Lessons Learned from National Heart, Lung, and Blood Institute Covid-19 Clinical Trials.

AbstractIn response to the Covid-19 pandemic, the National Heart, Lung, and Blood Institute launched five multisite clinical trials testing candidate host tissue-directed medical interventions to hasten recovery, improve function, and reduce morbidity and mortality. Speed, flexibility, and collaboration were essential. This article from the Steering and Executive committees describes the Collaborating Network of Networks for Evaluating Covid-19 and Therapeutic Strategies (CONNECTS) research program that enrolled 6690 participants and evaluated 18 intervention strategies using 10 molecular agents across the care continuum (outpatient, inpatient, and post discharge), and reports lessons learned from this initiative. Successes include rapid trial execution through collaboration and adaptive platform designs. Challenges that impeded efficiency included time required to execute subcontracts, constraints on clinical research workforce, and limited research infrastructure in nonacademic settings.

ApoA-I Infusions and Burden of Ischemic Events After Acute Myocardial Infarction: Insights From the AEGIS-II Trial.

BACKGROUND: Following an acute myocardial infarction (AMI), patients remain at risk for subsequent cardiovascular (CV) events. In the AEGIS-II trial, CSL112, a human apolipoprotein A-I derived from plasma that enhances cholesterol efflux, did not significantly reduce the first occurrence of CV death, myocardial infarction (MI), or stroke through 90 days compared with placebo. However, an analysis involving only the first event may not capture the totality of the clinical impact of an intervention because patients may experience multiple events. OBJECTIVES: This prespecified exploratory analysis examines the effect of CSL112 on total burden of nonfatal ischemic events (ie, recurrent MI and stroke) and CV death. METHODS: A total of 18,219 patients with AMI, multivessel coronary artery disease, and additional CV risk factors were randomized to either 4 weekly infusions of 6 g CSL112 (n = 9,112) or matching placebo (n = 9,107). A negative binomial regression model was applied to estimate the effect of CSL112 compared with placebo on the rate ratio (RR) of ischemic events. RESULTS: For CV death, MI, and stroke, there were numerically fewer total events at 90 days (503 vs 545 events; rate ratio [RR]: 0.88; 95% CI: 0.76-1.03, P = 0.11), and nominally significantly fewer total events at 180 days (745 vs 821 events, RR: 0.87; 95% CI: 0.77-0.99; P = 0.04) and 365 days (1,120 vs 1,211 events; RR 0.89; 95% CI: 0.80-0.99; P = 0.04). Subsequent events constituted 13% of events at 90 days, 17% at 180 days, and 22% at 1 year. Similar findings were seen with the total occurrence of nonfatal MI and CV death. When type II MIs, unlikely to be modified by enhancing cholesterol efflux, were excluded, there were nominally significant reductions in the total occurrence of nonfatal MI (excluding type 2) and CV death at all timepoints (90 days: RR: 0.81; 95% CI: 0.68-0.97; P = 0.02; 180 days: RR: 0.82; 95% CI: 0.71-0.95; P < 0.01; 365 days: RR: 0.86; 95% CI: 0.76-0.98; P = 0.02). CONCLUSIONS: In this prespecified exploratory analysis of the AEGIS-II trial, 4 weekly infusions of CSL112 among high-risk patients after AMI significantly reduced the total burden of nonfatal ischemic events and CV death at 180 and 365 days compared with placebo. (AEGIS-II [Study to Investigate CSL112 in Subjects With Acute Coronary Syndrome]; NCT03473223).

Apolipoprotein A-I Infusions and Cardiovascular Outcomes in Acute Myocardial Infarction According to Baseline LDL-Cholesterol Levels: The AEGIS-II Trial.

BACKGROUND AND AIMS: In the AEGIS-II trial (NCT03473223), CSL112, a human apolipoprotein A1 derived from plasma that increases cholesterol efflux capacity, did not significantly reduce the risk of the primary endpoint through 90 days versus placebo after acute myocardial infarction (MI). Nevertheless, given the well-established relationship between higher low-density lipoprotein cholesterol (LDL-C) and plaque burden, as well as greater risk reductions seen with PCSK9 inhibitors in patients with baseline LDL-C ≥100 mg/dL on statin therapy, the efficacy of CSL112 may be influenced by baseline LDL-C. METHODS: Overall, 18,219 patients with acute MI, multivessel coronary artery disease, and additional risk factors were randomized to either four weekly infusions of 6 g CSL112 or placebo. This exploratory post-hoc analysis evaluated cardiovascular outcomes by baseline LDL-C in patients prescribed guideline-directed statin therapy at the time of randomization (n=15,731). RESULTS: As baseline LDL-C increased, risk of the primary endpoint at 90 days lowered in those treated with CSL112 compared with placebo. In patients with LDL-C ≥100 mg/dL at randomization, there was a significant risk reduction of cardiovascular death, MI, or stroke in the CSL112 vs. placebo group at 90, 180, and 365 days (hazard ratio 0.69 [0.53-0.90], 0.71 [0.57-0.88], and 0.78 [0.65-0.93]). In contrast, there was no difference between treatment groups among those with LDL-C <100 mg/dL at baseline. CONCLUSIONS: In this population, treatment with CSL112 compared to placebo was associated with a significantly lower risk of recurrent cardiovascular events among patients with a baseline LDL-C ≥100 mg/dL. Further studies need to confirm that CSL112 efficacy is influenced by baseline LDL-C.

Triglyceride Levels, Alirocumab Treatment, and Cardiovascular Outcomes After an Acute Coronary Syndrome.

BACKGROUND: It is unknown whether clinical benefit of proprotein convertase subtilisin/kexin type 9 inhibitors is associated with baseline or on-treatment triglyceride concentrations. OBJECTIVES: This study sought to examine relations between triglyceride levels and the effect of alirocumab vs placebo on cardiovascular outcomes using prespecified and post hoc analyses of the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial. METHODS: Patients with recent acute coronary syndrome (ACS) (n = 18,924) and elevated atherogenic lipoproteins despite optimized statin therapy were randomized to alirocumab 75 to 150 mg or matching placebo every 2 weeks subcutaneously. Major adverse cardiovascular events (MACE) were examined in relation to continuous or dichotomous triglyceride concentrations. RESULTS: Median baseline triglyceride concentration was 129 mg/dL. In both treatment groups, a 10-mg/dL higher baseline concentration was associated with an adjusted MACE HR of 1.008 (95% CI: 1.003-1.013; P < 0.005). Baseline triglycerides ≥150 vs <150 mg/dL were associated with a HR of 1.184 (95% CI: 1.080-1.297; P < 0.005). Versus placebo, alirocumab reduced low-density lipoprotein cholesterol from baseline (average, 54.7%) and reduced MACE (HR: 0.85; 95% CI: 0.78-0.93). At month 4, triglyceride levels were reduced from baseline by median 17.7 mg/dL (P < 0.001) and 0.9 mg/dL (P = NS) with alirocumab and placebo, respectively. A 10-mg/dL decline from baseline in triglycerides was associated with lower subsequent risk of MACE with placebo (HR: 0.988; 95% CI: 0.982-0.995; P < 0.005) but not with alirocumab (HR: 0.999; 95% CI: 0.987-1.010; P = 0.82). CONCLUSIONS: Among patients with recent ACS on optimized statin therapy, baseline triglycerides was associated with cardiovascular risk. However, the reduction in triglycerides with alirocumab did not contribute to its clinical benefit. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).

Milvexian vs apixaban for stroke prevention in atrial fibrillation: The LIBREXIA atrial fibrillation trial rationale and design.

BACKGROUND: Direct oral anticoagulants are the standard of care for stroke prevention in eligible patients with atrial fibrillation and atrial flutter; however, bleeding remains a significant concern, limiting their use. Milvexian is an oral Factor XIa inhibitor that may offer similar anticoagulant efficacy with less bleeding risk. METHODS: LIBREXIA AF (NCT05757869) is a global phase III, randomized, double-blind, parallel-group, event-driven trial to compare milvexian with apixaban in participants with atrial fibrillation or atrial flutter. Participants are randomly assigned to milvexian 100 mg or apixaban (5 mg or 2.5 mg per label indication) twice daily. The primary efficacy objective is to evaluate if milvexian is noninferior to apixaban for the prevention of stroke and systemic embolism. The principal safety objective is to evaluate if milvexian is superior to apixaban in reducing the endpoint of International Society of Thrombosis and Hemostasis (ISTH) major bleeding events and the composite endpoint of ISTH major and clinically relevant nonmajor (CRNM) bleeding events. In total, 15,500 participants from approximately 1,000 sites in over 30 countries are planned to be enrolled. They will be followed until both 430 primary efficacy outcome events and 530 principal safety events are observed, which is estimated to take approximately 4 years. CONCLUSION: The LIBREXIA AF study will determine the efficacy and safety of the oral Factor XIa inhibitor milvexian compared with apixaban in participants with either atrial fibrillation or atrial flutter. TRIAL REGISTRATION: ClinicalTrials.gov NCT05757869.

Aspirin Dosing for Secondary Prevention of Atherosclerotic Cardiovascular Disease in Male and Female Patients: A Secondary Analysis of the ADAPTABLE Randomized Clinical Trial.

Importance: Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality in the US. Although aspirin is recommended for secondary prevention of ASCVD, there was no difference in safety and effectiveness of aspirin dosed daily at 81 mg or 325 mg in the ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) randomized clinical trial. However, it is unknown whether differences by sex exist in the safety and effectiveness of the different aspirin doses. Objective: To evaluate sex-specific differences in the safety and effectiveness of 2 aspirin doses in the ADAPTAPLE trial. Design, Setting, and Participants: The ADAPTABLE study was an open-label, pragmatic, randomized clinical trial that randomly assigned participants with chronic, stable ASCVD to 81 mg vs 325 mg of aspirin daily. Using Cox proportional-hazard models, male and female participants were compared for outcomes. In addition, it was assessed whether sex was an effect modifier in the association between aspirin dose and outcomes. The ADAPTABLE trial was conducted at 40 medical centers and 1 health plan. Eligible patients were 18 years and older and had established ASCVD. Study data were analyzed from December 2021 to March 2024. Interventions: Patients received 81 mg or 325 mg of aspirin daily for the secondary prevention of ASCVD. Main Outcomes and Measures: The primary effectiveness outcomes included all-cause death and hospitalization for myocardial infarction (MI) or stroke. The primary safety outcome was hospitalization for major bleeding requiring transfusion. Results: A total of 15 076 patients (median [IQR] age, 67.6 [60.7-73.6] years; 10 352 male [68.7%]) were followed up for a median (IQR) of 26.2 (19.0-34.9) months. Overall, 4724 (31.3%) were female, and 2307 of the female participants (48.8%) received aspirin 81 mg. Compared with males, female participants were younger (median [IQR] age, 66.3 [59.4-72.6] years vs 68.2 (61.4-73.9) years, less likely to self-report White race (3426 [72.5%] vs 8564 [82.7%]), more likely to smoke (564 [12.9%] vs 818 [8.4%]), and more likely to have a history of peripheral arterial disease (1179 [25.7%] vs 2314 [23.0%]). The primary effectiveness outcome of all-cause death and hospitalization for MI or stroke occurred in 379 female participants (8.1%) and 780 male participants (7.1%). There was no significant interaction by sex for the primary effectiveness end point between the 2 aspirin doses (female adjusted hazard ratio [aHR], 1.01; 95% CI, 0.82-1.26 and male aHR, 1.06; 95% CI, 0.91-1.23; P interaction term for sex = .74). During the trial, female participants had fewer revascularization procedures (237 [5.0%] vs 680 [6.6%]; aHR, 0.79; 95% CI, 0.68-0.92; P = .002) but had a higher risk of hospitalization for stroke (aHR, 1.72; 95% CI, 1.27-2.33; P < .001). Among female participants, there was a slightly higher rate of bleeding in the 81-mg aspirin cohort compared with the 325-mg cohort (20 [0.83%] vs 13 [0.52%]; aHR, 2.21; 95% CI, 1.04-4.70; P interaction term for sex = .07). There were no significant differences between female and male participants regarding aspirin dose adherence. Conclusions and Relevance: In this secondary analysis of the ADAPTABLE trial, there were no significant sex-specific differences in the effectiveness and safety of 2 aspirin doses for secondary prevention of ASCVD events. Trial Registration: ClinicalTrials.gov Identifier: NCT02697916.

Alirocumab and cardiovascular outcomes according to sex and lipoprotein(a) after acute coronary syndrome: a report from the ODYSSEY OUTCOMES study.

BACKGROUND: The ODYSSEY OUTCOMES trial (NCT01663402) compared the effects of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab with placebo on major adverse cardiovascular events (MACE) in patients with recent acute coronary syndrome (ACS). OBJECTIVE: We assessed efficacy and safety of alirocumab versus placebo according to sex and lipoprotein(a) level. METHODS: This prespecified analysis compared the effects of alirocumab versus placebo on lipoproteins, MACE (coronary heart disease death, non-fatal myocardial infarction, fatal/non-fatal ischemic stroke, unstable angina requiring hospitalization), death, total cardiovascular events, and adverse events in 4762 women and 14,162 men followed for a median of 2.8 years. In post-hoc analysis, we evaluated total cardiovascular events according to sex, baseline lipoprotein(a), and treatment. RESULTS: Women were older, had higher baseline low-density lipoprotein cholesterol (LDL-C) levels (89.6 vs 85.3 mg/dL) and lipoprotein(a) (28.0 vs 19.3 mg/dL) and had more co-morbidities than men. At 4 months, alirocumab lowered LDL-C by 49.4 mg/dL in women and 54.0 mg/dL in men and lipoprotein(a) by 9.7 and 8.1 mg/dL, respectively (both p < 0.0001). Alirocumab reduced MACE, death, and total cardiovascular events similarly in both sexes. In the placebo group, lipoprotein(a) was a risk factor for total cardiovascular events in women and men. In both sexes, reduction of total cardiovascular events was greater at higher baseline lipoprotein(a), but this effect was more evident in women than men (pinteraction=0.08). Medication adherence and adverse event rates were similar in both sexes. CONCLUSIONS: Alirocumab improves cardiovascular outcomes after ACS irrespective of sex. Reduction of total cardiovascular events was greater at higher baseline lipoprotein(a).

Limb Outcomes With Ticagrelor Plus Aspirin in Patients With Diabetes Mellitus and Atherosclerosis.

BACKGROUND: Ticagrelor reduced major adverse cardiovascular events (MACE) and increased bleeding in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease. Limb events including revascularization, acute limb ischemia (ALI), and amputation are major morbidities in patients with T2DM and atherosclerosis. OBJECTIVES: This study sought to determine the effect of ticagrelor on limb events. METHODS: Patients were randomized to ticagrelor or placebo on top of aspirin and followed for a median of 3 years. MACE (cardiovascular death, myocardial infarction, or stroke), limb events (ALI, amputation, revascularization), and bleeding were adjudicated by an independent and blinded clinical events committee. The presence of peripheral artery disease (PAD) was reported at baseline. RESULTS: Of 19,220 patients randomized, 1,687 (8.8%) had PAD at baseline. In patients receiving placebo, PAD was associated with higher MACE (10.7% vs 7.3%; HR: 1.48; P < 0.001) and limb (9.5% vs 0.8%; HR: 10.67; P < 0.001) risk. Ticagrelor reduced limb events (1.6% vs 1.3%; HR: 0.77; 95% CI: 0.61-0.96; P = 0.022) with significant reductions for revascularization (HR: 0.79; 95% CI: 0.62-0.99; P = 0.044) and ALI (HR: 0.24; 95% CI: 0.08-0.70; P = 0.009). The benefit was consistent with or without PAD (HR: 0.80; 95% CI: 0.58-1.11; and HR: 0.76; 95% CI: 0.55-1.05, respectively; Pinteraction = 0.81). There was no effect modification of ticagrelor vs placebo based on PAD for MACE (Pinteraction = 0.40) or TIMI major bleeding (Pinteraction = 0.3239). CONCLUSIONS: Patients with T2DM and atherosclerosis are at high risk of limb events. Ticagrelor decreased this risk, but increased bleeding. Future trials evaluating the combination of ticagrelor and aspirin would further elucidate the benefit/risk of such therapy in patients with PAD, including those without coronary artery disease. (A Study Comparing Cardiovascular Effects of Ticagrelor Versus Placebo in Patients With Type 2 Diabetes Mellitus [THEMIS]: NCT01991795).

Apolipoprotein A1 Infusions and Cardiovascular Outcomes after Acute Myocardial Infarction.

BACKGROUND: Cardiovascular events frequently recur after acute myocardial infarction, and low cholesterol efflux - a process mediated by apolipoprotein A1, which is the main protein in high-density lipoprotein - has been associated with an increased risk of cardiovascular events. CSL112 is human apolipoprotein A1 derived from plasma that increases cholesterol efflux capacity. Whether infusions of CSL112 can reduce the risk of recurrent cardiovascular events after acute myocardial infarction is unclear. METHODS: We conducted an international, double-blind, placebo-controlled trial involving patients with acute myocardial infarction, multivessel coronary artery disease, and additional cardiovascular risk factors. Patients were randomly assigned to receive either four weekly infusions of 6 g of CSL112 or matching placebo, with the first infusion administered within 5 days after the first medical contact for the acute myocardial infarction. The primary end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes from randomization through 90 days of follow-up. RESULTS: A total of 18,219 patients were included in the trial (9112 in the CSL112 group and 9107 in the placebo group). There was no significant difference between the groups in the risk of a primary end-point event at 90 days of follow-up (439 patients [4.8%] in the CSL112 group vs. 472 patients [5.2%] in the placebo group; hazard ratio, 0.93; 95% confidence interval [CI], 0.81 to 1.05; P = 0.24), at 180 days of follow-up (622 patients [6.9%] vs. 683 patients [7.6%]; hazard ratio, 0.91; 95% CI, 0.81 to 1.01), or at 365 days of follow-up (885 patients [9.8%] vs. 944 patients [10.5%]; hazard ratio, 0.93; 95% CI, 0.85 to 1.02). The percentage of patients with adverse events was similar in the two groups; a higher number of hypersensitivity events was reported in the CSL112 group. CONCLUSIONS: Among patients with acute myocardial infarction, multivessel coronary artery disease, and additional cardiovascular risk factors, four weekly infusions of CSL112 did not result in a lower risk of myocardial infarction, stroke, or death from cardiovascular causes than placebo through 90 days. (Funded by CSL Behring; AEGIS-II ClinicalTrials.gov number, NCT03473223.).

Effect of Reconstituted Human Apolipoprotein A-I on Recurrent Ischemic Events in Survivors of Acute MI.

BACKGROUND: The AEGIS-II trial hypothesized that CSL112, an intravenous formulation of human apoA-I, would lower the risk of plaque disruption, decreasing the risk of recurrent events such as myocardial infarction (MI) among high-risk patients with MI. OBJECTIVES: This exploratory analysis evaluates the effect of CSL112 therapy on the incidence of cardiovascular (CV) death and recurrent MI. METHODS: The AEGIS-II trial was an international, multicenter, randomized, double-blind, placebo-controlled trial that randomized 18,219 high-risk acute MI patients to 4 weekly infusions of apoA-I (6 g CSL112) or placebo. RESULTS: The incidence of the composite of CV death and type 1 MI was 11% to 16% lower in the CSL112 group over the study period (HR: 0.84; 95% CI: 0.7-1.0; P = 0.056 at day 90; HR: 0.86; 95% CI: 0.74-0.99; P = 0.048 at day 180; and HR: 0.89; 95% CI: 0.79-1.01; P = 0.07 at day 365). Similarly, the incidence of CV death or any MI was numerically lower in CSL112-treated patients throughout the follow-up period (HR: 0.92; 95% CI: 0.80-1.05 at day 90, HR: 0.89; 95% CI: 0.79-0.996 at day 180, HR: 0.91; 95% CI: 0.83-1.01 at day 365). The effect of CSL112 treatment on MI was predominantly observed for type 1 MI and type 4b (MI due to stent thrombosis). CONCLUSIONS: Although CSL112 did not significantly reduce the occurrence of the primary study endpoints, patients treated with CSL112 infusions had numerically lower rates of CV death and MI, type-1 MI, and stent thrombosis-related MI compared with placebo. These findings could suggest a role of apoA-I in reducing subsequent plaque disruption events via enhanced cholesterol efflux. Further prospective data would be needed to confirm these observations.

Safety of the PCSK9 inhibitor alirocumab: insights from 47 296 patient-years of observation.

The ODYSSEY OUTCOMES trial, comprising over 47 000 patient-years of placebo-controlled observation, demonstrated important reductions in the risk of recurrent ischaemic cardiovascular events with the monoclonal antibody to proprotein convertase subtilisin/kexin type 9 alirocumab, as well as lower all-cause death. These benefits were observed in the context of substantial and persistent lowering of low-density lipoprotein cholesterol with alirocumab compared with that achieved with placebo. The safety profile of alirocumab was indistinguishable from matching placebo except for a ∼1.7% absolute increase in local injection site reactions. Further, the safety of alirocumab compared with placebo was evident in vulnerable groups identified before randomization, such as the elderly and those with diabetes mellitus, previous ischaemic stroke, or chronic kidney disease. The frequency of adverse events and laboratory-based abnormalities was generally similar to that in placebo-treated patients. Thus, alirocumab appears to be a safe and effective lipid-modifying treatment over a duration of at least 5 years.

Variation in Health Status With Invasive vs Conservative Management of Chronic Coronary Disease.

BACKGROUND: The ISCHEMIA trial found that patients with chronic coronary disease randomized to invasive strategy had better health status than those randomized to conservative strategy. It is unclear how best to translate these population-level results to individual patients. OBJECTIVES: The authors sought to identify patient characteristics associated with health status from invasive and conservative strategies, and develop a prediction algorithm for shared decision-making. METHODS: One-year disease-specific health status was assessed in ISCHEMIA with the Seattle Angina Questionnaire (SAQ) Summary Score (SAQ SS) and Angina Frequency, Physical Limitations (PL), and Quality of Life (QL) domains (range 0-100, higher = less angina/better health status). RESULTS: Among 4,617 patients from 320 sites in 37 countries, mean SAQ SS was 74.1 ± 18.9 at baseline and 85.7 ± 15.6 at 1 year. Lower baseline SAQ SS and younger age were associated with better 1-year health status with invasive strategy (P interaction = 0.009 and P interaction = 0.004, respectively). For the individual domains, there were significant treatment interactions for baseline SAQ score (Angina Frequency, PL), age (PL, QL), anterior ischemia (PL), and number of baseline antianginal medications (QL), with more benefit of invasive in patients with worse baseline health status, younger age, anterior ischemia, and on more antianginal medications. Parsimonious prediction models were developed for 1-year SAQ domains with invasive or conservative strategies to support shared decision-making. CONCLUSIONS: In the management of chronic coronary disease, individual patient characteristics are associated with 1-year health status, with younger age and poorer angina-related health status showing greater benefit from invasive management. This prediction algorithm can support the translation of the ISCHEMIA trial results to individual patients. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).

Sex Differences in Revascularization, Treatment Goals, and Outcomes of Patients With Chronic Coronary Disease: Insights From the ISCHEMIA Trial.

BACKGROUND: Women with chronic coronary disease are generally older than men and have more comorbidities but less atherosclerosis. We explored sex differences in revascularization, guideline-directed medical therapy, and outcomes among patients with chronic coronary disease with ischemia on stress testing, with and without invasive management. METHODS AND RESULTS: The ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial randomized patients with moderate or severe ischemia to invasive management with angiography, revascularization, and guideline-directed medical therapy, or initial conservative management with guideline-directed medical therapy alone. We evaluated the primary outcome (cardiovascular death, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest) and other end points, by sex, in 1168 (22.6%) women and 4011 (77.4%) men. Invasive group catheterization rates were similar, with less revascularization among women (73.4% of invasive-assigned women revascularized versus 81.2% of invasive-assigned men; P<0.001). Women had less coronary artery disease: multivessel in 60.0% of invasive-assigned women and 74.8% of invasive-assigned men, and no ≥50% stenosis in 12.3% versus 4.5% (P<0.001). In the conservative group, 4-year catheterization rates were 26.3% of women versus 25.6% of men (P=0.72). Guideline-directed medical therapy use was lower among women with fewer risk factor goals attained. There were no sex differences in the primary outcome (adjusted hazard ratio [HR] for women versus men, 0.93 [95% CI, 0.77-1.13]; P=0.47) or the major secondary outcome of cardiovascular death/myocardial infarction (adjusted HR, 0.93 [95% CI, 0.76-1.14]; P=0.49), with no significant sex-by-treatment-group interactions. CONCLUSIONS: Women had less extensive coronary artery disease and, therefore, lower revascularization rates in the invasive group. Despite lower risk factor goal attainment, women with chronic coronary disease experienced similar risk-adjusted outcomes to men in the ISCHEMIA trial. REGISTRATION: URL: http://wwwclinicaltrials.gov. Unique identifier: NCT01471522.

Age and Aspirin Dosing in Secondary Prevention of Atherosclerotic Cardiovascular Disease.

BACKGROUND: In patients with atherosclerotic cardiovascular disease, increasing age is concurrently associated with higher risks of ischemic and bleeding events. The objectives are to determine the impact of aspirin dose on clinical outcomes according to age in atherosclerotic cardiovascular disease. METHODS AND RESULTS: In the ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) trial, patients with atherosclerotic cardiovascular disease were randomized to daily aspirin doses of 81 mg or 325 mg. The primary effectiveness end point was death from any cause, hospitalization for myocardial infarction, or hospitalization for stroke. The primary safety end point was hospitalization for bleeding requiring transfusion. A total of 15 076 participants were randomized to aspirin 81 mg (n=7540) or 325 mg (n=7536) daily (median follow-up: 26.2 months; interquartile range: 19.0-34.9 months). Median age was 67.6 years (interquartile range: 60.7-73.6 years). Among participants aged <65 years (n=5841 [38.7%]), a primary end point occurred in 226 (7.54%) in the 81 mg group, and in 191 (6.80%) in the 325 mg group (adjusted hazard ratio [HR], 1.23 [95% CI, 1.01-1.49]). Among participants aged ≥65 years (n=9235 [61.3%]), a primary end point occurred in 364 (7.12%) in the 81 mg group, and in 378 (7.96%) in the 325 mg group (adjusted HR, 0.95 [95% CI, 0.82-1.10]). The age-dose interaction was not significant (P=0.559). There was no significant interaction between age and the randomized aspirin dose for the secondary effectiveness and the primary safety bleeding end points (P>0.05 for all). CONCLUSIONS: Age does not modify the impact of aspirin dosing (81 mg or 325 mg daily) on clinical end points in secondary prevention of atherosclerotic cardiovascular disease.

Relating Lipoprotein(a) Concentrations to Cardiovascular Event Risk After Acute Coronary Syndrome: A Comparison of 3 Tests.

BACKGROUND: Lipoprotein(a) is a risk factor for cardiovascular events and modifies the benefit of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors. Lipoprotein(a) concentration can be measured with immunoassays reporting mass or molar concentration or a reference measurement system using mass spectrometry. Whether the relationships between lipoprotein(a) concentrations and cardiovascular events in a high-risk cohort differ across lipoprotein(a) methods is unknown. We compared the prognostic and predictive value of these types of lipoprotein(a) tests for major adverse cardiovascular events (MACE). METHODS: The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) compared the PCSK9 inhibitor alirocumab with placebo in patients with recent acute coronary syndrome. We compared risk of a MACE in the placebo group and MACE risk reduction with alirocumab according to baseline lipoprotein(a) concentration measured by Siemens N-latex nephelometric immunoassay (IA-mass; mg/dL), Roche Tina-Quant turbidimetric immunoassay (IA-molar; nmol/L), and a noncommercial mass spectrometry-based test (MS; nmol/L). Lipoprotein(a) values were transformed into percentiles for comparative modeling. Natural cubic splines estimated continuous relationships between baseline lipoprotein(a) and outcomes in each treatment group. Event rates were also determined across baseline lipoprotein(a) quartiles defined by each assay. RESULTS: Among 11 970 trial participants with results from all 3 tests, baseline median (Q1, Q3) lipoprotein(a) concentrations were 21.8 (6.9, 60.0) mg/dL, 45.0 (13.2, 153.8) nmol/L, and 42.2 (14.3, 143.1) nmol/L for IA-mass, IA-molar, and MS, respectively. The strongest correlation was between IA-molar and MS (r=0.990), with nominally weaker correlations between IA-mass and MS (r=0.967) and IA-mass and IA-molar (r=0.972). Relationships of lipoprotein(a) with MACE risk in the placebo group were nearly identical with each test, with estimated cumulative incidences differing by ≤0.4% across lipoprotein(a) percentiles, and all were incrementally prognostic after accounting for low-density lipoprotein cholesterol levels (all spline P≤0.0003). Predicted alirocumab treatment effects were also nearly identical for each of the 3 tests, with estimated treatment hazard ratios differing by ≤0.07 between tests across percentiles and nominally less relative risk reduction by alirocumab at lower percentiles for all 3 tests. Absolute risk reduction with alirocumab increased with increasing lipoprotein(a) measured by each test, with significant linear trends across quartiles. CONCLUSIONS: In patients with recent acute coronary syndrome, 3 lipoprotein(a) tests were similarly prognostic for MACE in the placebo group and predictive of MACE reductions with alirocumab at the cohort level. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01663402.

Comparative Effectiveness of Aspirin Dosing in Cardiovascular Disease and Diabetes Mellitus: A Subgroup Analysis of the ADAPTABLE Trial.

OBJECTIVE: Patients with diabetes mellitus (DM) and concomitant atherosclerotic cardiovascular disease (ASCVD) must be on the most effective dose of aspirin to mitigate risk of future adverse cardiovascular events. RESEARCH DESIGN AND METHODS: ADAPTABLE, an open-label, pragmatic study, randomized patients with stable, chronic ASCVD to 81 mg or 325 mg of daily aspirin. The effects of aspirin dosing was assessed on the primary effectiveness outcome, a composite of all-cause death, hospitalization for myocardial infarction, or hospitalization for stroke, and the primary safety outcome of hospitalization for major bleeding. In this prespecified analysis, we used Cox proportional hazards models to compare aspirin dosing in patients with and without DM for the primary effectiveness and safety outcome. RESULTS: Of 15,076 patients, 5,676 (39%) had DM of whom 2,820 (49.7%) were assigned to 81 mg aspirin and 2,856 (50.3%) to 325 mg aspirin. Patients with versus without DM had higher rates of the composite cardiovascular outcome (9.6% vs. 5.9%; P < 0.001) and bleeding events (0.78% vs. 0.50%; P < 0.001). When comparing 81 mg vs. 325 mg of aspirin, patients with DM had no difference in the primary effectiveness outcome (9.3% vs. 10.0%; hazard ratio [HR] 0.98 [95% CI 0.83-1.16]; P = 0.265) or safety outcome (0.87% vs. 0.69%; subdistribution HR 1.25 [95% CI 0.72-2.16]; P = 0.772). CONCLUSIONS: This study confirms the inherently higher risk of patients with DM irrespective of aspirin dosing. Our findings suggest that a higher dose of aspirin yields no added clinical benefit, even in a more vulnerable population.

Aspirin Dosing for Secondary Prevention of Atherosclerotic Cardiovascular Disease in Patients Treated With P2Y12 Inhibitors.

Background The ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) was a large, pragmatic, randomized controlled trial that found no difference between high- versus low-dose aspirin for secondary prevention of atherosclerotic cardiovascular disease. Whether concomitant P2Y12 inhibitor therapy modifies the effect of aspirin dose on clinical events remains unclear. Methods and Results Participants in ADAPTABLE were stratified according to baseline use of clopidogrel or prasugrel (P2Y12 group). The primary effectiveness end point was a composite of death, myocardial infarction, or stroke; and the primary safety end point was major bleeding requiring blood transfusions. We used multivariable Cox regression to compare the relative effectiveness and safety of aspirin dose within P2Y12 and non-P2Y12 groups. Of 13 815 (91.6%) participants with available data, 3051 (22.1%) were receiving clopidogrel (2849 [93.4%]) or prasugrel (203 [6.7%]) at baseline. P2Y12 inhibitor use was associated with higher risk of the primary effectiveness end point (10.86% versus 6.31%; adjusted hazard ratio [HR], 1.40 [95% CI, 1.22-1.62]) but was not associated with bleeding (0.95% versus 0.53%; adjusted HR, 1.42 [95% CI, 0.91-2.22]). We found no interaction in the relative effectiveness and safety of high- versus low-dose aspirin by P2Y12 inhibitor use. Overall, dose switching or discontinuation was more common in the high-dose compared with low-dose aspirin group, but the pattern was not modified by P2Y12 inhibitor use. Conclusions In this prespecified analysis of ADAPTABLE, we found that the relative effectiveness and safety of high- versus low-dose aspirin was not modified by baseline P2Y12 inhibitor use. Registration https://www.clinical.trials.gov. Unique identifier: NCT02697916.

Effectiveness and Safety of Enteric-Coated vs Uncoated Aspirin in Patients With Cardiovascular Disease: A Secondary Analysis of the ADAPTABLE Randomized Clinical Trial.

Importance: Clinicians recommend enteric-coated aspirin to decrease gastrointestinal bleeding in secondary prevention of coronary artery disease even though studies suggest platelet inhibition is decreased with enteric-coated vs uncoated aspirin formulations. Objective: To assess whether receipt of enteric-coated vs uncoated aspirin is associated with effectiveness or safety outcomes. Design, Setting, and Participants: This is a post hoc secondary analysis of ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness), a pragmatic study of 15 076 patients with atherosclerotic cardiovascular disease having data in the National Patient-Centered Clinical Research Network. Patients were enrolled from April 19, 2016, through June 30, 2020, and randomly assigned to receive high (325 mg) vs low (81 mg) doses of daily aspirin. The present analysis assessed the effectiveness and safety of enteric-coated vs uncoated aspirin among those participants who reported aspirin formulation at baseline. Data were analyzed from November 11, 2019, to July 3, 2023. Intervention: ADAPTABLE participants were regrouped according to aspirin formulation self-reported at baseline, with a median (IQR) follow-up of 26.2 (19.8-35.4) months. Main Outcomes and Measures: The primary effectiveness end point was the cumulative incidence of the composite of myocardial infarction, stroke, or death from any cause, and the primary safety end point was major bleeding events (hospitalization for a bleeding event with use of a blood product or intracranial hemorrhage). Cumulative incidence at median follow-up for primary effectiveness and primary safety end points was compared between participants taking enteric-coated or uncoated aspirin using unadjusted and multivariable Cox proportional hazards models. All analyses were conducted for the intention-to-treat population. Results: Baseline aspirin formulation used in ADAPTABLE was self-reported for 10 678 participants (median [IQR] age, 68.0 [61.3-73.7] years; 7285 men [68.2%]), of whom 7366 (69.0%) took enteric-coated aspirin and 3312 (31.0%) took uncoated aspirin. No significant difference in effectiveness (adjusted hazard ratio [AHR], 0.94; 95% CI, 0.80-1.09; P = .40) or safety (AHR, 0.82; 95% CI, 0.49-1.37; P = .46) outcomes between the enteric-coated aspirin and uncoated aspirin cohorts was found. Within enteric-coated aspirin and uncoated aspirin, aspirin dose had no association with effectiveness (enteric-coated aspirin AHR, 1.13; 95% CI, 0.88-1.45 and uncoated aspirin AHR, 0.99; 95% CI, 0.83-1.18; interaction P = .41) or safety (enteric-coated aspirin AHR, 2.37; 95% CI, 1.02-5.50 and uncoated aspirin AHR, 0.89; 95% CI, 0.49-1.64; interaction P = .07). Conclusions and Relevance: In this post hoc secondary analysis of the ADAPTABLE randomized clinical trial, enteric-coated aspirin was not associated with significantly higher risk of myocardial infarction, stroke, or death or with lower bleeding risk compared with uncoated aspirin, regardless of dose, although a reduction in bleeding with enteric-coated aspirin cannot be excluded. More research is needed to confirm whether enteric-coated aspirin formulations or newer formulations will improve outcomes in this population. Trial Registration: ClinicalTrials.gov Identifier: NCT02697916.

Personalized digital behaviour interventions increase short-term physical activity: a randomized control crossover trial substudy of the MyHeart Counts Cardiovascular Health Study.

Aims: Physical activity is associated with decreased incidence of the chronic diseases associated with aging. We previously demonstrated that digital interventions delivered through a smartphone app can increase short-term physical activity. Methods and results: We offered enrolment to community-living iPhone-using adults aged ≥18 years in the USA, UK, and Hong Kong who downloaded the MyHeart Counts app. After completion of a 1-week baseline period, e-consented participants were randomized to four 7-day interventions. Interventions consisted of: (i) daily personalized e-coaching based on the individual's baseline activity patterns, (ii) daily prompts to complete 10 000 steps, (iii) hourly prompts to stand following inactivity, and (iv) daily instructions to read guidelines from the American Heart Association (AHA) website. After completion of one 7-day intervention, participants subsequently randomized to the next intervention of the crossover trial. The trial was completed in a free-living setting, where neither the participants nor investigators were blinded to the intervention. The primary outcome was change in mean daily step count from baseline for each of the four interventions, assessed in a modified intention-to-treat analysis (modified in that participants had to complete 7 days of baseline monitoring and at least 1 day of an intervention to be included in analyses). This trial is registered with ClinicalTrials.gov, NCT03090321. Conclusion: Between 1 January 2017 and 1 April 2022, 4500 participants consented to enrol in the trial (a subset of the approximately 50 000 participants in the larger MyHeart Counts study), of whom 2458 completed 7 days of baseline monitoring (mean daily steps 4232 ± 73) and at least 1 day of one of the four interventions. Personalized e-coaching prompts, tailored to an individual based on their baseline activity, increased step count significantly (+402 ± 71 steps from baseline, P = 7.1⨯10-8). Hourly stand prompts (+292 steps from baseline, P = 0.00029) and a daily prompt to read AHA guidelines (+215 steps from baseline, P = 0.021) were significantly associated with increased mean daily step count, while a daily reminder to complete 10 000 steps was not (+170 steps from baseline, P = 0.11). Digital studies have a significant advantage over traditional clinical trials in that they can continuously recruit participants in a cost-effective manner, allowing for new insights provided by increased statistical power and refinement of prior signals. Here, we present a novel finding that digital interventions tailored to an individual are effective in increasing short-term physical activity in a free-living cohort. These data suggest that participants are more likely to react positively and increase their physical activity when prompts are personalized. Further studies are needed to determine the effects of digital interventions on long-term outcomes.