Ticagrelor With or Without Aspirin After Complex PCI

BackgroundWhether a regimen of ticagrelor monotherapy attenuates bleeding complications without increasing ischemic risk in patients undergoing complex percutaneous coronary intervention (PCI) is unknown.ObjectivesThe purpose of this study was to evaluate the effect of ticagrelor monotherapy versus ticagrelor plus aspirin in patients undergoing complex PCI from the randomized, double-blind, placebo-controlled TWILIGHT (Ticagrelor with Aspirin or Alone in High-Risk Patients after Coronary Intervention) trial.MethodsIn the TWILIGHT trial, after 3 months of ticagrelor plus aspirin, event-free and adherent patients remained on ticagrelor and were randomly assigned to receive aspirin or placebo for 1 year. Complex PCI was defined as any of the following: 3 vessels treated, ≥3 lesions treated, total stent length >60 mm, bifurcation with 2 stents implanted, atherectomy device use, left main PCI, surgical bypass graft or chronic total occlusion as target lesions. Bleeding and ischemic endpoints were evaluated at 1 year after randomization.ResultsAmong 7,119 patients randomized in the main trial, complex PCI was performed in 2,342 patients. Compared to ticagrelor plus aspirin, ticagrelor plus placebo resulted in significantly lower rates of Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding (4.2% vs. 7.7%; hazard ratio [HR]: 0.54; 95% confidence interval [CI]: 0.38 to 0.76). BARC type 3 or 5 bleeding was also significantly reduced (1.1% vs. 2.6%; HR: 0.41; 95% CI: 0.21 to 0.80). There were no significant between-group differences in death, myocardial infarction, or stroke (3.8% vs. 4.9%; HR: 0.77; 95% CI: 0.52 to 1.15), nor in stent thrombosis.ConclusionsAmong patients undergoing complex PCI who initially completed 3 months of ticagrelor plus aspirin, continuation of ticagrelor monotherapy was associated with lower incidence of bleeding without increasing the risk of ischemic events compared to continuing ticagrelor plus aspirin. (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention [TWILIGHT]; NCT02270242)     

Ticagrelor Monotherapy Versus Ticagrelor With Aspirin in Patients With ST-Segment Elevation Myocardial Infarction

ObjectivesThe aim of this study was to assess whether the effects of ticagrelor monotherapy after 3-month dual-antiplatelet therapy (DAPT) are consistent among patients presenting with ST-segment elevation myocardial infarction (STEMI), non–ST-segment elevation myocardial infarction, and unstable angina treated with drug-eluting stents.BackgroundTicagrelor monotherapy after short-term DAPT has not been investigated in patients with STEMI.MethodsThis was a pre-specified, stratified, subgroup analysis of the STEMI cohort from the TICO (Ticagrelor Monotherapy After 3 Months in the Patients Treated With New Generation Sirolimus Stent for Acute Coronary Syndrome) trial, which constituted 36% of the total population. The primary outcome was a composite of major bleeding and major adverse cardiac and cerebrovascular events (MACCE; death, myocardial infarction, stent thrombosis, stroke, or target vessel revascularization). The secondary outcomes were major bleeding and MACCE.ResultsThe incidence of the primary outcome was 4.4% in patients with STEMI (n = 1,103), 6.0% in those with non–ST-segment elevation myocardial infarction (n = 1,027), and 4.1% in those with unstable angina (n = 926), without statistical significance (p = 0.09). Compared with ticagrelor-based 12-month DAPT, ticagrelor monotherapy after 3-month DAPT showed consistent effects on the primary outcome across clinical presentations (p for interaction [p_int] = 0.64). Furthermore, the effect of ticagrelor monotherapy on the reduction of major bleeding was consistent across clinical presentations (p_int = 0.36). The effect of ticagrelor monotherapy on MACCE was also consistent in patients with STEMI, without evidence of a higher risk for MACCE (p_int = 0.14).ConclusionsThis pre-specified subgroup analysis revealed no heterogeneity in the effects of ticagrelor monotherapy after 3-month DAPT, compared with 12-month DAPT, for the primary outcome, major bleeding, and MACCE across clinical presentations including STEMI, though larger studies are needed to demonstrate these findings with adequate power. (Ticagrelor Monotherapy After 3 Months in the Patients Treated With New Generation Sirolimus Stent for Acute Coronary Syndrome [TICO Study]; NCT02494895)     

Ticagrelor With or Without Aspirin After PCI: The TWILIGHT Platelet Substudy

BackgroundAn evolving strategy in the setting of percutaneous coronary intervention (PCI) involves withdrawal of acetylsalicylic acid (ASA), or aspirin, while maintaining P2Y₁₂ inhibition. However, the pharmacodynamic effects of this approach on blood thrombogenicity and platelet reactivity remain unknown.ObjectivesThis study sought to compare the antithrombotic potency of ticagrelor alone versus ticagrelor plus ASA among high-risk patients undergoing PCI with drug-eluting stents.MethodsThis was a mechanistic substudy within the TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) trial, which randomized patients undergoing PCI to ticagrelor plus placebo versus ticagrelor plus ASA following 3 months of dual antiplatelet therapy. Substudy participants were enrolled after randomization, at which time ex vivo assays to quantify thrombus size under dynamic flow conditions and platelet reactivity were performed. Pharmacodynamic assessments were repeated 1 to 6 months thereafter. The primary endpoint was thrombus size at the post-randomization visit with platelet reactivity following stimuli to arachidonic acid, collagen, adenosine diphosphate, and thrombin as secondary endpoints. Results were analyzed using analysis of covariance.ResultsA total of 51 patients were enrolled, among whom 42 underwent perfusion assays at baseline and follow-up with a median time between studies of 1.5 months. The adjusted mean difference in post-randomization thrombus area was similar between groups: −218.2 μm² (95% confidence interval [CI]: −575.9 to 139.9 μm²; p = 0.22). Markers sensitive to cyclo-oxygenase-1 blockade, including platelet reactivity in response to arachidonic acid (mean difference: 10.9 U; 95% CI: 1.9 to 19.9 U) and collagen (mean difference: 9.8 U; 95% CI: 0.8 to 18.8 U) stimuli were higher among patients receiving placebo, whereas levels of platelet reactivity were similar with adenosine diphosphate and thrombin.ConclusionsAmong high-risk patients receiving drug-eluting stents, the antithrombotic potency of ticagrelor monotherapy is similar to that of ticagrelor plus ASA with respect to ex vivo blood thrombogenicity, whereas markers sensitive to cyclo-oxygenase-1 blockade are increased in the absence of ASA. (Platelet Substudy of the TWILIGHT Trial; NCT04001374).     

Ticagrelor With or Without Aspirin in High-Risk Patients With Diabetes Mellitus Undergoing Percutaneous Coronary Intervention

BackgroundP2Y₁₂ inhibitor monotherapy with ticagrelor after a brief period of dual antiplatelet therapy can reduce bleeding without increasing ischemic harm after percutaneous coronary intervention (PCI). The impact of this approach among patients with diabetes mellitus (DM) remains unknown.ObjectivesThe purpose of this study was to examine the effect of ticagrelor monotherapy versus ticagrelor plus aspirin among patients with DM undergoing PCI.MethodsThis was a pre-specified analysis of the DM cohort in the TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients after Coronary Intervention) trial. After 3 months of ticagrelor plus aspirin, patients were maintained on ticagrelor and randomized to aspirin or placebo for 1 year. The primary endpoint was Bleeding Academic Research Consortium 2, 3, or 5 bleeding. The composite ischemic endpoint was all-cause death, myocardial infarction, or stroke.ResultsPatients with DM comprised 37% (n = 2,620) of the randomized cohort and were characterized by more frequent comorbidities and a higher prevalence of multivessel disease. The incidence of Bleeding Academic Research Consortium 2, 3, or 5 bleeding was 4.5% and 6.7% among patients with DM randomized to ticagrelor plus placebo versus ticagrelor plus aspirin (hazard ratio: 0.65; 95% confidence interval: 0.47 to 0.91; p = 0.012). Ticagrelor monotherapy was not associated with an increase in ischemic events compared with ticagrelor plus aspirin (4.6% vs. 5.9%; hazard ratio: 0.77; 95% confidence interval: 0.55 to 1.09; p = 0.14). In the overall trial population, there was no significant interaction between DM status and treatment group for the primary bleeding or ischemic endpoints.ConclusionsCompared with ticagrelor plus aspirin, the effect of ticagrelor monotherapy in reducing the risk of clinically relevant bleeding without any increase in ischemic events was consistent among patients with or without DM undergoing PCI. (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention [TWILIGHT]; NCT02270242)     

Rivaroxaban Plus Aspirin in Obese and Overweight Patients With Vascular Disease in the COMPASS Trial

BackgroundDirect oral anticoagulants are administered in fixed doses irrespective of body weight, but guidelines recommend against their use in patients with extremes of body weight.ObjectivesThis study determined the effects of dual-pathway inhibition antithrombotic regimen (rivaroxaban 2.5 mg twice daily plus aspirin 100 mg/day) compared with aspirin Halone across a range of patient body mass indexes (BMIs) and body weights.MethodsThis was a secondary analysis of the COMPASS (Cardiovascular OutcoMes for People using Anticoagulation StrategieS) trial, which included patients with chronic coronary artery disease or peripheral artery disease. Efficacy and safety outcomes were studied in relation to BMI: (normal 18.5 ≤BMI <25 kg/m², overweight 25 ≤BMI <30 kg/m², obese ≥30 kg/m²) and body weight (≤70 kg, 70 < weight ≤90 kg, and >90 kg; as well as ≤120 kg vs. >120 kg).ResultsAmong 27,395 randomized patients, 6,459 (24%) had normal BMI, 12,047 (44%) were overweight, and 8,701 (32%) were obese. The combination of rivaroxaban and aspirin compared with aspirin produced a consistent reduction in the primary outcome of cardiovascular death, stroke, or myocardial infarction, irrespective of BMI or body weight. For 18.5 ≤BMI <25 kg/m²: 3.5% vs. 5.0%; hazard ratio (HR): 0.73 (95% credible interval [CrI]: 0.58 to 0.90); 25 ≤ BMI <30 kg/m²: 4.3% vs. 5.1%; HR: 0.80 (95% CrI: 0.66 to 0.96); BMI ≥30 kg/m²: 4.2% vs. 6.1%; HR: 0.71 (95% CrI: 0.57 to 0.86). For body weight ≤70 kg: 4.1% vs. 5.3%; HR: 0.75 (95% CrI: 0.62 to 0.91); 70 < weight ≤90 kg: 4.1% vs. 5.3%; HR: 0.76 (95% CrI: 0.65 to 0.89); >90 kg: 4.2% vs. 5.7%; HR: 0.74 (95% CrI: 0.61 to 0.90). Effects on bleeding, mortality, and net clinical benefit were consistent irrespective of BMI or bodyweight.ConclusionsThe effects of dual-pathway antithrombotic therapy are consistent irrespective of BMI or body weight, suggesting no need for dose adjustments in the ranges of weights and BMI of patients enrolled in the COMPASS trial. Further studies need to address this problem in relation to greater extremes of body weight. (Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease [COMPASS]; NCT01776424)     

Rivaroxaban Plus Aspirin in Patients With Vascular Disease and Renal Dysfunction: From the COMPASS Trial

BackgroundChronic kidney disease is associated with an increased risk of both bleeding and ischemic cardiovascular events.ObjectiveThe purpose of this study was to determine the balance of risks and benefits from the dual pathway antithrombotic regimen (rivaroxaban 2.5 mg twice daily [bd] plus aspirin, compared with aspirin) in vascular patients with or without moderate renal dysfunction.MethodsThis was a secondary analysis of the COMPASS (Cardiovascular OutcoMes for People using Anticoagulation StrategieS) trial involving 27,395 patients with chronic coronary or peripheral artery disease.ResultsIn COMPASS, 21,111 patients had an estimated glomerular filtration rate (GFR) at baseline of ≥60 ml/min, 6,276 had a GRF of <60 ml/min. Both the primary efficacy outcome (cardiovascular death, myocardial infarction, or stroke) and major bleeding were more frequent in those with renal dysfunction, and the frequency of these outcome events was inversely related to GFR. However, the primary outcome was consistently reduced with rivaroxaban 2.5 mg bd plus aspirin, irrespective of GFR category (GFR ≥60 ml/min, 3.5% rivaroxaban plus aspirin, 4.5% aspirin alone, hazard ratio [HR]: 0.76, 95% confidence interval [CI]: 0.64 to 0.90; GFR <60 ml/min, 6.4% rivaroxaban plus aspirin, 8.4% aspirin alone, HR: 0.75; 95% CI: 0.60 to 0.94). Major bleeding was more frequent with rivaroxaban 2.5 mg plus aspirin versus aspirin alone in those with GFR ≥60 ml/min (2.9% rivaroxaban plus aspirin, 1.6% aspirin alone, HR: 1.81; 95% CI: 1.44 to 2.28) and similarly in those with GFR <60 ml/min (3.9% rivaroxaban plus aspirin, 2.7% aspirin alone, HR: 1.47, 95% CI: 1.05 to 2.07).ConclusionsThe benefits of the dual pathway COMPASS regimen (rivaroxaban 2.5 mg bd plus aspirin), versus aspirin alone, are preserved in patients with moderate renal dysfunction without evidence of an excess hazard of bleeding.     

Ticagrelor vs Prasugrel in a Contemporary Real-World Cohort Undergoing Percutaneous Coronary Intervention

BackgroundPotent P2Y₁₂ agents such as ticagrelor and prasugrel are increasingly utilized across the clinical spectrum of patients undergoing percutaneous coronary intervention (PCI). There is a paucity of data supporting their use in a patient population inclusive of both acute coronary syndrome (ACS) and chronic coronary syndrome (CCS) patients.ObjectivesThe authors compared the efficacy and safety of ticagrelor and prasugrel in a real-world contemporary PCI cohort.MethodsConsecutive patients undergoing PCI between 2014 and 2019 discharged on either prasugrel or ticagrelor were included from the prospectively collected institutional PCI registry. Primary endpoint was the composite of death and myocardial infarction (MI), with secondary outcomes including rates of bleeding, stroke, and target vessel revascularization at 1 year.ResultsOverall, 3,858 patients were included in the study (ticagrelor: n = 2,771; prasugrel: n = 1,087), and a majority (48.4%) underwent PCI in the context of CCS. Patients prescribed ticagrelor were more likely to be female, have a history of cerebrovascular disease, and have ACS presentation, while those receiving prasugrel were more likely to be White with a higher prevalence of prior revascularization. No difference in the risk of death or MI was noted across the groups (ticagrelor vs prasugrel: 3.3% vs 3.1%; HR: 0.88; 95% CI: 0.54-1.43; P = 0.59). Rates of target vessel revascularization were significantly lower in the ticagrelor cohort (9.3% vs 14.0%; adjusted HR: 0.71; 95% CI: 0.55-0.91; P = 0.007) with no differences in stroke or bleeding. The results were consistent in patients with CCS (HR: 0.84; 95% CI: 0.46-1.54) and ACS (HR: 1.18; 95% CI: 0.46-1.54), without evidence of interaction (P = 0.37), and confirmed across multivariable adjustment and propensity score stratification analysis.ConclusionsIn this contemporary patient population undergoing PCI, prasugrel and ticagrelor were associated with similar 1-year efficacy and safety.     

Impact of Age on the Safety and Efficacy of Ticagrelor Monotherapy in Patients Undergoing PCI

ObjectivesThe aim of this study was to assess the impact of age on the safety and efficacy of ticagrelor monotherapy after percutaneous coronary intervention (PCI).BackgroundAs the risk for bleeding and ischemic complications after PCI increases with age, the authors conducted a pre-specified analysis of the TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) trial to evaluate the possible benefits of ticagrelor monotherapy according to age.MethodsThe TWILIGHT trial enrolled patients undergoing PCI with drug-eluting stents who fulfilled at least 1 clinical and 1 angiographic high-risk criterion. Age ≥65 years was a clinical entry criterion. After 3 months of dual-antiplatelet therapy with ticagrelor, event-free patients were randomized to ticagrelor plus placebo or ticagrelor plus aspirin for an additional 12 months. The primary endpoint was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding. The key secondary endpoint was the composite of all-cause death, myocardial infarction, or stroke.ResultsA total of 3,113 patients (47.7%) were ≥65 years of age. At 1 year after randomization, ticagrelor monotherapy significantly reduced BARC type 2, 3, or 5 bleeding (4.5% vs. 8.2%; hazard ratio: 0.53; 95% confidence interval: 0.40 to 0.71) without increasing ischemic events (4.2% vs. 4.4%; hazard ratio: 0.96; 95% confidence interval: 0.68 to 1.35) compared with ticagrelor plus aspirin among patients ≥65 years of age. These findings were consistent in patients <65 years of age with respect to the primary (p_interaction = 0.62) and key secondary (p_interaction = 0.77) endpoints and across different age categories.ConclusionsA strategy of ticagrelor monotherapy following 3 months of dual-antiplatelet therapy significantly reduced clinically relevant bleeding compared with ticagrelor plus aspirin without an increase in ischemic events, irrespective of age.     

Aspirin for Primary Prevention of Cardiovascular Events

BackgroundThe efficacy and safety of aspirin for primary prevention of cardiovascular disease (CVD) remain debatable.ObjectivesThe purpose of this study was to examine the clinical outcomes with aspirin for primary prevention of CVD after the recent publication of large trials adding >45,000 individuals to the published data.MethodsRandomized controlled trials comparing clinical outcomes with aspirin versus control for primary prevention with follow-up duration of ≥1 year were included. Efficacy outcomes included all-cause death, cardiovascular (CV) death, myocardial infarction (MI), stroke, transient ischemic attack (TIA), and major adverse cardiovascular events. Safety outcomes included major bleeding, intracranial bleeding, fatal bleeding, and major gastrointestinal (GI) bleeding. Random effects DerSimonian-Laird risk ratios (RRs) for outcomes were calculated.ResultsA total of 15 randomized controlled trials including 165,502 participants (aspirin n = 83,529, control n = 81,973) were available for analysis. Compared with control, aspirin was associated with similar all-cause death (RR: 0.97; 95% confidence interval [CI]: 0.93 to 1.01), CV death (RR: 0.93; 95% CI: 0.86 to 1.00), and non-CV death (RR: 0.98; 95% CI: 0.92 to 1.05), but a lower risk of nonfatal MI (RR: 0.82; 95% CI: 0.72 to 0.94), TIA (RR: 0.79; 95% CI: 0.71 to 0.89), and ischemic stroke (RR: 0.87; 95% CI: 0.79 to 0.95). Aspirin was associated with a higher risk of major bleeding (RR: 1.5; 95% CI: 1.33 to 1.69), intracranial bleeding (RR: 1.32; 95% CI: 1.12 to 1.55), and major GI bleeding (RR: 1.52; 95% CI: 1.34 to 1.73), with similar rates of fatal bleeding (RR: 1.09; 95% CI: 0.78 to 1.55) compared with the control subjects. Total cancer and cancer-related deaths were similar in both groups within the follow-up period of the study.ConclusionsAspirin for primary prevention reduces nonfatal ischemic events but significantly increases nonfatal bleeding events.     

Bleeding and Ischemic Outcomes With Ticagrelor Monotherapy According to Body Mass Index

BackgroundThere is a paucity of data regarding the safety and efficacy of different antiplatelet regimens according to standardized body mass index (BMI) categories.ObjectivesThe aim of this study was to investigate bleeding and ischemic outcomes according to BMI in the TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) trial.MethodsThe TWILIGHT trial randomized high-risk patients to ticagrelor plus aspirin or ticagrelor plus placebo at 3 months after percutaneous coronary intervention. In this secondary analysis, patients were stratified by standard BMI categories, as recommended by the European Society of Cardiology Working Group on Thrombosis (normal weight [BMI 18.5-24.99 kg/m²], overweight [BMI 25-29.99 kg/m²], and obese [BMI ≥30 kg/m²]) and by median BMI, as prespecified in the protocol.ResultsAmong 7,038 patients randomized and with available BMI, 1,807 (25.7%) were normal weight, 2,927 (41.6%) were overweight, and 2,304 (32.7%) were obese. In normal-weight, overweight, and obese patients, ticagrelor monotherapy, compared with ticagrelor plus aspirin, reduced the primary endpoint of Bleeding Academic Research Consortium type 2, 3, or 5 bleeding (normal weight: HR: 0.48 [95% CI: 0.32-0.73]; overweight: HR: 0.57 [95% CI: 0.41-0.78]; obese: HR: 0.63 [95% CI: 0.44-0.91]; P for interaction = 0.627), without any increase in the composite ischemic endpoint of all-cause death, myocardial infarction, or stroke (normal weight: HR: 1.36 [95% CI: 0.84-2.19]; overweight: HR: 0.92 [95% CI: 0.63-1.35]; obese: HR: 0.84 [95% CI: 0.56-1.25]; P for interaction = 0.290). These findings were consistent with the prespecified analysis by median BMI.ConclusionsAmong high-risk patients undergoing percutaneous coronary intervention, ticagrelor monotherapy, compared with ticagrelor plus aspirin, reduced bleeding events without any increase in ischemic risk across different BMI categories.     

Ticagrelor or Prasugrel in Patients With Acute Coronary Syndrome in Relation to Estimated Glomerular Filtration Rate

ObjectivesThe aim of this study was to assess the safety and efficacy of ticagrelor versus prasugrel for patients with acute coronary syndrome (ACS) according to their estimated glomerular filtration rates (eGFRs).BackgroundThe outcomes of ticagrelor versus prasugrel in patients with ACS according to eGFR have not been defined.MethodsPatients (n = 4,012) were categorized into 3 groups: low eGFR (<60 mL/min/1.73 m²), intermediate eGFR (≥60 and <90 mL/min/1.73 m²), and high eGFR (≥90 mL/min/1.73 m²). The primary endpoint was a composite of all-cause death, myocardial infarction, and stroke; the secondary safety endpoint was Bleeding Academic Research Consortium types 3 to 5 bleeding, both at 1 year.ResultsPatients with low eGFRs had a higher risk for the primary endpoint compared with patients with intermediate eGFRs (adjusted HR: 1.89; 95% CI: 1.46-2.46]) and those with high eGFRs (adjusted HR: 2.33; 95% CI: 1.57-3.46). A risk excess for low eGFR was also observed for bleeding (adjusted HR: 1.55 [95% CI: 1.12-2.13] vs intermediate eGFR; adjusted HR: 1.59 [95% CI: 1.01-2.50] vs high eGFR). However, eGFR did not affect the relative efficacy and safety of ticagrelor versus prasugrel. In patients with low eGFR, the primary endpoint occurred in 20.5% with ticagrelor and in 14.7% with prasugrel (HR: 1.47; 95% CI: 1.04-2.08; P = 0.029); there was no significant difference in bleeding.ConclusionsThese results show that among patients with ACS, reduction of eGFR is associated with increased risk for ischemic and bleeding events but has no significant impact on the relative efficacy and safety of ticagrelor versus prasugrel. (Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome [ISAR-REACT 5]; NCT01944800)     

Ticagrelor or Prasugrel in Patients With Acute Coronary Syndromes and Diabetes Mellitus

ObjectivesThe aim of this study was to assess the efficacy and safety of ticagrelor versus prasugrel in patients with diabetes mellitus (DM) presenting with acute coronary syndromes (ACS) in whom invasive therapy was planned.BackgroundThe efficacy and safety of ticagrelor versus prasugrel in patients with ACS with DM undergoing invasive treatment remain unknown.MethodsThis pre-specified analysis of the ISAR-REACT (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment) 5 trial included 892 patients with ACS with DM and 3,124 patients with ACS without DM randomized to prasugrel or ticagrelor. The primary endpoint was a composite of death, myocardial infarction, or stroke; the safety endpoint was Bleeding Academic Research Consortium types 3 to 5 bleeding (both assessed 12 months after randomization).ResultsThe primary endpoint occurred in 51 patients (11.2%) in the ticagrelor group and 55 patients (13.0%) in the prasugrel group in the DM cohort (hazard ratio: 0.84; 95% confidence interval: 0.58 to 1.24; p = 0.383) and in 132 patients (8.6%) in the ticagrelor group and 81 patients (5.2%) in the prasugrel group in the non-DM cohort (hazard ratio: 1.70; 95% confidence interval: 1.29 to 2.24; p < 0.001). There was a significant treatment arm–by–diabetic status interaction (p_int = 0.0035). Bleeding Academic Research Consortium types 3 to 5 bleeding occurred in 27 patients (6.9%) in the ticagrelor group and 19 patients (5.5%) in the prasugrel group (p = 0.425) in the DM cohort and in 68 patients (5.2%) in the ticagrelor group and 60 patients (4.6%) in the prasugrel group in the non-DM cohort (p = 0.500).ConclusionsDM seems to affect the efficacy of ticagrelor and prasugrel in patients with ACS. In patients with DM, the efficacy of ticagrelor was comparable with that of prasugrel. (Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome [ISAR-REACT 5]; NCT01944800)     

Aspirin for primary prevention: Is this the end of the road?

Aspirin is one of the oldest and most commonly used cardiovascular drugs. Despite there being high-quality evidence supporting the use of aspirin for patients with known cardiovascular disease, a definitive consensus regarding its use for patients at risk for cardiovascular disease (and without established cardiovascular disease) has never been reached. Many randomized control trials have produced conflicting results, and consequently, society guidelines have issued differring recommendations. Three major trials were published in 2018, which supplement the existing data on aspirin's role in primary prevention and provide further guidance on this contentious issue. This article reviews the history of aspirin through the last two decades, with special emphasis on these new trials.     

Effect of Ticagrelor on Left Ventricular Remodeling in Patients With ST-Segment Elevation Myocardial Infarction (HEALING-AMI)

ObjectivesThe aim of this study was to evaluate the effect of ticagrelor versus clopidogrel on left ventricular (LV) remodeling after reperfusion of ST-segment elevation myocardial infarction (STEMI) in humans.BackgroundAnimal studies have demonstrated that ticagrelor compared with clopidogrel better protects myocardium against reperfusion injury and improves remodeling after myocardial infarction.MethodsIn this investigator-initiated, randomized, open-label, assessor-blinded trial performed at 10 centers in Korea, patients were enrolled if they had naive STEMI successfully treated with primary percutaneous coronary intervention (PCI) and at least 6-month planned duration of dual-antiplatelet treatment. The coprimary endpoints were LV remodeling index (LVRI) (a relative change of LV end-diastolic volume) measured on 3-dimensional echocardiography and N-terminal pro–B-type natriuretic peptide level at 6 months.ResultsAmong initially enrolled patients with STEMI (n = 336), 139 in each group completed the study. LVRI at 6 months was numerically lower with ticagrelor versus clopidogrel (0.6 ± 18.6% vs. 4.5 ± 16.5%; p = 0.095). Ticagrelor significantly reduced the 6-month level of N-terminal pro–B-type natriuretic peptide (173 ± 141 pg/ml vs. 289 ± 585 pg/ml; p = 0.028). These differences were prominent in patients with pre-PCI TIMI (Thrombolysis In Myocardial Infarction) flow grade 0. By multivariate analysis, ticagrelor versus clopidogrel reduced the risk for positive LV remodeling (LVRI >0%) (odds ratio: 0.56; 95% confidence interval: 0.33 to 0.95; p = 0.030). The LV end-diastolic volume index remained unchanged during ticagrelor treatment (from 54.7 ± 12.2 to 54.2 ± 12.2 ml/m²; p = 0.629), but this value increased over time during clopidogrel treatment (from 54.6 ± 11.3 to 56.4 ± 13.9 ml/m²; p = 0.056) (difference −2.3 ml/m²; 95% confidence interval: −4.8 to 0.2 ml/m²; p = 0.073). Ticagrelor reduced LV end-systolic volume index (from 27.0 ± 8.5 to 24.7 ± 8.4 ml/m²; p < 0.001), whereas no reduction was seen with clopidogrel (from 26.2 ± 8.9 to 25.6 ± 11.0 ml/m²; p = 0.366) (difference −1.8 ml/m²; 95% confidence interval: −3.5 to −0.1 ml/m²; p = 0.040).ConclusionsTicagrelor was superior to clopidogrel for LV remodeling after reperfusion of STEMI with primary PCI. (High Platelet Inhibition With Ticagrelor to Improve Left Ventricular Remodeling in Patients With ST Segment Elevation Myocardial Infarction [HEALING-AMI]; NCT02224534)     

Ticagrelor Monotherapy After PCI in High-Risk Patients With Prior MI: A Prespecified TWILIGHT Substudy

ObjectivesThe aim of this study was to evaluate if patients with prior myocardial infarction (MI) could benefit from ticagrelor monotherapy in terms of bleeding reduction without any compromise in ischemic event prevention.BackgroundPatients with history of MI who undergo percutaneous coronary intervention (PCI) remain at risk for recurrent ischemic events. The optimal antithrombotic strategy for this cohort remains debated.MethodsIn this prespecified analysis of the randomized TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients after Coronary Intervention) trial, the authors evaluated the impact of history of MI on treatment effect of ticagrelor monotherapy versus ticagrelor plus aspirin in patients undergoing PCI with drug-eluting stent with at least 1 clinical and 1 angiographic high-risk feature and free from adverse events at 3 months after index PCI. The primary endpoint was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding, and the key secondary endpoint was the composite of all-cause death, MI, or stroke, both at 12 months after randomization.ResultsA total of 1,937 patients (29.7%) with and 4,595 patients (70.3%) without prior MI were randomized to ticagrelor and placebo or ticagrelor and aspirin. At 1 year after randomization, patients with prior MI experienced higher rates of death, MI, or stroke (5.7% vs 3.2%; P < 0.001) but similar BARC types 2 to 5 bleeding (5.0% vs 5.5%; P = 0.677) compared with patients without prior MI. Ticagrelor monotherapy consistently reduced the risk for the primary bleeding outcome in patients with (3.4% vs 6.7%; HR: 0.50; 95% CI: 0.33-0.76) and without (4.2% vs 7.0%; HR: 0.58; 95% CI: 0.45-0.76; P_interaction = 0.54) prior MI. Rates of the key secondary ischemic outcome were not significantly different between treatment groups irrespective of history of MI (prior MI, 6.0% vs 5.5% [HR: 1.09; 95% CI: 0.75-1.58]; no prior MI, 3.1% vs 3.3% [HR: 0.92; 95% CI: 0.67-1.28]; P_interaction = 0.52).ConclusionsTicagrelor monotherapy is associated with significantly lower risk for bleeding events compared with ticagrelor plus aspirin, without any compromise in ischemic prevention, among high-risk patients with history of MI undergoing PCI. (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention [TWILIGHT]; NCT02270242)     

Contrast Ultrasound,Sonothrombolysis and Sonoperfusion in Cardiovascular Disease: Shifting to Theragnostic Clinical Trials

Contrast ultrasound has a variety of applications in cardiovascular medicine, both in diagnosing cardiovascular disease as well as providing prognostic information. Visualization of intravascular contrast microbubbles is based on acoustic cavitation, the characteristic oscillation that results in changes in the reflected ultrasound waves. At high power, this acoustic response generates sufficient shear that is capable of enhancing endothelium-dependent perfusion in atherothrombotic cardiovascular disease (sonoperfusion). The oscillation and collapse of microbubbles in response to ultrasound also induces microstreaming and jetting that can fragment thrombus (sonothrombolysis). Several preclinical studies have focused on identifying optimal diagnostic ultrasound settings and treatment regimens. Clinical trials have been performed in acute myocardial infarction, stroke, and peripheral arterial disease often with improved outcome. In the coming years, results of ongoing clinical trials along with innovation and improvements in sonothrombolysis and sonoperfusion will determine whether this theragnostic technique will become a valuable addition to reperfusion therapy.     

Ticagrelor to Reduce Myocardial Injury in Patients With High-Risk Coronary Artery Plaque

ObjectivesThe goal of this study was to determine whether ticagrelor reduces high-sensitivity troponin I concentrations in patients with established coronary artery disease and high-risk coronary plaque.BackgroundHigh-risk coronary atherosclerotic plaque is associated with higher plasma troponin concentrations suggesting ongoing myocardial injury that may be a target for dual antiplatelet therapy.MethodsIn a randomized, double-blind, placebo-controlled trial, patients with multivessel coronary artery disease underwent coronary ¹⁸F-fluoride positron emission tomography/coronary computed tomography scanning and measurement of high-sensitivity cardiac troponin I. Patients were randomized (1:1) to receive ticagrelor 90 mg twice daily or matched placebo. The primary endpoint was troponin I concentration at 30 days in patients with increased coronary ¹⁸F-fluoride uptake.ResultsIn total, 202 patients were randomized to treatment, and 191 met the pre-specified criteria for inclusion in the primary analysis. In patients with increased coronary ¹⁸F-fluoride uptake (120 of 191), there was no evidence that ticagrelor had an effect on plasma troponin concentrations at 30 days (ratio of geometric means for ticagrelor vs. placebo: 1.11; 95% confidence interval: 0.90 to 1.36; p = 0.32). Over 1 year, ticagrelor had no effect on troponin concentrations in patients with increased coronary ¹⁸F-fluoride uptake (ratio of geometric means: 0.86; 95% confidence interval: 0.63 to 1.17; p = 0.33).ConclusionsDual antiplatelet therapy with ticagrelor did not reduce plasma troponin concentrations in patients with high-risk coronary plaque, suggesting that subclinical plaque thrombosis does not contribute to ongoing myocardial injury in this setting. (Dual Antiplatelet Therapy to Reduce Myocardial Injury [DIAMOND]; NCT02110303)     

Safety and Performance Outcomes of a Self-Expanding Transcatheter Aortic Heart Valve: The BIOVALVE Trials

ObjectivesThe aim of this study was to assess the safety and performance of a newly introduced transfemoral self-expanding supra-annular transcatheter heart valve.BackgroundTranscatheter aortic valve replacement has become an established procedure, and newer transcatheter heart valves aim to supplement the current armamentarium.MethodsBIOVALVE-I is a prospective, single-center feasibility study enrolling 13 high-risk patients with severe aortic stenosis, and BIOVALVE-II is a multicenter pilot study enrolling a further 55 patients under the same protocol.ResultsPatients’ mean age was 82.4 ± 5.3 years, 57.4% had concomitant coronary artery disease, 50.0% had renal insufficiency stage ≥3, 32.4% had diabetes mellitus, 29.4% had current anemia, 19.1% had chronic obstructive pulmonary disease, 19.1% were frail, and 17.6% had prior cerebrovascular events. The primary endpoint, early safety according to the Valve Academic Research Consortium-2 guidelines, was observed in 13 patients (19.1%). One patient (1.5%) died through 30 days of a noncardiac cause, and 4 patients (7.8%) died through 180 days. Disabling stroke occurred at 30 days in 1 patient (1.5%) and at 180 days in 2 patients (3.2%). New permanent pacemakers up to 30 days were implanted in 9 patients (13.4%). Two patients (3.8%) had moderate or severe paravalvular leakage at 30 days and 4 (9.1%) at 6 months, mean effective orifice area was 2.0 ± 0.4 cm² and 1.9 ± 0.5 cm², and mean gradient was 6.4 mm Hg at 30 days and 6 months.ConclusionsClinical outcomes with the Biovalve self-expanding transcatheter heart valve were similar to those seen in other first-in-human studies with first-generation devices for severe aortic stenosis.     

Statistical Appraisal of 6 Recent Clinical Trials in Cardiology: JACC State-of-the-Art Review

In the past 12 months, many important new clinical trials in cardiology have had their first conference presentation and publication. This paper presents a constructive critical appraisal of 6 key studies. In time order of first presentation, they are CABANA, ATTR-ACT, COAPT, DECLARE, REDUCE-IT, and AUGUSTUS. For each study, the aim herein is to document and interpret the main findings, paying attention to new findings, their research context, and study limitations. These topical examples also provide methodological insights pertinent to future clinical trials research.     

Cangrelor in Patients With Coronary Artery Disease Pretreated With Ticagrelor: The Switching Antiplatelet (SWAP)-5 Study

BackgroundThere are no studies specifically designed to rule out a drug-drug interaction (DDI) when cangrelor is used among patients who have been pretreated with ticagrelor.ObjectivesThis study sought to rule out a DDI among cangrelor-treated patients who have been pretreated with ticagrelor.MethodsIn this prospective, randomized, double-blind, placebo-controlled, crossover, pharmacokinetic (PK) and pharmacodynamic (PD) study, patients with coronary artery disease (N = 20) were pretreated with a 180-mg ticagrelor loading dose and after 1 hour randomized to placebo or cangrelor (bolus and infusion for 2 hours). Patients crossed over after 1 to 4 weeks of washout. PK analysis included ticagrelor plasma levels and its active metabolite. PD assessments included VerifyNow P2Y₁₂ reaction units (PRU), light transmittance aggregometry, vasodilator-stimulated phosphoprotein, and Total Thrombus-Formation Analysis System. PK/PD assessments were performed at 7 time points.ResultsCompared with placebo, adding cangrelor to patients pretreated with ticagrelor resulted in a significant reduction in PRU at 30 minutes and 1 hour after starting infusion. At 2 hours after stopping cangrelor/placebo infusion, PRU were low and similar in both groups (16.9 vs 12.6; mean difference: 4.3; 95% CI: ?28.6 to 37.3), meeting the noninferiority primary endpoint (predefined noninferiority margin 45 PRU). Consistent findings were shown with all PD assays. PK tracked PD findings with no differences between groups in plasma levels of ticagrelor and its metabolite.ConclusionsCompared with placebo, the use of cangrelor in patients pretreated with ticagrelor results in enhanced platelet inhibition with no differences in PK/PD profiles after discontinuation of drug infusion indicating the absence of a DDI. (PD and PK Profiles of Switching Between Cangrelor and Ticagrelor Following Ticagrelor Pre-treatment [SWAP-5]; NCT04634162)