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Prof. Pablo Aguiar-Souto
Prof. Carlo Di Mario,
One-third of all significant coronary stenoses at angiography are CTOs, but only 10-15% of them are treated with percutaneous coronary intervention (PCI). However, reopening of CTO has been shown not only to alleviate anginal symptoms but also to improve left ventricular ejection fraction, decrease the need for coronary bypass graft surgery (CABG) and improve long-term survival.
Coronary lesions are chronic total occlusions (CTOs) when
Approximately one-third of all significant coronary stenoses at angiography are CTOs, but only 10-15% of them are treated with percutaneous coronary intervention (PCI) while the majority is treated medically or referred for surgery (2).
As for stable lesions, indication for revascularisation of CTO is justified
The main cause of the large discrepancy between the prevalence of CTO and lesions treated percutaneously is not lack of indications but the perception that CTO revascularisation has low immediate success, a high periprocedural complication rate and that it offers poor long-term clinical benefit. On the contrary, unlike treatment of nonocclusive lesions for stable angina, successful reopening of CTO has been shown not only to alleviate anginal symptoms but also to improve left ventricular ejection fraction, decrease the need for coronary bypass graft surgery (CABG) and improve long-term survival.
Opening a CTO in the presence of well-developed collaterals may not be required if the distal myocardium is believed to be receiving a sufficient blood supply. An elegant study using Doppler and flow wires was designed to test collateral function and functional reserve in patients with CTO and its response to pharmacological stress (3). It revealed that only 7% of patients had a sufficient increase in collateral flow during stress to reach a normal coronary flow reserve of >2 while a reduction in absolute flow during hyperaemia occurred in one-third of patients. These results suggest that even in “well-collateralised” CTOs, maximal hyperaemic distal flow is functionally insufficient so recanalization provides extra benefit.
The OAT trial (4) tested in 2166 patients, the hypothesis that routine PCI for total occlusion of the infarct-related artery 3 to 28 days after acute myocardial infarction would reduce the composite end point of death, reinfarction or advanced heart failure. The trial demonstrated no effect of PCI on outcome and a trend to more frequent reinfarction and higher 4-year cumulative event rate.
The conclusions of this trial, however do not apply to real CTO lesions because patients enrolled had recent occlusions (8 days median duration), functional (TIMI 1) and complete occlusions. The trial had an unexpectedly low recanalisation success rate of 87% and excluded patients symptomatic or patients with large areas of viable myocardium at risk. In low risk patients (young, small area of myocardium at risk, single vessel disease and preserved LVEF) it is obviously impossible to find differences between hard end-points such as death or myocardial infarction.
The COURAGE trial (5) was a strategy-driven trial randomizing 2287 patients to optimal medical therapy with or without PCI. The main result revealed no difference by treatment in the primary end point of death or MI for a median follow-up of 4.6 years. Several points related to patient-selection bias and PCI procedure weaken these conclusions and limit their generalisation to CTO cases. As the OAT trial, COURAGE excluded more than 90% of the patients who were evaluated, suggesting a super-selected study population. In particular, cases with revascularisation within the previous 6 months and coronary anatomy unsuitable for PCI (i.e most CTOs) were excluded. Additionally, in the randomised patients, revascularisation was incomplete: two thirds of the patients had multivessel disease but 59% received only one stent in the PCI group. The ischaemic burden measured by stress myocardial perfusion single photon emission computed tomography (MPS) was measured in selected patients in a recently published post hoc analysis (6) showing that ischaemia reduction was greater in the PCI group. In the patients with more severe pre-treatment ischaemia, a lower unadjusted risk for death or MI was observed.
The long-term effect of percutaneous revascularisation of CTO on left ventricular ejection fraction (LVEF) and remodeling results are promising, even though the information available is still insufficient . Chung MC et al (7) repeated ventriculograghy six months after PCI of CTO and showed a significant improvement in-global LVEF (4% on average), but a higher increase (8%) in the group of patients without previous MI in the territory of distribution of the opened CTO. Longer follow-up (3 years) and more accurate cardiac imaging tests (8), showed a significant reduction in LV volumes, an increase in segmental wall thickening and a trend to improved LVEF. The practical message is that both early and late improvements in regional LV function can be expected in the distribution territory of CTO lesions if patients are properly selected with myocardial viability testing and the extension of transmural scar testing.
Recent reports add evidence to the initial studies of Hoye et al (9) who evaluated a total of 874 CTO patients for the occurrence of major adverse cardiac events (MACE) including death, myocardial infarction (MI) and the need for repeat revascularisation. Procedural success rate was 65.1% and stents were used in 81%. At 5 years, survival was 93.5% after successful recanalisation vs 88% after failed recanalisation. Freedom of MACE was also significantly higher in patients with successful PCI.
Aziz et al (10) reported the results obtained in 543 CTO cases with a 69.4% rate of success and compared survival rates in patients with successful revascularisation and in patients with failed revascularisation. After nearly two years of follow up, the mortality rate was 2.5% in patients with successful recanalisation versus 7.3% in those who failed recanalisation. The crude hazard ratio for death with CTO failure was 3.92 (95% confidence intervals 1.56-10.07; P = 0.004). The rate of CABG was significantly lower in the successful PCI group (3.2% vs 21.7%, p<0.001).
A number of predictors of procedural success have been reported in literature. Blunt occlusion stumps, heavy calcification, proximity to a side branch, presence of bridging collaterals, and indeterminate occlusion duration seem to impact the likelihood of procedural success unfavorably (11-14).
To evaluate the trends in procedural success, in-hospital and long-term outcomes after PCI for CTO over the last 25 years in the Mayo Clinic (15), 1262 patients were divided into 4 groups according to the period the intervention was performed. They considered group 1 (percutaneous transluminal angioplasty), group 2 (early stent era), group 3 (BMS era) and group 4 (DES era). The procedural success rates increased between PTCA only and all the stent groups (51% versus 72%, 73% and 70%, respectively). In-hospital mortality (2%, 1%, 0.4% and 0%, p<0.009), emergency CABG and rates of major adverse cardiac events were significantly lower in the 2 most recent cohorts compared with those treated before. Compared with the present era, in-hospital major adverse cardiac events and 1-year TVR rates have declined by approximately 50%.
The main reason for failure is the impossibility of a guide-wire or balloon to pass through the occlusion and many methods are being described to improve success rates, from better selection of guiding support catheters to the development of dedicated guidewires or alternative devices and complex CTO techniques. Today, the procedural success rate varies widely from <60-70% in the presence of one or more unfavourable predictive factors to >90% with favourable characteristics and highly experienced CTO-operators (1,16).
Many complications have been described including vessel perforation, impairment of collateral flow, retrograde dissection with branch occlusion or perforation, guidewire entrapment, and those derived from contrast overload and high radiation dose.
However Suero et al (17), have shown that total in-hospital complications were similar among the CTO patients (n=2007) compared to a matched non-CTO cohort. New-generation wire perforation occurred in 4 out of 420 consecutive cases (1.5%), two contained and two requiring pericardiocentesis due to cardiac tamponade. Also in the Mayo Clinic Registry (15) and according to the time of intervention, a significant improvement over time of in-hospital outcome was observed when a successful PCI was completed. In-hospital mortality (2%, 1%, 0.4%, and 0%, p = 0.009), emergency coronary artery bypass grafting (15%, 3%, 2%, and 0.7%, p < 0.001), and rates of major adverse cardiac events (8%, 5%, 3%, and 4%, p = 0.052) decreased over time.
The long term success after implantation of bare metal stents (BMS) for CTO has been limited by high rates of restenosis and re-occlusion. A large amount of data has demonstrated that drug-eluting stents (DES) are effective in reducing restenosis compared to BMS in various patient and lesion subsets.
Sirolimus-eluting stents (SES) showed a significantly lower in-stent (7% vs 36%, p<0.001) and in-segment restenosis (11% vs 41%, p<0.00001) rate at 6-months of follow-up leading to a lower target lesion revascularisation (TLR) and vessel revascularisation (TVR) rate compared to BMS in a randomised trial. Reocclusion rates, described in 8% of CTO versus 1.8% of non-CTO, has shown a significant decrease (p<0.04) with sirolimus-eluting stents from 13% (BMS) to 4% (18). After a follow-up of 18 months, the composite endpoint of death, MI or TLR was significantly lower (p=0.005) in the DES group (8.1%) than in BMS group (21.6%) and the difference was due to the reduction in TLR (19).
Different authors (20,21) tried to explain the OAT trial results and hypothesised that recanalisation could lead to loss of previously developed collaterals and re-exposure the myocardial area to future reinfarctions. Because the OAT trial included patients with 1- or 2-vessel coronary disease, and PCI on the noninfarct-related arteries was permitted, >85% of patients in the intervention group had no coronary arteries with significant obstructions after PCI, a situation that would cause the functional regression of existing collaterals. In cases of subsequent plaque rupture and total occlusion of any of the 3 coronary arteries occurred (expected in 5% to 15% of patients with acute coronary syndromes over the first 1 to 2 years), the impaired collateral flow after new acute occlusion would immediately predispose to greater myocardial reinfarction, which could explain the negative effects of the OAT study.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
Conclusions Management of patients with chronic total occlusions remains challenging. Most of these patients have multivessel coronary artery disease, have undergone previous revascularisation and have other complex target lesions usually considered unsuitable for percutaneous intervention.
Lifestyle modifications and aggressive control of other cardiovascular risk factors (statins, betablockers and ACE inhibitors) are mandatory. With the exception of the most obvious indications, magnetic resonance imaging or myocardial perfusion scans should be performed to evaluate the extension and severity of inducible ischemia in the CTO related myocardium, stratify the patients and guide therapeutic decision making.
In this setting, percutaneous coronary intervention of CTO by well-experienced operators has been shown to alleviate anginal symptoms, improve left ventricular function, reduce redo surgery and improve long-term survival.
Proven and Potential Benefits of Opening a Chronic Total Occlusion of a territory with ischaemia and viability Alleviate anginal symptoms (13, 15) Improved global and segmental left ventricular systolic function (7,8) Reduced left ventricular volumes (8) Reduced need of further coronary artery bypass grafting (15) Prolonged survival (9,10)
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3.- Werner GS, Surber R, Ferrari M, Fritzenwanger M, Figulla HR.The functional reserve of collaterals supplying long-term chronic total coronary occlusions in patients without prior myocardial infarction. Eur Heart J. 2006;27:2406-12.
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5.- Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503-16.
6.- Shaw LJ, Berman DS, Maron DJ et al. Results From the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation COURAGE Trial Nuclear Substudy. Circulation 2008;117;1283-1291.
7.- Chung CM, Nakamura S, Tanaka K, Tanigawa J, Kitano K, Akiyama T, Matoba Y, Katoh O. Effect of recanalization of chronic total occlusions on global and regional left ventricular function in patients with or without previous myocardial infarction. Catheter Cardiovasc Interv. 2003:368-74.
8.- Kirschbaum SW, Baks T, van den Ent M, Sianos G, Krestin GP, Serruys PW, de Feyter PJ, van Geuns RJ. Evaluation of left ventricular function three years after percutaneous recanalization of chronic total coronary occlusions. Am J Cardiol. 2008;101:179-85.
9.- Hoye A, VanDomburg RT, Sonnenschein K and Serruys PW. Percutaneous coronary intervention for chronic total occlusions: the Thoraxcenter experience 1992-2002. European Heart Journal 2005;26:2630–2636.
10.- Aziz S, Stables RH, Grayson AD, Perry RA, Ramsdale DR. Percutaneous coronary intervention for chronic total occlusions improved survival for patients with successful revascularization compared to a failed procedure. Catheter Cardiovasc Interv. 2007;70:15-20.
11.- Stone GW, Colombo A, Teirstein PS, Moses JW, Leon MB, Reifart NJ, Mintz GS, Hoye A, Cox DA, Baim DS et al. Percutaneous recanalization of chronically occluded coronary arteries: procedural techniques, devices, and results. Catheter Cardiovasc Interv. 2005;66(2):217-36.
12.- Kinoshita I, Katoh O, Nariyama J, Otsuji S, Tateyama H, Kobayashi T, Shibata N, Ishihara T, Ohsawa N. Coronary angioplasty of chronic total occlusions with bridging collateral vessels: immediate and follow-up outcome from a large single-center experience. J Am Coll Cardiol. 1995;26(2):409-15.
13.- Olivari Z, Rubartelli P, Piscione F, Ettori F, Fontanelli A, Salemme L, Giachero C, Di Mario C, Gabrielli G, Spedicato L, Bedogni F; TOAST-GISE Investigators. Immediate results and one-year clinical outcome after percutaneous coronary interventions in chronic total occlusions: data from a multicenter, prospective, observational study (TOAST-GISE). J Am Coll Cardiol. 2003;41:1672-8.
14.- Barlis P, Kaplan S, Dimopoulos K, Tanigawa J, Schutlz C, Di Mario C. An indeterminate occlusion duration predicts procedural failure in the recanalization of coronary chronic total occlusions. Catheter Cardiovasc Interv 2008;71:621-8.
15.- Prasad A, Rihal CS, Lennon RJ, Wiste HJ et al. Trends in outcomes after percutaneous coronary intervention for chronic total occlusions. A 25-year experience from the Mayo Clinic. J Am Coll Cardiol 2007;49:1611–8.
16.- Tsuchikane E. The evolution of CTO angioplasty: Lessons learned from the Japanese CTO Club and experience at the Toyohashi Heart Center. Reported at Fifth International Chronic Total Occlusion Summit.
17.- Suero JA, Marso SP, Jones PG, Laster SB, Huber KC, Giorgi LV, Johnson WL and Rutherford BD. Procedural Outcomes and Long-Term Survival Among Patients Undergoing Percutaneous Coronary Intervention of a Chronic Total Occlusion in Native Coronary Arteries: A 20-Year Experience. J Am Coll Cardiol 2001;38:409 –14.
18.- Suttorp MJ, Laarman GJ, Rahel BM, Kelder JC, Bosschaert MA, Kiemeneij F, Ten Berg JM, Bal ET, Rensing BJ, Eefting FD, Mast EG. Primary Stenting of Totally Occluded Native Coronary Arteries II (PRISON II): a randomized comparison of bare metal stent implantation with sirolimus-eluting stent implantation for the treatment of total coronary occlusions. Circulation. 2006;114:921-8.
19.- De Felice F, Fiorilli R, Parma A, Menichelli M, Nazzaro MS, Pucci E, Dibra A, Musto C, Violini R. Clinical outcome of patients with chronic total occlusion treated with drug-eluting stents. Int J Cardiol 2008: In Press.
20.- Epstein SE, Pichard AD, Kent KM, Satler L, Suddath WO, Lindsay J, Waksman R. The late open-coronary artery hypothesis: dead, or not definitively tested? Am J Cardiol. 2007:100:1810-4.
21.- Werner GS, Emig U, Mutschke O, Schwartz G, Bahrmann P, Figulla HR. Regression of collateral function after recanalization of chronic total coronary occlusions: a serial assessment by intracoronary pressure and Doppler recordings. Circulation 2003; 108:2877-82.
Authors Contact Information. Carlo Di Mario MD, PhD, FRCP, FESC, FACC, FSCAI. President-Elect of the European Association of Percutaneous Cardiovascular Interventions (EAPCI) Department of Cardiology. Royal Brompton Hospital, Sydney Street, London SW3 6NP, United Kingdom. Telephone: (+44) 20 7352 8121 Fax number: (+44) 20 7351 8473 E-mail: firstname.lastname@example.org
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