Polypharmacy as New Risk Factor of Major Bleeding in Patients Undergoing Coronary Stent Implantation ― Which Come First, the Chicken or the Egg? ―
論文ID: CJ-23-0720
詳細
論文ID: CJ-23-0720
Polypharmacy describes the case of patients taking ≥5 drug types and it is generally associated with poor clinical outcomes.1 Regarding cardiovascular diseases, polypharmacy has been mainly reported in elderly patients with atrial fibrillation (AF). A meta-analysis of randomised trials related to direct oral anticoagulants revealed that polypharmacy could increase bleeding events and all-cause death in patients with AF.2 The All Nippon Atrial Fibrillation in the Elderly (ANAFIE) registry enrolled 32,275 patients with AF, and the proportion of polypharmacy was approximately 60%, with increasing numbers of drugs tending to be associated with an increased incidence of clinical outcomes, including major bleeding, cardiovascular events and all-cause death.3
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What about your outpatient prescriptions? Based on robust data from numerous randomised clinical trials (RCTs), after percutaneous coronary intervention (PCI) clinicians aggressively prescribe for secondary prevention with multiple oral drugs, including statins, ezetimibe and antihypertensive and antithrombotic drugs.4 Additionally, recent guideline-directed medical therapy (GDMT) recommendations are to add 4 drugs (β-blockers, mineralocorticoid-receptor antagonists, sodium–glucose cotransporter 2 inhibitors and angiotensin receptor–neprilysin inhibitors) if the patient has heart failure with reduced ejection fraction.5 However, it remains contentious whether all drugs proven to be effective in RCTs translate into real-world clinical practice because polypharmacy generally occurs for older patients with frailty and multimorbidities (i.e., chronic kidney disease, heart failure, cerebrovascular disease, active cancer and dementia)3 and they are traditionally excluded from RCTs; thus, the research results should be carefully interpreted.6 Therefore, assessing the association of polypharmacy using GDMT with adverse events using registry data that reflect real-world clinical practice would be useful.
In this issue of the Journal, Yamamoto et al7 using data from the CREDO-Kyoto PCI/CABG Registry Cohort 3, comprising 12,291 patients who were reliably on dual antiplatelet therapy (DAPT) and had undergone initial stent implantation, reveal for the first time a significant relationship between polypharmacy and major bleeding in patients undergoing PCI.7 Let us consider their main findings in some detail. The proportion of patients with polypharmacy (i.e., ≥5 drugs at discharge) was as high as 88%, despite the patients being younger than those enrolled in the ANAFIE registry.3 This could be due to the difference in patients’ background between AF and ischaemic heart disease, but Yamamoto et al explain that polypharmacy was mainly associated with increased use of medications to treat hypertension, heart failure and diabetes. The CREDO-Kyoto PCI/CABG Registry Cohort 3 enrolled patients between 2011 and 2013 and is somewhat outdated; hence, from a current perspective, polypharmacy based on GDMT is expected to increase the number of medications due to the introduction of new drugs for heart failure and diabetes. In other words, using ≥5 drugs may become common as the optimal medical therapy for secondary prevention after PCI. Thus, the definition of polypharmacy may need to be reconsidered.
The patients in the present study were stratified by tertiles of the number of medications at discharge (Tertile 1 [≤5], Tertile 2 [6–7] and Tertile 3 [≥8]) and were compared in terms of the cumulative 5-year incidence of major bleeding after PCI to elucidate this uncertainty. As anticipated, the higher number of medications was significantly associated with an increased risk of major bleeding (Tertile 1 [12.5%], Tertile 2 [16.5%] and Tertile 3 [20.4%], P<0.001), and this finding remained even after adjusting for confounding factors.
Appropriate PolypharmacySo how do we address the higher risk of major bleeding in patients with polypharmacy? We need to find a compromise between the benefits of GDMT and the risks of polypharmacy. A key to achieving a compromise in this dilemma may be the concept of ‘appropriate polypharmacy’ (Figure). GDMT should always be introduced with the aim of reducing the risk of major bleeding and death. Intensive drug uptitration is also important for achieving optimal medical therapy based on the concept of treat-to-target. Shared-decision making is necessary, and the goals of treatment and the treatments preferred by the patient should be discussed to build optimal patient–healthcare provider relationships. Simultaneously, clinicians should routinely evaluate the potential risks of each drug comprising the polypharmacy, that is, the risk of drug-to-drug interactions, adverse reactions and difficulties with drug adherence.8 Additionally, assuming that reducing the number of drugs could reduce the incidence of major bleeding, introducing a polypill, which involves combining multiple key medications with different therapeutic objectives into a single pill, would be beneficial.9
The shift from traditional to appropriate polypharmacy. ACE-i, angiotensin-converting-enzyme inhibitor; ARB, angiotensin II receptor blocker; B-blocker, β-blocker; DAPT, dual antiplatelet therapy; GDMT, guideline-directed medical therapy; PPI, proton pump inhibitor; SNRI, serotonin norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.
The underlying reasons for the higher risk of polypharmacy for major bleeding after PCI may be multifactorial, such as advanced age, comorbidities, frailty and coronary anatomic complexity, but these factors are unfortunately difficult to modify.7 However, the findings of the present study may have a silver lining. The duration of DAPT in this registry was 70% at 1 year and 30% at 3 years, which is quite longer than current practice. Another highlight of appropriate polypharmacy is that it must be discontinued when the benefit from the prescribed drug no longer outweighs the potential for harm, and DAPT is representative.10 Very short DAPT can reduce the number of drugs, and the STOP-DAPT2 trial, a 1-month DAPT previously established by Yamamoto et al, demonstrated that early single-antiplatelet therapy can reduce bleeding complications.11
Polypharmacy itself may be a mirror of a patient’s vulnerability. Therefore, whether polypharmacy or patient vulnerability is the risk for major bleeding is an example of the “chicken or the egg” dilemma. As a clinician, I hope that appropriate polypharmacy does not constitute a bleeding risk, but the relationship between appropriate polypharmacy and major bleeding must be investigated in future clinical trials.
This study by Yamamoto’s group is a valuable report that alerts us to the crucial relationship between major bleeding and traditional polypharmacy, in which most patients were already being treated with ≥5 drugs after PCI, and simultaneously indicates the inevitability of a shift to appropriate polypharmacy.
