Contemporary management of hypertension was profoundly changed by the SPRINT trial, which demonstrated that intensive systolic blood pressure (SBP) lowering to a target of <120 mmHg reduced major adverse cardiovascular events (MACE) and all-cause mortality compared to a standard <140 mmHg target in high-risk patients excluding diabetes [1]. This finding strongly advocated for a “lower is better” paradigm. However, the generalizability of this paradigm to patients with established coronary artery disease (CAD) remains highly contentious. A substantial body of evidence, most notably from the CLARIFY registry, supports a “J-curve” phenomenon in this population [2]. In this large cohort of stable CAD patients, an SBP < 120 mmHg and a diastolic blood pressure (DBP) < 70 mmHg were associated with an increase in adverse cardiovascular outcomes, including mortality [2]. This physiological plausibility, wherein excessive lowering of DBP, the primary determinant of coronary perfusion pressure, may precipitate myocardial ischemia in the presence of severe coronary artery stenosis, has been a clinical concern for decades. While SPRINT supports lower SBP targets, CAD observational data suggests the existence of a hemodynamic floor [1, 2]. The patient population in the AFIRE trial, namely individuals with both atrial fibrillation (AF) and stable CAD, lies at the epicenter of this conflict [3]. This multi-morbid cohort, often with diabetes, heart failure (HF) or prior stroke, was largely excluded from SPRINT. Therefore, applying SPRINT-like intensive targets to this vulnerable population represents potentially harmful extrapolation with insufficient evidence. A post-hoc analysis of AFIRE, which stratified patients according to SBP, provides crucial data to explore this vulnerable intersection [4].

The AFIRE trial compared rivaroxaban monotherapy with combination therapy consisting of an oral anticoagulant plus a single antiplatelet agent in patients with AF and stable CAD [3]. The trial was stopped early for mortality benefit, demonstrating that rivaroxaban monotherapy was non-inferior for efficacy and superior for safety [3]. The post-hoc analysis by Yamanaka et al. divided the AFIRE cohort (n = 2135) by the median baseline SBP of 126 mmHg, creating a Low SBP group (≤126 mmHg; mean 114.0 mmHg) and a High SBP group (>126 mmHg; mean 139.1 mmHg) [4]. The analysis yielded two crucial findings. First, Low SBP was confirmed as a potent marker of risk. Compared to the High SBP group, the Low SBP group had a significantly higher rate of the primary efficacy endpoint (HR, 1.50; 95% CI, 1.13–1.98). This elevated risk was driven primarily by all-cause mortality (HR, 1.61) and unstable angina requiring revascularization (HR, 3.19). Most critically, this risk persisted even after rigorous propensity score matching (PSM) (HR, 1.38; 95% CI, 1.01–1.88). The persistence of this association after PSM indicates that low SBP is unlikely to represent merely a passive surrogate for measured confounders. Instead, low SBP may lie on the causal pathway itself, for example by precipitating hypoperfusion, or it may serve as a proxy for potent unmeasured confounders. Second, the analysis demonstrated that SBP functions as a powerful treatment effect modifier. In the Low SBP group (≤126 mmHg), rivaroxaban monotherapy was associated with a substantial reduction in both the primary efficacy endpoint (HR, 0.60; 95% CI 0.41–0.86) and the primary safety endpoint (HR, 0.40; 95% CI 0.22–0.74), whereas in the High SBP group (>126 mmHg), no significant differences were observed for efficacy (HR, 0.91; 95% CI 0.58–1.40) or safety (HR, 0.99; 95% CI 0.52–1.89). The interaction p value for the safety endpoint was statistically significant (p = 0.046), confirming that the bleeding benefit of monotherapy is greater in patients with lower SBP (≤126 mmHg).

The elevated risk in the Low SBP group warrants further explanation. Why is this group, with a mean SBP of 114 mmHg, at such high risk? The first hypothesis is that of simple reverse causation, in which low SBP is a marker of advanced disease. The Low SBP group had a higher prevalence of HF, prior MI, and renal dysfunction. Low SBP is a well-established independent predictor of mortality in HFrEF [5]. The second hypothesis is causal hypoperfusion, consistent with the J-curve phenomenon. A mean SBP of 114 mmHg, likely accompanied by a DBP < 70 mmHg, may directly compromise coronary perfusion and thereby help explain the observed threefold increase in unstable angina [4]. A third, more nuanced hypothesis concerns intolerance to guideline-directed medical therapy (GDMT). Low SBP is a major barrier to the initiation and up-titration of key cardioprotective agents, including ACE inhibitors or angiotensin receptor blockers, angiotensin receptor-neprilysin inhibitors, beta blockers, mineralocorticoid receptor antagonists, and sodium–glucose cotransporter 2 inhibitors [6]. In addition, underlying renal dysfunction may further restrict the use or dosing of these therapies. The multivariable and PSM models accounted for a history of HF but could not adjust for intolerance to, or underuse of, GDMT, which therefore remains an important unmeasured confounder. Consequently, patients in the low SBP group are likely to receive suboptimal doses of these life-prolonging cardioprotective agents. In this context, the high mortality risk in this group is probably due to not only the hemodynamic effects of low blood pressure itself, but also undertreatment of the underlying cardiovascular disease.

This post-hoc analysis provides a critical contribution to the contemporary “less is more” paradigm in antithrombotic therapy. Whereas previous studies have primarily addressed whether de-escalation strategies are safe and effective [3, 7], the present analysis addresses the equally important question of in whom de-escalation is most critical [4]. The optimal candidates do not appear to be low risk patients, but rather those at high risk and vulnerability, in whom the bleeding risk is greatest, and the potential net clinical benefit of simplified antithrombotic therapy is maximized. In the Low SBP group, rivaroxaban monotherapy conferred a dual advantage, reducing both the primary efficacy end point and major bleeding compared with combination therapy. The safety benefit, corresponding to a 60% relative reduction in major bleeding, is readily explained by the extreme vulnerability of frail patients with renal dysfunction and HF to bleeding under combination therapy. More noteworthy is the concomitant 40% reduction in MACE and death. This pattern is consistent with accumulating evidence that bleeding itself is a powerful trigger of subsequent ischemic and fatal events [8, 9]. In another post hoc analysis of AFIRE, major bleeding in patients with AF and stable CAD was associated with an approximately twofold higher incidence of subsequent MACE and an almost eightfold increase in risk within 30 days after the bleed [8]. Likewise, in a large percutaneous coronary intervention (PCI) cohort, spontaneous bleeding was independently associated with long term mortality, with a prognostic impact comparable to that of myocardial infarction [9]. In the Low SBP group of the present analysis, combination therapy substantially increased major bleeding relative to monotherapy; each bleeding event can lead to interruption of antithrombotic therapy, transfusion, hemodynamic instability, and chronic anemia. In patients whose coronary perfusion is already constrained by low perfusion pressure, anemia and instability are potent drivers of demand ischemia, including type 2 myocardial infarction and unstable angina. Thus, the apparent efficacy advantage of rivaroxaban monotherapy is likely mediated by the prevention of bleeding and its downstream consequences, whereas combination therapy may undermine ischemic protection through its own iatrogenic harm.

This analysis yielded several clinically relevant implications [4]. First, together with observational data from CLARIFY [2], it suggested that intensive SBP-lowering targets in SPRINT are likely inappropriate and potentially harmful in patients with AF and stable CAD, in whom the nadir of the J-shaped association between SBP and risk appears to lie in the range of 120–140 mmHg. Second, SBP can serve as a simple bedside tool to guide antithrombotic de-escalation. In patients with lower SBP, HF and CAD, the traditional instinct to intensify antithrombotic therapy with combination regimens is likely misguided. The AFIRE supports an alternative paradigm in which these highly vulnerable patients derive greater net clinical benefit from simplified rivaroxaban monotherapy, and in which a lower SBP should prompt consideration of de-escalation rather than escalation of antithrombotic therapy. This post hoc analysis remains hypothesis generating and requires prospective confirmation. AFIRE enrolled patients with stable CAD at least 1 year after PCI, so its findings cannot be directly extrapolated to the early post-PCI phase. In that setting, the recently reported OPTIMA-AF trial has now shown that in patients with AF undergoing PCI, a strategy of 1 month of dual therapy with a direct oral anticoagulant plus a P2Y12 inhibitor followed by oral anticoagulant monotherapy is non-inferior to 12 months of dual therapy for death or thromboembolic events, while substantially reducing major or clinically relevant non-major bleeding [10]. These findings raise the possibility that in patients with lower SBP, an early transition to monotherapy or to a very short course of dual therapy may be particularly advantageous. They also highlight the need for future trials that specifically target this high-risk phenotype and evaluate strategies to disrupt the vicious cycle in which low blood pressure both heightens vulnerability to hemodynamic compromise and bleeding and constrains the use of intensive antithrombotic and cardioprotective therapies. Taken together, these findings call for a vulnerability-guided, patient-centered approach to antithrombotic therapy that strives to prevent thrombosis while rigorously protecting patients from treatment-induced harm (Figure).