R&D Literature Review Nov 2019

BCIS R&D Group

 

Literature Review November 2019

 

Prepared by: Michael Mahmoudi, Aung Myat & Julian Gunn

 

Stable CAD & ACS

 

Consistent benefits with complete revascularization in STEMI patients

Complete Revascularization with Multivessel PCI for Myocardial Infarction

NEJM 2019; 381:1411-21
Four intermediate-sized trials have shown that complete revascularization in patients presenting with STEMI and multivessel CAD is safe and reduces the risk of repeat revascularization. A general strategy of complete revascularization has not been shown to reduce the risk of hard endpoints such as death or MI. The COMPLETE trial randomized 4041 patients presenting with STEMI and multivessel CAD to either complete revascularization (n=2016) or culprit-lesion-only PCI (n=2025). Nonculprit lesions were considered angiographically significant if they were associated with at least 70% stenosis on visual estimation or with 50-69% stenosis accompanied by FFR<0.8. Patients randomized to complete revascularization were to have routine staged PCI of all suitable nonculprit lesions regardless of if there were clinical symptoms or there was evidence of ischaemia within 45 days of randomization. The first coprimary outcome was the composite of death from CV causes or new MI; the second coprimary outcome was the composite of death from CV causes, new MI, or ischaemia-driven revascularization. Safety outcomes included major bleeding and contrast-associated acute kidney injury. At a median follow-up of 3 years, the first coprimary was lower in the complete revascularization group (7.8% vs. 10.5%; HR, 0.74; 95% CI, 0.60-0.91; p=0.004). The second coprimary endpoint was also lower in the complete revascularization group (8.9% vs. 16.7%; HR, 0.51; 95% CI, 0.43-0.61; p<0.001). The rates of major bleeding, stroke, stent thrombosis, and acute kidney injury were similar in the two groups.

 

PCI and CABG excel at 5 years

Five-Year Outcomes after PCI or CABG for Left Main Coronary Disease

NEJM 2019; 381:1820-30
The role of PCI in patients with left main CAD is not clearly established. The EXCEL trial randomized 1905 patients with left main CAD of low or intermediate SYNTAX score (<32) to either PCI with the cobalt-chromium everolimus-eluting stents or CABG. The primary endpoint was the composite of death from any cause, stroke, or MI at 3 years. Major secondary endpoints included the primary endpoint at 30 days and the composite of death, stroke, MI, or ischemia-driven revascularization at 3 years. Long-term additional secondary outcomes included these measures and their components at 5 years, as well as therapy failure (definite stent thrombosis or symptomatic graft stenosis or occlusion), all revascularizations, and all cerebrovascular events (stroke or transient ischemic attack). At 5 years, the primary endpoint was similar in the PCI and CABG groups (22.0% vs. 19.2%; difference, 2.8 percentage points; 95% CI, −0.9-6.5; p=0.13). Death from any cause was greater in the PCI group (13.0% vs. 9.9%; difference, 3.1 percentage points; 95% CI, 0.2-6.1). The incidences of definite cardiovascular death (5.0% vs. 4.5%; difference, 0.5 percentage points; 95% CI, −1.4-2.5) and MI (10.6% vs. 9.1%; difference, 1.4 percentage points; 95% CI, −1.3-4.2) were similar. All cerebrovascular events were less frequent with PCI (3.3% vs. 5.2%; difference, −1.9 percentage points; 95% CI, −3.8-0), although the incidence of stroke was not significantly different between the two groups (2.9% vs. 3.7%; difference, −0.8 percentage points; 95% CI, −2.4-0.9). Ischemia-driven revascularization was greater in the PCI group (16.9% vs. 10.0%; difference, 6.9 percentage points; 95% CI, 3.7-10.0).

 

Further support for PCI in mutilvessel CAD

Percutaneous coronary intervention versus coronary artery bypass grafting in patients with three-vessel or left main coronary artery disease: 10-year follow-up of the multicentre randomised controlled SYNTAX trial

Lancet 2019;394:1325-34
The original SYNTAX trial was an international multicentre randomised controlled trial performed in 85 hospitals across 18 North American and European countries. Patients with de novo 3-vessel or left main coronary artery disease were randomised in a 1:1 fashion to revascularisation either by PCI with a first-generation drug-eluting stent versus coronary artery bypass graft surgery. The original trial spawned the concept of a Heart Team reaching a consensus on anatomic complexity that would allow for presumed equipoise in terms of suitability for PCI or CABG. Published in 2009, the trial demonstrated 1 year MACCE to be significantly higher in the PCI group (17.8% vs. 12.4% for CABG; p=0.002), driven primarily by the need for repeat revascularisation after coronary stenting. Rates of death and MI were similar, but stroke occurred significantly more often after CABG. At 5-year follow-up, published in the Lancet in 2013, CABG remained superior for complex lesions (high or intermediate SYNTAX scores, ≥33 and 23-32 respectively), driven by significantly higher rates of repeat revascularisation and MI in the PCI arm. Interestingly, in less complex disease (low SYNTAX scores 0-22) or left main coronary disease (low or intermediate SYNTAX scores), PCI was found to be an acceptable mode of revascularisation. The latter finding was the basis upon which the EXCEL trial pitted a second-generation DES versus CABG for left main coronary artery disease with low or intermediate SYNTAX scores. At 10-year follow-up of the SYNTAX trial, life status was complete for the vast majority of the original cohort (93% PCI vs. 95% CABG). There was no significant difference in all-cause mortality between either revascularisation modality (HR 1.17, 85% CI 0.97-1.41; p=0.092). All-cause mortality rates favoured CABG after stratification by 3-vessel disease (HR1.41, 95% CI 1.10-1.80) but remained equivalent for left main coronary artery disease (HR 0.90, 95% CI 0.68-1.20; p value for interaction=0.019). The latter lending further credence to the results emanating from the 3- and 5-year follow-up data from EXCEL. There was also no treatment-by-subgroup interaction relative to diabetes status. How transferable these results are in an age of newer-generation DES where the haemodynamic significance of a lesion is routinely assessed by invasive physiology remains a topic of contention.

 

DEBs are finding indications beyond in-stent restenosis

Drug-coated balloon for treatment of de-novo coronary artery lesions in patients with high bleeding risk (DEBUT): a single-blind, randomised, non-inferiority trial

Lancet 2019;394:230-39
There is limited data on the clinical effectiveness of drug-coated balloons (DCB) for the treatment of obstructive coronary lesions in standard-sized vessels in those with high bleeding risk. Previous trials have focussed on comparing drug-coated balloons against first- and second-generation DES in small coronary artery disease. The Drug-Eluting Balloon in stable and Unstable angina (DEBUT) trial was a non-inferiority trial of 208 patients randomised to DCB (n=102) or bare-metal stent (BMS: n=106). An individual was deemed at high bleeding risk if they had just one recognised risk factor from a list of 11 pre-specified variables. No reference was made to established high bleeding risk scores such as HAS-BLED, ATRIA or CRUSADE. Moreover the predominant factors determining a high bleeding risk in the trial were age ≥80, baseline anaemia or thrombocytopenia and chronic oral anticoagulation use. In its favour the trial protocol did mandate an objective measure of ischaemia in the context of stable CAD, either by non-invasive imaging or pressure wire study before inclusion in the trial. Randomisation took place after the initial balloon predilation of the target lesion, subsequent dissection or >30% recoil of the target vessel precluded trial entry. Dual antiplatelet therapy was continued for 1 month after the procedure, in the context of both stable CAD and ACS. Aspirin was continued for 6 months in those presenting on oral anticoagulation. At 9-months the primary composite endpoint of MACE (CV mortality, non-fatal MI, or ischaemia-driven TLR) had occurred in just one patient (1%) in the DCB group versus 15 patients (14%) in the BMS group (p<0.0001 for non-inferiority and p=0.00034 for superiority). There were no cases of acute vessel closure after DCB treatment and no patients required TLR in the DCB arm versus 6 patients (6%) after BMS implantation. There was no significant difference in bleeding events. Key to the success of the DCB strategy was optimal lesion preparation, which was adhered to stringently in the trial. The difference between DCB versus BMS remained significant up to 36-month follow-up, which was a pre-specified secondary endpoint.

 

MgBRS provides further conflicting results for bioresorbable enthusiasts

Magnesium-Based Resorbable Scaffold versus Permanent Metallic Sirolimus Eluting Stent in Patients with ST-Segment Elevation Myocardial Infarction: The MAGSTEMI Randomized Clinical Trial

Circ 2019 Online
The use of first generation poly-L lactic acid-based bioresorbable scaffolds has been hampered by safety concerns. Magnesium-based bioresorbable scaffold (MgBRS) has short resorption period as well as being thromboresistant. Given the lack of data regarding the performance of MgBRS, the MAGSTEMI trial was designed to compare the in-stent/scaffold vasomotion between MgBRS and permanent metallic sirolimus-eluting stent (SES) at 12-month follow-up in 150 STEMI patients undergoing PPCI. The primary endpoint was the rate of increase (≥3%) after nitroglycerin in mean lumen diameter of the in-stent/scaffold segment with superiority of MgBRS over SES. Main secondary endpoints included angiographic parameters of restenosis, the device-oriented composite endpoint, their individual components, and device thrombosis rate. At 1-year follow-up, the primary endpoint was higher in the MgBRS group (56.5% vs. 33.8%; p=0.01). Late lumen loss was lower in the SES group (in-segment: 0.39±0.49mm vs. 0.02±0.27); p<0.001; in-device: 0.61±0.55 vs. 0.06±0.21; p<0.001). The device-oriented composite endpoint was higher in the MgBRS due to an increase in ischaemia driven TLR (16.2% vs. 5.2%; p=0.03). Definite ST rates were similar (1.4% vs. 2.6%; p=1.0). Endothelial function assessment at device segment was more pronounced in the MgBRS group (-8.3±3.5% vs. -2.4±1.3%; p=0.003).

 

Antiplatelet Therapy

 

Ticagrelor monotherapy for high risk PCI?

Ticagrelor with or without Aspirin in High-Risk Patients after PCI

NEJM 2019 Online
Despite the use of DAPT in patients presenting with ACS or who have undergone PCI, the risk of ischaemic complications remains significant. The TWILIGHT trial was designed to test the hypothesis that in patients undergoing PCI who are at high risk of ischemic or haemorrhagic complications and who have completed a 3-month course of DAPT with ticagrelor plus aspirin, continued treatment with ticagrelor monotherapy would be superior to ticagrelor plus aspirin. The primary endpoint was BARC type 2, 3, 04 5 bleeding. The key secondary endpoint was death from any cause, nonfatal MI, or nonfatal stroke. Clinical criteria for high risk were age ≥ 65 years, female sex, troponin positive ACS, established vascular disease, diabetes mellitus, and CKD. Angiographic criteria included multivessel CAD, stent length >30mm, a thrombotic target lesion, bifurcation lesion treated with two stents, an obstructive left main or proximal LAD lesion, and a calcified target lesion treated atherectomy. The study enrolled 9006 patients and 7119 underwent randomization after 3 months of DAPT. At 1 year the primary endpoint was lower in the ticagrelor monotherapy group (4% vs. 7.1%; HR, 0.56; 95% CI, 0.45-0.68; p<0.001). The incidence of death from any cause, nonfatal MI or stroke was 3.9% in both groups (difference, -0.06 percentage points; 95% CI, -0.97-0.84, HR, 0.99; p<0.001 for noninferiority).

 

Should prasugrel replace ticagrelor in ACS patients?

Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes

NEJM 2019; 381:1524-34
The safety and efficacy of prasugrel versus ticagrelor in patients with ACS has not been adequately compared in a head to head fashion. The ISAR-REACT-5 trial randomized 4018 patients, who presented with ACS and for whom invasive evaluation was planned, to receive either ticagrelor or prasugrel. Patients who were assigned to ticagrelor received the loading dose as soon as possible after randomization and maintained at 90mg BD. Prasugrel was started at a loading dose of 60mg and maintained at 10mg OD. A reduced maintenance dose of 5mg OD was recommended in patients who were ≥ 75 years old, and in those who had a body weight < 60 Kg. The primary endpoint (a composite of death, MI, or stroke at 1 year) was lower in the prasugrel group (6.9% vs. 9.3%; HR, 1.36; 95% CI, 1.09-1/70; p=0.006), with a number needed to treat of 42. This result was driven by a significant reduction of 1.8 percentage points in the incidence of recurrent MI and no significant between-group difference in the incidence of major bleeding (4.8% vs. 5.4%; p=0.46).

 

Ticagrelor not indicated in type II DM and stable CAD

Ticagrelor in Patients with Stable Coronary Disease and Diabetes

NEJM 2019; 381:1309-20
The PARTHENON clinical development program for ticagrelor has included four randomized, controlled, double blind trials across the spectrum of CV disease (PLATO, SOCRATES, EUCLID, PEGASUS-TIMI 54). The THEMIS study, the final PARTHENON trial, examined the safety and efficacy of ticagrelor in 19220 patients who were 50 years of age or older and who had type 2 diabetes mellitus and stable CAD to receive either ticagrelor plus aspirin or placebo plus aspirin. Patients with a previous history of MI or stroke were excluded. The presence of stable CAD was determined by one of the following: history of PCI or CABG or documentation of angiographic stenosis of at least 50% in at least one coronary artery. After a median follow-up of 39.9 months, the primary composite efficacy outcome of CV death, MI or stroke favoured DAPT with ticagrelor (7.7% vs. 8.5%; HR, 0.90; 95% CI 0.81-0.99; p=0.04), but the incidence of TIMI major bleeding was higher (2.2% vs. 1.0%; HR, 2.32; 95% CI, 1.82-2.94; p<0.001), and there was an excess of intracranial haemorrhage (0.7% vs. 0.5%; hazard ratio, 1.71; 95% CI, 1.18-2.48; p=0.005). There was no reduction in the composite outcome of irreversible harm, which was defined as death from any cause, MI, stroke, fatal bleeding, or intracranial haemorrhage (10.1% vs. 10.8%; hazard ratio, 0.93; 95% CI, 0.86-1.02).

 

Another positive milestone for personalized medicine

A Genotype-Guided Strategy for Oral P2Y12 Inhibitors in Primary PCI

NEJM 2019; 381:1621-31
Given the genetic variants in CYP2C19 the Popular Genetics trial was designed to determine whether a CYP2C19 genotype-guided strategy for selection of oral P2Y12 inhibitors could reduce bleeding risk without increasing thrombotic risk in patients with STEMI undergoing PPCI. 2488 were randomized to receive either a P2Y12 inhibitor on the basis of early CYP2C19 genetic testing (genotype-guided group) or standard treatment with either ticagrelor or prasugrel (standard treatment group) for 12 months. In the genotype-guided group, carriers of CYP2C19*2 or CYP2C19*3 loss-of-function alleles received ticagrelor or prasugrel, and noncarriers received clopidogrel. There were two primary outcomes. The first was the combined outcome of net adverse clinical events, which included death from any cause, MI, definite stent thrombosis, stroke, PLATO major bleeding at 12 months. The second was PLATO major or minor bleeding at 12 months. The primary combined outcome was lower in the genotype-guided group (5.1% vs. 5.9%; absolute difference, −0.7 percentage points; 95% CI, −2.0-0.7; p<0.001 for noninferiority). The primary bleeding outcome was also lower in the genotype-guided group (9.8% vs. 12.5%; HR, 0.78; 95% CI, 0.61-0.98; p=0.04).

 

Coronary Physiology

 

Utilization of coronary physiology to guide CABG

Graft patency after FFR-guided versus angiography-guided coronary artery bypass grafting. The GRAFFITI trial

EuroIntervention 2019 Online
In contrast to the wealth of data supporting the use of physiological indices to guide PCI, there are few to guide CABG. The GRAFFITI trial was a multi-centre, multi-national study of 172 patients undergoing coronary angiography, with either a chronic or acute presentation, having a significant lesion of the LMS or LAD and at least one more major vessel, making them potentially suitable for CABG. These patients then all underwent pressure wire examination. They were then randomised to FFR vs. visually guided CABG. The primary endpoint was graft patency at 12 months. Patients had a median three lesions. Compared to the angiography-guided group, the FFR-guided group received fewer anastomoses (3.0 vs. 2.0; p=0.004). One-year angiographic follow-up showed no difference in overall graft patency, death, MI, TVR or stroke.

 

Size does matter in CTO PCI

Relationship between Extent of Ischaemic Burden and Changes in Absolute Myocardial Perfusion after Chronic Total Occlusion Percutaneous Coronary Intervention

EuroIntervention 2019 Online
In this single centre study, 193 consecutive patients who had undergone successful CTO PCI underwent [15O]H2O PET at three months. They had also had a similar scan before PCI. The change in perfusion defect size, quantitative hyperaemic myocardial blood flow (MBF) and coronary flow reserve (CFR) in the CTO area were compared. Patients were subdivided according to the size of the perfusion defect into limited (0-1 segment, N=15), moderate (2-3 segments, N=61) and large (≥4 segments, N=117) defects. The median reductions in defect size were 1 [0-1], 2 [1-3], and 4 [2-5] segments in patients in these groups, respectively (all p<0.01). Hyperaemic MBF and CFR improved significantly regardless of baseline defect size. This study appears to support the concept that the larger the area of myocardium supplied by a CTO, the larger the potential benefit with successful revascularization.

 

Crush, Calcification, & Beyond

 

The rise of coronary lithotripsy as an alternative to rotablation

Safety and Effectiveness of Coronary Intravascular Lithotripsy for Treatment of Severely Calcified Coronary Stenoses. The Disrupt II Study

Circ Cardiovasc Interv 2019; 12:e008434
The feasibility of coronary intravascular lithotripsy (CIVL) to modify coronary calcification has been confirmed in the Disrupt CAD I study. The Disrupt II study was designed to confirm the safety and efficacy of CIVL in 120 patients in whom 94.2% had severe calcification. Delivery and use of the CIVL was achieved in all patients. Post CIVL angiographic luminal gain was 0.83±0.47mm, and residual stenosis was 32.7±10.4%, which further decreased to 7.8±7.1% post DES implantation. The primary endpoint of in-hospital MACE defined as cardiac death, MI, or TVL was 5.8%. There was no procedural abrupt vessel closure, slow or no reflow, or perforations. In 47 patients who underwent OCT post CIVL, calcium fracture was identified in 78.7% of lesions with 3.4±2.6 fractures per lesion.

 

A double crush for distal LMS disease

3-Year Outcomes of the DKCRUSH-V Trial Comparing DK Crush With Provisional Stenting for Left Main Bifurcation Lesions

JACC Intv 2019; 12:1927-37
The Double Kissing Crush versus Provisional Stenting for Left Main Distal Bifurcation Lesions (DKCRUSH-V) randomized trial demonstrated lower TLF and ST at 1-year follow-up in the DK crush group. The aim of the current study was to evaluate the 3-year clinical outcomes of the DKCRUSH-V study. At 3 years, TLF remained lower in the DK group (8.3% vs. 16.9%; p=0.005), driven by increased target vessel MI (1.7% vs. 5.8%; p=0.017) and target lesion revascularization (5.0% vs. 10.3%; p=0.029). Definite or probable ST was also lower in the DK group (0.4% vs. 4.1%; p=0.006).

 

Grave consequences of stent thrombosis

Incidence and predictors of outcomes after a first definite coronary stent thrombosis

EuroIntervention 2019 Online
The authors performed a retrospective analysis of the clinical outcomes of all 695 cases of definite stent thrombosis occurring in two major European centres, Rotterdam and Bern, over the period 1996-2017. They also presented their intravascular imaging findings. The mean age was 63 years and 76% were male. The timing of thrombosis was front-loaded after the index event (IQR 3-551, median 22 days) but with a very long ‘tail’ so that numbers were evenly divided between early and late or very late. Intravascular imaging was performed in 197 cases. In patients with early stent thrombosis, a quarter was associated with malapposition, a quarter with under-expansion and a quarter with edge dissection. In the late cases, 2/3 was associated with neotherosclerosis and 1/3 with malapposition. At 5 years after the thrombosis event, MACE occurred in 44%, of which cardiac death accounted for 20%; 18% experienced a further MI, TVR was required in 25% and repeat definite stent thrombosis occurred in 12%. Predictors of adverse outcomes after stent thrombosis were the presence of cardiogenic shock, location in the LAD, prior CVA/TIA or peripheral vascular disease, multivessel disease and final TIMI flow <3. No specific treatment, such as thrombectomy or GP IIb/IIIa inhibitor, seemed to influence MACE although new generation P2Y12 inhibitors reduced the risk of MI.

 

The perivascular fat attenuation index (FAI) derived via CTCA is a promising tool for monitoring coronary inflammation

Association of Biologic Therapy with Coronary Inflammation in Patients with Psoriasis as Assessed by Perivascular Fat Attenuation Index

JAMA Cardiol 2019; 4:885-91
The link between systemic inflammatory disorders and CAD are well established. In psoriasis biological therapy has been found to be favourably associated with luminal coronary plaques. Whether these associations are related to direct anti-inflammatory effects are unknown. In this study of 134 patients who predominantly had low CV risk and moderate to severe skin disease, investigators examined changes in the perivascular fat attenuation index (FAI), a novel imaging biomarker to assess coronary inflammation by mapping spatial changes of perivascular fat composition via CTCA, at baseline and at 1 year follow-up. Of these patients, 82 received biologic psoriasis therapy (anti-TNF, anti-IL12/23, or anti-IL 17) for 1 year and 52 did not receive any biologic therapy and were given topical or light therapy (control group). Biologic therapy was associated with a significant decrease in FAI at 1 year (median FAI −71.22 HU at baseline vs. −76.09 HU at 1 year; p < 0.001) concurrent with skin disease improvement (median PASI, 7.7 at baseline vs. 3.2 at 1 year; p < 0.001), whereas no change in FAI was noted in those not receiving biologic therapy (median FAI, −71.98 at baseline vs. −72.66 at 1 year; p =0.39). The associations with FAI were independent of the presence of coronary plaque and were consistent among patients receiving different biologic agents.

 

The return of the polypill

Effectiveness of polypill for primary and secondary prevention of cardiovascular disease (PolyIran): a pragmatic, cluster-randomised trial

Lancet 2019;394:672-83
The premise underpinning the use of a polypill, containing a fixed-dose combination of an anti-hypertensive agent(s), cholesterol-lowering drug, and aspirin, for the primary and secondary prevention of cardiovascular disease appears intuitively to be a good idea. It should maximise patient compliance and has the potential to save money. This is potentially of greater value to those living in low- and middle-income countries, where healthcare provision can be disjointed at best and haphazard at worst. Despite these obvious benefits, the widespread use of a polypill has not gained significant traction globally, in the most part due to previous trials being hampered by small to moderate sample sizes and abbreviated follow-up durations thereby limiting their power to determine the long-term effects of polypills on hard endpoints. The PolyIran study was a cluster-randomised trial nested within the much larger Golestan Cohort Study in Iran. Between February 2011 and April 2013, 6838 individuals were randomised to a minimal care group (n=3417) versus a once-daily polypill (n=3421) cohort. Almost half of each group consisted of women. The two largest polypill trials to date had enrolled just over 2000 individuals each. Minimal care comprised regular education on a healthy lifestyle including diet, exercise, weight control and abstinence from smoking and opium consumption. Polypill one consisted of hydrochlorothiazide 12.5 mg, aspirin 81 mg, atorvastatin 20 mg, and enalapril 5 mg. Those who developed cough were changed to Polypill two in which valsartan 40 mg replaced enalapril. Follow-up extended to 60 months after the last patient was enrolled. The two largest polypill trials to date had previously followed-up to 12 weeks and 15 months. Nearly 11% of the entire cohort had pre-existing cardiovascular disease, and of these 79.8% were using cardiovascular drugs at baseline. By the end of the study 8.8% in the minimal care group had had a major CV event (a composite of ACS hospitalisation, fatal MI, sudden death, heart failure, PCI, and non-fatal and fatal stroke) versus 5.9% in the polypill group (HR 0.66, 95% CI 0.55-0.80). When stratified according to high adherence to the polypill the difference to minimal care was even more pronounced (HR 0.43, 95% CI 0.33-0.55). Adverse events were similar between the two groups. Given the relatively large sample size and extended follow-up period, this trial offers a significant contribution to the evidence base for polypills especially in the primary prevention of cardiovascular disease and will serve as a benchmark for future studies in this therapeutic area. Whether a fixed-dose combination is of relevance for secondary prevention of cardiovascular disease, particularly in the developed world where there is now an onus on optimising, and thus up-titrating drug doses, remains to be seen. The next logical step therefore would be to determine the non-inferiority of a fixed-dose combination polypill against standard of care in a secondary prevention setting where the comparator group would be encouraged to up-titrate individual components of the pharmacotherapeutic regimen.