The duration of dual antiplatelet therapy (DAPT) after coronary stenting has been evaluated in randomized studies with apparently conflicting results. Although longer exposure associates with more ...bleeding complications, late stent thrombosis (ST) and myocardial infarction are reduced. In addition, as new drug-eluting stents carry a lower risk of ST compared with the first-generation drug-eluting stents and possibly even bare-metal stents, a shift toward better protection from ST may have an effect on the duration and intensity of DAPT. Whether the duration of DAPT should be shorter or longer than the currently recommended 6 to 12 months is analyzed in this review, drawing on lessons from the most recent studies.
Patients who experience an acute coronary syndrome are at heightened risk of recurrent ischemic events, including stroke. Ezetimibe improved cardiovascular outcomes when added to statin therapy in ...patients stabilized after acute coronary syndrome. We investigated the efficacy of the addition of ezetimibe to simvastatin for the prevention of stroke and other adverse cardiovascular events in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), with a focus on patients with a stroke before randomization.
Patients who experienced acute coronary syndrome were randomized to a placebo/simvastatin or ezetimibe/simvastatin regimen and followed for a median of 6 years. Treatment efficacy was assessed for the entire population and by subgroups for the first and total (first and subsequent) events for the end points of stroke of any etiology, stroke subtypes, and the primary trial end point at 7 years.
Of 18 144 patients, 641 (3.5%) experienced at least 1 stroke; most were ischemic (527, 82%). Independent predictors of stroke included prior stroke, older age, atrial fibrillation, congestive heart failure, diabetes mellitus, myocardial infarction, and renal dysfunction. There was a nonsignificant reduction in the first event of stroke of any etiology (4.2% versus 4.8%; hazard ratio HR, 0.86; 95% confidence interval CI, 0.73-1.00;
=0.052) with ezetimibe/simvastatin versus placebo/simvastatin, driven by a significant 21% reduction in ischemic stroke (3.4% versus 4.1%; HR, 0.79; 95% CI, 0.67-0.94;
=0.008) and a nonsignificant increase in hemorrhagic stroke (0.8% versus 0.6%; HR, 1.38; 95% CI, 0.93-2.04;
=0.11). Evaluating total events, including the first and all recurrent strokes, ezetimibe/simvastatin reduced stroke of any etiology (HR, 0.83; 95% CI, 0.70-0.98;
=0.029) and ischemic stroke (HR, 0.76; 95% CI, 0.63-0.91;
=0.003). Patients who had experienced a stroke prior to randomization were at a higher risk of recurrence and demonstrated an absolute risk reduction of 8.6% for stroke of any etiology (10.2% versus 18.8%; number needed to treat=12; HR, 0.60; 95% CI, 0.38-0.95;
=0.030) and 7.6% for ischemic stroke (8.7% versus 16.3%; number needed to treat=13; HR, 0.52; 95% CI, 0.31-0.86;
=0.011) with ezetimibe added to simvastatin therapy.
The addition of ezetimibe to simvastatin in patients stabilized after acute coronary syndrome reduces the frequency of ischemic stroke, with a particularly large effect seen in patients with a prior stroke.
URL: https://www.clinicaltrials.gov. Unique identifier: NCT00202878.
The balance between benefit (ischemia protection) and risk (bleeding) is a key consideration in choosing the intensity of antiplatelet therapy for patients with acute coronary syndromes. The goals of ...this analysis were to identify baseline characteristics that independently predict bleeding and to determine how bleeding events impact the subsequent mortality in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel--Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38).
Multivariable Cox regression analyses adjusted for treatment, baseline, and procedural variables were used to determine the predictors for serious (TIMI major or minor) bleeding. To analyze the hazard ratio and time dependency of bleeding on mortality, we used iterative day-to-day landmark analyses after the bleed. From the 13 420 patients with acute coronary syndromes included in this analysis, 534 (4.0%) experienced a serious bleeding event. Variables with the highest strength of association with risk of serious bleeding were female sex, use of a glycoprotein IIb/IIIa inhibitor, duration of intervention, age, assignment to prasugrel, regional characteristics, admission diagnosis of ST-elevation myocardial infarction, femoral access for angiography, creatinine clearance, hypercholesterolemia, and arterial hypertension. Serious bleeding was associated with a significantly increased adjusted hazard ratio of 5.84 (95% confidence interval 4.11 to 8.29) for mortality. However, the hazard ratio did not differ statistically from baseline risk by 40 days after the bleeding event.
The major predictors of serious bleeding were a combination of patient and procedural characteristics and antiplatelet therapies. Although serious bleeding was strongly associated with mortality within the first month of the bleeding event, this association was not significant beyond 40 days.
http://www.clinicaltrial.gov. Unique identifier NCT00097591.
Patients with diabetes mellitus (DM) are at high risk for recurrent cardiovascular events after acute coronary syndromes, in part because of increased platelet reactivity. The Trial to Assess ...Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) showed an overall reduction in ischemic events with more intensive antiplatelet therapy with prasugrel than with clopidogrel but with more bleeding. We compared prasugrel with clopidogrel among subjects with DM in TRITON-TIMI 38.
We classified 13 608 subjects on the basis of preexisting history of DM and further according to insulin use. Prespecified analyses of the primary (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) and key secondary end points, including net clinical benefit (death, nonfatal myocardial infarction, nonfatal stroke, and nonfatal TIMI major bleeding) were compared by use of the log-rank test. We found that 3146 subjects had a preexisting history of DM, including 776 receiving insulin. The primary end point was reduced significantly with prasugrel among subjects without DM (9.2% versus 10.6%; hazard ratio HR, 0.86; P=0.02) and with DM (12.2% versus 17.0%; HR, 0.70; P<0.001, P(interaction)=0.09). A benefit for prasugrel was observed among DM subjects on insulin (14.3% versus 22.2%; HR, 0.63; P=0.009) and those not on insulin (11.5% versus 15.3%; HR, 0.74; P=0.009). Myocardial infarction was reduced with prasugrel by 18% among subjects without DM (7.2% versus 8.7%; HR, 0.82; P=0.006) and by 40% among subjects with DM (8.2% versus 13.2%; HR, 0.60; P<0.001, P(interaction)=0.02). Although TIMI major hemorrhage was increased among subjects without DM on prasugrel (1.6% versus 2.4%; HR, 1.43; P=0.02), the rates were similar among subjects with DM for clopidogrel and prasugrel (2.6% versus 2.5%; HR, 1.06; P=0.81, P(interaction)=0.29). Net clinical benefit with prasugrel was greater for subjects with DM (14.6% versus 19.2%; HR, 0.74; P=0.001) than for subjects without DM (11.5% versus 12.3%; HR, 0.92; P=0.16, P(interaction)=0.05).
Subjects with DM tended to have a greater reduction in ischemic events without an observed increase in TIMI major bleeding and therefore a greater net treatment benefit with prasugrel compared with clopidogrel. These data demonstrate that the more intensive oral antiplatelet therapy provided with prasugrel is of particular benefit to patients with DM.
Vorapaxar reduces cardiovascular death, myocardial infarction (MI), or stroke in patients with previous MI while increasing bleeding. Patients with diabetes mellitus (DM) are at high risk of ...recurrent thrombotic events despite standard therapy and may derive particular benefit from antithrombotic therapies. The Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-TIMI 50 trial was a randomized, double-blind, placebo-controlled trial of vorapaxar in patients with stable atherosclerosis.
We examined the efficacy of vorapaxar in patients with and without DM who qualified for the trial with a previous MI. Because vorapaxar is contraindicated in patients with a history of stroke or transient ischemic attack, the analysis (n=16 896) excluded such patients. The primary end point of cardiovascular death, MI, or stroke occurred more frequently in patients with DM than in patients without DM (rates in placebo group: 14.3% versus 7.6%; adjusted hazard ratio, 1.47; P<0.001). In patients with DM (n=3623), vorapaxar significantly reduced the primary end point (11.4% versus 14.3%; hazard ratio, 0.73 95% confidence interval, 0.60-0.89; P=0.002) with a number needed to treat to avoid 1 major cardiovascular event of 29. The incidence of moderate/severe bleeding was increased with vorapaxar in patients with DM (4.4% versus 2.6%; hazard ratio, 1.60 95% confidence interval, 1.07-2.40). However, net clinical outcome integrating these 2 end points (efficacy and safety) was improved with vorapaxar (hazard ratio, 0.79 95% confidence interval, 0.67-0.93).
In patients with previous MI and DM, the addition of vorapaxar to standard therapy significantly reduced the risk of major vascular events with greater potential for absolute benefit in this group at high risk of recurrent ischemic events.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00526474.
Dual antiplatelet therapy in older versus younger patients with acute coronary syndromes is understudied. Low-dose prasugrel (5 mg/d) is recommended for younger, lower-body-weight patients and ...elderly patients with acute coronary syndromes to mitigate the bleeding risk of standard-dose prasugrel (10 mg/d).
A total of 9326 medically managed patients with acute coronary syndromes from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial (<75 years of age, n=7243; ≥75 years of age, n=2083) were randomized to prasugrel (10 mg/d; 5 mg/d for those ≥75 or <75 years of age and <60 kg in weight) or clopidogrel (75 mg/d) plus aspirin for ≤30 months. A total of 515 participants ≥75 years of age (25% of total elderly population) had serial platelet reactivity unit measurements in a platelet-function substudy. Cumulative risks of the primary end point (cardiovascular death/myocardial infarction/stroke) and Thrombolysis in Myocardial Infarction (TIMI) major bleeding increased progressively with age and were ≥2-fold higher in older participants. Among those ≥75 years of age, TIMI major bleeding (4.1% versus 3.4%; hazard ratio, 1.09; 95% confidence interval, 0.57-2.08) and the primary end point rates were similar with reduced-dose prasugrel and clopidogrel. Despite a correlation between lower 30-day on-treatment platelet reactivity unit values and lower weight only in the prasugrel group, there was a nonsignificant treatment-by-weight interaction for platelet reactivity unit values among participants ≥75 years of age in the platelet-function substudy (P=0.06). No differences in weight were seen in all participants ≥75 years of age with versus without TIMI major/minor bleeding in both treatment groups.
Older age is associated with substantially increased long-term cardiovascular risk and bleeding among patients with medically managed acute coronary syndromes, with no differences in ischemic or bleeding outcomes with reduced-dose prasugrel compared with clopidogrel in elderly patients. No significant interactions among weight, pharmacodynamic response, and bleeding risk were observed between reduced-dose prasugrel and clopidogrel in elderly patients.
URL: http://www.clinicaltrials.gov/ct2/home. Unique identifier: NCT0069999.
Background We examined the prevalence of undiagnosed diabetes or prediabetes and associations with ischemic outcomes among non–ST-segment elevation acute coronary syndrome (ACS) patients. Methods We ...categorized 8795 EARLY ACS trial patients into one of the following groups: “known diabetes” (n = 2860 32.5%; reported on the case report form), “undiagnosed diabetes” (n = 1069 12.2%; no diabetes history and fasting glucose ≥126 mg/dL or hemoglobin A1c ≥6.5%), “prediabetes” (n = 947 10.8%; fasting glucose ≥110 to <126 mg/dL, or “normal” (n = 3919 44.5%). Adjusted associations of known diabetes, undiagnosed diabetes, and prediabetes (versus normal) with 30-day and 1-year outcomes were determined. Results Undiagnosed diabetes was associated with greater 30-day death or myocardial infarction (MI) (ORadj 1.28, 95% CI 1.05-1.57), driven primarily by greater 30-day mortality (ORadj 1.65, 95% CI 1.09-2.48). Known diabetic patients had 30-day death or MI outcomes similar to those of normal patients, but 30-day mortality was higher (ORadj 1.40, 95% CI 1.01-1.93). Prediabetic patients had 30-day death or MI outcomes similar to those of normal patients. One-year mortality was greater among known diabetic patients (HRadj 1.38, 95% CI 1.13-1.67) but not among those with undiagnosed diabetes or prediabetes. Conclusions Undiagnosed diabetes and prediabetes were common among high-risk non–ST-segment elevation ACS patients. Routine screening for undiagnosed diabetes may be useful since these patients seem to have worse short-term outcomes and deserve consideration of alternative management strategies.
THEMIS (The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study) (n = 19,220) and its pre-specified THEMIS-PCI (The Effect of Ticagrelor on Health Outcomes in ...Diabetes Mellitus Patients Intervention Study-Percutaneous Coronary Intervention) (n = 11,154) subanalysis showed, in individuals with type 2 diabetes mellitus (median duration 10.0 years; HbA
7.1%) and stable coronary artery disease without prior myocardial infarction (MI) or stroke, that ticagrelor plus aspirin (compared with placebo plus aspirin) produced a favorable net clinical benefit (composite of all-cause mortality, MI, stroke, fatal bleeding, and intracranial bleeding) if the patients had a previous percutaneous coronary intervention.
In these post hoc analyses, the authors examined whether the primary efficacy outcome (cardiovascular death, MI, stroke: 3-point major adverse cardiovascular events MACE), primary safety outcome (Thrombolysis In Myocardial Infarction-defined major bleeding) and net clinical benefit varied with diabetes-related factors.
Outcomes were analyzed across baseline diabetes duration, HbA
, and antihyperglycemic medications.
In THEMIS, the incidence of 3-point MACE increased with diabetes duration (6.7% for ≤5 years, 11.1% for >20 years) and HbA
(6.4% for ≤6.0%, 11.8% for >10.0%). The relative benefits of ticagrelor plus aspirin on 3-point MACE reduction (hazard ratio HR: 0.90; p = 0.04) were generally consistent across subgroups. Major bleeding event rate (overall: 1.6%) did not vary by diabetes duration or HbA
and was increased similarly by ticagrelor across all subgroups (HR: 2.32; p < 0.001). These findings were mirrored in THEMIS-PCI. The efficacy and safety of ticagrelor plus aspirin did not differ by baseline antihyperglycemic therapy. In THEMIS-PCI, but not THEMIS, ticagrelor generally produced favorable net clinical benefit across diabetes duration, HbA
, and antihyperglycemic medications.
Ticagrelor plus aspirin yielded generally consistent and favorable net clinical benefit across the diabetes-related factors in THEMIS-PCI but not in the overall THEMIS population.
Using data from the ODYSSEY OUTCOMES trial (NCT01663402), we sought to identify factors associated with the development of incident atrial fibrillation in patients with recent acute coronary syndrome ...without prior atrial fibrillation and to determine whether alirocumab treatment influenced risk of incident atrial fibrillation.
ODYSSEY OUTCOMES compared alirocumab treatment with placebo in 18,924 patients with recent acute coronary syndrome and dyslipidemia despite high-intensity or maximum-tolerated statin therapy. The primary outcome of major adverse cardiovascular events (MACE) comprised death from coronary heart disease, non-fatal myocardial infarction, fatal or non-fatal ischemic stroke, or unstable angina requiring hospitalization. Patients were classified as having previous atrial fibrillation (present prior to or at randomization) or no previous atrial fibrillation. A multivariable model was used to determine factors associated with incident atrial fibrillation.
Among 18,262 participants without prior atrial fibrillation at baseline, 499 (2.7%) had incident atrial fibrillation during follow-up. Older age, history of heart failure or myocardial infarction, and higher body mass index were significantly associated with incident atrial fibrillation. Treatment with alirocumab or placebo did not influence the cumulative incidence of atrial fibrillation (hazard ratio 0.91; 95% confidence interval, 0.77-1.09). Patients with vs without a history of atrial fibrillation had a higher incidence of MACE (8.8 vs 3.7 events per 100 patient-years), without significant interaction between atrial fibrillation and randomized treatment on risk of MACE (Pinteraction = .78).
While alirocumab did not modify risk of incident atrial fibrillation after acute coronary syndrome, it did reduce the risk of MACE, regardless of prior atrial fibrillation history. History of atrial fibrillation is an independent predictor of recurrent cardiovascular events after acute coronary syndrome.
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