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1st March 2023
Aspirin use for the prevention of myocardial infarction (MI) appears to be reduced by concomitant statin use in patients without atherosclerotic cardiovascular disease (ASCVD) without affecting the risk of a major bleed according to a meta-analysis by US researchers.
In 2019, US guidance suggested that aspirin should be used infrequently in the routine primary prevention of ASCVD because of lack of net benefit. More recently, the US Preventative Services Task Force has endorsed these earlier recommendations for primary prevention in adults aged between 40 and 59 with a 10% or higher, 10-year risk of CVD. While historically, aspirin was considered to reduce the risk of an MI, in the context of use with other strategies such as statins, one analysis concluded that the effect of aspirin on myocardial infarction risk was significantly attenuated, whereas its major bleeding and haemorrhagic stroke complications were retained.
For the current meta-analysis, researchers wanted to examine the impact on aspirin use with and without statins, specifically in those without ASCVD but at different levels of risk. The team included a range of risk levels from very low (< 5%) through to very high (> 30%). They included trials where patients were prescribed aspirin and followed for at least 12 months and the team determined the absolute risks for cardiovascular outcomes, major bleeding and mortality over 5 years.
Aspirin use with and without statins
In a total of 16 trials with 171,215 patients with a median age of 64 years (46% women), the use of aspirin alone was associated with a 15% lower risk of a myocardial infarction (risk ratio, RR = 0.85, 95% CI 0.77 – 0.95) although the drug did not reduce mortality. However, the drug lead to a higher risk of major bleeding (RR = 1.48, 95% CI 1.32 – 1.66, p < 0.001).
When considering the absolute benefits, the researched calculated that aspirin monotherapy in patients with a very low ASCVD risk, was likely to lead to 3 fewer myocardial infarctions (MIs) per 10,000 patients but 21 more major bleeds. In contrast, when taken in conjunction with a statin, there would be only 1 less MI but 20 more major bleeds. At the other extreme of ASCVD risk (i.e., > 30%), monotherapy might lead to 49 fewer MIs (but 98 major bleeds) but in combination with a statin, there would be 37 fewer MI’s but 94 major bleeds.
The authors concluded that among adults who did not have ASCVD, statin use with aspirin, appeared to attenuate to some extent aspirin’s clinical benefit but without influencing the bleeding risk, suggesting that the risk of a major bleed from taking aspirin exceeded its benefits across all levels of ASCVD risk.
Khan SU et al. Aspirin With or Without Statin in Individuals Without Atherosclerotic Cardiovascular Disease Across Risk Categories. JACC Adv 2023
16th September 2022
The benefits of statin therapy against cardiovascular disease are life-long because a large share of the benefit occurs later in life according to the results of a modelling study by researchers from Queen Mary University of London, UK and presented at European Society of Cardiology congress in Barcelona, Spain.
According to the 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice, the causal role of LDL-C, and other apo-B containing lipoproteins, in the development of atherosclerotic cardiovascular disease, is demonstrated beyond any doubt by genetic, observational, and interventional studies. Statin therapy is designed to lower LDL-C cholesterol and a 2016 meta-analysis of 26 randomised controlled trials with over 170,000 patients, found that all-cause mortality was reduced by 10% per 1·0 mmol/L LDL reduction, largely reflecting significant reductions in deaths due to coronary heart disease and other cardiac causes. Despite these clear benefits, there is some uncertainty about when to start and how long to persist, with statin therapy, to optimise the effects. In the present study, the UK researchers estimated the accumulation of benefit from statin therapy, according to age of initiation, using a microsimulation model that was developed using data on 118,000 participants of large international statin trials from the Cholesterol Treatment Trialists’ Collaboration and 500,000 individuals in the UK Biobank population cohort. The model used individual characteristics (e.g. age, sex) and disease histories to simulate the annual risk of heart attack, stroke, coronary revascularisation, diabetes, cancer, vascular death and nonvascular death for each participant. Treatment with a standard dose of statin (40 mg daily) was used to estimate the effect of therapy versus no therapy in these scenarios: (1) lifelong therapy (used until death or 110 years of age if earlier), (2) therapy stopped at 80 years of age, and (3) delayed initiation of therapy by five years in participants under 45 years of age. The benefit of statin therapy was measured in quality-adjusted life years (QALYs), which represents the length of life adjusted by health to reflect quality of life. For example, one QALY is equal to one year of life in perfect health. Benefits were also reported separately according to baseline cardiovascular risk, which refers to the likelihood of having a heart attack or stroke in the next 10 years, and is based on age, blood pressure, cholesterol levels, smoking status, and medical conditions
Statin therapy benefits
The researchers found that a large part of QALYs gained with statin therapy accrued later in life. The higher the participants’ 10-year cardiovascular risk, the larger and earlier the statin benefit accrued. Compared with lifelong statins, stopping therapy at 80 years of age, would erase a large share of the potential benefit, especially for people with relatively low cardiovascular risk.
According to lead author of the study Dr Runguo Wu ‘the study indicates that people in their 40s with a high likelihood of developing cardiovascular disease, and people of all ages with existing heart disease, should be considered for immediate initiation of cholesterol lowering treatment. Stopping treatment, unless advised by a doctor, does not appear to be a wise choice.’
They added that ‘our study suggests that people who start taking statins in their 50s but stop at 80 years of age instead of continuing lifelong, will lose 73% of the QALY benefit if they are at relatively low cardiovascular risk and 36% if they are at high cardiovascular risk – since those at elevated risk start to benefit earlier. Women’s cardiovascular risk is generally lower than men’s. This means that for women, most of the lifelong benefit from statins occurs later in life and stopping therapy prematurely is likely more detrimental than for men.’
It was also important to understand that the benefits of statin therapy was dependent upon an individual’s baseline risk. For example, for some one under 45 years of age at low cardiovascular risk, (i.e., less than 5% likelihood of heart attack or stroke in the next 10 years) a five-year delay in taking statins had little impact – they lost just 2% of the potential QALY benefit from lifelong therapy. However, the impact was larger in people under 45 years of age at high cardiovascular risk, meaning a more than 20% likelihood of heart attack or stroke in the next 10 years – they lost 7% of the potential QALY benefit from lifelong therapy. Dr. Wu said: “Again, this is because people at higher cardiovascular risk start to accrue benefit early on and have more to lose by delaying statin therapy than those at low risk.’
Benefit accrual with cardiovascular disease prevention and effects of discontinuation: a modelling study
18th May 2022
The PCSK9 inhibitor, alirocumab, given twice weekly in combination with a statin, to patients who underwent urgent percutaneous coronary intervention (PCI) after an acute myocardial infarction (MI) resulted in significantly greater coronary plaque regression in non-infarct-related arteries after 52 weeks compared to placebo. This was the conclusion of a randomised clinical trial by teams from Switzerland and Denmark.
It has been previously shown that the use of maximal dose statin therapy can produce a significant regression of coronary atherosclerosis when measured by the percent atheroma volume. Patients who have experienced an MI continue to be at risk of a subsequent event, highlighting the continued need for statin therapy. For example, one study of post-MI patients found how such individuals continue to be at risk of cardiovascular events beyond the first year after their initial MI. A further reason to continue statin therapy and to hopefully see regression of coronary atherosclerosis, comes from a study in those with acute coronary syndrome. The study revealed that subsequent major adverse cardiovascular events were equally attributable to recurrence at the site of initial or culprit lesions and to non-culprit or non-infarct-related arteries. It has also been shown that the combination of alirocumab and high dose statins in patients who experienced acute coronary syndrome 1 to 12 months earlier, reduces the risk of recurrent ischaemic cardiovascular events compared to placebo.
Although combining alirocumab with a statin reduces subsequent recurrent adverse cardiovascular events, little is known about how this combination impacts on plaque burden and composition. As a result, for the present study, the researchers undertook the Effects of the PCSK9 Antibody Alirocumab on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction (PACMAN-AMI) randomised trial. The study recruited adult patients (> 18 years) who underwent urgent percutaneous coronary intervention (PCI) of the culprit lesion for treatment of ST-elevation MI. Patients were randomised 1:1 to biweekly subcutaneous alirocumab (150mg) or placebo and which was started less than 24 hours after the PCI and given in combination with rosuvastatin 20mg daily for a total of 52 weeks. The availability of various imaging modalities enabled the team to take a closer look at how the combination therapy affected plaques. They used intravascular ultrasonography (IVUS), near-infrared spectroscopy and optical coherence tomography (OCT) on two non-infarct-related coronary arteries both at baseline and at the end of the study. The IVUS was used to assess changes in percent atheroma volume (PAV), whereas near-infrared provided a measure of the maximum lipid core burden index. This latter metric, provides an assessment of the lipid content of a plaque, such that lower values are associated with a reduced risk of adverse events. OCT can be used to assess minimal fibrous cap thickness with a thicker plaque being more stable and therefore less likely to rupture.
The primary outcome for the study was the change in IVUS PAV from baseline to week 52 and two secondary outcomes were changes in maximum lipid core burden index and OCT-derived minimal fibrous cap thickness.
Alirocumab and changes in percent atheroma volume
A total of 300 patients with a mean age of 58.5 years (18.7% women) and an overall mean LDL cholesterol level of 3.94mmol/l were randomised to alirocumab or placebo.
After 52 weeks of therapy, the mean LDL cholesterol level was 1.91mmol/l in the placebo group and 0.60mmol/l in the alirocumab group (p < 0.001).
For the primary endpoint, the change in mean PAV was significantly greater for alirocumab compared to placebo (-2.13% vs -0.92%, p < 0.001). The lipid core burden was also significantly reduced with alirocumab (mean change -79.4 vs -37.60, alirocumab vs placebo, p = 0.006). Finally, fibrous cap thickness also significantly increased with alirocumab compared to placebo (p = 0.01).
Based on these findings, the authors concluded by calling for future studies to examine whether the changes observed with alirocumab would lead to an improvement of clinical outcomes for patients.
Räber L et al. Effect of Alirocumab Added to High-Intensity Statin Therapy on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction: The PACMAN-AMI Randomized Clinical Trial. JAMA 2022
24th March 2022
Statin therapy is associated with only a modest absolute risk reduction in cardiovascular disease outcomes including all-cause mortality and myocardial infarction (MI). This was the important main finding from a meta-analysis of randomised trials by researchers from the HRB Centre for Primary Care Research, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
It widely thought that the key initiating event in atherogenesis is the retention of low-density lipoprotein (LDL) cholesterol and other cholesterol-rich lipoproteins within the arterial wall. As a result, a great deal of effect has been directed at reducing LDL cholesterol levels so that the treatment with a statin drug has become a well-recognised approach for lowering LDL cholesterol. While there are clearly benefits from the use of statins, in much of the published work, authors report relative rather than absolute risk reductions. This represents an important weakness for the interpretation of the data since readers tend to overestimate the effect of an intervention when the results are expressed in relative terms. In contrast, the absolute risk gives a better representation of the actual situation and also from the patient’s point of view, absolute risks often give more relevant information.
For the present meta-analysis, the Irish team analysed both the relative and absolute risks associated with the use of statin therapy for outcomes such as all-cause mortality, MI and stroke. They included trials which examined the efficacy of a statin on cardiovascular outcomes with a duration of at least 2 years, which enrolled more than 1,000 participants and where the comparator was either placebo or usual care.
Statin use and cardiovascular disease outcomes
A total of 21 trials with 1,255 to 20,536 participants, of which 33% were for primary prevention, were included in the analysis. The average trial follow-up period was 4.4 years and ranged from 1.9 to 6.1 years.
From the meta-analysis, the overall absolute risk reduction (ARR) for all-cause mortality was 0.8%, 1.3% for MI and 0.4% for stroke for individuals randomised to receive a statin compared to either placebo or usual care. The corresponding relative risk reductions (RRRs) were 9% (all-cause mortality), 29% (MI) and 14% (stroke). As an example, the authors calculated that with an ARR of 1.3% for MI, 77 patients (i.e., 1/0.013) would need to be treated for an average of 4.4 years to prevent one myocardial infarction.
In subgroup analysis (primary vs secondary prevention), the ARR was 0.6%, 0.7% and 0.3% for all-cause mortality, MI and stroke respectively, in primary prevention trials. The corresponding RRRs were 13%, 38% and 24%.
For secondary prevention, the ARRs were 0.9% (all-cause mortality), 2.2% (MI) and 0.7% (stroke) with the corresponding RRRs of 14%, 27% and 13%.
The researchers also examined the the potential mediating effect of LDL cholesterol reduction with the absolute and relative treatment effects but these findings were inconclusive. In other words, it was not possible to either prove or disprove an association between the magnitude of LDL cholesterol reduction and the size of a treatment effect.
An important finding from the analysis was the high level of statistically heterogeneity in the studies, ranging from 27% to 82%, which suggested that pooling of results could make the findings unreliable.
The authors concluded that the absolute risk reductions associated with the use of a statin drug are modest in comparison to the often quoted relative risk reductions. However, they added that given the high level of heterogeneity, these results should be interpreted with caution. Despite this limitation, they suggested that clinicians should communicate both ARRs and RRRs to patients to enable informed decision-making about the benefits of statin treatment.
Byrne P et al. Evaluating the Association Between Low-Density Lipoprotein Cholesterol Reduction and Relative and Absolute Effects of Statin Treatment: A Systematic Review and Meta-analysis Ann Intern Med 2022