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5th July 2022
The use of a cocoa flavanol supplement in older patients free of cardiovascular disease or cancer, failed to reduce the incidence of adverse cardiovascular events compared to placebo according the findings of a randomised, controlled trial by a the COSMOS research group.
Cocoa contains a number of flavan-3-ols and which have been reported to exhibit several health beneficial effects that occur via an antioxidant, anti-carcinogen, cardio-preventive, antimicrobial, anti-viral, and neuro-protective effects. In addition, the presence within cocoa of methylxanthines enhances the beneficial vascular effects commonly ascribed to cocoa flavanol intake. Much of the research on the cardiovascular benefits of cocoa has centred on the consumption of chocolate and a 2020 meta-analysis concluded that it could have a small inverse association with coronary heart disease and stroke but cautioned how this was based on low credibility evidence. Nevertheless, several, small scale studies have shown even among healthy individuals how regular intake of cocoa flavanols improved accredited cardiovascular surrogates of cardiovascular risk, demonstrating that dietary flavanols have the potential to maintain cardiovascular. While small scale studies appear to show that there are benefits cocoa, there have been no large-scale trials assessing the benefits of a cocoa flavanol supplement in comparison to a placebo.
For the present study, the US team undertook a randomised, placebo-controlled trial, which they termed the COcoa Supplement and Multivitamin Outcomes Study (COSMOS). The trial was designed to test whether a cocoa flavanol supplement and a multivitamin could prevent cardiovascular disease among older adults. Individuals were randomly assigned to one of four arms; active cocoa ((500 mg flavanols/day) and a multivitamin; active cocoa and placebo vitamin; active multivitamin and placebo or finally two placebos. The primary outcome was a composite of total cardiovascular outcomes which had several outcomes e.g., incident myocardial infarction, coronary revascularisation, cardiovascular mortality and hospitalisation for unstable angina. The secondary outcomes included a total of CVD and all-cause mortality and the individual components of the composite primary outcome.
Cocoa flavanol supplement and cardiovascular outcomes
A total of 21,442 individuals with a mean age of 72.1 years (59.1% female) were randomised and followed-up for a median of 3.6 years. During the follow-up, 410 participants taking the cocoa supplement and 456 taking placebo experienced a cardiovascular event and this difference was not statistically significant (hazard ratio, HR = 0.90, 95% CI 0.78 – 1.02, p = 0.11).
For the secondary outcome of cardiovascular death, there was a significant reduction among those assigned to the cocoa flavanol supplement (HR = 0.73, 95% CI 0.54 – 0.98) but the difference for each of the other secondary outcomes was non-significant. In addition, while the number of deaths was slightly lower among those taking the cocoa supplement compared to placebo (353 vs 397), this difference was non-significant.
The authors concluded while there were no apparent differences in the primary outcome, additional research was needed to further clarify if a cocoa flavanol supplement could reduce cardiovascular events.
Sesso HD et al. Effect of cocoa flavanol supplementation for the prevention of cardiovascular disease events: the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial Am J Clin Nutr 2022
27th April 2022
Using nitrates and phosphodiesterase type 5 (PDE5) inhibitors together does not seem to increase the risk of adverse cardiovascular (CV) outcomes, even though concomitant use of drugs from either class is contra-indicated. This was the key finding of a retrospective analysis by a team from the Research Division, Department of Cardiology, Herlev and Gentofte Hospital, Hellerup, Denmark.
Organic nitrates, which are vasodilators, are traditionally used for the treatment of angina and heart failure. Phosphodiesterase type 5 (PDE5) inhibitors are used for the treatment of erectile dysfunction but are also vasodilators and thus when taken together with nitrates, a synergistic effect occurs, enhancing the hypotensive effect of nitrates. Moreover, in one study, co-administration of sildenafil (a PDE5 inhibitor) with either isosorbide mononitrate of glyceryl trinitrate produced significantly greater reductions in blood pressure than from either nitrate alone thereby confirming the possible adverse effect of using these drugs together. In fact, in the summary of product characteristics for sildenafil, it states that ‘sildenafil was shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide donors (such as amyl nitrite) or nitrates in any form is therefore contraindicated.’
In a 2019 review it was found that the global prevalence of erectile dysfunction was high, ranging from between 3 and 76.5%. Whilst the use of a nitrate and PDE5 inhibitors is a known contra-indication, given how erectile dysfunction is a common problem, the Danish researchers believed it likely that the two classes of drugs might be co-prescribed. They set out to examine not only the extent of co-prescription of these drugs but also whether there was any evidence from a real-world setting, that this combination was associated with an increased level of adverse cardiovascular events. Using a Danish national registry, the team identified male patients aged 30 to 85 years of age with a history of ischaemic heart disease and continued prescriptions for nitrates as well as a new prescription for a PDE5 inhibitor. They considered two composite outcomes; one including cardiac arrest, shock, ischaemic stroke and a second which included angina, syncope and a diagnosis of an adverse drug-related event. These outcomes were primarily assessed within 14 days of PDE5 inhibitor exposure although 7, 21 and 28 days were also used because the exact time of PDE5 inhibitor use after filling a prescription was always going to be uncertain.
Nitrates and PDE5 inhibitors and adverse cardiovascular outcomes
A total of 249,541 men with ischaemic heart disease were identified, of whom 42,073, with a median age of 70 years, were prescribed oral nitrates. Between 2000 and 2018, the average yearly prescription rate for PDE5 inhibitors in those taking oral nitrates, increased from 0.9 to 19.7 per 100 persons per year.
In the subgroup of men prescribed oral nitrates, there were 16,948 cases of cardiac arrest, shock, myocardial infarction, ischaemic stroke or acute coronary arteriography during the follow-up period. However, there was no significant association between co-prescription of nitrates and PDE5 inhibitors (odds ratio, OR = 0.58, 95% CI 0.28 – 1.13) for a 14-day exposure window. Similarly, for the second outcome, there was also no significant increased risk (OR = 0.73, 95% CI 0.40 – 1.32) during a 14-day exposure window. There were also no significant differences for 7, 21 and 28-day exposure windows.
Based on these findings, the authors concluded that despite the known contra-indication, there was no apparent increased risk of adverse cardiovascular events from co-prescription of nitrates and PDE5 inhibitors.
Holt A et al. Adverse Events Associated With Coprescription of Phosphodiesterase Type 5 Inhibitors and Oral Organic Nitrates in Male Patients With Ischemic Heart Disease. A Case-Crossover Study Ann Intern Med 2022
22nd April 2022
Early glycaemic control in patients with type 2 diabetes leads to a reduction in the incidence of adverse cardiovascular outcomes according to the findings of a retrospective analysis by a team from the Department of Clinical & Experimental Medicine, University of Surrey, UK.
Patients with diabetes are deemed to be at a higher risk of death and adverse cardiovascular outcomes than those without the condition. Furthermore, poor control of diabetes defined by an increased level of glycated haemoglobin levels (HbA1c) is also a risk factor for myocardial infarction (MI). In fact, one study found that each 1% higher HbA1c was associated with an 18% greater risk of MI. In addition, the HbA1c levels 3 months post-diabetes diagnosis, has been found to be a strong predictor of subsequent mortality.
However, there is some uncertainty over whether tight glycaemic control in patients with a high HbA1c after diagnosis is associated with a subsequent reduction in adverse cardiovascular outcomes. For the present study, the UK researchers examined the effect of changes in HbA1c levels in the first year after a diagnosis of type 2 diabetes and how this impacted on the incidence of cardiovascular events. A further consideration was the effect of glycaemic variability on cardiovascular events as there is some evidence to show that having consistent glycaemic control reduces the risk of vascular events and death in type 2 diabetes.
The team reviewed the records of adults with a diagnosis of type 2 diabetes and an HbA1c level recorded at diagnosis and after 1 year and with an additional five measurements recorded over time. The HbA1c values were categorised into three groups: group A (HbA1c < 7.5%), group B (HbA1c 7.5% – 9.0%) and group C (HbA1c > 9.0%). The team then recorded the individual patient’s group status at the end of the first year, for instance, a status of A to A, meant that the person’s levels remained in group A, a C to A status meant that values transitioned from C to A during the first year and so on. A glycaemic variability score was also calculated, based on the number of times the HbA1c reading differed by more than 0.5% and the results categorised into 5 groups, depending on the level of variability (e.g., 0 – 20, 21 – 40 up to 81 – 100). The primary outcome of interest was the first occurrence of a major adverse cardiovascular event (MACE) which included myocardial infarction, coronary intervention, stroke, amputation/limb revascularisation.
Early glycaemic control and MACE
A total of 26,180 individuals with type 2 diabetes and a mean age of 68.7 years (43.9% female) were identified and included in the analysis.
The proportion of individuals categorised as A to A was 48%, whereas only 1.5% were categorised as C to A. A total of 2,300 MACE events occurred in the 26,180 individuals with type 2 diabetes and the median time to the first MACE was 635 days. Compared to those in the A to A group after the first year, individuals who transitioned from C to A had a significantly reduced risk of MACE (hazard ratio, HR = 0.75, 95% CI 0.60 – 0.94, p = 0.014). In addition, individuals who displayed the greater glycaemic variability (81 – 100) also had the highest risk for MACE (HR = 1.51, 95% CI 1.11 – 2.06, p = 0.0096) compared to those in the lowest (0 – 20) group.
The authors concluded that both transitioning to an HbA1c <7.5% within the first year after a type 2 diabetes diagnosis and lack of substantial glycaemic variability were both associated with reduced MACE events.
Whyte MB et al. Early and ongoing stable glycaemic control is associated with a reduction in major adverse cardiovascular events (MACE) in people with type 2 diabetes: primary care cohort study Diabetes Obes Metab 2022