Readdressing the validity of Repeat Revascularization outcome in PCI vs CABG trials

Pablo Lamelas –

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In the last decades multiple trials comparing the efficacy of PCI vs CABG incorporated repeat revascularization in the primary composite outcome, which favoured CABG repeatedly, and frequently these results influenced clinical guidelines. Repeat revascularization may sound like a reliable form of measuring treatment failure, but has many limitations that should be appraised. In this post we summarize our recently published article in JACC highlighting the limitations and providing recommendations. Note: Please refer to the original article if interested in images and/or references.

Limitations of repeat revascularization

Confounding by indication

In contrast to other patient-important outcomes that happen spontaneously (like a myocardial infarction or a stroke), repeat revascularization needs to be indicated. Those repeat revascularizations in the context of myocardial infarctions are already collected in the myocardial infarction outcome, in contrast to planned or urgent revascularizations without myocardial infarctions that follow a very complex path (filled with significant variability and subjectivity) from the patient, clinical cardiologist, interventionalist and many times the cardiac surgeon as well. Then, this outcome is confounded by indication.

For instance, patients that undergo PCI are more likely to have stress tests done during the first years after follow-up, and is also recommended more frequent stress tests to detect silent ischemia after a PCI than a CABG by imaging guidelines. These stress tests can be abnormal not only for silent ischemia (which may or may not be indicative of needing revascularization) but also false positives, concomitant microvascular dysfunction, or residual disease not candidate for further revascularizations (that happens more frequently, but not only, after PCI). Given an abnormal result, patients post PCI are more likely to be advanced to heart catheterization after a PCI than after a more invasive procedure like cardiac surgery.

Other contributing factor is that patients having an initial CABG have many differential diagnosis for chest pain (incision, sternum, musculoskeletal, pericarditis, pleural, etc), in contrast to post-PCI patients in which any kind of chest (even shoulder, jaw or arm) pain puts coronary origin in the top of the differential list. Indeed, in the SYNTAX trial patients undergoing repeat revascularization with an initial CABG had substantially worse health (angina questionnaire) than post PCI patients, evidencing very different symptom threshold to be advanced for a repeat revascularization.

CABG graft failure less likely to have repeat revascularization

In SYNTAX the vast majority of repeat revascularizations in the PCI group were in the previously stented segment (target lesion revascularization). However, we know that current generation DES durability is likely superior to most non-LIMA-LAD grafts (whatever are arterial or venous, with patency rates close to 90% at one year). So, why post PCI patient have more revascularizations then?

Is estimated that 80% of post CABG patients with at least one non-functioning graft undergoing a new catheterization do not have targets for revascularization. It is known that grafted territories progress coronary artery disease 5 to 10 times compared to non-grafted territories. Then, is common to find chronic total occlusions (or heavy plaque burden) in native arteries and degenerated or occluded grafts of the same territory, making revascularization attempts less palatable vs in-stent restenosis. Also, PCI of in-stent restenosis is a more benign procedure compared with venous graft PCI which is associated with no-reflow and periprocedural myocardial infarction, as well as shorter durability.

Independent (causal) impact of repeat revascularization

It has been described that patients that undergo a repeat revascularization do worse than those who doesn’t. That is also true for any other adverse variable, including those who have atrial fibrillation vs those who don’t, or those who suffer myalgia form statins vs those who don’t have it, etc. In large long-term cohorts, the impact of repeat revascularization is greatly attenuated when adjusted by myocardial infarction. In other words, the adverse prognosis of repeat revascularization mostly driven (or mediated) by associated myocardial infarction rather than the repeat revascularization itself. Then, is uncertain the true causal impact (specially its magnitude) of repeat revascularization in other patient important outcome like myocardial infarction and mortality.

Patient preferences

This is very interesting… Using repeat revascularization as a primary outcome in a PCI vs CABG trial: if a patient has a PCI today and a repeat PCI in one year (again, not a myocardial infarction, just a repeat PCI) in which patient likely discharged the same day of PCI and go back to usual life within 48hours, would be (methodologically) considered an inferior treatment (based on the repeat revascularization aspect only) than an initial CABG alone without new further revascularizations (that includes all the periprocedural issues we all know and several weeks sometimes a few months before going back to normal life). Or similarly, using repeat revascularization as a main outcome would consider equivalent a patient having an initial PCI and a second PCI in a year, to someone that had an initial CABG and a PCI in one year.

Not surprisingly research supports that patients do prefer PCI over CABG despite higher need of further revascularizations in the future, and even accept higher mortality risk as well. Most patients (50%+, and after being informed about the two alternatives in detail) prefer multivessel PCI over CABG even after quoting double mortality risk with PCI and up to three times more chances of a repeat revascularization with PCI. Evidence also shows that patients weight much more death, stroke and myocardial infarction than repeat revascularizations, even more than physicians do.

Last thought: not in the paper

Coronary artery disease is multi-factorial, nobody cures from it and everybody will die some day. Given all these aspects, preventive therapies (like medical therapy or revascularization for ¨prognostically important disease¨) just postpones myocardial infarctions and mortality. Then, if a patient receives today a multivessel PCI today and a CABG in 5 years, without myocardial infarctions in between, is this a failure of PCI? or we postponed the more invasive treatment for later? and if CABG done from the beginning with its limited (not eternal) graft durability, is better this or to have the CABG in 5 years in which we extend 5 years graft durability in patients life? In other words, in my opinion, if a patient survived a multivessel PCI without subsequent MIs for 5 years and then gets a CABG in 5 years, this maybe considered better than having a CABG from the beginning.

And some may say: well, we should still consider repeat revascularization in primary outcomes since its associated with adverse prognosis. Although this is true, the true magnitude (as stated before) is uncertain, but using the same thinking we should also include in the primary outcome other more important risk factors of adverse prognosis in the primary outcome like atrial fibrillation, mayor bleeding and kidney injury (all of them not favouring CABG, are more stronger predictors and happen soon after index procedure, vs repeat revascularization that happens way after index procedure).

Take home message

Recommendation

This is not about ignoring repeat revascularizations in clinical trials, but to consider its limitations in context as described above. Given all these aspects, we do not recommend using repeat revascularization in composite outcomes for clinical randomized trials, or when pooling or interpreting results from past trials. There are tools like differential weighting that could be applied. Still these deal with part of the problem (patient preferences), but not with other biases mentioned above that make PCI to have more repeat revascularizations than CABG.

Interestingly, reviewers (and friends of mine) raised the point that this issue of repeat revascularization being a biased or non-fair outcome in PCI vs CABG trials was already stablished in the academic world. However, against that statement, not only guidelines still mention that repeat revascularization is considered for recommendations, but also the only ongoing randomized trial comparing PCI vs CABG (FAME III) includes repeat revascularization in the primary outcome. Regardless, there was a need in the literature to readdress this issue in detail and supported with data, and here we are. Thanks for reading and have this reference in mind when debating this topic colleagues!