Gender differences in the treatment of cardiovascular disease and in the achievement of the LDL-C goal

Increased low-density lipoprotein cholesterol (LDL-C) is a key and modifiable driver of the risk of major cardiovascular events. It has been shown that for every 1 mmol/l reduction in LDL cholesterol, the number of serious cardiovascular events is reduced by 22% after 1 year.^7,8 According to data from the SANTORINI observational study, European women at high or very high CV risk received insufficient treatment and achieved to a lesser extent the LDL-C levels recommended by the guideline guidelines.¹

As part of the company's effort to expand medical knowledge to help protect people from cardiovascular disease (CVD), Daiichi Sankyo collaborates with and designs studies, such as SANTORINI, that investigate the underlying causes of the burden of CVD in Europe.

Data from a new sub-analysis of SANTORINI, based on 5,197 male patients with a mean age of 65 years and 2,013 women with a mean age of 66 years, show that women were undertreated compared to men, with fewer reaching guideline-recommended LDL-C levels during the study.¹

Although the proportion of patients who achieved LDL-C targets improved from baseline to the first year of follow-up, it was higher in males (22.9% and 33.3%, respectively) than in females (16.9% and 24.6%, respectively).1 Although guideline recommendations are similar, the number of women who did not receive any lipid-lowering therapy at baseline and one year of follow-up was higher (23.9% and 3.9%, respectively) than that of men (20.7% and 2.7%). ¹

"We know that the severity of cardiovascular disease is as high in women as in men, and that patients of both sexes continue to be undertreated.^9.10 But this new sub-analysis of the SANTORINI study further suggests that, in clinical practice, women as a group were being disproportionately undertreated and do not always reach the recommended LDL-C level targets," explains Professor David Nanchen, University of Lausanne, Centre for Primary Care and Public Health (Unisanté), Lausanne, Switzerland. "These findings underscore the need for broader care to better manage cardiovascular disease risk in women."

Therapeutic Adherence and Impact of Non-Adherence on Patient Outcomes

The efficacy of treatment of atrial fibrillation with oral anticoagulants depends on adherence and persistence. Thus, non-adherence to non-vitamin K antagonist oral anticoagulants (DOACs) has been associated with an increased risk of stroke in patients with atrial fibrillation (AF).²

In this context, Daiichi Sankyo committed to deepening the understanding of the global burden of cardiovascular disease in patients with non-valvular atrial fibrillation through the ETNA-AF program, which combines data from different non-interventional studies from Europe, East Asia, and Japan into a single database. More than 28,000 patients were included in the ETNA-AF registries and followed for four years in Europe and two years in non-European countries.¹¹

Results from a new post hoc sub-analysis of the ETNA-AF program showed that of the 9,417 patients [71.5% of the 13,164 enrolled] who completed the 4-year study, 87.4% persisted on edoxaban treatment.³ Both discontinuation of treatment and non-persistence were associated with factors such as increasing age, male sex, extreme body weight, low kidney function, heart failure, vascular disease, chronic liver disease, alcohol consumption, perception of frailty, chronic obstructive pulmonary disease, smoking, current AF symptoms, and ablation.³

"The high number of patients who maintained treatment with this drug during the 4 years of the study is good news for our efforts to mitigate the lack of therapeutic adherence²", states Professor Raffaele De Caterina, MD, PhD, FESC, director of the Cardiology Unit at the University Hospital of Pisa. We hope that the factors associated with non-persistence observed in the study will also help the development of treatment strategies in clinical practice, to the benefit of patient outcomes."

Treatment of patients with frailty and comorbidities

Barriers to recommending anticoagulation in the treatment of non-valvular AF (NVAF), such as complex multimorbidities, are significant in frail patients.¹² Therefore, the prescription of DOACs in the population of frail patients is <50%.¹² Doctors must weigh the risk of stroke and bleeding in their decision-making when prescribing.¹²

Since frailty is a common reason for choosing non-recommended doses of DOACs, four-year follow-up data from ETNA-AF were used to assess clinical outcomes in these patients. Patients with 'perceived' or objective frailty who were treated with a reduced (not recommended) dose of 30mg showed a higher rate of death from all causes compared to the recommended dose of 60mg (HR [95% CI]: 1.44[1,06,1,96]) with no significant effect on major bleeding. This suggests that the presence of frailty should not necessarily lead to dose reductions outside of those set out in the label.⁵

In a separate sub-analysis of the data, patients were divided into low, medium, and high tertiles based on body mass index (BMI), body surface area (BSA), and lean body mass (LBM). Thromboembolic event rates were low (0.7-0.9%/100 PE) and similar in all tertiles. However, higher rates of bleeding events were observed in the low tertiles ([2.2-2.4%]) versus the middle tertiles ([1.5-1.8%]) and high tertiles ([1.4-1.5%]) of BSA and LBM, suggesting that these variables, rather than BMI, should be taken into account when analysing outcomes in patients treated with this medicine.^4,6

"At Daiichi Sankyo, we continue our long-term commitment to providing scientific evidence to support the optimal treatment of patients with cardiovascular disease, and to finding solutions for people who have previously not received adequate treatment," said Stefan Seyfried, Vice President Medical Affairs, Specialty Medicines, at Daiichi Sankyo Europe GmbH.Our promise to patients is to continue to shine a light on the differences in treatment and unmet needs in cardiovascular care, with the goal of reducing the burden on patients and their loved ones."

References

________________________________

¹ Nanchen, D., et al. Contemporary LDL-cholesterol management in male and female patients at high-cardiovascular risk: results from the European observational SANTORINI study. Oral presentation, ESC Congress 30 August 2024.
² Vitolo, M., et al. The importance of adherence and persistence with oral anticoagulation treatment in patients with atrial fibrillation. European Heart Journal – Cardiovascular Pharmacotherapy. 2021. 7; (FI1): f81–f83
³ Diemberger, I., et al. Persistence and predictors for non-persistence to edoxaban therapy in patients with atrial fibrillation: 4-year follow-up data from the ETNA-AF-Europe study. ESC 2024
⁴ Boriani, G., et al. Impact of differences in body mass index, body surface area and lean body mass on clinical outcomes in patients with atrial fibrillation receiving edoxaban: 4-year follow-up data from ETNA-AF-Europe. ESC 2024
⁵ Fumagalli, S., et al. Edoxaban dose, frailty, and outcomes in patients with atrial fibrillation: the ETNA-AF-Europe 4-year follow-up. ESC 2024
⁶ Boriani, G., et al. Impact of body weight and body mass index on clinical outcomes of edoxaban therapy in atrial fibrillation patients included in the ETNA-AF-Global registry. ESC 2024
⁷ Cholesterol Treatment Trialists' (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet. 2010. 376(9753): 1670–1681
⁸ NHS England. Improving lipid management to reduce cardiovascular disease and save lives. Available at: https://www.england.nhs.uk/long-read/improving-lipid-management-to-reduce-cardiovascular-disease-and-save-lives/#:~:text=Raised%20LDL%20cholesterol%20is%20one,vascular%20events%20after%201%20year. Last accessed August 2024.
⁹ ESC. Cardiovascular Disease in Women. Available at: https://www.escardio.org/The-ESC/Advocacy/women-and-cardiovascular-disease. Last accessed August 2024.
¹⁰ Ray, K.K., et al. Treatment gaps in the implementation of LDL cholesterol control among high- and very high-risk patients in Europe between 2020 and 2021: the multinational observational SANTORINI study. Lancet. 2023. 29: 100624.
¹¹ Daiichi Sankyo Europe – About ENTA-AF (UK). Available at: https://www.daiichi-sankyo.eu/media/about-etna-af-uk/. Last accessed August 2024.
¹² Bul, M., et al. Frailty and oral anticoagulant prescription in adults with atrial fibrillation: A systematic review. Aging Medicine. 2022. 6(2): 195–206
¹³ Edoxaban Treatment in Routine Clinical Practice for Patients With Non Valvular Atrial Fibrillation (ETNA-AF-EU). Available at: https://clinicaltrials.gov/ct2/show/NCT02944019. Last accessed August 2024.
¹⁴ Edoxaban Treatment in Routine Clinical Practice for Patients With Atrial Fibrillation in Korea and Taiwan (ETNA-AF-KOR-TWN). Available at: https://clinicaltrials.gov/ct2/show/NCT02951039. Last accessed August 2024.
¹⁵ Edoxaban Treatment in Routine Clinical Practice for Patients With Non-Valvular Atrial Fibrillation (ETNA-AF-Hong Kong). Available at: https://clinicaltrials.gov/ct2/show/NCT03247582. Last accessed August 2024.
¹⁶ Edoxaban Treatment in Routine Clinical Practice for Patients With Non-Valvular Atrial Fibrillation (NVAF). Available at: https://clinicaltrials.gov/ct2/show/NCT03247569. Last accessed August 2024.
¹⁷ ETNA-AF-Japan. Available at: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000019728. Last accessed August 2024.