Feasibility and Clinical Outcomes of 48 mm Drug-Eluting Stents in the Management of Patients With Coronary Artery Disease

Background. Long coronary lesions represent a formidable challenge during percutaneous coronary intervention (PCI). Implantation of multiple contiguous stents may result in sections of overlapping stents or gaps of unstented segments and is an independent predictor of restenosis and major adverse cardiovascular events (MACEs). Objectives. The study goal was to assess the feasibility and short-term clinical outcomes of implanting 48 mm drug-eluting stents (DESs) for the treatment of long lesions in patients with coronary artery disease (CAD). Methods. This prospective study enrolled 300 patients, with a single CAD planned to undergo PCI with 48 mm DES. Clinical data, procedural outcomes, and follow-up to 6 months were obtained. MACEs were considered the combined study endpoint, defined as cardiac death, non-fatal myocardial infarction, unstable angina, and the need for target-lesion revascularization (TLR). Results. Among the 300 subjects enrolled, 80% were men and mean age was 60.8 ± 8.6 years. Procedural success rate was 97.3%. Failure of crossing was encountered in 4 patients due to severe tortuosity. Six-month clinical outcome was compared between diabetic (DM) (n= 90) and non-DM patients; 6-month cumulative MACEs were significantly lower in the non-DM group than in DM group (2.9% vs 13.3%, respectively; P=.01). Clinically driven TLR was 4% and 2 cardiac deaths were reported. The independent predictors of repeat revascularization were insulin-treated type 2 DM and reference vessel diameter (RVD) ≤2.75 mm. Conclusion. The use of 48 mm DES is feasible, safe, and cost effective in the treatment of long coronary lesions. Independent predictors of repeat revascularization are type 2 DM and RVD ≤2.75 mm.

J INVASIVE CARDIOL 2021;33(12):E960-E967. Epub 2021 November 24.

Key words: coronary artery disease, drug-eluting stents, percutaneous coronary intervention

Coronary artery disease (CAD) remains a major cause of morbidity and mortality throughout the world, despite all advances in medical therapies. Although the survival rate of patients with CAD has been steadily improving, CAD caused an estimated 17.3 million deaths in 2013.¹ Nine percent of all deaths in the North Africa and Middle East region result from CAD.²

Stent implantation has become the treatment of choice for patients with CAD during percutaneous coronary intervention (PCI).³ Stents, compared with simple balloon angioplasty, reduce overall mortality in non-acute CAD and reinfarction rates in acute CAD.⁴ Despite this tremendous development in PCI, long lesions, which represent a significant proportion of PCI, present specific challenges. Even with current-generation drug-eluting stent (DES) options, lesion length is a major predictor of adverse outcomes after PCI, including stent thrombosis (ST) and in-stent restenosis (ISR).^5,6

Coronary stenting is currently the technique of choice during PCI.⁷ Bare-metal stents demonstrated superiority over balloon angioplasty, and led to improved angiographic results and clinical outcomes. Despite that, neointimal hyperplasia and restenosis remained major limitations to bare-metal stent use.⁷

Subsequently, DES options were designed to minimize neointimal hyperplasia and decrease repeat revascularization, but an increased risk of late ST was unfortunately observed with the first generation of devices.⁸ Newer-generation DES options have been developed with consequent evolutions in stent design to ensure thinner struts as well as improved drug-eluting platforms and delivery systems to reduce both restenosis and acute, subacute, and late ST.⁸ They have shown superior safety and improved efficacy compared with first-generation DES devices. The current DES generation has an excellent performance and safety profile across a broad range of patients and allows PCI to be successfully completed even where anatomy is complex.^9,10

Moreover, the practice of interventional cardiology has progressed significantly, with improved adjunctive medical treatment and advances in technology other than coronary stenting, such as devices directed at specific technical problems (eg, rotablation and atherectomy catheters).¹⁰ Despite these tremendous advances, long lesions are a major predictor of adverse outcomes after PCI,¹¹ including ST and ISR.^5,6

Long lesions are often under-represented in clinical trials, partly due to the marked heterogeneity in definition and partly due to previously limited stent lengths.¹¹ Consequently, there are few data documenting outcomes in this patient cohort, and data are predominantly derived from subanalyses of larger trials where overlapped devices were used.^12,13 The use of ultra-long stents to cover the diseased segment in a single device is extremely appealing.

The current options for the elective treatment of long stenoses or bail-out treatment of long dissections include implantation of a single long stent, multiple contiguous stents, or spot stenting. As compared with using a single longer stent, the use of multiple stents leads to impaired vascular healing,¹⁴ often resulting in complications. There are data on “full-metal jacket” stenting or vessel reconstruction for diffuse coronary lesions. However, the total stented length as well as the overlapped segments predispose to adverse events. Technical difficulties with multiple stent implantations include long, overlapping segments that may lead to greater periprocedural complications including myocardial ischemia,¹⁵ stent fracture,¹⁶ late ST, and sidebranch occlusion.^17,18 Multiple contiguous stents have also been identified as an independent predictor of ISR.^19,20 Conversely, gaps of unstented segments may lead to geographical miss.^21,22  Moreover, these procedures are time consuming and expensive

The study was conducted on 300 patients who presented to the catheterization laboratory at 2 tertiary-care hospitals for PCI of coronary arteries with significantly long lesions (≥40 mm). We included patients >18 years of age, with single-vessel disease and undergoing PCI with a 48 mm stent for a significant long lesion. Informed consent was obtained from each patient. All enrolled patients were subjected to history taking, clinical evaluation, standard electrocardiogram, laboratory investigations, and echocardiography.

Preprocedural preparation. Aspirin 300 mg orally, was given as a loading dose before the procedure if the patient was not maintained on aspirin prior to PCI.^23,24 If the patient was not maintained on a P2Y₁₂ inhibitor or presented with an acute coronary syndrome, loading with either clopidogrel (600 mg orally) or ticagrelor (180 mg orally) was given before the procedure.^23,24 Ticagrelor was preferred in cases presenting with acute coronary syndrome.

PCI procedure. The transfemoral approach was used in most patients, usually utilizing a 6 Fr sheath. The transradial approach was used according to the operator’s experience and logistics. As soon as the arterial sheath was in place, a dose of 70-100 IU/kg unfractionated heparin was injected, with additional heparin doses given in order to maintain an activated clotting time of 250-350 seconds.

Coronary angiography was performed to assess the target lesion regarding the site of the stenosis/occlusion (target  vessel and site of lesion within the vessel);²⁵ degree of the stenosis, which was estimated from the percent reduction in luminal diameter compared with a non-affected proximal segment of the vessel by visual assessment and quantitative coronary angiography in several projections; TIMI flow grade; presence of thrombus and assessment of thrombus burden; presence of significant tortuosity; and presence of significant calcification.

Six Fr guiding catheters were utilized in most cases, and several types of guidewires were used, including floppy, intermediate, and hydrophilic wires. Although the guiding catheter and guidewire selections were influenced by criteria related to the vessel anatomy, lesion morphology, and the devices to be used, the selection was sometimes based upon the operator’s experience and preference. After the guidewire successfully crossed the target lesion, subsequent balloon predilation was done if needed and implantation of a 48 mm DES of appropriate diameter was attempted. Either Xience Xpedition (Abbott Vascular) or Eucalimus (Eucatech) was selected according to the availability of an appropriate size or the decision was left to the preference of the PCI operator. Planned overlap was not allowed except in the case of bail-out for stent edge dissection. Balloon postdilation using non-compliant balloons was done if indicated.

Post-PCI management. Post PCI, access site care was performed, and a 12-lead electrocardiogram was obtained. Patients were monitored in a coronary care unit that has continuous electrocardiographic monitoring with routine post-PCI care. Medications included the following: acetylsalicylic acid 75-100 mg/day for all patients without allergy; clopidogrel 150 mg/day for 14 days and 75 mg/day thereafter or ticagrelor 90 mg twice daily for at least 6 months (in cases of PCI for chronic coronary syndrome)^23,26 or 12 months (in cases of PCI for acute coronary syndrome);^24,26,27 statins in all patients without contraindications to achieve target low-density lipoprotein cholesterol levels;²⁸ and beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin-receptor blockers, as well as spironolactone when indicated (and if no contraindications existed).

Follow-up. Patients who complained of recurrent angina symptoms were reassessed clinically first, then by non-invasive imaging or invasive angiography if indicated. In case of admission, hospital records were screened for the occurrence of clinical events to confirm the obtained information. Follow-up data were classified into in-hospital or 6-month follow-up.

Definitions. Device success was defined as the successful crossability and deployment of the stent. Lesion success was defined as achievement of Thrombolysis in Myocardial Infarction (TIMI) flow grade 2 or 3 and myocardial blush grade 2 or 3 with <20% residual stenosis of the target lesion in the final angiogram. Procedural success was defined as lesion success without in-hospital major adverse cardiovascular events (MACEs). Any complications during the procedure were documented, along with the appropriate management.

Statistical analysis. Data were analyzed using the Statistical Package for Social Sciences, version 25 (SPSS). In all statistical tests, level of significance of .05 was used, below which the results were considered to be statistically significant.

Three hundred patients were included and 240 (80%) were men. Mean age was 60.8 ± 8.6 years. Smoking was the most common risk factor, in 162 patients (54%). Ninety patients (30%) had diabetes mellitus (DM), 106 (35%) had hypertension, 116 (39%) had dyslipidemia, and 52 (17%) had positive family history in first-degree relatives. A total of 152 patients (51%) presented with acute coronary syndromes, of whom 66 (43%) presented for emergency primary PCI for ST-segment elevation myocardial infarction (STEMI) and 148 (49%) presented with stable CAD. Among the 90 DM patients, only 31% were controlled (defined as hemoglobin [Hb] A1C ≤7%) at the time of presentation.

All subjects enrolled in the study had a single-vessel CAD. The left anterior descending (LAD) coronary artery was the most common target vessel for revascularization in 182 patients (61%), followed by the right coronary artery in 82 patients (27%), and left circumflex artery (LCX) or one of its obtuse marginal branches in 26 patients (9%). Ten patients (3%) had left main disease that extended to (or was associated with) a significant ostial or proximal LAD lesion.

Angiography revealed significant calcification in 22 patients (7%), significant tortuosity in 18 patients (6%), and chronic total occlusion in 20 patients (7%). Bifurcation lesions that ended with single-stent approach were observed in 42 patients (14%) while 14 patients were excluded from the study due to stenting of the sidebranch in addition to the main branch. An intracoronary fresh thrombus was visualized in 30 STEMI patients (10%), 12 of whom underwent thrombus aspiration.

All patients were loaded with either ticagrelor 180 mg (n = 194; 65%) or clopidogrel 300 mg (n = 106; 35%). The majority of the subjects underwent PCI through femoral access (n = 196; 65%), whereas 94 patients (31%) underwent PCI through radial access. In 10 patients (3%), radial access was shifted to femoral access due to difficult engagement or severe tortuosity.

Thrombus aspiration was done in 12 patients (4%). Balloon predilation was done in 220 cases (73%). Most subjects (n = 186; 63%) underwent implantation of 48 mm everolimus-eluting stents, while the rest (n = 110; 37%) underwent implantation of a 48 mm sirolimus-eluting stent. Patients who needed an additional stent overlapped with the 48 mm stent (due to lesion under-estimation) were excluded from the study. The most common stent diameters used were 3.5 mm (n = 88; 30%) and 3 mm (n = 86; 29%), followed by 2.75 mm (n = 72; 24%), 3.25 mm (n = 22; 7%), 4 mm (n = 18; 6%), and 2.5 mm (n = 10; 3%). After successful stent deployment, all stents were postdilated using non-compliant balloons up to high atmospheric pressures. Glycoprotein IIb/IIIa inhibitor was used in 38 patients (13%).

Successful delivery of the 48 mm stents was obtained in 296 patients (98.7%). Difficult crossing was met in 14 patients (4.7%) and was overcome by use of buddy-wire technique or with the use of a more supportive guide catheter. Failure of crossing was encountered in 4 patients (1.3%) due to the presence of severe tortuosity and calcification and unavailability of extension guide catheter in the catheterization laboratory at the time of the procedure. There were no cases of stent fracture or edge dissection. Slow flow was encountered in 18 cases that were treated with intracoronary verapamil, but there were no cases of no reflow. Procedural success rate was 97.3% due to the occurrence of 4 cases of pulmonary edema after presenting with anterior STEMI; they resolved after revascularization and were successfully weaned from mechanical ventilation (Table 1).

Access-site hematoma occurred in 20 patients (7%); all occurred with femoral access, and only 2 patients had significant anemia and needed blood transfusion. No access-site arterial dissection occurred (Table 1).

MACEs were encountered in 18 patients (6%). One patient died in the fourth month post PCI and another patient died in the fifth month, with probable ST. Both patients were non-compliant with dual-antiplatelet therapy (DAPT) and presented to the hospital with STEMI and arrested before coronary angiography was done. Six patients (2%) had myocardial infarction during follow-up, whereas 12 patients (4%) underwent ischemia-driven TLR (1 of them presented with acute myocardial infarction).

Follow-up coronary angiography was done for only 20 patients (7%). There were no cases of definite ST. DAPT compliance rate at 6 months was 95% (Table 1).

The MACE rate was higher in DM patients (13.3%) than in non-DM patients (2.9%), and this was statistically non-significant (P=.29). Among the DM patients themselves, uncontrolled patients (HbA1C >7) experienced a higher MACE rate than controlled patients (HbA1C ≤7) (19.4% vs 7.1%, respectively), and that difference was statistically significant (P=.01). Similarly, the MACE rate was higher in patients with dyslipidemia (12.1%) than in patients without dyslipidemia (2.2%), and this was statistically significant (P=.01) (Table 2).

The ischemia-driven TLR rate was higher in DM patients (6.7%) than in non-DM patients (0.9%), and this was statistically significant (P=.046). Among the DM patients, those who were uncontrolled (HbA1C >7) experienced higher repeat revascularization rate than those who were controlled (HbA1C ≤7) (9.6% vs 0%, respectively) and this difference was statistically significant (P=.01). The ischemia-driven TLR rate was higher in subjects with dyslipidemia, hypertension, and positive family history (5.2%, 3.8%, and 3.8%, respectively) than in those without (1.1%, 2.1%, and 2.4%, respectively), although these differences were not statistically significant (Table 3).

The Xience Xpedition everolimus-eluting stent was implanted in 63% of patients, while 37% underwent implantation of the Eucalimus sirolimus-eluting stent. Subjects with implanted sirolimus-eluting stents experienced higher rates of MACE and ischemia-driven TLR compared with those who underwent everolimus-eluting stent implantation (9% vs 4.3%, respectively, for MACE rate; 5.5% vs 1.1%, respectively, for ischemia-driven TLR rate), although neither difference was statistically significant (P=.28 for MACE rate and P=.13 for TLR rate) (Table 4).

The MACE incidence was higher in the subgroup of patients who underwent smaller-diameter (≤2.75 mm) DES implantation than those who received larger stent sizes (≥3 mm) (9.8% vs 4.7%, respectively), but this difference was not statistically significant (P=.25). However, the stent size significantly affected the ischemia-driven TLR rate, as the subgroup of subjects with smaller stent diameters (≤2.75 mm) experienced higher TLR rate than those with larger stent diameters (≥3 mm) (7.3% vs 0.9%, respectively; P=.03) (Table 5).

Long lesions represent a substantial proportion of PCI procedures, particularly among patients with comorbid risk factors, such as smoking, diabetes, or chronic kidney disease, where diffuse disease is often evident.²⁹ In up to 30% of PCI procedures, this may require the use of multiple overlapping stents, either due to inadequate stent length or challenging crossability and deliverability of longer stents.³⁰

In the current study, all patients had complex anatomy in terms of lesion length (>20 mm). Moreover, many patients had additional complex features, especially the presence of tortuosity (n = 18; 6%), calcification (n = 22; 7.3%), or bifurcation (n = 42; 14%). Predilation was done in 75% of cases, whereas all stents were postdilated using non-compliant balloons. Patients who required the use of additional stent(s) overlapped with the 48 mm DES were excluded from the study. Despite the lesion complexity, we achieved device success in 296 patients (98.6%). Difficult crossing of the stent was encountered in 14 cases due to severely tortuous or calcific vessels, which was successfully overcome by extra support maneuvers, such as the use of buddy wire or further lesion preparation. The crossing failure in 4 lesions was probably due to the presence of severe tortuosity and calcification, despite the use of more supportive guiding catheters and use of the buddy-wire technique; however, a guiding extension catheter was not available in the catheterization laboratory at the time of the procedure. These 4 lesions were finally treated by 2 short, overlapping stents. Procedural success occurred in 292 patients (97.3%) due to the occurrence of 4 cases of intraprocedural pulmonary edema, which resolved after the procedure. This rate was comparable to what was achieved in other similar studies. Tan et al³¹ observed significant tortuosity in 15 lesions (11.6%) and moderate to heavy calcification in 46 lesions (35.7%). In all cases, balloon predilation was done and scoring balloons were used in 48 cases (37.2%), in addition to the use of non-compliant balloons in 39 cases (30.2%). Successful crossing and deployment of the 48 mm device was achieved in 100% of patients included in this series. Procedural success was 99.2% due to 1 case of subacute ST on day 2 post PCI.

MACE rate in our study was 6% (n = 18). Two patients died during the first 6 months post PCI with possible ST. They were non-compliant with DAPT and upon presentation with severe chest pain, arrested in the emergency room. Six patients (2%) had myocardial infarction during follow-up, 2 of whom underwent coronary angiography and TLR. An additional 10 patients underwent ischemia-driven TLR due to the presence of ISR (ischemia-driven TLR rate was 4%; n = 12). There were no cases of definite ST. DAPT compliance rate at 6 months was 95%. These results were comparable to previous reports in the literature. In a study of procedural safety and 12-month patient outcomes after treatment with 48 mm everolimus eluting stents, Tan et al³¹ reported 1-year MACE rate of 3.3%, TLR rate of 0.8% (n = 1), and cardiac death rate of 3%. ST rate was 1.6% (n = 2), but was not definite ST, while DAPT adherence rate was 96.7% (n = 119).

Although available data show that stent overlap in the treatment of long lesions delivers acceptable outcomes, this strategy is less than ideal for several reasons. The use of multiple devices increases the probability of geographical miss, due to under-appreciation of the lesion length. On the other hand, when stents of excessive length are used, the length of overlap might obstruct big sidebranches or impair their blood flow. Moreover, a double layer of the metal stent may further increase a tendency toward ISR and ST or may complicate the delivery of additional devices through the overlapped stents.

Jones et al³² studied the use of 48 mm everolimus-eluting stents for the percutaneous treatment of long coronary lesions in 610 patients who had long coronary lesions (defined as ≥40 mm). A total of 305 patients with a single implanted 48 mm stent were propensity matched with 305 patients who underwent PCI with multiple overlapping stents. Those with a single 48 mm stent experienced lower MACE rates compared with those who received multiple overlapping stents (4.6% vs 8.1%, respectively; P=.04). This difference was mainly driven by reduced rates of TLR.

As for patients with DM, the data are somehow contradictory. In our study, DM was associated with an increased risk of ischemia-driven TLR (6.7% in DM vs 0.9% in non-DM; P=.01). Our results are in accord with Genuardi et al,³³ who studied 48 mm everolimus-eluting stent implantation and found that DM was associated with increased risk of TLR (P=.02). Hur et al³⁴ found that DM patients exhibited significantly higher rates of MACE at 2 years (8.0% DM vs 3.7% non-DM), all-cause mortality (3.9% DM vs 1.4% non-DM), reinfarction (2.8% DM vs 1.2% non-DM), and TLR (3.5% DM vs 1.3% non-DM) than non-diabetic patients (all P<.01). Lee et al³⁵ stated that diabetes was the only independent predictor of diffuse-type ISR by stepwise multiple regression analysis (odds ratio, 3.3; 95% confidence interval, 1.4-7.4; P<.001). In contrast, Hermiller et al³⁶ demonstrated that individuals with and without DM had similar recurrences of restenosis after undergoing DES implantation.

The advent of newer DES generations markedly improved outcomes after PCI. This is related to the stent’s metal design, the polymer used, and the type, pharmacokinetics, and pharmacodynamics of the drug used. Among the 300 subjects in our study, 48 mm stents were implanted in 296 subjects. Of them, a cobalt-chromium Xience Xpedition everolimus-eluting stent was used in 186 patients (62.8%), while a cobalt-chromium Eucalimus sirolimus-eluting stent was used in 110 patients (37.2%). MACE and TLR tended to occur more often in those with the older-generation Eucalimus DES than in those with the newer-generation Xience Xpedition stent (MACE and ischemia-driven TLR rates, 9% and 5.5% for Eucalimus vs 4.3% and 1.1% for Xience Xpedition, respectively), but these differences were not statistically significant (P=.28 for MACE and P=.13 for ischemia-driven TLR). Rajesh et al³⁷ found no significant difference in outcomes between the groups treated with sirolimus- vs everolimus-eluting stents.

Reference vessel diameter significantly affected the 6-month follow-up in our study, where ISR and TLR rates were higher when the diameter of the implanted stent was ≤2.75 mm (P=.01). These results augmented previous studies in the literature. Wan et al³⁸ studied the predisposing clinical and stent-related factors for coronary ISR by examining 318 stents implanted in 189 patients with invasive coronary angiography. ISR occurred in 19 patients (10%) and 25 stents (7.9%). They highlighted that ISR occurred significantly more often in stents with diameters <3 mm than in stents with diameters ≥3 mm (53.8% vs 28.9%, respectively; P=.02). Goldberg et al³⁹ studied the predictors of diffuse and aggressive intra-stent restenosis by evaluating 456 coronary lesions with ISR for the type of restenosis using quantitative coronary angiography. They found that diffuse restenosis (defined as follow-up lesion length ≥10 mm) and aggressive restenosis (defined as either an increase in lesion length from the original lesion or a restenotic narrowing tighter than the original) were associated with a smaller reference artery diameter <3 mm (P<.01), longer lesion length (P<.001), smaller baseline minimal lumen diameter (P=.02), and a smaller final minimal lumen diameter (P=.03). ISR may trigger an acute coronary syndrome as a result of either superimposed thrombus, aggressive hyperplasia, or both.⁴⁰ Newer-generation DES options demonstrated better results in terms of vascular healing than the older generation, including a lower incidence of both thrombus formation and fibrin deposition.

Study limitations. The main limitations of this study are the short period of follow-up, non-usage of intravascular ultrasound or optical coherence tomography for final stent optimization, and lack of a control group utilizing an overlapping stent strategy.

The results of the current study revealed that the use of 48 mm DES for treating long coronary lesions, is feasible and associated with good short-term outcomes. It is therefore likely that PCI of ultra-long lesions using this device will continue to increase and replace the strategy of overlapping stents. In addition to its potential for clinical benefit, this method may also provide cost savings over multiple shorter devices. The major drawback to any ultra-long DES is reduction in trackability, particularly through tortuous anatomy, although this is rarely problematic when cases are selected appropriately. The main predictors of ISR and need for repeat revascularization are presence of DM (especially if uncontrolled) and small reference vessel diameter.

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