Achieving post-percutaneous coronary intervention low-density lipoprotein-cholesterol goals: Science versus reality

Dyslipidaemia is one of the most important modifiable risk factors and is estimated to cause 4.5% of total deaths and 2% of total disability adjusted life years globally. ¹ The new European Society of Cardiology/European Atherosclerosis Society guidelines on the management of dyslipidaemia ² reflect the consistent evidence from genetic and clinical studies showing that low-density lipoprotein-cholesterol (LDL-C) is causal for cardiovascular disease (CVD) and should be the main target of treatment. ³ The guidelines emphasize that cardiovascular risk reduction is proportional to the absolute reduction in LDL-C and the risk of the patient. ² Recent studies in very high-cardiovascular risk patients have shown further benefit from reducing LDL-C to lower than previous goals without a J curve or adverse events. ⁴ This has led to a more stringent approach against dyslipidaemia, particularly in high and very high-cardiovascular risk patients in the new 2019 guidelines. ²

Patients who have undergone percutaneous coronary interventions (PCI) are at very high risk for further cardiovascular events. In a large analysis of 21 randomized controlled trials of patients undergoing elective or primary PCI between 1999 and 2016, five year mortality was 10% and half of the deaths were cardiovascular. ⁵ These findings emphasize that there is room for improvement and these patients should be treated aggressively to reduce residual risk and further events.

In this issue of European Journal of Preventive Cardiology, Harris et al. ⁶ assess the use of lipid-lowering therapy (LLT) and achievement of lipid goals in a nationwide cohort of very high-risk patients who underwent PCI between January 2011 and December 2017. Their striking findings demonstrate the significant under-implementation of the guidelines. Less than half of the very high-risk patients achieved the 2016 guideline-recommended LDL-C goals, whereas only 23% reached the 2019 goals. Despite the fact that both National Institute for Health and Care Excellence and European guidelines recommend high-intensity statins in these patients, only 68.5% of patients presenting with acute coronary syndrome were prescribed high-intensity statins. About half of the patients who did not reach the LDL-C goal were prescribed a high-intensity statin, around 2% were prescribed combination therapy and 6–8% did not receive any LLT at all. Furthermore, among patients that had experienced CVD events within two years prior to the index PCI, only 61.5% had their lipid profile checked within the follow-up period and 6.2% of those that did not achieve the 2019 LDL-C goal had no LLT prescription. ⁶

These findings do not come as a surprise considering previous information from EUROASPIRE and DYSIS studies showing under-implementation of previous guidelines. The DYSIS-II study, ⁷ which enrolled very high-risk patients from 18 countries in Asia, Europe and the Middle East, showed that LDL-C targets (LDL-C < 70 mg/dL) were achieved in only less than one-third of patients with stable coronary artery disease and less than one-fifth of patients with acute coronary syndrome. Ninety-five per cent of patients were taking LLT at follow-up, the intensity of statin therapy was moderate and combination therapy was infrequent. ⁷ The most recent EUROASPIRE study (EUROASPIRE-V) ⁸ showed that LLT was used in 84% (varying between 75% and 98% within countries) of patients at very high risk. At follow-up after discharge, only half of the patients were on high-intensity LLT. ⁸ Disappointingly, down titration or interruption of LLT occurred due to physician advice in two out of five cases. ⁸ In a cohort of coronary artery bypass graft patients, an improvement in each component of the lipid profile was reported to be associated with reduced mortality at follow-up. ⁹

Another important finding of the study by Harris et al. ⁶ is that a gender disparity against females still exists. Being a female was a significant predictor of not having the lipid profile checked after PCI and not achieving the 2019 guideline-recommended goals. ⁶ The gender gap that had been previously described in earlier cohorts still seems to persist despite all the efforts and campaigns. In the recent EUROASPIRE-V study, females were less likely to receive LLT, high-intensity LLT and achieve the optimal LDL-C goals. ⁸

The cardiovascular benefits seen in randomized trials that drive the guidelines will be replicated in real life only if the guidelines are implemented. Unfortunately, despite great scientific progress, effective therapies and good will, there is still a gap between science and reality. The gap will increase even further with the more aggressive goals of the new 2019 guidelines. ²

To close this gap, a collaborative effort between the healthcare system, the healthcare provider and the patient is necessary. The healthcare system should have guideline-based reimbursement policies, and allow sufficient monitoring and time spent between physician and patient. Physicians should know and follow the guidelines and have enough time to spend with the patient for shared decision making. Physicians, as part of national societies, should also take the initiative to set up national databases and investigate how scientific evidence obtained from international guidelines matches with geographic, sociocultural and genetic variability in their own populations. ¹⁰ Patients should be educated to take responsibility for their own health. Age, comorbidity, low health literacy, social factors and cost are all determinants of adherence to medications. However, it has been shown that even if medications are provided for free, non-adherence is still a problem. Statin intolerance (which is mostly perceived due to the nocebo effect and rarely real) is another reason for non-adherence and should be handled according to guideline recommendations. Negative news in the media about LLT also negatively affects adherence to therapy and cardiovascular outcomes. ¹¹

Several measures have been useful to increase implementation, including systemic prevention programmes with multidisciplinary teams, using electronic health records and pharmacy care. However, we clearly need new strategies and a paradigm shift to adapt to the changing landscape. Healthcare systems must evolve to meet these challenges. Integrating technology to healthcare will improve adherence, access to resources and data monitorization. ¹² With more patients becoming digitally enabled, using mobile technologies to distribute information, send reminders and track medication has been shown to improve adherence moderately. ¹³ However, quality and effectiveness of these measures need to be monitored.

With the goals becoming more aggressive in very high-risk patients, more patients will need high-intensity lipid lowering. Modelling studies have shown that if patients are fully adherent to high-intensity statins and use ezetimibe in combination if necessary, most will achieve the goals with oral medications alone, since a 65% decrease in LDL-C can be expected. ¹⁴ For the remaining few, proprotein convertase subtilisin/kexin type 9 inhibitors may be used. However, in real life, high-intensity statins and combination therapy are vastly underutilized. New therapeutic options for combination therapy, such as bempedoic acid and inclisiran, may offer additional advantages. These medications will increase our options for combination therapy and help statin intolerant patients reach the goals, and biannual dosing with inclisiran may help close the treatment gap in selected patients if cardiovascular outcome studies are positive.^15,16

There is substantial evidence to show not only that lower LDL-C is better but also that earlier LDL-C reduction is better. ³ While aggressive LDL-C lowering is necessary to regress or stabilize atherosclerotic plaques, the cumulative effect of LDL-C can be prevented by small reductions in LDL-C starting from early ages. ¹⁷ Maintaining optimal lipid levels throughout life will minimize the rate of progression of atherosclerotic plaques where even small reductions in LDL-C will have a significant effect on cardiovascular outcomes.