Elevated LDL triglycerides linked to higher risk of atherosclerotic cardiovascular disease

1st February 2023

Higher LDL triglyceride levels are associated with a greater risk of atherosclerotic cardiovascular disease and its components

Danish and UK researchers examining data from the Copenhagen General Population Study, have determined that higher LDL triglyceride levels are linked to an elevated risk of atherosclerotic cardiovascular (ASCV) disease and its components such as myocardial infarction, ischaemic stroke and peripheral artery disease.

It is well recognised that a higher low-density lipoprotein (LDL) level is directly linked with the development of ASCV. Moreover, it has previously been shown that LDL contains a mixture of phospholipids, cholesterol and its esters and around 6% triglycerides. However, the role of triglycerides in ASCV has achieved much less attention in comparison to LDL, possibly because of a lack of randomised, clinical trial evidence.

As a result, in the current study, researchers wanted to better understand the potential role of LDL triglycerides (LDLT) in the development of ASCV and hypothesised that it was likely that higher LDLT levels would in fact be linked to greater risk of ASCV. The team used data obtained in the Copenhagen Population study, in which the lipid levels were measured in nearly 70,000 patients, either by a direct assay or from assessment by nuclear magnetic resonance. The researchers then performed a meta-analysis incorporating their findings from the Copenhagen study with previous studies.

LDL triglycerides and atherosclerotic cardiovascular disease

Levels of LDLT had been measured via a direct assay in 38,081 individuals and by NMR in 30,208 and who were followed for a median of 3 and 9.2 years respectively.

Using the results from measurement of LDLT direct assay, researchers calculated that for every 0.1mmol/l increase in LDLT, there was a 26% higher risk of ASCV (hazard ratio, HR = 1.26, 95% CI 1.17 – 1.35). The risks were similarly elevated for ischaemic heart disease (HR = 1.27), myocardial infarction (HR = 1.28), ischaemic stroke (HR = 1.22) and slightly higher for peripheral artery disease (HR = 1.38). Using the NMR-derived data gave rise to similar elevated risks for ASCV and its components.

When these results were included into the meta-analysis, giving a total participant population in excess of 110,000, a comparison of the highest to lowest LDLT quartile, revealed a risk ratio (RR) for ASCV of 1.5 (95% CI 1.35 – 1.66). Again, the risk ratios were also significantly elevated for ASCV components.

The authors concluded that elevated LDLT were robustly associated with an increased risk of ASCV and its components.

Citation
Balling M et al. Elevated LDL Triglycerides and Atherosclerotic Risk. Am J Coll Cardiol 2023

Hand-held and high-end vascular ultrasound devices show good agreement for carotid disease detection

25th February 2022

Hand-held carotid ultrasound has been demonstrated to have good agreement with conventional duplex ultrasound in ruling out carotid disease

A hand-held carotid ultrasound device shows an acceptable level of agreement with conventional duplex ultrasound for the examination of patients with suspected transitory ischaemic attack (TIA) or ischaemic stroke. This was the conclusion by a team of researchers from the Department of Internal Medicine, Levanger Hospital, Norway.

According to the World Stroke Organisation, 1 in 4 adults over the age of 25 will have a stroke in their lifetime and in 2019, there were 12·2 million incident cases of strokes, accounting for 11.6% of all global deaths.

Moreover, the presence of narrowing of the carotid artery or carotid stenosis, has been found to be associated with increased risk of ischaemic stroke. Carotid endarterectomy as a treatment, has been found to be of some benefit for patients with 50% to 69% symptomatic stenosis, in reducing the risk of stroke.

However, carotid stenosis cannot be adequately assessed through a physical examination and carotid ultrasonography has become a reproducible imaging method used to detect carotid atherosclerosis.

But could a hand-held carotid and hence much more portable, ultrasound device be just as reliable for the examination of patients with suspected TIA or an ischaemic stroke compared to a conventional high-end vascular ultrasound (HIGH)? This was the essential question addressed in the current study by the Norwegian team.

They included patients admitted to a community hospital with a suspected stroke or transient ischaemic attack. The patients were examined using a hand-held carotid ultrasound and the severity of carotid stenosis graded on a 7-point ordinal scale from 1 (normal) to 7 (occluded). Following this initial assessment, a HIGH was performed by a second cardiologist who remained unaware of the findings from the hand-held device and graded the degree of stenosis using the same scale.

The results of the two scans were then compared by weighted Cohen’s Kappa and which is designed to assess the level of agreement between the two techniques. Scores range from 0 to 1 with 0.41 – 0.60 rated as moderate agreement, 0.61 – 0.80 as substantial and over 0.81 as almost perfect agreement.

Hand-held carotid ultrasound agreement with HIGH

A total of 80 patients with a mean age of 71.5 years (47.5% women) were included in the study, 27.5% of whom, had a previous history of cardiovascular ischaemic events (i.e., ischaemic stroke, TIA, or myocardial infarction). From the total cohort, 11% were found to have a greater than 50% internal carotid stenosis (ICS) on examination. Overall, 77.5% of patients were discharged with a diagnosis of ischaemic stroke or TIA.

The overall agreement between the hand-held device and HIGH for the classification of the degree of internal carotid stenosis was 69%. In addition, the weighted Kappa agreement between the hand-held device and HIGH was 0.76 (95% CI 0.66 – 0.85). Nevertheless, there was evidence that the hand-held device overestimated ICS compared to HIGH when there was >50% occlusion (odds ratio for agreement = 0.15, 95% CI 0.06 – 0.42) using < 50% stenosis as the reference.

In discussing their results, the authors stated that there was a strong correlation between ICS grading between the hand-held carotid device and HIGH. They concluded that examining the level of carotid stenosis with a hand-held device was a reliable method for ruling out significant carotid artery disease.

But given the potential for overestimation when the carotid stenosis was greater than 50%, the authors suggested that the hand-device device should not be used for detailed classification of carotid disease.

Citation
Saxhaug LM et al. Reliability and agreement of point-of-care carotid artery examinations by experts using hand-held ultrasound devices in patients with ischaemic stroke or transitory ischaemic attack Open Heart 2022

Salt substitutes reduce risk of strokes and cardiovascular events

6th September 2021

Greater use of salt substitutes reduces the risk of new cardiovascular events in those with a history strokes and over 60 years of age.

There are two types of stroke: ischaemic (caused by a clot) and haemorrhagic (caused by a bleed) and the main risk factors for a stroke include hypertension, coronary artery disease, diabetes and obesity. The main factor responsible for strokes is hypertension and it has been estimated that, world-wide, a raised blood pressure, accounts for 54% of all strokes. Moreover, evidence suggests that a reduction of salt intake can reduce blood pressure, leading to a decrease in the risk of strokes. The use of salt substitutes, in which sodium is replaced by potassium, can also lower blood pressure, although the evidence for a beneficial effect on cardiovascular disease and mortality is sparse.

With an absence of randomised trial data examining the impact of salt substitution on cardiovascular outcomes, a team led by researchers from the George Institute for Global Health, Sydney, Australia, established the Salt Substitute and Stroke Study (SSaSS) in 600 rural villages in China. The team enrolled adults with a history of stroke or those who were 60 years of age and older and with poorly controlled blood pressure. This was defined as a systolic > 140mmHg if receiving treatment or > 160mmHg if not on treatment. Individuals were then randomised to receive, free-of-charge, salt substitutes, which contained 25% potassium chloride and asked to use this instead of regular salt for cooking, seasoning food etc. The primary outcome was stroke and secondary outcomes were major cardiovascular events, comprising a composite of non-fatal stroke, non-fatal acute coronary syndrome or death from vascular causes. The main safety outcome was clinical hyperkalaemia and in order to track electrolyte levels, every 12 months, a subgroup of participants provided 24-hour urinary electrolyte excretion.

Findings
A total of 20,995 individuals with a mean age of 65.4 years (49.5% female) were enrolled and randomised to either arm and followed up for 4.74 years. Overall, 72.6% of participants had a history of stroke, 88.4% a history of hypertension. Among those with hypertension, 79.3% were prescribed at least one anti-hypertensive and the mean sample blood pressure was 154/89.

In participants using salt substitutes, the rate of strokes was lower (rate ratio, RR = 0.86, 95% CI 0.77–0.96, p = 0.006) compared to regular salt users. In addition, both the rate of major cardiovascular events (RR = 0.87) and death (RR = 0.88) were significantly lower in the salt substitute group. Analysis of electrolyte samples during follow-up, also showed that sodium excretion was lower in those using salt substitutes. In terms of safety, there was no significant difference in the level of hyperkalaemia (p = 0.76).

The authors concluded that the use of salt substitutes in those with both hypertension and a prior stroke led to a significant reduction in not only future strokes but also major cardiovascular outcomes.

Citation
Neal B et al. Effect of Salt Substitution on Cardiovascular Events and Death. N Engl J Med 2021

COVID-19 an independent risk factor for myocardial infarction and ischaemic stroke

23rd August 2021

A swedish population-based study has shown infection COVID-19 to be an risk factor for both myocardial infarction and ischaemic stroke.

Although COVID-19 is a considered to be predominately respiratory infection, a review from the end of 2020, established that infection can also result in adverse cardiovascular outcomes. For example, one study of 3,334 COVID-19 patients in the US, found a 1.6% incidence of ischaemic strokes, and an 8.9% incidence of myocardial infarction. This rate was much higher than in a Danish observational study of 5119 patients, of whom, only 0.3% experienced an acute myocardial infarction. However, many of the adverse cardiovascular outcomes have reported among those hospitalised with COVID-19 and there is a lack of data on this disease burden following infection with the virus at the population level.

This was the reason for a study led by a team from the Department of Public Health and Clinical Medicine, Umea University, Umea, Sweden. The researchers sought to quantify the relative risk of both ischaemic stroke and myocardial infarction following infection with COVID-19 using a large, nationwide register within Sweden. The team used two methods of study; the self-controlled case series (SCCS) method and a matched control cohort. In the SCCS method, an individual acts as their own control, so that only those who experience an event are included and serves as an alternative to the cohort or case-controlled study design. For comparative purposes, the researchers also used a more traditional matched cohort study. The period of study was February to September 2020 and the researchers calculated the incidence rate ratio (IRR) of both cardiovascular events following onset of COVID-19. Since an adverse cardiovascular event could have occurred on the same day as infection with COVID-19, it is possible that the event occurred independently of infection with the virus and the team therefore performed two separate analyses using either day 0 (i.e., day of exposure to COVID-19) and one excluding day 0.

Findings
Using the national registry, a total of 86,742 individuals were diagnosed with COVID-19 during the period of study with a median age of 48 years (43% male). In the SCCS study there were 186 acute myocardial infarctions, of whom 39 patients died. When day 0 was excluded, the IIR for acute myocardial infarction was 2.89 (95% CI 1.51 – 5.55) for the first week, 2.53 (95% CI 1.29 – 4.94) for the second week, although not significant for weeks 3 and 4 (IIR = 1.60, 95% CI 0.84 – 3.04). However, when day 0 was included, the IIR was significantly higher (IIR = 8.44, 95% CI 5.45 – 13.08) for the first and second weeks, but again, not significant for the third and fourth weeks. The corresponding values for ischaemic stroke were also significantly increased during the first week when day 0 was excluded (IIR = 2.97, 95% CI 1.71 – 5.15) and when day 0 was included (IIR = 6.18, 95% CI 4.06 – 9.42). In the matched cohort analysis, similar, significant increased risk were observed for both acute myocardial infarction and ischaemic stroke, irrespective of whether day 0 was included.
Based on these findings from two independent methods, the authors concluded that COVID-19 is an independent risk factor for both acute myocardial infarction and ischaemic stroke.

Citation
Katsoularis I et al. Risk of acute myocardial infarction and ischaemic stroke following COVID-19 in Sweden: a self-controlled case series and matched cohort study. Lancet 2021

Ticagrelor and aspirin superior to aspirin alone in ischaemic stroke

20th November 2020

It is known that only a quarter of patients who experience an ischaemic stroke with a disability will improve over time and are at an increased risk of subsequent death.

Thus any intervention that is able to reduce disability by reducing a subsequent ischaemic stroke is a major objective of immediate therapy. Although the use of aspirin in combination with clopidogrel has been shown to reduce the risk of further stroke and myocardial infarction, to date, evidence for a beneficial effect from adding ticagrelor to aspirin in terms of a reduction in the burden of disability after a stroke is lacking.

In an analysis, researchers from the Department of Neurology and Stroke Center, University of Paris, France, sought to examine whether combing both drugs reduced the 30-day risk of disabling stroke or death. Disability was measured using the modified Rankin Scale (mRS) which ranges from 0 to 6, in which 0-1 represents no disability, 2-5 increasing disability and 6, death. Patients were enrolled if they were 40 years of age and older, with a non-cardioembolic acute ischaemic stroke and a stroke scale score of 5 or less (higher scores indicate more severe stroke). They were randomised to ticagrelor or matching placebo 1:1 and a loading dose of 180mg was given as soon as possible after randomisation, followed by a daily dose of 180mg (90mg twice daily). In addition, all patients received 300 to 325 mg of aspirin on the first day, followed by 75 to 100mg until day 30. The main outcome measure was the time to the occurrence of disabling stroke or death within 30 days, measured by the mRS scale.

Findings
A total of 11,016 patients with a mean age of 68.1 years (42.6% female) were included in the study. A primary end point with a mRS > 1 at day 30 (that is. disabling stroke or death) occurred in 221 (4.0%) of patients taking ticagrelor and in 260 (4.7%) of those taking placebo. This provided a number needed to treat of 133. In other words, treating 133 patients with ticagrelor and aspirin for 30 days, avoided 1 disabling stroke or death at day 30. Furthermore, disability burden (based on the mRS scale) was reduced by 23%.

Reference
Amarenco P et al. Ticagrelor added to aspirin in acute ischemic stroke
or transient ischemic attack in prevention of disabling stroke: A randomized clinical trial. JAMA Neurol doi:10.1001/jamaneurol.2020.4396