1600 patients. The trialists identified vulnerable plaques in a two-step process. First the lesion had to be greater than 50% on angiography but non–flow-limiting by fractional flow reserve (FFR = 0.80). Those criteria excluded about 2000 patients.
The second step involved intracardiac imaging — by a variety of methods, at the discretion of the operator. For a plaque to be considered vulnerable, it had to meet two of four intracardiac imaging criteria. The two most common qualifying criteria were minimal luminal diameter < 4 mm2and plaque burden = 70% by standard ultrasound.
The primary endpoint was a composite of cardiovascular death, target-vessel myocardial infarction, ischemia-driven target-vessel revascularization, or hospitalization for unstable or progressive angina. The trial had up to 7.9 years of follow-up (median, 4.3 years), but the primary endpoint was assessed at 2 years.
Patients were 65 years of age on average, 73% were men, and approximately one third of them also had PCI of a non-target lesion. In the PCI arm, 9% of patients crossed over to medical therapy alone and 1% of those in the medical arm received preventive PCI.
Preventive Stenting Results
At 2 years, a primary outcome event occurred in three patients (0.4%) in the PCI arm and 27 patients (3.4%) in the control arm.
The authors reported this as an absolute risk difference of –3.0% (95% CI, -4.4 to -1.8; P =·.0003). Converting to relative risk yields a hazard ratio of 0.11 (95% CI, 0.03-0.36). Each component of the primary endpoint favored the PCI arm. A secondary composite endpoint of death, any myocardial infarction, and any revascularization also favored PCI (risk difference, -2.2%; 95% CI, -4.1 to -0.2).
There was very early separation of the Kaplan-Meier curves. All the benefit occurred within months, and then the curves remained parallel. By 7 years, the risk difference in the primary outcome was -2.9%, but this no longer met statistical significance.
There were four procedure-related adverse events in the PCI arm vs one in the control arm.
Vulnerable Plaque: The Holy Grail
I like the idea of this study. It is bold. It dares to find the holy grail of cardiology: to both identify and treat the vulnerable plaque.
But it's going to take more robust data to accomplish these lofty goals. The authors conclude that their findings "support consideration to expand indications for PCI to include non–flow-limiting high-risk vulnerable plaques."
I strongly disagree.
The first and perhaps most important issue is the small number of events in the 2-year analysis. In a trial of more than 1600 patients, there were only 24 fewer (mostly nonfatal) primary outcome events in the PCI arm.
Longer follow-up exposes the fragility of that result. As the number of events accrued, the difference in events lessened. At 4 and 7 years, the lower rates of the primary outcome in the PCI arm no longer met statistical significance. If the treatment was as good as an 89% lower hazard rate would suggest, you'd expect more events to strengthen, not weaken, confidence in the treatment effect.
Adding to the surprise in this large effect size was the fact that the first third of patients who received PCI for a vulnerable plaque had an absorbable stent; these are now discontinued due to higher event rates. This should have blunted any positive effect of PCI.
The small number of events occurred because the authors substantially overestimated the rate of outcome events. They expected a 12% rate of events in the control arm, but the actual rate was 3.4%. That is not even close and leads to less confidence in the estimate of treatment effect.
Another issue is the open-label design. Two of the four components of the primary endpoint require judgement decisions. Knowing whether the patient has a stent could influence the decision to admit them for chest pain or perform target-vessel revascularization.
Another factor favoring the lower rate of cardiac events in the PCI arm was that far more of these patients were taking P2Y12 inhibitors at 2 years: 79% vs 42% of the medical therapy group.
There were also missing data in 50 patients (3%). That's not terrible, but, as the authors write, given the low event rates, they could not exclude the chance that this affected the primary outcome.
Clinical translation of these results would be difficult. Most intracoronary imaging in the trial was done with ultrasonography, but newer methods such as near-infrared spectroscopy to assess lipid-rich plaque were also used. The trial was done in South Korea, Japan, Taiwan, and New Zealand, where intracoronary imaging is more widely used. Uptake of any imaging in the US community is low and not uniform; multiple experts in PCI messaged me that many doctors have little experience with some of the newer imaging techniques used in this trial.
Attention Must Be Paid, But...
Any therapy that reduces major cardiac outcomes by 89% deserves attention. Attention, however, is not the same as acceptance.
While I wish the journal editors and reviewers disallowed the enthusiastic conclusion of the authors, trials like PREVENT should be published.
The value in this study is not in changing practice in the cath lab; it's way too early for that. The value of this trial is that it provides a signal of hope in conquering the mystery of the vulnerable plaque.
It's a beginning, a signal curious enough to warrant further studies — which are ongoing in multiple countries.
Finally, I worry that the enthusiasm from the ACC meeting could induce expanding use of PCI. It should not.
You can celebrate the boldness (and potential) of PREVENT without overinterpreting the results. I urge leadership in interventional cardiology to speak plainly that this study should not influence current PCI decisions.
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.
Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
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