Decline in the Proportion of Cardiovascular Deaths Attributed to Myocardial Infarction May Shape Future Lipid-Lowering Strategies

Understanding the shifting balance between nonfatal myocardial infarction (MI) and cardiovascular death (CVD) may help clinicians gauge the impact of lipid-lowering therapies and optimize their clinical strategies, ultimately improving outcomes for patients at high risk for atherosclerotic cardiovascular disease. A study presented at the 75th Annual Scientific Session of the American College of Cardiology, in New Orleans, showed that changes in the MI-to-CVD ratio provides a novel lens for assessing therapy impact and may inform design strategies for future clinical trials. 

The balance between nonfatal MI and CVD has shifted significantly over the past decades, due to improved acute care and prevention, along with a rise in the prevalence of chronic, non-ischemic heart conditions. Historically, heart attack was frequently fatal. However, advances in revascularization and the adoption of drug-eluting stents have transformed myocardial infarction into a manageable chronic condition in many cases, shifting the burden of mortality to other cardiovascular causes. 

“When we designed lipid-lowering therapies in the past, it was all based on the idea that, by reducing cholesterol, we reduced myocardial infarction as a direct effect, and that will reduce cardiovascular death,” lead author Raunak Nair, MD, a cardiology fellow at the Cleveland Clinic, in Cleveland, Ohio, said in an interview. “Cardiovascular death comprises not just myocardial infarction but also sudden cardiac death, aortic aneurysm, pulmonary embolism, all these cardiovascular etiologies. So, in the [earlier trials], we had a ratio of 4. Over time, we have become so good at decreasing [the rates of] myocardial infarction that now our MI-to-CVD ratio is around 1 in the [most recent] trials.”  

Nair and colleagues reviewed landmark randomized trials of statins and non-statin therapies, including ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and bempedoic acid. The analysis included 20 trials spanning three decades, from the first statin trial in 1994, to the CLEAR Outcomes trial analyzing the impact of bempedoic acid on cardiovascular outcomes. Sample sizes ranged from 1,255 people to nearly 28,000 participants. All patients were on statin therapy, alone or in combination with another agent. The results showed that the MI-to-CVD ratio declined over time, reflecting advances in low-density lipoprotein cholesterol targets, antiplatelet therapies, and revascularization strategies. 

While the MI-to-CVD ratio captures the mechanistic impact of therapies designed to decrease atherogenic lipoprotein levels, with the decline in myocardial infarction rates, larger sample sizes and longer follow-up periods may be needed to optimize study design and interpretability. “If we want to design [new] trials, [these findings] give us an idea of what kind of ratio we might be aiming for,” Nair explained. “That helps us to focus our resources, to not cancel out drugs that may have life-changing implications, to give them a chance - and also understand how long we should expect a trial to last before making a premature analysis.” The author noted that the declining MI-to-CVD ratio indicates progress, but it also signals the need for changes in the design of clinical trials investigating novel lipid-lowering therapies, which will inform clinical practice for decades to come.