R&D Literature Review April 2018

BCIS R&D Group


Literature Review April 2018


Journal scanning: Michael Mahmoudi, Vijay Kunadian

Editing: Nick Curzen





Increasing evidence that prognosis is associated with extent of ischaemia… time for get pressure wiring?

Clinical implications of three-vessel fractional flow reserve measurement in patients with coronary artery disease       

Lee et al. European Heart Journal, Volume 39,  11, 14 March 2018,  945–951


The investigators in this trial sought to determine the clinical implications of 3 vessel FFR (total physiologic atherosclerotic burden= total sum of FFR in 3 vessels). They recruited 1136 patients who underwent FFR measurement in three vessels in the 3V FFR-FRIENDS study. The patients were classified into high and low 3V-FFR groups according to the median value of 3V-FFR (2.72). Mean % angiographic diameter stenosis was 43.7 ± 19.3% and mean FFR was 0.90 ± 0.08. There was a negative correlation between 3V-FFR and estimated 2-year MACE rate which consisted of a composite of cardiac death, myocardial infarction and ischaemia-driven revascularization, P < 0.001. The patients in low 3V-FFR group showed a higher risk of 2-year MACE than those in the high 3V-FFR group (7.1% vs. 3.8%, P = 0.01) driven by the higher rate of ischaemia-driven revascularization in the low 3V-FFR group (6.2% vs. 2.7%, P = 0.008). The authors concluded that patients with high total physiologic atherosclerotic burden assessed by 3V-FFR showed higher risk of 2-year clinical events than those with low burden driven by ischaemia-driven revascularization for both functionally significant and insignificant lesions at baseline.


Yet more evidence that it is lesion-specific ischaemia that determines outcome, not anatomy

Angiography Versus Hemodynamics to Predict the Natural History of Coronary Stenoses:  Fractional Flow Reserve Versus Angiography in Multivessel Evaluation 2 Substudy.

Cicarelli et al. Circulation. 2018;137:1475–1485. DOI: 10.1161/CIRCULATIONAHA.117.028782


This paper reports on the natural history of patients in the FAME 2 trial (that compared OMT with PCI in patients with symptoms and FFR positive lesions). It focuses on 607 patients from the trial in whom no revascularisation was performed. The primary end point, defined as vessel-oriented clinical end point (VOCE) at 2 years, was a composite of prospectively adjudicated cardiac death, vessel related myocardial infarction, vessel-related urgent, and non urgent revascularization. The stenoses were divided into 4 groups according to FFR and %DS values: positive concordance (FFR≤0.80; DS≥50%), negative concordance (FFR>0.80; DS<50%), positive mismatch (FFR≤0.80; DS<50%), and negative mismatch (FFR>0.80; DS≥50%). The rate of VOCE was highest in the positive concordance group (log rank: X2=80.96; P=0.001) and lowest in the negative

concordance group. The rate of VOCE was higher in the positive mismatch group than in the negative mismatch group (hazard ratio, 0.38; 95% confidence interval, 0.21–0.67; P=0.001). There was no significant difference in VOCE between the positive concordance and positive mismatch groups (FFR≤0.80; hazard ratio, 0.77; 95% confidence interval, 0.57–1.09; P=0.149) and no significant difference in rate of VOCE between the negative mismatch and negative concordance groups (FFR>0.80; hazard ratio, 1.89; 95% confidence interval, 0.96–3.74; P=0.067).  The conclusion from these data is that physiology is a more important determinant of

the natural history of coronary stenoses than anatomy.

This is a very important paper:  it adds strong support to the previously available data that continues to be routinely ignored in many hands:  the outcome for a coronary lesion is determined by its ability to cause ischaemia to a much greater extent than how severe it looks. (There is a theme here!)




FFR-guided therapy: better clinical outcome and resource utilisation

Clinical Outcomes and Cost-Effectiveness of Fractional Flow Reserve-Guided Percutaneous Coronary Intervention in Patients with Stable Coronary Artery Disease. Three-Year Follow-Up of the FAME 2 Trial (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation).

W Fearon, et al. Circ 2018; 137:480-87


The FAME 2 trial has indicated that the rate of the primary end point (a composite of death from any cause, nonfatal MI, or urgent revascularization within 2 years) is lower in patients undergoing PCI plus optimal medical therapy in lesions with FFR<0.8 compared to medical therapy alone (8.1% vs. 19.5%; p<0.001). This difference was driven by a reduction by a lower rate of urgent revascularization in the PCI group (4% vs. 16.3%; p<0.001). The current paper evaluated the long-term clinical outcomes, effects on quality of life, and cost effectiveness of the two strategies. Major adverse cardiac events (defined as death, MI, and urgent revascularization) was lower in the PCI group (10.1% vs. 22%; p<0.001). This was driven by a lower rate of urgent revascularization (4.3% vs. 17.2%; p<0.001). Mean initial costs were higher in the PCI group ($9944 vs. $4440 p<0.001) but by 3 years were similar in both groups ($16792 vs. 16737; p=0.94). The incremental cost-effectiveness ratio for PCI compared to optimal medical therapy was $17300 per quality-adjusted life-years at 2 years and $1600 per quality-adjusted life-years at 3 years. In this study, FFR guided revascularization appears to be associated with improved long-term outcomes and is economically sound compared to optimal medical therapy alone.

See the theme?





Safety of TAVI… when will we decide surgery on site is no longer necessary?

Incidence and outcomes of emergent cardiac surgery during transfemoral transcatheter aortic valve implantation (TAVI): insights from the European Registry on Emergent Cardiac Surgery during TAVI (EuRECS-TAVI)         

Eggebrecht et al. European Heart Journal, Volume 39, Issue 8, 21 February 2018, Pages 676–684


The investigators in this study sought to evaluate the incidence and outcomes of emergency surgery in the setting of transfemoral TAVI procedures in a contemporary real world multicentre registry consisting of 27 760 patients from 79 centres. Less than 1% of patients needed emergency surgery. Left ventricular perforation by the guidewire (28.3%) and annular rupture (21.2%) were the key reasons for emergency surgery in this study. Immediate procedural mortality (<72 h) of TF-TAVI patients requiring ECS was 34.6%. Overall in-hospital mortality was 46.0%, and highest in patients with annular rupture (62%). Patients aged >85 years, annular rupture and immediate surgery were independent predictors of in-hospital mortality. One year of survival of patients surviving the in-hospital period was only 40.4%. In this interesting analysis the investigators have demonstrated that the need for emergency surgery in the setting of TF-TAVI in low.  Of note emergency surgery saved lives in just under 50% of cases with very high 1-year mortality.

The authors of this paper did not make it controversial but it surely raises an important & controversial question for us, bearing in mind how infrequently emergency surgery is required:  at what stage will we decide that on site surgery is no longer necessary in the Uk, as has already been done in Germany and other places? Remember the same debate with PCI?


Valve in valve TAVI- who gets coronary obstruction and what are the risks?

Incidence, predictors, and clinical outcomes of coronary obstruction following transcatheter aortic valve replacement for degenerative bioprosthetic surgical valves: insights from the VIVID registry 

Ribeiro et al. European Heart Journal, Volume 39, Issue 8, 21 February 2018, Pages 687–695


The investigators conducted this study to determine the incidence, predictors, and clinical outcomes of coronary obstruction in transcatheter valve-in-valve procedures for failed aortic bioprosthesis. They studied 1612 aortic procedures in the VIVID registry. The virtual transcatheter valve to coronary ostium distance (VTC) was determined using CT analysis.  37 patients (2.3%) had clinically evident coronary obstruction. Coronary obstruction was more common in stented bioprostheses with externally mounted leaflets or stentless bioprostheses than in stented with internally mounted leaflets bioprostheses (6.1% vs. 3.7% vs. 0.8%; P < 0.001). VTC distance was shorter in coronary obstruction patients in relation to controls (3.24 ± 2.22 vs. 6.30 ± 2.34 P < 0.001). Use of a stentless or stented bioprosthesis with externally mounted leaflets was associated with coronary obstruction (P<0.001) and a shorter VTC distance predicted coronary obstruction (P < 0.001). Importantly in this study, coronary obstruction in this setting was associated with excess 30-day mortality vs. controls (52.9% vs. 3.9%, P < 0.001).





Any difference between prasugrel or ticagrelor for primary PCI?

1-Year Outcomes of Patients Undergoing Primary Angioplasty for Myocardial Infarction Treated With Prasugrel Versus Ticagrelor.    Z Motovska, et al.       JACC 2018; 71:371-81

The multicentre PRAGUE-18 study was the first randomized head-to-head comparison of prasugrel and ticagrelor in 1,230 patients presenting with AMI and undergoing PPCI. The early outcomes focusing on the hospitalization phase did not show any significant differences between the two agents regarding their safety or efficacy. The 1-year data examined the combined end point of cardiovascular death, MI, or stroke as well as the risk of major ischemic events related to an economically motivated post-discharge switch to clopidogrel. PRAGUE-18 demonstrated no difference between prasugrel and ticagrelor with regards to cardiovascular death (3.3% vs. 3.0%; p=0.77), MI (3.0% vs. 2.5%; p=0.61), stroke (1.1% vs. 0.7%; p=0.42), all-cause death (4.7% vs. 4.2%; p=0.65). The rates of definite stent thrombosis (1.1% vs. 1.5%; p=0.54) and TIMI major bleeding (0.9% vs. 0.7%; p=0.75) were also similar. Economically motivated switch to clopidogrel was lower with prasugrel than ticagrelor (34.1% vs. 44.1%; p=0.003) but this did not lead to differences in major cardiovascular events.


*Most surprising?

Prasugrel associated with lower mortality then clopidogrel or ticagrelor after primary PCI in real world practice

Association of different antiplatelet therapies with mortality after primary percutaneous coronary intervention.

Olier et al. Heart. 2018 Feb 2. pii: heartjnl-2017-312366. doi: 10.1136/heartjnl-2017-312366. [Epub ahead of print]


Thanks to the Mamas Mamas productions, this paper reports on the outcome of 89,000 patients undergoing primary PCI in the UK between 2007 and 2014 according to which P2Y12 inhibitor they received. In the main multivariate logistic regression analysis, prasugrel was associated with significantly lower mortality than clopidogrel at both 30 days (OR 0.87, 95% CI 0.78 to 0.97, P=0.014) and 1 year (OR 0.89, 95% CI 0.82 to 0.97, P=0.011) post PCI. Ticagrelor was not associated with any significant differences in mortality compared with clopidogrel at either 30 days (OR 1.07, 95% CI 0.95 to 1.21, P=0.237) or 1 year (OR 1.058, 95% CI 0.96 to 1.16, P=0.247). Finally, ticagrelor was associated with significantly higher mortality than prasugrel at both time points (30 days OR 1.22, 95% CI 1.03 to 1.44, P=0.020; 1 year OR 1.19 95% CI 1.04 to 1.35, P=0.01). In this very large real world series derived from the BCIS database, patients given prasugrel after primary pci had a significantly lower 30 day and 1 year mortality than those on clopidogrel or ticagrelor, even after adjusting for variables.

Seems likely that antiplatelet therapy may need to be personalised to the patient ?


Ticagrelor for widespread prevention therapy: reduced ischaemic events but more than double the bleeding…

Ticagrelor for Secondary Prevention of Atherothrombotic Events in Patients With Multivessel Coronary Disease.                      

S Bansilal, et al.   JACC 2018; 71:489-96.


The PEGASUS-TIMI 54 trial assessed the benefits of ticagrelor in reducing the risk major adverse cardiovascular events (MACE) defined as a composite of cardiovascular death, MI, or stroke in 21,162 patients who had had a MI 1 to 3 years earlier and followed for a median of 33 months. The current publication evaluated the safety and efficacy of patients with prior MI and multivessel CAD (MVD). MVD was defined as presence of >50% stenosis in ≥ 2 separate major coronary territories at the time of the index event. A total of 12,558 patients had MVD. Ticagrelor was associated with reductions in the risk of MACE (7.9% vs. 9.4%; p=0.004) and coronary events (6.0% vs. 7.7%; p<0.0001), including a 36% reductions in coronary death. However, Ticagrelor was also associated with an increased risk of TIMI major bleeding (2.5% vs. 1.1%; p<0.0001).




Rivoraxaban and aspirin for prevention: fewer ischaemic events but 50% increase in bleeding…

Rivaroxaban With or Without Aspirin in Patients With Stable Coronary Artery Disease: An International, Randomised, Double-Blind, Placebo-Controlled Trial.       

S Connolly, et al. The Lancet 2018; 391:205-18    


The safety and efficacy of rivaroxaban, either alone or in combination with aspirin, in patients with stable CAD has not been investigated. The COMPASS investigators randomised 24,824 such patients to either rivaroxaban 2.5mg twice daily plus aspirin 100mg/day, rivaroxaban 2.5mg twice daily alone, or aspirin 100mg/day alone. Eligible patients with CAD had to have had a MI in the past 20 years, multivessel VAD, history of stable or unstable CAD, previous multivessel PCI or CABG. Multivessel CAD was defined as stenosis of at least 50% of diameter in two or more coronary arteries confirmed by coronary angiography, by non-invasive imaging or by stress studies suggesting substantial ischemia in two or more coronary artery territories. The primary end point was the occurrence of MI, stroke, or cardiovascular death. The combination of rivaroxaban plus aspirin was associated with a significant reduction in the primary end point compared to aspirin alone (4% vs. 6%; HR=0.74, 95% CI: 0.65-0.86; p<0.0001) but the combination of rivaroxaban and aspirin was associated with a greater rate of major bleeding (3% vs. 2%; HR=1.66, 95% CI: 1.37-2.03; p<0.0001). Treatment with rivaroxaban alone did not improve the primary end point as compared to aspirin alone (5% vs. 6%; HR=0.89, 95% CI: 0.78-1.02; p=0.9) and was associated with a greater rate of bleeding (3% vs. 2%; HR=1.51, 95% CI: 1.23-1.84; p<0.0001). The combination of rivaroxaban plus aspirin was also associated with reductions in the rate of mortality when compared with aspirin alone (3% vs. 4%, HR=0.77, 95% CI: 0.65-0.90; p=0.001).

Both of the previous papers highlight that we are increasingly being presented with the dilemma:  should we treat everyone in a particular patient subset in order to prevent some of them having an ischaemic event, whilst exposing all of them to the increased risk of bleeding?  





*Most controversial

Bioabsorbable polymer DES… non-inferior or better?   

A sirolimus-eluting bioabsorbable polymer-coated stent (MiStent) versus an everolimus-eluting durable polymer stent (Xience) after percutaneous coronary intervention (DESSOLVE III): a randomised, single-blind, multicentre, non-inferiority, phase 3 trial.             

R de Winter, et al. The Lancet 2018; 391:431-40

The DESSOLVE III study compared the non-inferiority of the MiStent, a fully bioabsorbable polymer coated DES containing a microcrystalline form of sirolimus, with the Xience stent in an all-comer population. 1,398 eligible patients, aged ≥ 18 years of age who required PCI in a lesion with a reference vessel diameter of 2.5-3.75, were randomized to either the MiStent or the Xience stent. The primary end point was a non-inferiority comparison of a device orientated composite end point defined as cardiac death, target vessel MI, or clinically indicated target lesion revascularization. At 12 months, the primary end point had occurred in 5.8% of the MiStent group and 6.5% of the Xience group (absolute difference -0.8%; 95% CI: 3.3-1.8; pnon-inferiority=0.0001). The rate of definite stent thrombosis was low and similar in both groups (0.4% vs. 0.7%; p=0.48). Is the bioabsorbable polymer actually better than the conventional polymer DES… or is it just equivalent, in which case: where is the advantage?


*Most Predictable

BVS: not the answer

Three-Year Outcomes With the Absorb Bioresorbable Scaffold. Individual-Patient-Data Meta-Analysis From the ABSORB Randomized Trials.     Z Ali, et al. Circ 2018; 137:464-479


Randomized trials of the Absorb bioresorbable vascular scaffold (BVS) met criteria for non-inferiority compared to metallic DES within the first year of implantation but persistent risk of adverse events between 1 and 2 years has been identified. This paper reports on individual-patient-data of the 4 BVS randomized trials through 3-year follow-up. The current study includes 3389 patients with CAD of whom 2164 were randomized to the Absorb BVS and 1225 to the cobalt-chromium everolimus-eluting stents. The primary efficacy outcome was target lesion failure (defined as cardiac death, target vessel MI, or ischemic driven target lesion revascularization) and the primary safety outcome was device thrombosis. BVS was associated with greater rate of target lesion failure (11.7% vs. 8.1%, RR=1.38, 95% CI: 1.1-1.73; p=0.006) driven by greater target vessel MI (7.8% vs. 4.2%; RR=1.72, 95% CI: 1.26-2.35; p=0.0006) and ischemia driven target lesion revascularization (6.6% vs. 4.4%, RR=1.44, 95% CI: 1.05-1.98; p=0.02). Device thrombosis was also higher with the BVS (2.4% vs. 0.6%, RR=3.71, 95% CI: 1.7-8.11; p=0.001).

Probably time to accept once and for all that this version of a BVS is worse than modern DES… it surely raises questions: 1. are there lessons to be learned about the adoption of new devices in routine practice before the definitive validation data are available?  (You know who you are!)     2. is this the end for the bioabsorbable concept?




Importance of speed in STEMIs with cardiogenic shock

Impact of treatment delay on mortality in ST-segment elevation myocardial infarction (STEMI) patients presenting with and without haemodynamic instability: results from the German prospective, multicentre FITT-STEMI trial        

Scholz et al. European Heart Journal, Volume 39, 13, 1 April 2018, 1065–1074


The aim of this study was to investigate the effect of contact-to-balloon time on mortality in STEMI patients with and without haemodynamic instability. The investigators from Germany used data from the Feedback Intervention and Treatment Times in ST-Elevation Myocardial Infarction (FITT-STEMI) trial consisting of n = 12 675 STEMI patients.  They evaluated the prognostic relevance of first medical contact-to-balloon time in patients who used emergency medical service transportation and were treated with PPCI. Patients were stratified by cardiogenic shock (CS) and out-of-hospital cardiac arrest (OHCA). The investigators found that in patients with CS without OHCA every 10-min treatment delay resulted in 3.31 additional deaths in 100 PCI-treated patients compared to OOHA with and without arrest and stable patients (P<0.0001). This trial suggest that in patients with cardiogenic shock the time elapsing from the first medical contact to primary PCI is a strong predictor of an adverse outcome reiterating that time is of essence and the need for immediate PCI avoiding all possible delays with PCI treatment.




On the threshold of a new therapeutic era that targets inflammation directly to reduce acute CV events

Relationship of C-reactive Protein Reduction to Cardiovascular Event Reduction Following Treatment with Canakinumab: a Secondary Analysis from the CANTOS Randomised Controlled Trial.

P Ridker, et al. The Lancet 2018; 391:319-28


The CANTOS trail demonstrated that canakinumab, an IL-1ß antibody, at a dose of 150mg every 3 months, reduces the rate of recurrent cardiovascular events in patients with previous MI and hsCRP ≥ 2mg/L. The current study evaluated the effects of canakinumab on rates of major cardiovascular events (MACE), cardiovascular mortality, and all-cause mortality according to on-treatment hsCRP concentrations. Patients on canakinumab who achieved hsCRP < 2mg/L had 25% reduction in MACE (HR=0.75; 95% CI: 0.66-0.85; p<0.0001) whereas there was no significant benefit for those who achieved hsCRP ≥ 2mg/L (HR=0.9; 95% CI: 0.79-1.02; p=0.11). Specifically, in patients achieving on-treatment hsCRP < 2mg/L, cardiovascular mortality (HR=0.69; 95% CI:0.56-0.85; p=0.0004) and all-cause mortality (HR=0.69; 95% CI:0.58-0.81; p<0.0001) were reduced by 31% whereas no significant reductions were observed in patients with hsCRP ≥ 2mg/L . The reductions in hsCRP concentration may thus serve as a biomarker for patients that are most likely to benefit from canakinumab therapy.

The prospect of treating the chronic vascular inflammation that leads to atheroma formation and the acute inflammation that leads to ACS/AMI is increasingly attractive and this is our first glimpse of that new therapeutic armoury.





Mitraclip: where are we now?

Outcome after percutaneous edge-to-edge mitral repair for functional and degenerative mitral regurgitation: a systematic review and meta-analysis

Chiarito et al.  Heart. 2018 Feb;104(4):306-312


The authors undertook a systematic review and meta-analysis to evaluate the differences in terms of safety and efficacy of percutaneous edge-to-edge mitral repair using MITRACLIP comparing patients with functional and degenerative mitral regurgitation (MR). The authors included 9 studies consisting of 2615 patients. At 1 year, there were no significant differences among groups in terms of patients with MR grade≤2 (58% vs. 54%; p=0.40). There was a lower rate of mitral valve re-intervention in patients with functional MR compared with degenerative MR (4% vs. 10%; p=0.04) with similar one-year mortality between groups at 16%. New York Heart Association class III/IV was greater in functional vs. degenerative groups (16% vs. 8%; p<0.01) and likewise re-hospitalisation for heart failure (23% vs. 14%; p=0.03). This meta-analysis suggests that percutaneous edge-to-edge repair is likely to be an efficacious and safe option in patients with both functional and degenerative MR. However large, randomised studies are needed to determine the clinical impact of Mitraclip procedures in the 2 mitral valve aetiologies/conditions.






CTO: where are we now?

Predictors of successful chronic total occlusion percutaneous coronary interventions: a systematic review and meta-analysis

Wang et al.   Heart. 2018 Mar;104(6):517-524


This study evaluated the positive and negative predictors of technical and clinical success for PCI of chronic total occlusions (CTO). The authors conducted a systematic review and meta-analysis of studies published between 2000 and 2016 analysing rates of CTO PCI success with respect to demographic and angiographic characteristics. Clinical success was defined as technical success without major adverse cardiac events. 61 studies, totalling 69 886 patients, were included. History of MI, PCI, CABG, stroke/transient ischaemic attack and peripheral vascular disease were associated with reduced technical or clinical success. Angiographic parameters such as PCI on left anterior descending CTOs, multivessel disease, presence of bridging collaterals, moderate-to-severe calcification, >45 degree vessel bending, tortuous vessel, blunt stump and ostial lesions were associated with reduced technical and clinical success. Of these, novel predictors included prior PCI, prior stroke, peripheral vascular disease, presence of multivessel disease and bridging collaterals. These findings might help clinicians while discussing the success rate of CTO procedures with patients and also in patient selection.