Strokes and Transient Ischemic Attacks Occurrence During Annual Dual Antiplatelet Therapy.

BACKGROUND: The incidence of stroke/TIA during annual dual antiplatelet therapy (ADAPT) for acute coronary syndrome (ACS) remains high. Some evidence suggests that shorter than ADAPT may diminish such risk, still providing adequate vascular protection. However, the precise timing of strokes/TIA occurrences during ADAPT is unclear but may be important for determining optimal preventive treatment duration. STUDY QUESTION: The precise timing of secondary cerebrovascular events over ADAPT. STUDY DESIGN: Access was gained to the FDA-issued Platelet Inhibition and Outcomes (PLATO) trial data set on which post hoc analyses of stroke/TIA timing after ticagrelor and clopidogrel on top of aspirin was explored. MEASURES AND OUTCOMES: Events were counted and plotted over time from day 1 till day 365 after the index ACS event. RESULTS: Among 18,624 enrollees, 252 strokes and 49 TIAs were reported. After the exclusion of entries with missing dates, unclear randomization codes, and events beyond 1-year follow-up, 238 strokes and 45 TIAs were analyzed. Overall, most frequent strokes/TIAs occurred within the first day after qualifying ACS, with the gradual declines after day 7 and day 40 reaching background counts thereafter. The strokes/TIAs patterns did not differ much between P 2 Y12 inhibitors except for twice more events at day 1 and excess exclusions after day 365 in the ticagrelor arm. CONCLUSIONS: Most cerebrovascular events emerged very early after ACS despite ADAPT. This large hypothesis-generating evidence may justify shorter than the ADAPT duration after ACS. Twice more events at day 1 and excess late ticagrelor exclusions in PLATO deserve further scrutiny. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00391872.

The FDA and PLATO Investigators death lists: Call for a match.

PURPOSE: The FDA-issued PLATO trial dataset revealed that some primary death causes (PDCs) were inaccurately reported favouring ticagrelor. However, the PLATO Investigators operated the shorter death list of uncertain quality. We compared if PDC match when trial fatalities were reported to the FDA and by the PLATO Investigators. METHOD: The FDA list contains precisely detailed 938 PLATO deaths, while shorter investigators dataset consists of 905 deaths. We matched four vascular (sudden, post-MI, heart failure and stroke), and three non-vascular (cancer, sepsis and suicide) PDC between death lists. RESULTS: There were more sudden deaths in the shorter list than in the FDA dataset (161 vs 138; P < .03) and post-AMI (373 vs 178; P < .001) but fewer heart failure deaths (73 vs 109; P = .02). Stroke numbers match well (39 vs 37; P = NS) with only two ticagrelor cases removed. Cancer matched well (32 vs 31; P = NS), and sepsis cases were identical (30 vs 30; P = NS). However, two extra clopidogrel suicides in the shorter list are impossible to comprehend. CONCLUSIONS: The PLATO trial PDCs were mismatched between FDA and investigators sets. We are kindly asking the ticagrelor sponsor or/and concerned PLATO Investigators to clarify the PDC dataset match.

All-Cause Mortality and Cardiovascular Outcomes With Non-Vitamin K Oral Anticoagulants Versus Warfarin in Patients With Heart Failure in the Food and Drug Administration Adverse Event Reporting System.

BACKGROUND: Many patients with heart failure (HF) are treated with warfarin or non-vitamin K oral anticoagulants (NOACs). Randomized outcome-driven comparisons of different anticoagulant strategies in HF are lacking. Data from international, government-mandated registries may be useful in understanding the real-life use of various anticoagulants and how they are linked to outcomes. STUDY QUESTION: To assess 2015 annual all-cause mortality, myocardial infarction, and stroke rates co-reported for warfarin and NOACs in subjects with and without HF in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. STUDY DESIGN: We extracted and examined outcome cases in subjects with HF and on warfarin, dabigatran, rivaroxaban, apixaban, or edoxaban and stratified these according to anticoagulants. MEASURES AND OUTCOMES: Annual all-cause mortality, myocardial infarction, and stroke in FAERS. ANALYSIS METHOD: Odds ratio (OR) and χ(Equation is included in full-text article.)for oral anticoagulants from FAERS with and without HF among complete primary reports issued in 2015. RESULTS: FAERS reported 137,026 HF cases, with death co-reported in 42,942 (31.3%). In total, 11,278 (8.2%) HF patients were treated with anticoagulants, with more prescribed warfarin (n = 8260) than all NOACs combined (n = 3018). Very few reports for edoxaban were available. Warfarin consistently displayed a signal for excess adverse events compared to NOACs: OR (95% confidence interval) for the composite of mortality, myocardial infarction, and stroke were 1.91 (1.76-2.07) versus apixaban, 1.92 (1.81-2.03) versus dabigatran, 4.09 (3.38-4.37) versus rivaroxaban, and 2.64 (2.53-2.76) versus all NOACs combined (all P < 0.001). Warfarin, compared to all NOACs combined, demonstrated higher rates of all-cause mortality [OR = 2.69 (95% confidence interval, 2.49-2.90)], myocardial infarction [5.30 (4.17-6.74)], stroke [OR = 8.85 (6.61-11.84)], and ischemic stroke [OR = 12.73 (8.87-18.27); all P < 0.001]. CONCLUSIONS: Annual 2015 FAERS profiles in HF patients reveal that warfarin was numerically dominant. Warfarin was associated with higher risk of death, myocardial infarction, and stroke compared to NOACs. These observational data provide real-world insight into a potential safety benefit of NOACs over warfarin in the setting of HF.

Body Mass Index and Plasma P-Selectin before Coronary Stenting Predict High Residual Platelet Reactivity at 6 Months on Dual Antiplatelet Therapy.

BACKGROUND: High residual platelet reactivity (HRPR) during dual antiplatelet therapy (DAPT) may impact clinical outcomes following percutaneous coronary interventions (PCI). However, whether any biomarkers assessed before PCI at DAPT loading may predict delayed maintenance HRPR is not clear. OBJECTIVE: The aim of this study was to determine whether conventional clinical or laboratory indices at loading before stenting may predict HRPR at 6 months of maintenance DAPT. METHODS: The study was designed on a single-center prospective cohort, and included 94 pre-PCI patients. All patients underwent elective PCI with drug-eluting stent implantation, and received DAPT with aspirin and clopidogrel. Platelet reactivity was assessed with 5 µmol/L of adenosine diphosphate-induced light transmission aggregometry before PCI, but after 24 h of DAPT loading, and repeated at 6 months. Baseline clinical characteristics, CYP2C19 polymorphism, C-reactive protein, soluble P-selectin, CD40L, interleukin-6, PAI-1 levels, and von Willebrand factor activity were analyzed. RESULTS: The incidence (light transmission aggregometry <50%) of prestent HRPR was 16%. By univariate regression, body mass index (BMI; p = 0.02), total cholesterol (p = 0.01), low-density lipoproteins (p = 0.004), CYP2C19*2 allele carriage (p = 0.006), soluble P-selectin (p = 0.009), and von Willebrand factor (p = 0.04) were linked to future HRPR. However, multivariate regression analysis suggested that only BMI and P-selectin were independent predictors of HRPR. CONCLUSIONS: Platelet reactivity before elective stenting is associated with numerous biomarkers; however, only BMI and soluble P-selectin were independent predictors of future HRPR during maintenance-phase DAPT. This may be important for future tailored antiplatelet strategies in patients with metabolic syndrome and diabetics.

Vorapaxar and Amyotrophic Lateral Sclerosis: Coincidence or Adverse Association?

BACKGROUND: Vorapaxar, a novel antiplatelet thrombin PAR-1 inhibitor, is currently approved for post myocardial infarction and peripheral artery disease indications with concomitant use of clopidogrel and/or aspirin. The vorapaxar safety profile was acceptable. However, aside from heightened bleeding risks, excesses of solid cancers and diplopia, there were more amyotrophic lateral sclerosis (ALS) diagnoses after vorapaxar. STUDY QUESTION: To assess the Food and Drug Administration (FDA) reviews on the potential association of vorapaxar with ALS. STUDY DESIGN: The review the public FDA records on reported adverse events after vorapaxar. MEASURES AND OUTCOMES: Incidence of ALS after vorapaxar and placebo. RESULTS: The ALS risk appears very small, about 1 case per 10,000 treated subjects, but quite probable. Indeed, there were overall 2 placebo and 4 vorapaxar ALS incidences in the Phase III clinical trials. CONCLUSIONS: Potential adverse association of vorapaxar with ALS risks may be related to off-target neuronal PAR receptor(s) blockade beyond platelet inhibition.

Filing Sources after Oral P2Y12 Platelet Inhibitors to the Food and Drug Administration Adverse Event Reporting System (FAERS).

BACKGROUND: The US Food and Drug Administration Adverse Event Reporting System (FAERS) is a global passive surveillance database that relies on voluntary reporting by health care professionals and consumers as well as required mandatory reporting by pharmaceutical manufacturers. However, the initial filers and comparative patterns for oral P2Y12 platelet inhibitor reporting are unknown. We assessed who generated original FAERS reports for clopidogrel, prasugrel, and ticagrelor in 2015. METHODS: From the FAERS database we extracted and examined adverse event cases coreported with oral P2Y12 platelet inhibitors. All adverse event filing originating sources were dichotomized into consumers, lawyers, pharmacists, physicians, other health care professionals, and unknown. RESULTS: Overall, 2015 annual adverse events were more commonly coreported with clopidogrel (n = 13,234) with known source filers (n = 12,818, or 96.9%) than with prasugrel (2,896; 98.9% out of 2,927 cases) or ticagrelor (2,163, or 82.3%, out of 2,627 cases, respectively). Overall, most adverse events were filed by consumers (8,336, or 44.4%), followed by physicians (5,290, or 28.2%), other health care professionals (2,997, or 16.0%), pharmacists (1,125, or 6.0%), and finally by lawyers (129, or 0.7%). The origin of 811 (4.7%) initial reports remains unknown. The adverse event filing sources differ among drugs. While adverse events coreported with clopidogrel and prasugrel were commonly originated by patients (40.4 and 84.3%, respectively), most frequently ticagrelor reports (42.5%) were filed by physicians. CONCLUSION: The reporting quality and initial sources differ among oral P2Y12 platelet inhibitors in FAERS. The ticagrelor surveillance in 2015 was inadequate when compared to clopidogrel and prasugrel. Patients filed most adverse events for clopidogrel and prasugrel, while physicians originated most ticagrelor complaints. These differences justify stricter compliance control for ticagrelor manufacturers and may be attributed to the confusion of treating physicians with unexpected fatal, cardiac, and thrombotic adverse events linked to ticagrelor.

Predicting Successful Recanalization in Patients with Native Coronary Chronic Total Occlusion: The Busan CTO Score.

BACKGROUND: The optimal strategy to manage chronic total occlusion (CTO) remains unclear. The Japanese CTO multicenter registry (J-CTO) score is an established tool for predicting successful recanalization. However, it does not take into account nonangiographic predictors for final technique success. In the present study, we designed and tested a scoring model called the Busan single-center CTO registry (B-CTO) score combining clinical and angiographic characteristics to predict successful CTO recanalization in Korean patients. METHODS: Prospectively enrolled CTO patients (n = 438) undergoing coronary intervention (1999-2015) were assessed. The B-CTO score comprises 6 independent predictors: age 60-74 years and lesion length ≥20 mm were assigned 1 point each, while age ≥75 years, female gender, lesion location in the right coronary artery, blunt stump, and bending >45° were assigned 2 points each. For each predictor, the points assigned were based on the associated odds ratio by multivariate analysis. The lesions were classified into 4 groups according to the summation of points scored to assess the probability of successful CTO recanalization: easy (score 0-1), intermediate (score 2-3), difficult (score 4-5), and very difficult (score ≥6). CTO opening was designated as the primary endpoint regardless of the interventional era or the skill of the operator. RESULTS: The final success rate for B-CTO was 81.1%. The probability of successful recanalization for patient groups classified as easy (n = 64), intermediate (n = 148), difficult (n = 134), and very difficult (n = 92) was 95.3, 86.5, 79.1 and 65.2%, respectively (p for trend <0.001). When compared to the J-CTO, the B-CTO score demonstrated a significant improvement in discrimination as indicated by the area under the receiver-operator characteristic curve (AUC 0.083; 95% CI 0.025-0.141), with a positive integrated discrimination improvement of 0.042 and a net reclassification improvement of 56.0%. CONCLUSIONS: The B-CTO score has been designed and validated in Korean patients with native coronary CTO and is an improved tool for predicting successful recanalization. Wider application of the B-CTO score remains to be explored.

Troponin I and D-Dimer for Discriminating Acute Pulmonary Thromboembolism from Myocardial Infarction.

BACKGROUND: Acute pulmonary thromboembolism (APTE) is a life-threatening condition, often manifesting with chest pain, dyspnea, and increased cardiac biomarkers including cardiac troponin I (CTI) and D-dimer. Therefore, APTE is often misdiagnosed with classical non-ST elevation myocardial infarction (NSTEMI), resulting in unnecessary coronary interventions and a delay of therapy. OBJECTIVES: Our aim was to distinguish APTE from NSTEMI based on CTI and D-dimer levels. METHODS: Complete clinical and laboratory data sets from APTE patients (n = 123) were compared with matched NSTEMI patients (n = 123) who presented with chest pain. The APTE diagnosis was confirmed by chest tomography, angiography, or radionuclide ventilation-perfusion scan, while NSTEMI was established by clinical symptoms, cardiac biomarkers, and coronary angiography. Clinical characteristics, CTI (initial and peak), and D-dimer levels at presentation were retrospectively analyzed. RESULTS: The clinical characteristics were not different between APTE and NSTEMI patients. However, significantly lower initial CTI (0.2 ± 0.5 vs. 4.4 ± 9.5 ng/ml) and peak CTI (0.7 ± 2.7 vs. 17.1 ± 20.4 ng/ml), but higher initial D-dimer (9.8 ± 9.4 vs. 1.6 ± 3.6 ng/ml), distinguished APTE from NSTEMI. By receiver operating characteristic curve analysis, the cutoff values for initial CTI, peak CTI, and D-dimer were 0.25, 0.98, and 3.18 ng/ml, respectively. CONCLUSION: Patients with APTE exhibited lower initial and peak CTI but higher D-dimer levels than NSTEMI patients. Assessing cardiac biomarkers is useful for differentiating APTE from NSTEMI. Further large randomized biomarker studies are urgently needed to facilitate a better APTE diagnosis since clinical characteristics are not particularly helpful.

Incidence and Causes for Early Ticagrelor Discontinuation: A "Real-World" Dutch Registry Experience.

OBJECTIVES: The PLATO trial revealed superiority of ticagrelor over clopidogrel for the prevention of atherothrombotic events in patients with acute coronary syndrome. However, adverse events such as bleeding, dyspnea, and bradycardia were frequently reported, potentially leading to excess early ticagrelor discontinuation (ETD), later confirmed in the PEGASUS trial. We here evaluated the incidence and causes for ETD in a real-world patient cohort in a high-volume nonacademic percutaneous coronary intervention center in the Netherlands. METHODS: In a retrospective single-center registry, all patients discharged from the hospital with a new ticagrelor prescription were screened for ETD. Follow-up data were obtained using the hospital electronic patient file records and confirmed by telephone contact with the patient and/or general practitioner, if necessary, to complement the data. RESULTS: Ticagrelor was prescribed in 354 patients between December 2011 and December 2012. The follow-up data were available in 301 patients with a mean follow-up duration of 330 days. ETD or switching to another antiplatelet agent occurred in 73 patients (24.3%), mostly due to dyspnea (11.6%), bleeding (3.7%), or planned major surgery (2.7%). CONCLUSIONS: Almost one quarter of ticagrelor patients were discontinued prematurely or switched to another antiplatelet agent within 1 year, mostly due to dyspnea or bleeding.

Should the Dose of Antiplatelet Drugs Be Adjusted for Body Weight? The Example of Vorapaxar.

BACKGROUND: In contrast to the vast majority of pharmaceuticals on the market, antiplatelet agents are widely prescribed in a uniform, 'one size fits all' manner, without conventional dose adjustments. However, strong evidence yielded from clinical trials repeatedly suggests that patients with a low body weight (LBW), the elderly and those with renal or hepatic impairment may benefit from reduced doses, while younger, heavier patients, males and diabetics may benefit from a dose escalation. Vorapaxar, a thrombin protease-activated receptor-1 inhibitor, has been tested in the TRA2P and TRACER clinical trials, but its efficacy and safety in patients with a LBW is unclear. OBJECTIVE: To determine the impact of LBW on primary end point rates (PER) and bleeding risk after vorapaxar, as yielded from the TRA2P and TRACER secondary FDA review. RESULTS: The LBW (<60 kg) groups in TRA2P (n = 1,852; 7%) and TRACER (n = 1,046; 8%) were small. However, the PER repeatedly suggested inferiority of vorapaxar over placebo in both the successful TRA2P study (10.6 vs. 8.4%; p = 0.012) and the failed TRACER study (19.3 vs. 18.2%; p = not significant). In TRA2P, the PER monotonically escalated with increasing weight for placebo, while those in the vorapaxar arm formed a flat U- or J-shaped distribution across the weight quintiles. In TRACER, the PER by weight quintile appear much higher, but also more random than in TRA2P. The bleeding rates in TRA2P were higher for the 2 lowest-weight quintiles with both placebo and vorapaxar. In TRACER, bleeding rates were more than doubled when compared to TRA2P, and they varied little by weight quintile, with a slight decrease for the heaviest patients in the placebo population and being the highest in the 2 lowest-weight quintiles after vorapaxar. CONCLUSION: The FDA analyses revealed no definite proof that LBW is associated with reduced efficacy of vorapaxar. While these data are striking, they can be explained by better outcomes in LBW placebo patients already sufficiently treated with dual-antiplatelet therapy. In contrast to efficacy, both TRA2P and TRACER definitely suggest that bleeding rates after vorapaxar are higher in patients with LBW. Dose adjustment for antiplatelet agents may soon become a reality.

Noninvasive Predictors of Malignant Arrhythmias.

BACKGROUND: Prediction and potential prevention of sudden cardiac death (SCD) due to malignant ventricular arrhythmia (MVA) represent an obvious unmet medical need. We estimated the prognostic relevance of numerous biomarkers associated with future MVA development in patients with coronary artery disease (CAD) over 2 years of follow-up. METHODS: Patients with stable documented CAD (n = 97) with a mean age of 61 ± 10 years were prospectively enrolled in a single-center observational cohort study. Heart failure was diagnosed in 68% of the patients (NYHA class II-III). The mean left ventricular ejection fraction (LVEF) was 50 ± 13%, while 20% of patients had LVEF ≤35%. Sixty-two patients underwent myocardial revascularization during the follow-up (mean 25 ± 11 months). Clinical characteristics (age, gender, diabetes, history of coronary disease and arrhythmias, prior interventions and antecedent medications), noninvasive electrophysiological markers [microvolt T-wave alterations, signal-averaged electrocardiography, QT interval duration and alteration, and heart rate turbulence (HRT) and HR variability], laboratory indices [serum creatinine and creatinine clearance, brain natriuretic peptide (BNP), NT-proBNP, and C-reactive protein and troponin T levels] were assessed with regard to the MVA prognosis. RESULTS: MVA was diagnosed in 11 patients during the prospective follow-up. Prior percutaneous coronary intervention (p < 0.05), MVA or syncope (p < 0.05), on-pump coronary artery bypass grafting during follow-up (p < 0.01), LVEF ≤47% (p < 0.01), a left atrium size ≥4.7 cm (p < 0.05), left atrium index (p = 0.01), filtered QRS duration (p < 0.05), abnormal HRT (x03C7;2 = 6.2, p = 0.01) or turbulence slope (x03C7;2 = 9.5, p < 0.01), BNP ≥158 pg/ml (p < 0.01) and NT-proBNP ≥787 pg/ml (x03C7;2 = 4.4, p < 0.05) were significantly associated with MVA risk by univariate analysis. However, only prior MVA or syncope [odds ratio (OR) 11.1; 95% confidence interval (CI) 2.8-44.4; p < 0.01], abnormal HRT (x041E;R 13.6; 95% CI 2.8-66.1; p < 0.01) and plasma BNP (x041E;R 14.3; 95% CI 3.2-65.0; p < 0.01) remained independent predictors of MVA occurrence by multivariate Cox regression analysis. CONCLUSION: Prior syncope or MVA, HRT and elevated plasma BNP were independent MVA predictors, advocating for the prospective screening of high-risk CAD patients for potential SCD awareness.

Asymptomatic Pulmonary Embolism after Ablation.

BACKGROUND: Pulmonary embolism (PE) is a life-threatening event with a broad presentation spectrum ranging from asymptomatic cases to sudden cardiac arrest. It is unclear if right atrial emboli cause PE in patients with atrial fibrillation (AF) or if mild PE itself increases right cardiac pressure provoking AF. OBJECTIVE: To determine the incidence and predictors of asymptomatic PE in patients undergoing AF ablation. METHOD AND RESULTS: Patients (n = 93) were screened and those with previous or current symptomatic PE or venous thromboembolism, pulmonary hypertension, increased right heart pressures detected on echocardiography, a history of stroke, transient ischemic attack, coagulopathy or cancer and inappropriate contrast for the evaluation of pulmonary arterial tree were excluded. The remaining AF patients (n = 71) underwent guided ablation controlled with 3-dimensional, left atrial and pulmonary venous computed tomography. The asymptomatic PE was defined by using the modified Miller score by 2 independent assessors in 6 patients. Univariate logistic regression showed that age (OR: 1.094, 95% CI 1.007-1.188, p = 0.033), diabetes (OR: 12.000, 95% CI 1.902-75.716, p = 0.008), CHA2DS2-VASc score (OR: 2.800, 95% CI 1.304-6.013, p = 0.008), and pulmonary artery diameter (OR: 1.221, 95% CI 1.033-1.444, p = 0.019) were significantly associated with PE. However, multivariate analysis revealed that the CHA2DS2-VASc score (p = 0.047) remained the exclusive significant predictor for asymptomatic PE. CONCLUSION: The incidence of random asymptomatic PE in AF patients is high (>8%). The CHA2DS2-VASc score can predict silent PE. Since patients with a high CHA2DS2-VASc score are already anticoagulated, our results do not change clinical practice but are noteworthy in terms of the cause-effect relationship between AF and PE.

Clopidogrel response variability: impact of genetic polymorphism and platelet biomarkers for predicting adverse outcomes poststenting.

The aim of this study was to triage platelet reactivity and adverse vascular outcomes after dual antiplatelet therapy due to percutaneous coronary intervention (PCI) dependent on CYP2C19*2 and CYP2C19*3 genotypes in patients with coronary artery disease. Fifty-five patients with coronary artery disease were studied serially pre-PCI and post-PCI. Platelet reactivity was assessed by conventional light transmission aggregometry, VerifyNow Analyzer, and thromboelastography with platelet mapping. Genetic testing was performed with allele-specific real-time polymerase chain reaction. Adverse events included vascular death, acute myocardial infarction, repeated PCI, definite stent thrombosis, and angina recurrence. The common genotype (GG) was found in 39 patients, heterozygous polymorphism CYP2C19 (GA) G681A allele was detected in 14 patients, and the rare homozygous polymorphism CYP2C19 (AA) G681A allele was exhibited in 2 patients. There were no CYP2C19*3 (Trp212Ter) carriers among index patients. The platelet reactivity was higher in patients with heterozygous and homozygous carriers compared with GG genotype. The largest differences were observed among GG, GA, and AA genotypes, which correlated with the average values of platelet aggregation (P = 0.02). There was a significant link between adverse events and high platelet reactivity assessed by light transmission aggregometry (P = 0.002). We found a trend between different genotype and VerifyNow readings (P = 0.057); moreover, their cumulative impact on adverse events was significant (P = 0.041). Platelet reactivity is higher in patients with heterozygous and homozygous carriers of CYP2C19*2 versus common genotype and may predict an increased risk of clopidogrel response variability and/or experiencing adverse cardiac events.

The Dual Antiplatelet Therapy Trial after the FDA Update: Noncardiovascular Deaths, Cancer and Optimal Treatment Duration.

BACKGROUND: The landmark Dual Antiplatelet Therapy (DAPT) trial revealed an impressive reduction of stent thrombosis and myocardial infarction after prolonged 30-month DAPT compared to the conventional 12-month regimen. However, aside from the expected extra bleeding risks, more cancers and noncardiovascular deaths (NCVD) were observed in the 30-month DAPT arm. OBJECTIVE: We aimed to comprehend the totality of DAPT trial evidence in the light of the FDA medical review. RESULTS: A significant excess of solid cancers that was picked up after prasugrel treatment in the TRITON trial (Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes) and later observed with vorapaxar treatment in the TRACER trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) has now been confirmed by the FDA DAPT review for 30-month therapy with prasugrel [hazard ratio (HR) 1.3] and clopidogrel (HR 1.2). The latest randomized evidence with antiplatelet agents rejected the drug-specific cancer risks, clearly indicating the class effect. The NCVD risks were elevated after treatment with both thienopyridines, but were more prominent after clopidogrel treatment (HR 1.91) than prasugrel treatment (HR 1.17). About half of the NCVD were considered to be caused by cancers occurring after the 24 months of extended antiplatelet therapy. Impression: The DAPT trial confirmed that long-term antiplatelet therapy is associated with cancer that contributes to NCVD. Based on the full disclosure of cancer data by the DAPT study, it can be reflected that the optimal duration of antiplatelet therapy with thienopyridines should be limited to no more than 2 years. This duration allows the preservation of most vascular benefits while avoiding additional cancers and NCVD. © 2015 S. Karger AG, Basel.

Independent Predictors of Major Adverse Events following Coronary Stenting over 28 Months of Follow-Up.

BACKGROUND: Despite recent advances in stent design and constantly improving protective pharmacological strategies, complications and adverse events following percutaneous coronary interventions (PCI) are still major factors influencing morbidity and mortality. Therefore, predicting secondary vascular occlusions represents an unmet medical need. OBJECTIVE: The aim of our study was to triage clinical and laboratory predictors of major adverse clinical events (MACE) following coronary stenting. METHODS: This was a prospective, case-controlled, single-center study, which included 94 consecutive patients with documented coronary disease who underwent PCI with drug-eluting stent (DES) implantation. All patients received dual antiplatelet therapy with aspirin and clopidogrel. Numerous clinical characteristics and laboratory biomarkers were assessed before stenting and were correlated with poststenting MACE over the mean follow-up of 28 months. MACE included death, nonfatal myocardial infarction, target vessel revascularisation, stroke, stent thrombosis, angina recurrence and instent restenosis. RESULTS: Twenty-three patients experienced MACE. Independent MACE predictors after PCI with DES implantation were antecedent diabetes mellitus (RR = 0.45; 95% CI 0.20-0.97; p = 0.045), prior thrombolytic therapy (RR = 0.42; 95% CI 0.27-0.83; p = 0.039), baseline plasminogen activator inhibitor -1 (PAI-1; p = 0.008) and plasma von Willebrand factor (vWF) activity (p = 0.007). Other clinical characteristics and laboratory indices showed no correlation with MACE. CONCLUSIONS: Background diabetes mellitus, prior thrombolytic therapy, PAI-1 and vWF prestenting activity may be useful for MACE prediction over 28 months of follow-up.

Response to Dual Antiplatelet Therapy Does Not Impact Bleeding Risks in Patients Undergoing Oral Surgery after Acute Coronary Syndromes.

INTRODUCTION: Oral surgery (OS) in patients on antecedent dual antiplatelet therapy (DAPT) may be associated with extra bleeding risks. Monitoring platelet activity in such patients may be beneficial for safety when performing OS. OBJECTIVES: The aim of this study was to assess whether platelet function during DAPT impacted the risk of bleeding following OS in patients with acute coronary syndromes (ACS). PATIENTS AND METHODS: Patients who required OS on top of DAPT with aspirin and clopidogrel (n = 55) for invasively treated ACS were included. The control group (n = 33) consisted of patients who underwent OS with no antiplatelet agent. Platelet aggregation before OS was assessed with a Multiplate® analyzer. Bleeding during OS and at days 1, 3, 7 and 10 after surgery was serially evaluated. RESULTS: All 88 patients completed the study. An incomplete response to aspirin or clopidogrel was observed in 43.6% of the patients. In 11% of the cases, an excessive response to clopidogrel was demonstrated. No excessive bleeding upon OS was exhibited in either group during the entire follow-up. Platelet aggregation values and the use of DAPT did not impact the performance of OS. CONCLUSION: Therapy with clopidogrel and aspirin after ACS does not seem to increase the risk of real-life bleeding following OS, regardless of the platelet activity response to DAPT. © 2015 S. Karger AG, Basel.

Aspirin 'resistance': impact on no-reflow, platelet and inflammatory biomarkers in diabetics after ST-segment elevation myocardial infarction.

BACKGROUND: The no-reflow (NR) phenomenon exists despite percutaneous coronary intervention (PCI), and is especially prevalent in diabetics. The causes(s) of NR are not fully elucidated, but may be associated with impaired residual platelet and inflammatory reactivity during dual-antiplatelet therapy. OBJECTIVE: To assess the relationship between dual-antiplatelet therapy, NR and conventional biomarkers suggestive of platelet and inflammatory response in diabetics following ST-segment elevation myocardial infarction (STEMI) treated with PCI. METHODS: Sixty diabetics with (n = 27) and without NR (n = 33) were prospectively enrolled. All patients were treated with clopidogrel and aspirin. Platelet and inflammatory biomarkers were assessed serially in the peripheral blood and right atrium before and after PCI and then at 24 h, 7 days and 30 days. RESULTS: Arachidonic acid (AA)-induced platelet aggregation and the serum thromboxane B2 level before and after PCI (in the peripheral and right atrium blood) were significantly higher in the NR patients than in those with no NR. AA-induced aggregation >100 (AUC*min) before PCI predicted NR in diabetic patients with 96.2% sensitivity and 38.5% specificity (AUC 0.66; 95% CI 0.52-0.71; p = 0.029). There were no other correlations between NR and platelet reactivity (collagen, adenosine diphosphate, thrombin receptor agonist peptide-induced aggregation, vasodilator-stimulated phosphoprotein platelet reactivity index, soluble P-selectin, soluble CD40 ligand, platelet-derived growth factor AB and the level of platelet-monocyte aggregates) or between NR and inflammatory indices (i.e. high-sensitivity C-reactive protein, interleukin 6 and interleukin 10). CONCLUSION: An inadequate response to aspirin, but not to clopidogrel, may be associated with the occurrence of the NR phenomenon in diabetics with STEMI who have been treated with primary PCI.

Impact of valve surgery on serum osteopontin levels in patients with mitral regurgitation.

OBJECTIVE: Osteopontin (OPN), a sialoprotein present within atherosclerotic lesions, especially in calcified plaques, is linked to the progression of coronary artery disease and heart failure. We assessed the impact of valve surgery on serum OPN and left ventricular (LV) function in patients with mitral regurgitation (MR). METHODS: Thirty-two patients with severe MR scheduled for surgery were included in the study. Echocardiography markers were assessed preoperatively and at 3 months following the surgery and matched with the serum OPN levels. RESULTS: Valve surgery was associated with a reduction of the ejection fraction (EF) from 55.2 ± 6.3 to 48.8 ± 7.1% after surgery, p < 0.001. Following surgery, the OPN level was significantly higher than preoperatively (mean 245, range 36-2,284 ng/ml vs. 76, 6-486 ng/ml, p = 0.007). Preoperative OPN exhibited a slight negative correlation with the EF (r = -0.35, p = 0.04), and a moderate correlation with vena contracta (r = -0.38, p = 0.02). There were no other meaningful correlations between conventional echocardiographic parameters and OPN. CONCLUSION: Following valve surgery due to severe MR, patients exhibited a decrease in EF and an increase in OPN levels. The assessment of preoperative OPN failed to strongly predict probable LV dysfunction.

Effect of aliskiren and valsartan combination versus aliskiren monotherapy on hemostatic biomarkers in hypertensive diabetics: Aliskiren and Valsartan Impact in Diabetics pilot trial.

Valsartan is known to inhibit platelet activity in both in vitro and ex vivo clinical setting, whereas aliskiren in vitro modulates antithrombin-III in plasma. The authors tested how aliskiren and valsartan combination versus aliskiren monotherapy will affect hemostatic biomarkers in mild-to-moderate hypertensive diabetics in the frame of the Aliskiren and Valsartan Impact in Diabetics (AVID) trial. A total of 52 patients with type 2 diabetes and mild-to-moderate hypertension were equally randomized to aliskiren (150-300 mg/d) and valsartan (160 mg/d) versus aliskiren (150-300 mg/d) alone for 4 weeks. A total of 25 biomarkers were serially measured, of which 16 are related to platelet function, 6 to coagulation, and 3 to fibrinolysis. Aliskiren monotherapy has no significant impact on any of the assessed biomarkers. In contrast, valsartan on top of aliskiren provided significant inhibition of ADP-induced platelet aggregation (P=0.032), decreased shear-induced activation measured with PFA-100 analyzer (P=0.041), and diminished expression of GP IIb/IIIa activity (P=0.027) measured by PAC-1 antibody, GP Ib (CD42b, P=0.033), vitronectin receptor (CD51/61, P=0.046), P-selectin (CD62p, P=0.026), lysosome-associated membrane protein (CD107a, P=0.042), and CD40-ligand (CD154, P=0.048). In AVID trial, valsartan in combination with aliskiren mildly but significantly inhibited platelets, confirming previous observations. In contrast, aliskiren monotherapy does not enhance antithrombin activity, suggesting that previous data probably represent a laboratory artifact. Importantly, these randomized data were generated on top of low-dose daily aspirin, supporting extra benefit for combination use of angiotensin receptor blockers and renin inhibitors in high-risk diabetic population.

Fatal sepsis and systemic inflammatory response syndrome after off-label prasugrel: a case report.

Aggressive dual antiplatelet therapy is associated not only with more bleeding, impaired wound healing, and potentially more solid cancer rates but it also causes higher infection risks including sepsis, and systemic inflammatory response syndrome (SIRS). This may be especially true considering the alarming off-label use of prasugrel. A 65-year-old white male patient with a history of myocardial infarction treated with percutaneous coronary intervention and implantation of 2 bare metal stents, was treated with off-label clopidogrel for 4 years, including a double daily dose (150 mg) for the initial 13 months. Still on clopidogrel, the patient was hospitalized with suspected pneumonia. A diagnostic cardiac catheterization revealed a 60%-70% blockage of the mid left anterior descending, but there was no need for coronary intervention. At discharge, clopidogrel 75 mg/d was switched over to off-label prasugrel 10 mg/d on top of aspirin (81 mg/d). On day 3 after prasugrel was given, a football-sized bruise appeared on the patient's lower right abdomen, but computed tomography results were unremarkable. On day 6 after administration of prasugrel, the patient became dizzy, disoriented, confused, experienced difficulty breathing, severe headache, weakness, intensive petechial rash covering the entire body, and breathing difficulty requiring ventilation. Within 24 hours, the patient was unable to correctly identify his age; his eyes were pale in color to almost colorless and when hearing a sound he would turn his entire head toward the sound and he appeared to be blind. His lungs, liver, and kidneys began to show signs of failure over the next 5-9 days. Sixteen days after the administration of the first prasugrel dose, the patient died of sepsis complicated with SIRS. Aggressive off-label use of clopidogrel (double dose for 13 months, and >4 years overall duration), followed by off-label switchover to the highest daily dose (10 mg) prasugrel may trigger sepsis and fatal SIRS. The mechanism responsible for such harmful association is probably indirect, and involves the weakening of platelet-neutrophil-endothelial crosstalk necessary to combat infections, and/or keep inflammation from spreading.