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15th November 2022
The use of pemafibrate in patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia and low levels of HLD cholesterol, failed to lower the incidence of adverse cardiovascular outcomes compared to placebo according to a randomised, doubler-blind, placebo-controlled trial by US researchers.
Elevated levels of triglycerides confer an increased risk of cardiovascular disease but whether reducing levels also reduces adverse cardiovascular events such as myocardial infarction is actually less clear. For example, in a trial with fenofibrate while there was a 25% reduction in mean triglyceride levels, there was no difference in the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke. Pemafibrate is a peroxisome proliferator-activated receptor modulator which lowers plasma triglycerides and increase HDL cholesterol and both of these effects are associated with cardiovascular benefit. Moreover, the drug is superior to fenofibrate at lowering serum triglycerides and has a good renal and hepatic safety profile.
But whether the drug also reduced adverse cardiovascular outcomes in patients with type 2 diabetes is uncertain and was the subject of the present trial. Included patients had triglyceride levels between 2.3 and 5.6 mmol/l and HDL cholesterol levels < 1 mmol/l. The primary endpoint was the first occurrence of a major adverse cardiovascular event and which was a composite that included myocardial infarction, ischaemic stroke and hospitalisation for unstable angina.
Pemafibrate and cardiovascular outcomes
A total of 10,497 patients with a median age of 64 years (27.5% female) were included and randomised to pemafibrate (5,240) or placebo. and followed by a median of 3.4 years. Two thirds of those enrolled were a secondary prevention cohort and 95% of the whole study population were prescribed a statin.
The median reduction in triglyceride levels was 31.1% in the pemafibrate group and 6.9% in the placebo group. In addition, HDL cholesterol levels rose by 8.3% in those taking pemafibrate but only 3.1% in the placebo arm.
The primary endpoint occurred in a similar number of patients and the difference was not significant (Hazard ratio, HR = 1.03, 95% CI 0.91 – 1.15, p = 0.67). Mortality from any cause was also similar and non-significant (HR = 1.04, 95% CI 0.91 – 1.20).
The authors concluded that while pemafibrate reduced triglyceride levels by over 30% in patients with type 2 diabetes, there was no significant reduction in the risk of adverse cardiovascular events.
Citation
Das Pradham A et al. Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk N Eng J Med 2022
4th November 2022
There is an elevated risk of several adverse cardiovascular outcomes among patients hospitalised with COVID-19 but the risk of both venous thromboembolism and death is still significant in non-hospitalised cases compared to a group of uninfected, matched controls. These were the key findings from a prospective analysis of participants in the UK Biobank by UK researchers.
Studies have suggested that infection with COVID-19 is a risk factor for acute myocardial infarction and ischaemic stroke. Moreover, a retrospective study has revealed how cardiac arrhythmia is also a clinical sequelae following an acute infection with the virus. Nevertheless, whether these adverse cardiovascular events are restricted to patients with more severe disease, i.e., those who are hospitalised, or whether there is an increased risk among patients with less severe disease remains unclear. In the present study, UK researchers examined if exposure to COVID-19 was associated with incident cardiovascular disease and mortality. The used data from the UK Biobank and identified those infected with COVID-19, linking to Public Health England laboratory information to identify PCR test results. These individuals were then propensity matched to 2 control patients based on a number of factors including age, sex, body mass index, various co-morbidities (e.g., hypertension, diabetes), smoking status and ethnicity. The researchers considered several adverse cardiovascular outcomes including myocardial infarction (MI), venous thromboembolism (VTE), cardiovascular disease (CVD) mortality, stroke, heart failure, atrial fibrillation and pericarditis. In a further analysis, the team assessed if the risk of these adverse cardiovascular outcomes reduced over time.
Adverse cardiovascular outcomes and COVID-19
A total of 471,227 individuals with a median age of 69 years (44.7% male) were included in the analysis which included 17,871 COVID-19 patient cases. Individuals were followed-up for an average of 141 days. Among those with COVID-19, the majority (80%) were not hospitalised and in the hospitalised cohort (3567), 75.7% had primary diagnosis of COVID-19 whereas the remainder had COVID-19 recorded as a secondary diagnosis.
Among non-hospitalised COVID-19 patients (14,304), there was a more than two-fold higher risk of VTE compared to uninfected controls (Hazard ratio, HR = 2.74, 95% CI 1.38 – 5.45, p = 0.004). Additionally, there was a significantly increased risk of death (HR = 10.23, 95% 7.63 – 13.7, p < 0.0001). Interestingly, the risk of incident MI among the non-hospitalised COVID-19 group was significantly lower (HR = 0.19, 95% CI 0.06 – 0.65, p = 0.008).
In contrast to the non-hospitalised group, patients hospitalised with COVID-19 had significantly elevated risks of MI (HR = 9.9), heart failure (HR = 21.6), atrial fibrillation (HR = 14.9), VTE (HR = 27.6) and cardiovascular mortality (HR = 8.76). Furthermore, there were also increased adverse cardiovascular risks in patients for whom COVID-19 was the secondary diagnosis, e.g., MI (HR = 22.2), heart failure (HR = 13.1), atrial fibrillation (HR = 29.3) and cardiovascular mortality (HR = 14.6).
Next researchers examined the interaction with time and considered the risk of events 30 days before and after their acute infection. Although the risks for atrial fibrillation, VTE and heart failure were largely attenuated after 30 days, these risks still remained significant, e.g., for VTE (HR = 3.97) and heart failure (HR = 2.78).
The authors concluded that while infection with COVID-19 is associated with a higher risk of adverse cardiovascular outcomes, the risks are largely confined to hospitalised patients and highest within the first 30 days following infection.
Citation
Raisi-Estabragh Z et al. Cardiovascular disease and mortality sequelae of COVID-19 in the UK Biobank Heart 2022
3rd November 2022
Elevated levels of both C-reactive protein (CRP) levels and lipoprotein A (LpA) in those with coronary heart disease undergoing a percutaneous coronary intervention (PCI) result in a greater risk of major adverse cardiovascular and cerebrovascular events according to the results of a study by Chinese researchers.
The risk of a recurrent vascular event in patients with established cardiovascular disease remains even in those with optimal treatment. For example, one study has found that when risk factors are modified to achieve guideline recommended targets, the residual 10-year risk while < 10% in 47% of patients is >30% in 9%. One factor associated with this residual risk is inflammation and it has been found that patients who have low CRP levels after statin therapy, had better clinical outcomes than those with higher CRP levels, regardless of the resultant level of LDL cholesterol. Furthermore, clinical and genetic research studies have also shown that lipoprotein A has a crucial role in the pathogenesis of cardiovascular disease. In fact, it has been found that elevated LpA levels during treatment of cardiovascular disease are related to cardiovascular-related death when CRP levels are > 2 mg/L. Nevertheless, much less is known about the relationship between CRP and LpA levels in patients undergoing PCI.
For the present study, the Chinese team set out to examine the joint and independent association between LpA and CRP levels among patients with coronary artery disease who underwent a PCI. The researchers used data from a prospective, observational cohort at a national tertiary care centre and identified patients undergoing PCI and where LpA and CRP levels had been measured. Patients were followed-up for 5 years after discharge and the team set the primary endpoint as major adverse cardiac and cerebrovascular events (MACCE), which was a composite of all-cause mortality, myocardial infarction, unplanned revascularisation and ischaemic stroke.
C-reactive protein and lipoprotein A levels and MACCE
A total of 10,424 patients with a mean age of 58.4 years (77.2% male) were included in the analysis. The median level of LpA was 18.53 mg/dL and CRP 1.62 mg/L. After 5 years of follow-up, the primary endpoint (MACCE) occurred in 20.5% of participants.
Multivariable analysis showed that when LpA levels were > 30 mg/dL there was a higher risk of MACCE (Hazard ratio, HR = 1.14, 95% CI 1.05 – 1.25, p < 0.05) compared to levels below 30 mg/dL. Similarly, CRP levels above 2 mg/L were also significantly associated with a greater risk of MACCE (HR = 1.10, 95% CI 1.01 – 1.20, p < 0.05).
But when both LpA and CRP were higher than 30 mg/dL and 2 mg/L respectively, in fully adjusted models, there was a 22% higher risk of MACCE (HR = 1.22, 95% CI 1.07 – 1.39, p < 0.05).
The authors concluded that elevated LpA levels were associated with a higher risk of adverse cardiovascular events and that this risk was even higher when C-reactive protein levels were above 2 mg/L. They suggested that measuring levels of both could help identify high-risk individuals and who might benefit from further therapeutic interventions.
Citation
Yuan D et al. Lipoprotein(a), high-sensitivity C-reactive protein, and cardiovascular risk in patients undergoing percutaneous coronary intervention Atherosclerosis 2022
1st September 2022
A polypill which contains aspirin, ramipril and atorvastatin given to patients who have experienced a previous myocardial infarction reduces the risk of a subsequent adverse cardiovascular outcome according to the findings of a randomised trial by the SECURE investigators.
Medication adherence is used to define the extent to which a patient takes medication as prescribed by their healthcare providers. Higher levels of adherence are associated with better treatment outcomes although poor adherence leads to considerable morbidity, mortality, and avoidable health care costs. In a meta-analysis specifically focusing on cardiovascular medicine, only 60% of included participants had good adherence, i.e., ≥ 80%. However, the authors estimated that ∼9% of all cardiovascular disease (CVD) cases could be attributable to poor adherence. In contrast, good adherence to cardiac therapies could be associated with a 20% lower risk of CVD and a 35% reduced risk of all-cause mortality, irrespective of most clinically relevant patient and study characteristics.
The use of a polypill is designed to simplify a medication regime and in a meta-analysis of three large trials, it was concluded that the fixed-dose combination (i.e., polypill) substantially reduced cardiovascular disease, myocardial infarction, stroke, revascularisation, and cardiovascular death in primary cardiovascular disease prevention. But it is less clear whether the polypill is an effective strategy for secondary prevention. As a result, researchers undertook the Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE) trial, which compared the efficacy of a polypill compared to usual care as a means of reducing major cardiovascular outcomes in older patients. To be included in the trial, patients were required to have a history of a myocardial infarction within the previous six months and at least one risk factor such as diabetes, kidney dysfunction or prior stroke, although those receiving oral anticoagulation were excluded. Individuals were randomised 1:1 to the polypill which contained aspirin 100 mg, ramipril 2.5, 5 or 10 mg and atorvastatin 40 mg although the dose of statin could be reduced to 20 mg (using a similar lower dose polypill) based on blood test results and a patient’s history. Treatment adherence was assessed using the Morisky Medication Adherence Scale (MMAS), which ranges from 0 to 8 with higher scores reflecting better adherence. The primary outcome was a composite of cardiovascular death, non-fatal type 1 myocardial infarction, non-fatal ischaemic stroke or urgent coronary revascularisation. A key secondary outcome was a composite of cardiovascular death, non-fatal type 1 myocardial infarction, non-fatal ischaemic stroke.
Polypill and cardiovascular outcomes
A total of 2466 patients were randomised, 1237 with a mean age of 75.8 years (69% male) to the polypill and followed for a a median of 36 months.
The primary outcome occurred in 9.5% of those assigned to the polypill and 12.7% of those assigned to usual care (hazard ratio, HR = 0.76, 95% CI 0.60 – 0.96, p = 0.02). The main secondary outcome also occurred in less patients taking the polypill (HR = 0.70, 95% CI 0.54 – 0.90, P = 0.005).
After 24 months, 74.1% of those receiving the fixed-dose combination had a high level of adherence (MMAS score of 8) compared to 63.2% in the usual care group.
The authors concluded that the use of a cardiovascular polypill could serve as a substitute for separate drugs and decrease the risk of recurrent cardiovascular events.
Citation
Castellano JM et al. Polypill Strategy in Secondary Cardiovascular Prevention N Eng J Med 2022
1st June 2022
A 2018 global review of cardiovascular disease (CVD) in patients with type 2 diabetes found a prevalence of 32.2% and noted that CVD mortality accounts for approximately half of all deaths in these patients. In 1998, results from the UK Prospective Diabetes Study showed that metformin use reduced all-cause mortality by 36%. Moreover, a study of the long-term effects of lifestyle interventions in people with impaired glucose tolerance found that such interventions delayed the onset of type 2 diabetes, as well as reducing the incidence of cardiovascular and all-cause mortality. With a potential cardiovascular and mortality benefit from both metformin or lifestyle interventions aimed at weight reduction and increased physical activity, the Diabetes Prevention Program Research Group examined the value of each intervention in a randomised trial (the Diabetes Prevention Program (DPP) study) which was published in 2002. The study assigned 3234 non-diabetic participants with elevated fasting and post-load plasma glucose concentrations, to either placebo, metformin (850mg twice daily), or a lifestyle-modification programme. The results showed that both metformin and lifestyle interventions, reduced the incidence of diabetes in persons at high risk by 58% and 31% respectively over an average of 2.8 years.
Based on these findings, the researchers invited pre-diabetic participants from the original DPP to enrol in a follow-on study to determine whether metformin and lifestyle interventions could reduce the incidence of adverse cardiovascular outcomes. Participants continued with the same dose of metformin (850mg twice daily) and the lifestyle intervention. The primary outcome was the first occurrence of a major cardiovascular event which was pre-specified as non-fatal myocardial infarction, non-fatal stroke or fatal CVD.
Metformin or lifestyle interventions and CVD outcomes
A total of 3234 individuals with a baseline mean age of 51 years (68% women) and with a mean fasting blood insulin level of 160 pmol/L, were followed for a median of 21 years and of whom, 1073 were assigned to placebo, 1082 metformin and 1079 a lifestyle intervention.
During the period of follow-up, 310 individuals experienced an adverse cardiovascular event; 101 for patients assigned to metformin and 111 to the lifestyle intervention. These events did not differ significantly compared with placebo (hazard ratio, HR = 1.03, 95% CI 0.78 – 1.37, p = 0.81, metformin vs placebo) and a hazard ratio of 1.14 (95% CI 0.87 – 1.40, p = 0.34) for lifestyle vs placebo. When considering non-fatal myocardial infarctions and strokes separately, there no significant differences for either intervention compared to placebo.
The authors concluded that despite the value of each intervention to reduce the risk of developing overt type 2 diabetes, neither was associated with a reduced risk of cardiovascular events in pre-diabetic patients.
Citation
Goldberg RB et al. Effects of Long-term Metformin and Lifestyle Interventions on Cardiovascular Events in the Diabetes Prevention Program and Its Outcome Study Circulation 2022
31st May 2022
SGLT-2 inhibitors and metformin when initiated for patients with type 2 diabetes have been shown to have the same cardiovascular outcomes such as myocardial infarction, stroke and death although use of SFLT-2 inhibitors is associated with a slightly lower risk of both hospitalisation and death due to heart failure. These were the key findings from a cohort study analysis by a team based at Harvard University, Boston, USA.
Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) such as empagliflozin, although primarily used in the management of type 2 diabetes, have also been shown to reduce cardiovascular events when added to standard care. In addition, evidence from the UK Prospective Diabetes Study showed that patients assigned to metformin had risk reductions of 32% for any diabetes-related endpoint, 42% for diabetes-related death and 36% for all-cause mortality. Thus, although SGLT-2 inhibitors and metformin are primarily diabetic treatments, it is apparent that both are associated with cardiovascular benefits in diabetic patients. Furthermore, using SGLT-2 inhibitors and metformin as a first-line combination therapy for patients with type 2 diabetes has been suggested as a cost-effective strategy for the management of both type2 diabetes and cardiovascular disease. However, what remains uncertain, is the relative cardiovascular benefits of using either a SGLT-2 inhibitor or metformin as mono-therapy in patients with type 2 diabetes.
In the present study, the US team used information held within two large commercial health insurance databases to compare the incidence of cardiovascular events when either treatment was initiated as mono-therapy. The researchers focused on adults (> 18 years of age) with a diagnosis of type 2 diabetes and those who had new prescription for SGLT-2 inhibitors or metformin. Individuals were followed-up until the occurrence of a study outcome, death or discontinuation of treatment. There were two primary outcomes of interest; a composite of acute myocardial infarction, stroke or all-cause mortality (referred to as ‘mortality’) and a composite of hospitalisation for heart failure or all-cause mortality (HHF). For secondary outcomes, the authors individually assessed the effect of either treatment on different components of the two composites. Individuals were propensity-matched 1:2 (SGLT-2i: metformin).
SGLT-2 inhibitors and metformin
A total of 8,613 first-time SGLT-2i patients were matched to 17,226 metformin users, with a mean age of 60 years (approximately 51% male). Individuals prescribed SGLT-2i were followed for a mean of 10.7 months and metformin users for 12.2 months.
The risk of the composite mortality outcome was not significantly different between the two treatments (hazard ratio, HR = 0.96, 95% CI 0.77 – 1.19). However, SGLT-2i inhibitor use was associated with a lower risk of HHF (HR = 0.80, 95% CI 0.66 – 0.97).
When each of the outcomes were analysed separately, only hospitalisation for heart failure was significantly lower (HR = 0.78, 95% CI 0.62 – 0.97) in those prescribed a SGLT-2i.
Based on these findings, the authors concluded that first-line treatment of type 2 diabetes with SGLT-2i or metformin was associated with a similar risk of adverse cardiovascular outcomes although SGLT-2i use was linked to a lower risk of hospitalisation and mortality due to heart failure. However, the called for a randomised trial to provide more robust evidence to confirm these findings.
Citation
Shin JH et al. Cardiovascular Outcomes in Patients Initiating First-Line Treatment of Type 2 Diabetes With Sodium–Glucose Cotransporter-2 Inhibitors Versus Metformin. A Cohort Study Ann Intern Med 2022
27th April 2022
A higher avocado intake reduces the risk of cardiovascular disease according to the findings from two large prospective studies reported by researchers from Harvard T.H. Chan School of Public Health, Boston, USA.
Cardiovascular disease (and which also includes coronary heart disease) represents the leading cause of death globally. Interestingly, studies suggest that there is a valid association between several dietary factors and patterns with coronary heart disease. One healthy food is avocado, which contains a large amount (71%) of monounsaturated fatty acids and helps to promote healthy blood lipid profiles, enhancing the bioavailability of fat soluble vitamins and phyto-chemicals from the avocado or other fruits and vegetables. In fact, there are data showing how avocado consumption is associated with a reduced risk of metabolic syndrome and other work has indicated that eating at least one avocado each day provides a beneficial effect on cardio-metabolic risk factors that extended beyond their heart-healthy fatty acid profile. Furthermore, a recent systematic review found that avocado intake increased serum HDL-cholesterol concentrations, prompting the authors to suggest that the association between avocado intake and cardiovascular risk should be confirmed by well-conducted prospective observational studies or long-term trials.
For the present study, the US team examined the association between a higher avocado intake and cardiovascular outcomes. They turned to data held in both the Nurse’s Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), which are two prospective cohort studies which were initiated in the 1970’s and 1980’s respectively. In both of these cohort studies, participants were asked to complete validated questionnaires asking about lifestyle and diet every 2 years and from this information, the researchers were able to determine how much avocado was consumed. This was then categorised as never or less than once a month, 1 – 3 times per month, weekly and > twice a week. The primary outcome of interest was incident cases of total cardiovascular disease, which was a composite of several adverse cardiovascular outcomes e.g., fatal coronary heart disease. The main secondary outcome related to strokes.
Higher avocado intake and adverse cardiovascular outcomes
A total of 68,786 women from the NHS and 41,701 men from the HPFS who were free of cardiovascular disease and stroke at baseline were included and followed for 30 years (median for men was 13.3 years and 14.2 for women). During follow-up there were a total of 14,274 cases of cardiovascular disease (CVD) in both NHS and HPFS.
After adjustments were made for dietary and lifestyle factors, compared to those who did not eat avocados, individuals with a higher avocado intake (> twice/week) week had a 16% lower risk of CVD (hazard ratio, HR = 0.84, 95% CI 0.75 – 0.95) and a 21% lower risk of coronary heart disease (HR = 0.79, 95% CI 0.68 – 0.91). However, there was no significant reduction for stroke.
The authors calculated that for each half serving/day increase in avocado intake, the pooled hazard ratio for CVD was 0.80. In fact, the authors added that by replacing half a serving/day of margarine, butter, egg, yoghurt, cheese or processed meats with the equivalent amount of avocado would be associated with a 16 to 22% lower risk of CVD.
Citation
Pacheco LS et al. Avocado Consumption and Risk of Cardiovascular Disease in US Adults J Am Heart Assoc 2022
11th April 2022
Coffee intake (whether ground or instant) of at least 2 – 3 cups per day has been found to be associated with significant reductions in the risk of developing cardiovascular disease (CVD), arrhythmias, as well as cardiovascular and all-cause mortality. This is according to the findings of three studies analysing data held within the UK Biobank.
Although coffee contains caffeine, it is also a rich source of phenolic compounds including chlorogenic acids which contribute to coffee’s antioxidant activity. Moreover, coffee intake at midlife has been associated with a lower risk of dementia and Alzheimer’s disease compared with those drinking no or only little coffee. However, the cardiovascular benefits from drinking coffee are less clear with one study finding that in men, the risk of nonfatal myocardial infarction was not associated with coffee drinking. In contrast, a large prospective study observed that coffee consumption was inversely associated with total and cause-specific mortality.
Due to these conflicting results, three studies presented at the American College of Cardiology Scientific Session have examined cardiovascular and mortality benefits disease associated with coffee intake.
In the first study, effects of habitual coffee consumption on incident cardiovascular disease, arrhythmia, and mortality: findings from UK BIOBANK, researchers from the University of Melbourne, Australia, included data from 382,535 individuals with a mean age of 57 years (52% female) and assessed the effect of coffee intake over a 10-year period. The results showed that a coffee intake of 2 – 3 cups/day was significantly associated (for all associations, p < 0.01) with the lowest risk for developing CVD (Hazard ratio, HR = 0.91, 95% CI 0.88 – 0.94), coronary heart disease (HR = 0.90), heart failure (HR = 0.85) and all-cause mortality (HR = 0.86). They found a U-shaped relationship between higher coffee intake and incident arrhythmia which was also lowest at 2 – 3 cups/day (HR = 0.92).
In the second study, regular coffee intake is associated with improved mortality in prevalent cardiovascular disease, the Australian team focused on the effect of coffee in patients with existing cardiovascular disease. With a population of 502,543 individuals, again followed for 10 years, CVD was subsequently diagnosed in 342,279 participants, of whom, 19.6% died. The team found that coffee intake was safe at all levels and that survival was improved again at 2 – 3 cups/day (HR = 0.92, 95% CI 0.86 – 0.99, p = 0.03). Among 24,111 participants diagnosed with an arrhythmia, drinking only one cup of coffee per day was associated with the lowest mortality risk (HR = 0.85) and specifically in those with atrial fibrillation or flutter, one cup of coffee per day was associated with improved survival (HR = 0.82, p < 0.01).
In the third study, ground, instant or decaffeinated coffee? Impact of different coffee subtypes on incident arrhythmia, cardiovascular disease and mortality, the team wondered if there were any differential cardiovascular benefits depending on how the coffee was prepared. Overall, they found that drinking between 1 and 5 cups of coffee per day were associated with a reduced risk of arrhythmia, CVD, CHD, heart failure and stroke. The greatest reduction in risk for CVD was seen with drinking 2 – 3 cups/day of ground coffee (HR = 0.83, 95% CI 0.79 – 0.87) but there was still a significant, albeit smaller, reduction in risk from consuming instant coffee (HR = 0.91, 95% CI 0.88 – 0.95).
Finally, in the third study, the authors showed that drinking 2 – 3 cups/day of decaffeinated coffee was associated with a mortality benefit (HR = 0.85, 95% CI 0.80 – 0.91, p < 0.01), leading the authors to conclude that non-caffeine compounds within coffee are likely to be important factors associated with greater survival among coffee drinkers.
Given these findings, the authors suggested that coffee intake should be considered as part of a healthy diet.
24th March 2022
The use of a cocoa extract containing flavanols did not reduce the overall incidence of cardiovascular events but did lower the incidence of cardiovascular deaths. This was the main finding of a randomised trial by researchers from the Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, US.
Flavan-3-ols, which are a subclass of flavonoids, represent a type of poly-phenolic substances which are present in a range of plants such as cocoa and cocoa containing foods such as chocolate. Furthermore, research demonstrates a beneficial effect of cocoa on blood pressure, insulin resistance, and vascular and platelet function. As well as flavonoids, a cocoa extract typically contains other ingredients such as epicatechin and the methylxanthines, theobromine and caffeine. In fact, studies suggest how the presence of these latter components mediate an increased plasma concentration of epicatechin metabolites that coincides with enhanced vascular effects. To date, much research which has focused on the cardiovascular effect of cocoa containing products such as chocolate, and suggests a small inverse association between consumption and both coronary heart disease and stroke. However, there is a lack of data from large-scale trials, on the cardiovascular benefits of a flavanol-rich cocoa extract which contains all the bioactive compounds present in the cocoa bean.
As a result, the US team undertook the Cocoa Supplement and Multivitamin Outcome Study (COSMOS), a pragmatic, randomised trial which sought to examine the effect of a cocoa extract on cardiovascular disease and cancer in older adults. For the present study, the authors have only reported on the cardiovascular outcomes.
The team recruited adults over 65 years of age, who were initially free of major cardiovascular disease and given either a cocoa extract containing 500 mg/day of cocoa flavanols and a multivitamin supplement or matching placebo. All participants were required to stop taking cocoa supplements (although chocolate could still be eaten) and a blood biomarker of flavanol intake were initially measured and repeated after years 1, 2 and 3. The primary outcome was a composite of total cardiovascular disease (CVD) outcomes including myocardial infarction (MI), stroke, cardiovascular mortality and coronary revascularisation. The authors then set the secondary outcomes as the individual components of the primary outcome, i.e., cardiovascular death, stroke etc.
Cocoa extract and cardiovascular outcomes
A total of 21,442 individuals with a mean age of 72.1 years (59.1% female) were randomised to cocoa (10,719) or placebo and followed for a median of 3.6 years. Based on an analysis of plasma samples, there was a three-fold higher increase compared to placebo, in the levels of flavanol biomarker and this did not differ between follow-up assessment.
During the follow-up period there were 866 confirmed cardiovascular events, 410 in those taking the cocoa extract and 456 in the placebo group, giving a hazard ratio, HR of 0.90 (95% CI 0.78 – 1.02, p = 0.11).
For the secondary outcomes, only cardiovascular death was significantly different (HR = 0.73, 95% CI 0.54 – 0.98).
The authors concluded that while the cocoa extract did not reduce the primary outcome, longer follow-up of trial participants may further elucidate the relationship between consumption of the extract and cardiovascular events.
Citation
Sesso HD et al. Effect of Cocoa Flavanol Supplementation for Prevention of Cardiovascular Disease Events: The COSMOS Randomized Clinical Trial Am J Clin Nutr 2022
18th February 2022
The cardiovascular disease burden among those who survived an infection with COVID-19 appears to be huge and present even for those not originally hospitalised during the acute phase of their infection. This is according to a study by researchers from the Clinical Epidemiology Center, Research and Development Service, Missouri, US.
Studies among patients who were originally hospitalised because of a COVID-19 infection have found higher rates of subsequent cardiovascular disease. In fact, it has been found that COVID-19 is a risk factor for acute myocardial infarction and ischaemic stroke. However, many of the studies linking infection with COVID-19 and subsequent adverse cardiovascular outcomes relate to patients who were originally hospitalised because of their infection. As a result, these individuals might have had a number of co-morbidities that increased their cardiovascular disease risk burden. In the absence of a comprehensive assessment of the cardiovascular effects of COVID-19 at 12 months and among individuals treated in different care settings, the authors of the current study, set out to address this important knowledge gap.
The team used the US department of Veterans Affairs national healthcare databases to build a cohort of individuals who had survived for at least 30 days after an acute COVID-19 infection and two other groups; one consisting of Veterans Affairs members with no evidence of a COVID-19 infection and a historical cohort (i.e., prior to the current pandemic) from 2017. The researchers followed these three cohorts to estimate the risks of pre-specified incident cardiovascular outcomes and further analysed these outcomes with respect to the existence of prior cardiovascular disease and according to their particular care settings.
Cardiovascular disease burden and COVID-19
The overall sample included 153,760 individuals with a mean age of 61.4 years (89% male) who had COVID-19, 5,637,647 contemporary controls and 5,859,411 historical controls. All three groups were followed for a median of 347.3 days.
Among those with COVID-19, there was a 52% increased risk of stroke (hazard ratio, HR = 1.52, 95% CI 1.43 – 1.62) compared to contemporary controls and a 49% increased risk of a transient ischaemic attack (HR = 1.49). Increased risks were also found for dysrhythmias including atrial fibrillation (HR = 1.71) and sinus tachycardia (HR = 1.84) and thromboembolic disorders such as a pulmonary embolism (HR = 2.93) and deep vein thrombosis (HR = 2.09).
The authors then used the composite endpoint of major adverse cardiovascular events (MACE) which included myocardial infarction, stroke and any of the pre-specified outcomes. Compared to the contemporary control group, the risk of MACE was 55% higher (HR = 1.55) and for any cardiovascular outcome (HR = 1.63).
The cardiovascular disease burden after a COVID-19 infection was also higher than for contemporary controls among those who did not have prior cardiovascular disease. Furthermore, these risks were still elevated, compared to those in the contemporary group, irrespective of the care setting where patients were treated, e.g., non-hospitalised, hospitalised and intensive care .
The authors concluded that their study had demonstrated a substantial cardiovascular disease burden among those who had experienced an acute infection with COVID-19, even among those without prior disease and in any care setting in comparison to those without an infection.
Citation
Xie Y et al. Long-term cardiovascular outcomes of COVID-19 Nat Med 2022
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