During the past 30 years, the development and application of potent antiplatelet agents have contributed to a dramatic reduction in thrombotic events in patients who received percutaneous coronary intervention (PCI). A steady increase in bleeding complications was subsequently observed during hospitalization and postdischarge despite the use of bleeding avoidance strategies. Additionally, with the wide application of a score-based strategy to initiate anticoagulation therapy in atrial fibrillation (AF) patients for stroke prevention, efforts have been made to identify clinically occult AF episodes using mobile devices or long-term implantable devices.[3,4] However, the recently published Implantable loop recorder detection of atrial fibrillation to prevent stroke (LOOP) study, demonstrated that the use of continuous electrocardiographic monitoring by an implantable loop recorder, although yielding a threefold increase in AF detection and anticoagulation initiation, did not lead to a significant reduction in the risk of stroke or systemic arterial embolism, but a numerically higher incidence of major bleeding. The abovementioned evidence highlights the importance of identifying high-risk profiles associated with bleeding complications and implementing appropriate approaches for risk reduction.
The advent of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, which can lower low-density lipoprotein cholesterol (LDL-C) to levels not previously achievable by statins, has made “the lower the better” the current paradigm in LDL-C reduction for atherosclerotic cardiovascular disease (ASCVD) prevention. However, our recent report based on the Chinese population, as well as previous findings on Western populations[8-10] and East Asian populations,[11,12] demonstrated a close relationship between the serum cholesterol level and bleeding risk in patients on dual antiplatelet therapy (DAPT), that is, the lower the LDL-C levels were, the higher the risk for bleeding complications was. Epidemiological studies have also shown that low LDL-C levels are associated with a higher risk for AF.[13,14] Taking into account well-established evidence of the association between low LDL-C and increased risk for hemorrhagic stroke, it is reasonable to assume that the initiation of anticoagulation therapy may increase the risk of intracranial hemorrhage in AF patients with low LDL-C levels. In this review, we focus on recent evidence and the clinical implications of low-cholesterol-level-related bleeding risk in patients on antithrombotic therapy, as well as unsettled issues concerning the mechanisms involved and future work in this area, which may provide a personalized approach to reduce the bleeding risk.
Aggressive lipid-lowering and cardiovascular and all-cause mortality
The results from recent outcome studies, that is, the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) and the Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY OUTCOMES) trials, have provided evidence of the effectiveness of monoclonal PCSK9 inhibitors (PCSK9i) on top of statin-based strategy in reducing LDL-C levels and preventing major cardiovascular events among patients with either chronic coronary syndrome or recent acute coronary syndrome (ACS). Based on the main findings of these two large randomized controlled trials (RCTs), lipid-lowering recommendations in recent guidelines from the American Heart Association (AHA) and European Society of Cardiology (ESC) have been modified toward more aggressive goals,[17,18] thereby fortifying the robust impact of a lifelong approach for LDL-C reduction.
Note that the FOURIER and the ODYSSEY OUTCOMES trials both utilize a composite outcome as the primary efficacy endpoint (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization).[15,16] However, a recent meta-analysis questioned the appropriateness of the use of non-fatal myocardial infarction as a surrogate for cardiovascular and all-cause mortality by showing low values of the coefficient of determination (R2, which lies between 0 and 1, where a good surrogate should have an R2 ≥ 0.8) between non-fatal myocardial infarction and cardiovascular (R2 = 0.11) and all-cause mortality (R2 = 0.02) in 144 RCTs published in the most influential medical journals (New England Journal of Medicine, Lancet, and JAMA). This result indicates that a reduction in myocardial infarction per se does NOT necessarily correspond to a reduction in mortality. The surprising finding is attributable to the wide use of high-sensitivity troponin testing to include smaller myocardial infarctions and type 2 myocardial infarction that have a lower impact on mortality in contemporary practice. However, the positive findings on the composite endpoint from the FOURIER and the ODYSSEY OUTCOMES trials were mainly driven by a reduction in non-fatal myocardial infarction: in terms of a cardiovascular and all-cause mortality benefit, the separate findings from the FOURIER and the ODYSSEY OUTCOMES trials,[15,16] as well as the recent meta-analyses incorporating these two trials,[20,21] remain inconclusive. In the subgroup analysis, the mortality benefit of PCSK9i was only observed among patients with baseline LDL-C > 100 mg/dL, both before and after incorporating the results of the ODYSSEY OUTCOMES trial. Notably, according to data derived from ClinicalTrial.gov, in the FOURIER trial on participants with 3 years of follow-up, the cumulative all-cause mortality rate was 4.75% for the evolocumab group and 4.28% for the placebo group [Figure 1]. Data derived from the ClinicalTrial.gov for a total of 33 lipid-lowering and four outcome trials showed that PCSK9i even did not reduce myocardial infarction nor stroke/transient ischemic attack compared with placebos.
Apart from the ODYSSEY OUTCOMES trial on patients who had had an ACS 1 to 12 months earlier, there is limited real-world evidence of the impact of PCSK9i therapy on cardiovascular outcomes in patients with a very high risk of ASCVD (as defined by at least two severe ASCVD events or one severe event combined with at least two high-risk factors). A recent observational study in China compared the efficacy and safety of evolocumab on top of statin therapy for 434 ACS patients against 434 propensity score-matched cohorts treated with statins alone. Current guidelines are an LDL-C target <55 mg/dL for this population. During a 6-month follow-up period, evolocumab treatment was associated with a numerically higher incidence of major adverse cardiovascular events (5/434 vs. 2/434; hazard ratio [HR]: 2.52, 95% confidence interval [CI]: 0.49–12.97) despite 47.7% of the evolocumab group and 18.4% in statin-alone group achieving an LDL-C goal of ≤55 mg/dL. Note that recent population-based cohort studies from Denmark, Korea, China, and US demonstrated a U-shaped association between baseline LDL-C levels and all-cause mortality. As the optimal goal of lipid-lowering as a lifelong approach is improving health, longevity and well-being should always be a top priority. Therefore, further long-term follow-up studies are required to fully address the cardiovascular and all-cause mortality benefits of PCSK9i.
Low LDL-C levels and risk for hemorrhagic stroke
In the past two decades, reports based on East Asian populations[31-35] and Caucasian females have provided evidence of an association between low LDL-C levels and risk for hemorrhagic stroke in the general population not on antithrombotic therapy. Moreover, a numerically higher incidence of hemorrhagic stroke was observed in the high-dose statin arm in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels trial. Indeed, we also found that in ACS patients treated with PCI, there was a negative linear association between admission LDL-C levels and in-hospital hemorrhagic stroke: the multivariable-adjusted odds ratio (OR) was 0.80 (95% CI: 0.66–0.97) per 30 mg/dL increase of LDL-C. However, the clinical implications should be interpreted with caution, considering the overwhelmingly high incidence of preventable ischemic strokes vs. the relatively low incidence of hemorrhagic stroke: the cumulative incidence of hemorrhagic stroke reported in long-term cohort studies were 0.80% to 1.60% during 9 to 20 years of follow-up,[33-35] whereas the incidence of ischemic stroke was threefold to fivefold higher than that of hemorrhagic stroke in China. Therefore, the impact of low cholesterol levels on hemorrhagic stroke should not be overemphasized for the purpose of preventing ischemic stroke and overall ASCVD at the population level.
The association between low cholesterol and the increased risk for hemorrhagic stroke in another clinical scenario deserves particular attention. Recent observational studies showed that low LDL-C was associated with a higher risk for AF.[13,14] The potential mechanisms underlying this phenomenon are unclear and may be related to alterations in cardiac ion channel handling by cholesterol.[39,40] Intracranial hemorrhage is the most serious complication of anticoagulation therapy, as for patients on DAPT. Therefore, it is speculated that in patients with low-LDL-C-related AF, the initiation and optimal dosing of anticoagulation therapy should be prudent, and a careful revaluation of the risk of hemorrhagic stroke vs. thromboembolic complications in these patients is warranted. Notably, in the 2020 ESC guideline for the diagnosis and management of AF, low LDL-C has been listed as a modifiable risk factor for intracranial hemorrhage.
Low LDL-C levels and the bleeding risk in patients on DAPT
To reduce the bleeding risk in patients on DAPT, reports based on Western populations have provided numerous prediction models for in-hospital,[42-44] 30-day, and 1-year[46,47] risks of bleeding complications. Whereas a definition of ischemic event exists, the lack of a standardized definition for bleeding events is a major limitation of these score-based prediction models that has hampered clinical application. Another limitation of these studies is that the analytic approaches used are mainly based on potential predictor selection by a cutoff P value, followed by forward/backward selection. These semiautomatic stepwise regression methods should be used with caution: considering the inherent methodological limitations, that is, multiple comparison-related low P values that are difficult to correct and the influence of multicollinearity, predictor selection should be dependent on the study design and expertise on the subject matter can be valuable in making the appropriate adjustment.
Interestingly, a literature search uncovered a couple of studies demonstrating an association between cholesterol levels and bleeding risk [Table 1]. In the Reduction of Atherothrombosis for Continued Health (REACH) registry, during >2 years of follow-up of 68,236 patients (of which 54.2% were on aspirin) with established cerebrovascular disease, coronary artery disease, peripheral arterial disease, or at least three atherosclerosis risk factors, hypercholesterolemia (HC) was associated with a 23% reduction in bleeding risk, and further identified as an independent predictor for the bleeding risk score. This finding was confirmed in the prasugrel vs. clopidogrel in patients with ACSs (The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON)-TIMI38) trial, consisting of a 14.5-month follow-up of ACS patients undergoing planned PCI (100% on DAPT): a protective association was found between HC and thrombolysis in myocardial infarction (TIMI) major or TIMI minor bleeding (HR: 0.82, 95% CI: 0.68–0.99). In two studies on East Asian populations, Chen et al and Ueshima et al independently confirmed the protective association of higher cholesterol levels against bleeding academic research consortium (BARC) type ≥2 bleeds (excluding BARC type 4) in ACS patients undergoing PCI (86% on DAPT) during a 1-year follow-up and in patients implanted with everolimus eluting stents during a 3-year follow-up, respectively. Notably, the finding that hypocholesterolemia was associated with an 85% increase in bleeding risk in the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment trial warrants the need to delineate the relationship between LDL-C levels and bleeding risk in patients on DAPT. However, given that lipid-lowering is the current paradigm for ASCVD prevention, all authors are cautious about their findings and have only mentioned the association between cholesterol levels and bleeding risk in the main text of their publications, with the exception of one study from Japan based on a hypothesis-driven approach.
Table 1 -
Characteristics of studies reporting the association between cholesterol levels and the bleeding risk in patients on antithrombotic
||Cholesterol levels and bleeding risk
|Chen et al
||ACS undergoing PCI
||BARC type ≥2 bleeding event (excluding BARC type 4)
||HR for LDL-C (per 1.0 mmol/L increase): 0.60; 5% CI: 0.39–0.91; during 1 year
|Ueshima et al
||Everolimus eluting stent implantation
||HR for HC: 0.42; 95% CI: 0.20–0.88; during 3 years
|Ducrocq et al
||Established CBVD, CAD, PAD, or at least three atherosclerosis risk factors
||Aspirin 54.2%; other antiplatelet 11.5%
||Non-fatal hemorrhagic stroke or bleeding leading to both hospitalization and transfusion
||OR for HC: 0.77; 95% CI: 0.67–0.89; during 21 months
|Hochholzer et al
||ACS undergoing PCI
||TIMI major or TIMI minor bleeding
||HR for HC: 0.82; 95% CI: 0.68–0.99; during 14.5 months
|Iijima et al
||Low-to-intermediate risk PCI
||DAPT (100%) and peri-procedural anticoagulation
||Intracranial, intraocular, or retroperitoneal hemorrhage, clinically overt blood loss, or transfusion of ≥2 U of packed RBCs or whole blood
||OR for low cholesterol: 1.85; 95% CI: 1.32–2.63; within 30 days
ACS: Acute coronary syndrome; BARC: Bleeding Academic Research Consortium; CAD: Coronary artery disease; CBVD: Cerebrovascular disease; CI: Confidence interval; DAPT: Dual antiplatelet therapy; GUSTO: Global use of strategies to open occluded arteries; HC: Hypercholesterolemia; HR: Hazard ratio; LDL-C: Low-density lipoprotein cholesterol; OR: Odds ratio; PAD: Peripheral arterial disease; PCI: Percutaneous coronary intervention; RBC: Red blood cell; TIMI: Thrombolysis in myocardial infarction.
Based on the abovementioned evidence derived from a data-driven analytic approach, we hypothesized that there is a dose-response relationship between LDL-C levels and platelet responsiveness, where low LDL-C confers a risk for increased bleeding and high LDL-C levels are associated with a reduced risk. We had the opportunity to analyze data from the Improving Care for Cardiovascular Disease in China-ACS project that was jointly initiated in 2014 by the Chinese Society of Cardiology and AHA to improve the clinical outcomes of ACS patients. For 42,378 enrolled ACS patients from 240 hospitals, we demonstrated a non-linear negative association between admission LDL-C levels and the risk of in-hospital major bleeds, where a threshold LDL-C < 70 mg/dL resulted in a 49% increase in the bleeding risk of patients compared with those with LDL-C ≥ 70 mg/dL. We also used a data-driven approach to identify potential markers for an increased bleeding risk: using a forward algorithm for predictor selection, an admission LDL-C < 70 mg/dL was consistently identified as an independent predictor for different criterion-defined major in-hospital bleeds [Figure 2]. Interestingly, preadmission statin use was associated with a slight but non-significant increase in the bleeding risk, whereas major in-hospital bleeds were reduced by combining in-hospital statin use with β-blockers and angiotensin-converting enzyme inhibitors/angio-tensin-receptor blockers, that is, guideline-directed medical therapy for ACS patients, probably due to the relatively low potency of statin-induced LDL-C-lowering during hospitalization and the pleotropic effects of statin on mortality benefit.
Potential mechanisms and perspectives of the low-cholesterol-related bleeding risk
The mechanisms underlying low-cholesterol-related bleeding risk are not clear. In terms of the risk for hemorrhagic stroke, it has been speculated that adequate lipid levels are essential for maintaining normal membrane integrity and fluidity, and low cholesterol exposure may consequently predispose individuals to weakening of endothelial cells and enhancement of blood-brain barrier permeability,[51-53] which may underlie the pathogenesis of the low-cholesterol-level-related risk for hemorrhagic stroke.
In addition, emerging evidence supports a role in cholesterol metabolism and platelet function. The PCSK9 concentration is a key modulator of LDL-C metabolism that has been positively associated with LDL-C levels. A recent study showed increased platelet sensitivity to aspirin in hypercholesterolemic patients on 12 months of PCSK9i therapy. This finding could be mechanistically explained by the hampered response of PCSK9/CD36-mediated downstream cyclooxygenase-1/thromboxane A2 signaling pathways in platelets. Moreover, because cholesterol serves as the key component of platelet lipid rafts, which are essential for the signaling pathway during thrombus formation, platelet responsiveness to aggregation agonists is significantly reduced in the case of in vitro cholesterol depletion and LDL-apheresis.[56-58] Importantly, these observations could be reversed in HC and against a background of platelet cholesterol efflux defects, in which P2Y12 signaling-mediated platelet hyperreactivity and aggregability are potentiated. Another possible mechanism is that cholesterol is a positive regulator of thrombocytopoiesis in the bone marrow, which is supported by our finding that there is a linear, positive association between LDL-C and platelet counts.
Baseline anemia is an independent marker for bleeding risk in post-PCI patients.[61,62] Recent studies have demonstrated that cholesterol metabolism is linked to erythro-cytopoiesis and red-blood-cell biology. For example, hypocholesterolemia is a common phenomenon observed in chronic anemia with enhanced erythropoietic activity due to increased cholesterol requirements by proliferating erythroid cells, whereas correction of anemia leads to a rise in serum cholesterol levels.[63,64] This finding is supported by a report based on the US National Health and Nutrition Examination Survey revealing a positive association between LDL-C levels and hemoglobin in the general population. In this regard, a recent fundamental study showed that deficiency of PCSK9 was associated with worsened anemia in a mouse model of sickle cell disease due to increased hemolysis, which provides evidence of PCSK9 as a novel modifier for anemia severity.
Gastrointestinal bleeding is the predominant hemorrhagic complication in patients on DAPT following PCI, especially among patients with a history of peptic ulcers. Interestingly, potential long-term on-target side effects of PCSK9i were evaluated in a recent study examining the association between an LDL-C lowering variant and the PCSK9 gene (T allele of rs1159147) in the UK Biobank, and a previously unrecognized link was demonstrated between this variant and the risk for a peptic ulcer (OR: 1.145, 95% CI: 1.043–1.256, P = 0.005). Considering that aggressive lipid-lowering and high-intensity antith-rombotic therapies are the current paradigm for ASCVD secondary prevention, this finding may have important clinical implications, but requires confirmation by external validation and mechanistic studies. As the gastrointestinal epithelium requires constant renewal driven by stem cells due to mechanical assault from intestinal contents, low cholesterol levels may lead to crypt hypoproliferation in the intestinal tract and may therefore contribute to delayed ulcer healing. The potential mechanisms underlying a low-cholesterol-related bleeding risk and the clinical implications are summarized in Figure 3.
Conclusion and perspective
In recent years, novel therapeutic strategies targeting the three traditional modifiable cardiovascular risk factors, that is, hypertension, hyperglycemia, and hyperlipidemia, have contributed to great success in the reduction of ASCVD risk. Currently, the cardiology community appears to be comfortable with a strategy of “aggressive lowering” of blood cholesterol, which appears to be safe and effective in reducing ASCVD risk. However, “aggressive lowering” would never be applied to the management of blood pressure and blood glucose levels because of resulting acute and life-threatening side effects. One should keep in mind that the currently available evidence for ASCVD risk reduction achieved by aggressive lipid-lowering mainly derives from large RCTs with median follow-up durations of no more than 3 years. The advent of PCSK9i in clinical practice does provide new hope and overt clinical benefit for the indicated patients, that is, those with familial HC. Considering the growing generalizability of aggressive lipid lowering as a life-long approach and the prevailing concept that “lower is better,” the benefit-harm trade-offs of such a strategy, as well as the LDL-C threshold or a “sweet spot” for all-cause mortality, should be thoroughly evaluated. Current evidence from observational studies confirms associations between low cholesterol levels and increased risks for hemorrhagic stroke, AF, and bleeding complications during DAPT. Therefore, efforts should be made to reduce these risks, including the use of gastrointestinal prophylaxis, optimal invasive approaches, and blood pressure control, as well as careful choice of antithrombotic medications. Additionally, future studies are warranted to elucidate the molecular mechanisms of how low cholesterol exposure contributes to an increased risk of bleeding complications.
This work was supported by the National Key R&D Program of China (Grant Nos. 2020YFC2004700 and 2020YFC2004706), the National Natural Science Foundation of China (Grant No. 81970304), and the Tianjin Municipal Science and Technology Commission (Grant No. 18ZXZNSY00290).
Conflicts of interest
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