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Recent Randomized CTO T.....


Recent Randomized CTO T.....


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.


Statins for VTE prevention: Extending pleiotropic effects to the venous side<.....

Statins for VTE prevention: Extending pleiotropic effects to the venous side<.....

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.


Risk Prediction of Atrial Fibrillation Based on Electrocardiographic Interatrial Block.....

Risk Prediction of Atrial Fibrillation Based on Electrocardiographic Interatrial Block.....

                                                                                                                                  -Dr Akshay Mehta


Skov MW, Ghouse J, Kühl JT, Platonov PG, Graff C, Fuchs A, et al. Risk prediction of atrial fibrillation based on electrocardiographic interatrial block. Journal of the American Heart Association. 2018 May 30;7(11). pii: e008247.

Key Points :

1. The aim of the study was to test whether Interatrial Block (IAB) can improve risk prediction of AF in 152 759 primary care patients aged 50 to 90 years from 2001 to 2011.

2. For the study, individuals with P‐wave ≥ 120 ms and the presence of none, 1, 2, or 3 biphasic P‐waves in inferior leads were identified.

3. A dose‐response relationship between the number of biphasic P‐waves in inferior leads and the hazard of AF during follow‐up was observed.

4. Although the highest effect of IAB on the absolute risk of AF was observed in individuals aged 60 to 70 years with CVD, individuals with advanced IAB and no CVD had a higher risk of AF than patients with CVD and no IAB



FAME- 2 at 5 YEARS: Five-Year Outcomes with PCI Gui.....


FAME- 2 at 5 YEARS: Five-Year Outcomes with PCI Gui.....

Hybrid Coronary Revascularization in Selected Patients With Multivessel Disease 5-Year.....

Hybrid Coronary Revascularization in Selected Patients With Multivessel Disease 5-Year.....

Deferred vs. performed revascularization for coronary stenosis with grey-zone fraction.....

Deferred vs. performed revascularization for coronary stenosis with grey-zone fraction.....

Reviewed by Dr Akshay Mehta

Key Points:

1. The prognosis for deferred and performed revascularization in coronary stenosis with FFR values in the grey zone (0.75–0.80) was evaluated in 1334 native coronary stenosis in as many number of patients.

2.  The primary outcome, a composite of death, target-vessel myocardial infarction (MI), and target vessel revascularization (TVR) as well as overall  mortality and spontaneous MI did not differ between the groups, whereas myocardial infarction (mainly periprocedural) was significantly higher in the performed group and target vessel revascularization was significantly higher in the deferred group.

Study Protocol:

Out of all patients in The Interventional Cardiology Research In-cooperation Society Fractional Flow Reserve (IRIS-FFR) registry, which is a prospective, multicenter registry designed for investigating the prognosis of coronary stenosis assessed using FFR in routine clinical practice, patients with a de novo native coronary artery stenosis with an FFR value in the grey zone (0.75–0.80) were enrolled for this study. The decision regarding revascularization for such patients was at the operator’s discretion. 

Follow-ups were conducted during hospitalization, at 30 days, 6 months, and 12 months after the index procedure and subsequently at 6 month intervals. The patients’ clinical status, interventions, and adverse events were recorded at each follow up.


During a median follow-up of 2.9 years, overall mortality did not differ between the groups (2.5% in deferred group vs. 2.0% in performed group; aHR 0.82, 95% CI 0.34–2.00; P = 0.66). The performed group showed a significantly higher risk of target vessel MI (0.7% vs. 3.2%; aHR 0.27, 95% CI 0.09–0.80; P = 0.02), mainly because of a higher risk of periprocedural MI but the incidence of spontaneous MI did not differ between the groups (0.7% vs. 0.5%; aHR 1.85, 95% CI 0.35–9.75; P = 0.47). Definite stent thrombosis did not occur. The risk of TVR was higher in the deferred group (5.9% vs. 3.7%; aHR 2.17, 95% CI 1.17–4.02; P = 0.01).

The clinical outcomes on subgroup analysis and propensity score matching showed a similar trend.

The indications for TVR were angina with CCS III or IV, ischemia documented by non-invasive test or angiographic progression to more than 90% diameter stenosis.

ACS and multivessel disease were the dominant predictors for major adverse cardiac events in both the groups.


For coronary stenosis with grey-zone FFR values, revascularization was associated with a high risk of periprocedural MI which was offset by a high risk of TVR in the deferred group, without any significant difference in overall clinical outcomes including mortality.


Although an observational study, it is based on the largest cohort of prospectively enrolled patients with the longest follow-up duration that could give clinically relevant information for the issue of FFR in the grey zone.

The other strengths were: adjudication by an independent committee, adjustment for potential confounders, and vessel-level outcomes.

Questions that beg for answers are the reasons for revascularizing some lesions as compared to others, information about baseline symptoms, and upstream stress tests.

Like prior several non-randomized, observational studies, the same message appears from this study, namely that death and myocardial infarction remain uncommon in the FFR grey zone. Subsequent TVR takes place in more number of deferred stenoses with a higher incidence of periprocedural MI in the revascularization group.

Suggested Readings:

  1. Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van't Veer M, et al. FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360:213–224.


  1. De Bruyne B, Fearon WF, Pijls NHJ, Barbato E, Tonino P, Piroth Z, et al. FAME 2 Trial Investigators. Fractional flow reserve-guided PCI for stable coronary artery disease. N Engl J Med  2014;371:1208–1217.


  1. Zimmermann FM, Ferrara A, Johnson NP, van Nunen LX, Escaned J, Albertsson P, et al. Deferral vs. performance of percutaneous coronary intervention of functionally non-significant coronary stenosis: 15-year follow-up of the DEFER trial. Eur Heart J  2015;36:3182–3188.


  1. Courtis J, Rodés-Cabau J, Larose E, Déry J-P, Nguyen CM, Proulx G, et al. Comparison of medical treatment and coronary revascularization in patients with moderate coronary lesions and borderline fractional flow reserve measurements. Catheter Cardiovasc Interv  2008;71:541–548.


  1. Lindstaedt M, Halilcavusogullari Y, Yazar A, Holland-Letz T, Bojara W, Mügge A, et al. Clinical outcome following conservative vs revascularization therapy in patients with stable coronary artery disease and borderline fractional flow reserve measurements. Clin Cardiol  2010;33:77–83


  1. Adjedj J, De Bruyne B, Flore V, Di Gioia G, Ferrara A, Pellicano M, et al. Significance of intermediate values of fractional flow reserve in patients with coronary artery disease. Circulation 2016;133:502–508.


  1. Agarwal SK, Kasula S, Edupuganti MM, Raina S, Shailesh F, Almomani A, et al. Clinical decision-making for the hemodynamic “gray zone” (FFR 0.75-0.80) and long-term outcomes. J Invasive Cardiol  2017;29:371–376.


  1. Yamashita J, Tanaka N, Shindo N, Ogawa M, Kimura Y, Sakoda K, et al. Seven-year clinical outcomes of patients with moderate coronary artery stenosis after deferral of revascularization based on gray-zone fractional flow reserve. Cardiovasc Interv Ther 2015;30:209–215.


  1. Shiono Y, Kubo T, Tanaka A, Ino Y, Yamaguchi T, Tanimoto T, et al. Long-term outcome after deferral of revascularization in patients with intermediate coronary stenosis and gray-zone fractional flow reserve. Circ J 2014;79:91–95.


  1. Petraco R, Sen S, Nijjer S, Echavarria-Pinto M, Escaned J, Francis DP, et al. Fractional flow reserve-guided revascularization: practical implications of a diagnostic gray zone and measurement variability on clinical decisions. JACC Cardiovasc Interv 2013;6:222–225.

11. Johnson NP and  Zimmermann FM. Yellow traffic lights and grey zone fractional flow reserve values: stop or go? European Heart Journal, 2018:39(18):1620–1622.



Patients with myocardial infarction (MI) and multi-.....


Patients with myocardial infarction (MI) and multi-.....

Mobile Phone Detection of Atrial Fibrillation with Mechanocardiography The MODE-AF Stu.....

Mobile Phone Detection of Atrial Fibrillation with Mechanocardiography The MODE-AF Stu.....

Heart Failure with Mid-Range Ejection Fraction: A No Man's Land In Search Of Its M.....

Heart Failure with Mid-Range Ejection Fraction: A No Man's Land In Search Of Its M....., cited on April 25, 2018.

Cleland JGF, Bunting KV, Flather MD, Altman DG, Holmes J, Coats AJS, et al. Beta-blockers in Heart Failure Collaborative Group; Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials, European Heart Journal, 2018;39(1): 26–35