Figure 1. A) and B): LAO projection with cranial angulation showing a CTO from the RCA proximal thir...

Figure 2. A) and B): recanalization and plain balloon angioplasty (PBA). C): QCA after PBA. QCA: qua...

Figure 3. A) and B): Stent implantation in the LAD 3 thirds. C) and D): QCA of LAD segments before a...

Figure 4. A) and B): RAO projection with cranial angulation and RAO projection of the LAD showing th...

History

Yet despite the introduction of the modern technology of drug-eluting stents (DES), over the last decade we have seen a reduction of revascularization procedures including the most common one in the United States (1), the percutaneous coronary intervention (PCI).

Also, in landmark randomized clinical trials (RCT) that compared DES and myocardial revascularization surgery (MRS) with long-term follow-up periods, a higher rate of spontaneous acute myocardial infarction (AMI) after 30 days was consistently observed with the PCI compared to the MRS (2-5). As a matter of fact, and yet despite the fewer target vessel revascularizations compared to BMS implantations within the first year following the PCI, this difference did not grow any shorter. Actually, there was a higher rate of adverse events with DES, suggestive of late loss of efficacy in DES compared to BMS and MRS (6-8). The reasons for these findings are still under discussion.

Also, in the largest RCT of second-generation DES vs BMS, no statistically significant differences were seen between both revascularization strategies (8).

Back in 2014, we disclosed the clinical findings at the 5-year follow-up of a RCT with BMS implantation followed by oral rapamycin (OR). This trial confirmed a reduction of late cardiovascular adverse events. Also, it was cost-effective when compared to first-generation DES (9). These results are consistent with other RCTs (10-11); however, no definitive conclusions were drawn from these small sample studies and this strategy was not included in the clinical practice guidelines.

The objective of this case presentation is to show the findings of a patient with long-term angiographic follow-up. This patient had multiple factors for ISR and was treated with a combination of BMS and OR for 2 weeks.

CASE PRESENTATION

This is the case of a 67-year-old male patient who presented with progressive angina, arterial hypertension, dyslipidemia, obesity with metabolic syndrome, maximum values of blood sugar levels, and former heavy smoker. The patient was admitted to our center on October 4, 2013. He presented with progressive angina of 1-month duration. The functional test performed confirmed the presence of anterior and lower extensive ischemia that suggested that territories from the left anterior descending coronary artery (LAD) and right coronary artery (RCA) had been compromised. Therefore, a cine coronary arteriography was performed (Figure 1).

The cine coronary arteriography revealed the presence of a large segment of the CTO from the LAD proximal third. The left circumflex artery (LCx) showed an intermediate injury (50% through visual estimation) in the middle third. The RCA also showed the presence of a CTO in the proximal third (Figure 1 A, B, C, and D). The SYNTAX score was 33 while the ERACI score, 22 (2,12). Combined therapy with immunosuppressants and BMS was decided and agreed with the patient and his general physician. Based on our own experience (9,10) the patient received a loading dose of 10 mg of oral rapamycin that was administered when the PCI was performed. Afterwards, the antegrade recanalization of the LAD with a Runthrough NS intermediate guidewire (Terumo, Japan) was attempted using 1.5 mm and 2.0 mm Ryujin support balloons (Terumo, Japan). Both the reference diameter (RD) and the minimal lumen diameter (MLD) measured with the quantitative coronary angiography (QCA) after the plain balloon angioplasty (PBA) were 2.43 mm, and 0.28 mm respectively (Figure 2 A, B, and C). Then, three 3.0 mm x 20 mm, 2.5 mm x 20 mm, and 2.25 mm x 24 mm BMSs (Liberté Boston Scientific, Massachusetts United States) were implanted with an overall stent length of 64 mm. The RD and DLM after stent implantation were 2.19 mm and 1.61 mm, and the DLM increased with nitroglycerin to 1.82 mm (Figure 3 A, B, C, and D). The procedure ended with a PBA performed in a diagonal branch. After the PCI performed on the LAD, we saw that the RCA filled through collateral circulation. Both the moderate injury of the left circumflex artery and the CTO of the RCA were not operated. Instead, they were treated with medical therapy (Figure 1).

After the PCI, the patient received aspirin, atorvastatin, and bisoprolol indefinitely. Three mg per day of OR were indicated for a total of 13 days after the PCI. The patient also received a 75 mg dose of clopidogrel for 3 months. Lifestyle changes and a strict control of the sugar levels were recommended. The patient remained asymptomatic for a long period of time with myocardial perfusion controls without ischemia.

Six years after the procedure, in February 2020, the patient showed variable dyspnea of 1-month duration, lower limb swelling, and overeating. At that time the sugar blood levels were 119 mg/dL. The patient’s myocardial perfusion study revealed the presence of moderate lower limb and apical ischemia without changes on the electrocardiogram. Therefore, a cine coronary arteriography is performed (Figure 4 A and B) that shows no significant injuries on the LAD. The QCA showed a 2.19 mm and 1.61 mm RD and DLM, respectively, with a total loss at the 76-month follow-up of 0.21 mm. The filling of the RCA occurred through collateral circulation without changes to the LCx injury (Figure 4 A and B).

The vascular vasoreactivity testing performed with adenosine (dose of 140 µg/kg/min) through a central venous catheter confirmed the improvement of the DLM and the RD that measured 2.34 mm and 2.56 mm post-adenosine, respectively, indicative of normal vasoreactivity (figure 4 C and D).

The patient’s risk factors were strictly controlled and followed by salt restriction, and physical exercise recommendations.

The patient was monitored 1 month later and remained asymptomatic until the last control was performed 6 months later.

Discussion

This was the case of a patient who was recanalized due an entire LAD CTO from its proximal to its distal segments with 3 BMSs plus a 2-week course of OR. The patient also showed a CTO on the RCA, moderate injuries to the LCx, and received conservative therapy. Six years later a new cine coronary arteriography is performed that reveals the patency of the LAD without ISR in any of the stents implanted.

This patient had multiple clinical and angiographic risk factors for ISR like metabolic syndrome, presence of a CTO, extensive occluded segment, fine reference diameter, and multiple BMSs. Yet despite all this, the patient remained asymptomatic and ISR-free for 76 months after the initial angioplasty with normal vasomotility after the injection of adenosine.

The findings of this case should not be surprising since numerous small randomized clinical trials that compared immunosuppressant therapy to anti-inflammatory therapy administered orally after the implantation of a BMS have consistently proved the benefits of reducing ISR (9-11).

Also, in a randomized clinical trial that compared OR and BMS vs first-generation DES, the ORAR II trial, we proved that, at the 5-year follow-up (9), this strategy was cost-effective compared to first-generation DES, at all time, in 200 patients including diabetics (28%), small vessels (36%), and multiple vessel disease (48%). The composite of death, spontaneous AMI, and stroke at the 5-year follow-up showed a RR = 2.08, 1.10-3.91 P =. 01 favorable to the OR/BMS strategy. Still, this difference in the composite endpoint was similar at the 1-year (RR = 0.60, 0.27-1.30 P =. 34) and 3-year follow-up (RR = 0.49, 0.22-1.09 P =. 08) suggestive that DES have a greater efficacy loss over time. By the time the patient was being treated, the 5-year follow-up findings of this clinical trial had already been submitted for publication (9). An interesting finding of this last study was that the stent overlapping rate of every patient was 31%.

We should mention that despite the significant safety increase of the latest DES designs, the presence of early neoatherosclerosis and endothelial dysfunction are still important limiting factors for the long-term evolution of these devices. This may be due to the polymer used, but mostly to the local action of the immunosuppressant drug, and the fact that they are responsible for the cardiovascular and noncardiac adverse events reported in the long-term (2-5,13,14). A recent and extensive meta-analysis of 23 RCTs reported, for the first time, an increase of cardiovascular and noncardiac mortality associated with the angioplasty when DES and MRS studies were compared. However, no differences between BMS and MRS (15) were found, which may be indicative of a specific correlation between noncardiac mortality and the use of DES.

As long as these 2 problems with the technology of DES remained unsolved, early neoatherosclerosis, and endothelial dysfunction, strategies like the one described here should not be ruled out.

Conclusions

In this case of an extremely long follow-up of a patient with multiple angiographic and clinical risk factors for ISR, we saw favorable disease progression with complete patency of the blood vessel treated including normal vessel reactivity.

1. Chang M, Ahn JM, Lee CW, et al. Long-Term Mortality After Coronary Revascularization in Nondiabetic Patients with Multivessel Disease. J Am Coll Cardiol 2016;68(1):29-36.

2. Holm NR, Mäkikallio T, Lindsay MM, et al. NOBLE investigators. Percutaneous coronary angioplasty versus coronary artery bypass grafting in the treatment of unprotected left main stenosis: updated 5-year outcomes from the randomised, non-inferiority NOBLE trial. Lancet 2020;395(10219):191-9.

3. Stone GW, Kappetein AP, Sabik JF, et al. EXCEL Trial Investigators. Five-Year Outcomes after PCI or CABG for Left Main Coronary Disease. N Engl J Med. 2019;381(19):1820-30.

4. Piccolo R, Bonaa KH, Efthimiou O, et al. Coronary Stent Trialists’ Collaboration. Drug-eluting or bare-metal stents for percutaneous coronary intervention: a systematic review and individual patient data meta-analysis of randomised clinical trials. Lancet 2019 Jun 22;393(10190):2503-10.

5. Park DW, Ahn JM, Yun SC, et al. Ten-Year Outcomes of Stents versus Coronary-Artery Bypass Grafting for Left Main Coronary Artery Disease.J Am Coll Cardiol 2018;72(23 Pt A):2813-22.

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7. Rodríguez AE, Palacios I, Rodríguez-Granillo AM, et al. ORAR-3 investigators. Comparison of cost-effectiveness of oral rapamycin plus bare-metal stents versus first generation of drug-eluting stents (from the Randomized Oral Rapamycin in Argentina [ORAR] 3 trial). Am J Cardiol 2014;113(5):815-21.

8. Cassese S, De Luca G, Ribichini F, et al. ORAl iMmunosuppressive therapy to prevent in-Stent rEstenosiS (RAMSES) cooperation: a patient-level meta-analysis of randomized trials. Atherosclerosis 2014;237(2):410-7.

9. Deftereos S, Giannopoulos G, Raisakis K, et al. Colchicine treatment for the prevention of bare-metal stent restenosis in diabetic patients. J Am Coll Cardiol 2013;61(16):1679-85.

10. Rodriguez AE, Fernández-Pereira C, Mieres J, Santaera O, Antoniucci D; ERACI IV investigators. Modifying angiographic syntax score according to PCI strategy: lessons learnt from ERACI IV Study. Cardiovasc Revasc Med 2015;16(7):418-20.

11. Park SJ, Kang SJ, Virmani R, Nakano M, Ueda Y. In-stent neoatherosclerosis: a final common pathway of late stent failure. J Am Coll Cardiol 2012;59(23):2051-7.

12. Toya T, Sara JD, Corban MT, et al. Assessment of peripheral endothelial function predicts future risk of solid-tumor cancer. Eur J Prev Cardiol 2020;27(6):608-18.

13. Gaudino M, Hameed I, Farkouh ME, et al. Overall and cause-specific mortality in randomized clinical trials comparing percutaneous interventions with coronary bypass surgery. A Meta-analysis. JAMA Intern Med 2020 Oct 12;e204748.

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Six-year angiographic follow-up of a chronic total coronary occlusion successfully treated with BMS implantation followed by oral rapamycin

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