Both forms of cardiovascular disease associated with higher cancer risk

26th April 2023

Atherosclerotic and non-atherosclerotic cardiovascular disease (CVD) increase the risk of cancer developing at multiple sites

A heart healthy lifestyle reduces the risk of cancer which suggests that both conditions share risk factors. This relationship appears to be bi-directional such that cancer patients with CVD risk factors have an increased chance of an adverse cardiac event. Some evidence also points to atherosclerotic CVD itself being a risk for the development of cancer. However, whether all forms of CVD increase cancer risk and if there is a relationship with the cancer type remains unclear.

In the current study, researchers sought to investigate the association between both atherosclerotic and non-atherosclerotic cardiovascular disease with the development of cancer. In a retrospective examination of an insurance claims database, the team identified patients initially free from cancer. These individuals were then categorised as having either atherosclerotic cardiovascular disease or non-atherosclerotic disease. This latter group had for instance, valvular heart disease, arrhythmias or congenital heart disease. In their analysis, the researchers made adjustments for age, sex, diabetes, hypertension, chronic kidney disease and hyperlipidaemia.

CVD and cancer risk

There were a total 27,195,088 individuals with data for analysis. Those with CVD had a 12% higher risk of developing cancer than those without the disease. (Hazard ratio, HR = 1.12, 95% CI 1.11 – 1.13). This risk was elevated for both atherosclerotic disease (HR = 1.20) and non-atherosclerotic disease (HR = 1.11).

Both forms of cardiovascular disease also linked to a higher incidence of a number of cancers. For example, atherosclerotic cardiovascular disease increased the risk of lung cancer more than two-fold (HR = 2.78). But this was slightly lower for non-atherosclerotic CVD (HR = 1.73).

Citation
Bell CF et al. Risk of Cancer After Diagnosis of Cardiovascular Disease. J Am Coll Cardiol CardioOnc. 2023

Aspirin use benefits reduced by statins in those without atherosclerotic disease

1st March 2023

The benefits of aspirin use in myocardial infarction are offset by statin use in patients without atherosclerotic cardiovascular disease

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.

Citation
Khan SU et al. Aspirin With or Without Statin in Individuals Without Atherosclerotic Cardiovascular Disease Across Risk Categories. JACC Adv 2023

Elevated LDL triglycerides linked to higher risk of atherosclerotic cardiovascular disease

1st February 2023

Higher LDL triglyceride levels are associated with a greater risk of atherosclerotic cardiovascular disease and its components

Danish and UK researchers examining data from the Copenhagen General Population Study, have determined that higher LDL triglyceride levels are linked to an elevated risk of atherosclerotic cardiovascular (ASCV) disease and its components such as myocardial infarction, ischaemic stroke and peripheral artery disease.

It is well recognised that a higher low-density lipoprotein (LDL) level is directly linked with the development of ASCV. Moreover, it has previously been shown that LDL contains a mixture of phospholipids, cholesterol and its esters and around 6% triglycerides. However, the role of triglycerides in ASCV has achieved much less attention in comparison to LDL, possibly because of a lack of randomised, clinical trial evidence.

As a result, in the current study, researchers wanted to better understand the potential role of LDL triglycerides (LDLT) in the development of ASCV and hypothesised that it was likely that higher LDLT levels would in fact be linked to greater risk of ASCV. The team used data obtained in the Copenhagen Population study, in which the lipid levels were measured in nearly 70,000 patients, either by a direct assay or from assessment by nuclear magnetic resonance. The researchers then performed a meta-analysis incorporating their findings from the Copenhagen study with previous studies.

LDL triglycerides and atherosclerotic cardiovascular disease

Levels of LDLT had been measured via a direct assay in 38,081 individuals and by NMR in 30,208 and who were followed for a median of 3 and 9.2 years respectively.

Using the results from measurement of LDLT direct assay, researchers calculated that for every 0.1mmol/l increase in LDLT, there was a 26% higher risk of ASCV (hazard ratio, HR = 1.26, 95% CI 1.17 – 1.35). The risks were similarly elevated for ischaemic heart disease (HR = 1.27), myocardial infarction (HR = 1.28), ischaemic stroke (HR = 1.22) and slightly higher for peripheral artery disease (HR = 1.38). Using the NMR-derived data gave rise to similar elevated risks for ASCV and its components.

When these results were included into the meta-analysis, giving a total participant population in excess of 110,000, a comparison of the highest to lowest LDLT quartile, revealed a risk ratio (RR) for ASCV of 1.5 (95% CI 1.35 – 1.66). Again, the risk ratios were also significantly elevated for ASCV components.

The authors concluded that elevated LDLT were robustly associated with an increased risk of ASCV and its components.

Citation
Balling M et al. Elevated LDL Triglycerides and Atherosclerotic Risk. Am J Coll Cardiol 2023

Moderate-intensity statin therapy and ezetimibe non-inferior to high-intensity mono-therapy

22nd July 2022

A moderate-intensity statin and ezetimibe regime in atherosclerotic cardiovascular disease is non-inferior to high-intensity statin therapy

A moderate-intensity dose statin combined with ezetimibe is non-inferior to high-intensity statin mono-therapy in patients with atherosclerotic cardiovascular disease (ASCVD) and has a lower incidence of drug discontinuation or dose reduction due to adverse statin events, according to a 3-year randomised trial by South Korean researchers.

High-intensity statin regimes lower LDL cholesterol and improve vascular outcomes in comparison to less intense regimes. This was clearIy shown in a meta-analysis of 26 randomised trial with over 170,000 patients, in which high-intensity statin therapy produced a highly significant reduction in major vascular events such as coronary death or non-fatal myocardial infarction, compared to less intensive regimens. Nevertheless, whilst effective, statin drugs are associated with intolerance and which has an overall prevalence of 9.1% but which reduces to 5.9%, depending on the definition used by various organisations. In addition, higher potency statins have been found to be associated with a 15% higher risk of new onset diabetes compared to lower potency agents.

One potential solution to using high-intensity (or high dose) statins is to use a moderate-intensity regime but with the addition of ezetimibe. Indeed, one 2014 systematic review of 36 trials found that moderate-intensity statin therapy with ezetimibe, decreased LDL cholesterol level 5% to 15% more than high-intensity mono-therapy among patients with ASCVD. Although the authors of the review advocated a lower-intensity statin-ezetimibe combination for high-risk patients who were either intolerant or unresponsive to statins, they cautioned on the absence of long-term clinical benefits and harms from using this approach. Consequently and with a need to gather much needed evidence, the South Korean team undertook the RAndomised Comparison of Efficacy and Safety of lipid lowerING with statin mono-therapy versus statin–ezetimibe combination for high-risk cardiovascular disease (RACING) trial. The purpose of the trial was to compare the 3-year clinical efficacy and safety of moderate-intensity statin with ezetimibe to high-intensity statin mono-therapy in patients who are at very high risk for cardiovascular disease. Individuals were randomised 1:1 to either ezetimibe and rosuvastatin 10 mg daily or high-intensity mono-therapy (rosuvastatin 20 mg daily). The primary endpoint was the occurrence of cardiovascular death, major cardiovascular events or non-fatal strokes within 3 years. For the secondary endpoints, the researchers considered the proportion of patients whose LDL cholesterol was reduced to under 70 mg/dL (1.81 mmol/L) over the 3 years. They set the test for non-inferiority as an upper level of the 95% confidence interval between the two groups, of less than 2%.

Moderate-intensity statin therapy and cardiovascular outcomes

A total of 3780 patients with ASCVD and a mean age of 64 years (75% male) were randomised equally to either intervention and the median duration of follow-up was 3 years.

The primary endpoint occurred in 9.1% of those receiving combination therapy and 9.9% of those with mono-therapy (hazard ratio, HR = 0.92, 95% CI 0.75 – 1.13, p = 0.43). Since the upper level of the confidence interval was 1.3% (less than the pre-specified 2%) the authors declared non-inferiority for the two regimes. Moreover, the mortality rates were not significantly different (HR = 1.34, 95% CI 0.46 – 3.85, p = 0.59).

For the secondary outcome of LDL lowering, 72% in the combination regime and 58% of those on mono-therapy, achieved the target of < 70 mg/dL (p < 0.0001).

Interestingly, discontinuation rates or dose reductions due to adverse effects were significantly less for those receiving combination therapy (4.8% vs 8.2%, p < 0.0001).

The authors concluded that the combination of moderate-intensity statin therapy and ezetimibe was non-inferior to high-intensity statin therapy but also that the combination gave rise to a lower incidence of drug discontinuation or dose reduction due to adverse effects and a higher proportion of patients reaching their LDL cholesterol level.

Citation
Kin BK et al. Long-term efficacy and safety of moderate-intensity statin with ezetimibe combination therapy versus high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease (RACING): a randomised, open-label, non-inferiority trial Lancet 2022