Chronic Total Occlusion -To open or not to open

The true prevalence of Chronic Total Occlusion CTO is not known as the large number of CTOs occurs in-patient who is asymptomatic or minimally symptomatic and never undertakes a diagnostic angiography.

CTO though are found one in every three to five diagnostic catheterization yet more often than not they are not vascularized and accounts for only 8% of all PCIs and more often they are referred for CABG.The in syntax study, the prevalence of CTO in PCI arm was only 10% while in CABG arm was 40% .

Since CTO-PCI did not get widespread acceptance in the cardiology community and there became 2 groups of interventional cardiologist, one who is doing CTO-PCI and others who are not doing CTO-PCI?

Maybe because of the CTO interventions are more demanding in terms of patience, expertise, knowledge, equipment and are less rewarding in terms of demonstrated superiority over the medical therapy. They are time intensive, resource intensive and complex procedures and sometimes are associated with dangerous complications like perforations, kidney failure, radiational injuries, acute occlusion and even death.

Recently in 2017, the landscape of CTO-PCI has changed dramatically. The ORBITA trial raised questions on the PCI in general and lot of lay press question the relevance of putting a stent.

The DECISION CTO trial showed routine CTO-PCI+OMT is not superior to OMT alone in reducing cardiovascular outcomes and the EXPLORE TRIAL[7] in which an additional CTO PCI was done within 1 week after primary PCI did not find overall benefit for CTO PCI in terms of LVEF or LVEDV.The REVASC trial also questioned the CTO-PCI for improving the left ventricular functions.

EURO-CTO trial randomized 363 patients 2:1 to CTO-PCI and to optimum medical therapy. The success rate of CTO opening was 86.3% and the crossover was only 7% from medical therapy to CTO-PCI group.“The Seattle angina questionnaire (SAQ) to study the quality of life and baseline and at 5 years showed significant improvement in the CTO-PCI group in all aspect of questionnaire especially in angina frequency and angina severity”

The open CTO registry was reported as the largest registry for CTO-PCI and showed the patient with the successful opening of CTO fared much better in terms of angina frequency and physical limitation as compared to the patients where the CTO could not be opened. It also showed where the predominant symptoms were breathlessness the opening of CTO helped a lot in elevating the symptoms.

There is a high controversy in the trial reports as well as there is an absence of identification of the groups where a significant relief is definitely achieved for CTO-PCI. The common perception of the cardiology community especially non-interventional remain even today that success can only be achieved in 50-60% of patients with CTO-PCI and only 50% of the cardiology community actually think that opening CTO only something help in elevating symptoms.

We need to understand the role of stress test in-patient with CAD and CTO. In open CTO registry stress test was mandatory before every PCI instable angina pectoris. In a patient with an intermediate and high-risk stress test, there was very significant improvement in symptoms with CTO-PCI and even in a patient with low-risk stress test CTO-PCIwas also associated with good meaning full robust resolutions of symptom (Salisbury et al. Am J Cardiol 2018; Epub.)

Clarifying thisGalassiEur Heart J; 2016(37): 2692-2700) recommended an algorithm where by

In-patient with severe refractory angina even with normal valve motion or hypokinesis in the CTO territory, the CTO must be opened to relief the symptoms.

In-patient with severe refractory angina with aknesis or dyskinesis in CTO territory, if , viability is present, CTO PCI is indicated.

In-patient with severe refractory angina if viability is not present then medical treatment is indicated.

In-patient with no refractory angina symptoms and there is normal wall motion or hypokinesis in CTO territory if the ischemic burden is > 10% CTO PCI is indicated.

In-patient with no refractory angina symptoms with there is normal wall motion or hypokinesis in CTO territory, if ischemic burden is < 10% medical therapy is indicated.

Questions are still raised whether the CTO-PCI should be offered to only those with symptoms or it should also be attempted even in patients without symptoms. The consensus of the experts remains if the patient is having LV dysfunctions and severe symptoms; an opening of CTO-PCI is likely to have significant improvement in their symptoms.Inpatients with large ischemic burden because of CTO, CTO-PCI is also likely to have definite improvement.

In some patients with normal or near-normal ejection fraction, the improvement in symptoms will be difficult to assess. If there are no symptoms before the procedure, the symptomatic improvement may be difficult to assess. It is also felt that many a time patient thinks that the symptoms of breathlessness are related to age and they adapt to those symptoms as feeling being asymptomatic. It is only after the CTO-PCI they feel the difference in their perception of the symptoms.

One special population has now been noticed that where the CTO-PCI is done in surgical turndown patients or as a part of the strategy for complete revascularization in high risk indicated patient. The result of which are keenly awaiting as an outcome of the optimal registry.

In conclusion, we have to treat the patient, not the angiogram. The procedure of CTO-PCI should be carefully discussed with the patient and shared decision should be taken up with the patient having discussed regarding the risk and potential benefits as well as the current limitation to current evidence.

RISK STRATIFICATION OF CTO

The presence of CTO identifies a subset of patients with a poor clinical outcome if the patient has a future myocardial infarction.

All CTOs are not similar and as dissimilar are all patients with CTO.

It is considered as a hallmark of a previous MI, which has not been treated with reperfusion and had been or not had been supported by the development of collaterals with varied damages to the myocardium.

The risk stratification of a particular CTO in identifying a subset of patients, which are going to have poor clinical outcomes with a subsequent event, is an important decision assessing the risk and benefits of the CTO-PCI.

While the duration of a CTO is often difficult to diagnose but many time a previous incidence of MI treated medically often gives a fair idea of the age of the CTO. “More aged is the lesion more difficult is to open”.The other parameters of procedural difficulties like that of a blunt stump, the presence of side branch, calcification and tortucity, poor distal target and long lesions identify the risk of being a failed procedure and increasing the risk-benefit ratio.

Location of CTO and its impact on the myocardial segmental vascular supply and the benefits of revascularization is an important assessment to be done before attempting the CTO-PCI.

A distal RCA CTO impacting the supply of PDA and PLV branches and having robust collateral from LAD and OM shall have lesser benefits of CTO-PCI than a proximal or mid LAD CTO having poor collaterals from RCA or LCX.

In this regard, the myocardium at risk myocardium jeopardy assessment become a critical dimension where the amount of myocardium at risk and the amount of myocardium benefited from the CTO-PCI becomes important for assessing the risk benefit ratio of the procedure.

The traditional teaching of anterior, lateral, inferior or posterior MI has to be shunt in favor of the assessment of the myocardial focused angiographic assessment.

Kalbfleisch&Hort (1977) in an elegant study has reported the territorial percentage of supply by the various branches. With LAD 49-53%, LCX 18-27%, with RCA 18-33%. He defined SEPTUM to be the most important area of the myocardium having a dual supply by LAD and PDA septal perforators. While staying the importance of CTO revascularization, it is an important to also study the following:

Length, location and dominance of the CTO vessel in directly assessing the percentage of myocardial segments at risk / supported by the donner vessels

Size, location, and extent of diffuseness of the disease in the donner vessel supplying the at-risk segments of the myocardium

The clinical and biochemical factors suggesting the presence of diffused atheroscotic disease not only in epical cardial but also in myocardial circulation

Assessment of Viability or hibernating myocardium in the myocardial segments eligible for revascularization

Allow the variations of myocardial supply by the anomalous coronary artery or by the previously grafted vessel

Assess the viability and the benefits to the septal myocardium which amounts to the major portion of the LV by revascularization.

The risk benefits of CTOs do not only depends on its locations or its procedure success but also on the condition and diffuseness of lesions in other arteries. A CTO in LAD with a defused disease in LCX and RCA becomes important and shall be extremely beneficial in event of future closer of those diseased arteries and apart from the visible angiography stenosis the microcirculation disease and the diffuseness of atherioclosis is also be kept in mind while assessing the risk and benefit of doing a CTO PCI.

CTO-PCI IN LOW ISCHEMIC BURDEN

Strategy for revascularization has markedly changed since the development of DES stents and marked improvement in the anti-thrombotic therapy.The complications of the PCI have been dramatically reduced and so was the increase in its uses across all sorts of condition and the lesions.

The role of PCI in treating stable angina pectoris compared with lone medical therapy in patients suffering from an objective evidence of myocardial ischemia and significant coronary artery disease without established prognostics indications for coronary revascularization was studied in randomized COURAGE trial [8]where during the medium follow up of 4.5 years the medical therapy was equal to PCI in terms of MACE and angina free status. These patients were having more than 70% significant stenosis but the ischemic burden was low.

The DECISION CTO trial, also randomized patients to CTO-PCI + OMT (n=417) or OMT (n=398). In PCI arm, patients underwent CTO-PCI using DES.Revascularization in all non-CTO lesions within the vessel diameter of 2.5mm for a patient with multi coronary artery disease was also recommended. All patient were given guidelines derived OMT.

CTOs located in a distal coronary artery, 3 different vessel CTOs, 2 proximal CTOs, left main CTO, in-stent restenosis, Graft CTO and high-risk patient with LV dysfunction and severe co-morbidity were excluded and most of the patients were belonging to stable angina pectoris with a low ischemic load.

Decision CTO indirectly re-conformed the same fact as that of COURAGE trial that the symptoms and the ischemic burden is more important than oculo-stenosis while deciding for the strategy of management of revascularization.

In EXPLORE trial revascularization was attempted in CTOs in a non-infarct artery after AMI, no benefit was achieved by CTO-PCI in terms of LVEF or LVEDP yet in CTO-PCI in left anterior descending artery was found to be beneficial may be only because the ischemic burden relieved was high.

The risk-benefit ratio of the CTO-PCI in stable angina pectoris with low ischemic burden will also tilt unfavorably because CTO intervention requires a special expertise, more special equipment and sometimes dangerous complications and worse outcome specially in patients with CTO who also have multivessel disease and who had an unsuccessful recanalization.

POTENTIAL MORTALITY BENEFITS

Suero&Colleague[9]JACollCardiolin 2001 published the largest study on 2000 patients followed up for 10years. Patient who underwent unsuccessful single vessel CTO and were subjected to bypass surgery derived mortality benefits even when CTO was surgically bypassing then the medical therapy.

The study also demonstrated that coronary artery disease is a continuous spectrum to with the best outcomes derived in single vessel CTO and successful recanalization and the worst outcome were in multi vessel disease, multiple CTOs and unsuccessful recanalization.

TOASTGISE Study[10] (Clinical Trials Immediate Results and One-Year Clinical Outcome after Percutaneous Coronary Interventions in Chronic Total Occlusions) in 2003, includes 376 patients in CTOs and followed them for 1 year. Investigator reported less cardiac death in successful CTO PCI group.

In 10years’ experience by ERASMUS MC[11]age 74 consecutive patients were treated successfully, the survival benefit was most apparent in multi vessel disease.

PRASAD & COULLEAGUES[12] published the MAYO CLINIC experience in1 1262 patients and demonstrated mortality benefits with a successful PCI than with unsuccessful attempt.

SAFLEY AND COLLEAGUES[13]demonstrated that the LAD revascularization but not of left circumflex or right coronary artery were independently protected of higher survival at 5year but LEE AND COLLEAGUE[14]from Korea did not show a benefit of CTO revascularization and so was in Washington hospital center[15] experience of 172 patients with 2 years follow up and there were no mortality benefits so is the DECISION CTO and EXPLORE.

The major limitation of all these studies discussed is that they excluded patients in whom CTO recanalization not attempted because of complex angiography picture, significant co-morbidity, multiple CTOs in multiple vessel disease.

This again indicates that the CTO recanalization does not help in asymptomatic patients where the ischemic burden is low yet it can definitely provide mortality benefits when the ischemic burden is high, the lesion is effecting LAD and are indicated for revascularization by PCI.

This brings our attention to a special group of complex high risk indicated patient where despite of guidelines and appropriateness criteria are recommending a surgical intervention, the surgery is not undertaken because of a higher risk of mortality and unsuitability of the coronary tree.

These patients (CHIP) become again indicated for PCI and invariably are having multiple CTOs and very heavy ischemic burden. CTO angioplasty becomes lifesaving in these patients.

ANGINA RELIEF AND QUALITY OF LIFE

In our experience, recanalization of CTO is most commonly referred to for the purpose of relieving angina symptoms when the full guideline directed OMT is not helpful in controlling the symptoms.

In Stable angina pectoris patients when CTO is recanalization the improvement in angina class occurs significantly.In Heart Lung & Blood Institute, 94% patients showed no angina of the improvement of their symptoms at 2 years, there were some studies like BELL AND COLLEAUGES[16] andNOGUCHI AND COLLEAUGE[17] found that there was an increasing need of CABG in failed CTO-PCI showing the need of that persistent angina symptoms were the driver for CABG.

But these studies were done balloon angioplasty Era and has less relevance today, the latest EURO CTO Trial[18] which attempted to look systematically on this issued in first Randomized trial of PCI vs optimized medical therapy results showed a high procedural success rate with PCI and low procedural risk with no death and 0.4% MACCE.

Improvement in clinical symptoms was more pronounced in patients treated with PCI than with optimal medical therapy, based on the Seattle angina questionnaire (SAQ) subscales of physical limitation and angina frequency. The PCI group also showed a trend to improved quality of life and significantly greater absolute freedom from angina.

The same was studied in a single centre prospective cohort analysis at UK using the same Seattle angina questionnaire UK version.Patient with successful revascularization had less physical activity limitation, rarer angina episodes, and greater patient satisfaction compared with patients with a failed procedure (P< 0.03 for all 3 components) with improved overall acceptable quality level scores.

The QOL with SAQ Seattle has also studied in FACTOR trial [19]125 patients filled up the form at the baseline and 1 month after CTO PCI. The benefit after CTO PCI was greatest in-patient who is symptomatic at baseline compared to the asymptomatic patient.

IMPROVEMENT OF LV FUNCTIONS

In the presence of LV dysfunction, it’s a challenge to identify a right person who might benefit from revascularization of a CTO because the viability of the re-perfused segment is of immense importance to predict the recovery of LV function with CTO-PCI.

The methods like the evaluation of Q wave on ECG evaluation of history of chest pain or previous MI or advance imaging like positron emission tomography and cardiac MRI has been used to predict which patient might have LV function improvement after revascularization.

SIRNES AND COLLEAGUES [20] assessed left ventriculography at baseline and at 6 months in-patient with successful CTO-PCI. The regional radial shortening was increased in recanalized artery territory

CHUNG AND COLLEAUGE[21]studied a symptomatic patientwith prior MI and well matched patient of Non MI. the subgroup of the patient with MI who had grade III collateral had similar improvement as that of group I with without MI the presence of collaterals in some way protected the viability of myocardium.

WERNER AND COLLEAGUES[22] demonstrated that the collateral are important but you cannot predict the recovery of LV functions on the basis of because the LV function recovery depends upon integrity of myocardial circulation.

Erasmus medical centre studied the utility of CTI recanalization of dysfunction yet viable segments of myocardium using pre-intervention and post intervention cardiac MRI study. They found that end-systolic and end-diastolic dimensions of the ventricle improved after successful recanalization of the occluded artery.

KINGS COLLEGE London[23] also evaluated the pre-procedure and post-procedure (CTO-PCI) EF and transmural extent of infarction by MRI after recanalization, and showed improvement in global EF and segmental wall thickening after CTO recanalization. They also suggested that the extent of transmural infarction noted on pre-procedure MRI could help predict the extent of expected improvement.

IMPROVEMENT IN ISCHEMIC BURDEN

The relationship between successful PCI and Ischemic reduction was studied by safely and colleague (Ref 30), they used myocardial perfusion imaging (MPI) before and after CTO-PCI. The result was stratified by initial MPI summed difference score(SDS). The SDS was converted to a percentage of Ischemic Myocardium. The patient was stratified into 4 groups, SDS<4 - Normal or minimal ischemia (<5% of ischemic myocardium), SDS4-8 mild ischemia (5%-9% ischemic myocardium), SDS 9-13 moderate ischemia (10%-16% ischemic myocardium), SDS>13 severe ischemia (>16% ischemic myocardium).

If the ischemic burden as defined by SDS > 4, that means 5% decrease in ischemic myocardium has taken place with CTO-PCI which has been associated with decrease risk of death and MI in COURAGE nuclear study[24].

The study concluded that the mean reduction of CTO-PCI was 6.26%. The baseline ischemic burden if it was more than 12.5% it was predictive of improvement after CTO-PCI. The baseline ischemic burden if < 6.5% than it was predictive of harm CTO-PCI. If the reduction of ischemic burden if > 5% the patient experienced mortality and clinical benefits.

It was SINGLE CENTRE trial wouldlimit its applicability however the thought makes the basis of the concept and reason for CTO-PCI.

SUMMARY

CTO PCI is fast emerging as a sub specialty of percutaneous coronary intervention.

With improvement in experience, backup of research, newer techniques and devices CTO PCI is becoming easy with > 90% success and is being attempted more often in complex high risk patient.

In complex high risk indicated patient (CHIP) where surgical intervention is not possible because of unsuitability of coronary artery or very high surgical risk CTO-PCI becomes necessary for relief of symptoms as well as prolonging the life and in simple low risk indicated patients (SLIP) CTO-PCI is recommended for relief of symptoms of angina, decreasing the ischemic burdenand improvement of LV functions and possible mortality benefit in selected coronary anatomy and high ischemic burden.

The door has opened for the performance of randomized controls trial of CTO-PCI in high risk indicated patients (CHIP), as well as simple low risk, indicated patient with uncontrolled symptoms and high ischaemic load.