Bleeding Risk Scores and Scales of Frailty for the Prediction of Haemorrhagic Events in Older Adults with Acute Coronary Syndrome: Insights from the FRASER study.

PURPOSE: Hitherto, no study has yielded important information on whether the scales of frailty may improve the ability to discriminate the risk of haemorrhages in older adults admitted to hospital for acute coronary syndrome (ACS). The aim of this study is to investigate whether frailty scales would predict the 1-year occurrence of haemorrhagic events and if they confer a significant incremental prognostic value over the bleeding risk scores. METHODS: The present study involved 346 ACS patients aged ≥ 70 years enrolled in the FRASER study. Seven different scales of frailty and PARIS, PRECISE-DAPT and BleeMACS bleeding risk scores were available for each patient. The outcomes were the 1-year BARC 3-5 and 2 bleeding events. RESULTS: Adherence to antiplatelet treatment at 1, 6 and 12 months was 98%, 87% and 78%, respectively. At 1-year, 14 (4%) and 30 (9%) patients presented BARC 3-5 and 2 bleedings, respectively. Bleeding risk scores and four scales of frailty (namely Short Physical Performance Battery, Columbia, Edmonton and Clinical Frailty Scale) significantly discriminated the occurrence of BARC 3-5 events. The addition of the scales of frailty to bleeding risk scores did not lead to a significant improvement in the ability to predict BARC 3-5 bleedings. Neither the bleeding risk scores nor the scales of frailty predicted BARC 2 bleedings. CONCLUSIONS: Both the bleeding risk scores and the scales of frailty predicted BARC 3-5 haemorrhages. However, integrating the scales of frailty with the bleeding risk scores did not improve their discriminative ability. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov: NCT02386124.

Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial.

BACKGROUND: The optimal duration of dual-antiplatelet therapy and the risk-benefit ratio for long-term dual-antiplatelet therapy after coronary stenting remain poorly defined. We evaluated the impact of up to 6 versus 24 months of dual-antiplatelet therapy in a broad all-comers patient population receiving a balanced proportion of Food and Drug Administration-approved drug-eluting or bare-metal stents. METHODS AND RESULTS: We randomly assigned 2013 patients to receive bare-metal, zotarolimus-eluting, paclitaxel-eluting, or everolimus-eluting stent implantation. At 30 days, patients in each stent group were randomly allocated to receive up to 6 or 24 months of clopidogrel therapy in addition to aspirin. The primary end point was a composite of death of any cause, myocardial infarction, or cerebrovascular accident. The cumulative risk of the primary outcome at 2 years was 10.1% with 24-month dual-antiplatelet therapy compared with 10.0% with 6-month dual-antiplatelet therapy (hazard ratio, 0.98; 95% confidence interval, 0.74-1.29; P=0.91). The individual risks of death, myocardial infarction, cerebrovascular accident, or stent thrombosis did not differ between the study groups; however, there was a consistently greater risk of hemorrhage in the 24-month clopidogrel group according to all prespecified bleeding definitions, including the recently proposed Bleeding Academic Research Consortium classification. CONCLUSIONS: A regimen of 24 months of clopidogrel therapy in patients who had received a balanced mixture of drug-eluting or bare-metal stents was not significantly more effective than a 6-month clopidogrel regimen in reducing the composite of death due to any cause, myocardial infarction, or cerebrovascular accident. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00611286.

Antiplatelet and antithrombotic treatment after primary percutaneous coronary intervention: balancing safety and efficacy.

Antiplatelet therapy has been shown to significantly reduce the risk of serious vascular events in high-risk patients, including those with a prior acute ischemic event. The long-term use of antiplatelet agents is a key component of secondary prevention measures following acute coronary syndromes, including ST-segment elevation myocardial infarction. While minimizing ischemic recurrences, an intensified antiplatelet regimen also invariably leads to an increased risk for bleeding, which can in turn lead to treatment discontinuation and worse overall cardiovascular outcomes. Thus, a critical balance between efficacy and safety must be pursued in clinical practice. Selection of agents and their combination, dose optimization, and a customized approach based on genotype or assessment of on-treatment phenotype are discussed in the context of available evidence.

Randomized comparison of 6- versus 24-month clopidogrel therapy after balancing anti-intimal hyperplasia stent potency in all-comer patients undergoing percutaneous coronary intervention Design and rationale for the PROlonging Dual-antiplatelet treatment after Grading stent-induced Intimal hyperplasia study (PRODIGY).

BACKGROUND: The optimal duration of clopidogrel therapy after coronary stenting is debated because of the scarcity of randomized controlled trials and inconsistencies arising from registry data. Although prolonged clopidogrel therapy after bare metal stenting is regarded as an effective secondary prevention measure, the safety profile of drug-eluting stents itself has been questioned in patients not receiving ≥ 12 months of dual-antiplatelet therapy. HYPOTHESIS: Twenty-four months of clopidogrel therapy after coronary stenting reduces the composite of death, myocardial infarction, or stroke compared with 6 months of treatment. STUDY DESIGN: PRODIGY is an unblinded, multicenter, 4-by-2 randomized trial. All-comer patients with indication to coronary stenting are randomly treated-balancing randomization-with bare metal stent (no active late loss inhibition), Endeavor Sprint zotarolimus-eluting stent (Medtronic, Santa Rosa, CA) (mild late loss inhibition), Taxus paclitaxel-eluting stent (Boston Scientific, Natick, MA) (moderate late loss inhibition), or Xience V everolimus-eluting stent (Abbott Vascular, Santa Clara, CA) (high late loss inhibition). At 30 days, patients in each stent group are randomly allocated to receive 24 or up to 6 months of clopidogrel therapy-primary end point randomization. With 1,700 individuals, this study will have >80% power to detect a 40% difference in the primary end point after sample size augmentation of 5% and a background event rate of 8%. SUMMARY: The PRODIGY trial aims to assess whether 24 months of clopidogrel therapy improves cardiovascular outcomes after coronary intervention in a broad all-comer patient population receiving a balanced mixture of stents with various anti-intimal hyperplasia potency.

The Assessment of Scales of Frailty and Physical Performance Improves Prediction of Major Adverse Cardiac Events in Older Adults with Acute Coronary Syndrome.

BACKGROUND: The number of older adults admitted to hospital for acute coronary syndrome (ACS) has increased worldwide. The aim of this study was to determine which scale of frailty or physical performance provides incremental improvements in risk stratification of older adults after ACS. METHODS: A prospective cohort of 402 older (≥70 years) ACS patients were enrolled. Data about baseline characteristics, Global Registry of Acute Coronary Events (GRACE), and Thrombolysis in Myocardial Infarction (TIMI) risk scores were collected. Before hospital discharge, seven scales of frailty and physical performance were measured. The 1-year occurrence of adverse events (cardiac death, reinfarction, and cerebrovascular accident [MACCE] and all-cause mortality) was recorded. RESULTS: Out of the 402 patients, 43 (10.5%) had a MACCE and 35 (8.7%) died. Following adjustment for confounding factors, scales of frailty and physical performance were associated with adverse events. Among the scales, the addition of short physical performance battery (SPPB) produced the highest incremental value over the initial model generated by baseline characteristics both for MACCE (ΔC-statistic 0.043, p = .04; integrated discrimination improvement (IDI) 0.054, p = .001; net reclassification improvement (NRI) 0.752, p < .001) and all-cause mortality (ΔC-statistic 0.063, p = .02; IDI 0.061, p < .001; NRI 1.022, p < .001). The addition of SPPB scale on top of GRACE or TIMI risk scores led to a considerable improvement in the prediction of MACCE and all-cause mortality (about 15% and 20%, respectively). CONCLUSIONS: The assessment of the physical performance with SPPB scale before hospital discharge increases the ability to predict adverse events in older ACS patients and may be useful in the clinical decision-making process. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov NCT02386124.

Relation of QRS Duration to Response to Cardiac Resynchronization Therapy in Patients With Left Bundle Branch Block.

Left ventricular (LV) dyssynchrony (LVdys) is a necessary condition for successful cardiac resynchronization therapy (CRT). Despite left bundle branch block (LBBB) representing a reliable surrogate of LVdys, not all LBBB patients will respond to CRT. Our aim was to investigate the relation between QRS duration and LVdys in patients with LBBB who underwent CRT. We retrospectively studied 165 patients with LBBB who underwent CRT implantation according to the current guidelines. A 6-month reduction of LV end-systolic volume ≥15% identified responders to CRT. Baseline LVdys was defined as the delay between peak systolic velocities of the interventricular septum and lateral wall assessed by color-coded tissue Doppler imaging. Baseline characteristics of responders (61%) and nonresponders (39%) were comparable except for larger QRS complex (172 ± 24 vs 160 ± 16 ms, p <0.001) and lower degree of LVdys (46 ± 42 vs 72 ± 31 ms, p <0.001) in nonresponders. Receiver-operating characteristic curve analysis demonstrated that an optimal cut-off value of 3 for the ratio of QRS duration and LVdys (QRS/LVdys) yielded a sensitivity of 66% and specificity of 80% to predict nonresponsiveness to CRT; QRS/LVdys >3 remained an independent predictor at multivariate analysis. In patients with nonischemic origin of cardiomyopathy, the linear regression analysis documented a significant inverse relation between QRS duration and LVdys, as dyssynchrony progressively decreased as QRS widening increased (p = 0.006). This was not evident in patients with ischemic origin. In conclusion, in LBBB patients with nonischemic origin and marked QRS widening, the absence of LVdys may account for a lower response to CRT compared with patients with intermediate QRS widening.

Two-year outcomes after first- or second-generation drug-eluting or bare-metal stent implantation in all-comer patients undergoing percutaneous coronary intervention: a pre-specified analysis from the PRODIGY study (PROlonging Dual Antiplatelet Treatment After Grading stent-induced Intimal hyperplasia studY).

OBJECTIVES: This study sought to assess device-specific outcomes after implantation of bare-metal stents (BMS), zotarolimus-eluting Endeavor Sprint stents (ZES-S), paclitaxel-eluting stents (PES), or everolimus-eluting stents (EES) (Medtronic Cardiovascular, Santa Rosa, California) in all-comer patients undergoing percutaneous coronary intervention. BACKGROUND: Few studies have directly compared second-generation drug-eluting stents with each other or with BMS. METHODS: We randomized 2,013 patients to BMS, ZES-S, PES, or EES implantation. At 30 days, each stent group received up to 6 or 24 months of clopidogrel therapy. The key efficacy endpoint was the 2-year major adverse cardiac event (MACE) including any death, myocardial infarction, or target vessel revascularization, whereas the cumulative rate of definite or probable stent thrombosis (ST) was the key safety endpoint. RESULTS: Clinical follow-up at 2 years was complete for 99.7% of patients. The MACE rate was lowest in EES (19.2%; 95% confidence interval [CI]: 16.0 to 22.8), highest in BMS (32.1%; 95% CI: 28.1 to 36.3), and intermediate in PES (26.2%; 95% CI: 22.5 to 30.2) and ZES-S (27.8%; 95% CI: 24.1 to 31.9) groups (chi-square test = 18.9, p = 0.00029). The 2-year incidence of ST in the EES group (1%; 95% CI: 0.4 to 2.2) was similar to that in the ZES-S group (1.4%; 95% CI: 0.7 to 2.8), whereas it was lower compared with the PES (4.6%, 95% CI: 3.1 to 6.8) and BMS (3.6%; 95% CI: 2.4 to 5.6) groups (chi-square = 16.9; p = 0.0001). CONCLUSIONS: Our study shows that cumulative MACE rate, encompassing both safety and efficacy endpoints, was lowest for EES, highest for BMS, and intermediate for PES and ZES-S groups. EES outperformed BMS also with respect to the safety endpoints with regard to definite or probable and definite, probable, or possible ST. (PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY [PRODIGY]; NCT00611286).

Triple antiplatelet therapy in acute coronary syndromes.

Heightened platelet activity plays a critical role in thrombus formation, which is central to acute coronary syndromes (ACS), including non-ST-segment elevation (NSTE)-ACS (comprising unstable angina pectoris and non-ST-segment elevation myocardial infarction [NSTEMI]) and ST-segment elevation myocardial infarction (STEMI), and has been implicated in poor clinical outcome. Platelets not only impact coronary thrombus but are major contributors to microcirculatory dysfunction and vascular inflammation. Efforts to inhibit platelet function, including antiplatelet therapy, are paramount to the management of ACS; thus, a growing recognition of the various pathways driving platelet activity has given rise to the need for multiple agents that impart complimentary mechanisms of action. While only inhibiting platelet activation will still allow for aggregation, i.e. the binding of glycoprotein (GP) IIb/IIIa receptors to fibrinogen, solely blocking aggregation may leave platelet-activating pathways free to sustain the production and release of various pro-inflammatory and pro-thrombotic compounds. The benefit of 'triple antiplatelet therapy', referring to the combination of aspirin, a thienopyridine or non-thienopyridine adenosine diphosphate (ADP)/P2Y12 receptor blocker and a GPIIb/IIIa inhibitor (GPI), has been demonstrated in patients with NSTE-ACS who ultimately undergo percutaneous coronary intervention (PCI) and are determined to be at an elevated risk for ischaemic events, and in patients undergoing primary PCI. It is therefore recommended by the European Society of Cardiology (ESC) and American College of Cardiology/American Heart Association. Furthermore, the rationale for adding a GPI, particularly in patients with STEMI, is backed by studies that have shown negligible effects of a 600 mg clopidogrel loading dose, despite being administered 4 hours prior to PCI. Moreover, it has been observed that the physiological state of STEMI may deem dual antiplatelet therapy ineffective, because during an acute event the absorption of clopidogrel may be impaired. Nonetheless, there is still considerable variability with respect to the use of triple antiplatelet therapy such as that documented in the Euro Heart Survey. The perception that the mortality benefit afforded by adding a GPI to dual oral antiplatelet therapy does not outweigh the risk is a likely factor. This may be fuelled by results of trials such as BRAVE-3, which, inconsistent with those for On-TIME 2, failed to prove the value of adding a GPI to dual oral antiplatelet therapy in patients with STEMI. Subsequent analyses have indeed demonstrated the positive benefit-risk ratio associated with adding a GPI and determined that the timing of GPI administration could have an impact on clinical outcome related to its impact on infarct size in patients with STEMI. Additionally, it has been presumed that a synergistic effect exists between P2Y12 inhibitors and GPIs. Triple antiplatelet therapy has a significant role to play in the management of patients with ACS managed with PCI. An understanding of patient risk status and timing of symptoms and bleeding risk is crucial to patient selection and ensuring that this therapy is optimized. Though no interaction has been noted in trials of newer, more potent antiplatelet agents, future studies are key to determining the role of this strategy in the era of these more potent agents.