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Cardiology Research Review™

Welcome to the latest issue of Cardiology Research Review. In this issue, a large population-based study in the UK reports that ACEIs may increase the risk of lung cancer, particularly if used for more than 5 years. Although the magnitude of the observed association is modest, it could translate into large absolute numbers of patients at risk for lung cancer and the findings therefore need to be further investigated. Also in this issue, the DAPT-STEMI trial reports that 6 months of DAPT should be sufficient after primary PCI with a drug-eluting stent in patients with STEMI, the VEST investigators report disappointing outcomes for a wearable cardioverter-defibrillator after acute MI, and the ASCEND investigators report that aspirin may not have a net benefit when used for primary prevention in diabetic patients.

We hope you enjoy these and the other selected studies, and look forward to any feedback you might have.

Kind regards,Professor Alexander Sassealexandersasse@researchreview.co.nz

In this issue: ACEIs and lung cancer risk

6 vs 12 months of DAPT after drug-eluting stent implantation for STEMI

Wearable cardioverter-defibrillator after MI

Restrictive vs liberal transfusion during cardiac surgery

Aspirin for primary prevention in diabetic patients

Single vs dual antiplatelet therapy after TAVI

Feasibility of fully automated echocardiogram interpretation

Real-world clinical utility of CTCA-derived fractional flow reserve

Cardiac auscultation for detecting valvular heart disease in primary care

Neurological complications after TAVI vs SAVR

Angiotensin converting enzyme inhibitors and risk of lung cancerAuthors: Hicks B et al.

Summary: This population-based study in the UK determined the risk of lung cancer associated with the use of ACEIs and angiotensin receptor blockers (ARBs). 992,061 patients that were newly treated with antihypertensive drugs in 1995–2015 were identified from the United Kingdom Clinical Practice Research Datalink. The cohort was followed for a mean of 6.4 years, during which time 7952 incident lung cancer events occurred (crude incidence, 1.3 per 1000 person-years). Cox proportional hazards models showed that the use of ACEIs was associated with an increased risk of lung cancer compared with ARBs (incidence rate, 1.6 vs 1.2 per 1000 person-years; HR, 1.14). Associations were evident after 5 years of ACEI use (HR, 1.22) and increased with longer treatment durations.

Comment: This would be a difficult topic. ACEIs have been associated with accumulation of bradykinin and substance P which can be found in lung cancer tissue, hence concerns were raised a while back. Previous studies have not shown such an association but were felt to not address the matter well enough. That is why this large, population-based study was conducted to determine whether the use of ACEIs, compared with use of ARBs, is associated with an increased risk of lung cancer. Clinical Practice data from the UK was correlated with a database on lung cancer. Over 300,000 patients on ACEIs were identified, and the incidence of lung cancer was around 1.3%. The main outcome is that the risk of lung cancer was increased by 14% by ACEIs; ARBs did not influence this particular outcome. The authors realise the possible implications of these findings, as millions of patients will be on treatment with ACEIs worldwide.

Reference: BMJ 2018;363:k4209Abstract

Issue 77 – 2018

Abbreviations used in this issueACEI = angiotensin-converting enzyme inhibitorCTCA = computed tomography coronary angiographyDAPT = dual antiplatelet therapyHR = hazard ratioMI = myocardial infarctionOR = odds ratioPCI = percutaneous coronary interventionSAVR = surgical aortic valve replacementSTEMI = ST-elevation MITAVI = transcatheter aortic valve implantation New Zealand Research Review subscribers can claim CPD/CME points for time spent reading our reviews

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Six months versus 12 months dual antiplatelet therapy after drug-eluting stent implantation in ST-elevation myocardial infarction (DAPT-STEMI)Authors: Kedhi E et al.

Summary: This multicentre, non-inferiority trial compared 6 vs 12 months of DAPT after PCI with a drug-eluting stent in patients with STEMI. 1100 patients with STEMI who underwent PCI and received a second generation zotarolimus-eluting stent were included. 870 patients who were event-free after taking DAPT for 6 months were randomised 1:1 to receive single antiplatelet therapy (SAPT) or DAPT for an additional 6 months. The primary end-point (a composite of all-cause mortality, MI, revascularisation, stroke, or major bleeding within 18 months post-randomisation) occurred in 4.8% of patients receiving SAPT and 6.6% of patients receiving DAPT (HR, 0.73; p=0.004 for non-inferiority).

Comment: DAPT with first-generation drug-eluting stents in MI is currently recommended for 12 months, as a compromise between bleeding and thrombosis. Second-generation drug-eluting stents came yet with more data; use of DAPT for 6 months in stable coronary artery disease and 12 months in MI is accepted. The authors of this trial were trying to re-establish if the extension to 12 months of DAPT after STEMI remains best practice. DAPT consisted of clopidogrel, prasugrel and ticagrelor as the second drug according to local clinical practice. The trial showed that limiting DAPT to 6 months in patients that were event-free resulted in a non-inferior clinical outcome. Generally, event rates with second-generation stents were lower when compared to previous trials. We will have to watch how this will influence guidelines, but it would be a case for shortening DAPT to 6 months in the STEMI setting.

Reference: BMJ 2018;363:k3793Abstract

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Wearable cardioverter-defibrillator after myocardial infarctionAuthors: Olgin J et al., for the VEST Investigators

Summary: This study investigated the use of a wearable cardioverter-defibrillator after acute MI. 2302 patients with acute MI and an ejection fraction ≤35% were randomised 2:1 to receive a wearable cardioverter-defibrillator plus guideline-directed therapy (device group) or to receive guideline-directed therapy only (controls). Participants in the device group wore the device for a median 18.0 hours per day. Arrhythmic death within 90 days (primary end-point) occurred in 1.6% of patients in the device group compared with 2.4% of controls (relative risk, 0.67; p=NS). Death from any cause occurred in 3.1% and 4.9% of patients in the respective groups (relative risk, 0.64; p=0.04). Of the 48 patients in the device group who died within 3 months, 12 were wearing the device at the time of death.

Comment: Previously trials have failed to demonstrate a benefit for early implantation of a defibrillator after MI, and a delay of 40–90 days is proposed. Hence the question was whether bridging this time by using a wearable defibrillator might be beneficial. However, despite the intuitive concept no benefit from wearing a defibrillator vest was shown. Interestingly, 0.6% of patients wearing the vest received inappropriate shocks. Trial design might have contributed to this but also towards the end of the trial the vests were only worn 41% of the time. When analysed ‘as-treated’ there might have been a benefit for wearing the defibrillator vest but overall, with all its limitations, this is a negative trial.

Reference: N Engl J Med 2018;379:1205-15Abstract

Six-month outcomes after restrictive or liberal transfusion for cardiac surgeryAuthors: Mazer C et al., for the TRICS Investigators and Perioperative Anesthesia Clinical Trials Group

Summary: This study compared 6-month outcomes after a restrictive versus liberal transfusion strategy in patients undergoing cardiac surgery who were at moderate to high risk for death. 5243 adult patients were randomised to a restrictive red-cell transfusion strategy (transfusion if haemoglobin (Hb) <7.5 g/dL intraoperatively or postoperatively) or a liberal red-cell transfusion strategy (transfusion if Hb <9.5 g/dL intraoperatively or postoperatively in the intensive care unit [ICU], or <8.5 g/dL in a non-ICU ward). At 6 months after surgery, the primary composite outcome (death from any cause, MI, stroke, or new-onset renal failure with dialysis) had occurred in 17.4% of patients in the restrictive-threshold group and 17.1% of patients in the liberal-threshold group (p=0.006 for noninferiority).

Comment: Intuition in surgery for ischaemic heart disease might be to load the patient up with plenty of erythrocytes. However, the presented paper follows up on a previous study offering liberal vs restricted use of blood transfusion around the time of cardiac surgery, now with 6-month results. The updated data confirm that there was essentially no difference between both approaches to blood transfusion. And this includes all analysed subgroups including baseline Hb <10 g/dL, associated co-morbidities, and age. This continues to support a restrictive approach in the use of blood transfusion, however keep in mind that in this trial the rate of non-red blood cell blood products was identical and the difference between restrictive and liberal use of transfusion was 52% vs 73% of ≥1 unit red cells transfused.

Reference: N Engl J Med 2018;379:1224-33Abstract

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Single versus dual antiplatelet therapy after transcatheter aortic valve implantationAuthors: Hu X

Summary: This systematic review and meta-analysis compared the use of DAPT and single antiplatelet therapy (SAPT) after TAVI. A search of PubMed, Embase, Ovid Medline, Web of Science, and Cochrane Central Register of Controlled Trials identified 7 trials (n=1445) that were suitable for inclusion. Three of the studies were randomised, controlled trials, and the other 4 were observational articles. Mean age was 82.1 years. Meta-analysis of the data found no significant differences in 30-day all-cause mortality, 6-month all-cause mortality, or 1-year all-cause mortality between DAPT and SAPT. However, DAPT was associated with an increased risk of 30-day (OR, 2.91; p<0.01), 6-month (OR, 2.54; p<0.001), and 1-year major and lethal bleeding (OR, 2.65; p=0.041) compared with SAPT.

Comment: In this meta-analysis of 7 studies and 1445 patients the question of post-TAVI antiplatelet medication was addressed. About half of the patients had been on aspirin plus clopidogrel (DAPT), the other half were either on aspirin or clopidogrel alone (SAPT). There was no difference for mortality or stroke when comparing the groups. Bleeding was more common in the DAPT group (16.2% vs 6.4%). Certainly, randomised trials will need to clarify this in the future but at this stage there might be more harm than benefit for DAPT after TAVI in this group of elderly patients.

Reference: Cardiology 2018;141:52-65Abstract

Fully automated echocardiogram interpretation in clinical practiceAuthors: Zhang J et al.

Summary: This study evaluated the feasibility and diagnostic accuracy of fully automated echocardiogram interpretation in clinical practice. 14,035 echocardiograms spanning a 10-year period were used to develop algorithms for automated identification of 23 viewpoints and segmentation of cardiac chambers across 5 common views. Results were compared with manual segmentation and measurements from 8666 echocardiograms obtained during routine clinical practice. Overall, automated measurements were found to be comparable or superior to manual measurements across 11 internal metrics, such as the correlation of left atrial and ventricular volumes. Hypertrophic cardiomyopathy, cardiac amyloidosis, and pulmonary arterial hypertension were detected with c statistics of 0.93, 0.87, and 0.85, respectively.

Comment: Automated echo reporting, artificial intelligence. OK, why not? In this study clever algorithms were developed and tested that tried to automatically interpret echo images. The authors of the study used echocardiograms that had been shown to be diagnostic previously by conventional interpretation. The algorithms also used information from the patients’ records to (for example) identify patients treated for pulmonary artery hypertension. Echo views could be identified and measurements including global longitudinal strain were obtained. The paper is not so much about how much information could be extracted but that it is generally feasible. And automated image analysis will continue to evolve and improve. However, the authors believe that echo image acquisition by inexperienced operators could be successfully combined with automated echo reporting, not in keeping with the actual study protocol. The paper does underestimate that the acquisition of useful echo images requires technical skill and the incremental benefit of an automated reporting over the technical knowledge of the person acquiring the images might be minimal.

Reference: Circulation 2018;138:1623-35Abstract

Effects of aspirin for primary prevention in persons with diabetes mellitusAuthors: The ASCEND Study Collaborative Group

Summary: This study evaluated the use of aspirin for primary prevention in patients with diabetes. 15,480 adult patients who had diabetes but no evident cardiovascular disease were randomised to receive aspirin 100 mg/day or matching placebo. During a mean follow-up of 7.4 years, serious vascular events (MI, stroke/transient ischaemic attack, or death from any vascular cause, excluding any confirmed intracranial haemorrhage) occurred in 8.5% of aspirin recipients compared with 9.6% of placebo recipients (rate ratio, 0.88; p=0.01). In contrast, major bleeding events occurred in 4.1% and 3.2% of patients in the respective groups (rate ratio, 1.29; p=0.003), with most of the excess being gastrointestinal bleeding and other extracranial bleeding.

Comment: Another contemporary review of aspirin use, here in the potentially more vulnerable group of patients with diabetes and no documented vascular disease. Around 15,000 patients were observed with a follow-up of 7.5 years. Aspirin worked in preventing vascular events (HR, 0.88; p=0.01). However, major bleeding was more common with aspirin (HR, 1.29; p=0.003). There was no effect on cancer or nonvascular outcomes. When just looking at fatal events, aspirin prevented more events than were caused by bleeding. So, what is the net effect for diabetic patients? It will also depend on the overall predicted 5-year risk, so among a number of other trials recently published about aspirin a review of our guidelines might be warranted.

Reference: N Engl J Med 2018;379:1529-39Abstract

Independent Content: The selection of articles and writing of summaries and commentary in this publication is completely independent of the advertisers/sponsors and their products.Privacy Policy: Research Review will record your email details on a secure database and will not release them to anyone without your prior approval. Research Review and you have the right to inspect, update or delete your details at any time.Disclaimer: This publication is not intended as a replacement for regular medical education but to assist in the process. The reviews are a summarised interpretation of the published study and reflect the opinion of the writer rather than those of the research group or scientific journal. It is suggested readers review the full trial data before forming a final conclusion on its merits.Research Review publications are intended for New Zealand health professionals.

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MERRY CHRISTMAS & A HEALTHY, HAPPY 2019!

Independent commentary by Professor Alexander Sasse.Professor Alexander Sasse is Consultant Cardiologist, Director of Cardiac Imaging and Head of the Cardiology Department at Wellington Hospital. His clinical interests include the various modalities of cardiac imaging, structural heart disease, general cardiology and the prevention of stroke. He went to medical school and did his training in Germany (Bonn/Aachen) and has been a Cardiologist since 2004. FOR FULL BIO CLICK HERE

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Real-world clinical utility and impact on clinical decision-making of coronary computed tomography angiography-derived fractional flow reserve: lessons from the ADVANCE RegistryAuthors: Fairbairn T et al.

Summary: This analysis of data from the ADVANCE Registry examined the use of CTCA for non-invasive assessment of patients with stable chest pain in real-world settings. 5083 patients with symptoms of coronary artery disease and atherosclerosis on CCTA were enrolled at 38 international sites in 2015–2017. The impact of a CTCA and CTCA-derived fractional flow reserve (FFRCT) diagnostic pathway on decision-making, downstream invasive coronary angiography (ICA), revascularisation, and major adverse cardiovascular events (MACE) was determined. The primary end-point (reclassification between core lab CTCA alone and CTCA + FFRCT-based management plans) occurred in 66.9% of patients. Non-obstructive coronary artery disease was significantly lower in ICA patients with FFRCT ≤0.80 compared with those with FFRCT >0.80 (OR, 0.19; p<0.001). Overall, 72.3% of patients undergoing ICA with FFRCT ≤0.80 were revascularised. No death/MI occurred within 90 days in patients with FFRCT >0.80, whereas 19 MACE (HR, 19.75; p=0.0008) and 14 death/MI events (HR, 14.68; p=0.039) occurred in patients with FFRCT ≤0.80.

Comment: The angiography data from CTCA can be run through sophisticated computers to analyse the fluid dynamics and generate a fractional flow reserve (FFRCT). This technique has been propagated by a few select centres and data in clinical practice are lacking; especially since the addition of FFRCT to a CTCA incurs significant extra costs which is strangely not mentioned by the authors. This multicentre trial did FFRCT in cases of coronary stenoses in the range of 30–90%; a positive FFRCT was deemed to be a value ≤0.80. The primary end-point was the reclassification rate between CTCA alone vs CTCA and FFRCT-based management plans as determined by the core laboratory. The trial was funded by the company providing the FFRCT calculation. There is much to say about this trial, and the role of CTCA in different health systems, but the authors feel that FFRCT changed the treatment decision in about two-thirds of patients and the general trend was clearly towards more revascularisation and more testing. There is also not much on correlation with invasive FFR, never mind information on outcome. This topic will require more work. If regular CTCA provides appropriate treatment decisions in only one-third of patients I wonder what we have been doing wrong so far and what previous CTCA trials were good for.

Reference: Eur Heart J 2018;39(41):3701-11Abstract

Cardiac auscultation poorly predicts the presence of valvular heart disease in asymptomatic primary care patientsAuthors: Gardezi S et al.

Summary: This study evaluated the accuracy of cardiac auscultation for diagnosing valvular heart disease in asymptomatic primary care patients. 251 patients (aged >65 years) who were undergoing echocardiography also received cardiac auscultation by an experienced general practitioner (GP). Newly detected valvular heart disease was classified as mild (mild regurgitation of any valve or aortic sclerosis) or significant (at least moderate regurgitation or mild stenosis of any valve). Newly identified valvular heart disease was common on echocardiography, with mild disease in 68% of patients and significant disease in 14%. Detection of mild valvular heart disease by GPs was modest overall (sensitivity 32%, specificity 67%) but slightly better for significant valvular heart disease (sensitivity 44%, specificity 69%).

Comment: The presented study tried to assess how many asymptomatic patients over 65 years might have relevant valvular heart disease and how well auscultation works. From a group of 251 patients, 14% had significant valvular heart disease per echo. Cardiologists had a sensitivity to hear significant murmur of 31%, though specificity was 81%. GPs were not much different. While the authors are cautious in their interpretation, they do come to the conclusion that auscultation did not provide useful discriminative information for the diagnosis of valvular heart disease in an asymptomatic elderly population. There are at least two problems here: how do we find patients with relevant heart disease if auscultation does not work, and if auscultation is so imprecise what is the threshold for echo referral?

Reference: Heart 2018;104:1832-35Abstract

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Neurological complications after transcatheter versus surgical aortic valve replacement in intermediate-risk patientsAuthors: Durko A et al.

Summary: This analysis of data from the SURTAVI trial compared neurological complications after TAVI versus SAVR in intermediate-risk patients. Patients with severe, symptomatic aortic stenosis at intermediate surgical risk were randomised to undergo TAVI or SAVR and were evaluated for neurological events and quality of life at 30 days, 6 months, and 12 months post-procedure. The rates of 30-day stroke (5.4% vs 3.3%; p≤0.031) and post-procedural encephalopathy (7.8% vs 1.6%; p<0.001) were higher after SAVR than TAVI, but the 12-month rate of stroke did not differ significantly between groups. Quality of life after an early stroke was significantly lower in SAVR than TAVI patients at 30 days but was similar at 6 and 12 months.

Comment: Increasing experience of heart teams and improvements of TAVI systems have improved mortality and periprocedural complications. SURTAVI trial data were evaluated for neurological complications, with a focus on stroke but also delirium and encephalopathy in quite a rigorous and systematic way. Despite using older generation devices in this trial, the outcome clearly favoured TAVI over SAVR in all of the neurological outcomes. Often under-represented but quite relevant for patients was that encephalopathy was more frequent after SAVR than after TAVR (7.8% vs 1.6%; p<0.001). These were to a large proportion intermediate-risk patients, highlighting that it is not only safe but potentially also beneficial to offer TAVI in this risk group of patients.

Reference: J Am Coll Cardiol 2018;72(18):2109-19Abstract

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