INTRODUCTION

The guidelines for PCI have been recently revised by ACC/AHA/SCAI (2005)1 and European Society of Cardiology (2005).2 In India API expert consensus document on management of ischemic heart disease has been published in June 2006.3

Atherosclerosis leading to myocardial ischemia usually involves left anterior descending artery (LAD) in about 60-75%, right coronary artery (RCA) in about 25-40% and left circumflex artery (LCx) in 5-30% cases. Often lesions are mixed affecting multiple vessels. Left main coronary artery (LMCA) is involved in 5-7%.4 The lesion in LMCA may be located at origin, main stem and distal part involving the bifurcation (LCx or LAD). Very often lesion in LMCA is mixed with lesion in other coronary arteries.

LMCA disease is defined as unprotected under the following circumstances:-
a) no history of CABG
b) CABG to RCA only
c) CABG performed earlier but there is no patent graft to LAD or LCX or LMCA territory.

Presence of stenosis of unprotected left main coronary artery (ULMCA) constitutes an important subset which requires coronary artery bypass surgery for revascularization.1,2 The coronary artery surgery study (CASS) has demonstrated one-year and five-year survival rates of 90% and 85% respectively after surgical revascularization of ULMCA disease in contrast to much lower survival rates with medical treatment. In a recent study one-year survival rate for ULMCA stenting was 72% compared to protected LMCA stenting of 95% with target lesion revascularization (TLR) at one-year of 20% for all patients.5 CABG is thus regarded as an accepted gold standard treatment for ULMCA disease. Medical treatment and PCI using bare metal stent (BMS) are associated with high rate of early mortality and restenosis requiring target vessel revascularization (TVR). Drug eluting stents (DES) have ushered a revolution in the field of PCI since early 2003. DES implantation has greatly reduced major adverse cardiac events (MACE). Restenosis rates have been greatly reduced and results are approaching those obtained after CABG.

Ravel trial (2005)6 was a multicentric study from France, Germany, Netherlands, Belgium, Mexico and Brazil. It was a randomized trial involving 238 patients with a three year follow-up. BMS were implanted in 118 patients while DES in 120 patients with multivessel coronary disease. Complete data were available in 94.2% of patients treated with DES and 94.1% of patients treated with BMS. The cumulative 1yr, 2yr and 3 year event free survival rates were 99.2%, 96.5% and 93.% for TLR and 95.8%, 92.3% and 87.9% for target vessel failure (TVF), respectively in sirolimus-eluting stent (SES) group versus 79.9%, 75.9% and 75% for TLR and 71.2%, 69.4% and 67.3% for TVF in BMS (control) groups (p< 0.001) for both comparison at 3 years. Rates of MACE at 3 years were 15.8% in SES group versus 33.1% in BMS (control) group (p=0.002). One patient in SES group died of cardiac cause between 1-3 years while 3 patients died of possible cardiac cause in BMS group. It was concluded that treatment of de novo coronary stenosis with SES was associated with a sustained clinical benefit, low rate of TLR and low MACE up to 3 years after device implantation.

Serruys (2005)7 during the Annual Conference of American College of Cardiology, presented data of Arterial Revascularization Therapies Study (ARTS II) a 12 month follow-up of „Late Breaking Clinical Trial‰ report. A total of 607 patients treated with SES stents were enrolled in a non-randomized registry and their outcome after 12 months follow-up were compared with ARTS I study in which 602 patients underwent CABG and 600 patients underwent PCI using BMS. The restenosis rates were 30.3% in BMS group, 7.4% in SES group and 3.7% in CABG group. It was argued that SES implantation might save the patients from fear and pain of surgery while giving equal benefits of survival and reduced rates of restenosis and need for repeat revascularization.

There has been recent reports of off-level use of PCI with DES in ULMCA disease in which results obtained with DES implantation have been compared with those obtained with BMS implantation.

Park et al (2005)8 reported clinical and angiographic outcomes following elective SES implantation and compared these with those of BMS implantation. Elective SES implantation de novo ULMCA stenosis was performed in 102 consecutive patients from March 2003 to March 20004 and the data was compared to those from 121 patients treated with BMS during 2001 2002. Compared to BMS group the DES group received more direct stenting, with fewer debulking atherectomies and had more segment and bifurcation stenting. Procedural success was 100%. During periprocedural period, there was no death, stent thrombosis, Q wave MI, or emergent CABG during hospitalization. SES group had a lower late lumen loss (0.05 µ 0.57mm vs 1.27 µ 0.90mm, p < 0.001) and a lower six month angiographic restenosis rate (7% vs 30.3% p < 0.001) versus the BMS group. At 12 months, the rate of freedom from death, MI or TLR was 98.0 µ 1.4% in SES group and 81.4 µ 3.7% in BMS group (p = 0.003). It was concluded that SES implantation for ULMCA stenosis was safe with regards to acute and mid-term complications and was more effective in preventing restenosis compared to BMS implantation. Bifurcation LMCA lesions were, however, considered inappropriate for PCI due to technical difficulties in stent implantation and relative higher rates of restenosis.

Valgimigli et al (2005)9 reported short and long term outcome after DES implantation for PCI of ULMCA from Rotterdam (Netherlands), Cardiology Hospital Registries (Research and T Search). From April 2001 to Dec. 2003, 181 patients underwent PCI for LMCA. The first cohort consisted of 86 patients (19 protected LM) treated with BMS and a second cohort consisted of 95 patients (15 protected LM) treated with SES implantation. The two cohorts were well balanced in baseline characteristics. At a median follow-up of 503 days (331-873 days), the cumulative incidence of MACE was 24% in DES group v/s 45% in BMS group. Total mortality did not differ in two cohorts. MI rate was lower (4%) in DES group compared to BMS group (12%). TVR was 6% in DES group v/s 23% in BMS group. Authors concluded that if PCI is undertaken for LMCA disease, DES implantation should be the preferred strategy since it reduces the cumulative incidence of MI and the need for TVR compared with BMS implantation.

Chieffo et al (2005)10 reported from University of Milan, Italy their study on the safety and efficacy of PCI in ULMCA in 149 patients, where 85 were treated with DES and 64 with BMS implantation. Patients treated with DES had lower LVEF (51.1 µ 11% v/s 57.4 µ 13%, p =0.002), were more often diabetic (21.2% vs 10.9%, p = 0.12) and more frequent distal left involvement of LMCA (81.2% vs 58.8%, p = 0.003). DES patients required larger stents (24.3 µ 12 v/s 15.8µ 8.6mm, p = 0.004). Despite higher risk and lesion profile, MACE at 6months follow-up was lower in DES than in BMS group (20% vs 35.9%, p = 0.039). More over mortality and cardiac deaths were less in DES group than BMS group (3.5% vs 14.1%). The authors concluded that DES implantation in ULMCA was safe with better clinical outcome than BMS implantation. However, the incidence of restenosis was high in both groups (19% in DES vs 30.6% in BMS).

Price et al (2006)11 evaluated the clinical and angiographic outcome of 50 patients with ULMCA disease undergoing SES implantation. The target lesion involved the distal LMCA in 47 patients (94%) and both LMCA branches required stenting in 42 patients (84%). Surveillance angiographies were performed at three and nine months follow-up. In lesion restenosis occurred in 21 patients (42%). Target lesion revascularization (TLR) was done in 19 patients (38%) over a mean follow-up of 276 µ 57 days. TLR was ischemic driven in 7 patients only and remained asymptomatic in others. Late loss was significantly greater with LCx. The authors concluded that intervention of ULMCA by DES was safe but late restenosis occurred in 21 patients (42%) with serial angiographic follow-up. The restenosis was at the ostia of LCx in 10 (48%), both LCx and LAD ostia in 5 (24%), at LAD ostia in 2 (9.5%) and in LMCA in 4 (19%). Restenosis was focal, most often involving the LCx ostium and was asymptomatic in many patients. Table 1 shows the summary of the results of DES implantation in ULMCA disease in above trials mentioned.8-11

Lee et al (2006)12 evaluated the clinical outcome of consecutive ULMCA disease treated with CABG or PCI with DES implantation from April 2003 to 2005. 123 patients were treated with CABG and 50 patients with DES implantation. Compared to CABG group, the PCI group had less men (50% vs 76% for CABG, p < 0.01), more patients with chronic renal insufficiency (CRI) (16% vs 5% for CABG, p < 0.02) and more patients presenting with anginal pains (46% vs 25%, p < 0.01). High risk patients were present more often in PCI than CABG group (64% vs 46%, p = 0.04). Nine patients (18%) who underwent PCI were refused CABG after surgical consultation.

Details are summarized in Table 2. Disease location in LMCA was at ostium in 42%, main stem (or mid) in 20% and distal in location in 60% patients. During CABG, majority of patients received three grafts and 96% patients received an internal mammary artery to LAD. During in-hospital stay there were six deaths in CABG and one in PCI group. Major adverse cardiac and cerebrovascular events (MACE) rates for CABG were 17% and for PCI group 2%. Seven patients required repeat surgery for bleeding in CABG group during immediate post operative period. Hospital stay for CABG and PCI patients was 7.6 µ 4.9 and 3.9 µ 4.5 days respectively. The mean intermediate follow-up was 6.7 µ 6.2 months for CABG group and 5.6 µ 39 months for PCI group. MACE free survival at six and twelve months was 83% and 75% in CABG group versus 89% and 83% in PCI group (p= 0.20). In conclusion, PCI with DES was found to be a viable alternative to CABG with no increase in early and intermediate MACE in ULMCA disease.

To summarize, PCI with DES can be considered reasonable if revascularization is essential to save the life and to improve the cardiovascular outcome in patient who is not suitable for CABG. Regarding durability and long term follow-up more randomized studies with longer follow-up are necessary. Diabetes mellitus and distal ULMCA disease are still problem for PCI. Novel stents are now being developed and future will decide the type of DES best suited to terminal segment stenosis of ULMA involving the orifice of LCx or LAD or both. Faxon (2006)13 in his expert opinion emphasizes that the majority of LMCA lesions are located in the distal bifurcation segment for which there is still no ideal stenting approach. If LCx is small or not diseased, single stent approach (LMCA into LAD) with balloon rescue of LCx if needed has much to recommend. But since most cases have LCx which is both large and diseased, CABG may be the ideal answer in such case. Further trials are underway that may help answer important remaining questions.

DES are more effective than BMS in reducing restenosis and related target vessel revascularization mainly by limiting intimal hyperplasia. However thrombosis in DES between 1 and 6 mths and afterwards is more common with DES than BMS. This could partly be related to the reduction of dual antiplatelet therapy which currently is recommended for 1mth after BMS, for 3 months after sirolimus eluting stent (SES) and for 6mths after paclitaxel eluting stents (PES).

DES implantation is often associated with incomplete neointimal endothelial coverage 3-6months after implantation, whereas endothelial coverage is usually complete within 30 days after BMS implantation.14 Incomplete neointimal coverage in DES may lead to sub-clinical / clinical thrombus formation. Late adverse stent thrombosis (LAST) is defined as angiographic stent thrombosis occurring at least one-month after DES implantation and associated with TIMI flow of 0 or 1 or presence of flow limiting thrombus (TIMI flow 1 or 2). In a recent study from Netherlands there were 8 LAST events in seven patients out of 2006 patients treated with DES implantation. Five were on aspirin alone at the time of diagnosis and none were receiving clopidogrel which had been stopped 5 days to 23 months prior to the LAST event. The LAST occurred 2-26 months after DES implantation.15 Late clinical events after clopidogrel discontinuation may limit the benefits of DES (BASKET LATE Investigators Trial 2006).16 In this study 746 non-selected patients with 1133 stented lesions surviving 6 months without major events were followed for one-year after discontinuation of clopidogrel. Out of 746 patients 502 had received DES implantation and 244 had received BMS implantation. After discontinuation of clopidogrel, death / MI occurred in 4.9% in DES group vs 1.3% in BMS group. Documented late stent thrombosis and related death / MI were twice as frequent in DES vs BMS (2.6% vs 1.3%). Authors concluded that after discontinuation of clopidogrel there is an increase in cardiac death or non-fatal MI related to LAST in DES group. Findings of BASKET-LATE study have important clinical implications:-

(a) Benefits of lower stent thrombosis during early months after DES implantation need to be balanced against the cost of LAST events.

(b) Whether prolonged / lifelong dual antiplatelet therapy is beneficial to prevent the LAST events. This needs to considered against the possible increase in major bleeding episodes.

(c) New strategies must be searched to reduce the LAST events e.g. new platelet regimes, new stents (bio-absorbable or endothelialization promoting stents).

(d) Consider individual factors such as resistance to aspirin and clopidogrel

In short BASKET-LATE report should be taken as a warning to the potential hazards of LAST events after DES implantation. LAST may be a serious complication with high mortality requiring urgent revascularization by CABG. Predictors of LAST include discontinuation of antiplatelet drugs, diabetes mellitus, renal insufficiency, bifurcation stents, long length stents and low LVEF.17 Distal LMCA lesion is a major predictor of outcome following PCI. Complex angiographic morphology, stent mal-apposition, smaller maximal balloon diameter and persistent dissection are the other contributing factors for adverse outcome. Vexing problem of late stent thrombosis is now becoming clearer in 3-4 years follow-up after the introduction of DES in late 2002. Meta-analysis of late adverse stent thrombosis following PCI was presented in the European Society of Cardiology scientific congress, September 2006. While full details are yet to be published, the summary has recently been published in October 2006. The patients were followed up to 3 years to evaluate hard end points of death or Q wave MI. The meta-analysis concluded that death and Q wave MI were significantly increased in patients receiving DES compared to BMS at the end of 3 years.18

CONCLUSIONS

Patients with ULMCA should be considered for CABG, although data is fast accumulating on the procedural safety and long term survival of percutaneous intervention (PCI) with drug eluting stents (DES) implantation.

PCI may be considered as an alternative to CABG under the following circumstances:-

1. Patient refusing for surgery (CABG)

2. Patient considered unsuitable for CABG by cardiac surgeon in view of co-morbidities or complications e.g. cardiogenic shock, advanced age, poor LVEF, limited life expectancy, renal insufficiency, COPD, unsuitable distal target vessels.

3. LMCA lesion localized to ostium or shaft where stenting can be done safely

Every interventional cardiologist should not attempt this procedure in ULMCA stenosis. The institutional and operator competency should assure the quality as defined by ACC/AHA/SCAI 2005 guidelines update for PCI. The operator should have technical expertise and should have worked as a part of team of interventional cardiologist performing stenting in bifurcation lesions or LMCA stenting. The institution must have advanced facilities for intravascular ultrasound (IVUS), angioscopy, rotablator and onsite cardiac surgery in addition to the usual facilities. Confirmation by IVUS for optimal stent deployment would be preferable. Need for GpIIb/IIIa blockers / intra-aortic balloon pump (IABP) before or during PCI should be considered as per requirement.

DES implanted patients in ULMCA disease should continue dual antiplatelet drug therapy indefinitely. They require to be followed by serial angiographic studies between 3-9 months after implantation and possibly later in life to detect restenosis at the earliest occasion when they can be offered repeat PCI or CABG. Patients with diabetes mellitus, renal insufficiency and other co existing disease require careful evaluation before any revascularization methodology. Terminal segment involving bifurcation of LMCA with ostial LCx disease may need special DES which are under research and development.

Problems of treating ULMCA in India with DES vs CABG will centre on availability of expertise, cost of procedure and cost of continued medical treatment (especially dual antiplatelet therapy for life). However, in patients in who CABG is contraindicated due to associated co-morbidities it will remain a suitable option.

Abbreviations and Acronyms
1. CABG : Coronary Artery Bypass Surgery
2. PCI : Percutaneous Intervention
3. ULMCA : Unprotected Left Main Coronary Artery
4. BMS : Bare Metal Stent
5. DES : Drug Eluting Stent
6. MACE : Major Adverse Cardiac Events
7. TVR : Target Vessel Revascularization
8. TLR : Target Lesion Revascularization
9. TVF : Target Vessel Failure
10. LMCA : Left Main Coronary Artery
11. RCA : Right Coronary Artery
12. LAD : Left Anterior Descending Artery
13. LCX : Left Circumflex Artery
14. MI : Myocardial Infarction
15. HTN : Hypertension
16. DM : Diabetes Mellitus
17. CRI : Chronic Renal Insufficiency
18. PVD : Peripheral Vascular Disease

REFERENCES

1. Smith SC, Feldman TE, Hirshfeld JW, Jacobs AK, Kern MJ, King III SB, Morrison DA, OÊNeill WW, Schaff HV, Whitlow PL, Williams DO, Antman EM, Smith SC, Adams CD, Anderson JL, Faxon DP, Fuster V, Jalperin JL, Hiratzka LF, Hunt SA, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B. ACC/AHA/SCAI 2005 Guidelines Update for Percutaneous Coronary Intervention Summary Article. JACC 2006;47:216-35.

2. Silber S, Albertsson P, Aviles FF, Camici PG, Colombo A, Hamm C, Jorgensen E, Marco J, Nordrehaug JE, Ruzyllo W, Urban P, Stone GW, Wijns W: Guidelines for Percutaneous Coronary Interventions The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. European Heart Journal 2005;26:804-47.

3. Sharma S, Bhargava B, Vakil VK, Panja M, Karthikeyan G, Kerkar P. API Expert Consensus Document on Management of Ischemic Heart Disease. J Assoc Physicians India 2006;54:46980.

4. Stone PH, Goldschlager N. Left main coronary artery disease; review and appraisal. Cardiovascular Med 1979;4:165-77.5. Kelly MP, Klugherz BD, Hashemi SM, Meneveau NF, Johnston JM, Matthai WH, Bankar VS, Herrman HC, Hirshfeld JW, Kimmel SE, Kolansky DM, Horwitz PA, Schiele F, Bassand JPL, Wilensky RL. One year clinical outcome of protected and unprotected left main coronary artery stenting. Eur Heart J 2003;24:1554-9.

6. Fajadet J, Morice MC, Bode C, Barragan P, Serruys PW, Wijns W, Constantini CR, Guermonprez JL, Eltchaninoff H, Blanchard D, Bartorelli A, Laarman GJ, Perin MA, Sousa JE, Schuler G, Molnar F, Guagliumi G, Colombo A, Hayashi EB, Wulfert E. Maintenance of long term benefit with sirolimus-eluting coronary stents 3 year result of the RAVEL trial. Circulation 2005;111:1040-4.

7. Serruys PW. Arterial Revascularization Therapies Study- Part II 12mth follow-up. Presented at American College of Cardiology Late Breaking Clinical Trial, Orlando, FL 2005.

8. Park SJ, Kim YH, Lee BK, Lee SW, Lee CW, Hong MK, Kim JJ, Mintz GS, Park SW. Sirolimus eluting stent implantation for unprotected left main coronary artery stenosis: comparison with bare metal stent implantation. JACC 2005;45:351-6.

9. Valgimigli M, Mieghem AGV, Ong ATL, Aoki J, Granillo GAR, McFadden EP, Kappetein AP, Feyter JJ, Smits PC, Regar E, Giessen WJV, Sianos G, Jaegere P, Domburn RTV, Serruys PW. Short and long term clinical outcomes after drug eluting stent implantation for the percutaneous treatment of left main coronary artery disease: Insights from the Rapamycin Eluting and Taxus Stent evaluated at Rotterdam Cardiology Hospital Registries (Research and T-Search). Circulation 2005;111:1383-9.

10. Chieffo A, Stankovic G, Bonizzoni E, Tsagalou E, Iakovou I, Montorfano M, Airoldi F, Michev I, Sangiorgi MG, Carlino M, Vitrella G, Colombo A. Early and mid term results of drug-eluting stent in unprotected left main. Circulation 2005;111:791-5.

11. Price MJ, Cristea E, Sawhney N, Kao JA, Moses JW, Leon MB, Costa RA, Lansky AJ, Teirstein Pl. Serial angiographic follow-up of sirolimus eluting stent for unprotected left main coronary artery revascularization. JACC 2006;47:871-7.

12. Lee MS, Kapoor N, Jamal F, Czer L, Aragon J, Forrester J, Kar S, Dohad S, Kass R, Eigler N, Trento A, Shah PK, Makkar RR. Comparison of coronary artery bypass surgery with percutaneous coronary intervention with drug eluting stents for unprotected left main coronary artery disease. JACC 2006;47:864-70.

13. Faxon DP. Expert opinion: Unprotected left main coronary lesion should be treated with coronary artery bypass surgery. Cardio-Source Review Journal 2006;15:30-3.

14. Kotani J, Awata M, Nanto S, Uematsu M, Oshima F, Minamiguchi H, Mintz GS, Nagata S. Incomplete neointimal coverage of sirolimus eluting stents angioscopic findings. JACC 2006;47:2108-111.

15. Ong ATL, McFadden EP, Reager E, Jaegere PPT, Domburg RJ, Serruys PW. Late angiographic stent thrombosis (LAST) events with drug eluting stents. JACC 2005;45:2088-92.

16. Pfisterer M, Rocca HPB, Buser PT, Rickenbacher P, Hunziker P, Mueller C, Jeger R, Bader F, Osswald S, Kaiser C. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents. JACC 2006;48:under publication.

17. Iakovou I, Schmidt T, Bonizzoni E, Ge L, Sangiorgi GM, Stankovic G, Airoldi F, Chieffo A, Montorfano M, Carlino M, Michev I, Corvaja N, Briguori C, Gerckens U, Grube E, Colombo A. Incidence, predictors and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126-30.

18. Camenzind E: Drug Eluting stents late thrombosis: Meta-analysis. Cardiosource Review Journal 2006;15:50.