R&D Literature Review Sept 2020

BCIS R&D Group


Literature Review September 2020

Prepared by: Michael Mahmoudi, Julian Gunn, Paul Morris & Aung Myat

Edited by Michael Mahmoudi


Stable CAD & ACS


Colchicine as a potent anti-inflammatory agent

Colchicine in patients with chronic coronary disease.

NEJM 2020 Online

A number of studies have indicated that colchicine may have clinical benefits in patient with coronary artery disease (CAD). The low-dose colchicine (LoDoCo2) trial randomized 5522 patients with stable chronic coronary artery disease (CAD) to either colchicine 0.5mg daily (N=2762) or placebo (N=2760). Patients 35 to 82 years of age were eligible if they had any evidence of coronary disease on invasive coronary angiography or computed tomography angiography or a coronary artery calcium score of at least 400 Agatston units. Patients were required to have been in a clinically stable condition for at least 6 months before enrolment. Patients were excluded if they had moderate to severe renal impairment, severe heart failure, severe valvular heart disease, or known side effects from colchicine. At a median follow-up of 28.6 months, the primary endpoint (a composite of cardiovascular death, spontaneous MI, ischemic stroke, or ischemia-driven coronary revascularization) was lower in the colchicine group (6.8% vs. 9.6%; incidence: 2.5 vs. 3.6 events per 100 person-years; HR, 0.69; 95% CI: 0.57-0.83; p<0.001). The secondary endpoint (a composite of cardiovascular death, spontaneous MI, or ischemic stroke) was also lower in the colchicine group (4.2% vs. 5.7%; incidence: 1.5 vs. 2.1 events per 100 person-years; HR: 0.72; 95% CI: 0.57-0.92; p=0.007). The incidence rates of spontaneous MI or ischemia-driven coronary revascularization (composite endpoint), cardiovascular death or spontaneous MI (composite endpoint), ischemia driven coronary revascularization, and spontaneous MI were also significantly lower in the colchicine group. The incidence of death from non-cardiovascular causes was higher in the colchicine group (incidence: 0.7 vs. 0.5 events per 100 person-years; HR: 1.51; 95% CI: 0.99-2.31). The individual causes of death have not permitted a clear interpretation of this finding. The effects of colchicine were consistent in the prespecified subgroups defined according to sex, age (>65 years vs. ≤65 years), smoking status, hypertension, diabetes, prior acute coronary syndrome, prior coronary revascularization, atrial fibrillation, statin dose, and ezetimibe use.


Time to reconsider a strategy of 12 Months DAPT

Effect of ticagrelor monotherapy vs. ticagrelor with aspirin on major bleeding and cardiovascular events in patients with acute coronary syndrome. The TICO randomized clinical trial.

JAMA 2020; 323:2407-16

Bleeding complications following PCI are associated with increased risk of morbidity and mortality. The current study tested the hypothesis whether a strategy of switching to ticagrelor monotherapy following a 3-months course of dual antiplatelet therapy (DAPT) reduced the 1-year net adverse clinical events defined as a composite of major bleeding and adverse cardiac and cerebrovascular events (death, MI, stent thrombosis, stroke, or target vessel revascularization). Prespecified secondary outcomes included major bleeding and major adverse cardiac and cerebrovascular events. The study randomized 3056 ACS patients (36% with STEMI) to receive either ticagrelor monotherapy after 3-months of DAPT (N=1527) or ticagrelor-based 12-month DAPT (N=1529). The average was 61 years, 79% were men, 27% had diabetes, and all patients were treated with the Orsiro drug-eluting stent. The primary outcome was lower in the ticagrelor monotherapy after a 3-month course of DAPT (absolute difference, -1.98 (95% CI:-3.5% – -0.45%) HR: 0.66 (95% CI: 0.48-0.92); p=0.01). This difference was driven by a reduced risk of major bleeding in the ticagrelor monotherapy after a 3-month course of DAPT (1.7% vs. 3%; HR: 0.56; 95% CI: 0.34-0.91; p=0.02). The incidence of major adverse cardiac and cerebrovascular events was similar in both groups (2.3% vs. 3.4%; HR: 0.69; 95% CI: 0.45-1.06; p=0.09). A prespecified subgroup analysis showed that ticagrelor monotherapy had a consistent effect on the primary outcome across subgroups except in patients with multivessel disease who did better with 12-month DAPT. The results of TICO have been confirmed in three additional meta-analysis. For example, McClure and colleagues (JAHA 2020; 9:e017109) undertook a meta-analysis of 5 muticenter trials including GLOBAL LEADERS, STOPDABT2, SMART-CHOICE, TWILIGHT and TICIO which in total included 32361 patients of whom16898 had a history of ACS demonstrated that compared to a 12 months course of DAPT, a strategy of P2Y12 inhibitor monotherapy from 1 to 3 months after DAPT substantially reduces the risk of major and fatal bleeding. This strategy was also associated with a potentially protective effect for MACE and all-cause mortality.


De-escalation of DAPT-Time to change duration of DAPT

Prasugrel-based de-escalation of dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (HOST-REDUCE-POLYTECH-ACS): an open-label, multicentre, non-inferiority randomised trial.

Lancet 2020 Online

The concept of de-escalation is based on the hypothesis that there is a temporal change of ischaemic and bleeding risks after PCI. Immediately after PCI, especially in patients with ACS, the risk of thrombosis is greatest because the patient has a thrombotic milieu and the culprit coronary artery needs to recover from balloon-induced injury and dissection with exposure of the subendothelial tissue to blood. Upon endothelialisation of the implanted stent, the constant bleeding risk from using potent P2Y12 inhibitors comes sharper into focus and is maintained thereafter for the total duration of DAPT. This South Korean study was conducted at 35 hospitals to investigate the feasibility of a prasugrel-based dose de-escalation strategy in ACS patients proceeding to PCI. All ACS patients with at least 1 culprit coronary lesion in a native coronary artery requiring stent deployment were eligible for recruitment. From September 2014 to December 2018, 2338 patients were randomised to the de-escalation arm (N=1170) or to standard therapy (N=1168). All patients received loading doses of aspirin and prasugrel. After PCI all patients received 100 mg aspirin and 10 mg prasugrel once a day up to 30 days. Thereafter the de-escalation group took 5 mg of prasugrel once daily as maintenance and the conventional arm continued on prasugrel 10 mg once daily. Both arms continued aspirin. DAPT was recommended for a minimum of a year although this duration could be adjusted in the case of clinical events. The primary endpoint was net adverse clinical events, defined as a composite of all-cause death, non-fatal myocardial infarction, stent thrombosis, clinically driven revascularisation, stroke, and bleeding events of grade 2 or higher according to Bleeding Academic Research Consortium (BARC) criteria, at 1 year. Mean age was 58.8 years. At 1 year, the primary endpoint occurred in 82 patients (7.2%) in the de-escalation group and 116 patients (10.1%) in the conventional group (absolute risk reduction -2.9%, Pnon-inferiority<0.0001; HR: 0.70; 95% CI: 0.52-0.92, Pequivalence=0.12). There was no increase in ischaemic risk (0.76 [0.40-1.45]; p=0.40), and the risk of bleeding events was significantly lower (0.48 [0.32-0.73]; p=0.0007) in favour of the de-escalation group. In post-hoc subgroup analyses, the clinical effect of de-escalation was consistent regardless of subgroup (age, sex, diabetes, chronic kidney disease, smoking status, type of ACS, ejection fraction, polyvascular disease, or stent length), with no significant interaction noted. The investigators were quick to emphasise the trial results were only applicable to east Asian ACS patients, so may not necessarily be generalisable to other ethnic cohorts.


Mortality benefit with PCI in patient with stable angina

Survival of Patients With Angina Pectoris Undergoing Percutaneous Coronary Intervention With Intracoronary Pressure Wire Guidance.

JACC 2020; 75:2785-99

The impact of coronary revascularization on hard clinical endpoint in patients with stable angina is controversial. The objective of the current study was to compare the association of FFR-guided versus angiography-guided PCI with long-term mortality, restenosis, and stent thrombosis and periprocedural complications (defined as in-hospital occurrence of procedure related death, neurological complications, cardiac tamponade, vessel perforation, vessel occlusion and major bleeding) in patients with stable angina registered in the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Between 2005-2016, a total of 23860 patients underwent PCI; FFR was used in 3367 patients and 20493 patients underwent PCI without intracoronary pressure measurements. Patients in the FFR group were younger, more likely to be men, and more likely to have hypertension, hyperlipidaemia, and previous PCI. After a median follow-up of 4.7 years, the adjusted risk estimates for all-cause mortality (HR: 0.81; 95% CI: 0.73-0.89; p<0.001) and stent thrombosis and restenosis (HR: 0.74; 95% CI: 0.57-0.96; p=0.022) was lower in the FFR group. The periprocedural complications were similar between the two groups (OR: 0.96; 95% CI: 0.77-1.19; p=697). Limitations of the study included lack of data regarding the rates of MI and the investigators were unable to distinguish between cardiac and non-cardiac death. There were important baseline differences between the two groups that may have influenced the results including patients in the FFR group were more likely to receive current generation DES, more likely to undergo PCI via the radial route, and more likely to receive ticagrelor as opposed to clopidogrel.


Trimetazidine safe but not particularly effective post PCI

Efficacy and safety of trimetazidine after percutaneous coronary intervention (ATPCI): a randomised, double-blind, placebo-controlled trial.

Lancet 2020;396:830-838

Trimetazidine is an antianginal agent widely used outside of Europe and the US. It works by enhancing the metabolic efficiency of the myocardium under threat of ischaemia but does not mediate any haemodynamic effects. The ATPCI trial was a large international multicentre randomised, double-blind, placebo-controlled study conducted in patients who had had successful PCI for either stable angina or NSTE-ACS within 30 days of study enrolment and subsequent randomisation. The primary efficacy endpoint was the composite of cardiac death; hospital admission for a cardiac event; recurrent or persistent angina leading to adding, switching, or increasing the dose of one of the evidence-based antianginal therapies; or recurrent or persistent angina leading to coronary angiography. From September 2014 to June 2016, 6007 patients were randomised to trimetazidine at 35 mg twice daily (N=2998) or matching placebo (N=3009) on top of standard antianginal therapy. The primary efficacy endpoint event rate was lower than expected so follow-up was extended for a further 12 months. Overall median follow-up was 47.5 months. The frequencies of primary composite endpoint events were similar between trimetazidine (700 [23·3%] patients) and placebo (714 [23·7%]; HR: 0∙98; 95% CI: 0∙88–1∙09; p=0∙73), as were the frequencies of the components analysed individually. Neither all-cause mortality nor the composite of hospital admission for myocardial infarction (fatal or non-fatal) or cardiac death, or any of the other secondary endpoints were modified by assigned treatment. The investigators concluded that trimetazidine did not reduce the risk of cardiac events compared with placebo. In the ATPCI population, where atherosclerotic burden was generally low (approximately half had only single-vessel disease) and most recruits had preserved left ventricular function, combining successful PCI with optimal preventive and antianginal therapy was probably sufficient for symptom control in most cases. Importantly the study drug was not associated with any safety issues.


Age not a barrier to revascularization in NSTEMI patients

Invasive versus non-invasive management of older patients with non-ST elevation myocardial infarction (SENIOR-NSTEMI): a cohort study based on routine clinical data.

Lancet 2020;396:623-34

The very elderly (≥80 years old) are typically under-represented in randomised trials of NSTE-ACS management. Furthermore, the evidence base used to support contemporary practice guidelines in the elderly comprise mainly observational data and meta-analyses. Randomised controlled trial data are scant, heterogeneous in relation to what age stratum is designated elderly and beset by small sample populations. There have been just two randomised trials of optimal NSTE-ACS management strategy conducted specifically in the very elderly (≥80 years). The Italian Elderly ACS Study and the Norwegian After Eighty trial. The UK multicentre RINCAL trial has completed but had to end prematurely due to slow recruitment. The results are awaiting formal publication. The much larger BHF-funded SENIOR RITA (NCT03052036) trial is also looking at optimal management strategy in the elderly, but here the cut-off for enrolment is ≥75 years. This trial is aiming to recruit 1668 participants with an estimated study completion date of 2029. Here SENIOR-NSTEMI is yet another retrospective observational cohort study designed to estimate the effect of invasive versus non-invasive management of NSTE-ACS in patients aged ≥80 years on survival using routinely collected clinical data from 5 academic medical centres hosting NIHR BRCs in the UK via the NIHR Health Informatics Collaborative. Notably, the investigators have employed statistical methods to minimise the effects of immortal time bias in particular whereby previous registry studies had assigned, rightly or wrongly, those patients who died early in the course of their presentation to the non-invasive arm of their analysis before an invasive strategy could even be considered. Overall the records of 1976 patients from a study period starting in January 2008 to April 2017 were included in the analysis. Propensity scores were derived for those with high probabilities for a conservative or invasive strategy, leaving 1500 patients that could have been amenable to either strategy. The median age was 86 (IQR 82-89). Overall the adjusted cumulative 5-year mortality was 36% in the invasive arm and 55% in the conservative arm (HR 0.68, 95% CI 0.55-0.84). An invasive strategy was associated with a lower incidence of hospital admission for heart failure (HR 0.67, 95% CI 0.48-0.93). This is an important study, albeit based on retrospective observational data, that helps to strengthen the advocacy for early intervention in those patients ≥80 years old presenting with NSTE-ACS.


Focus on the culprit lesion in cardiogenic shock

Multivessel Versus Culprit-Vessel Percutaneous Coronary Intervention in Cardiogenic Shock.

JACC Cardiovasc Interv. 2020; 13:1171-78

There are conflicting studies on the optimal revascularization strategy in patients with multivessel CAD (MVCAD) who present with STEMI and cardiogenic shock. The landmark CULPRIT-SHOCK trial showed improved survival at 30 days when using a strategy of culprit vessel only PCI (CV-PCI) as opposed to multivessel PCI (MV-PCI). To date, studies comparing revascularization strategies with the aid of mechanical circulatory support (MCS) have been limited. The National Cardiogenic Shock Initiative (NCSI) trial, encompassing 57 hospitals in the US, sought to assess clinical outcomes associated with the use of a shock protocol emphasizing early MCS and PCI in patients presenting with acute MI and cardiogenic shock (AMICS). The algorithm is based upon (1) early identification and cath lab activation for patients presenting with AMICS, (2) early use of MCS, and (3) routine use of invasive haemodynamic monitoring with PA catheter to guide management of MCS and use of inotropes. Of 198 patients with MVCAD , 126 (64%) underwent MV-PCI and 72 (36%) underwent CV-PCI. The MV-PCI group had a trend toward more severe impairment of cardiac output and worse lactate clearance on presentation, and cardiac performance was significantly worse at 12 hours. 24 hours from PCI, the haemometabolic derangements were similar. Survival rates (69.8% vs. 65.3%; p=0.51) and acute kidney injury (29.9% vs. 34.2%; p=0.64) were similar between the MV-PCI and CV-PCI groups. The major strength of this study is that patients were treated using a robust protocol as defined by the NCSI and differs from other studies in that patients were treated with early and aggressive use of MCS. However, major limitations include lack of randomization, modest sample size, and the decision to perform nonculprit PCI was left at the discretion of the operator. It is feasible to assume that more straightforward nonculprit lesions were selected for PCI whilst more complex lesions were deferred for potential surgical revascularization at a later date.


Stents and Balloons


BioFreedom not as good as Orsiro in SORT OUT IX

Randomized Comparison of the Polymer-Free Biolimus-Coated BioFreedom Stent With the Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Orsiro Stent in an All-Comers Population Treated With Percutaneous Coronary Intervention. The SORT OUT IX Trial.

Circ 2020; 141:2052-63

Although the biolimus A9-coated BioFreedom stent, a stainless-steel drug-coated stent free from polymer has shown superiority to BMS, its performance against modern DES has not been tested. The Scandinavian Organization for Randomized Trials with Clinical Outcome IX (SORT OUT IX) was designed to compare the safety and efficacy of BioFreedom drug-coated stent with the biodegradable polymer sirolimus-eluting stent (Orsiro) in reducing clinical outcomes in 3151 patients undergoing PCI. Mean age was 66.3 ± 10.9 years, 19.3% had diabetes, and 53% presented with ACS). The primary endpoint, MACE, was defined as the composite of cardiac death, MI not related to any segment other than the target lesion, or target lesion revascularization. The trial was powered to assess noninferiority for MACE events of the BioFreedom (N=1572) with the Orsiro stent (N=1579) with a predetermined noninferiority margin of 0.021.  At 1 year, the primary endpoints 5% in the BioFreedom stent group and 3.7% in the Orsiro stent group (HR:1.34;95% CI: 0.96-1.89; p for noninferiority=0.14, p for superiority=0.09). The BioFreedom stent therefore did not meet the criteria for noninferiority driven by a higher risk of target lesion revascularization (3.5% vs. 1.3%; p<0.0001). This may be due to the thicker stent struts in the BioFreedom stent (120 micometers) than the Orsiro stent (60-80 micrometers). The rates of cardiac mortality (1% vs. 1.8%; p=0.06) and MI not related to other lesion (1.7% vs. 1.6%; p=0.99) were similar in both groups. In the LEADERS FREE and LEADERS FREE II trials, the BioFreedom stent were superior to BMS suggesting that its efficacy may lie somewhere between BMS and contemporary DES.


Biologically coated stents may represent a new paradigm in PCI

Titanium-Nitride-Oxide–Coated Versus Everolimus-Eluting Stents in Acute Coronary Syndrome. The Randomized TIDES-ACS Trial.

JACC Cardiovasc Interv. 2020; 13:1697-1705

Three randomized trials with 5 years of follow-up have indicated that a stainless steel, titanium-nitride-oxide-coated stent resulted in superior clinical outcomes compared with zotarolimus-eluting stents and everolimus-eluting stents. Stent coating with a vapor deposition of titanium in a mixed nitrogen-oxygen atmosphere aims to achieve inhibition of platelet aggregation while limiting neointimal hyperplasia without an antiproliferative drug. The Comparison  Titanium-Nitride-Oxide Coated Bioactive-Stent (Optimax) to the Drug (Everolimus) Eluting Stent (Synergy) in Acute Coronary Syndrome (TIDES-ACS) trial of 1491 ACS patients sought to compare the safety and efficacy of the cobalt-chromium-based titanium-nitride oxide coated stent (TiNO) (N=989) with the Synergy stent (N=502). The trial met both its hypotheses of noninferiority concerning a composite of major adverse ischemic events at 12 months (6.3% vs. 7.0%; HR: 0.93; 95% CI: 0.71-1.22; p<0.001 for noninferiority) and superiority concerning a composite of ischemic and bleeding events at 18 months (3.7% vs. 7.8%; HR: 0.64; 95% CI: 0.51-0.80; p=0.001). Salient features in interpreting the data include few patients with diabetes (12%), two-thirds had single vessel disease, and only one-third had complex angiographic features.


To DEB or to DES-that is the question

Drug-Coated Balloon Angioplasty Versus Drug-Eluting Stent Implantation in Patients With Coronary Stent Restenosis.

JACC 2020; 75:2664-78

The optimal treatment strategy for in-stent restenosis (ISR) is uncertain. The Difference in Antirestenotic Effectiveness of Drug-Eluting Stent and Drug-Coated Balloon Angioplasty for the Occurrence of Coronary In-Stent Restenosis (DAEDALUS) study is a pooled analysis of individual patient data (N=1976) from 10 randomized clinical trials that sought to compare long-term outcomes between drug-coated balloon (DCB) angioplasty and repeat stenting with drug-eluting stent (DES) according to bare metal stent (BMS) and DES-ISR and individually assess the relative safety and efficacy of treatments between ISR types. A total of 710 patients with BMS-ISR (724 lesions) and 1248 patients with DES-ISR (1338 lesions) underwent treatment by DCB angioplasty or repeat stenting with DES. The primary safety endpoint was a composite of all-cause death, MI, or target lesion thrombosis. The primary efficacy endpoint was target lesion revascularization (TLR) defined as any revascularization, percutaneous or surgical, due to recurrent stenosis of the target lesion segment. At 3-year follow-up, in patients with BMS-ISR, the primary safety (8.7% vs. 7.5%; HR: 1.13; 95% CI: 0.65-1.96) and efficacy (9.2% vs. 10.2%; HR: 0.83; 95% CI: 0.51-1.37) endpoints were similar with both treatments. In patients with DES-ISR, the risk of the primary efficacy endpoint was higher with DCB angioplasty than with repeat DES implantation (20.3% vs. 13.4%; HR: 1.58; 95% CI: 1.16-2.13) whereas the risk of the primary safety endpoint was numerically lower (9.5% vs. 13.3%; HR: 0.69; 95% CI: 0.47-1.00). Regardless of the treatment used, the risk of TLR was lower in BMS-versus DES-ISR (9.7% vs. 17.0%; HR: 0.56; 95% CI: 0.42-0.74), whereas safety was not significantly different between ISR types. Several limitations of the analysis are noteworthy. Firstly, post-procedure minimum lumen diameter was less and percent residual stenosis greater in the DCB arm despite randomization. Second, although 1-year TLR was increased after DCB, binary angiographic restenosis rates were similar across all the trials. Third, a signal for hazard with restenting was observed with non-significant trends for all-cause death, cardiac death, and for death, MI, and target lesion thrombosis. Finally, the DCB in the DAEDALUS study were paclitaxel whilst the newer sirolimus DCB may be more effective in suppressing neointimal hyperplasia and restenosis.


More data in favour of Biodegradable polymer coated stents

Final 3-year outcomes of MiStent biodegradable polymer crystalline sirolimus-eluting stent versus Xience permanent polymer everolimus-eluting stent. Insights from the DESSOLVE III all-comers randomized trial.

Circ Cardiovasc Interv. 2020; 13:e008737

A number of studies have confirmed the superiority of ultrathin-strut biodegradable polymer second-generation DES to first generation DES and noninferiority to the thin-strut second-generation permanent polymer DES. Data on the longer-term performance of ultrathin DES is lacking. The Multicentre Randomized Study of the MiStent Sirolimus Eluting Absorbable Polymer Stent System for Revascularization of Coronary Arteries (DESSOLVE III) trial randomized 1398 all-comers patients with any ischemic coronary syndrome and any type of lesion (left main, SVG, CTO, bifurcation, ISR) to either the MiStent sirolimus eluting stent (N=703) or a Xience stent (N=695). The primary endpoint was device-oriented composite endpoint, defined as the composite of cardiac death, target vessel MI, or clinically indicated target lesion revascularization. The secondary endpoint was patient-oriented composite endpoint, defined as the composite of all-cause mortality, MI, or any revascularization. At 3 years, the primary endpoint was similar in both groups (10.5% vs. 11.5%; p=0.55). Rates of cardiac death (3.9% vs. 3.8%; p=0.88), target vessel MI (3.2% vs. 2.5%; p=0.43), and clinically indicated target lesion revascularization (5.2% vs. 6.5%;p=0.30) were similar in both groups. The risk of patient oriented composite endpoint was also similar in both groups (22.7% vs. 22.9%; p=0.34).


Catheter Based Valvular Intervention


Antiplatelet therapy post TAVI

Aspirin with or without clopidogrel after transcatheter aortic valve implantation.

NEJM 2020 Online

Dual antiplatelet therapy with aspirin and clopidogrel for a period of 3 to 6 months is recommended after TAVI in patients who do not have an indication for anticoagulation. Although small studies have indicated that such combination is associated with a lower incidence of ischemic events than aspirin alone, although dual antiplatelet therapy was associated with an increased risk of bleeding in the ARTE trial. Cohort A of the POPular TAVI trial (Antiplatelet Therapy for Patients Undergoing Transcatheter Aortic-Valve Implantation) compared aspirin alone (N=343) with aspirin plus clopidogrel for 3 months (N=347) in patients undergoing TAVI who did not have an established indication for long-term oral anticoagulation. The two primary outcomes were all bleeding (including minor, major, and life-threatening or disabling bleeding), and non-procedure-related bleeding over a period of 12 months. The two secondary outcomes were a composite of death from cardiovascular causes, non-procedure-related bleeding, stroke, or MI and a composite of death from cardiovascular causes, ischemic stroke, or MI at 1 year for both outcomes sequentially for noninferiority and superiority. At 12 months, the rate of bleeding of any type was lower in the aspirin alone group (15.1% vs. 26.6%; RR, 0.57; 95% CI: 0.42-0.77; p=0.001). Non-procedure-related bleeding was also lower in the aspirin alone group (15.1% vs. 24.9%; RR, 0.61; 95% CI: 0.44-0.83; p=0.005).   The first secondary endpoint (composite of bleeding, death, stroke or MI) was also lower in the aspirin alone group (23% vs. 31.3%; difference -8.2 percentage points; 95% CI for noninferiority: -14.9-1-.5; p<0.001; RR, 0.74; 95% CI for superiority: 0.57-0.95; p=0.04). The second secondary endpoint (composite of thromboembolic events including death from CV causes, ischemic stroke, or MI) were 9.7% in the aspirin group and 9.9% in the aspirin plus clopidogrel group indicating that aspirin alone was noninferior to combined therapy (difference -0.2 percentage points; 95% CI for noninferiority: -4.7-4.3; p=0.004) but it was not superior (RR, 0.98; 95% CI for superiority: 0.62-1.55; p=0.93).


Leaflet thrombosis an issue in both surgical & TAVI devices

Subclinical Leaflet Thrombosis in Transcatheter and Surgical Bioprosthetic Valves. PARTNER 3 Cardiac Computed Tomography Sub-study.

JACC 2020; 75:3003-15

Subclinical leaflet thrombosis characterized by hypoattenuated leaflet thickening (HALT) and reduced leaflet motion (RLM) seen on high resolution 4D CT is found with significant frequency both in transcatheter and surgical bioprosthetic valves. Given the expansion of TAVI across the full spectrum of surgical risks, the US FDA has FDA mandated CT ancillary studies to be incorporated into TAVI trials of patients at low surgical risk to understand the natural history of subclinical leaflet thrombosis of transcatheter and surgical bioprosthetic valves and its association with valve haemodynamic and clinical outcomes. The PARTNER 3 CT substudy was a randomized trial embedded in the PARTNER 3 randomized trial of TAVI with current generation balloon-expandable valve compared with standard surgical AVR in patients at low surgical risk with symptomatic severe aortic stenosis. Patients were eligible for inclusion if they had no pre-existing indication for anticoagulation and no contraindication to undergo a CT scan. Patients underwent cardiac 4D-CT at 30 days and 1 year after TAVI or SAVR . Treating investigators were blinded to the results of the CT scans. Primary imaging endpoints of interest were the percent HALT and RLM at 30 days and 1 year. HALT was significantly higher in the TAVI group at 30 days (13% vs. 5%; p=0.03) but not at 1 year (28% vs. 20%; p=0.19). The presence of HALT fluctuated over time, such that amongst patients with HALT at 30 days spontaneous resolution was observed at 1 year in 56% of cases. Conversely, amongst patients without HALT at 30 days, new HALT was observed in 21% of patients at 1 year. HALT at any time point was associated with higher rates of valve thrombosis, stroke, TIA, and thromboembolic complications. The presence of HALT did not significantly alter the mean aortic valve gradient at 30 days or 1 year. When placed in the context of the ancillary GALLILEO 4D-study where a rivaroxaban-based strategy did not translate into significant improvements in valve haemodynamic as evaluated with TTE or reduction in thromboembolic events, a strategy of routine anticoagulation after TAVI appears to have an unfavourable risk-benefit balance.


Incidence & predictors of IE in TAVI

Infective Endocarditis After Transcatheter Aortic Valve Replacement.

JACC 2020; 75:3020-30

The incidence of infective endocarditis following TAVI, the responsible microorganisms, and the outcome of such patients has not been adequately elucidated. Using the Swiss Transcatheter Aortic Valve Implantation Registry, the current study examined the incidence of TAVI prosthetic valve endocarditis, risk factors for developing the disease, and the downstream incidence of stroke and mortality. Between 2011-2018, 7203 patients underwent TAVI at 15 Swiss centres. During follow-up of 14832 patient-years, endocarditis occurred in 149 patients. The incidence of peri-procedural, delayed-early, and late endocarditis was 2.59, 0.71, and 0.40 events per 100 person-years respectively. Enterococcus species were the most common microorganism in early endocarditis (30.1%). Younger age, male sex, lack of predilatation, and treatment in the cath lab as opposed to a hybrid operating room were independently associated with endocarditis. In a case-control matched analysis, patients with endocarditis were at increased risk of mortality (HR: 6.55; 95% VI: 4.44-9.67) and stroke (HR: 4.03; 95% CI: 1.54-10.52). Of note, the modified Duke criteria had a very low sensitivity with only 63% of patients meeting a definite diagnosis. Furthermore, echocardiographic appearances were normal or inconclusive in 47.7%.


Neurocognitive impairment post TAVI

Evolution, Predictors, and Neurocognitive Effects of Silent Cerebral Embolism During Transcatheter Aortic Valve Replacement.

JACC Cardiovasc Interv. 2020; 13:1291-1300

Histopathological examination of embolic debris captured during TAVI has confirmed its dual origin from both the aortic valve and the aortic wall. In addition to symptomatic stroke or TIA, systematic performance of brain imaging after TAVI has shown a high incidence of silent cerebral ischaemic lesions (SCILs) raising concerns for increased risk of cognitive impairment post TAVI. The current study examined the incidence, time course, and predictors of SCILs and their impact on neurocognition in 96 patients who underwent cerebral MRI within 7 days prior to and again post TAVI. The MRI was repeated after 3 months if results were abnormal. Patients with neurological or neurocognitive impairment were excluded. SCILs were observed in 76% of patients, distributed in all vascular territories, with a median number of 2 lesions, a median diameter of 4.5mm, and a median total volume of 140 mm3. Independent predictors of SCIL occurrence were higher baseline age-related white matter change score, and the use of self-expanding or mechanically expanded bioprostheses. SCIL occurrence was associated with a more pronounced transient neurocognitive decline early after TAVI and lower recovery at follow-up. Important limitations of the study included the low number of patients enrolled, slow recruitment (6 patients per year per centre), limited follow-up with the last evaluation at 3 months post TAVI, and the modest magnitude of change in the Mini Mental State Examination and Montreal Cognitive Assessment scores raising the question of whether these changes are clinically meaningful.


Encouraging long-term data for TAVI

Long-term clinical outcome and performance of transcatheter aortic valve replacement with a self-expandable bioprosthesis.

EHJ 2020; 41:1876-86

TAVI has transformed the management of severe aortic stenosis, first in high-risk, frail, elderly patients, then in patients at moderate surgical risk and increasingly, in those in lower risk groups. Initially, evidence demonstrated superiority to standard care in inoperable patients and non-inferiority to surgery in high and medium risk groups. However, questions regarding long term outcomes had to remain uncomfortably unanswered until sufficient time had elapsed to allow appropriate analysis. TAVI has been available for little over a decade now and studies with ≥ 5 years follow-up data are emerging. In this study, outcomes following implantation of the first-generation self-expandable CoreValve bioprosthesis were studied in 999 patients, across eight Italian centres. These were predominantly elderly patients (mean age 82 y), at high surgical risk (mean Log-EuroSCORE 23) with reasonable LV function and severe valve disease (mean gradient 53 mmHg). Femoral access was used in 84% and 74% were under local anaesthetic. Follow up was for a median of 4.4 years with the longest at 11 years. Cumulative incidence functions (which control for increasing mortality rates over time) were used to analyse 8-year data. Overall mortality was 78% with median survival of 4.2 years. 36% of deaths were deemed to be cardiovascular in nature. In surviving patients NYHA remained at ≤ 2 in 79% and trans valvular gradient did not change from discharge (9±6 mmHg). Although paravalvular leak was common (CT sizing was not used routinely), there was no significant change in PVL over time. Moderate and severe structural valve deterioration at 8 years were 3.0% and 1.6% respectively. Late BVF was 2.5%. The study is one of the biggest studies of long term TAVI outcomes and is multicentre. Similar to other recent registry reports, the mortality in this elderly, frail, high risk group was high. However, it is reassuring that, in surviving patients, measures of valve function (gradient and PVL) and metrics of device failure did not reveal any overt red flags in terms of safety. Although unavoidable, perhaps the greatest problem when interpreting this uncontrolled study is common to many long-term observational studies; by the time they are reported, there has been considerable evolution in device design, implant technique, supporting medical therapy and, as is the case with TAVI, the age and frailty of the patients.




More is better in LM PCI

Are higher operator volumes for unprotected left main stem percutaneous coronary intervention associated with improved patient outcomes? A survival analysis of 6724 procedures from the British Cardiovascular Intervention Society National Database.

Circ Cardiovasc Interv. 2020; 13:e008782

A historical debate regarding operator volume and patient outcome in all field of medicine has continued to the present day. This study has examined the relationship between operator volume and patient survival after unprotected left main PCI ((ULMS-PCI) utilising data from the British Cardiovascular Intervention Society National Database (BCIS). A total of 6724 ULMS-PCI procedures were analysed between 2012-2014 and 4 quartiles of annualized volumes (Q1-Q4) were generated.  Operator volume ranged from 1 to 54 cases/year. In Q1, 347 operators performed a median of 2 procedures/year; in Q2, 134 operators performed a median of 5 procedures/year; in Q3, 59 operators performed a mean of 10 procedures/year, and in Q4, 29 operators performed a mean of 21 procedures/year. Higher volume operators tackled patients with greater morbidity and greater complexity of disease burden. Adjusted in-hospital survival (OR: 0.39; 95% CI: 0.24-0.67; p<0.001), in-hospital major adverse cardiac and cerebral events (OR: 0.41; 95% CI: 0.27-0.62; p<0.001), and 12-month survival (OR: 0.54; 95% CI: 0.39-0.73; p<0.001) were lower in Q4 operators than Q1 operators. The authors have identified a lower volume threshold of ≥ 16 ULMS-PCI cases/year to be associated with improved patient survival.




What is the optimal bifurcation technique?

Multicentre, randomized comparison of two-stent and provisional stenting techniques in patients with complex coronary bifurcation lesions: the DEFINITION II trial.

EHJ 2020; 41:2523-36

The optimal bifurcation strategy is yet to be determined despite a number of landmark studies favouring a provisional single stent strategy. The current study was designed to assess the benefits of two-stent techniques in patients with DEFINITION criteria-defined complex coronary bifurcation lesions. Consecutive patients (N=653) were enrolled if they presented with silent ischaemia, stable or unstable angina (50%), or MI > 24 hours prior to treatment (22%). All bifurcation lesions were Medina 1,1,1 or 0, 1, 1 with reference vessel diameter (RVD) in the SB ≥ 2.5mm by visual estimation and had to meet the DEFINITION criteria. The DEFINITIONS criteria, developed from a previous registry, consists of any one major criterion (SB lesion length >10mm with diameter stenosis of SB >70% for distal LM bifurcation lesions or >90% for non-LM bifurcation lesions) plus any two minor criteria (moderate-to-severe calcification, multiple lesions, bifurcation angle < 45° or > 70°, main vessel RVD < 2.5mm, thrombus-containing lesions, or main vessel lesion length >25mm). Patients were randomised to either a provisional (N=325) or two-stent strategy (N=328; 77.8% DK-crush and 17.9% culotte); 62.5% of lesions in the trial were LAD/diagonal and 28.7% at the LMS. At the 1-year follow-up, the primary endpoint of target lesion failure (TLF) (defined as the composite of cardiac death, target vessel MI, or clinically driven target lesion revascularization) was greater in the provisional group (11.4% vs. 6.1%; HR: 0.52; 95% CI: 0.30-0.90; p=0.019). The difference was driven by lower 1-year rates of target vessel MI (HR: 0.43; 95% CI: 0.20-0.90; p=0.025) and clinically driven target lesion revascularization (HR: 0.43; 95% CI: 0.19-1.0; p=0.049). There were no differences in the rates of cardiac death, all-cause death, or stent thrombosis. Of note, the Kaplan-Meier curves examining the main endpoint are unusual in that all the events seemed to occur immediately after the index procedure, and well before 30 days, with few events between then and the 12-month timepoint. Looking back at the definitions of the primary endpoint, it turns out that this must have comprised peri-procedural infarcts (defined according to enzyme rise or ECG change) or angiography defined vessel failure. This rather important aspect of the study is not explored in the prose of the results or the discussion.


DK-crush may be the optimal bifurcation strategy??

Clinical Outcomes Following Coronary Bifurcation PCI Techniques. A Systematic Review and Network Meta-Analysis Comprising 5,711 Patients.

JACC Cardiovasc Interv. 2020; 13:1432-44

Despite robust randomized data favouring a provisional one stent strategy, the optimal technique for bifurcation lesions remains unresolved. The current meta-analysis of 21 randomized controlled trials including 5711 patients treated using 5 bifurcation techniques (provisional (N=1952), T stenting/T and protrusion (N=392), crush (1361), culotte (N=1101), and DK-crush (N=905)) studied MACE, cardiac death, MI, target vessel or lesion revascularization and stent thrombosis. Patients had a mean age of 64±10 years, 71% were men, 22% had diabetes, and 50% presented with stable angina. Over a median follow-up of 12 months, DK-crush was associated with a lower rate of MACE compared with other techniques (OR vs. provisional: 0.39; 95% CI: 0.26-0.55). This was driven by a reduction in target vessel revascularization (OR vs. provisional 0.39; 95% CI: 0.26-0.55) and target lesion revascularization (OR vs. provisional: 0.36; 95% CI: 0.22-0.57). There were no differences in the rates of all-cause death, cardiovascular death, MI and stent thrombosis among the five techniques studied. DK-crush was associated with significantly fewer MIs compared to classic crush (OR: 0.38; 95% CI: 0.1400.86). DK-crushed ranked first in probability of being the best treatment for all outcomes, followed by culotte and provisional stenting. T/TAP and crush were least likely to be the best treatment. Pairewise meta-analyses showed that the benefit of 2-stent techniques was observed in bifurcation lesions with side branch length ≥ 10mm whereas no difference was observed in outcomes between 1 and 2 stent techniques in bifurcation lesions with side branch lesion length < 10mm.


MIRACLE2 may streamline management for OOHCA

A practical risk score for early prediction of neurological outcome after out-of-hospital cardiac arrest: MIRACLE2

EHJ 2020 Online

The management of patients presenting with an out-of-hospital cardiac arrest (OOHCA) is variable depending upon the presence or absence of ST-elevation on the presenting ECG and the patient’s premorbid status. Despite many approaches that may improve survival, a significant proportion of patients still sustain poor outcomes due to hypoxic brain injury. The purpose of this study was to develop a practical point-based risk score that can be applied to patients with OOHCA on arrival to a Heart Attack Centre (HAC) to reflect long-term prognosis and support clinical decision making. The study included 1055 patients aged ≥ 18 years presenting with an OOHCA and return of spontaneous circulation between May 2012-December 2017 of whom 373 were included in the King’s Out of Hospital Cardiac Arrest Registry. Inclusion criteria were the presence of ST-elevation on the ECG and patients without ST-elevation if there if there was absence of a noncardiac aetiology. Prediction modelling and multivariable logistic regression were used to identify predictors of poor neurological outcome classified as Cerebral Performance Category 3-5 (severe disability-death) at 6-month follow-up. This was externally validated in two independent cohorts comprising 473 patients. Seven independent predictors of outcome were identified: missed (unwitnessed) arrest, initial non shockable rhythm, nonreactive pupils, age (60-80 years: 1 point; >80 years: 3 points), changing intra-arrest rhythms, low pH < 7.20, and epinephrine administration (2 points). The MIRACLE2 score had an AUC=0.90 in the development and 0.84/0.91 in the validation cohorts. Three risk score were identified: MIRACLE2 ≤ 2: 5.6%risk of poor outcome;  MIRACLE2 3-4: 55.4% risk of poor outcome; MIRACLE2 ≥ 5: 92.3% risk of poor outcome. The MIRACLE2 had a superior discrimination to the OHCA score and the Cardiac Arrest Hospital Prognosis Score, but it performed as well as the Target Temperature Management score. These findings help define subgroup of patients where an early invasive strategy may be futile. Since the risk score was derived and validated in retrospective populations, there is now a requirement to prospectively validate it in larger cohorts and across different health care systems prior to its routine use.


Novel markers of plaque instability

Progression of ultrasound plaque attenuation and low echogenicity associates with major adverse cardiovascular events.

EHJ 2020; 41:2695-73

Although several pathological features of atherosclerotic plaque are known to be associated with instability and ACS, accurately identifying lesions likely to erode or rupture remains a scientific and clinical ambition. It is challenging because neither the anatomical (angiography, OCT, IVUS) nor physiological (FFR, iFR, CFR) tests that we use, and rely upon, can accurately characterise or predict plaque behaviour. In this study two specific IVUS ‘signature’ appearances were studied: (a) attenuated plaque (AP) characterized by a hypoechoic area with deep ultrasonic attenuation in the absence of calcium and (b) echolucent plaque (ELP) characterized by an intraplaque zone of absent or low echogenicity. The authors sought to associate these imaging biomarkers with clinical outcomes in a post hoc analysis of patients with one or more stenosis (≥20%) at invasive angiography.  Patients underwent IVUS at baseline and again after two years of medical therapy. IVUS was performed in arteries with no stenoses >50%, and no previous revascularisation and with no evidence that it was the culprit of a previous MI. Core laboratory, manually traced, AP and ELP, were performed at 1mm intervals. Of the 1497 patients studied, 18.8% had AP or ELP at baseline. These tended to be males, with an ACS history, diabetic, and had higher percentage stenoses and total atheroma volumes. These patients had a twofold increase in MACE compared with those without AP/ELP at baseline (8.2% vs. 3.9% p<0.01). 10.7% experienced either new or increased AP/ELP. In these patients MACE was even higher compared to those that did not experience progression (10.0% vs. 4.1%, p<0.001). Differences were driven by MI, revascularisation and stroke, as there were no deaths. Interestingly, many patients experienced a decrease in AP/ELP, demonstrating that vulnerable plaque can heal or regress with OMT. The focus on signature appearances appears to be a pragmatic approach that could aid translation into real world practice. Although the criteria and algorithms for calculating the ELP and AP indices appears complicated, the algorithms could likely be automated if this is commercially opportune. However, the proverbial ‘elephant in the room’ is the relevance to real-world clinical practice?  It will be fascinating to see if the results of studies like this one will translate into clear clinical benefit, i.e. will any medical or interventional treatment strategies be shown to improve clinical outcomes when targeted specifically at patients with high risk imaging appearances?


ACE inhibitors are safe in the COVID-19 era

Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study.

Lancet 2020; 395:1705-14

The SARS-CoV-2 virus uses the angiotensin-converting enzyme 2 (ACE2) as the receptor for its spike protein to invade host cells and replicate. There is a high degree of homology between ACE2 and ACE, and so naturally there was concern that those taking ACE inhibitors or angiotensin receptor blockers (ARBs) may be predisposed to a more severe episode of COVID-19 if infected. Renin-angiotensin-aldosterone system (RAAS) inhibitors also upregulate the expression of ACE2. Impromptu cessation of these drugs, however, could cause inadvertent harm to those patients with ischaemic heart disease, hypertension, heart failure, or chronic kidney disease secondary to diabetes, already taking them. The very conditions which are notably prevalent in patients with the most severe COVID-19 infections. To study the putative detrimental effect of RAAS inhibitors, investigators from seven hospitals in Madrid performed a case-population study in which 1139 PCR-confirmed cases of COVID-19 were compared against 10 controls per case (N=11390), individually matched for age, sex, region, and date of hospital admission extracted from a primary healthcare database. The study found no significant increase in the risk of COVID-19 requiring hospital admission associated with the administration of ACE inhibitors or ARBs, either as monotherapy or in combination with other drugs. When stratified according to age, sex, diabetes, hypertension, and baseline cardiovascular risk, no significant interaction was observed with any of these variables, other than diabetes, for which RAAS inhibitors were associated with a significantly reduced risk of hospital admission in the context of COVID-19 infection. The investigators have postulated a possible imbalance of ACE:ACE2 in favour of ACE in the lungs of diabetics underpinning this interesting result. This would mean greater ACE activity with simultaneous downregulation of ACE2 by SARS-CoV-2 which would lead to a more serious infection unless there was RAAS inhibitor protection opposing this.