Morning physical activity linked to lowest risk of cardiovascular disease

8th December 2022

Morning physical activity is associated with the greatest risk reduction for cardiovascular disease and stroke compared to a midday pattern

Individuals with higher levels of morning physical activity have the lowest risk of incident cardiovascular disease and stroke compared to those who have a midday peak pattern according to an analysis by Dutch researchers.

Cardiovascular diseases (CVD) are the leading cause of global mortality with an estimated 17.9 million lives lost each year. One modifiable factor linked to CVD is physical activity (PA) and data suggests that PA is not only associated with lower risk for of CVD but that the greatest benefit is seen for those who engage in higher levels of activity. However, emerging evidence suggests that the timing of PA may also be an important and influential factor. For example, in a study of more than 7,000 women, researchers found that women who are less active during morning hours may be at higher risk of obesity. In addition, an exercise-based trial which considered the impact of exercise timing on weight loss, showed that morning physical activity led to a significantly higher weight loss compared to evening activity. But mornings might not always be best as a study in men with type 2 diabetes observed that those who undertook high intensity interval training (HIIT) in an afternoon compared to morning session, had better glucose control.

In trying to better understand the impact of the timing of physical activity on the risk of incident CVD, the Dutch researchers collected physical activity data from participants in the UK-Biobank through triaxial accelerometer over a 7-day period which collected 24-hour mean activity levels. The team then used this data to create four different clusters of physical activity: cluster 1 represented the average pattern among the total biobank population which peaked around midday; cluster 2 were those with an early morning peak; cluster 3 a late morning peak and cluster 4, those with an evening peak. Regression analysis was used based on two models, the first (model 1) was adjusted for age and gender, and the second (model 2) additionally adjusted for body mass index and smoking status.

Morning physical activity and cardiovascular outcomes

A total of 86,657 individuals with a mean age of 61.6 years (58% female) were included and followed for 6 years during which time there were 2,911 cases of incident CVD and 796 strokes.

In an analysis based on model 1, participants who had higher levels of morning or later morning (clusters 2 and 3) physical activity, had a 11% (hazard ratio, HR = 0.89, 95% CI 0.80 – 0.99) and 16% (HR = 0.84, 95% CI 0.77 – 0.92) respectively, lower incidence of incident CVD compared to those in cluster 1. However, only those in cluster 3 (late morning physical activity) had a significantly reduced risk of stroke (HR = 0.83, 95% CI 0.70 – 0.98) and ischaemic stroke (HR = 0.79, 95% CI 0.64 – 0.97). Interestingly, when the researchers used model 2, the benefits were no longer statistically significant apart from a reduced risk of ischaemic stroke for those in cluster 3 (HR = 0.73, 95% CI 0.57 – 0.94).

In subgroup analysis based on gender and using model 2, there were statistically significant reductions in the risk of incident CVD but only among women who were either early and later morning exercisers. In addition, the risk of ischaemic stroke was only significantly lower among women in cluster 3 (HR = 0.56, 95% CI 0.38 – 0.83). When stratifying by participant levels of activity (i.e., either less or more active) and using model 2, although there were reductions in the risk of both CVD and stroke, among those who were more active, these reductions were non-significant.

The authors concluded that morning physical activity was associated with lower risks of incident cardiovascular diseases and that these findings highlighted the potential importance of chrono-activity in CVD prevention.

Citation
Albalak G et al. Setting your clock: associations between timing of objective physical activity and cardiovascular disease risk in the general population. Eur J Prev Cardiol 2022

Early Alzheimer’s disease cognitive decline slowed by lecanemab

An RCT has found that the cognitive decline in early Alzheimer’s disease and amyloid burden can be significantly reduced with lecanemab

The cognitive decline present in patients with early Alzheimer’s disease (AD) as well as the amyloid burden are significantly reduced compared to placebo, in those treated with lecanemab according to the results of a randomised, double-blind, phase 3 trial by US researchers.

There are an estimated 55 million across the world living with dementia of whom, approximately 60 to 70% have the most common form, Alzheimer’s disease. Currently available treatments such as cholinesterase inhibitors and memantine, do not alter disease progression but can help with some symptoms. Current thinking the pathophysiology of Alzheimer’s disease is based on the amyloid β-protein (Aβ peptides) theory which purports that in the early stages, there is an imbalance between production and clearance of Aβ peptides and which is a very early, often initiating factor in Alzheimer’s disease (AD). This leads to a build-up of Aβ peptides, and one therapeutic approach gaining interest is the use of monoclonal antibodies directed against amyloid-β (Aβ). In a 2021 systematic review of such antibodies directed against Aβ, there were clinical improvements but with small effect sizes.

In the current study, researchers examined the value of one such monoclonal antibody, lecanemab. Although in a phase 2b proof of concept trial in patients with early Alzheimer’s disease, the drug did not change clinical progression of the disease, it did demonstrate a reduction in brain amyloid accompanied by a consistent reduction of clinical decline in several endpoints. The current study was designed to evaluate the efficacy of lecanemab in patients with early Alzheimer’s disease, i.e., either mild cognitive impairment or mild dementia due to AD and with evidence of amyloid protein as assessed by either PET scan or CSF fluid measurement. Participants were randomised 1:1 to either intravenous lecanemab (10 mg/kg every two weeks) or placebo. The primary endpoint was the change from baseline after 18 months in the Clinical Dementia Rating Sum of Boxes (CDR-SB) which ranges from 0 to 18 and for which higher scores indicate greater cognitive impairment. There were several secondary endpoints, one of which was the change in amyloid burden on PET scanning whereas others assessed changes in cognition.

Early Alzheimer’s disease and change in cognition

A total of 1734 participants with a mean age of 71.2 years (52.3% women) were included and randomised to lecanemab (859) or placebo. The mean baseline CDR-SB score was approximately 3.2 in both groups.

The adjusted mean change from baseline in CDR-SB score was less with lecanemab (1.21) compared to placebo (1.66), i.e., there was less decline in cognition and the mean difference of -0.45 (95% CI -0.67 to -0.23) was statistically significant (p < 0.001).

In a subgroup of 698 participants, the mean amyloid level reduced by -55.48 centiloids in the lecanemab group and by 3.64 in the placebo group (mean difference = -59.12, 95% CI -62.64 to -55.60, p < 0.001).

There were also significant and positive changes favouring lecanemab in the cognition-related outcomes.

The overall incidence of adverse effects was similar between the two groups although lecanemab use resulted in a higher incidence of infusion-related reactions compared to placebo (26.4% vs 7.4%).

The authors concluded that the use of lecanemab reduced markers of amyloid in early Alzheimer’s disease and gave rise to moderately less decline on measures of cognition compared to placebo. They called for longer trials to determine the efficacy and safety of lecanemab in early Alzheimer’s disease.

Citation
van Dyck CH et al. Lecanemab in Early Alzheimer’s Disease. N Eng J Med 2022 DOI: 10.1056/NEJMoa2212948

GSK3036656 shows bactericidal activity after 14 days in pulmonary tuberculosis

GSK3036656 is a first-in-class antibacterial which has shown promise as a potential treatment for patients with tuberculosis

Preliminary findings suggest that GSK3036656 has the potential to be a component of future treatments to address the tuberculosis (TB) epidemic according the manufacturer GSK.

It has been estimated by the World Health Organisation that in 2021, tuberculosis affected 10.6 million people and led to 1.6 million deaths, so that globally, it was the 13th leading cause of death and the second leading infectious killer after COVID-19.

TB can affect bone, the central nervous system and many other organ systems, but is primarily a pulmonary disease and caused by Mycobacterium tuberculosis, which is carried in aerosol droplets onto lung alveolar surfaces. Current therapy involves the use of isoniazid and rifampicin for 6 months although both pyrazinamide and ethambutol are added during the first 2 months.

Given the need for prolonged treatment, the early findings for GSK3036656 are promising. The drug has a unique mode of action, targeting the aminoacyl-tRNA synthetase enzymes that mediate protein synthesis. Inhibiting these enzymes terminates protein synthesis and subsequently achieve an antibacterial action and GSK3036656 acts to inhibit one of these aminoacyl-tRNA synthetase enzymes, leucyl-tRNA synthetase.

GSK3036656 clinical efficacy

Data announced by GSK comes from a clinical trial designed to examine the early bactericidal activity, safety and tolerability of the drug in up to four sequential cohorts of subjects with rifampicin-susceptible tuberculosis. In the trial, participants were randomised in a 3:1 ratio to receive either GSK3036656 at doses 1 mg, 5 mg, 15 mg, and 30 mg or standard-of-care (SoC) regimen for drug sensitive TB.

The anti-mycobacterial activity was assessed in terms of its ability to reduce the number of viable TB cells which are able to multiply (i.e., colony forming units – CFU) and in the time to detect bacterial growth in culture (time to positivity – TTP). This latter marker indicates the time from the beginning of culture incubation to the detection of bacterial growth. Ideally, this marker should increase as a shorter TTP is likely to reflect a higher bacterial concentration in blood which may be associated with severe infection.

For the current study the primary outcome was the rate of change in log₁₀colony forming units (CFU)/ml in direct respiratory sputum samples from baseline to Day 14 (EBA CFU_0-14). The main secondary outcome was the rate of change in time to sputum culture positivity (EBA TTP) over the same timeframe (EBA TTP_0-14).

The results showed that after 14 days, of the four doses, GSK3036656 30 mg had the highest bactericidal activity with a decline in CFU of -0.138 log₁₀CFU/mL (95% CI -0.167 – 0.109) and an increase in TTP of 0.22 log₁₀CFU/mL (95% CI 0.019 – 0.024). Researchers also examined PET CT images of the lungs which showed a reduction in TB disease over 14 days in all participants taking GSK3036656 30mg. As well as proving to be effective, the treatment was generally well tolerated with no serious adverse events identified.

GSK will now be testing their oral therapy in Phase IIb/c studies as a part of different drug regimens to determine the appropriate partner agents and the optimal regimen durations. The overall aim is therefore to identify a GSK3036656-containing regimen with sufficient tolerability, efficacy and short enough duration to progress to Phase III with a high probability of success.

Subcutaneous foslevodopa foscarbidopa infusion improves control in Parkinson’s disease

An RCT has found that subcutaneous foslevodopa foscarbidopa improved symptom control in advanced Parkinson’s disease compared to oral therapy

A subcutaneous infusion of foslevodopa and foscarbidopa to patients with advanced Parkinson’s disease, led to an increase in treatment ‘on time’ and a reduction in ‘off time’ but without troublesome dyskinesia according to the results of a randomised, double-blind, double-dummy, active-controlled trial by US and Australian researchers.

Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disease characterised by both motor and non-motor features with the former symptoms attributed to the loss of striatal dopaminergic neurons. The incidence of Parkinson’s disease increases with age and globally, there are an estimated 10 million people living with the condition.

The gold standard treatment is levodopa (L-dopa) which has been used in clinical practice since the 1960’s and is a precursor of dopamine which crosses the blood-brain barrier, thus increasing dopamine production in the brain and helping to manage Parkinsonism symptoms. In addition, carbidopa, a decarboxylase inhibitor, is added to levodopa formulations to decrease the peripheral conversion of L-dopa to dopamine, reduce gastrointestinal side effects and increase central nervous system levodopa bioavailability. However, as PD progresses higher and more frequent doses of treatment are required, and this leads to dyskinesias at high dopamine concentrations and increased “off” time when levels fall back. Consequently, patients with advanced Parkinson’s experience periods where they have good disease control (referred to as ‘on time’) and times of poor motor control and mobility (i.e., ‘off time’). In an effort to mitigate these fluctuations in levodopa, researchers examined a soluble levodopa-carbidopa phosphate prodrug (foslevodopa foscarbidopa) and which releases the two main treatments once in the circulation, as a continuous, subcutaneous infusion. This early study demonstrated consistent and stable LD plasma exposure, supporting further studies of this treatment. 

For the current study, researchers undertook a 12-week randomised, double-blind, double-dummy, active-controlled study in patients with levodopa-responsive advanced Parkinson’s disease that was inadequately controlled on current therapy, including at least 2·5 hours of average daily off time. Participants were randomly assigned 1:1, to either continuous subcutaneous infusion of foslevodopa foscarbidopa plus oral placebo or to oral immediate-release levodopa-carbidopa plus continuous subcutaneous infusion of placebo solution. The primary efficacy endpoint was the change from baseline to week 12 in hours of average on time without troublesome dyskinesia and off time.

Foslevodopa foscarbidopa and treatment outcome

A total of 141 participants with a mean age of 66.4 years (30% women) were randomised to foslevodopa foscarbidopa (74) or oral levodopa carbidopa and the mean duration of PD was 8.58 years.

Compared to oral levodopa-carbidopa, participants assigned to foslevodopa foscarbidopa showed a significantly greater increase in on time without troublesome dyskinesia (mean change from baseline = 2·72 vs 0·97 hours) and this mean difference (MD) of 1.75 hours was statistically significant (p = 0.0083). There was also a significantly reduced ‘off time’ compared to oral therapy (MD = -1.79, p = 0.0054).

The most frequent adverse events in the foslevodopa foscarbidopa group were infusion site adverse events including erythema (27%), pain (26%), cellulitis (19%) and oedema (12%), most of which were non-serious and mild-moderate in severity.

The authors concluded that foslevodopa foscarbidopa has a favourable benefit-risk profile and represented a potential non-surgical alternative for patients with advanced Parkinson’s disease.

Citation
Soileau MJ et al. Safety and efficacy of continuous subcutaneous foslevodopa-foscarbidopa in patients with advanced Parkinson’s disease: a randomised, double-blind, active-controlled, phase 3 trial. Lancet Neurol 2022.

Longer rivaroxaban course reduces risk of recurrent venous thromboembolism

5th December 2022

A longer course of rivaroxaban following an isolated distant deep vein thrombosis significantly reduces the risk of a recurrent thrombosis

Taking rivaroxaban for 12 weeks rather than 6, following an isolated deep vein thrombosis, significantly reduces the risk of a recurrent thromboembolic event over the next two years according to the results of a randomised, double-blind, placebo-controlled trial by Italian researchers.

An isolated distal deep vein thrombosis (DVT) accounts for between a quarter and a half of all leg DVTs. Moreover, left untreated, an isolated distal DVT can extend to the proximal veins or cause a pulmonary embolism in between 1% and 22% of cases. Treatment of an isolated DVT involves the use of anticoagulants both therapeutically and prophylactically although the duration of the therapy to prevent recurrent events is uncertain. In a meta-analysis of studies, it was clearly shown that anticoagulant therapy reduced the risk of venous thromboembolism in patients. However, the review also found that there was a lower rate of recurrent venous thromboembolism in patients who received longer than 6 weeks of anticoagulant therapy.

With a suggestion that longer duration anticoagulation appeared to reduce the risk of a recurrent thromboembolic event, in the present study, researchers compared the impact on recurrent events of either a 6- or 12-week course of rivaroxaban. They recruited patients diagnosed with a symptomatic isolated distal DVT of the leg and who were then given rivaroxaban 15 mg twice daily for three weeks and then 20 mg daily for a further three weeks. At this point, participants who had not developed any thrombotic and haemorrhagic events, were randomised 1:1 to either continue with rivaroxaban 20 mg daily or matching placebo for a further 6 weeks. The primary efficacy outcome was a recurrent venous thromboembolism during the follow-up and the primary safety outcome was major bleeding, after randomisation.

Rivaroxaban and recurrent thromboembolism

A total of 402 individuals with a mean age of 65 years (58% women) were included and randomised to rivaroxaban (200) or placebo and followed for 24 months.

A recurrent thromboembolism occurred in 11% of rivaroxaban patients and 19% of those assigned to placebo (relative risk, RR = 0.59, 95% CI 0.36 – 0.95, p = 0.03). A recurrent isolated distal DVT recurred significantly less frequently, occurring in 8% and 15% of the rivaroxaban and placebo groups respectively (p = 0.02). However, a proximal or pulmonary embolism occurred in an equally small number of patients in each group and there were no major bleeding events.

The authors concluded that giving rivaroxaban for 3 months in patients with and isolated distal DVT who did not experience any events during the first 6 weeks of therapy reduced the risk of recurrent venous thromboembolism.

Citation
Ageno W et al. Rivaroxaban treatment for six weeks versus three months in patients with symptomatic isolated distal deep vein thrombosis: randomised controlled trial. BMJ 2022

Sutimlimab approved in Europe for cold agglutinin haemolytic anaemia

Sutimlimab (brand name Enjaymo) has been granted approval by the EMA for haemolytic anaemia in adult patients with cold agglutinin disease

According to the manufacturer, Sanofi, sutimlimab (Enjaymo) has been approved for the management of adult patients who have haemolytic anaemia with cold agglutinin disease.

Cold agglutinin disease (CAD) is a rare, autoimmune disorder and which is characterised by premature haemolysis (i.e., destruction of red blood cells). The termed “cold” refers to the fact that the autoantibodies (termed ‘cold agglutinins’) cause haemolysis at cold temperatures, usually 3 to 4^oC. Haemolytic anaemias are due to the production of autoantibodies (IgM) directed against surface antigens on red blood cells.

This IgM-antigen complex is a potent trigger of the classic complement pathway, binds to the C1 complement complex and which in turn, activates C1s, a C1 complex serine protease. CAD affects about one person per million every year, and mostly develops between the ages of 40 and 80 years. The condition impacts the lives of an estimated 12,000 people in the US, Europe and Japan and is associated with profound fatigue and increased risk of thromboembolic events and mortality.

Prior to the introduction of sutimlimab, there have been no effective treatments for CAD and supportive therapy such as cold avoidance has been of limited value although there has been some benefit from rituximab. Sutimlimab is a first-in-class, humanised monoclonal antibody designed to target and block C1s and in doing so, inhibits the activation of the complement cascade in the immune system and C1-activated haemolysis.

Sutimlimab clinical efficacy

Two clinical trials have provided the evidence to support the EMA approval of sutimlimab. The first trial, CADENZA, was a 26-week randomised, placebo-controlled phase 3 study, to assess safety and efficacy of the drug in patients with CAD and without a recent (i.e., within 6 months prior to enrolment) transfusion history. Enrolled participants had a haemoglobin (Hb) level less than 10.0 g/dL and were randomised 1:1 to sutimlimab (6.5 g if body weight was <75 kg; 7.5 g if body weight was ≥75 kg) or placebo and which was administered by IV infusion over 60 minutes on day 0, day 7, and every 14 days thereafter through week 25.

The primary endpoint was a composite of Hb increase from baseline of ≥1.5 g/dL at the treatment assessment time-point, absence of blood transfusions from week 5 to week 26, and avoidance of protocol-prohibited CAD medications from week 5 to week 26. Patients receiving sutimlimab had significantly greater odds of achieving the composite primary endpoint than placebo (odds ratio, OR = 15.9, 95% CI 2.9 – 88.0, p < 0.01).

In the second trial, CARDINAL, which was also for 26 weeks, the primary end point was a normalisation of the haemoglobin level to 12 g/dL or an increase in Hb of 2 g/dL or more from baseline and no red-cell transfusion or use of medications prohibited by the protocol. A total of 13 patients (54%) achieved the primary endpoint.

Enjaymo received a marketing authorisation valid throughout the EU on 15 November 2022 and this follows an FDA approval in February 2022.

Statin induced muscle symptoms not improved with vitamin D

Statin induced muscle symptoms may be helped by vitamin D but a recent trial found that supplementing did not affect the discontinuation rate

Supplementing with vitamin D did not reduce statin induced muscle aches and pains or discontinuation rates compared to placebo according to the results of a randomised trial by US researchers.

Statins therapy is a recognised treatment for reducing the risk of all-cause and cardiovascular mortality and cardiovascular events and these benefits are even greater among those with a higher baseline risk. Nevertheless, it has become widely recognised that statin induced muscular symptoms is a common real-world problem, even with average dosage statin therapy and which has a large impact on patients’ life. Moreover, these effects can lead to discontinuation and therefore reducing the cardiovascular disease benefit. In a 2015 meta-analysis, it was shown that low vitamin D levels were associated with myalgia in patients on statin therapy. In fact, a prospective study found in many cases, statin intolerance due to myalgia, myositis or myopathy in patients with low serum vitamin D levels, could be resolved by supplementing with the vitamin. However, to date, no randomised, placebo-controlled trials have addressed the value of supplementing with vitamin D on either statin induced muscular symptoms or drug discontinuation rates.

The current study was part of the VITAL trial that explored the value of both vitamin D and omega-3 fatty acids on cardiovascular and cancer outcomes. Researchers identified a sub cohort within VITAL prescribed statin therapy and who had been randomised to vitamin D or placebo. In both cohorts, baseline vitamin D levels had been recorded. The primary endpoint of the study was the development of muscle symptoms while taking a statin and the main secondary endpoint was statin discontinuation.

Statin induced muscle symptoms and vitamin D

Statins were initiated in 1033 participants with a mean age of 66.8 years (49% female) and 1050 individuals were assigned to placebo and followed for a mean of 4.8 years.

During follow-up, statin induced muscle symptoms were reported by 31% of those assigned to vitamin D and placebo, giving an adjusted odds ratio, OR of 0.97 (95% CI 0.80 – 1.18, p = 0.78).

In addition, the discontinuation rate was 13% in both groups (OR = 1.04, 95% CI 0.80 – 1.35, p = 0.78). When looking at the incidence of statin related muscle symptoms and serum vitamin D levels, a similar proportion of participants in both groups reported muscle problems where levels were either below 20 ng/mL or below 30 ng/mL.

The authors concluded that vitamin D supplementation did not prevent statin associated muscle symptoms or reduce the rate of drug discontinuation irrespective of pre-treatment vitamin D levels.

Citation
Hlatky MA et al. Statin-Associated Muscle Symptoms Among New Statin Users Randomly Assigned to Vitamin D or Placebo. JAMA Cardio 2022

Telmisartan fails to improve disease severity among patients hospitalised with COVID-19

An RCT has found that the use of telmisartan failed to improve disease severity among patients hospitalised with COVID-19 compared to placebo

Telmisartan given to patients hospitalised due to COVID-19 but not requiring oxygen, provided no benefit (in terms of improvement in disease severity score) compared to placebo according to the findings of randomised, double-blind, placebo-controlled trial by Australian and Indian researchers.

The COVID-19 virus gains entry into cells via the angiotensin converting enzyme 2 (ACE2) receptor and makes use of the serine protease TMPRSS2 for protein priming. ACE2 is a key regulator of the renin-angiotensin system, responsible for degrading angiotensin II and thereby counteracting its pro-inflammatory effect mediated through the angiotensin II type 1 receptor (ATR1). Consequently, it is possible that blockage of the ATR1) receptor with angiotensin receptor blockers (ARBs) such as telmisartan, may represent a safe, low-cost solution for reducing COVID-19 respiratory outcomes. In fact, a prospective study has already demonstrated that angiotensin converting enzyme inhibitors and ARBs are associated with reduced risks of COVID-19 disease after adjusting for a wide range of variables. However, randomised trials with ARBs to date have been equivocal. For example, one trial using losartan concluded that initiation of the drug to hospitalised COVID-19 patients did not improve the arterial partial pressure of oxygen to fraction of inspired oxygen ratio at 7 days compared to placebo. Furthermore, use of losartan did not reduce hospitalisations among outpatients prescribed the drug. In contrast, a study using telmisartan 80 mg twice daily, among patients hospitalised with COVID-19, showed that the drug reduced C-reactive protein (CRP) plasma levels compared to placebo.

In order to provide more data on the value of ARBs, in the current trial researchers randomised patients hospitalised with COVID-19, 1:1 to either telmisartan 40 mg daily or matching placebo. The primary outcome was COVID-19 disease severity (based on the World Health Organisation (WHO) Clinical Progression Scale) assessed after 14 days. The WHO scale ranges from 1 to 7 with lower scores indicating less severe disease.

Telmisartan and COVID-19 disease severity outcome

A total of 788 participants with a mean age of 49 years (64 % male) were randomised to either telmisartan (393) or placebo. The baseline overall WHO scale score was 3, equating to hospitalised but not requiring oxygen.

At day 14, the WHO score had improved to 1 (i.e., not admitted to hospital and with no activity limitations) in 384 telmisartan patients with 382 assigned to placebo (Odds ratio, OR = 1.51, 95% CI 1.02 – 2.23, p = 0.98). There were also no significant differences when the primary outcome was examined in different subgroups based on gender, co-morbidities or hypertension. In fact, the trial was stopped when a pre-specified futility rule was met.

Based on these findings, the authors concluded that there was no evidence of benefit, based on disease severity score, from the use of telmisartan in hospitalised patients with COVID-19 and who had predominately mild disease.

Citation
Jardine MJ et al. Angiotensin receptor blockers for the treatment of covid-19: pragmatic, adaptive, multicentre, phase 3, randomised controlled trial. BMJ 2022

Myocarditis rate higher in younger people following mRNA vaccination

Although the myocarditis rate after mRNA vaccination is low these rates appear to higher in those aged 18 – 30 compared to older adults

The overall myocarditis rate following a mRNA vaccination for COVID-19 is generally low but is higher than expected among those aged 12 to 29 years of age according to the findings of a post-marketing observational study by Canadian researchers.

Although there has been a huge uptake of COVID-19 vaccines, hesitancy remains a significant challenge with acceptance rates ranging from 53.6 to 84.4%. In fact, a US survey of 5,088,772 individuals identified that almost half (49.2%) of vaccine hesitant respondents reported fear of side effects. One such adverse effect following vaccination and which was not identified during the clinical trials was myocarditis with one US surveillance study concluding that the risk of myocarditis after receiving mRNA-based COVID-19 vaccines was increased across multiple age and sex strata and highest after the second vaccination dose in adolescent males and young men. However, little is known about the incidence of the condition following a third vaccination dose and this was the subject of the current study in which the Canadian team compared the myocarditis rate after a first, second and third dose compared to the background or expected rate.

The team used an integrated COVID-19 surveillance platform which contained all COVID-19-related data including infections and hospital or intensive care admissions. They focused on individuals aged 12 years and older and set the primary outcome as hospital admission or an emergency department visit for myocarditis.

Myocarditis rate and mRNA vaccination

During the study period (December 2020 to March 2022), a total of 1,025,385 doses of an mRNA vaccine (mRNA-1273 and BNT162b) were administered.

A total of 99 incident cases of myocarditis were identified within 7 days of vaccination, giving a rate per 100,000 of 0.97 (95% CI 0.78 – 1.17). The expected rate was 0.13 (95% CI 0.06 – 0.28) so that the observed:expected (OE) ratio was 14.81. The observed rate was higher in males than females (1.64 vs 0.35) and occurred in younger men (median age males = 28 vs median age females = 45).

Within 21 days following vaccination, there were 141 cases of myocarditis with an OE ratio of 7.03 (95% CI 5.92 – 8.29). As with the 7-day risk period, the 21-day incidence rate was higher in men than women (2.15 vs 0.67). In fact, when researchers looked at the incidence rate across different ages, the rates were much higher among those aged 12 – 29. For example, the incidence rate was 2.95 (ages 12 – 17) and 2.97 (ages 18 – 29) compared to 0.77 (ages 50 – 59) and 0.71 (ages 60 – 69).

Interestingly, the incidence myocarditis in both the 7 and 21-day post-vaccination periods reduced after the second dose. For example, the incidence rate during the first 7 days after the first vaccination was 0.18, 1.90 after the second dose but 0.76 after the third dose.

When comparing vaccines, there was a much higher rate of myocarditis following mRNA-1273 compared to BNT162b (1.44 vs 0.74). In addition, the incidence rate was highest among males aged 18 – 29 after the second dose (22.97 vs 5.84, mRNA vs BNT162b).

The authors concluded that although absolute rates of myocarditis were low, their findings support the preferential use of the BNT162b2 vaccine over the mRNA-1273 vaccine for people aged 18-29 years.

Citation
Naveed Z et al. Observed versus expected rates of myocarditis after SARS-CoV-2 vaccination: a population-based cohort study. CMAJ 2022

Higher olive oil intake linked to lower CVD and all-cause mortality risk

2nd December 2022

An analysis suggests that a higher olive oil intake is inversely associated with the risk of cardiovascular and all-cause mortality

An olive oil intake of around 20g/day is associated with a reduced risk of both cardiovascular and all-cause mortality according to the results of a meta-analysis of prospective studies by Greek and Chinese researchers.

Olive oil contains a number of plant polyphenols that have health benefits including anti-mutagenic, anti-inflammatory, anti-thrombotic, anti-atherogenic, and anti-allergic effects. In addition, the monounsaturated fatty acids present in olive oil and in particular, oleic acid, might have positive impacts on lipid peroxidation. In fact, a 2019 network meta-analysis examining the role of olive oil in the modification of metabolic factors such as glucose and circulating lipids, found that olive oil polyphenols increased HDL-cholesterol and that overall, the beneficial effect of olive oil were more pronounced in subjects with an established metabolic syndrome or other chronic conditions/diseases. Furthermore, while some analyses indicate that a higher olive oil intake is associated with lower risk of coronary heart disease, other studies that have examined the link between dietary fat intake (including olive oil) and cardiovascular disease (CVD) events, have found no association.

Trying to provide more definitive evidence, in the present study, researchers performed a meta-analysis of prospective cohort studies to investigate the relationship between olive oil consumption and risk of CVD and all-cause mortality. The team included studies in which the exposure of interest was olive oil consumption and where the recorded outcomes were total CVD or all-cause mortality.

Olive oil intake and cardiovascular and all-cause mortality outcomes

A total of 13 prospective cohort studies were included and the duration of follow-up ranged from 4 to 28 years. Most of the studies collected the dietary data on olive oil intake from food-frequency questionnaires.

In an assessment of CVD risk, the pooled relative risk (RR) for the highest versus the lowest olive oil intake was 0.85 (95% CI 0.77 – 0.93, p < 0.001). In subgroup analysis, this relationship was independent of the region of study, sample size, follow-up duration, sex, or even the type of olive oil.

In terms of all-cause mortality and again comparing the highest and the lowest levels of intake, there was a significant reduction in all-cause mortality (RR: 0.83, 95% CI 0.77 –0.90, p < 0.001). As with CVD risk, there was no significant impact of any of the examined factors in subgroup analysis.

When the researchers looked at the amount of olive oil consumed, the relative risk for CVD for each 5g/day increment was 0.96 (95% CI 0.93 – 0.99, p = 0.005) and this was a similar order of magnitude for all-cause mortality. Interestingly, the reduction in CVD risk was largely attenuated with an intake above 20 g/day and there were also no preventive mortality effects when intake exceeded 20 g/day.

The authors concluded that consuming up to 20g/day of olive oil was associated with a reduced CVD and all-cause mortality risk but that there were no apparent benefits from exceeding this amount.

Citation
Xia M et al. Olive oil consumption and risk of cardiovascular disease and all-cause mortality: A meta-analysis of prospective cohort studies. Front Nutr 2022