Recent Randomized CTO Trials- Clearing the Haze?

                                                                                                                                                          - Dr. Akshay Mehta

Although chronic total occlusion (CTO) of a coronary artery is detected in up to 18% of patients with stable coronary artery disease (CAD) and in 18–50% patients with coronary artery disease during coronary angiography; the question which still continues to be debated, forty years after introduction of percutaneous coronary intervention (PCI), is whether opening of these occlusions are beneficial.

Extensive observational studies suggest benefits (outcomes, exercise capacity, depression etc.)  with CTO recanalization compared to medical therapy; however, they suffer from  selection bias and lack of blinding. This is applicable for those studies which involved opening a well collateralized CTO.

In randomized studies which have compared successful CTO PCI with failed PCI, the complications associated with the latter magnify the benefits with the former.

Hence what was long needed were prospective randomized studies comparing CTO PCI with optimal medical therapy (OMT).

A few recent studies foot the bill.

1. The EXPLORE trial  (Evaluating Xience and Left Ventricular Function in Percutaneous Coronary Intervention on Occlusions After ST-Elevation Myocardial Infarction)  randomized 304 patients who underwent primary PCI for ST-elevation myocardial infarction and had a concomitant non-infarct-related CTO to OMT alone or CTO PCI at 7 days after treating the culprit vessel, along with OMT. Both the primary endpoint of magnetic resonance imaging (MRI)-derived left ventricular ejection fraction and end-diastolic volume, as well as the secondary hard clinical endpoint of cardiac death, MI, or CABG were comparable at 4 months in both groups.

2. In the prospective, randomized Drug-Eluting Stent Versus Optimal Medical Therapy In Patients With Coronary Chronic Total Occlusion (DECISION-CTO) trial, the goal was to assess the safety and efficacy of CTO-PCI + OMT (n = 417) compared with OMT (n = 398) among patients with at least one CTO.

Patients with stable angina (74%), unstable angina (20%) or acute MI (6%) were randomized to the two groups and PCI to non CTO and CTO lesions were done after randomization within 30 days.

The CTO-PCI procedure was a success in 91% of the cases.

At the 3-year follow-up, in the intention-to-treat population, the primary end point [major adverse cardiac events (MACE) at 3 years (all-cause mortality, MI, stroke, repeat revascularization)],occurred in 20.6% patients in the optimal-medical-therapy group vs 19.6% patients in the PCI group (adjusted HR 0.91; p = 0.54).

There were no significant differences between the optimal-medical-therapy group and the PCI group in rates of death (4.4% and 3%, respectively; p = 0.25), MI (10.7% and 8.4%, respectively; p = 0.24), stroke (1.3% and 1.0%, respectively; p = 0.11) or repeat revascularization (10.4% and 8.6%, respectively; p = 0.38).

The Seattle Angina Questionnaire (SAQ) physical limitation, angina stability, treatment satisfaction, angina frequency, and quality-of-life scores were comparable in the two groups, throughout the follow-up.

Thus, in patients with CTO of a coronary artery, medical therapy was not inferior to PCI for the primary outcome of a composite of death, MI, stroke, or any revascularization at 3 years.

Moreover, patients who had optimal medical therapy alone did not report worse angina or quality of life at 3 years than patients who underwent PCI of the completely occluded vessel.

Although it is the first randomized trial comparing the two strategies for CTO, DECISION-CTO suffered from slow enrollment, early termination, high loss to follow-up and reasonably high crossover (about 20%).

Also, since non-CTO lesions were treated after randomization and were not evenly matched for disease severity, that itself could explain the equivalence of the two treatment arms. However, as an initial treatment strategy in clinical practice, OMT for a CTO and PCI for non CTO lesions seems to be as good as PCI for both CTO and non CTO lesions, which is the main message of the trial.

3. Euro CTO was conducted between March 2012 and May 2015 at 26 European centers with expert operators. Although originally planned to enroll 1200 patients for its safety outcome at 3 years, due to slow recruitment only 396 patients with stable coronary disease were randomly assigned to receive PCI with a biolimus-eluting stent plus OMT or OMT. Patients with multi-vessel disease had non-CTO lesions treated before randomization. The primary end point was SAQ five subscales at 12 months.

The procedural success rate was 86.3% and PCI complication rate 2.9%. Ten OMT patients (7.3%) crossed over to PCI because of ongoing angina. At 12 months, MACE rates were comparable in the PCI and OMT groups (5.2% vs 6.7%; p = 0.52).

ACS patients and very symptomatic patients were excluded.

At a median follow up of 19 months, angina frequency score (p = 0.003) and the quality-of-life score (p = 0.007) had improved for PCI compared with optimal medical therapy (intention to treat). There was no improvement in the other parameters of SAQ (physical limitation, angina stability, and treatment satisfaction) for PCI compared with optimal medical therapy.

This is a path breaking trial, the difference from DECISION-CTO being that non-CTO lesions in this trial (Euro CTO) were treated before randomization and baseline assessment, so only the difference in CTO treatment would affect SAQ changes.

Thus, the following can be summarized from these recent RCT’s of CTO PCI:

1. Success rates of CTO PCI which in earlier years were at 50% to 60% have changed in the last 5 to 10 years to 85 to 90%, mainly due to improved wires and wire techniques, specific crossing devices, dissection and re-entry methods, dual injection of contralateral coronary arteries, and retrograde techniques.

2. Against that, the complication rates have reduced to approximately 3% in expert hands (including a minority of deaths) which depends on patient age, lesion complexity, and crossing techniques used and can be pre-assessed with scoring systems.

3. The RCT’s till now have not shown or have not been powered to show reduction in MACE with CTO PCI.

4. They have mainly shown improved symptomatic status and quality of life in trials which have recruited mildly symptomatic or stable patients.

5. Therein too, to remove the placebo effect of CTO PCI on quality of life (QoL),  there is a need for a well-designed and adequately powered sham-controlled, randomized clinical trial to definitively answer the question of the impact of CTO PCI on patient symptoms. The Sham-controlled Intervention to Improve QoL in CTOs trial (SHINE-CTO), currently enrolling patients at some of its 15 sites, may provide the answer by end of this year 2018.

Till then, in view of length of the procedures, risks of contrast-induced nephropathy, bleeding, radiation injury and costs, CTO attempts should probably be reserved for highly symptomatic patients on maximally tolerated medical therapy with evidence of significant residual ischemia. This procedure should be performed by experienced operators at dedicated centers to achieve optimal results, keeping patient preferences also in mind.

Suggested readings :

1. Werner GS, Martin-Yuste V, Hildick-Smith D, Boudou N, Sianos G, Gelev V, et al. A randomized multicentre trial to compare revascularization with optimal medical therapy for the treatment of chronic total coronary occlusions. Eur Heart J. 2018 Jul 7;39(26):2484–93.

2. Fefer P, Knudtson ML, Cheema AN, Galbraith PD, Osherov AB, Yalonetsky S, et al. Current perspectives on coronary chronic total occlusions: The Canadian Multicenter Chronic Total Occlusions Registry. J Am Coll Cardiol.2012;59:991–7.

3. Tajti P, Brilakis ES. Chronic total occlusion percutaneous coronary intervention: Evidence and controversies. J Am Heart Assoc.2018;doi:10.1161/JAHA.117.006732.

4. Henriques JP, Hoebers LP, Råmunddal T, Laanmets P, Eriksen E, Bax M, et al; EXPLORE Trial Investigators. Percutaneous intervention for concurrent chronic total occlusions in patients with STEMI: The EXPLORE trial. J Am Coll Cardiol.2016;68:1622–32.

5. Park S. Drug-eluting stent implantation versus optimal medical treatment in patients with chronic total occlusion (DECISION-CTO). American College of Cardiology’s 66th Annual Scientific Session & Expo; Washington, DC; 2017.

Take Home Messages

1. Statins may have an added benefit for primary prevention of VTE in people at high CV risk due to multiple risk factors, though not primarily given for the same.

2. They may be particularly useful for secondary prevention, especially in people with unprovoked VTE who cannot continue long term anticoagulants as recommended, due to adverse effects. 

There often is a rebound phenomenon after the anticoagulant treatment is withheld, in which several markers of coagulation, including D-dimer levels, increase. Statins may serve a useful purpose in such patients by safely preventing coagulation and increase in D-dimer.

Of course, both the above observations now need to be proven in large randomized trials aimed at VTE as the primary end point.

Suggested readings:

1. Biedermann JS,   Kruip M,  van der Meer FJ,   Rosendaal FR, Leebeek FWG,   Cannegieter SC,   et al. Rosuvastatin use improves measures of coagulation in patients with venous thrombosis. European Heart Journal, 2018 May 14;39(19):1740–1747

2. Glynn RJ, Danielson E, Fonseca FA, Genest J, Gotto AMJr, Kastelein JJ, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med  2009;360:1851–1861.

3. Kunutsor SK, Seidu S, Khunti K. Statins and secondary prevention of venous thromboembolism: pooled analysis of published observational cohort studies. Eur Heart J 2017;38:1608–1612.

4. Migliacci R, Becattini C, Pesavento R, Davi G, Vedovati MC, Guglielmini G, et al. Endothelial dysfunction in patients with spontaneous venous thromboembolism. Haematologica 2007;92:812–818.