Thoughts on secondary prevention after percutaneous coronary intervention in Japan

Currently, aspirin and statins are regarded as the bottom-line treatment regimen for secondary prevention after percutaneous coronary intervention. However, even after implementation of aspirin and statin therapy, there remains a residual risk of cardiovascular events. Endeavours to reduce cardiovascular events further have been targeted at more intensive antithrombotic and lipid-lowering therapies.

Putting the results from the previous trials into perspective, the use of more intensive antithrombotic therapy could reduce ischaemic cardiovascular events, but has consistently increased the bleeding events in patients with stable coronary artery disease (CAD) including post-PCI patients1,2,3. Furthermore, there are signs emerging of increased mortality in the case of prolonged dual antiplatelet therapy (DAPT) as compared with shorter DAPT4. Therefore, we should balance the benefits and risks when considering more intensive antithrombotic therapy as a secondary preventive measure in patients with stable CAD after PCI. Theoretically, more intensive antithrombotic therapy would be best suited in those patients with a high thrombotic risk but low bleeding risk, who should be identified by estimating the thrombotic and bleeding risks separately and individually. We should estimate the absolute thrombotic and bleeding risks of the individual patients by applying the appropriate risk scores to the most contemporary long-term follow-up database in the geographic and/or ethnic population of interest. Therefore, we have developed the CREDO-Kyoto (Coronary REvascularization Demonstrating Outcome study in Kyoto) thrombotic and bleeding risk scores from a large Japanese database of patients who underwent first coronary revascularisation5. The CREDO-Kyoto thrombotic and bleeding risk scores have demonstrated modest accuracy in stratifying the thrombotic risk and bleeding risk separately in the validation cohort from other Japanese PCI studies. We found substantial overlap of the predictors between the thrombotic and bleeding risk scores. Chronic kidney disease, atrial fibrillation, peripheral vascular disease and heart failure emerged as the common predictors for both thrombotic and bleeding events. Reflecting the overlap of the risk predictors, a large proportion of high thrombotic risk patients also had high bleeding risk. For this group of patients, a more intensive antithrombotic therapy would not be appropriate (Figure 1). Patients with high thrombotic risk but low bleeding risk accounted for a very small proportion of the Japanese CAD population, which could be explained by the relatively lower thrombotic risk but comparable bleeding risk in Japanese patients as compared with Western patients. Therefore, more intensive antithrombotic therapy might not be the way to go for further prevention of cardiovascular events in the vast majority of Japanese patients with stable CAD after PCI.

Figure 1. Distribution of thrombotic and bleeding risk based on the CREDO-Kyoto thrombotic and bleeding risk scores.

A large proportion of high thrombotic risk patients also had a high bleeding risk. Patients with high thrombotic risk but low bleeding risk represented a very small proportion of the Japanese CAD population. CAD: coronary artery disease; CREDO-Kyoto: Coronary REvascularization Demonstrating Outcome study in Kyoto

More intensive lipid-lowering therapy is much safer than more intensive antithrombotic therapy. Based on the several previous “more versus less statins” trials, the current American College of Cardiology (ACC)/American Heart Association (AHA) guideline recommends high-intensity statin therapy in patients with clinical atherosclerotic cardiovascular disease6. However, high-intensity statin therapy is not widely implemented in daily clinical practice, particularly in Asia, at least partly because there has been no previous “more versus less statins” trial in Asia. We conducted a large randomised controlled trial comparing high-dose (4 mg/day) versus low-dose (1 mg/day) pitavastatin in 13,054 Japanese patients with stable CAD (Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease [REAL-CAD]), which is the largest ever “more versus less statins” trial, and the first trial of this type conducted in Asia. High-dose as compared with low-dose pitavastatin significantly reduced the risk of the primary endpoint (a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischaemic stroke, or unstable angina requiring emergency hospitalisation) (4.3% versus 5.4%, respectively, HR 0.81, 95% CI: 0.69-0.95, p=0.01)7. The favourable effect of high-dose pitavastatin was demonstrated regardless of the baseline low-density lipoprotein cholesterol (LDL-C) level. Relative risk reduction for the primary endpoint in the REAL-CAD trial conducted in Japan was remarkably comparable to that in the Treating to New Targets (TNT) trial conducted outside Japan, although the absolute event rate was much higher in the TNT trial than in the REAL-CAD trial (Figure 2)8. A positive result in a large randomised controlled trial does not always lead to a strong recommendation to adopt the tested intervention in real clinical practice. However, in the case of high-dose statins, we should strongly recommend adopting it in Japanese clinical practice, considering the robust risk reduction seen in Japanese patients, proven safety of long-term statin use during more than 30 years of clinical experience, its reasonably low cost, and the issue of “what is the optimal statin dose?”.

Figure 2. Primary endpoint results in the REAL-CAD and TNT trials.

ATV: atorvastatin; CHD: coronary heart disease; CI: confidence interval; CV: cardiovascular, HR: hazard ratio; LDL-C: low-density lipoprotein cholesterol; MI: myocardial infarction; NNT: number needed to treat; REAL-CAD: Randomised Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease; TNT: Treating to New Targets; UA: unstable angina

Beyond the high-intensity statins, the efficacy of non-statin LDL-C-lowering agents in reducing cardiovascular events has long been debated. A few years ago, the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) demonstrated that ezetimibe inhibiting intestinal absorption of cholesterol significantly reduced cardiovascular events with a 6.4% relative risk reduction in 18,144 patients with acute coronary syndrome (ACS)9. More recently, the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) and ODYSSEY Outcomes trials demonstrated that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (evolocumab and alirocumab, respectively) promoting LDL receptor recycling significantly reduced cardiovascular events with a 15% relative risk reduction in 27,546 patients with atherosclerotic cardiovascular disease and in 18,924 patients with ACS10. These non-statin LDL-C-lowering agents also appeared to be safe, and might be promising for secondary prevention in very high-risk patients. However, in real-world clinical practice, the decision to implement more intensive intervention should be based on consideration of the efficacy (relative risk reduction) and safety of a given intervention, absolute cardiovascular event risk of a given patient, and the cost of the intervention. The role of more intensive lipid-lowering interventions beyond “high-intensity statin” therapy would be very limited in Japanese CAD patients, in whom the cardiovascular event risk is relatively low, and therefore the cost-effectiveness balance is unfavourable for these expensive interventions.