Dual antiplatelets therapy prescription trends and mortality outcomes among senior citizens with acute coronary syndrome: insights from the Malaysian National Cardiovascular Disease Database

The global population is ageing, posing significant healthcare challenges and economic implications. Malaysia, a multi-ethnic, upper-middle-income country in Southeast Asia with a population of 32 million,^[1] is also facing these challenges, mainly related to non-communicable diseases, especially cardiovascular disease (CVD).^[2]

Acute coronary syndrome (ACS) is a critical healthcare challenge in Malaysia, with an increasing incidence among the ageing population, particularly those aged 60 years and above.^[3] It is a significant cause of morbidity and mortality in this demographic, requiring comprehensive and evidence-based management strategies. Among these strategies, dual antiplatelet therapy (DAPT) is crucial in preventing recurrent ischaemic events and improving patient outcomes.^[4] However, complex patient profiles, the availability of diverse pharmacological options, and evolving clinical evidence necessitate a clear and concise framework to guide clinicians in making informed decisions regarding antiplatelet therapy in this population.

This study aimed to examine the 5-year trend in the demographic and clinical characteristics of senior citizen patients with ACS and the prescription of on-discharge DAPT using the multicentre National Cardiovascular Disease Database. The ultimate goal is to assist healthcare providers in optimising the use of DAPT in ACS patients in this age group, ensuring the best possible balance between preventing ischaemic events and minimising bleeding risks, especially in the Malaysian population. The study aims to improve the quality of care provided to ACS patients aged 60 years and above in Malaysia.

METHODS

Study Design and Population

This retrospective observational cohort study utilised data from the National Cardiovascular Disease-Acute Coronary Syndrome (NCVD-ACS) registry, Malaysia’s largest prospective single disease registry.^[5] The registry is governed by the Ministry of Health Malaysia and managed by the National Heart Association of Malaysia.^[6]

The study identified all consecutive adult Malaysian citizens aged 60 years and above who were admitted with ACS between January 2013 and December 2017 (n = 3718). ACS diagnosis, including ST-segment elevation myocardial infarction and non-ST-segment elevation ACS (NSTE-ACS), comprising non-ST-segment elevation myocardial infarction and unstable angina, were defined according to established guidelines.^[7–9] Variables extracted from the NCVD-ACS registry included demographic information (age, gender, and ethnicity) and clinical characteristics (clinical presentation, risk factors, and comorbidities). Malaysia’s major ethnicities are Malays, Chinese and Indians, with all other minority ethnicities categorised as ‘Other Malaysians’. Patient data were entered into the registry at a single point and followed up with the National Registration Department to determine 1-year all-cause mortality (365 days from hospital discharge).

To address potential concerns regarding the sample size, thorough data quality checks were performed to minimise bias and ensure the reliability of results. Detailed information on percutaneous coronary intervention (PCI) procedures, such as drug-eluting stents, was not included as it is available in another registry, the NCVD-PCI registry.^[10] This study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for reporting transparency.^[11]

Ethics

The Medical Review and Ethics Committee, the Ministry of Health Malaysia approved the study protocol with the approval code NMRR-19-4066-52389 (IIR). No patient or public involvement was involved in developing the research question or outcome.

Statistical Analysis

Comparisons of clinical characteristics between patients prescribed and not prescribed DAPT at discharge were analysed using the Student’s t-test and the Pearson’s chi-squared test, as appropriate. Categorical data are presented as counts (percentages), while continuous data, such as age, are presented as mean ± SD. Trend in DAPT prescription over the study period were analysed using the linear trend test. Variations in prescribing DAPT at discharge were analysed using multivariate logistic regression, adjusting for demographics, risk factors and comorbidities, and presented as an adjusted odds ratio (aOR) with 95% CI. Statistical analyses were performed with SPSS 26.0 (SPSS Inc., IBM, Armonk, NY, USA) with a significance level set at 5%.

Propensity Score: Inverse Proportional Weighting (IPW)

The association between DAPT prescription at discharge and 1-year all-cause mortality was examined using the Cox proportional hazard regression model with propensity score IPW for risk adjustment. IPW was chosen as it aligns with the estimand of interest (average treatment effect on all individuals). Risk adjustment was performed with all variables associated with ACS based on published literature, clinical plausibility and the P-value < 0.05 in the univariate Cox proportional hazard regression analyses. Only patients with complete information for all variables were included, with 1% of outliers removed (trimming) to avoid extreme weights and improve treatment exposure compatibility.^[12,13]

RESULTS

The study found that the majority of Malaysian senior citizens with ACS were prescribed on-discharge DAPT, with 3222 out of 3718 patients receiving this treatment. Among the DAPT combinations, four main combinations were identified, all of which included aspirin. The most common DAPT combination was aspirin-clopidogrel (AC) (77%, n = 2828), followed by aspirin-ticagrelor (AT) (8.61%, n = 316). Due to the low prescription rates of aspirin-ticlopidine (0.56%, n = 21) and aspirin-prasugrel (0.22%, n = 8), these combinations were not further analysed. Throughout the consecutive studied period (2013–2017), the prescription of DAPT significantly increased (linear trends test, P < 0.001), similarly for both AC and AT combinations (Figure 1).

Figure  1.  Trends of prescription for on-discharge DAPT and the two DAPT combination in acute coronary syndrome patients in the NCVD-ACS registry (2013-2017).

DAPT: dual antiplatelet therapy; NCVD-ACS: the Malaysian National Cardiovascular Disease-Acute Coronary Syndrome.

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Demographic and Clinical Characteristics Associated with the Prescription of DAPT

The mean age of ACS patients receiving DAPT was68 ± 6.74 years. The study noted a decreasing trend in DAPT prescription with increasing age, although this trend was more stable for AC combinations. Despite more men being admitted, DAPT prescription rates were similar for both genders, with over 75% receiving AC and less than 10% receiving AT combinations. Regarding ethnic groups, over 80% of Indians (84%) and Malay (82%) received DAPT prescriptions. Meanwhile, between the two DAPT combinations, AC showed a higher prescription percentage in those diagnose with NSTE-ACS (75%) compared to ST-segment elevation myocardial infarction (72%). In patients who underwent coronary artery bypass grafting, AT was prescribed at lower rates (4%) (Table 1).

Table  1.  Demographic and clinical characteristics of patients prescribed with DAPT, AC and AT on day of discharge from 2013 to 2017.

Demographic/Clinical characteristics	Overall (n = 3718)	DAPT (n = 3222, 87%)	AC (n = 2828, 77%)	AT (n = 316, 9%)
Gender
Men	71.95%	88.04%	77.68%	9.27%
Women	28.05%	83.13%	75.26%	7.00%
Age, yrs
60-64	34.64%	89.75%	77.87%	10.71%
65-69	27.25%	86.77%	76.51%	9.38%
70-74	18.07%	83.78%	75.30%	8.04%
75-79	12.26%	85.09%	78.29%	5.04%
≥ 80	7.77%	81.66%	76.82%	3.81%
Ethnic group
Malay	43.36%	88.46%	78.66%	9.31%
Chinese	25.49%	84.26%	76.04%	6.40%
Indian	21.41%	89.70%	75.88%	12.44%
Other Malaysians	8.74%	77.54%	74.46%	2.77%
Acute coronary syndrome stratum
ST-segment elevation myocardial infarction	37.25%	91.41%	73.29%	17.33%
Non-ST-segment elevation acute coronary syndrome	62.75%	83.84%	79.21%	3.47%
Intervention
Percutaneous coronary intervention	35.10%	93.26%	71.80%	20.46%
Coronary artery bypass grafting	1.66%	77.05%	75.41%	1.64%
Risk factors
Hypertension	75.69%	85.61%	76.87%	7.78%
Diabetes mellitus	51.10%	85.68%	75.26%	9.27%
Dyslipidaemia	44.94%	85.64%	7.08%	7.36%
Tobacco smoking	45.35%	89.50%	79.42%	9.02%
Family history	32.71%	83.96%	74.84%	7.65%
Other factors
Body mass index > 23.0 kg/m2	73.64%	86.92%	76.30%	9.46%
Congestive heart failure	7.10%	81.44%	75.76%	3.79%
Chronic kidney disease	10.19%	82.85%	77.84%	3.69%
Chronic lung disease	4.92%	78.14%	73.77%	3.83%
Cerebrovascular disease	4.95%	84.24%	75.54%	8.15%
Peripheral vascular disease	0.59%	86.36%	81.82%	–
Cardiogenic shock	4.90%	86.81%	73.08%	12.64%
Angina within 2 weeks	61.92%	85.49%	75.02%	9.47%
Data are presented as %. AC: aspirin-clopidogrel; AT: aspirin-ticagrelor; DAPT: dual antiplatelet therapy.

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Prescription Variations

Patients with the history of tobacco smoking (aOR = 1.41, 95% CI: 1.11–1.78, P = 0.01) and those who underwent PCI (aOR = 2.53, 95% CI: 1.95–3.28, P < 0.001) were more likely to be prescribed DAPT. Patients from the Chinese (aOR = 0.76, 95% CI: 0.60–0.97, P = 0.03) and Other Malaysian (aOR = 0.45, 95% CI: 0.33–0.62, P < 0.001) ethnic groups were less likely to be prescribed DAPT compared to the Malay ethnic group. Additionally, patients with a family history of CVD (aOR = 0.79, 95% CI: 0.64–0.97, P = 0.03) and the angina within the past two weeks (aOR = 0.69, 95% CI: 0.56–0.85, P < 0.001) were less likely to be prescribed DAPT. Significantly higher odds of being prescribed AC were observed in those with a history of tobacco smoking. However, patients from Other Malaysian (ref = Malay, aOR = 0.73, 95% CI: 0.55–0.97, P = 0.03) ethnic groups, those with diabetes mellitus (aOR = 0.84, 95% CI: 0.71–0.99, P = 0.04), a family history of CVD (aOR = 0.74, 95% CI: 0.62–0.88, P = 0.001) and chronic lung disease (aOR = 0.69, 95% CI: 0.48–0.97, P = 0.04) were significantly less likely to receive AC (Table 2).

Table  2.  Variations in DAPT, AC, and AT prescriptions on the day of hospital discharge for Malaysian elderly with acute coronary syndrome.

Demographic/Clinical characteristics	DAPT			AC			AT
	aOR (95% CI)	P-value		aOR (95% CI)	P-value		aOR (95% CI)	P-value
Gender
Men (reference)
Women	0.85 (0.67–1.08)	0.19		0.94 (0.77–1.15)	0.56		0.90 (0.64–1.26)	0.54
Age
60-64 (reference)
65-69	0.79 (0.61–1.03)	0.08		0.91 (0.75–1.11)	0.36		0.97 (0.72–1.32)	0.86
70-74	0.67 (0.50–0.89)	0.01		0.83 (0.66–1.04)	0.096		0.99 (0.69–1.43)	0.97
75-79	0.82 (0.59–1.14)	0.24		0.97 (0.75–1.27)	0.85		0.66 (0.41–1.09)	0.11
≥ 80	0.711 (0.49–1.03)	0.07		0.87 (0.63–1.20)	0.40		0.75 (0.38–1.49)	0.41
Ethnic group
Malay (reference)
Chinese	0.76 (0.60–0.97)	0.03		0.83 (0.68–1.01)	0.06		0.80 (0.57–1.12)	0.19
Indian	1.27 (0.95–1.70)	0.10		0.94 (0.76–1.15)	0.53		1.42 (1.04–1.92)	0.03
Other Malaysians	0.45 (0.33–0.62)	< 0.001		0.73 (0.55–0.97)	0.03		0.33 (0.16–0.67)	0.002
Acute coronary syndrome stratum
ST-segment elevation myocardial infarction (reference)
Non-ST-segment elevation acute coronary syndrome	0.81 (0.63–1.05)	0.12		1.45 (1.20–1.74)	< 0.001		0.31 (0.23–0.42)	< 0.001
Intervention
Percutaneous coronary intervention	2.53 (1.95–3.28)	< 0.001		0.71 (0.60–0.84)	< 0.001		7.76 (5.65–10.68)	< 0.001
Risk factors
Hypertension	0.87 (0.67–1.14)	0.33		1.06 (0.87–1.29)	0.57		0.82 (0.61–1.11)	0.20
Diabetes mellitus	0.85 (0.68–1.05)	0.12		0.84 (0.71–0.99)	0.04		1.16 (0.89–1.53)	0.27
Dyslipidaemia	1.03 (0.84–1.26)	0.79		1.02 (0.87–1.21)	0.76		0.95 (0.73–1.24)	0.70
Tobacco smoking	1.41 (1.11–1.78)	0.01		1.32 (1.10–1.59)	0.003		0.85 (0.63–1.14)	0.27
Family history	0.79 (0.64–0.97)	0.03		0.74 (0.62–0.88)	0.001		1.50 (1.10–2.03)	0.01
Other factors
Body mass index > 23.0 kg/m2	1.03 (0.83–1.29)	0.79		0.84 (0.70–1.01)	0.06		1.44 (1.05–1.97)	0.02
Congestive heart failure	0.91 (0.64–1.28)	0.58		0.91 (0.67–1.24)	0.56		0.84 (0.42–1.69)	0.62
Chronic kidney disease	0.99 (0.73–1.35)	0.95		1.04 (0.80–1.37)	0.76		0.70 (0.38–1.26)	0.23
Chronic lung disease	0.62 (0.42–0.92)	0.02		0.69 (0.48–0.97)	0.04		0.78 (0.34–1.78)	0.55
Cerebrovascular disease	0.86 (0.56–1.31)	0.48		0.88 (0.62–1.25)	0.47		1.18 (0.65–2.16)	0.59
Peripheral vascular disease	1.09 (0.31–3.84)	0.89		1.36 (0.45–4.15)	0.59		–	1.00
Cardiogenic shock	0.68 (0.43–1.09)	0.11		0.91 (0.64–1.29)	0.60		0.81 (0.49–1.32)	0.39
Angina within 2 weeks	0.69 (0.56–0.85)	< 0.001		0.74 (0.63–0.88)	< 0.001		1.00 (0.76–1.31)	0.99
AC: aspirin-clopidogrel; AT: aspirin-ticagrelor; DAPT: dual antiplatelet therapy.

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Prescription variation was also evident in the AT prescription. Lower rates of AT were observed in Other Malaysian (ref = Malay, aOR = 0.33, 95% CI: 0.16–0.67, P = 0.002) ethnic group and those diagnosed with NSTE-ACS (aOR = 0.31, 95% CI: 0.23–0.42, P < 0.001). Conversely, significantly higher odds of prescription of AT were reported in those of the Indian ethnic group (ref = Malay, aOR = 1.42, 95% CI: 1.04–1.92, P = 0.03), those with a family history of CVD (aOR = 1.50, 95% CI: 1.10–2.03, P = 0.01), abnormally high body mass index (aOR = 1.44, 95% CI: 1.05–1.97, P = 0.02), and those who underwent PCI (aOR = 7.76, 95% CI: 5.65–10.68, P < 0.001) (Table 2).

Outcome and Survival Analysis: 1-year All-cause Mortality

Despite an increasing trend in 1-year all-cause mortality, approximately 15% (441/3222) of deaths were reported. Senior citizens with ACS-prescribed DAPT demonstrated significantly better 1-year survival than those without (aOR = 0.58, 95% CI: 0.48–0.72, P < 0.001), like those prescribed AC (aOR = 0.70, 95% CI: 0.58–0.85, P < 0.001). The protective effect of DAPT was insignificant for those prescribed AT combination (P > 0.05). However, further survival analysis comparing AC and AT showed that patient prescribed the latter had significantly higher patient survival (aOR = 0.21, 95% CI: 0.11–0.40, P < 0.001) (Figure 2).

Figure  2.  Cox survival curves comparing patients prescribed on-discharge (A) DAPT, (B) AC, (C) AT versus those not prescribed and (D) AT compared to AC using propensity score inverse proportional weighting.

AC: aspirin-clopidogrel; AT: aspirin-ticagrelor; DAPT: dual antiplatelet therapy.

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DISCUSSION

Over the past decade, Malaysia has seen an annual growth rate of approximately 5% in its elderly population, attributed to healthcare advancements leading to increased life expectancy and a declining birth rate.^[14] There is no universal consensus on the definition of elderly, but this study focuses on those aged 60 years and above. Admissions of elderly with ACS have increased, as shown in this study, consistent with age being a significant risk factor for atherosclerosis. Managing ACS in older people presents challenges due to age-related physiological changes, comorbidities, and altered drug reactions, affecting pharmacokinetics and pharmacodynamics.^[15]

Trends of Prescription

Despite guideline recommendations, elderly patients, both with or without comorbidities, are underrepresented in landmark clinical studies, influencing physician’s treatment decisions.^[16] Elderly patients with ACS receive less aggressive treatment compared to younger patients.^[17] One standard treatment is DAPT, including aspirin.^[18,19] Over the five years, the use of DAPT significantly increased, with AC being the most frequently prescribed combination. Clopidogrel is favoured in elderly patients due to its lower bleeding risk.^[20,21] However, recommendations lean towards third-generation antiplatelets, including ticagrelor, for all patients with ACS.^[21] A discernible shift towards AT combinations was observed in this study, indicating a preference for newer agents in recent years. The increased prescription of these newer antiplatelets has also been reported in other registries.^[20] However, the numbers of elderly patients prescribed with the newer agents reported in the NCVD-ACS registry were still far behind.

Prescription Variations

Despite access to free or low-cost healthcare for retirees (retirement age is typically 60 years old) in Malaysia, there are notable variations in DAPT prescriptions among multiethnic elderly patients. Prescription variations are influenced by ethnicities, scheduled PCI, and comorbidities. Elderly patients with NSTE-ACS and those undergoing PCI were significantly more likely to receive DAPT, particularly AT. However, patients with chronic lung disease and a history of angina were less likely to be prescribed DAPT. The TRITON-TIMI 38 study showed that despite the newer antiplatelets significantly reducing rates of ischemic events, they lack overall clinical benefits in much older patients.^[22]

A large proportion of elderly patients with ACS had established or newly diagnosed diabetes mellitus. These patients were less likely to be prescribed AC despite the GEPRESS study’s recommendation.^[23] This is seen as them being less rigorously treated,^[24] as higher platelet reactivity has been demonstrated, especially in elderly patients with diabetes mellitus.^[25] Other than clopidogrel, despite the higher rates of platelet reactivity, the TRITON-TIMI 38 trial and PLATO trial have reported a more significant reduction in ischemic event observed in patients with diabetes mellitus with the use of third-generation P2Y12 receptor blockers such as ticagrelor.^[26] However, the Elderly ACS 2 study sided with the benefit carried by clopidogrel.^[27]

1-year All-cause Mortality

Elderly ACS patients prescribed with DAPT, including AC or AT, demonstrated significantly higher survival rates than those not receiving DAPT. The benefit of AT was noteworthy despite its lower prescription rate than AC. These findings suggest a potential benefit of newer antiplatelet agents, such as ticagrelor, in improving outcomes in patients with ACS.^[28] The benefits of ticagrelor usage in DAPT were reported in the PLATO multicenter, double-blind, randomised trial, with no significant difference found in the rates of major bleeding between ticagrelor and clopidogrel.^[29] The PLATO trial also demonstrated that clopidogrel and ticagrelor reduced cardiovascular mortality in the older subgroup (patient aged ≥ 75 years).^[30] Further research is needed to confirm these associations and elucidate the underlying mechanisms and variations, especially in the patient’s past medical history of the disease. The lack of a statistically significant protective effect in the AT group compared to the non-AT group (HR = 0.873, 95% CI: 0.592–1.289, P = 0.495) is likely due to the smaller sample size in the AT group (n = 316), which may have reduced the study’s power to detect a significant difference. Although newer antiplatelets have shown superior benefits over clopidogrel, particularly in younger and lower-risk patients, their efficacy in the elderly remains unclear. To fully evaluate the effectiveness and safety of newer antiplatelets in elderly patients, more extensive studies with longer follow-up are necessary. Due to the limitations of the NCVD-ACS registry, which only provide data on whether a prescription is given but not a specific duration of treatment, the nuances of DAPT therapy, such as the length of treatment, were not explored. As a result, the analysis of this study could not assess the impact of DAPT duration on patient outcomes.

This study faced limitations related to number of patient and data completeness, particularly concerning drug and stent use. To address these issues, future research should focus on larger studies that include more comprehensive data collection, ideally incorporating information from the PCI registries. Such studies would help determine the optimal treatment duration and evaluate the impact of different stents following PCI. Additionally, there is a need for expanded, prospective studies on newer antiplatelet medications, particularly in older populations, to better assess their long-term benefits and risks.

STRENGTH AND LIMITATION

The study aim to aid clinical practice in managing ACS in elderly patients. The findings of this study, anchored in vast local patient data, would contribute to improving adherence to guidelines in managing ACS in this country. Leveraging the NCVD-ACS registry, this study provides valuable pharmacoepidemiological insights into CVDs in the country. The propensity score covariates covariates adjustment model and the IPW approach provided robust alternatives for risk adjustments. While the one-time capturing method of the registry reduces duplicate patient entries, the lack of follow-up data, detail of the prescribed medications, geographical data and complete intervention, mainly PCI, and history limit medication adherence assessment. Due to the limitations of the NCVD-ACS registry, which only provides data on whether a prescription is given but not the specific duration of treatment, the nuances of DAPT therapy, such as the length of treatment, were not explored. As a result, the analysis of this study could not assess the impact of DAPT duration on patient outcomes.

Despite the growing elderly population, the number of patients included in this study in general was still considerably low, as participation in the registry is voluntary, which may limit the generalizability of the findings. Future studies should focus on the limitations addressed while optimising DAPT regimens and evaluating their impact on long-term outcome in the elderly population and the nation.

CONCLUSIONS

Managing ACS in elderly patients requires considering age-related change and individual factors. There was an increasing trend towards using DAPT and adopting newer antiplatelet agents with improved survival benefits. However, the optimal treatment strategies for elderly patients with ACS remain uncertain. Further research and guidelines tailored to this population are needed to improve outcomes.