R&D Literature Review Jan 2020

BCIS R&D Group

 

Literature Review January 2020

 

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

 

Stable CAD & ACS

 

Benefits of complete revascularization in STEMI patients are long lasting

Long-term follow-up of complete versus lesion-only revascularization in STEMI and multivessel disease. The CvLPRIT Trial.

JACC 2019; 74:3083-94
Multivessel coronary artery disease (CAD) may be present in up to 50% of patients presenting with STEMI. In such patients, there is increasing evidence that complete revascularization of both the infarct related artery (IRA) and non-culprit lesion(s) either at the time of PPCI or within a relatively short time frame of the index procedure will provide prognostic benefits. The CvLPRIT (Complete Versus Lesion-Only Primary PCI Trial) is the first study to provide data regarding the long-term efficacy of such an approach. The original study recruited 296 patients, with 150 randomized to complete revascularization (CR), and 146 randomized to IRA-only PCI. At a median follow-up of 5.6 years, the primary MACE (all-cause death, MI, heart failure, and ischemia-driven revascularization) endpoint was lower in the CR group (24% vs. 37.7%; HR: 0.57; 95% CI: 0.37-0.87; p=0.0079). The composite endpoint of all cause death/MI was lower in the CR group (10% vs. 18.5%; HR: 0.47; 95% CI: 0.25-0.89; p=0.0175). In a landmark analysis from 12 months to final follow-up, there was no significant difference between MACE, death/MI, and individual components of the primary endpoint suggesting that the majority of the benefits occurred in the early phase and was maintained during longer-term follow-up. It is noteworthy that the vast majority of new revascularization that occurred between 12 months and long-term follow-up in the IRA group were located in the original non-IRA lesion.

 

Left main PCI remains the Achilles heel of interventional cardiology

Percutaneous coronary angioplasty versus coronary artery bypass grafting in the treatment of unprotected left main stenosis: updated 5-year outcomes from the randomised non-inferiority NOBLE trial

Lancet 2020; 395:191-199
Hot on the heels of EXCEL reporting its 5-year outcomes in September 2019, the NOBLE trial published its own 5-year results in December 2019. In brief, NOBLE was a prospective, randomised, open-label, non-inferiority trial which randomised patients 1:1 with left main coronary artery disease (LMCAD) to either PCI or CABG. Patients were recruited from 36 centres in northern Europe, whereas EXCEL recruited from Europe, North and South America, and the Asia Pacific region. EXCEL also recruited patients with low to moderate anatomic complexity (SYNTAX score ≤32), whereas NOBLE did not stipulate a SYNTAX score level of complexity but instead recruited patients with left main lesions visually assessed as >50% or ≤0.80 by fractional flow reserve in the ostium, mid-shaft, or bifurcation, with no more than 3 additional complex lesions (i.e. CTOs, bifurcation lesions needing a 2-stent strategy or lesions with calcified or tortuous vessel morphology). At 3 years, the primary composite endpoint of MACCE (consisting of all-cause mortality, non-procedural MI, any repeat coronary revascularisation, and stroke) were 28% for PCI (121 events) and 18% for CABG (80 events), HR 1.51 (95% CI 1.13-2.00), exceeding the limit for non-inferiority, with CABG shown to be significantly better than PCI (p=0.0044). At 5 years, the Kaplan-Meier estimates of MACCE were 28% (165 events) for PCI and 19% (110 events) for CABG, HR 1.58 (95% CI 1.24-2.01). The difference was driven by significantly higher rates of non-procedural MI (p=0.0002) and repeat revascularisation (p=0.0009) seen in the PCI arm. Therefore CABG was again found to be superior for the primary composite endpoint (p=0.0002).
How prognostically significant is repeat revascularization as an endpoint in this context? EXCEL did not include ischemia driven revascularization (IDR) as a component of the primary endpoint. The principal investigators considered IDR undeserving of parity with critical outcomes such as death, stroke or extensive MI. The justification being repeat revascularization was of no greater clinical consequence than many other adverse perioperative outcomes that would have favoured PCI (when compared to CABG), such as major bleeding, acute kidney injury, arrhythmia, or serious wound infection. Indeed, without repeat revascularization as the major driving force, PCI would have reached equipoise with CABG for the management of symptomatic LMCAD in the NOBLE trial. Moreover, patients may be more willing to accept the likelihood of a repeat percutaneous intervention in the medium to long term over the invasive nature of CABG and the inherently higher risk of perioperative complications. NOBLE also excluded peri-procedural MI from its primary endpoint despite general acceptance that the prognostic implications of an MI tend not to be predicated by when it occurs, but the territorial extent to which it occurs. Greater harmonisation of individual and combined endpoint definitions for future trials is required.

 

The lipid content of coronary lesions may be a novel marker of vulnerability

Identification of patients and plaques vulnerable to future coronary events with near-infrared spectroscopy intravascular ultrasound imaging, a prospective cohort study

Lancet 2019; 394:1629-1637
The desire to accurately detect vulnerable plaques in non-obstructed coronary arteries and be able to predict their likelihood of causing a major adverse cardiovascular event has long been seen as the Holy Grail of interventional cardiology. Identification of thin cap fibroatheroma (TCF) was previously regarded as the most likely substrate for vulnerable plaques. Attempts to image TCF using intravascular ultrasound (IVUS) have, however, been hampered by its inability to identify lipid core and the need for high-level core laboratory support. Focus has thus shifted to detection of lipid-rich plaques (LRP), which are known to cause the majority of coronary deaths from autopsy studies. Near-infrared spectroscopy (NIRS) has been developed to impart unique spectral differences between cholesterol and collagen to readily differentiate LRP from normal vessels or fibrotic and calcified plaques. It is incorporated with IVUS in a dual modality probe, allowing simultaneous analysis of structure and plaque composition. NIRS provides both a graphical result as a yellow area on a red background and a numerical value to indicate LRP size (known as the Lipid Core Burden Index which has a maximum level of 4mm [maxLCBI4mm]). According to previous validation studies, a maxLCBI4mm of >400 is associated with vulnerable plaque causing MI. NIRS is FDA approved.
The LRP study enrolled 1563 patients with suspected CAD proceeding to cardiac catheterization ± PCI and scanned non-culprit lesion segments using NIRS-IVUS. Patient- and plaque-level hierarchical hypotheses were set, each assessing the association between maximum LCBI4mm with non-culprit major adverse cardiovascular events (NC-MACE). Of the 1271 patients with evaluable LCBI4mm, the mean number of arteries scanned per patient was 2.1 with ≥50 mm of eligible vessel in 89% (1135/1271) of patients. Over a 2-year follow-up, the cumulative incidence of NC-MACE was 9%. In patients with max LCBI4mm >400, the unadjusted hazard ratio (HR) was 2.18 (95% CI 1.48–3.22; p<0.0001) and adjusted HR was 1.89 (1.26–2.83; p=0.0021) on a patient level. On a plaque level for segments with a max LCBI4mm > 400, the unadjusted HR increased to 4.22 (95% CI 2.39–7.45; p<0.0001) and the adjusted HR to 3.39 (1.85–6.20; p<0.0001). There were few periprocedural complications (<0.5%). The LRP study is the largest prospective intracoronary imaging study to demonstrate that NIRS-IVUS is a safe and clinically user-friendly tool to appropriately identify patients and coronary segments at greater risk of future adverse coronary events.
But how do we use this information? On a patient level it might identify individuals that require a more intensive lipid-lowering regime and may stimulate greater focus on lifestyle modification. On the other hand such information could be incendiary to a patient that might now feel they are walking around with a ticking time bomb. Good communication will be essential in this scenario. On a plaque-level, prophylactic stenting of vulnerable segments in the absence of haemodynamic compromise may do more harm than good. We await the results of the PROSPECT II (NCT02171065) and PREVENT (NCT02316886) randomised studies comparing optimal medical therapy versus focal stenting plus optimal medical therapy to reduce NC-MACE using IC imaging.

 

Colchicine as a novel, inexpensive secondary prevention therapy post MI?

Efficacy and safety of low-dose colchicine after myocardial infarction.

NEJM 2019; 381:2497-2505
Inflammation is thought to play a central role in the pathogenesis of atherothrombosis. Although pharmacological therapy for secondary prevention (eg. aspirin and statins) appear to have salutary effects on inflammation, the identification of an effective anti-inflammatory agents has remained elusive. The COLCOT investigators evaluated the effects of low dose colchicine (0.5mg OD) on cardiovascular outcomes as well as its long-term safety profile in 4745 patients recruited within 30 days after a MI. The primary efficacy endpoint was a composite of death from cardiovascular causes, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization. After a median follow-up of 22.6 months, the primary endpoint was lower in the colchicine group than the placebo group (5.5% vs. 7.1%; HR: 0.77; 95% CI: 0.61-0.96; p=0.02). This result was driven predominantly by lower risks for angina and stroke. A significant effect on death from cardiovascular causes or MI was not shown. Overall, the incidence of adverse events was similar in the two groups; however, some gastrointestinal side effects such as nausea were more frequent in the colchicine group as were pneumonias. Of note, 1.9% of the patients were lost to follow-up, 0.6% withdrew consent, and nearly 19% of the patients in both treatment groups stopped receiving colchicine or placebo prematurely. These factors may have obscured the true cardiovascular treatment effect or adverse-event profile.

 

Gender disparity in NSTEMI patients

Outcomes of Women Compared With Men After Non–ST-Segment Elevation Acute Coronary Syndromes.

JACC 2019; 74:3013-22
Women present with CAD at a later age and with a higher burden of comorbidities than men. They are also more likely to present with atypical symptoms and less likely to be treated with guideline-directed medical therapy. Ten TIMI trials including 68,730 patients with NSTEMI, 29% of whom were women, sought to determine whether outcomes differed between women and men after NSTEMI and if any observed differences were due to differences in baseline comorbidities, treatment strategies, or if gender itself was associated with the risk of cardiovascular events during follow-up.
In this study women were older and more frequently had hypertension, diabetes, previous heart failure, and renal disease than men. Women were at similar risk of MACE (CV death, MI, or stroke) compared with men (HR: 1.04; 95% CI 0.99-1.09; p=0.16) but at higher risk of all-cause death (HR: 1.12; 95% CI: 1.01-1.24; p=0.03). After adjustment for baseline differences, risks of MACE ( HR: 0.93; 95% CI: 0.88-0.98; p<0.01) and all-cause death (HR: 0.84; 95% CI: 0.78-0.90; p<0.0001) were lower among women than men.

 

Physiology & Imaging

 

Moving beyond coronary stenosis in patients with stable chest pain

1-Year Outcomes of Angina Management Guided by Invasive Coronary Function Testing (CoerMicA)

JACC Cardiovasc Interv 2020; 13:33-45
Approximately 50% of patients presenting with stable chest pain may not have significant epicardial coronary stenosis. Coronary microvascular dysfunction has emerged as an important diagnosis in such patients and is associated with an increased risk of MACE independently of conventional risk factors.
The CorMicA trial involving 151 patients with ischemia and no obstructive coronary disease found that an interventional diagnostic procedure (IDP) to rule in or rule out a disorder of coronary vasomotion was feasible and resulted in improved anginal symptoms at 6 months in patients whose IDP results were disclosed compared to the blinded control group. Results at 1 year have shown that the intervention group had improvements in angina by 27% (difference 13.6 units; 95% CI: 7.3-19.9; p<0.001) and EQ-5D index (mean difference 0.11 units; 95% CI: 0.03-0.19; p=0.1). After a median follow-up of 19 months, MACE (mortality, MI, unstable angina, heart failure hospitalization and cerebrovascular events) were similar in both groups (12% vs. 11%; p=0.8).

 

FFR based deferral of coronary revascularization remains a safe practice

Two-Year Outcomes After Deferral of Revascularization Based on Fractional Flow Reserve
The J-CONFIRM Registry

Circ Cardiovasc Interv 2020; e008355
There is overwhelming evidence in support of FFR-guided revascularization. Whether deferral of coronary lesions with FFR<0.80 is safe in real world practice is less clear cut. The J-CONFIRM registry (Long-Term Outcomes of Japanese Patients With Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicentre Registry) prospectively enrolled 1263 patients with 1447 lesions in whom revascularization was deferred based on FFR. The primary endpoint was the cumulative 2-year incidence of target vessel MI and clinically driven TVR. The mean FFR was 0.86±0.06. At 2 years, target vessel failure rate was 5.5% in deferred lesion, driven by a 5.2% rate of clinically driven TVR. The rates of cardiac death and target vessel related MI was 0.41% and 0.41% respectively. Independent predictors of 2-year target vessel failure were FFR value (per 0.01 decrease; HR: 1.07; 95% CI: 1.04-1.11; p<0.001), left main lesion (HR: 5.89; 95% CI: 2.72-12.8; p<0.001), Moderate to severe calcific lesions (HR: 2.49; 95% CI: 1.36-4.58; p=0.003), haemodialysis (HR: 2.9; 95% CI: 1.11-7.58; p=0.03), and right coronary artery lesion (HR: 1.78; 95% CI: 1.02-3.11; p=0.042).

 

Even More data for deferral of coronary lesions

Outcomes with Deferred Versus Performed Revascularization of Coronary Lesions with Gray-Zone Fractional Flow Reserve Values

Circ Cardiovasc Interv 2019;12:e008315
The management of coronary lesions with FFR values in the gray zone (0.75-0.80) has remained debateable. A meta-analysis of 7 observational studies including 2683 patients comparing a strategy of deferred versus performed revascularization of coronary lesions with gray zone FFR values has reported similar rates of MACE (12.54% vs. 11.25%; OR: 1.64; 95% CI: 0.78-3.44; p=0.19), cardiac mortality (1.25% vs. 0.72%; OR: 1.78; 95% CI: 0.58-5.46; p=0.31), and MI (1.28% vs. 2.66%; OR: 0.79; 95% CI: 0.22-2.79; p=0.71). Deferral of revascularization was associated with a higher incidence of TVR (9.12% vs. 5.78%; OR: 1.85; 95% CI: 1.03-3.33; p=0.04).

 

IC or IV Adenosine-Route does not matter

Individual Lesion-Level Meta-Analysis Comparing Various Doses of Intracoronary Bolus Injection of Adenosine with Intravenous Administration of Adenosine for Fractional Flow Reserve Assessment

Circ Cardiovasc Interv 2020; e007893
The current literature is modestly sized and inconclusive with regards to the equivalence of intravenous (IV) versus intracoronary (IC) adenosine for FFR measurement. A lesion-level meta-analysis including 1972 FFR measurements and 1413 lesions comparing IC and IV (140 μg/kg) from 16 studies has shown a strong correlation (correlation coefficient=0.915; p<0.001) between IC-FFR and IV-FFR. Mean FFR was 0.81±0.11 for IC adenosine and 0.81±0.11 for IV adenosine (p<0.001). A non-clinically relevant mean difference of 0.006 between the two methods were noted. When stratified by the IC adenosine dose, mean difference between IC and IV-FFR were 0.004, 0.011, 0r 0.000 FFR units for low dose (<40μg), intermediate dose (40-99μg) and high dose (100μg) IC adenosine respectively.

 

IMR remains the gold standard for assessment of microvascular function

Pressure-bounded coronary flow reserve to assess the extent of microvascular dysfunction in patients with ST-elevation acute myocardial infarction

EuroIntervention 2019 Dec 24. doi: 10.4244/EIJ-D-19-00674
The importance of microvascular function in both stable and ACS patients is increasingly recognised. In patients with STEMI, elevated microvascular resistance is associated with increased infarct size, complication rates, and adverse prognosis. Given the limitations of current indices of microvascular function (including time and cost), the current study examined whether ‘pressure-bound coronary flow reserve’ (pb-CFR) defined as the interval between the minimum and the maximum possible CFR values would represent a simpler and quicker way for assessing microvascular function at the time of PPCI. In addition to pb-CFR, IMR and CFR were measured with a pressure and temperature sensitive wire. Coronary physiological indices were measured in the infarct-related artery before and /or post-PPCI. Cardiac MRI was performed at 48 hours and six months. In 148 STEMI patients, pb-CFR improved with PCI, was predictive of myocardial injury at 48 hours, demonstrated an association with IMR and was also mildly predictive of microvascular obstruction. However, it was not predictive of LV ejection fraction. IMR outperformed both pb-CFR and CFRthermo in predicting all the key outcomes, prognostic markers and endpoints. Furthermore, pb-CFR was indeterminant in 21% of cases post-PCI. Thus, it seems that in the search for a tool that can provide accurate data regarding microvascular function, IMR remains the current gold standard.

 

Can avoiding IVUS in complex PCI be justified?

Effect of Intravascular Ultrasound–Guided Drug-Eluting Stent Implantation. 5-Year Follow-Up of the IVUS-XPL Randomized Trial.

JACC Cardiovasc Interv 2020; 13:62-71
The advantages of IVUS-guided PCI in reducing cardiac death and repeat revascularization have been confirmed in a multitude of studies. The IVUS-XPL (Impact of Intravascular Ultrasound Guidance on the Outcomes of Xience Prime Stents in Long Lesions) investigators report on the 5 years clinical results of their study in which 1400 patients with long coronary lesions (implanted stent length ≥28mm) were randomised to either IVUS-guided (n=700) or angiography guided (n=700) PCI with an everolimus-eluting stent. The primary outcome was the composite of MACE defined as cardiac death, target lesion-related MI, or ischemia driven TLR. At 5 years follow-up, IVUS-guided PCI was associated with a lower MACE rate (5.6% vs. 10.7%; HR: 0.50; 95% CI: 0.34-0.75; p=0.001). The difference was driven by a lower rate of TLR (4.8% vs. 8.4%; HR: 0.54; 95% CI: 0.33-0.89; p=0.007). By landmark analysis, MACE events between 1 and 5 years was lower in the IVUS-guided PCI group (2.8% vs. 5.2%; HR: 0.53; 95% CI: 0.29-0.95; p=0.03). Of note, the study was originally designed for 2 years follow-up and not 5 years and the optimal IVUS-guided attainment of an expansion index >1.0 is fairly aggressive by most comparisons.

 

Catheter Based Valvular Intervention

 

Rivaroxaban not appropriate for routine use in patients undergoing TAVI

A Controlled trial of rivaroxaban after transcatheter aortic valve replacement.

NEJM 2020; 382:12-29
Early leaflet thrombosis of TAVI valves has been identified in more than 15% of patients and could be a treatable contributor to future adverse events. Whether routine anticoagulation could prevent leaflet thrombosis and ultimately improve clinical outcomes was the focus of the GALILEO trial. The trial randomized 1644 patients without an established indication for oral anticoagulation following TAVI to either rivaroxaban 10mg daily plus aspirin 75-100mg daily for the first 3 months or aspirin 75-100mg daily plus clopidogrel 75mg daily for the first 3 months. The primary efficacy outcome was the composite of death or thromboembolic events. The primary safety outcome was major, disabling, or life-threatening bleeding. The trial was terminated early due to safety concerns.
After a median of 17 months, death or a first thromboembolic event was greater in the rivaroxaban group (incidence rates 9.8 and 7.2 per 100 person-years respectively; HR:1.35; 95% CI: 1.01-1.81; p=0.04). Bleeding was more common in the rivaroxaban group (4.3 and 2.8 per 100 person-years; HR: 1.50; 95% CI: 0.95-2.37; p=0.08) as was death (5.8 and 3.4 per 100 person-years; HR: 1.69; 95% CI: 1.13-2.53). Of note, most of the deaths in the rivaroxaban group were sudden or were due to non- cardiovascular causes, and a minority of the patients who had died had died of a bleeding event. In addition, 37% of the patients discontinued rivaroxaban during the trial, and most deaths occurred long after drug discontinuation.

 

Novel intervention for tricuspid regurgitation

Transcatheter edge-to-edge repair for reduction of tricuspid regurgitation: 6-month outcomes of the TRILUMINATE single-arm study

Lancet 2019; 394:2002-2011
There is a paucity of definitive interventions for severe symptomatic secondary or functional tricuspid regurgitation (TR). Treatment is usually conservative despite an association with adverse outcomes independent of concomitant cardiac or valvular pathology. Only expert-level consensus is available to guide the timing of surgical tricuspid valve repair, which in the main is usually performed in combination with left-sided heart surgery. This has paved the way for the development of transcatheter-based intervention for TR. Given that tricuspid leaflet malcoaptation is the predominant defect in TR, an edge-to-edge clip technique, successfully adopted for treating mitral regurgitation (MitraClip), represents the most promising opportunity to effectively manage functional TR.
The TRILUMINATE study is a prospective multicenter single-arm study aimed at evaluating the safety and effectiveness of the TriClip transcatheter tricuspid valve repair system. Patients were eligible for the study if they had ≥moderate TR, ≥NYHA Class II, and had been adequately treated with optimal medical therapy but were regarded as high risk for surgery. Patients were excluded if they had a pulmonary artery systolic pressure >60 mmHg, prior tricuspid valve intervention or a pacemaker lead implanted in the right ventricle. The primary efficacy endpoint was a reduction in TR by at least one echocardiographic grade by 30 days and the primary safety endpoint was a composite of major adverse events at 6 months. The trial has completed recruiting and the follow-up is ongoing. This paper presented the first 6- month outcomes. From August 2017 to November 2018, 85 patients successfully received TriClip implantation. There was a 100% successful implantation rate. Of those, 71 patients (86%) had achieved a reduction in severity by at least 1 grade at 30 days (p<0.0001). At 6 months, only 3 (4%) of 84 patients had a documented major adverse event. There were, however, no device embolization, MI, or strokes. One patient withdrew prior to 6-month follow-up. Overall, TriClip appears to be a safe and feasible percutaneous method of managing significant functional TR, the caveat being this was not a randomized trial and therefore cannot be definitive regarding any medium- to long-term reduction in morbidity or mortality, for instance in comparison with conservative therapy or surgical intervention.

 

Miscellaneous

 

Troponin rise post PCI confers an adverse prognosis

Peri-procedural elevated myocardial biomarkers predict adverse clinical outcomes following elective percutaneous coronary intervention: a comprehensive dose-response meta-analysis of 24 prospective studies with 44972 patients

Eurointervention 2019 DOI: 10.4244/EIJ-D-19-00737
How many of us request a troponin after PCI? Perhaps we would rather not know. Do we send the patient home, regardless? Do we look at the results or collect the data systematically? In the acute patient, is it just a marker of the underlying condition? In these days of ‘duty of candour’, do we discuss the possible implications of a large troponin rise (‘procedure related’, a ‘troponin blip’) with the patient? Is it meaningful to include peri-procedural markers in composite trial endpoints? This is a particularly important point when dissecting out the results of landmark trials. The authors performed a meta-analysis to evaluate the dose-response relationship between biomarker elevation and the risk of all-cause mortality and MACE following elective PCI. Many of us are not fans of meta-analyses, which have problems associated with publication bias, accessing patient-level data, mixed outcome measures, and variable follow-up periods, to name but four. But the authors worked according to the best standards, known as the MOOSE (Meta-analysis of Observational Studies in Epidemiology) guidelines, and searched for studies between 1979 and 2018. Inevitably, the endpoints shifted from CK-MB to troponin in that study period and, rather than reporting a continuous variable, most studies reported the number in each group (1-3, 3-5, and >5 fold above the upper limit of normal, for example). And there was a lot of data manipulation to express results in a common format. With all those caveats, what they found was a post-procedural troponin >3-fold the 99th centile, and CK-MB > the 99th centile, were associated with increased mortality and MACE. For example, the OR for death if the troponin was 3-5 ULN was 1.5. Of course, it is impossible to correct for every variable, and it is highly likely that the higher marker elevations are found in patients with more extensive, complex or severe disease, and this may well be in the more co-morbid or frail, whose mortality is inevitably going to be higher than the others. Nevertheless, this study serves as a reminder that, on balance, a significant troponin rise at the time of elective PCI is not good for you, and it makes sense to minimise it whenever possible. This may, for instance, have implications for the extent of disease treated, the striving for ‘perfection’, or the drive to complete revascularisation. PCI is a trade-off. One has to know when to stop.