Feature | ESC 2019: Global Cardiovascular Health

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The theme of this year's European Society of Cardiology (ESC) Congress was Global Cardiovascular Health, with presentations highlighting differences in prevalence, clinical manifestations, prevention strategies, diagnostic modalities and management of cardiovascular diseases around the world.

Several global studies focused on heart failure (HF) treatments, risk factors and outcomes in diabetic patients. Other important studies examined anticoagulation therapy and the occurrence of cardiovascular events in certain populations.

Heart Failure

Dapagliflozin reduces cardiovascular events in patients with HF and reduced ejection fraction (HFrEF) with and without diabetes, according to late-breaking results of the DAPA-HF trial. "The relative and absolute risk reductions in death and hospitalization were substantial, clinically important and consistent across important subgroups, including patients without diabetes," said principal investigator John J.V. McMurray, MD, FACC.

A total of 4,744 patients with HFrEF received dapagliflozin or placebo added to standard therapy. At a median follow-up of 18.2 months, the risk of cardiovascular death, HF hospitalizations and urgent HF visits was reduced with dapagliflozin (16.3 percent) vs. placebo (21.2 percent; hazard ratio [HR], 0.74; p<0.00001). The primary outcome components were also reduced with dapagliflozin vs. placebo: worsening HF (HR, 0.70; p<0.00004) and cardiovascular death (HR, 0.82; p=0.029). Dapagliflozin was well tolerated, with no significant difference between groups.

"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," McMurray said. "The trial shows that dapagliflozin reduces death and hospitalization, and improves health-related quality of life, in patients with heart failure and reduced ejection fraction, with and without diabetes. The clinical implications are potentially huge – few drugs achieve these results in heart failure and dapagliflozin does even when added to excellent standard therapy," he concluded.

Although the PARAGON-HF trial failed to show a significant benefit of sacubitril-valsartan compared with valsartan alone in patients with HF and preserved EF (HFpEF), promising results were demonstrated in some subgroups. "Sacubitril-valsartan reduced the primary endpoint by 13 percent but this just failed to reach statistical significance, with a p-value of 0.059," presenter Scott D. Solomon, MD, FACC, said.

In the largest randomized trial so far in patients with HFpEF, 4,822 patients with HF and left ventricular ejection fraction (LVEF) ≥45 percent were assigned to receive sacubitril-valsartan or valsartan alone. After a median follow-up of 35 months, death from cardiovascular causes occurred in 8.5 percent of the sacubitril-valsartan group vs. 8.9 percent of the valsartan alone group. Hospitalizations for HF occurred in 690 patients receiving sacubitril-valsartan vs. 797 patients in the valsartan alone group.

"While the overall benefit was just short of statistical significance," said Solomon, "analyses indicated benefits on secondary endpoints, including an increase in the number of patients with NYHA class improvements and a reduction in those diagnosed with worsening renal failure." Subgroup analysis showed that women treated with sacubitril-valsartan had a 27 percent reduction in the primary endpoint vs. women receiving valsartan alone. Additionally, patients with LVEF ≤57 percent had a reduction in the primary endpoint of 22 percent.

"We believe our findings may translate into clinically worthwhile benefits for certain groups of patients, particularly those with HF with ejection fraction that is not in the conventional 'reduced' range, but is below normal," concluded Solomon.

The open-label PROVE-HF trial exploring the mechanism of sacubitril-valsartan benefit in patients with HFrEF found that reduced NT-proBNP concentrations achieved with sacubitril-valsartan were significantly correlated with signs of reverse cardiac remodeling after one year of treatment. The 794 enrolled patients received sacubitril-valsartan after discontinuing all angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.

The median NT-proBNP concentration decreased from 816 pg/mL at baseline to 455 pg/mL at 12 months, correlating with a mean increase in LVEF from 28.2 percent to 37.8 percent; a mean decrease in LV end-diastolic volume index from 86.93 to 74.15 mL/m2; and a mean decrease in LV end-systolic volume index from 61.68 to 45.46 mL/m2 (p<0.001 for all). Left atrial volume index and the ratio of early transmitral Doppler velocity/early diastolic annular velocity also significantly decreased (p<0.001 for both).

The investigators noted that although improvement in cardiac structure and function was present at six months, further improvements in LVEF and volumes were observed at 12 months, with 25 percent of patients experiencing an absolute LVEF increase of more than 13 percent. "The observed reverse cardiac remodeling may provide a mechanistic explanation for the effects of sacubitril-valsartan in patients with HFrEF," they concluded.

Based on results from the BB-Meta-HF study, beta-blockers are still effective in preventing death in patients with HFrEF and sinus rhythm, even in those with moderate or moderately-severe kidney dysfunction. Researchers analyzed data from 10 randomized trials enrolling 16,740 patients with HFrEF.

After a median follow-up of 1.3 years, results showed that renal dysfunction was independently associated with higher mortality, and cause of death was more often due to progressive HF in patients with more severe renal impairment.

Beta-blockers significantly reduced mortality in the 13,861 patients in sinus rhythm, with an absolute risk reduction for all-cause mortality of 4.7 percent in patients with an estimated glomerular filtration rate (eGFR) of 30-44 mL/min/1.73 m2, the lowest range tested. Beta-blockers did not lead to deterioration in eGFR in patients with renal impairment and adverse events were not increased compared with placebo.

"In our study, worsening renal function did not appear to be caused by beta-blocker therapy and all patients were already on ACE inhibitors. Nonetheless, worsening renal function was linked to poor outcomes and this highlights the importance of preserving kidney function by working with renal specialists," said principal investigator Dipak Kotecha, MD.

Patients with diabetes are at greater risk for HF and subsequent death following myocardial infarction (MI) than patients without diabetes, according to results from the FAST-MI registry. Researchers analyzed data on 12,660 patients hospitalized for MI in France between 2005 and 2015 to determine whether patients with diabetes were more likely than those without to develop HF during their hospital stay and for one year after. They also compared five-year mortality in patients with diabetes readmitted for nonfatal HF within one year after the MI vs. diabetic patients who did not develop HF.

Nearly 25 percent of patients hospitalized for acute MI had diabetes. During hospitalization for MI, 32 percent of patients with diabetes developed HF compared with 17 percent of those without diabetes. Adjusted analysis showed that patients with diabetes had a 56 percent higher risk of developing HF than patients without diabetes.

Among those who survived MI, 5.1 percent of patients with diabetes were hospitalized for nonfatal HF during the following year compared with 1.8 percent of those without diabetes, equating to a 44 percent increased risk of HF in patients with diabetes. Patients with diabetes who were hospitalized for HF during the year following MI had an adjusted 73 percent higher risk of five-year mortality vs. those without HF.

"Our study shows that diabetes is associated with a considerably increased risk of developing HF after a heart attack. Furthermore, diabetic patients who develop HF in the year after a heart attack have a much higher risk of dying in the following years," said Nicolas Danchin, MD. "More efforts are needed to prevent diabetes. In addition, better management is required for diabetic patients who have a heart attack to avoid heart failure and its detrimental long-term consequences," he concluded.

Global Noncommunicable Diseases

Two reports from the PURE study provide understanding of global noncommunicable diseases (NCDs) and guidance on population-level prevention strategies. The PURE study is the only large prospective international cohort study including low-income countries (LIC), middle-income countries (MIC), and high-income countries (HIC).

For the first report, researchers followed 162,534 middle-aged adults for a median of 9.5 years. They found that cardiovascular death was 2.5 times more common in LIC compared with HIC and there was a substantially lower rate of first hospitalization and medications for cardiovascular disease in LIC and MIC vs. HIC. The incidence of cardiovascular disease per 1,000-person years was 7.1, 6.8 and 4.3 in LIC, MIC and HIC, respectively.

"The world is witnessing a new epidemiologic transition among the different categories of noncommunicable diseases, with cardiovascular disease no longer the leading cause of death in HIC," said lead author Gilles R. Dagenais, MD.

Researchers also examined the relative contributions of 14 modifiable risk factors (population attributable factor [PAF]) among 155,722 community-dwelling, middle-aged people without a history of cardiovascular disease. They reported that 70 percent of cardiovascular disease cases and deaths are due to PAFs. Metabolic risk factors contributed the most to cardiovascular disease globally (41.2 percent), with hypertension (22.3 percent) the leading metabolic risk factor.

In LIC and MIC, household air pollution, poor diet, low education and low grip strength were larger contributing factors compared with HIC. Metabolic risk factors, including high cholesterol, abdominal obesity and diabetes, played a larger role in causing cardiovascular disease in HIC vs. LIC.

"While long-term cardiovascular disease prevention and management strategies have proved successful in reducing the burden in HIC, a change in tack is required to alleviate the disproportionately high impact of cardiovascular disease in LIC and MIC," said principal investigator Salim Yusuf, DPhil, FACC. "Governments in these countries need to start by investing a greater portion of their gross domestic product in preventing and managing noncommunicable diseases including cardiovascular disease, rather than focusing largely on infectious diseases."

Dual vs. Triple Anticoagulation Therapy

Edoxaban-based dual antithrombotic therapy (DAT) is noninferior to vitamin K antagonist (VKA)-based triple antithrombotic therapy (TAT) after PCI in patients with atrial fibrillation (AFib), according to results of the ENTRUST-AF PCI trial presented by Andreas Goette, MD.

In this open-label, masked outcome evaluation study, patients with AFib were randomized to post PCI DAT consisting of edoxaban plus a P2Y12 inhibitor (n=751) or TAT with a VKA plus a P2Y12 inhibitor and aspirin (n=755). The median time from PCI to randomization was 4.1 hours. The primary endpoint was a composite of major or clinically relevant bleeding within 12 months in the intention-to-treat population.

The primary endpoint occurred in 17 percent of patients in the DAT group compared with 20 percent of those in the TAT group, translating to an annualized event rate of 20.7 percent with DAT vs. 25.6 percent with TAT (HR, 0.83; p=0.0010 for noninferiority). The annualized event rates for the main efficacy composite outcome of cardiovascular death, stroke, systemic embolic events, MI and definite stent thrombosis were 7.3 percent in the DAT group and 6.0 percent in the TAT group.

The investigators concluded that edoxaban-based DAT is noninferior for bleeding compared with VKA-based TAT, without significant differences in ischemic events.

RACE Registry: Life-Threatening Events Rare in Endurance Races

Life-threatening events (LTE) during long-distance races are rare and survival is high, according to a study of the RACE Paris Registry. A total of 1,073,722 runners participating in 46 consecutive long-distance races were included. Researchers examined the cases of cardiovascular events occurring within 30 minutes before, during or within two hours after a race.

Of the 36 participants who had an LTE, 11 had exertional heat stroke and 25 had a major cardiovascular event. The LTE rate was 3.35 per 100,000 participants, with major cardiac events occurring at a rate of 2.32 per 100,000 participants. The rate of sudden cardiac arrest was 1.67 per 100,000 participants, with a mortality rate of 0.19 per 100,000 participants.

One-third of patients experiencing an LTE had a history of myocardial ischemia. According to the investigators, more than half of LTEs that occur during long-distance races can be prevented.

Keywords: ACC Publications, Cardiology Magazine, ESC Congress, ESC 19, Adrenergic beta-Antagonists, Air Pollution, Aminobutyrates, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Atrial Fibrillation, Benzopyrans, Aspirin, Cholesterol, Cause of Death, Death, Sudden, Cardiac, Developed Countries, Diabetes Mellitus, Diet, Fibrinolytic Agents, Follow-Up Studies, Glomerular Filtration Rate, Government, Gross Domestic Product, Heart Failure, Heat Stroke, Hospitalization, Hypertension, Incidence, Intention to Treat Analysis, Insurance, Hospitalization, Length of Stay, Hemorrhage, Myocardial Infarction, Myocardial Ischemia, Obesity, Abdominal, Numbers Needed To Treat, Percutaneous Coronary Intervention, Prospective Studies, Pyridines, Quality of Life, Research Personnel, Registries, Specialization, Risk Factors, Stents, Stroke, Stroke Volume, Tetrazoles, Thiazoles, Thrombosis, Tolonium Chloride, Vitamin K, Random Allocation

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