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20th December 2022
Use of a purified eicosapentaenoic acid (EPA) formulation in patients with coronary artery disease prescribed statins, reduced the incidence of adverse cardiovascular outcomes such as myocardial infarction and stroke compared to a control group not taking the formulation, according to the findings of a study by Japanese researchers presented at the American Heart Association (AHA) conference in Chicago.
Statin therapy leads to a reduction of cardiovascular events in both primary and secondary prevention. Since no treatment is fully effective in all patients, one therapy that has attracted interest over many years has been the omega-3 polyunsaturated fatty acids (PUFAs). However, recent studies with PUFAs have been contradictory with one trial in patients with elevated triglyceride levels despite the use of statins, finding that the risk of ischaemic events, was significantly lower among those who received 2 g of icosapent ethyl twice daily (a highly purified EPA) than among those who received placebo. In contrast, a second trial, again in statin-treated patients, concluded that the addition of omega-3 to usual background therapies resulted in no significant difference in a composite outcome of major adverse cardiovascular events.
Due to these contrary findings, The Japanese team sought greater clarity of the role of PUFAs and presented data from the Randomized Trial for Evaluating the Secondary Prevention Efficacy of Combination Therapy – statin and EPA (RESPECT-EPA) trial. Participants, all of whom had chronic coronary artery disease and were treated with statin therapy, were randomised to highly purified EPA (1800 mg/day) or control groups (i.e., no EPA therapy) and the primary endpoint was cardiovascular death, non-fatal myocardial infarction, non-fatal ischaemic stroke, unstable angina pectoris, and clinically indicated coronary revascularisation. A further inclusion criterion was a low EPA/arachidonic acid ratio (< 0.40).
Highly purified EPA and cardiovascular outcomes
A total of 2506 participants with a mean age of 68 years (17% female), of whom 45% had diabetes, were included and randomised to the highly purified EPA (icosapent ethyl 1800 mg daily, n = 1,249) or control and followed for 5 years.
The primary outcome occurred in 10.9% of the icosapent ethyl group vs. 14.9% of the control group (p = 0.055). For the secondary outcomes, sudden cardiac death, myocardial infarction, unstable angina, or coronary revascularisation, this occurred in 8.0% in the icosapent ethyl group vs. 11.3% in the control group (p = 0.031). However, there was a higher incidence of gastrointestinal disorders in the icosapent ethyl group (3.4% vs 1.2%, p < 0.001).
The authors concluded that among Japanese patients with chronic coronary artery disease and treated with statin therapy, icosapent ethyl may be associated with a reduction in adverse cardiovascular outcomes.
Bavry AA et al. Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy–Statin and Eicosapentaenoic Acid – RESPECT-EPA. Presented at the American Heart Association Scientific Sessions, Chicago, IL, November 6, 2022
16th September 2022
Dietary changes are likely to have the greatest impact on adverse cardiovascular events in thosse with stage 1 hypertension according to data presented at the American Heart Association Hypertension Scientific Session, 2022 by researchers from the University of California, San Francisco, US.
According to the American College of Cardiology 2017 guidelines, stage 1 hypertension is 130-139 or 80-89 mm Hg. Using a of hypertension as a systolic blood pressure 140 mm Hg or greater and diastolic blood pressure 90 mm Hg or greater, or taking medication for hypertension, research estimates that the number of people aged 30-79 years with hypertension doubled from 1990 to 2019, from 331 million women and 317 men to 626 million women and 652 million men in 2019.
In the latest study, the US team estimated that widespread adoption of lifestyle changes, such as limiting heavy alcohol consumption and exercising regularly, may prevent thousands of deaths and save a huge amount of health care costs over the next 10 years. One simple dietary change would be adoption of the dietary approaches to stop hypertension (DASH) diet. In fact, the DASH diet has been shown to be accompanied by significant blood pressure reductions in adults with and without hypertension.
In the present study, researchers set out to simulate heart disease and stroke events, mortality and health care costs between 2018 and 2027. They used 2015-2018 NHANES estimates and defined individuals as lower-risk, based on not having diabetes, chronic kidney disease, or cardiovascular disease (CVD) and a predicted <10% 10-year CVD risk. Inputs for effects of dietary modification, sustained weight loss, physical activity, smoking cessation, and alcohol moderation on SBP were from published meta-analyses and trial data.
Dietary changes and stage 1 hypertension
For an estimated 8.7 million U.S. adults (50.6% women) aged 35-64 with lower-risk stage 1 hypertension, 5.5 million (61%) had regular healthcare access. Controlling BP to <130 mmHg in the full target population could prevent 27,000 cardiovascular disease events, avoid 2800 deaths and save an associated $16 million healthcare costs. They added that the largest benefit would be seen from adoption of the DASH diet with an estimated 16,000 CVD events prevented among men and 11,000 among women. Similarly, a reduction in dietary sodium would also avoid approximately 11,000 events in men and 6,000 in women. They concluded that substantial health and economic benefits could result from widespread adoption of non-pharmacologic interventions in lower-risk U.S. adults with stage 1 hypertension.
According to Dr Kendra Sims, co-lead researcher of the study ‘Our results provide strong evidence that large-scale, healthy behaviour modifications may prevent future heart disease, related complications and excess health care costs.’ They added that ‘unfortunately, the availability and affordability of healthy food sources does not easily allow people to follow the DASH diet. Clinicians should consider whether their patients live in food deserts or places with limited walkability. Health counselling should include addressing these specific challenges to blood pressure control.’
Projected Impact Of Non-pharmacologic Management Of Stage 1 Hypertension Among Lower-risk U.S. Adults Hypertension 2022
5th April 2022
Using a lower doses of pioglitazone provides greater risk reductions for adverse cardiovascular outcomes such as myocardial infarction and stroke among patients with insulin resistance and with less adverse effects. This was the finding of an exploratory analysis by researchers from the Stroke Prevention & Atherosclerosis Research Centre, Western University, Ontario, Canada.
Insulin resistance represents a syndrome whereby insulin fails to exert its normal effect in insulin-sensitive target tissues. However, the presence of insulin resistance also promotes cardiovascular disease via changes in classic cardiovascular risk factors and down-regulation of the insulin signalling pathways in different tissues. Thiazolidinedione drugs such as pioglitazone, are insulin sensitisers that act on intracellular metabolic pathways to enhance insulin action and increase insulin sensitivity in the target tissues. However, as well as these positive insulin-related effects, pioglitazone also has vasodilatory effects and was found to reduce blood pressure in diabetic patients with elevated levels despite already receiving at least 3 antihypertensive drugs. Moreover, given that insulin resistance is a risk factor for stroke and myocardial infarction, a 2016 study in patients without diabetes, but insulin resistance and a recent history of ischaemic stroke or transient ischaemic attack, found that pioglitazone use over a 4-year period, reduced the incidence of fatal or non-fatal stroke or myocardial infarction compared to placebo. However, despite these benefits, there are concerns over the side-effects of the drug which include weight gain, oedema and heart failure. In fact, a systematic review and meta-analysis assessing the effects of pioglitazone treatment as a secondary prevention measure in cardiovascular disease, concluded that while the drug lowered the risk of recurrent MACE, stroke, or MI, it did not lower the risk for all-cause mortality but actually increased the risk of developing heart failure.
Whether pioglitazone use at a lower dose would could still offer the same cardiovascular benefits as observed at the higher dose but with a lower incidence of adverse effects is uncertain and was the subject of the current study by the Canadian team.
The researchers used data from the Insulin Resistance Intervention in Stroke Trial (IRIS), which randomised participants to either pioglitazone or placebo. The dose of the drug was initiated at 15mg and titrated upwards to to 45mg. However, in cases where this dose was not tolerated, participants could be down-titrated to a lower, and better-tolerated dose. For the present analysis, the team examined the outcomes among patients taking either lower or higher doses of pioglitazone. They chose the mode dose of study drug, which was defined as the most frequent dose taken over the period of study. The primary outcome was the incidence of myocardial infarction or stroke and the effect on the adverse outcomes of weight gain, oedema and heart failure was also examined.
Pioglitazone doses and outcomes
A total of 1938 patients with a mean age of 63.2 years (57.8% male) were included in the analysis. A mode dose of < 15 mg was taken by 28.2% of participants, 15 mg/day in 6.6% of cases, 30 mg/day in 4.6% of cases and finally 45 mg/day in 60.6% of cases. All individuals were followed-up for a median of 4.8 years.
There was no effect on the primary outcome in those taking the lowest mode dose (< 15mg/day). Combing mode doses of 15 or 30mg/day and compared to 45mg/day, the pooled, adjusted hazard ratio for stroke/myocardial infarction was 0.48 (95% CI 0.30 – 0.76, p = 0.002) and lower than for the 45mg dose (hazard ratio, HR = 0.74, 95% CI 0.59 – 0.94, p = 0.01). The development of type 2 diabetes was similar between the 15/30 and 45mg/day dose (HR = 0.34 vs 0.31, 15/30 mg vs 45mg).
For the three adverse effects considered, the hazard ratios were lower for the 15/30mg/day than the 45mg/day but not statistically different. For example, for heart failure, the hazard ratio for the 15/30mg/day dose was 0.41 (95% CI 0.11 – 1.55) and 1.71 (95% CI 1.03 – 2.86) for the 45 mg/day dose.
The authors concluded that doses less than the maximal 45mg provided similar levels of efficacy but, more importantly, with a reduced incidence of adverse effects.
Spence JD et al. Efficacy of lower doses of pioglitazone after stroke or transient ischaemic attack in patients with insulin resistance Diabetes Obes Metab 2022
28th March 2022
Both recurrent cardiovascular events (CVs) and death have been found to occur mainly within the first 6 months after the primary event according to a real-world analysis of registry data by researchers from the Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland.
Cardiovascular disease (CVD) is the leading cause of deaths and disability worldwide and the World Health Organization estimates that CVD is response for 17.9 million lives lost each year. Despite falls in the mortality rates of CVD across Europe, more than 4 million people continue to die each year from the disease, with more than 1.4 million dying prematurely, before the age of 75 years. Moreover, recurrent cardiovascular events are not uncommon and one study among patients with acute coronary syndrome (ACS) found that 9% of patients experienced a recurrent cardiovascular event in the post-ACS setting during a median follow-up of 1 year.
But which factors are associated with an increased risk of recurrent CVs and death among secondary prevention patients, and when are these most likely to occur, was the subject of the present, registry-based study by the Finnish team. They undertook a retrospective analysis, using hospital data, of adult patients who experienced their first atherosclerotic cardiovascular disease (ACVD) event between 2012 and 2016. The team defined an ACVD event as a myocardial infraction (MI), unstable angina (UA), ischaemic stroke (IS) or a transient ischaemic attack (TIA). In addition, a recurrent event as a new diagnosis of the same condition as the index event, a minimum of 7 days from the first episode and all mortality data were retrieved from the hospital database.
Characteristics of cardiovascular events
In total, 48,405 adults with a median age of 71.5 years (53.8% male) were followed for a mean of 2.2 years. Among the whole cohort, 40.1% had an IS, 29.4% and MI and 19.5% a TIA as their index event. Co-morbidities included hypertension (12.9%) and diabetes (16.7%).
Among the current CVs, death was the most common subsequent event (61.5%) and a recurrent event occurred in 38.5% of patients. It was also clear that the category of subsequent events mirrored the initial episode (i.e., a second MI after the first). The cardiovascular events rate also increased after each recurrence. For instance, the combined recurrent/deaths events rate increased from 13.4 per 100 patient-years for the first event, to 36.8 for the third recurrent event.
In terms of the time to the recurrent event, after 6 months, 14% of patients had suffered any recurrent event or had died. This stabilised over time, so that after 5 years, 41.5% of patients had either suffered an event or died.
When considering the risk factors most significantly associated with risk of subsequent cardiovascular events, this increased with each increased year of age (hazard ratio, HR = 1.02 (95% CI 1.02 – 1.02, p < 0.001). Other significant factors included the presence of diabetes (HR = 1.21, 95% CI 1.11 – 1.32, p < 0.001) and hypertension (HR = 1.18). The risk of death was also significantly associated with male gender (HR = 1.18) but the only co-morbidity was diabetes (HR = 1.63, 95% CI 1.53 – 1.73, p < 0.001). Moreover, male gender and diabetes were also significantly associated with the risk of recurrency to death.
The authors concluded that given their findings, an acute CV event should be promptly followed by secondary prevention measures.
Toppila I et al. Cardiovascular event rate and death in high‐risk secondary prevention patient cohort in Finland: A registry study Clin Cardiol 2022
22nd February 2022
Undertaking physical activity for a minimum of 20 minutes every day is associated with a significant reduction in the risk of cardiovascular disease in elderly patients, according to the results of a longitudinal study by a team of researchers from the department of Cardio-thoraco-Vascular Sciences and Public Health, University of Padua, Italy.
There is already good evidence demonstrating that higher recreational and non-recreational physical activity is associated with a lower risk of mortality and CVD events. In addition, the risk of cardiovascular disease has been found to reduce in a linear manner with increasing levels of physical activity up to around 41%. However, whilst there are clear health benefits derived from engaging in greater levels of physical activity, few of the reviewed studies focused on older (≥65 years) adults. Furthermore, there is little evidence on the association of activity trajectories and specific cardiovascular outcomes, though where this has been examined, the authors concluded that cardiovascular health trajectories may be associated with subsequent CVD risk.
With an increasingly ageing population, for the present study, the Italian team sought to explore the relationship between different trajectories of activity and cardiovascular events in older men and women. The team turned to the Progetto Veneto Anziani study which has followed over 3,000 Italians aged 65 years and older from 1995 and who had follow-up visits after 4 and 7 years. Individuals underwent physical examinations and completed various medical questionnaires, assessing smoking status, alcohol use, co-morbidities etc and morbidity and mortality data collection was extended until 2018. The levels of physical activity were collected at baseline and at follow-up appointments and individuals were subsequently categorised as active if they engaged in > 20 minutes of activity each day or inactive if < 20 minutes each day. Based on information collected from participants, the researchers defined four separate exercise trajectories: stable-low (i.e., essentially inactive); high-decreasing (active – inactive); low-increasing (inactive-active) and finally stable-high (maintaining activity). Outcomes of interest were a diagnosis of cardiovascular disease (CVD), coronary heart disease (CHD), heart failure (HF) and stroke.
Physical activity and cardiovascular outcomes
A total of 2754 individuals with a mean age of 75.1 years (60.2% female) were included and followed-up for a period of 20 years. During the 20-year follow-up, there were 1037 incident cardiovascular events.
The rates of incident coronary heart disease and heart failure were significantly associated with being active compared to inactive. For example, there was a lower risk of CVD (hazard ratio, HR = 0.74, 95% CI 0.58 – 0.94), CHD (HR = 0.66, 95% CI 0.50 – 0.87) and HF (HR = 0.72, 95% CI 0.53 – 0.98) in men but not for strokes. In contrast, none of these relationships were significant for women. However, physical activity was associated with a significantly reduced risk of overall mortality in both men (HR = 0.72, 95% CI 0.62 – 0.84) and women (HR = 0.81, 95% CI 0.72 – 0.92).
Considering the dose-response relationship, the risk reduction for any incident cardiovascular event was associated with doing at least 20 minutes of activity each day for those aged 70. Using trajectories of physical activity and using the stable-low category as the reference point, for any cardiovascular disease, the fully adjusted hazard ratio was 0.48 (95% CI 0.27 – 0.86) for men in the stable-high category, i.e., a 52% reduced risk of CVD in those who maintained high levels of activity in later life. Nevertheless, this association was not significant for women.
The authors concluded that greater amounts of physical activity in older adults was associated with a reduced risk of CHD and heart failure and that a minimum of 20 minutes each day of moderate to vigorous activity should be recommended for the greatest cardiovascular benefits.
Amidei CB et al. Association of physical activity trajectories with major cardiovascular diseases in elderly people Heart 2022
4th October 2021
As a drug class, the sodium-glucose cotransporter-2 inhibitors (SGLT2is) have been shown in a systematic review to have a moderate effect on major adverse cardiovascular events in patients with established atherosclerotic cardiovascular disease. Moreover, the same review identified how SGLT2is can also reduce hospitalisation for heart failure (HF) and progression of renal disease regardless of existing atherosclerotic cardiovascular disease. In addition to these positive effects on cardiovascular outcomes, SGLT2is have been shown to reduce 24-hour blood pressure (BP) in diabetic patients. Nevertheless, this blood pressure-lowering effect is of concern in those with HF, especially as between 15 and 20% of HF patients have low systolic BP and therefore at a higher risk of in-hospital and post-discharge mortality.
In an effort to evaluate whether the baseline systolic BP affected outcomes associated with the use of empagliflozin, an international team, led by researchers from Saarland University, Germany, enrolled patients in the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction (EMPEROR-Reduced) trial. Patients with class II, III, or IV heart failure and an ejection fraction of less than 40% were randomised in a 1:1 fashion to either empagliflozin (10mg daily) or placebo in addition to their usual therapy for heart failure. For the study, patients were grouped according to their baseline systolic BP, as <110mmHg, 110–130mmHg or > 130mmHg and the primary outcome in the EMPEROR-Reduced trial was a composite of adjudicated cardiovascular death or hospitalisation for heart failure. For the present study, the researchers focused on whether the baseline systolic BP influenced the outcomes of cardiovascular death and hospitalisations for HF in patients given empagliflozin compared to placebo.
A total of 3730 patients were randomised to either empagliflozin (1863) or placebo and all patients had a left ventricular ejection fraction of less than 30%. Over a median of 16 months, the event rate per 100 patients years (pys) of follow-up, the primary outcome increased from 16.5 among the high SBP group to 20.8 for the intermediate group, and to 26.3 per 100 among the patients with low SBP (p=0.0015). Compared with placebo, treatment with empagliflozin significantly decreased the risk of cardiovascular death among the low systolic BP (hazard ratio, HR = 0.78, 95% CI 0.61–1.00), intermediate (HR = 0.71, 95% CI 0.58–0.87) and high (HR = 0.82. 95% CI 0.62–1.09) groups. However, while there were reductions in rates of HF hospitalisation with empagliflozin compared with placebo, this was only significant for patients with intermediate (110–130mmHg) systolic BP (HR = 0.66, 95% CI 0.50–0.88).
The authors concluded that empagliflozin reduced the risk of cardiovascular death and the number of HF hospitalisations and that this effect occurred independently of the baseline systolic BP.
Bohm M et al. Empagliflozin Improves Cardiovascular and Renal Outcomes in Heart Failure Irrespective of Systolic Blood Pressure. J Am Coll Cardiol 2021.
6th September 2021
Smoking is a risk factor for cardiovascular disease (CVD) and responsible for 1 of every 4 CVD deaths although smoking is a very preventable CVD risk factor. In one observational study of over 8,000 former heavy (i.e., more than 20 cigarettes/day) it was found that within 5 years of cessation, there was a 39% reduced risk of CVD among those who quit, compared to current smokers. Other evidence indicates a potential dose-response relationship between smoking and ischaemic stroke, such that any reduction is beneficial. However, while a meta-analysis has found that reduced use of cigarettes decreases the risk of lung cancer, the impact on CVD was less clear. This led a team from the Department of Family Medicine/Supportive Care Centre, Seoul, Korea, to compare the effect of either smoking cessation or reduction on the risk of cardiovascular disease outcomes. The team used a Korean national health database and collected information of individuals over 40 years of age who had undergone two health examinations in 2009 and again in 2011 to determine any changes in smoking behaviour. A smaller subgroup who had undergone a third examination in 2013 were also included. The team focused on a group of current smokers and excluded those with prior CVD or cancer and used information on smoking status obtained from a biennial national health examination self-administered questionnaire. Individuals were classed as heavy smokers (> 20 cigarettes/day), moderate smokers (10 – 19/day) and light smokers (< 10/day). Compared with the first examination in 2009, participants were then categorised as quitters, reducers I (> 50% reduction), reducers II (20 – 50% reduction), sustainers (reduced by < 20%) and increasers (>20% in smoking). The primary endpoints for the study were newly diagnosed stroke and myocardial infarction (MI) and secondary endpoints included overall mortality, fatal strokes and fatal Mis. Many other health parameters were collected included age, sex, body mass index, duration of smoking, alcohol consumption, levels of exercise, co-morbidities, all of which were adjusted for in the analyses.
A total of 897,975 current smokers with a mean age of 53 years (94.5% male) were followed over 6.2 years. There were a total of 17,748 strokes and 11,271 MI events during the follow-up period. Among smokers, 52.8% were classed as heavy, 37.3% as moderate and the remainder as light during their first examination. Among smoking quitters, there was a significantly reduced risk of stroke (adjusted Hazard ratio, aHR = 0.77, 95% CI 0.74 – 0.81) and MI (aHR = 0.74) compared to sustainers. In addition, smoking cessation was also associated with a significant reduction in all-cause mortality (aHR = 0.92, 95% CI 0.89 – 0.94). However, among reducers I and II, the risk of both stroke and MI were not significantly lower. For example, for reducers I, stroke aHR = 1.02 (95% CI 0.97 – 1.08) and MI aHR = 0.99 (95% CI 0.92 – 1.06).
At the third examination in 2013, quitters who had relapsed to either the level of reducer I, II, sustainer or increaser, had a 42 to 66% increased risk of stroke and a 54 – 69% increased risk of MI compared to quitters, depending where they were in terms of their relapsed level of smoking.
The authors concluded that only smoking cessation and not reduction was associated with a reduced risk of adverse cardiovascular outcomes.
Jeong SM et al. Smoking cessation, but not reduction, reduces cardiovascular disease incidence. Eur Heart J 2021