Figure 1 A. Relationship between SYNTAX Score Strata and overall cause of death and major adverse cardiac ...

Figure 1 B. Forest Plot of MACE in low, intermediate and high SYNTAX Score. ATC: percutaneous coronary interventions...

Figure 2. Differences between SYNTAX I and SYNTAX II in number of 3 vessel diseases after FFR (left) and ...

Figure 3 A. Overall cause of death in left main stenosis randomized trials between PCI and CABG at 5 years ...

Figure 3 B. Overall cause of death at 10 years in left main stenosis and multiple vessel disease metaanalysis. IC: ...

Over the last 20 years in interventional cardiology, we have witnessed countless technological “advances” in and out of the cath lab including new invasive and non-invasive functional diagnostic procedures.

Fractional flow reserve (FFR), optical coherence tomography (OCT), multi-slice computed coronary tomography (MSCT), MSCT with functional assessment of lesions, etc. have been of great help to achieve a much more selective diagnosis of the target lesions, and the strategy that should be followed during stenting.1-5

Also, we have seen “advances” in the design of drug-eluting stents (DES) with the arrival of biocompatible, bioresorbable durable polymers, without polymers and/or with very thin struts that are associated with lower target vessel revascularization rates after stenting.6-9

Observational and randomized clinical trials of different DES designs showed better results with these new devices, and the functional analysis of the lesion using FFR.1,10-11

However, these technological advances did not improve disease progression when percutaneous coronary intervention (PCI) was compared to coronary artery bypass graft (CABG) or traditional medical therapy in randomized clinical trials. And this should be a cause for concern for all new generations of interventional cardiologists and industry itself because it can impact the clinical practice of future indications for PCI in chronic and/or elective patients.

The question we should ask ourselves is why don’t these technological advances bring better clinical outcomes. Instead, in terms of hard endpoints, the gap between CABG and PCI or PCI vs optimal medical therapy not only has not changed but somehow widened as the negative results of 9 out of 10 randomized clinical trials on multivessel disease (MV) and/or unprotected left main coronary artery (LMCA) conducted over the last years demonstrate (the Syntax, FREEDOM, Best, VA-Cardia, NOBLE, EXCEL, FAME3, ORBITA, and ISCHEMIA trials). Only the PRECOMBAT trial conducted by Park on the LMCA gave similar results at 5 years between CABG and PCI.12-22

The ISCHEMIA trial21,23-24 deserves its own chapter because, although the rate of myocardial infarction was significantly lower with the PCI, the significant increase of non-cardiac death in the invasive group of this trial (74% PCI) deserves an Editorial just to analyze and discuss these findings. Its similarities with the EXCEL18 trial should be a heads-up too. We should not forget that the ISCHEMIA trial included single vessel and multivessel disease. Only LMCAD was excluded, and the comparison was drawn against the optimal medical therapy.

It seems obvious that after all this time, the degree of anatomical complexity does not explain these results because, except for the Syntax I trial, the anatomical score created by the authors of this study is not predictive in favor of the PCI.25-26

Regardless of the anatomical risk score obtained, thorough meta-analyses of randomized studies have demonstrated that long-term results are favorable to CABG as shown on figure 1.26 Also, both the Syntax II registry and the FAME trials1-2,10-11,19 proved that, according to the Syntax score criterion, 3-vessel disease was later downgraded to 2-vessel disease when functional studies of the lesions like the FFR were used. As a matter of fact, the Syntax II registry demonstrated that only 37.2% of the 83.3% lesions initially considered 3-vessel disease turned out being 2-vessel disease after the FFR, which is clearly indicative that we are overestimating the severity of target lesions (Figure 2).

With this strategy in the Syntax II, after the FFR, 2.6 fewer stents per patient were implanted compared to the Syntax I (4.02 stents/patient; P < .001). Figure 2. The 5-year MACE and mortality rates of the Syntax II dropped 46% and 43%, respectively compared indirectly to the PCI group of the Syntax I (P < .001), which is somehow similar to results of the ERACI IV trial that used a modified anatomical score.27 Fewer stents implanted equal better 5-year results. This seems to be the takeaway from the Syntax II registry.

Similarly, it was interesting to see that, according to protocol, in the EXCEL18 trial, high Syntax anatomical scores were formally excluded. The operators who performed the angioplasties included 25% of the patients with anatomical Syntax scores > 32, which is indicative that investigators considered them as low or intermediate-risk patients for PCI. This reinforces the aforementioned hypothesis that, over the last few years, we’ve been overestimating the complexity of our patients with the anatomical Syntax score.

Of 3 questions asked at the foot of this Editorial, in my opinion, the most important reason to obtain persistent results over time is not stent design although it has been demonstrated that new DES designs bring about significant safety and efficacy improvements compared to former designs. Also, the benefits of DES compared to conventional stent designs (BMS) seem obvious regarding the efficacy and safety profile especially in the left anterior descending coronary artery. Still, these benefits did not translate into a lower mortality rate.28-30

However, there are some limitations that, in my opinion, are not easy to overcome since they would mostly refer to the local elution of immunosuppressant drug: early neo-atherosclerosis and endothelial dysfunction.31-36 They are both probably responsible for most adverse events reported at long-term follow-up that we saw in the clinical trials mentioned above.

Therefore, excluding stent design as the greatest predictor of persistent results in the long run after the PCI, I’ll focus on the last 2 parts of the title of this Editorial as the main causes for the aforementioned findings: revascularization strategy during angioplasty and patient selection.

Although it is plain to see that this Editorial is accompanied by many references, it shows the opinions of the author only, and that is exactly how it should be taken.

# Revascularization strategy during angioplasty

Now bringing Gruntzig back to memory we should say that plain old balloon angioplasty operated on the artery and the lesion responsible for ischemia without reshaping the target vessel.37 This is how, during the 1990s, the popular concept of optimal balloon angioplasty at the time38-39 was introduced for the very first time. Serruys called it a perfect synthesis with “stent-like results.”40 This way of performing angioplasties during the 1990s was completely eradicated since the arrival of DES. The consequence to this was that coronary restenosis was almost forgotten within the first year after DES implantation. I can still remember a SOLACI congress held in Mexico back in the first few years of the 2000s where I was asked to discuss optimal balloon angioplasties and when I said “with the arrival of DES, in the PCI era, this strategy will fall into oblivion.”

However, like we said before, the confidence that the use of DES brought to all interventional cardiologists thanks to the suppression of fibrointimal hyperplasia made us believe that stents could replace the coronary endothelium without causing additional damage. In my opinion, this was one of the biggest mistakes ever made in the era of the current PCI revascularization strategies.

We should not forget that arterial endothelium is an organ with very important and specific functions, and that the loss of these functions predisposes to more cardiac and non-cardiac adverse events.35,41 That is, we shouldn’t unnecessarily wish to replace the coronary artery endothelium for a DES because regardless of the DES design they all eventually develop endothelial dysfunction in their proximal and distal segments or inside the stent after implantation.36

If we analyze the trials mentioned above, the length of the stent implanted, and the number of stents implanted beyond the implantation criterion we’ll see that the numbers are quite similar. The Syntax I trial includes a first-generation DES with a median stent length of 88 mm that is similar to the BEST trial with its second-generation DES, and recently the FRAME 3 trial with its third-generation DES and use of FFR-guided angioplasty. In all these trials, interventional cardiologists seem to over-implant stents and forget that the arterial endothelium is an organ that should be spared and replaced under special circumstances only.

In conclusion, since they’re extremely confident with the devices currently used, the new generations of interventional cardiologist seem to forget all about endothelial physiology and histology. As a matter of fact, several generations of interventional cardiologists trained over the last 20 years have never gotten to know optimal post-balloon results and cannot finish a successful angioplasty procedure without DES implantation.

Having negative controlled studies regarding angioplasty time and time again, even compared to medical therapy, should be a call for reflection and the implementation of new teaching strategies for those who start practicing our specialty.

If we compare the Syntax II and the FAME 3 clinical trials with the same design of DES, and same use of FFR, we see that results were completely different11,19 The Syntax II respected the results of the functional analysis of the lesions and the rate of stenting was much lower with significant reduction of 5-year adverse events as shown on figure 2.

By contrast, in the FAME 3 trial, despite the use of FFR, the number of stents implanted did not go down or the total amount of stent length with a mean of 80 mm, which is similar to the original Syntax I and had negative results at 1 year. It is expected that these results will be even more unfavorable at the long-term follow-up.

The FAME 3 trial is a clear example of the erroneous strategy of DES implantation for the current generation of interventional cardiologists.

# Patient selection

This last section is directly associated with the strategy used during PCI.

If we study the 5-year results of LMCAD—shown on figure 3A of this meta-analysis—we’ll see that the mortality rate between PCI and CABG is the same (RR, 0.93%; CI, 0.7-1.21).42 But this is so because we included studies that used DES that are not available in the market anymore and, theoretically, had already become obsolete due to new designs. If we look at this graph, we’ll see that only in the last 2 studies—the NOBLE and the EXCEL—where we used stents in the routine clinical practice we’ll be surprised to see that results clearly favor CABG (RR, 0.78%; CI, 072-0.99), suggestive that both patient selection and the revascularization strategy are more important than stent design.

The same thing happens if we compare the results of CABG and PCI at 10 years in the meta-analysis shown on figure 3B: mortality is similar both in LMCAD and MV disease between CABG and PCI. Also, all these clinical trials were conducted with different stent designs and most outside the current routine clinical practice.

This figure forest plot43 clearly shows that in the subgroup of MV results tend to favor the angioplasty in the MASS II trial (RR, 0.95%; CI, 0.36-1.36), and be very detrimental in the Syntax I trial (RR, 1.35%; CI, 1.09-1.67). The MASS II trial used BMS while the SYNTAX I used first-generation DES.

In the studies of patients with LMCAD at 10 years including the LE MANS (RR, 0.70%; CI, 0.36-1.36), Syntax I (RR, 0.94; CI 0.74-1.20), and PRECOMBAT clinical trials (RR, 1.05%; CI, 0.70-1.57) no survival differences were seen between PCI or CABG regardless of the device used (Le Mans, BMS [65%], Syntax I and PRECOMBAT, first-generation DES).

The results of these 2 meta-analyses suggest that, unlike many other claim, PCI and CABG have similar long-term survival outcomes both regarding MV disease (RR, 1.16%; CI, 0.83-1.63) and/or LMCAD (RR, 0.94%; CI, 0.78-1.15). Also, these data favor patient selection and revascularization strategy during PCI as being more important compared to stent design to achieve long-term results.

In sum, technological advances are very important, but only if used reasonably. The Syntax II and FAME3 trials are opposite example of a good (Syntax II) and poor (FAME 3) revascularization strategy. Stenting should only be performed on lesions that trigger ischemia and/or in the presence of procedural complications.

The results from randomized clinical trials should be read, learned from, and reasoned so they can be applied in the routine clinical practice to confirm—if favorable—or discard such results—if unfavorable. What just can’t happen is making the same mistakes all over again.

To think that angioplasty in elective chronic patients should be abandoned and that the center of attention should be on structural heart disease and peripheral vascular disease would be a huge mistake. The latter are being treated in many parts of the Western world, China, India, Korea, Australia, etc. by specialists who are not interventional cardiologists.

The management of chronic coronary artery disease using PCI should be redesigned and rethought with new and old strategies.44-48 The meta-analyses conducted by Hlatky (2009, 2012),45-46, the most cited author in his field, as well as those conducted by Head (2018),47 and Gaudino48 (2020) speak for themselves, and should be recommended readings for those who start practicing interventional cardiology.

It all depends on how we want to learn history: by watching movies or reading books.

Dr. Alfredo E. Rodríguez, PhD, MD

Editor-in-chief. Argentine Journal of Interventional Cardioangiology (RACI)

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What is more important to have favorable long-term outcomes after a percutaneous coronary intervention: sent design, revascularization strategy or patient selection?

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