R&D Literature Review May 2020

BCIS R&D Group

 

Literature Review May 2020

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

Edited by Michael Mahmoudi

 

Stable CAD & ACS

 

Is there a role for revascularization in stable angina?

Invasive or conservative strategy for stable coronary artery disease?

NEJM 2020; 382:1395-1407

The preferred contemporary approach to the management of stable angina is not well defined. Two strategies are commonly used: (a) guideline based medical therapy including antianginal drugs as well as disease modifying agents and (b) an invasive strategy consisting of coronary angiography followed by PCI or CABG plus medical therapy.  The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial tested whether an initial invasive strategy would result in better outcomes than a conservative strategy in 5179 patients with stable angina and moderate or severe myocardial ischemia with regards to the primary endpoint of death from cardiovascular causes, MI, or hospitalization for unstable angina, heart failure, resuscitated cardiac arrest. Key exclusion criteria were GFR < 30, recent ACS, unprotected left main stenosis of at least 50%, LV ejection fraction < 35%, NYHA class III or IV heart failure, and “unacceptable angina” despite the use of medical therapy. The majority of patients also underwent CTCA at screening to confirm the presence of obstructive CAD and exclude left main disease. At 6 months, the cumulative event rate was 5.3% in the invasive strategy group and 3.4% in the conservative strategy group (difference 1.9 percentage points; 95% CI: 0.8-3.0); at 5 years, the cumulative event rates were also similar (16.4% vs. 18.2%; difference -1.8 percentage points; 95% CI: -4.7-1.0). The difference in outcomes was driven by results for MI and those results depended on the definition used in the analysis. Of note, patients in the invasive strategy reported fewer angina symptoms than patients in the conservative group although the magnitude of this benefit depended on angina frequency at baseline with 35% having no angina at baseline. The Kaplan-Meier curves showed a trend for a greater number of MI (predominantly procedural) in the invasive strategy group during the first 6 months of the trial but as the trial proceeded the curves crossed and more MI (predominantly spontaneous) occurred in the conservative group. Finally, at 4 years, the cumulative incidence of death from cardiovascular causes or MI based on the primary definition was higher in the conservative strategy group  (13.9% vs. 11.7%). It is possible that ISCHEMIA ended before a substantial difference in favour of the invasive strategy emerged.

 

Should morphine be replaced by another analgesic agent in ACS patients?

Morphine and cardiovascular outcomes among patients with non-ST-segment elevation acute coronary syndromes undergoing coronary angiography.

JACC 2020; 75:289-300

Morphine is routinely utilised in the management of acute chest pain in patients presenting with ACS. From a pharmacological perspective, morphine and other opiates delay gastric emptying thus compromising intestinal absorption of P2Y12 inhibitors. A number of small studies have demonstrated that morphine reduced active metabolite exposure and antiplatelet effects of clopidogrel, prasugrel, and ticagrelor in stable patients post ACS, in acute MI, and during elective PCI. The current study was designed to explore the association between morphine and ischemic events in 5,438 patients treated with clopidogrel in the context of non-ST-segment elevation ACS in the EARLY-ACS trial. Patients that were not treated with clopidogrel (n=3,462) were used as negative controls. At 96 hours, morphine use was associated with higher rates of the composite endpoint of death, MI, recurrent ischemia, or thrombotic bailout (OR: 1.40; 95% CI: 1.04-1.87; p=0.026). There was a trend for higher rates of death or MI at 30 days (OR: 1.29; 95% CI: 0.98-1.70; p=0.072). The results question a routine strategy of routine morphine use in ACS patients or delaying the administration of clopidogrel loading dose until the time of PCI when the effects of morphine may have subsided.

 

Antiplatelet therapy in elderly patients presenting with NSTEMI

Clopidogrel versus ticagrelor or prasugrel in patients aged 70 years or older with non-ST-elevation acute coronary syndrome (POPular AGE): the randomised, open-label non-inferiority trial.

Lancet 2020;395:1374-81

Landmark trials such as PLATO and TRITON-TIMI 38  have demonstrated the advantage of a more potent antiplatelet effect from ticagrelor or prasugrel versus clopidogrel. The elderly who are often at high risk from thrombotic and bleeding events have been underrepresented in such trials. Investigators from the Netherlands randomised 1002 patients aged ≥70 presenting with NSTE-ACS 1:1 to clopidogrel versus ticagrelor or prasugrel along with standard therapy for 12 months. There were two co-primary endpoints. The safety endpoint was any bleeding requiring medical intervention, defined as PLATO major or minor bleeding. The net clinical benefit outcome was a composite of all-cause death, MI, stroke and PLATO major or minor bleeding. The median age was 77 (IQR 73-81) in the clopidogrel arm (n=500) and 77 (IQR 73-82) in the ticagrelor arm (n=502). There were 64% men and 36% women recruited. Given the open-label construct of the trial, 95% (475/502) of those in the prasugrel/ticagrelor cohort were prescribed ticagrelor. This was to be expected given the contraindications and cautionary advice associated with prasugrel in those ≥75 years old. The primary bleeding endpoint was significantly lower in the clopidogrel arm (HR 0.71, 95% CI 0.54-0.94; p=0.02 for superiority). The net clinical benefit endpoint satisfied the non-inferiority threshold in the clopidogrel arm (absolute risk difference -4%, 95% CI -10.0-1.4; p=0.03) but not for superiority (HR 0.82, 95% CI 0.66-1.03; p=0.11). In essence, treatment with clopidogrel in elderly NSTE-ACS patients resulted in lower bleeding events but not at the cost of greater thrombotic events. The trial was not powered to test for differences in mortality. One of the most important findings of the study was the rate of study drug discontinuation. Only 53% of patients completed their 12-month course of ticagrelor compared to 78% in the clopidogrel cohort, predominantly due to bleeding, dyspnoea and need for chronic oral anticoagulation.

 

ONYX ONE supports shorter DAPT duration

Polymer-based or Polymer-free Stents in Patients at High Bleeding Risk.

NEJM 2020; 382:1208-18

The optimal duration of dual antiplatelet therapy particularly in patients at high bleeding risk who undergo PCI has not been determined. The ONYX ONE trial compared the polymer-based zotarolimus-eluting stent (ZES) (Resolute Onyx; Medtronic; n=1,003) with the polymer-free umirolimus-coated stent (UCS) (Biofreedom; BioSensors; n=993) in patients undergoing PCI and who were deemed at high-bleeding risk. After PCI, patients were treated with 1 month of DAPT, followed by single antiplatelet therapy. The primary outcome was death from cardiac causes, MI, or stent thrombosis. The secondary outcome was target lesion failure, a composite of death from cardiac causes, target vessel MI, or clinically indicated target lesion revascularization. Both outcomes were powered for noninferiority. At 1 year, the primary outcome occurred in 17.1% in the ZES group and 16.9% in the UCS group (risk difference, 0.2 percentage points; upper boundary of the one-sided 97.5% CI: 3.5; noninferiority margin, 4.1; p=0.01 for noninferiority). The secondary outcome occurred in 17.6% of the ZES group and 17.4% of the UCS group (risk difference, 0.2 percentage points; upper boundary of the one-sided 97.5% CI: 3.5; noninferiority margin, 4.4; p=0.007 for noninferiority). Important limitations of the trial included its single-blind nature, noninferiority testing of the primary and secondary outcomes, and lack of a control group taking DAPT for a longer duration.

 

Physiology & Imaging

 

Invasive physiology use remains  modest in stable CAD

Utilization and outcomes of measuring fractional flow reserve in patients with stable ischemic heart disease.

JACC 2020; 75:409-19

FFR/iFR guided revascularization is considered the gold standard for invasive assessment of ischemia. Despite evidence from clinical trials and recommendations from the American and European societies FFR/iFR use remains limited with large differences between countries and health systems. The current study sought to evaluate contemporary, real-world patterns of FFR use and its effect on outcomes in patients with stable ischemic heart disease and angiographically intermediate disease (40% to 69% stenosis by visual assessment. A total of 17,989 patients were identified through the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program. Over a period of 8 years (2009-2017), the rate of FFR use gradually increased from 14.8% to 18.5% in patients with intermediate lesions, and from 44% to 75% in patients undergoing PCI. One-year mortality was significantly lower in the FFR group (2.8% vs. 5.9%; p<0.001). After adjustment for patient, site-level, and procedural factors, FFR-guided revascularization was associated with a 43% lower risk of mortality at 1 year compared with angiography-only revascularization.

 

IVUS a MUST for left main PCI

Intravascular Imaging and 12-Month Mortality After Unprotected Left Main Stem PCI. An Analysis From the British Cardiovascular Intervention Society Database.

JACC Cardiovasc Interv 2020; 13:346-57 

Despite intravascular imaging being shown to improve PCI outcomes in both randomized trials and registries, its use to optimise PCI remains limited. The current study has utilised the UK National PCI Audit to explore temporal changes in and implications of the use of IVUS for unprotected LM PCI in 11,264 patients. Imaging guidance significantly increased from 30.2% of procedures in 2007 to 50.2% in 2014. The factors associated with imaging use included stable angina presentation (OR: 1.2; 95% CI :1.15-1.25; p<0.001), bifurcation LM disease (OR: 1.22; 95% CI: 1.14-1.30; p<0.001), previous PCI (OR: 1.32; 95% CI: 1.22-1.32; p<0.001).  After propensity scoring was performed to adjust for baseline imbalances between groups, imaging guidance was strongly associated with a lower rate of coronary complications, fewer in-hospital major adverse cardiovascular events, and 46% and 34% reductions in 30-day and 12-month mortality respectively. Greater mortality reductions were observed with higher operator LM PCI volume. In logistic regression modelling, imaging use was associated with improved 12-month survival.

 

Catheter Based Valvular Intervention

 

Self-expandable or balloon-expandable TAVI?

Balloon-Expandable Versus Self-Expanding Transcatheter Aortic Valve Replacement. A propensity-Matched Comparison from the FRANCE-TAVI Registry.

Circ 2020; 141:243-59

There are very few randomized head-to-head trials comparing the balloon with the self-expanding transcatheter aortic valve replacement devices. Despite the inherent differences in expansion mode, stent frame, and leaflet characteristics between the device types, which translate into some differences in hemodynamic function, paravalvular sealing, and periprocedural complications have been considered comparable. The FRANCE-TAVI  nationwide registry of 12,141 patients undergoing balloon-expandable (Edwards, n=8,038) or self-expandable (Medtronic, n=4,103) has reported on ≥ moderate paravalvular regurgitation, in-hospital mortality, and 2-year all-cause mortality. In propensity-matched analyses, the self-expandable cohort had higher rates of ≥ moderate paravalvular regurgitation (15.5% vs. 8.3%; RR: 1.9; 95% CI: 1.63-2.22; p<0.0001) and in-hospital mortality (5.6% vs. 4.2%; RR:1.34; 95% CI: 1.07-1.66; p=0.01). 2-year mortality was also higher in the self-expandable group (29.8% vs. 26.6%; HR: 1.17; 95% CI: 1.06-1.29; p=0.003).

 

The evolution of self-expandable TAVI

Three Generations of Self-Expanding Transcatheter Aortic Valves. A Report From the STS/ACC TVT Registry.

JACC Cardiovasc Interv 2020; 13:170-79

The ever-increasing improvements in transcatheter technology has advanced TAVI to equivalency or superiority to SAVR in multiple studies across the spectrum of surgical risk. The current report focuses on real-world data from the Society of Thoracic Surgeons/American College of Cardiology TVT Registry for patients undergoing TAVI with CoreValve, Evolut R, or Evolut PRO valves for the treatment of tricuspid aortic stenosis between January 2014 to September 2017. The valves analysed included the 23, 26, and 29mm sizes. Propensity matching was performed using the Evolut PRO group as the reference. In 18,874 patients undergoing TAVI, 5,514 patients received the CoreValve, 11, 295 Evolut R, and 2,065 Evolut PRO. At 30-days, there were fewer patients with more than mild AR for the unmatched (7.8% CoreValve, 5.2% Evolut R and 2.8% Evolut PRO; p<0.001) and matched populations (8.3% CoreValve, 5.4% Evolut R and 3.4% Evolut PRO; p=0.03). The mean aortic valve gradients at 30 days in the matched populations were <8 mmHg for all three valves (7.3 mmHg CoreValve, 7.5 mmHg Evolut R, and 7.2 mmHg Evolut PRO).

 

PARTNER-2 at 5 years

Five-Year Outcomes of Transcatheter or Surgical Aortic-Valve Replacement.

NEJM 2020; 382:799-809

To be established as first line therapy for the treatment of symptomatic, severe aortic stenosis, TAVI must prove to be as effective as SAVR in the long term. The PARTNER 2 cohort A trial involved 2,032 patients who were stratified according to intended transfemoral or transthoracic access and randomly assigned to undergo TAVR with the balloon-expandable SAPIENT XT valve or SAVR. TAVR was found to be noninferior to SAVR with regards to the primary outcome of death from any cause or disabling stroke at 2 years. The investigators have now confirmed that at 5 years, there was no difference in the incidence of death or disabling stroke between TAVI and SAVR (47.9% vs. 43.4%; HR: 1.09; 95% CI 0.95-1.25). A landmark analysis of events occurring between 2 and 5 years after the procedure showed a divergence of event rates in favour of surgery (HR: 1.27; 95% CI: 1.06-1.53). This late increase in risk with TAVR has also been reported with the self-expanding TAVI valve. Other salient findings included greater paravalvular regurgitation in the TAVI group, patients in the TAVI group had nearly three times as many valve-related hospitalizations and required 21 aortic valve reinterventions as compared to 6 in the surgery group.

 

Optimal antithrombotic therapy in TAVI patients

Anticoagulation with or without clopidogrel after transcatheter aortic-valve implantation.

NEJM 2020; 382:1696-1707

Bleeding risk is particularly relevant in patients undergoing TAVI, especially those receiving oral anticoagulation, given the typical age of the patients, the frequent presence of comorbidities, and the use of large-bore access catheters. Expert opinion has indicated that administration of clopidogrel may reduce the risk of stroke and other embolic complications that are due in part to thrombus formation on the bioprosthetic valves. The POPular TAVI trial (cohort B) tested the hypothesis that in patients receiving anticoagulation, the use of oral anticoagulants alone would be safer (n=157) than oral anticoagulants plus 3 months of clopidogrel (n=156). The two coprimary endpoints of the trial were all bleeding and non-procedural related bleeding within 12 months after TAVI. Bleeding was lower in the anticoagulation only group (21.7% vs. 34.6%; RR: 0.63; 95% CI: 0.43-0.90; p=0.01). Most bleeding events were at the access site. Non-procedural related bleeding was also lower in the anticoagulation only group (21.7% vs. 34%; RR: 0.64; 95% CI: 0.44-0.92; p=0.02). Important limitations of the study included the definitions used in the trial with bleeding occurring during TAVI or the index hospitalization being defined as non-procedure related even if it occurred at the access site. Details regarding baseline and procedural characteristics, including aspirin use, the specific direct-acting oral anticoagulant used by patients, and how often oral anticoagulants were withheld periprocedurally, are lacking.

 

TAVI for bicuspid aortic valve disease

Outcomes of Transcatheter Aortic Valve Replacement in Patients with Bicuspid Aortic Valve Disease. A Report from the Society of Thoracic Surgeons/American College of Cardiology Valve Therapy Registry.

Circ 2020; 141:1071-79

Patients with bicuspid aortic valve stenosis (BAVS) have been excluded from pivotal TAVI trials. The aim of the current study was to compare the outcomes of TAVI in patients with BAVS and tricuspid aortic valve stenosis (TAVS). There were 170,959 eligible procedures in the Society of Thoracic Surgeons/American College of Cardiology Valve Therapy Registry. Of these, 5,412 TAVI procedures were performed in patients with BAVS, including 3,705 with current generation devices. As compared to patients with TAVS, patients with BAVS were younger and had a lower STS score. With current generation devices, device success was 96.3%, and the incidence of 2+ AR was 2.7%. A lower 1-year adjusted risk of mortality was observed in patients with BAVS (HR: 0.88; 95% CI: 0.78-0.99) whereas no difference was observed in the 1-year adjusted risk of stroke (HR: 1.14; 95% CI: 0.94-1.39).

 

Miscellaneous

 

Evolution of renal denervation for hypertension

Alcohol-Mediated Renal Denervation Using the Peregrine System Infusion Catheter for Treatment of Hypertension.

JACC Cardiovasc Interv 2020; 13:471-84

The success of catheter-based renal denervation for the treatment of hypertension has remained variable. The Peregrine Catheter system has been developed to deliver small doses of pure dehydrated alcohol into the renal periadventitial space to ablate the afferent and efferent sympathetic nerve bundles. The current study examined the safety and efficacy of the infusion of 0.6ml of alcohol in 45 patients with uncontrolled hypertension taking 3 or more antihypertensive medications. Mean 24-hour ambulatory BP reduction at 6 months versus baseline was -11 mmHg for systolic BP and -7 mmHg for diastolic BP. Office systolic BP was reduced by -18/-10 mmHg at 6 months. Antihypertensive medications were reduced in 23% and increased in 5% of patients at 6 months. The primary safety endpoint, defined as the absence of periprocedural major vascular complications, major bleeding, acute kidney injury, or death within 1 month was met in 96% of patients. Two patients developed access site pseudoaneurysms. There were no death or instances of MI, stroke, TIA, or renal artery stenosis. There were two cases of minor vessel dissection that resolved without treatment.

 

BP control without the pills?

Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised, sham-controlled trial.

Lancet 2020; 395:1444-51

The SPYRAL HTN-OFF MED (SPYRAL Pivotal) trial was designed to assess the efficacy of renal denervation in the absence of antihypertensive medication. The study randomized 331 patients with office systolic blood pressure of 150-180 mmHg to either renal denervation or a sham procedure. The primary efficacy endpoint was baseline adjusted change in 24-hour systolic BP and the secondary efficacy endpoint was baseline adjusted change in office systolic BP from baseline to 3 months after the procedure. The primary and secondary efficacy endpoints were met, with posterior probability of superiority more than 0.999 for both. The treatment difference between the two groups for systolic BP was -3.9 mmHg and for office systolic BP  the difference was -6.5 mmHg. There were no major device-related or procedural related safety events up to 3 months after the procedure.

 

Very late stent outcomes

Stent-Related Adverse Events >1 Year After Percutaneous Coronary Intervention.

JACC 2020; 75:590-604

Many contemporary drug-eluting stent (DES) trials have focused on 1-year outcomes. The frequency and predictors of stent-related major adverse cardiovascular events (MACE) after the first year have not been extensively studied. Individual patient data from patients involved in 19 prospective, randomized metallic stent trials were examined for the frequency and predictors of very-late stent-related events and MACE by stent type. Amongst 25,032 patients, 3718, 7934, and 13380 were treated with bare metal stents (BMS), first generation DES (DES1) and second generation DES (DES2) respectively. MACE rates within 1 year after PCI were progressively lower following treatment with BMS versus DES1 versus DES2 (17.9% vs. 8.2% vs. 5.1% respectively; p<0.0001). Between years 1 and 5, very late MACE occurred in 9.4% of patients including 2.9% cardiac death, 3.1% MI, and 5.1% ischemia driven target lesion revascularization. Very late MACE occurred in 9.7%, 11%, and 8.3% of patients treated with BMS, DES1 and DES2 respectively (p<0.0001), linearly increasing between 1 and 5 years. The use DES1, age, coronary risk factors such as diabetes and smoking, and variables associated with extensive disease (eg. previous revascularization, calcification, multivessel disease) were identified as predictors of very late events.

 

It’s all about risk factor modification

Modifiable risk factors, cardiovascular disease, and mortality in 155722 individuals from 21 high-income, middle-income, and low-income countries (PURE): a prospective cohort study.

Lancet 2020;395:795-808

The Prospective Urban Rural Epidemiology (PURE) study was designed to standardise the prospective measurement of the effects of 14 modifiable risk factors on cardiovascular disease (CVD) and mortality across 21 countries categorised by different socio-economic strata. Between January 2005 to December 2016, investigators recruited 155,722 participants without a prior history of CVD who were then followed up for a median of 9.5 years. Behavioural risk factors were tobacco use, alcohol intake, diet quality, physical activity, and sodium intake. Metabolic risk factors included hypertension, dysglycaemia (or history of diabetes), non-HDL cholesterol, body mass index and waist-to-hip ratio as a surrogate of centripetal obesity. Education was the primary socioeconomic factor of interest. Symptoms of depression was measured as were grip strength and household and ambient air pollution. Important findings included a mean BMI, waist-to-hip ratio, and non-HDL cholesterol greatest in high-income countries, prevalence of hypertension highest in middle-income countries, and diabetes found most often in low-income countries. Tobacco was most strongly associated with CVD, followed by physical activity and poor diet. Hypertension had a stronger association with CVD than diabetes, elevated non-HDL cholesterol and obesity. In the overall cohort, hypertension was the strongest risk factor for CVD, followed by high non-HDL cholesterol, household air pollution, tobacco use, poor diet, low education, abdominal obesity, and diabetes. Elevated non-HDL cholesterol was the largest risk factor for MI, followed by hypertension and smoking.

 

Simple measures to reduce radiation exposure

Effectiveness of additional x-ray protection devices in reducing scattered radiation in radial intervention: the ESPRESSO randomized trial.

EuroIntervention 2020 Online

The incidence of radiation associated pathology correlates with length of career and the complexity cases undertaken. Radiation protection practice and training varies considerably between different centres and countries. It is remarkable how simple alterations to practice, can reduce dose, not just to the operator but also to the other staff in the lab. Over a career, these measures make a big difference. Modern interventional trends such as increasing patient BMI, and case complexity are all associated with increased operator x-ray dose. The ESPRESSO trial compared three basic radiation protection measures in the context of radial arterial access. The trial randomised 600 patients undergoing radial access intervention, prospectively, to ‘Shield only’ – a 60*76 cm, 0.5mm Pb, ceiling mounted Mavig shield, ‘Shield + curtain’ – as above, plus an attached 0.5 Pb curtain underhanging the shield, and ‘Shield + curtain + drape’ – as above, plus a 75*40 cm 0.5 Pb drape positioned over the waist. The drape was custom made and covered the patient’s lower abdomen and groin area.  All strategies were all used alongside standard lead apron and thyroid collar. Outcome measures were the radiation dose to the first and second operator and the patient with analysis on an intention to treat basis. There was a mixture of interventional cases including PCI (in 53%), diagnostic studies, left ventriculography and a small percentage of right heart catheterisation and even biopsy.  No cases crossed over. Patient and case characteristics were well balanced between groups. There were no between-group differences in screening or procedure time. The key results were no statistically significant differences in patient dose-area product. As compared with group 1 (shield only), group 2 (+ curtain) was associated with non-significant 3% dose reduction for first operator and 17% dose reduction in the second operator. Group 3 (+ curtain and drape) had a significant 19% dose reduction for first operator and 39% reduction for second operator. Most centres will be familiar with the equipment used in groups 1 and 2 but may not utilise the drape over the patient’s waist. This appears to be a particularly inexpensive (reusable) and simple to use strategy associated with considerable benefit in every case performed.