Management of Diffuse Coronary Artery Disease with an overview of Recent Trials

INTRODUCTION

Diffuse coronary artery disease (CAD) is defined as a coronary lesion >20 mm with pressure wire (PW) pullback showing a progressive, gradual decrease in pressure in the diseased segment without an abrupt pressure drop. It could involve a single, double, or all three vessels.^[1,2] Diffuse (CAD) is a management challenge and though the occurrence has been historically reported to be about 20%, a greater number requiring long stents are encountered in day to day practice.^[3-7] Diffuse CAD has two faces, namely, obstructive and non-obstructive and choosing the correct treatment modality depends on the presentation.^[8] In mild diffuse disease or with unsuitable anatomy, optimal medical therapy (OMT) is the sheet anchor. Van Beek et al. reported that OMT in diffuse left anterior descending (LAD) disease was not inferior to coronary artery bypass grafting (CABG) or stenting.^[9] Severe diffuse disease needs to be salvaged with interventions or surgery and they are not without drawbacks because longer stents are an independent predictor of target vessel failure and revascularization while CABG may be associated with incomplete revascularization, and need for prolonged mechanical supports.^[7-9]

DIFFUSENESS SCORE (DS)

There are several scoring systems to determine diffuseness of CAD including those by Kirali et al., Graham et al., etc. McNeal et al.^[5,8,10] developed a score, taking into account both luminal diameter and extent of the left ventricular myocardium supplied by the involved vessel. The left ventricle was categorized into eight segments, and each vessel weighted depending on the extent of myocardium it supplied.^[2] The total distal DS was a product of weightage and grade of vessel occluded. DS >18 had a higher complication rate when compared to non-diffuse disease.^[7]

PRESSURE STUDIES

Diffuse CAD influences catheter derived physiological indices which, in turn, determine percutaneous coronary intervention (PCI) outcomes.

Fractional flow reserve (FFR) is mandatory before revascularization of intermediate-coronary lesions.

Large randomized clinical trials have indicated that nonhyperemic pressure ratios (NHPRs) and like instantaneous wave-free ratio (iFR) is not inferior to FFR.^[1]

Quantitative coronary angiography (QCA) estimates the coronary stenosis by matching the stenosis diameter usually with the guiding catheter. A discordance between quantitative coronary analysis (QCA) and FFR was seen in more than 60%, that is, QCA abnormal/FFR normal in 43% and QCA normal/FFR abnormal in 23% in the (CVIT)-DEFER registry lead to reclassification of the disease in 35%. Imaging revealed that this disparity may be due to plaque eccentricity and variation in plaque ruptures and ulceration.^[1]

Similarly, Warisawa et al.^[1] reported that myocardial perfusion imaging evidence of inducible ischemia is less common in FFR/NHPR discordant cases, than in positive concordant cases. So with borderline physiology, clinical judgment should guide treatment decisions.^[1]

De Bruyne et al.^[1] showed that hyperemic pullback pressure gradients (PPGs), either motorized or manual (range 0–1), are useful in lesions with abnormal FFR (≤0.80), where a higher PPG index indicates more focal disease and a low (range: 0–0.47) indicates diffuse disease. Instantaneous FFR gradient per unit time ((dFFR[t]/dt) - instantaneous fractional flow reserve (FFR) gradient per unit time is a good alternative to PPG.

The disadvantage of physiologic measurements is the lack of physiologic/angiography correlation, need for motorized pullback systems, and adenosine infusion with its attendant cost and side effects.^[1]

VIRTUAL PCI

A promising angiography-derived index in diffuse CAD, which is superior to angiography alone and gives a virtual hemodynamic mapping of the coronary artery, is the quantitative flow ratio (QFR) which integrates 3D angiographic reconstruction of the vessel with flow dynamics, without PW or hyperemia and correlates well with FFR. HAWKEYE study reported that pre-PCI QFR discriminates the various CAD patterns and can predict the post-PCI results.^[11,12] Post hoc analysis of the HAWKEYE trial was done for detecting the functional pattern of CAD by identifying drops or progressive decline or both in the pre-PCI QFR virtual pullback and a quantitative QVPindex. This helped planning to go ahead with PCI or avoiding it. In the HAWKEYE trial, increased vessel-related cardiac events occurred at QFR values ≤0.89 which can have been avoided with pre-PCI QFR analysis.^[13]

Similar results have come from the favor and other studies.^[1]

Sukhjinder et al. reported that iFR pullback provided a physiological mapping of the entire vessel, to determine the functional disease extent and contribution of each stenosis to the total disease burden. It showed a good correlation between the expected and observed iFR pre- and post-treatment.^[14,15]

The reports of the iFR GRADIENT registry also indicated that online iFR pullback could predict PCI outcome in diffuse lesions.^[1]

The QFR index is the maximal drop of QFR over 20 mm from the ostium to the distal epicardial segment. The QFR index of 0 indicates diffuse disease and 1 is for focal stenosis.^[1,11,12] The use of QFR to guide PCI showed a 2.6% reduction of adverse events when compared to angiography-guided PCI.

Analysis from PANDA III, a multicentric trial comparing BuMA eG-Based BioDegradable Polymer Stent with EXCEL Biodegradable Polymer Sirolimus-eluting Stent in “Real-World” Practice) trial, Zhang et al. showed that a low residual QFR (≤0.92) was associated with higher coronary vascular events at 2 years.^[16]

REFINE RPG trial studied the resting full-cycle ratio (RFR) and diastolic pressure ratio (DPR) and iFR pullback pre-PCI which predicted the functional results post-PCI similar to iFR pullback. Therefore, physiological improvement and fewer and shorter treated coronary segments were possible with pre- and post-NHPR pullback.^[17]

PACIFIC-1 sub-study reported that the RFR and DPR correlated well with FFR, with a hyperemic-free strategy similar to FFR-guided revascularization.^[18]

INTRACORONARY IMAGING

Intracoronary imaging though costly and time consuming is useful for the accurate assessment of pre-PCI coronary morphology and for PCI optimization. The optical coherence tomography (OCT)-based FFR (OFR) overcomes the need for PW or hyperemia. OFR has an accuracy of 84%, practically nil intraobserver and interobserver variations, which can accurately evaluate de novo lesions and in-stent restenosis. Intravascular ultrasound (IVUS)-derived physiology has a sensitivity of 92%, and specificity of 91%, negative predictive value of 96%. IVUS-guided PCI is superior to angiography guided PCI in diffuse disease, decreasing the risk restenosis and target vessel revascularization (TVR) as was reported in a meta-analysis of seven randomized trials, and a lower likelihood of MACE as reported in the Impact of Intravascular Ultrasound Guidance on Outcomes of Xience Prime Stents in Long Lesions. (IVUS-XPL) trial even with long coronary lesions. Even with IVUS-guided PCI, suboptimal physiology was associated with suboptimal outcome.^[1]

In the FFR React trial, IVUS-guided post-PCI FFR optimization either by additional stenting or post-dilatation, significantly improved post-PCI FFR.^[19]

OCTIVUS Clinical Trial showed that OCT-guided PCI was not inferior to IVUS-guided PCI with regard to cardiac death target vessel-related myocardial infarction (MI) or TVR at 1 year.^[20]

In IVUS-XPL Randomized Trial, IVUS-guided versus angiographic-guided stent implantation showed a lower MACE in the former even 5 years after implantation.^[21]

The RENOVATE-COMPLEX-PCI trial, a randomized trial in patients with complex CAD reported that PCI guided with intravascular imaging showed better outcomes in terms of cardiac death, target vessel MI, and TVR compared to angiography guided PC in diffuse coronary lesions >38 mm.^[22] In secondary analysis of this trial, intravascular imaging guidance was superior to angiographic guidance particularly in non-diabetics and in diabetics with good glycemic control.^[23]

Major adverse cardiac events between 1 and 5 years occurred in 17 patients (2.8%) receiving IVUS guidance and in 31 patients (5.2%) receiving angiographic guidance.

DRUG-ELUTING STENTS (DESs)

Diffuse CAD is considered a difficult challenge for coronary stenting because the lesion length is an important predictor of restenosis. DESs have significantly annulled this relationship between stent length and restenosis. Five clinical trials, namely, Sirolimus-Eluting Stent in Coronary Lesions (SIRIUS), European Sirolimus-eluting stent in coronary artery disease (E-SIRIUS), Canadian Study of the Sirolimus-Eluting Stent in the Treatment of Patients With Long De Novo Lesions in Small Native Coronary Arteries (C-SIRIUS), DIRECT, and The SVET (Safety and Efficacy of Very-Long Stents) trial (SVET) reported that two or more overlapping sirolimus-coronary stents showed superior results compared to bare metal stents.^[24]

Long-term studies have revealed that stent length is an important predictor of stent failure in first-generation DES. Two large registries on newer-generation DES in diffuse CAD, namely, GRAND Drug eluting stent registry (GRAND-DES) registry with over 9,200 patients who were divided into two groups based on stent length and followed up for 2 years. Showed that at 2 years the primary endpoint, target lesion failure (TLF) (8.1% vs. 4.5%; P < 0.001), cardiac death (4.3% vs. 2.5; P < 0.001), and TLR (4.1% vs. 2.1%; P < 0.001) were more common with long-stent (≥40 mm).^[4]

The study by Youn et al. compared the results from ultra-long stent group (DES >48 mm) and the regular DES group which showed similar cardiac death, target vessel-related MI, and target lesion revascularization at 1-year follow-up.^[25]

A 44-year-old symptomatic male with diffuse right coronary artery (RCA) and left circumflex artery (LCX) disease underwent stenting of RCA and LCX [Figures 1a-b and 2a-b].

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Figure 1:

RCA diffuse disease (a) before and (b) after stenting. (RCA: Right coronary artery.)

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Figure 2:

LCX diffuse disease (a) before and after (b) stenting. (LCX: Left circumflex artery)

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DRUG-COATED BALLOONS (DCBs)

Several studies have shown DCB as good alternatives for DES in diffuse long-segment lesions as a part of “limit the amount of metal strategy” due to the complications with long stents and to reduce duration of antiplatelets in persons with bleeding risk.^[4,26] Development of very-long stents to reduce use of overlapping stents has not prevented stent failure and a combined DCB/DES or a only DCB strategy is an important alternative.^[4,27]

These results have highlighted the usefulness of paclitaxel-DCB where late lumen enlargement can be seen even at 5 months probably due to the drug effect on tunica adventitia.^[4]

In a study cohort of 373, primarily de novo, small and diffuse CAD, using the Magic Touch sirolimus-DCB, patients experienced low cardiac death (1.7%), low TLR and MACE, and no acute vessel closure.^[4]

Diabetes mellitus (DM) is considered an important risk factor for stent failure. Pan et al comparing the outcome of DCB in 1,156 patients with and without DM and at 1 year of follow-up showed similar MACE, cardiac death, or revascularization in both groups (P = 0.058), though the TLF and TLR were higher in DM patients.^[4,28]

A prospective, multicenter, and randomized trial comparing sirolimus-coated balloon versus paclitaxel-coated balloon for treating in-stent restenosis after DES showed no difference in clinical outcomes, death, MI, or revascularization in the two groups at 12 months.^[29]

DCBs VERSUS DES

PICCOLETO II compared the efficacy of new generation DCB with everolimus eluting stent (EES Abbott Vascular, USA) in vessels <2.75 mm and reported it to be superior to EES in terms of late-lumen loss (LLL) at the 6-month follow-up and a significant reduction in abrupt vessel closure and MACE (10.8% vs. 20.8%) after 3 years.^[4,30]

A randomized clinical trial by Yu et al. in large-vessel disease >2.25–4 mm compared paclitaxel DCB and new generation zotarolimus-eluting DES on LLL at 9 months and MACE at 12 months which showed non inferiority of DCB compared to DES.^[4,31]

A large trial of 1,025 patients by Rosenberg et al., comparing DCB with DES both in small and large vessel disease showed no significant differences in TLR (3.8% vs. 1%; P = 0.20) or MACE (5.7% vs. 6.11%; P = 0.903) between the two groups indicating that the results of DCB-only strategy were not related to vessel diameter.^[32]

Costopoulos et al. compared paclitaxel DCB/DES versus DCB only strategy. At the end of the 26 months, similar MACE frequency (20.8% vs. 22.7%; P = 0.74) and TVR (14.8% vs. 11.5%; P = 0.44) and TLR rates (9.6% vs. 9.3%; P = 0.84), in the DCB versus DCB/DES-only groups.^[4]

The HYPER was a prospective, multicenter trial studying diffuse CAD patients on hybrid treatment with DES and Restore Drug eluting balloon (DEB). It showed that 1-year primary endpoints such as cardiac death, target vessel MI was as low as 3.7% and procedural success was 96.2%. The 2-year Device oriented composite endpoint (DoCE) was 4.6%, which remained the same even in the 3-year analysis-Ielasi et al.^[4,33]

SPARTAN DCB trial compared paclitaxel-DCB-only and second-generation non-paclitaxel DES in 1550 patient with CAD lesion >26 mm for 5 years. The DCB group had better results than the DES group in terms of composite end point (cardiac death, MI, and TLR) and mainly in the TLR (3.0% vs. 11.0%, P = 0.12.^[4,34]

Jun et al. retrospectively studied use of DCB in 93 Chronic total occlusion (CTO) lesions associated with diffuse disease and found a low 2 year cardiac death of 2.4%, MI-3.6%, and no vessel thrombosis.^[4,35]

A large multicenter prospective study by Yang et al. to compared DCB alone or hybrid DCB/DES in long and diffuse coronary lesions. Though immediately after PCI, the DCB group had lower MLD and LLL, the 3-years TLR, MACE, and cardiac death were similar in both groups.^[4,36]

A meta-analysis of 10 randomized clinical trials (Drug-Coated Balloon Angioplasty Versus Drug-Eluting Stent Implantation in Patients With Coronary Stent Restenosis). conducted by Giacoppo et al. with paclitaxel DCB versus DES in Instent Restenosis (ISR) showed that the primary endpoint of all-cause death, MI, or target-lesion thrombosis was similar in both groups at 3 years.^[4,37]

A retrospective study on the use of DCB in 254 patients with 12 multi-vessel CAD where patients were assigned to either a 13 DCB ± DES or a DES-only strategy, reported after 2 years, that DCB group was associated with a lower MACE compared to the DES group 15 (3.9% vs. 11.0%; P = 0.002).^[4,38]

PICCOLETO III is a randomized trial for follow-up for 5 years, studying the usefulness of either a paclitaxel- or a sirolimus-DCB versus DES in complex lesions including very-long lesions.^[4]

TRANSFORM II trial is a randomized clinical trial comparing Sirolimus-coated DCB versus everolimus-eluting DES in de novo CAD with lesions up to 50 mm in small vessels 2–3 mm. The recruitment will close in 2025 and results will be reported in 2028.^[39]

BASKET-SMALL 2 trial compared DCB (B. Braun, Germany) vs. DES (75% EES, 25% paclitaxel-DES) for MACE and all-cause death in patients with vessels 2 and 3 mm. There were no significant differences in the two at 3-year follow-up in small coronary arteries but DCB was much superior to DES with regard to TVR, non-fatal MI, and MACE in very small coronary arteries.^[4,40]

PCI OPTIMIZATION

In 30%, even after successful PCI by angiography, physiological studies may show suboptimal findings and the HAWKEYE study showed that this was more common with diffuse than focal disease (33% vs. 8% P = 0.03).^[1,11-13]

Immediate post-PCI OFR revels coronary physiology and stent expansion and apposition within a single catheter. Simulated residual OFR is useful to determine the best stenting landmark to obtain the ideal functional result and to predict the amount of residual ischemia after PCI. The use of both simulated residual OFR and post-PCI OFR provides information to enable complete revascularization.

In the OxOPT-PCI study, post-PCI OFR correlated well with post-PCI wire-based FFR. Suboptimal post-PCI FFR values (<0.90) were due to missing the plaque, stent malposition, stent under expansion, and thrombus and major stent edge dissection which was picked up by OCT. Post-OCT, PCI optimization with stenting, or post-dilatation resulted in significant FFR increase to >0.90.^[1,41]

Similarly, the DEFINE PCI study showed iFR <0.90 in 24.0% after angiographically successful PCI of focal or diffuse disease.^[1]

Another trial which was IVUS-guided PCI optimization after suboptimal physiology and successful PCI in angiography was the FFR-REACT study - Fractional Flow Reserve-guided Percutaneous Coronary Intervention Optimization directed by High-Definition Intravascular Ultrasound versus Standard of Care.^[19]

Similar findings of suboptimal physiological finding after angiographic successful PCI were observed in the TARGET-FFR trial, but there was no reduction of TVF at 1-year follow-up.^[1]

DEFINE-GPS trial assessed the utility of physiology-guided stenting using iFR in combination with image-guided systems to provide superior PCI outcomes. Combined use of physiology and imaging PCI optimization gives more insight for long-term reduction of adverse events.^[1]

CABG

Diffuse CAD was at one time considered not amenable to revascularization. Studies have reported that patients with diffuse CAD managed surgically, fare better than on OMT.^[42] Despite this, CABG in diffuse CAD is a challenge, punctuated with the problems of incomplete revascularization, early graft occlusion, ventricular dysfunction, need for extended mechanical supports, and frequent hospitalization. Shapira et al.^[42] had reported on left internal thoracic artery (LITA) on lay patch after long-segment arteriotomy which was abandoned due to progressive aneurysmal dilatation. Since then several techniques were considered. The LITA is however considered the best vessel for grafting the LAD artery due to lasting patency and diminished likelihood for atherosclerosis. LAD reconstruction with or without endarterectomy by Kato et al.^[42], also gave give encouraging short- and long-term results. Ramasubrahmanyam et al.^[42] have reported that that endarterectomies should be reserved for heavily calcified lesions where vessel lumens are very narrow and unsuitable for conventional surgery. They felt that that plaque exteriorization and flap repair with LITA was a better technique to reduce thrombosis.^[22] Sequential anastomoses, usually with the LITA or rarely with the right internal thoracic artery for treating diffuse, multiple lesions has also been promising^[42,43] Overall, surgically managed diffuse CAD had good post-operative recovery with 2.43% versus 14% mortality in medically managed cases – Ramasubrahmanyam et al.^[42] Large viable area of myocardium is an indication for CABG even when it is difficult to find a normal segment for anastomosis. When the arteries are not ideal for grafting or with unhealthy conduits, less invasive techniques include “don’t touch the plaque” techniques such as jumping multi-bypass grafts, sequential bypass, and hybrid revascularization where there is a combined benefit of grafting the left internal mammary artery-to-LAD and, placement of stents in the other obstructed arteries. (5) Rarely, “Touch the plaque techniques” such as long-segment anastomosis, patch-plasty, and endarterectomy ± patch-plasty are employed in patients branded as unsuitable for surgery.^[5,44]

MANAGEMENT OF DIFFUSE SMALL VESSEL DISEASE

Stenting diffuse small vessel disease with lumen diameter of ≤2.0 mm is challenging and is associated with inadequate lesion coverage and distal edge dissection. Modified stenting strategy as reported from Chang Gung Memorial Hospital, Taiwan, by placing oversized DES in the largest diameter of the distal vessel with partial expansion of the distal edge of the DES to ensure more lesion coverage resulted in a lesser risk of edge dissection. The immediate and long-term procedural success was comparable to stenting in vessels >2 mm.^[45]

DUTCH PEERS (TWENTE II) trial, however, reported a 9.5% target lesion failure at the 2 years follow-up for lesions measuring <2.5 mm using second-generation DES^[45,46] and the BIO RESORT trial using three different second-generation stents in small vessels<2.5 mm had a Target vessel failure (TVF) rate of 7.0–9.5% at 3years.^[46]

CABG is another alternative in small vessels, but the in-hospital mortality and 1 year graft patency were worse than with PCI, particularly for LAD lesions.^[45] DCB is alternative in small vessels and has been shown to be non-inferior to DES.^[45]

DIFFUSE DISEASE IN MINOCA

MINOCA is not exactly a benign entity and has a 12-month all-cause mortality of 4.7%^[42] and intravascular imaging and pressure flow studies have shown diffuse disease in what seems as insignificant CAD by angiography.^[47] Management of MINOCA is usually OMT; however, PCI should be considered in high-risk culprit lesions detected by intravascular imaging.^[47]

STEM CELLS IN DIFFUSE CAD

Stem cell treatment has shown promise in IHD, not so much due to their incorporation into the injured myocardium but due to their paracrine function. Several pharmacologic and non-pharmacologic pretreatment to optimize stem cells for their homing potential are being studied.^[48]

CONCLUSION

People with diffuse CAD can lead productive lives with aggressive care and a heart-healthy lifestyle. CAD with anatomy unsuitable for revascularization has to be on OMT. Percutaneous and surgical revascularizations are not always feasible in diffusely diseased vessels. Pressure pullback techniques, hybrid physiology, and angiographic road map are facilitative in the management when stenting and CABG are the chosen option. A combination of imaging and physiology is sometimes mandatory for PCI optimization in diffuse disease. PCI in diffuse lesions of vessels ≤2.0 mm requires modified stenting strategies. DCBs have been shown to be safe, and effective as an alternate approach to overcome suboptimal results with DES and in patients with high bleeding risks. Need for better surgical techniques is mandatory. Stem cell therapy, although hypothetical now can become a reality in the future.