News from ESC 2019

The European Society of Cardiology (ESC) Congress is the world’s largest meeting of cardiovascular professionals. This year, more than 32,000 delegates from over 150 countries attended the Congress, held in conjunction with the World Congress of Cardiology in Paris, France, from 31st August to 4th September 2019. The theme of this year’s Congress was ‘Global cardiovascular health’ as discussed by ESC President, Professor Barbara Casadei (British Heart Foundation Centre of Research Excellence, University of Oxford). A global approach to cardiovascular disease (CVD) prevention is needed now more than ever with, for the first time in decades, an increase in premature CVD mortality rates in Western Europe. Additionally, as 80% of CVD deaths are in lower- and middle-income countries – and this will increase as obesity and diabetes rates soar – global approaches are an urgent priority. Here we provide an overview of key clinical trials and other news from the congress. Authors include Dr Richard Armstrong (Cardiology Research Fellow, St James’s Hospital, Dublin, Ireland), Dr Amar Puttana (Consultant in Diabetes and Endocrinology, Good Hope Hospital, Sutton Coldfield) and members of the BJC team.

Heart failure highlights

PARAGON-HF fails primary end point but benefits for some

Heart failure was a key theme of this year’s congress, accounting for more than 1,000 presentations. In the first hotline session of the Congress, the keenly awaited results from PARAGON-HF (Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction) were presented.¹

Up to 64 million people worldwide have heart failure, and that number is rising as the population ages. Evidence-based treatment has focused on about half of these patients who have heart failure with reduced ejection fraction (<40%). Heart failure with preserved ejection fraction (HFpEF), however, has been largely neglected and therefore represents a huge unmet clinical need. This group was studied in PARAGON-HF.

This study found that treatment of adult patients with HFpEF with the angiotensin-neprilysin inhibitor sacubitril/valsartan did not significantly impact the primary end point – a composite of total hospitalisation for heart failure and cardiovascular death. However, the data suggest there may be benefit in some patient groups, such as women and patients with an ejection fraction below the median.

PARAGON-HF was designed to test the hypothesis that sacubitril/valsartan would improve outcomes in HFpEF. A total of 4,822 patients were randomly assigned to sacubitril/valsartan or valsartan alone. The comparator was valsartan because most HFpEF patients already take a renin-angiotensin system inhibitor. Patients were required to have signs and symptoms of heart failure, a left ventricular ejection fraction ≥45%, evidence of natriuretic peptide elevation, and structural heart disease. Patients were followed up for a median of 34 months.

There were 894 primary events in the 536 patients in the sacubitril/valsartan group and 1,009 primary events in the 557 in the valsartan group (rate ratio 0.87, 95% confidence interval [CI] 0.75-1.01) driven by a decline in heart failure hospitalisation with no effect on cardiovascular death or all-cause mortality. There was heterogeneity in the population with respect to treatment response. In particular, there was greater benefit in patients with ejection fraction less than the median of 57%, with a 22% reduction in the primary end point, and in women, with a 28% reduction in the primary end point.

“Our data suggest that there may be differential benefit, with some patients, including those in the lower range of ejection fraction and women responding to a greater degree than others,” said co-principal investigator Professor Scott D Solomon (Brigham and Women’s Hospital, Harvard Medical School, Boston, USA). “We’ve known for some time that patients with this disorder have different characteristics and aetiologies. The PARAGON-HF results suggest that the impact of treatment may also vary.”

“The potential differential benefit in women is intriguing as women make up a much greater proportion of patients with HFpEF compared to HFrEF. Further analyses will explore these subgroup findings in detail to determine which patients with heart failure across a broad range of ejection fraction might benefit the most from sacubitril/valsartan,” he concluded.

Adding to this, Professor Gabriel Philippe Steg (Hôpital Bichat Assistance Publique, Paris, France) commented: “PARAGON-HF represents a very important development for the heart failure field as the patients enrolled are largely representative of those seen in routine practice.”

DAPA-HF: reductions in death and heart failure mortality

The sodium-glucose cotransporter-2 (SGLT2) inhibitor dapagliflozin reduced death and hospitalisations in patients with HFrEF, both with and without diabetes, in the DAPA-HF (Dapaglifozin in patients with Heart Failure and Reduced Ejection Fraction) trial, which included patients from 20 countries.² “The most important finding of all is the benefit in patients without diabetes. This is truly a treatment for heart failure and not just a drug for diabetes,” said principal investigator Professor John McMurray (University of Glasgow), presenting the study in the first hotline session of the Congress.

In DAPA-HF, 4,744 patients with heart failure and reduced EF were randomly allocated to dapagliflozin 10 mg once daily, or matching placebo. The primary end point was the composite of a first episode of worsening heart failure (hospitalisation for heart failure or an urgent heart failure visit requiring intravenous therapy) or death from cardiovascular causes.

The allocated treatments were given on top of standard care. Overall, 94% received an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker or angiotensin receptor–neprilysin inhibitor, 96% took a beta-blocker, and 71% took a mineralocorticoid receptor antagonist. Follow up was over a median of 18.2 months.

The primary outcome occurred in 386 of 2,373 (16.3%) patients in the dapagliflozin group and in 502 of 2,371 (21.2%) patients in the placebo group (hazard ratio [HR] 0.74; 95% CI 0.65–0.85; p<0.00001). The components of the primary outcome were also analysed separately. A total of 237 patients (10.0%) in the dapagliflozin group and 326 patients (13.7%) on placebo experienced a first episode of worsening heart failure (HR 0.70; 95% CI 0.59–0.83; p<0.00004) and 227 (9.6%) and 273 (11.5%), respectively, died from cardiovascular causes (HR 0.82; 95% CI 0.69–0.98; p=0.029).

Professor McMurray said: “Adverse events rarely required the discontinuation of treatment. There was no notable excess of any serious adverse event in the dapagliflozin group”. Overall, 178 (7.5%) patients in the dapagliflozin group had an adverse event related to volume depletion versus 162 (6.8%) in the placebo group, with no significant difference between the groups. Additionally, adverse events related to renal dysfunction did not differ between the two groups, occurring in 153 (6.5%) patients in the dapagliflozin group versus 170 (7.2%) patients in the placebo group. Major hypoglycaemia and lower limb amputation and fracture were infrequent and occurred at similar rates in the two treatment groups.

In his concluding remarks, Professor McMurray said: “The clinical implications (of DAPA-HF) are potentially huge – few drugs achieve these results in heart failure. Dapagliflozin achieved these results even when added to excellent standard therapy.”

DAPA-HF – a UK commentary

The results of the DAPA HF trial provide an exciting addition to the SGLT2 inhibitor story. We have known since the EMPA-REG OUTCOME trial (subsequently confirmed with the CANVAS/CANVAS-R and DECLARE trials) that this class has beneficial effects on reducing hospitalisation for heart failure. As a result, questions were asked as to why these medications were not being considered by other specialists dealing with cardiovascular risk management and heart failure. The notion has always been that these are ‘diabetes medications’ with some beneficial cardiovascular effects – the onus would always be on treating glycaemia first with heart failure benefits a secondary outcome.

The DAPA-HF results have potential to change this so that in the future, heart failure may be the first consideration for starting these medications. It must be stressed, however, that SGLT2 inhibitors are currently only licensed in those with type 2 diabetes (and dapagliflozin is also licensed in type 1 diabetes if certain criteria are met), with the heart failure benefits being a valuable side effect to be considered in the right population. DAPA-HF has provided more evidence that these medications need to be considered by all those managing people with type 2 diabetes and heart failure, though, it is important to remember their side effect profile requires careful counselling.

SGLT2 inhibitors remain important medications for glycaemic control but the path has been taken towards the next stage in their evolution. Publication of the full trial results is necessary, however, before further conclusions can be drawn. We should be hearing more from the trial in the future, including specific sub-analyses. Additionally, it would be interesting to assess the subset of patients with borderline diabetes and further follow up to compare development of diabetes in the group who were on treatment versus those who were not. Renal outcomes in this group will certainly form part of further exploratory analyses and may provide further potential which will be assessed in future trials of these medications on preventing renal deterioration in non-diabetic populations.

Amar Puttanna

Diabetes highlights

New diabetes guidelines launched

New ESC guidelines on diabetes, pre-diabetes and cardiovascular disease developed in collaboration with the European Association for the Study of Diabetes (EASD) were published at the start of Congress.³

A key message is that metformin is no longer first-line therapy in patients with diabetes. Instead, the glucagon-like peptide-1 (GLP-1) receptor agonists (liraglutide, semaglutide, or dulaglutide) and the SGLT2 inhibitors (empagliflozin, canagliflozin, or dapagliflozin) are now recommended in type 2 diabetes patients with established CVD or at high/very high risk of CVD. SGLT2 inhibitors are also recommended to lower the risk of heart failure hospitalisation. Metformin should, however, be considered in overweight patients with type 2 diabetes without CVD and at moderate cardiovascular risk.

The new diabetes guidelines also stress the importance of lifestyle intervention to avoid or delay the conversion of pre-diabetes states, but emphasise that moderate alcohol intake should not be promoted as a means to protect against CVD.

Although statins are the primary lipid lowering therapy for prevention of CVD, treatment is not recommended in women with diabetes of childbearing potential and should be used with caution in young people, due to limited evidence of benefit in these groups. Lipid goals also align with those in the new 2019 ESC/European Atherosclerosis Society (EAS) Dyslipidaemia Guidelines⁴ (see below).

Anticoagulation/antiplatelet highlights

THEMIS: ticagrelor plus aspirin reduce ischaemic events but increase bleeds

The combination of ticagrelor and aspirin reduced ischaemic events compared with aspirin alone in patients with stable coronary artery disease (CAD) and diabetes but at the cost of increased major bleeding. This was the key finding from the THEMIS (Ticagrelor in Patients with Stable Coronary Disease and Diabetes) trial.⁵

Ticagrelor protects against cardiovascular events when added to aspirin in patients with an acute coronary syndrome (ACS) and those with a history of prior myocardial infarction (MI), but it unknown whether there is benefit when added to aspirin in patients with diabetes and stable CAD without a history of prior MI or stroke. This was tested in the THEMIS trial.

The study enrolled 19,220 patients across 42 countries in North America, South America, Asia, Africa, Australia, and Europe. Patients were aged ≥50 years, had type 2 diabetes, and stable CAD (defined as a history of percutaneous coronary intervention [PCI], bypass grafting, or angiographic stenosis of ≥50% in at least one coronary artery). Patients with known prior MI or stroke were excluded. Patients were randomised to ticagrelor or placebo, on top of aspirin. The primary efficacy outcome was the composite of cardiovascular death, MI, or stroke. The primary safety outcome was Thrombolysis in Myocardial Infarction (TIMI) major bleeding.

With a median follow-up of 39.9 months, the incidence of the primary efficacy outcome was lower in the ticagrelor group than in the placebo group (7.7% vs. 8.5%; HR 0.90; 95% CI 0.81–0.99; p = 0.038). The incidence of TIMI major bleeding was higher in the ticagrelor group than the placebo group (2.2% vs. 1.0%; HR 2.32; 95% CI 1.82–2.94; p<0.001). There was also an excess of intracranial haemorrhage in the ticagrelor group (0.7% vs. 0.5%; HR 1.71; 95% CI, 1.18–2.48; p = 0.005).

Presenting the study in a hotline session at the Congress, Professor Deepak L Bhatt (Brigham and Women’s Hospital and Harvard Medical School, Boston, USA) said: “In the overall population studied in THEMIS, the reduction in important ischaemic events was somewhat counterbalanced by the increase in bleeding. Therefore, there was no net benefit from the addition of ticagrelor. It may, however, provide benefit in selective patients at low risk of bleeding and high-risk ischaemic events; the question is how to identify these patients?”.

THEMIS PCI

THEMIS-PCI was a pre-specified subgroup analysis of the main THEMIS trial,⁶ which aimed to identify patients with the best balance of benefit versus bleeding risk from ticagrelor. This analysis included 11,154 patients with a history of previous PCI. The results, presented by Professor Gabriel Philippe Steg, showed that the addition of ticagrelor provided a favourable net clinical benefit (9.3% vs. 11.0%: p=0.005), although at the cost of increased major bleeding, compared with patients without prior PCI where it did not. Within the PCI subgroup, those who had a stent derived greater benefit.

In concluding remarks, Professor Bhatt commented: “In patients with diabetes and stable coronary artery disease with a history of previous coronary artery stenting, who have tolerated dual antiplatelet therapy previously without any bleeding, prolonged therapy with ticagrelor and aspirin provides substantial gains in reducing the full spectrum of coronary, cerebral, and peripheral ischaemic events. Patients with diabetes and a history of PCI who have tolerated antiplatelet therapy, have high ischaemic risk, and low bleeding risk, may derive the most benefit.”

ISAR-REACT 5: prasugrel superior to ticagrelor in ACS

Prasugrel is superior to ticagrelor for reducing ischaemic events in patients with ACS and a planned invasive strategy, according to results of ISAR-REACT 5 (Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes), another study selected for presentation during a hotline session.⁷

While both prasugrel and ticagrelor are recommended for treatment within the first year of an ACS, the relative merits of each strategy in ACS patients is not known. The ISAR-REACT 5 trial tested the hypothesis that ticagrelor is superior to prasugrel in reducing the primary composite end point of death, MI, or stroke within 12 months in ACS patients intended for an invasive strategy. A total of 4,018 patients were enrolled from 23 centres in Germany and Italy and randomly allocated to prasugrel or ticagrelor.

At 12 months, the primary composite end point occurred in 9.3% of patients in the ticagrelor group versus 6.9% in the prasugrel group (HR 1.36; 95% CI 1.09–1.70; p = 0.006). The increased anti-ischaemic efficacy of prasugrel was not accompanied by an increased bleeding risk. Bleeding (BARC class 3 to 5) was observed in 5.4% of patients in the ticagrelor group and 4.8% of patients in the prasugrel group (HR 1.1; 95% CI 0.8–1.5; p = 0.46).

Commenting, principal investigator Professor Stefanie Schuepke (German Heart Centre Munich, Germany) said: “The results of this investigator-initiated, multicentre, randomised clinical trial support a prasugrel based strategy – without routine pretreatment in NSTE-ACS – as the first line antiplatelet therapy for ACS patients”.

AFIRE: NOAC monotherapy versus combination in CAD patients with AF

Findings from the AFIRE study presented in the same hotline session,⁸ show that monotherapy with the non-vitamin K oral anticoagulant (NOAC), rivaroxaban, is non-inferior to combination therapy in patients with atrial fibrillation (AF) and stable CAD, either not requiring intervention or more than one year after revascularisation.

Around 20% to 30% of AF patients also have CAD. Current ESC guidelines recommend the combination of oral anticoagulant and antiplatelet therapy in the first 12 months after revascularisation in these patients. Beyond 12 months, however, there is a lack of evidence-based clarity; guidelines recommend monotherapy with an oral anticoagulant but a substantial number of patients continue to be treated with combination therapy.

The AFIRE (AF and Ischaemic Events with Rivaroxaban in Patients with Stable CAD) study investigated whether rivaroxaban monotherapy was noninferior to combination therapy (rivaroxaban plus an antiplatelet agent) in patients with AF and stable CAD not requiring PCI or more than one year after PCI or coronary artery bypass grafting. A total of 2,236 patients from 294 centres in Japan were randomly assigned to rivaroxaban monotherapy or combination therapy (rivaroxaban plus an antiplatelet). The primary efficacy end point was stroke, systemic embolism, MI, unstable angina requiring revascularisation, and all-cause mortality. The primary safety end point was major bleeding according to the International Society on Thrombosis and Haemostasis criteria.

Due to higher rates of all-cause mortality in the dual therapy arm, the independent data and safety monitoring committee recommended early termination of the study in July 2018 after a median follow-up of 24.1 months. In the modified intention-to-treat population, the primary end point occurred in 89 (4.14%) patients on monotherapy and 121 (5.75%) patients on combination therapy, (HR 0.72; 95% CI 0.55–0.95; p<0.001 for noninferiority). In the assessment for superiority for the primary efficacy endpoint, which was not prespecified, the p value was 0.0188.

Safety analysis showed that the incidence of the primary safety end point was significantly lower in the monotherapy arm versus the combination therapy arm (1.62% vs. 2.76% per year; HR 0.59; 95% CI 0.39–0.89; p=0.0115). All-cause mortality was significantly lower for monotherapy compared with combination therapy (1.85% vs. 3.37%; HR 0.55; 95% CI 0.38–0.81). The occurrence of net adverse clinical events, a composite of all-cause death, MI, stroke, and major bleeding, was also lower in the monotherapy arm than the combination therapy arm (3.90% vs. 6.28% per year).

Principal investigator Dr Satoshi Yasuda (National Cerebral and Cardiovascular Centre, Suita, Japan) commented: “These data support the guideline recommendation to use oral anticoagulant monotherapy in patients with AF and stable CAD. However, as the study was stopped early because of higher rates of all-cause mortality in the dual therapy arm, caution is needed when interpreting the results”.

Angina highlights

Chronic coronary syndromes – new guidelines and a new name

In 2018, the ESC redefined what was previously described as stable coronary artery disease to chronic coronary syndromes (CCS). Coronary artery atherosclerosis is a dynamic condition, that can be significantly impacted by lifestyle factors, revascularisation and pharmacological therapy, and this dynamic process would best not be described using the term “stable” according to the guideline authors. Additionally, the change in nomenclature allows CCS to be seen on the same spectrum as acute coronary syndromes – as the two pathologies are significantly related.

At this year’s Congress, the ESC launched a new guideline document⁹ incorporating this new naming scheme to delineate the best pathway for diagnosis and management of this condition.

The spectrum of CCS is extremely varied, and the guideline document attempted to divide CCS into six clinical subsets:

1. suspected coronary artery disease with stable angina symptoms +/- dyspnoea
2. suspected coronary artery disease with new onset heart failure symptoms of left ventricular systolic dysfunction
3. asymptomatic or stable symptomatic patients within one year of acute coronary syndrome or coronary revascularisation
4. asymptomatic or symptomatic more than one year after initial diagnosis or revascularisation
5. angina with suspected vasopastic or microvascular disease
6. asymptomatic coronary artery disease detected at screening.

The guideline continues to strongly encourage lifestyle changes in the management of CCS. Healthy dietary changes, regular exercise and smoking cessation are all incorporated, as they can significantly impact outcomes even in the presence of advanced coronary artery disease.

New to the guidelines include:

• a class IIa recommendation for additional antithrombotic therapy for patients at high risk of ischaemia (with a low risk of bleeding) regardless of the presence of AF
• a class IIb recommendation for patients at moderate ischaemic risk, again if bleeding risk is low
• new recommendations for the timing of triple therapy post-PCI for patients who require oral anticoagulation.

Non-invasive diagnostic tests, such as coronary CT angiography, continue to be strongly recommended, with invasive angiography limited to patients at very high clinical likelihood, severe symptoms refractory to medical therapy, or typical angina at low workload. Invasive physiological assessment of lesion severity prior to intervention is recommended unless the lesion in question is very high grade (>90% stenosis).

The guidelines for medical therapy for angina have also been altered. Beta blockers or non-dihydropyridine calcium channel blockers remain first-line therapy, while long-acting nitrates are second line. If symptoms remain poorly controlled despite addition of nitrates, nicorandil, ranolazine, ivabradine or trimetazidine are recommended. New to the guidelines is the IIb recommendation for combination therapy of beta blocker or calcium channel blocker, with second-line drugs as an initial treatment strategy (according to heart rate, blood pressure and tolerance).

Controversially, the ORBITA study was effectively sidelined by the guideline authors, with the document suggesting that the limited trial size, short term observation time until crossover and insufficient power prevent the use of ORBITA data to inform guidelines. This purposeful omission of a much debated trial is controversial in itself, given that as a randomised control trial it demonstrated how effective optimal medical therapy can be in a selected patient population. This will undoubtedly spur further debate in the future.

Richard Armstrong

Clarifying the significance of CLARIFY

A further five-year update on the important CLARIFY (Prospective Observational Longitudinal Registry of Patients with CAD) registry¹⁰ was given during a hotline session. This registry is following 32,703 patients in 394 centres in 45 countries with stable CAD, assessing their risk for further events.

At five years, the primary outcome – defined as the composite of cardiovascular death or MI –was observed in 8.0% of the cohort. A significant discriminating factor was seen in the group with previous MI, as residual ongoing angina was seen to increase the rate of the primary outcome. In patients with previous MI and ongoing angina, the primary outcome was observed in 11.8% compared to 8.2% in those without angina. In patients without previous MI, rates were much lower regardless of the presence of anginal symptoms, with the primary outcome observed in 6.3% of patients with angina and 6.4% in those without angina.

Despite most patients being observed to have been offered therapy for blood pressure and cholesterol management, the recommended targets were missed in the majority of patients. Only 29% of patients met the target blood pressure of <130/80mmHg, and only 20.9% met the low-density lipoprotein cholesterol (LDL-C) target of <1.8mmol/L. Only 7.4% of patients observed had blood pressure and cholesterol within the targets of therapy.

CLARIFY has shed some light on how the diagnosis of stable CAD can impact outcome. It has been taken as a given that previous MI would predispose to a greater risk, but now with the added evidence that residual angina increases risk further, this may allow more intensive management of a higher risk cohort. The news that targets for blood pressure and cholesterol are not being met should encourage practice to push for greater control of these risk factors, particularly in the higher risk group which we have now observed.

The main learning points observed from CLARIFY are:

• previous MI leads to higher risk, and residual angina leads to higher risk again.
• blood pressure and cholesterol targets for secondary prevention are not being met and should be more aggressively treated.

Richard Armstrong

Revascularisation highlights

COMPLETE: full revascularisation better than only targeting the culprit lesion

In patients with ST-elevation MI (STEMI), opening the culprit artery with PCI reduces cardiovascular death or MI. As many patients also have multivessel CAD, it is uncertain whether additional PCI of non-culprit lesions provides further benefit. The COMPLETE (Complete Revascularisation with Multivessel PCI for MI) trial,¹¹ which was designed to address this evidence gap, showed that complete revascularisation reduced major cardiovascular events compared to culprit-lesion only PCI.

The trial enrolled 4,041 patients with STEMI and multivessel CAD from 140 centres in 31 countries. Patients were randomly allocated to complete revascularisation with additional PCI of angiographically significant non-culprit lesions (n=2,016), or to no further revascularisation (n=2,025). Randomisation was stratified by the intended timing of non-culprit lesion PCI: either during or after the index hospitalisation. Complete revascularisation was performed irrespective of whether patients had symptoms or not. All patients received guideline-directed medical therapy.

At a median follow-up of three years, the first co-primary outcome – a composite of cardiovascular death or MI – occurred in 158 (7.8%) patients in the complete revascularisation group compared to 213 (10.5%) in the culprit-lesion only group (HR 0.74; 95% CI; 0.60–0.91; p=0.004). The second co-primary outcome, which included ischaemia-driven revascularisation, occurred in 179 (8.9%) patients in the complete revascularisation group compared to 399 (16.7%) in the culprit-lesion only group (HR 0.51; 95% CI 0.43–0.61; p<0.001). There were no significant differences between groups with respect to the occurrence of stroke (p=0.27) or major bleeding (p=0.15), or with respect to other safety outcomes including acute kidney injury and NYHA class IV heart failure.

Presenting the findings in a Congress hotline sessions, principal investigator Professor Shamir R. Mehta (Population Health Research Institute, McMaster University, Hamilton, Canada) said: “COMPLETE is the first randomised trial to definitively show that complete revascularisation reduces hard cardiovascular events compared to culprit-lesion only PCI in patients with STEMI and multivessel coronary artery disease”.

The benefits emerged over the long term and were observed regardless of whether non-culprit lesion PCI was performed early, during the initial hospitalisation, or shortly after hospital discharge.

“These findings are likely to have a large impact on clinical practice and prevent many thousands of recurrent heart attacks globally every year,” he concluded.

SYNTAX: CABG versus PCI at ten years

Late-breaking results from the SYNTAX Extended Survival study¹² presented at the Congress, show 10-year survival rates are similar for coronary artery bypass graft (CABG) surgery and PCI with drug-eluting stents, in randomised patients with de novo three-vessel and left main CAD. Pre-specified subgroup analyses also showed that surgery provided a survival benefit in patients with three-vessel disease and more complex CAD, while no treatment differences were found in patients with left main disease.

The SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) trial was a non-inferiority trial that compared PCI using first-generation paclitaxel-eluting stents with CABG in patients with de novo three-vessel and left main CAD. Results were previously reported up to five years,¹³ with the latest presentation reporting 10-year all-cause mortality results.

In the SYNTAX study, 1,800 patients were randomly assigned to PCI (n=903) or CABG (n=897). At 10 years, 244 (27%) patients had died after PCI compared to 211 (24%) after CABG (HR 1.17; 95% CI 0.97–1.41; p=0.092). Among patients with three-vessel disease, 151 (28%) of 546 had died after PCI versus 113 (21%) of 549 after CABG (HR 1.41; 95% CI 1.10–1.80). Among patients with left main CAD, 93 (26%) of 357 had died after PCI versus 98 (28%) of 348 after CABG (HR 0.90; CI 0.68–1.20; p interaction=0.019). There was no treatment-by-subgroup interaction with diabetes.

While no significant differences in all-cause death emerged between PCI and CABG at 10 years, nonetheless CABG provided a significant survival benefit over PCI in patients with three-vessel disease, whereas no treatment differences were identified in patients with left main CAD. On this basis, the trial authors suggest that the decision to opt for PCI or CABG in patients with three-vessel disease or left main CAD should be decided by a multidisciplinary heart team that takes into consideration the presence or absence of mortality differences in patient subgroups. In addition, the overall coronary lesion complexity (e.g. SYNTAX score) and other cardiovascular risk factors of an individual patient, such as diabetes and additional comorbidities, together with a patient’s preference, should be included in the discussion.

First author Dr Daniel Thuijs (Erasmus University Medical Centre, Rotterdam, The Netherlands) concluded: “The SYNTAX Extended Survival study presents robust, clinically relevant, and complete 10-year randomised survival data and can aid a multidisciplinary heart team discussion in the process of deciding on the optimal treatment strategy for a patient with coronary artery disease requiring revascularisation”.

Lipids and lifestyle highlights

New ESC/EAS Dyslipidaemia Guidelines: lower LDL-C is better

In the three years since the 2016 ESC/EAS Dyslipidaemia Guidelines,¹⁴ two landmark studies with proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody therapy have reported: FOURIER with evolocumab in patients with stable CVD¹⁵ and ODYSSEY OUTCOMES with alirocumab in patients with ACS.¹⁶ Both definitively showed that lowering LDL C beyond current goals achieved with statin therapy (± ezetimibe) provided further reduction in cardiovascular events. Moreover, it was evident that there was no LDL C threshold value for clinical benefit.¹⁷

Based on these findings, LDL-C goals have been lowered in patients at high and very high risk of cardiovascular events. In the very high risk group (including those with CVD, and diabetes with target organ damage), the LDL-C goal is now <1.4 mmol/L (<55 mg/dL), and in patients at high risk, the LDL-C goal is <1.8 mmol/L (<70 mg/dL). In addition, the guidelines recommend that patients should also attain at least 50% reduction from baseline LDL-C levels. There is also recognition of the high cardiovascular risk associated with familial hypercholesterolaemia (FH), with individuals with FH and CVD or another risk factor regarded as being at very high risk.

According to Professor Francois Mach, Chairperson of the ESC/EAS Task Force (Geneva University Hospital, Switzerland), “LDL cholesterol levels should be lowered as much as possible, especially in high and very high-risk patients”.

Lipoprotein(a) also receives renewed emphasis with the guidelines recommending measurement at least once in all adults.

PURE: cancer overtaking CVD as the major cause of death in high-income countries

Insights from the ongoing PURE (ProspUrban Rural Epidemiology) Study, a prospective, population-based cohort study involving over 200,000 adults (35–70 years) from 27 countries, provided much food for thought. While CVD is the biggest killer globally, accounting for 40% of all deaths, cancer is now overtaking CVD as the major cause of death in higher income countries.¹⁸ In these countries, death from cancer was twice that from CVD. In contrast, among lower income countries, CVD remains the major cause of death, three-fold higher that that from cancer.

“These data suggest a transition in the major cause of non-communicable disease death as countries gain in wealth, which probably relates to improved access to healthcare and strategies to prevent and treat CVD in high-income countries,” said Dr Gilles Dagenais (Quebec Heart and Lung Institute, Canada).

Additional data from PURE, presented during a hotline session, show that nearly seven in 10 cases of CVD can be explained by modifiable risk factors.¹⁹ These not only include the usual suspects, such as high blood pressure, dyslipidaemia, smoking, diabetes, abdominal obesity, and lifestyle factors (poor diet and lack of physical activity), but also low education, depression, and air pollution. Importantly, low education status was the single largest risk factor for all-cause death.

Other ESC 2019 highlights

• ORION-11: this phase 3 trial of a new PCSK9 inhibitor inclisiran, injected twice a year, reduced LDL-C by 50% (time-averaged value) at 18 months in patients with CVD or risk equivalents and elevated LDL-C despite maximally tolerated statin therapy. The safety profile was also favourable.²⁰
• Pollution and winter are linked with an increase in angioplasty procedures for ACS, according to this report from Poland.²¹
• Men but not women who live alone have difficulties using warfarin, according to this report from Denmark.²²
• First reliable evidence of a link between major cardiovascular risk factors, i.e. cholesterol, blood pressure, body mass index and smoking in childhood/adolescence and CVD in adult life, according to this report from the International Childhood Cardiovascular Cohort (i3C) Consortium, University of Oxford.²³
• Infectious triggers may play a direct role in plaque destabilisation. Retention of pro-inflammatory bacteria in the plaque could provoke an inflammatory response and plaque rupture, according to this report from Italy.²⁴
• Aspirin should not be recommended for healthy people over 70, according to this report from the ASPREE trial, at Curtin University, Perth, Australia.²⁵
• Home-based and personalised education reduces hospitalisation in AF patients, according to late breaking results from the HELP-AF study, conducted by the University of Adelaide, Australia.²⁶
• Nearly one-third of patients with an implantable cardioverter defibrillator resume driving despite it being medically contraindicated, according to this report from Denmark.²⁷
• Statins are linked with reduced mortality in patients with peripheral arterial disease, even when started late after diagnosis, according to this report from Bern University Hospital, Switzerland.²⁸
• Influenza vaccination in hypertensive patients is associated with an 18% reduced risk of death during flu season, according to this report from Denmark.²⁹
• A community-based salt substitution (containing 75% sodium and 25% potassium) programme in Peru lowered blood pressure and cut new cases of hypertension.³⁰

References

1. Solomon SD, McMurray JJV, Anand IS, et al. Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med. 2019 (published online 1st September 2019). https://doi.org/10.1056/NEJMoa1908655
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