Question Is aspirin monotherapy noninferior to enoxaparin in preventing symptomatic venous thromboembolism (VTE) within 90 days following primary total hip or knee arthroplasty performed for osteoarthritis?
Findings In this cluster-randomized, crossover trial that included 9711 patients, treatment with aspirin vs enoxaparin resulted in symptomatic VTE (including below-knee VTE) in 3.45% vs 1.82% of patients, respectively. The difference failed to meet the noninferiority margin of 1% and was statistically significant for superiority of enoxaparin.
Meaning In patients undergoing hip or knee arthroplasty for osteoarthritis, aspirin compared with enoxaparin resulted in a significantly higher rate of symptomatic VTE, including below-knee VTE.
Abstract
Importance There remains a lack of randomized trials investigating aspirin monotherapy for symptomatic venous thromboembolism (VTE) prophylaxis following total hip arthroplasty (THA) or total knee arthroplasty (TKA).
Objective To determine whether aspirin was noninferior to enoxaparin in preventing symptomatic VTE after THA or TKA.
Design, Setting, and Participants Cluster-randomized, crossover, registry-nested trial across 31 hospitals in Australia. Clusters were hospitals performing greater than 250 THA or TKA procedures annually. Patients (aged ≥18 years) undergoing hip or knee arthroplasty procedures were enrolled at each hospital. Patients receiving preoperative anticoagulation or who had a medical contraindication to either study drug were excluded. A total of 9711 eligible patients were enrolled (5675 in the aspirin group and 4036 in the enoxaparin group) between April 20, 2019, and December 18, 2020. Final follow-up occurred on August 14, 2021.
Interventions Hospitals were randomized to administer aspirin (100 mg/d) or enoxaparin (40 mg/d) for 35 days after THA and for 14 days after TKA. Crossover occurred after the patient enrollment target had been met for the first group. All 31 hospitals were initially randomized and 16 crossed over prior to trial cessation.
Main Outcomes and Measures The primary outcome was symptomatic VTE within 90 days, including pulmonary embolism and deep venous thrombosis (DVT) (above or below the knee). The noninferiority margin was 1%. Six secondary outcomes are reported, including death and major bleeding within 90 days. Analyses were performed by randomization group.
Results Enrollment was stopped after an interim analysis determined the stopping rule was met, with 9711 patients (median age, 68 years; 56.8% female) of the prespecified 15 562 enrolled (62%). Of these, 9203 (95%) completed the trial. Within 90 days of surgery, symptomatic VTE occurred in 256 patients, including pulmonary embolism (79 cases), above-knee DVT (18 cases), and below-knee DVT (174 cases). The symptomatic VTE rate in the aspirin group was 3.45% and in the enoxaparin group was 1.82% (estimated difference, 1.97%; 95% CI, 0.54%-3.41%). This failed to meet the criterion for noninferiority for aspirin and was significantly superior for enoxaparin (P = .007). Of 6 secondary outcomes, none were significantly better in the enoxaparin group compared with the aspirin group.
Conclusions and Relevance Among patients undergoing hip or knee arthroplasty for osteoarthritis, aspirin compared with enoxaparin resulted in a significantly higher rate of symptomatic VTE within 90 days, defined as below- or above-knee DVT or pulmonary embolism. These findings may be informed by a cost-effectiveness analysis.
Enoxaparin prophylaxis did not result in a decrease in hospitalization or death.
Following recognition of the association between COVID-19 and arterial and venous thromboembolism (VTE), numerous randomized, controlled trials were conducted to identify the ideal intensity of anticoagulant prophylaxis. Among hospitalized patients, findings suggested that therapeutic dose anticoagulation benefits those on hospital wards but not those in the intensive care unit (NEJM JW Gen Med Dec 15 2021 and BMJ 2021 Oct 14; 375:n2400). Whether outpatients with symptomatic COVID-19 should receive primary VTE prophylaxis is unknown.
In the open-label OVID trial, investigators in Switzerland and Germany randomized 472 symptomatic outpatients with COVID-19 to receive enoxaparin (40 mg daily for 14 days) or no thromboprophylaxis. Included patients were older than 50 years with respiratory symptoms or fever and a positive COVID-19 test within 5 days. The primary composite endpoint included hospitalization or death within 30 days; secondary composite outcomes included venous or arterial thrombosis.
Roughly half the patients were enrolled prior to COVID-19 vaccination. The study was discontinued early when a predefined independent data review indicated little chance that enoxaparin would be deemed superior to observation. The primary outcome was experienced by 3% of patients in each arm. Arterial or venous thrombosis was experienced by 1% of patients in the enoxaparin group and 2% in the control group (95% CI, 0.09–2.74). No safety concerns were noted.
Comment
In this randomized study, primary VTE prophylaxis for symptomatic COVID-19 did not result in improved outcomes. The trial was not powered to demonstrate superiority regarding reduction in VTE risk. These results cannot be generalized to patients with prior VTE or arterial thrombosis, who may be at greater risk for recurrence — such patients were excluded from the trial.
“We are too weak to discover the truth by reason alone.”—Saint Augustine1
Patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) require an intense antithrombotic therapy to facilitate myocardial reperfusion and mitigate the risk of stent-related and spontaneous recurrent coronary events.2 Parental anticoagulation with unfractionated heparin, enoxaparin, bivalirudin, or argatroban is recommended during PCI to ensure effective antagonism of thrombin-mediated effects.2 At the completion of PCI, anticoagulation is usually interrupted unless concomitant indications exist (ie, atrial fibrillation, ventricular thrombosis, prolonged bed rest).2 Yet, it remains debated whether continuing anticoagulation following primary PCI—in the absence of specific indications—could provide additional clinical benefits.
Among STEMI patients, the rate of ischemic events occurring early after revascularization (within 48-72 hours) remains high and approximates 7% in large trials3,4; treatment with post-procedural anticoagulation (PPAC) in this acute phase may provide further ischemic protection.2 Yet, the potential gain of continuing anticoagulation should be weighed against the risk of bleeding, the occurrence of which has been associated with increased mortality.5 Major and clinically relevant nonmajor bleeding can occur in about 3% of patients during the first days after PCI, with a tendency to bleed that is more pronounced in STEMI than in other settings.6
Over the past 15 years, randomized and nonrandomized studies have been conducted in an effort to inform decision making on PPAC after STEMI.2,4 However, overall evidence remains inconclusive, and current guidelines reflect this uncertainty. The 2013 American College of Cardiology/American Heart Association STEMI guidelines abstain from discussing post-PCI anticoagulation.7 The 2017 European Society of Cardiology STEMI guidelines recommend against PPAC, except in case of a separate indication.8 Because of discordant guidelines positions, the decision-making surrounding PPAC largely varies in daily practice as a function of the institution and operator preference.2,5 This heterogeneity in treatment is undesirable, and an evidence-based standardization of PPAC after STEMI appears urgent.
In this issue of JACC: Cardiovascular Interventions, Yan et al9 report on the clinical value of PPAC after primary PCI among 34,826 STEMI patients without specific indications for anticoagulation from the CCC-ACS (Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome) registry. The CCC-ACS is a prospective, collaborative study of the Chinese Society of Cardiology and the American Heart Association, designed to improve the management of acute coronary syndrome patients in China. This analysis of a large, contemporary, real-world population is timely and provides observational evidence that PPAC could offer a mortality benefit after STEMI.9
Several aspects of this study deserve attention for a balanced interpretation of the results. The proportion of participants receiving PPAC was remarkable (75.4% of the cohort) if we consider that no solid evidence supports this attitude.7,8 This proportion diminished over time (2014-2019) from about 85% to 65%, probably because recent guidelines discourage this approach. The concomitant decline in bleeding rate over the same period is intriguing; yet, this variation is likely the result of extensive use of bleeding avoidance strategies in modern practice.
The definition used to select the PPAC group—all patients receiving any post-PCI anticoagulation without specific indications—appears broad enough to capture a heterogeneous population. PPAC consisted of low-molecular-weight heparin (LMWH) in the vast majority (91.8%) of cases; however, the type of LMWH and the specific anticoagulant used in the remaining 8.2% of patients were not reported. Granular information on treatment doses (ie, prophylactic, low, or full), duration, and crossover were not collected, precluding a comparative assessment of different regimens. Moreover, it is not exactly defined when PPAC was started (ie, immediately post-PCI or after temporal interruption) or concluded (ie, in the cardiac care unit or at discharge). Hence, the application of the results in clinical practice appears difficult.
The main study finding is that the use of PPAC after STEMI significantly reduced the relative risk of in-hospital mortality by approximately 40% without an excess of bleeding.9 Because of the nonrandomized nature of the analysis, the investigators implemented extensive adjustment models and sensitivity analyses to validate their results. Nevertheless, because relevant variables were not considered for adjustment (ie, type of P2Y12 inhibitor), it remains unclear whether and to what extent the results reflect the existence of unmeasured confounders. The mortality benefit associated with PPAC emerged early and was entirely attributable to reduced cardiovascular death. Of note, the adjusted risk of myocardial infarction, stent thrombosis, and stroke was numerically higher in the PPAC group, and therefore not suggestive of ischemic protection. The opposite directions of fatal and nonfatal cardiovascular events complicate results interpretation, also in light of the neutral effect of PPAC on major bleeding. Furthermore, the availability of in-hospital events only precludes the assessment of long-term treatment effects. Lastly, because the CCC-ACS study focused on Chinese patients essentially treated with post-PCI LMWH, whether the results apply to other ethnicities and drugs remain to be elucidated.
The investigation by Yan et al9 has the important merit to address a key question in the contemporary management of STEMI patients. The risks and benefits of anticoagulation continuation/interruption after PCI are not clearly defined, and understanding these concepts is critical for treatment optimization. Several PPAC regimens have been previously evaluated (Figure 1). A short course of once-daily low-dose enoxaparin (ie, limited to the cardiac care unit phase) might have favorable antithrombotic effects without increasing bleeding3; conversely, the prolonged use of high-dose LMWHs has been associated with a bleeding excess that offsets potential benefits.10 In the MATRIX (Minimizing Adverse Hemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox) trial, full-dose post-PCI bivalirudin infusion proved superior to low-dose or no post-PCI infusion in STEMI patients, and therefore, this regimen appears a viable option for PPAC.4 Fondaparinux has been associated with potential harm after primary PCI,11 and its role in this setting remains undetermined. Beyond parental agents, the efficacy and safety of oral anticoagulation with rivaroxaban at vascular doses (2.5 mg oral twice daily) have been investigated in patients with recent12,13 or remote14 myocardial infarction, demonstrating improved cardiovascular outcomes and reduced mortality at the cost of increased nonfatal bleeding.12,14
Download FigureDownload PowerPointFigure 1Anticoagulation After STEMIAntithrombotic regimens investigated after primary PCI. BID = twice daily; DAPT = dual antiplatelet therapy; IV = intravenous; od = once daily; PCI = percutaneous coronary intervention; SAPT = single antiplatelet therapy; SC = subcutaneous; STEMI = ST-segment elevation myocardial infarction; UFH = unfractionated heparin.
Based on available evidence, the selection of the optimal anticoagulation in STEMI patients requires careful considerations. Knowledge of the tradeoff between thrombotic and bleeding risks associated with each antithrombotic regimen represents the foundation for treatment personalization. In this regard, it is important to keep in mind that the tradeoff between these 2 risks varies from case to case and is not constant over time (Figure 1). The key strategy question “should we routinely continue anticoagulation after primary PCI?” is a simplification of a multitude of questions elaborating on treatment type, doses, timing, and duration, as well as the individual patient risk profile. Further investigations are required to define what constitutes the optimal combination therapy in various post-PCI scenarios.15 The land of anticoagulation after STEMI appears promising but has still to be fully explored.
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