A round-up of some of the most topical research presented at this year’s ESC

Cardiovascular disease is biggest killer globally but cancer overtakes in some countries

Cardiovascular disease remains the main cause of death globally, but cancer has overtaken it to become the leading cause of death in some high-income and upper-middle-income countries, according to the late-breaking results from the PURE study, which were presented in a Hot Line Session at ESC Congress 2019, together with the World Congress of Cardiology.

The PURE study was conducted in 21 countries (four high-income (HIC), 12 middle-income (MIC), and five-low-income (LIC)) and included urban and rural sites across five continents. Households were selected to broadly represent the sociodemographic composition of their community. This analysis included 162,534 community-dwelling adults aged 35-to-70 years. Participants were contacted at least every three years to ascertain their vital status and the occurrence of incident diseases and hospitalisations. Participants were followed for nearly 10 years.

Overall mortality was highest in LIC, intermediate in MIC, and lowest in HIC. This pattern was observed for all common causes of death except cancer, where the mortality rates in LIC, MIC, and HIC were similar.

Cardiovascular disease was the most common cause of death overall. But in HIC, cancer deaths occurred twice as often as cardiovascular deaths. In contrast, in LIC, cardiovascular deaths were three times more frequent than cancer deaths, with MIC being in between HIC and LIC. Put another way, the ratio of cardiovascular deaths to cancer deaths was 0.4 in HIC, 1.3 in MIC, and 3.0 in LIC.

“This epidemiologic transition may be partly due to improved strategies to prevent and treat cardiovascular disease in high-income countries,” said co-primary author Dr Gilles Dagenais of the Quebec Heart and Lung Institute, Canada. “Alongside this, apart from tobacco control, effective strategies to prevent and treat cancer have yet to yield large reductions in the incidence of most cancers or deaths from common cancers as it was documented for cardiovascular disease. While very recent advances in cancer treatment will be expected to ultimately deliver impactful improvements in cancer survival, this will require improved access and wider use of such treatments.”

Participants in HIC with cardiovascular disease were less likely to die from their disease compared to MIC and LIC. This paralleled the higher rates of medication use and hospitalisation for cardiovascular disease in HIC.

Prof Salim Yusuf, senior author of the study and Principal Investigator of PURE, said: “The high rates of cardiovascular disease and related mortality in low-income countries are likely related to gaps in access to, or availability of, healthcare. This was shown by the lower use of preventive medications and less frequent hospitalisation for cardiovascular disease. Improving access to quality healthcare is key to reducing deaths from cardiovascular and other diseases in low- and middle-income countries.”

He concluded: “As cardiovascular disease declines in many countries, cancer mortality is likely to become the leading cause of death in the future.”

The ESC Congress 2019 was held this year with the World Congress of Cardiology. More than 33,000 health professionals gathered over five days to attend more than 600 expert sessions covering the entire spectrum of cardiovascular medicine.

Complete revascularisation is superior to culprit-lesion only intervention

An international randomised trial, COMPLETE, has shown that complete revascularisation reduces major cardiovascular events compared to culprit-lesion only percutaneous coronary intervention (PCI). Late-breaking results of the trial were presented in a Hot Line Session at ESC Congress 2019 together with the World Congress of Cardiology and published in the New England Journal of Medicine.

Up to 50 per cent of patients with ST-segment elevation myocardial infarction (STEMI) have multi-vessel coronary artery disease. In STEMI patients, opening the culprit artery with PCI reduces cardiovascular death or myocardial infarction. It is unclear whether additional PCI of non-culprit lesions also prevents these events.

“The question of whether to routinely revascularise non-culprit lesions or manage them conservatively with guideline-directed medical therapy alone is a common dilemma,” said principal investigator Prof Shamir R Mehta of the Population Health Research Institute, McMaster University, Hamilton, Canada.

Observational studies suggest a reduction in clinical events with staged, non-culprit lesion PCI, but are limited by selection bias and confounding. Prior randomised trials found declines in composite outcomes with non-culprit lesion PCI but were not powered to detect improvements in hard, irreversible clinical outcomes, such as cardiovascular death or new myocardial infarction. While meta-analyses indicate a decline in cardiovascular death or myocardial infarction with non-culprit lesion PCI, there has been no single, large trial showing benefit on this clinically important outcome. The COMPLETE trial was designed to address this evidence gap.

A total of 4,041 patients with STEMI and multi-vessel coronary artery disease were enrolled from 140 centres in 31 countries. Patients were randomly allocated to complete revascularisation with additional PCI of angiographically significant non-culprit lesions, or to no further revascularisation. Randomisation was stratified by the intended timing of non-culprit lesion PCI, either during or after the index hospitalisation.

The first co-primary outcome was the composite of cardiovascular death or myocardial infarction; the second co-primary outcome also included ischaemia-driven revascularisation.

At a median follow-up of three years, the first co-primary outcome of cardiovascular death or myocardial infarction occurred in 158 patients (7.8 per cent) in the complete revascularisation group compared to 213 (10.5 per cent) in the culprit-lesion-only group (hazard ratio [HR] 0.74; 95 per cent CI 0.60–0.91; p=0.004).

The second co-primary outcome of cardiovascular death, myocardial infarction, or ischaemia-driven revascularisation occurred in 179 patients (8.9 per cent) in the complete revascularisation group compared to 399 (16.7 per cent) in the culprit-lesion-only group (HR 0.51; 95 per cent CI 0.43–0.61; p<0.001).

There were no significant differences between groups in the occurrence of stroke (p=0.27) or major bleeding (p=0.15).

Regarding the timing of non-culprit lesion PCI, complete revascularisation consistently reduced the first co-primary outcome in those stratified to receive non-culprit lesion PCI during the index hospitalisation (HR 0.77; 95 per cent CI 0.59–1.00) and after hospital discharge (HR 0.69; 95 per cent CI 0.49–0.97; interaction p=0.62).

Prof Mehta said: “COMPLETE is the first randomised trial to show that complete revascularisation reduces hard cardiovascular events compared to culprit-lesion-only PCI in patients with STEMI and multi-vessel 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.”

Most cardiovascular events and deaths are explained by risk factors

Nearly seven-in-10 cases of cardiovascular disease can be explained by modifiable risk factors such as high blood pressure, low education, smoking, dyslipidaemia, poor diet, abdominal obesity, strength and physical activity, diabetes, depression, and air pollution.

The late-breaking results from the 21-country PURE study were presented in a Hot Line Session at ESC Congress 2019 together with the World Congress of Cardiology and published in The Lancet. The study also found that low education was the largest risk factor for death.

The study enrolled 155,137 community-dwelling adults aged 35-to-70 without prior cardiovascular disease from high-, middle-, or low-income countries across five continents.

The researchers examined associations of 14 potentially modifiable risk factors with mortality and major cardiovascular disease (cardiovascular death, myocardial infarction, stroke, or heart failure) over a 10-year period.

The 14 risk factors were hypertension, abdominal obesity, primary education level or less, tobacco use, dyslipidaemia, diabetes, household (solid fuel for cooking) and ambient air pollution, low grip strength, low physical activity, poor diet, depression, excessive alcohol, and sodium intake above six grams per day.

The average age of the population was 50 years and 58 per cent were female. The proportions of participants from high-, middle-, and low-income countries were 11 per cent, 66 per cent, and 23 per cent, respectively. During the 9.5 years of follow-up, there were 10,234 deaths and 7,980 cases of major cardiovascular disease, of which 3,559 were heart attacks and 3,557 were strokes.

The 13 individual risk factors accounted for about 70 per cent of cardiovascular disease cases. The greatest contributors were hypertension (25.0 per cent), abdominal obesity (8.4 per cent), low education (8.1 per cent), tobacco (6.8 per cent), and dyslipidaemia (6.5 per cent). Hypertension was a larger risk factor for stroke than myocardial infarction. Additionally, ambient air pollution (a community exposure) added to the risk of cardiovascular disease.

The 13 modifiable risk factors accounted for 72 per cent of deaths, with the largest contributors being low education (16.0 per cent), smoking (11.0 per cent), hypertension (10.9 per cent), household pollution (8.4 per cent), poor diet (7.9 per cent), and low grip strength (7.6 per cent).

“The impact of low strength, low education and air pollution on mortality is not widely appreciated,” said Principal Investigator Prof Salim Yusuf of the Population Health Research Institute, McMaster University, Hamilton, Canada. “Associations with outcomes were generally similar for most risk factors in high-, middle-, and low-income countries. However, the contribution of some risk factors to cardiovascular disease and death varied according to how common they were in that country — for example smoking, obesity, education, and indoor air pollution from cooking with solid fuel.”

Prof Yusuf noted that high sodium intake contributed only modestly to major cardiovascular disease or death. “Our salt results are completely consistent with the majority of large studies examining associations between sodium intake and cardiovascular disease or death, and do not support the widely-held negative view that even a little salt is harmful. Only really high salt consumption, ie, more than 6g a day, has an adverse effect.

“Further, the dietary components that were protective included those that are commonly recognised, such as more fruits and vegetables, but also moderate consumption of nuts, dairy and unprocessed red meats. This means we need to rethink what constitutes a healthy or unhealthy diet,” he said.

ICD use linked with lower mortality in heart failure

Implantable cardioverter-defibrillator (ICD) use is associated with reduced short- and long-term mortality in patients with heart failure, according to late-breaking research presented in a Hot Line Session at the ESC Congress 2019 together with the World Congress of Cardiology and published in Circulation.

ESC guidelines recommend an ICD for primary prevention in symptomatic patients with heart failure with reduced ejection fraction (HFrEF), provided they are expected to survive substantially longer than one year with good functional status.

Principal investigator Dr Benedikt Schrage of the Karolinska Institutet in Stockholm, Sweden, said: “Most randomised trials on ICD use for primary prevention of sudden cardiac death in HFrEF enrolled patients more than 20 years ago. However, characteristics and management of HFrEF have substantially changed since then and it is not known whether ICD improves outcome on top of contemporary treatments. Furthermore, it is unclear whether ICD use is equally beneficial in subgroups such as both women and men or older and younger patients.”

This study investigated the association between ICD use and all-cause mortality in a contemporary HFrEF cohort with a focus on subgroups. The study population was compiled from patients in the Swedish Heart Failure Registry (SwedeHF) fulfilling ESC criteria for primary prevention ICD use. Propensity score matching was used to account for differences at baseline.

Of 16,702 eligible patients in SwedeHF, 1,599 (9.6 per cent) had an ICD.

The propensity-matched population consisted of 1,296 ICD users and 1,296 patients without an ICD. The researchers found that ICD use was associated with a 26 per cent relative reduction in the risk of all-cause mortality at one year and a 13 per cent relative reduction in the risk of all-cause mortality at five years. The five-year absolute risk reduction with ICD use was 3.1 per cent, leading to 33 patients needing to be treated to prevent one death in five years.

The short-term and long-term mortality benefit was consistent across subgroups, such as patients with or without ischaemic heart disease, males and females, patients under 75 and 75 and older, those enrolled earlier versus later in SwedeHF and thus receiving less or more contemporary treatment, and also for patients with or without cardiac resynchronisation therapy.

Dr Schrage said: “The study found that primary prevention ICD was associated with reduced short-term and long-term all-cause mortality in HFrEF overall and in several subgroups. Our findings support the current recommendations and call for better implementation of ICD use in clinical practice.”

Heart failure patients have similar odds of dementia-type brain lesions as stroke patients

A type of brain damage linked with dementia and cognitive impairment is as common in heart failure patients as it is in patients with a history of stroke, according to findings from the LIFE-Adult-Study presented at the ESC Congress 2019 together with the World Congress of Cardiology.

The probability of this damage, called white matter lesions (WML), was also linked to the duration of heart failure. Patients with a long-standing diagnosis had more WML compared to those more recently diagnosed.

“Up to 50 per cent of older patients with heart failure have cognitive impairment and heart failure is associated with an increased risk for dementia,” said study author Dr Tina Stegmann of Leipzig University Hospital, Germany. “However, it is still unclear what the pathological pathways are. Some investigators have identified changes in brain structure in patients with heart failure and cognitive dysfunction, but the findings are inconsistent.”

LIFE-Adult is a population-based cohort study conducted in Leipzig. Between 2011 and 2014, 10,000 residents aged 18-to-80 were randomly selected for inclusion in the study. Participants underwent assessments such as a physical examination and medical history, during which information on health conditions — including heart failure and stroke — was collected.

This subgroup analysis included the 2,490 participants who additionally underwent MRI of the brain. The purpose of the analysis was to determine the frequency and associated risk factors for WML in a population cohort and potentially discover a connection with heart failure.

Most participants in the subgroup analysis had no or mild WML (87 per cent), and 13 per cent had moderate or severe WML.

There were significant independent associations between WML and age, high blood pressure, stroke and heart failure. Patients with heart failure had a 2.5 greater probability of WML than those without heart failure. Similarly, stroke patients had a two times higher likelihood of WML than those with no stroke history.

The odds of WML increased as the period with heart failure lengthened, from 1.3 for a diagnosis less than three years, to 1.7 for a diagnosis of four-to-six years, and 2.9 for a diagnosis longer than six years.

Dr Stegmann said the connections between heart failure, stroke and WML could be due to shared risk factors, such as age and high blood pressure. In addition, there may be a causal link between heart failure and stroke. It is well known, for instance, that the risk of stroke is higher in patients with heart failure than without.

 “Studies are needed to see if WML could be a therapeutic target for treating cognitive decline in patients with heart failure,” she added.

Dr Stegmann concluded: “After cancer, dementia is the most feared disease by patients. But there is currently no clear indication to screen for WML in heart failure patients using brain MRI.”