Resistance on the Latest Oral and Intravenous P2Y12 ADP Receptor Blockers in Patients with Acute Coronary Syndromes: Fact or Myth?

Novel P2Y12 ADP receptor blockers (ADPRB) should be preferred in dual-antiplatelet therapy in patients with acute coronary syndrome. Nevertheless, there are still patients who do not respond optimally to novel ADP receptor blocker therapy, and this nonoptimal response (so-called "high on-treatment platelet reactivity" or "resistance") could be connected with increased risk of adverse ischemic events, such as myocardial re-infarction, target lesion failure and stent thrombosis. In addition, several risk factors have been proposed as factors associated with the phenomenon of inadequate response on novel ADPRB. These include obesity, multivessel coronary artery disease, high pre-treatment platelet reactivity and impaired metabolic status for prasugrel, as well as elderly, concomitant therapy with beta-blockers, morphine and platelet count for ticagrelor. There is no literature report describing nonoptimal therapeutic response on cangrelor, and cangrelor therapy seems to be a possible approach for overcoming HTPR on prasugrel and ticagrelor. However, the optimal therapeutic management of "resistance" on novel ADPRB is not clear and this issue requires further research. This narrative review article discusses the phenomenon of high on-treatment platelet reactivity on novel ADPRB, its importance in clinical practice and approaches for its therapeutic overcoming.

A multicentre, prospective, randomised controlled trial to assess the safety and effectiveness of cooling as an adjunctive therapy to percutaneous intervention in patients with acute myocardial infarction: the COOL AMI EU Pivotal Trial.

BACKGROUND: Despite primary PCI (PPCI), ST-elevation myocardial infarction (STEMI) can still result in large infarct size (IS). New technology with rapid intravascular cooling showed positive signals for reduction in IS in anterior STEMI. AIMS: We investigated the effectiveness and safety of rapid systemic intravascular hypothermia as an adjunct to PPCI in conscious patients, with anterior STEMI, without cardiac arrest. METHODS: Hypothermia was induced using the ZOLL® Proteus™ intravascular cooling system. After randomisation of 111 patients, 58 to hypothermia and 53 to control groups, the study was prematurely discontinued by the sponsor due to inconsistent patient logistics between the groups resulting in significantly longer total ischaemic delay in the hypothermia group (232 vs 188 minutes; p<0.001). RESULTS: There were no differences in angiographic features and PPCI result between the groups. Intravascular temperature at wire crossing was 33.3+0.9°C. Infarct size/left ventricular (IS/LV) mass by cardiac magnetic resonance (CMR) at day 4-6 was 21.3% in the hypothermia group and 20.0% in the control group (p=0.540). Major adverse cardiac events at 30 days increased non-significantly in the hypothermia group (8.6% vs 1.9%; p=0.117) while cardiogenic shock (10.3% vs 0%; p=0.028) and paroxysmal atrial fibrillation (43.1% vs 3.8%; p<0.001) were significantly more frequent in the hypothermia group. CONCLUSIONS: The ZOLL Proteus intravascular cooling system reduced temperature to 33.3°C before PPCI in patients with anterior STEMI. Due to inconsistent patient logistics between the groups, this hypothermia protocol resulted in a longer ischaemic delay, did not reduce IS/LV mass and was associated with increased adverse events.

Association of polymorphisms of platelet receptors GPIa (807C>T), GPVI (13254T>C), and P2Y12 (34C>T and H1/H2 haplotype) with increased risk of periprocedural bleeding in patients undergoing coronary angiography/percutaneous coronary intervention.

INTRODUCTION: Periprocedural bleeding related to coronary angiography (CAG) or percutaneous coronary intervention (PCI) is associated with worse prognosis. Determining genetic variations associated with increased bleeding risk may help to identify high-risk patients. AIM: To analyse the association between single nucleotide polymorphisms (SNPs) of crucial haemostatic platelet receptors (GPIa, GPVI, P2Y12) and the risk of periprocedural bleeding complications related to CAG/PCI. MATERIAL AND METHODS: The population consisted of 73 patients with ischaemic heart disease who developed bleeding complications within 30 days after CAG/PCI and 331 patients without bleeding. The frequency of SNPs of GPIa 807C/T, GPVI 13254T/C, P2Y12 32C/T, and P2Y12 H1/H2 haplotype was analysed using polymerase chain reaction (PCR) hybridization methods. RESULTS: The prevalence of variant alleles GPIa 807T, GPVI 13254C, P2Y12 34T, and P2Y12 H2 haplotype in the total study population was 56.7%, 20.3%, 56.2%, and 24.3%, respectively. The presence of variant alleles was not related to increased risk of periprocedural bleeding: GPIa 807C/T (OR = 1.29, 95% CI: 0.75-2.24, p = 0.334), GPVI 12354T/C (OR = 0.82, 95% CI: 0.40-1.64, p = 0.551), P2Y12 34C/T (OR = 0.71, 95% CI: 0.42-1.22, p = 0.189), P2Y12 H1/H2 haplotype (OR = 0.69, 95% CI: 0.35-1.36, p = 0.258). The frequency of the homozygous form of P2Y12 H2 haplotype was higher in the group of patients who developed bleeding (OR = 2.79, 95% CI: 0.51-13.77, p = 0.161). CONCLUSIONS: No significant association of the SNPs of GPIa 807C/T, GPVI 13254T/C, P2Y12 32C/T, and P2Y12 H1/H2 haplotype with increased risk of periprocedural bleeding was found in patients with ischaemic heart disease undergoing CAG/PCI.

Detection of occult paroxysmal atrial fibrilation by implantable long-term electrocardiographic monitoring in cryptogenic stroke and transient ischemic attack population: a study protocol for prospective matched cohort study.

BACKGROUND: Cardio-embolic etiology is the most frequently predicted cause of cryptogenic stroke/TIA. Detection of occult paroxysmal atrial fibrillation is crucial for selection of appropriate medication. METHODS: Enrolment of eligible cryptogenic stroke and TIA patients began in 2014 and will continue until 2018. The patients undergo long-term (12 months) ECG monitoring (implantable loop recorder) and testing for PITX2 (chromosome 4q25) and ZFHX3 (chromosome 16q22) gene mutations. There will be an appropriate control group of age- and sex-matched healthy volunteers. To analyse the results descriptive statistics, statistical tests for group differences, and correlation analyses will be used. DISCUSSION: In our study we are focusing on a possible correlation between detection of atrial fibrillation by an implantable ECG recorder, and PITX2 and/or ZFHX3 gene mutations in cryptogenic stroke/TIA patients. A correlation could lead to implementation of this genomic approach to cryptogenic stroke/TIA diagnostics and management. The results will be published in 2018. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02216370 .

Number of severe bleeding complications according to classification used: Is unified classification of bleeding complications really necessary?

BACKGROUND: To compare the number of severe periprocedural bleeding complications from the total number of bleeding complications associated with diagnostic selective coronary angiography or percutaneous coronary intervention (PCI) when using different classifications (TIMI, GUSTO, PLATO, BARC) and to relate these classifications to real hemodynamic status of evaluated patients. METHODS: We analyzed data from 106 patients who underwent invasive procedure for ischemic heart disease (selective coronary angiography/PCI) and suffered from any type of bleeding complication. RESULTS: The number of bleeding according to impacts on hemodynamic status and consequent treatment shows that 54.7% of all bleedings did not need any specific therapy. Bleeding leading to death, hemorrhagic shock, hemodynamic instability, administration of blood transfusion, surgical procedure and local treatment occurred in 6.6%, 1.9%, 5.7%, 14.2%, 2.8%, and 14.2%, respectively. The results comparing bleeding classifications demonstrate that the rate of severe bleeding complications may increase up to 4 times when different classifications are used on the same group of patients (TIMI 9.4%, GUSTO 15.1%, PLATO 39.2% and BARC 35.9%). The power of association between severe bleeding determined by these classifications and real hemodynamic compromise using Kendall's tau-c correlation is -0.4106 (95% CI -0.599 to -0.222), -0.5355 (95% CI -0.718 to -0.353), -0.5513 (95% CI -0.729 to -0.374) and -0.7552 (95% CI -0.897 to -0.612) for TIMI, GUSTO, PLATO and BARC, respectively. CONCLUSIONS: The data show significant dependence of percentage of severe periprocedural bleeding complications on selected classification. The strongest association between severe bleeding and real hemodynamic status was found for BARC classification as this classification seems to be promising for future general use.

Fluvastatin in the first-line therapy of acute coronary syndrome: results of the multicenter, randomized, double-blind, placebo-controlled trial (the FACS-trial).

BACKGROUND: Statins have been proved to be effective in reduction of mortality and morbidity when started in the early secondary prevention in stabilized patients after acute coronary syndrome (ACS). The safety and efficacy of statin administration directly in the first-line therapy in unstable ACS patients is not clear. The aim of our study was, therefore, to assess the effect of statin treatment initiated immediately at hospital admission of patients with ACS. METHODS: The trial was stopped prematurely after enrollment of one hundred and fifty-six patients with ACS that were randomized at admission to fluvastatin 80 mg (N = 78) or placebo (N = 78). Study medication was administered immediately after randomization and then once daily for 30 days; all patients were then encouraged to continue in open-label statin therapy and at the end of one-year follow-up 75% in the fluvastatin group and 78% in the placebo group were on statin therapy. RESULTS: We did not demonstrate any difference between groups in the level of C-reactive protein, interleukin 6, and pregnancy-associated plasma protein A on Day 2 and Day 30 (primary endpoint). Fluvastatin-therapy, however, significantly reduced one-year occurrence of major adverse cardiovascular events (11.5% vs. 24.4%, odds ratio (OR) 0.40, 95% CI 0.17-0.95, P = 0.038). This difference was caused mainly by reduction of recurrent symptomatic ischemia (7.7% vs. 20.5%, OR 0.32, 95% CI 0.12-0.88, P = 0.037). CONCLUSIONS: This study failed to prove the effect of fluvastatin given as first-line therapy of ACS on serum markers of inflammation and plaque instability. Fluvastatin therapy was, however, safe and it may reduce cardiovascular event rate that supports immediate use of a statin in patients admitted for ACS. TRIAL REGISTRATION: NCT00171275.

Thirty-day outcomes of direct carotid artery stenting with cerebral protection in high-risk patients.

BACKGROUND: Implantation of a carotid artery stent after predilation is a standard approach in the endovascular treatment of carotid artery stenoses. Stenting without predilation may be an alternative approach in a certain subset of patients. The present prospective, single-center registry was designed to evaluate the feasibility and safety of direct carotid artery stenting (DCAS) in high-risk patients. METHODS AND RESULTS: Symptomatic patients with stenosis >50% and asymptomatic patients with stenosis >70% were eligible for enrolment. Criteria for high-risk patients included: need or history of open heart surgery, history of myocardial infarction, multivessel coronary artery disease, left ventricular dysfunction (ejection fraction < or =40%), severe pulmonary or renal disease, significant contralateral carotid disease, previous endarterectomy, and age > or =80 years. All procedures were performed using a filter protection device. Patients underwent complete clinical examination before and after DCAS and at 30-day follow-up. A total of 83 consecutive patients (45 males, 68+/-9 years, 33% symptomatic) underwent 100 procedures and 103 stents were deployed successfully. The technical success rate of stenting was 100%. Predilation of carotid stenosis was necessary in 1 (1%) procedure. Carotid-artery stenoses before and after DCAS were 80+/-9% and 7+/-9%, respectively. The median fluoroscopic time for DCAS was 7 min. The overall rate of in-hospital major adverse cerebrovascular events (death, stroke, myocardial infarction) was 5% (2 minor strokes, 3 transient attacks). There was 1 (1%) minor stroke within the 30-day follow-up. CONCLUSION: DCAS is feasible and can be performed with an acceptable risk in high-risk patients.

Immediate effect of fluvastatin on lipid levels in acute coronary syndrome.

It is widely assumed that acute benefit of statin therapy is mediated especially by non-lipid effects. The immediate influence of statins on lipid levels in patients with acute coronary syndrome (ACS) is, however, not clear. A total of 64 consecutive patients with ACS were randomized at admission to fluvastatin 80 mg (Group 1, N = 32) or standard therapy without statin (Group 2, N = 32). The levels of total cholesterol (TC), low-density-lipoprotein cholesterol (LDL-C), high-density-lipoprotein cholesterol (HDL-C), and triglycerides (TG) were examined at admission and after 24 h. Baseline characteristics were comparable in both groups. In Group 1, fluvastatin significantly decreased the levels of TC by 14.5%, LDL-C by 17.2%, and HDL-C by 10.0% (P < 0.001); TG were not influenced. In Group 2 only marginal reductions in TC (by 4.1%, P = 0.03) and HDL-C (by 7.5%, P < 0.01) were detected; the levels of LDL-C and TG were not changed. As compared with Group 2, in Group 1 the final levels of TC (P = 0.02) and LDL-C (P = 0.01) were significantly lower. Fluvastatin therapy, when started at admission in patients with ACS, significantly reduces TC and LDL-C already after 24 h. We suggest that the lipid-lowering effect of statins in the therapy of ACS is probably as prompt as non-lipid effects.

Fluvastatin in the therapy of acute coronary syndrome: Rationale and design of a multicenter, randomized, double-blind, placebo-controlled trial (The FACS Trial)[ISRCTN81331696].

BACKGROUND: Activation of inflammatory pathways plays an important contributory role in coronary plaque instability and subsequent rupture, which can lead to the development of acute coronary syndrome (ACS). Elevated levels of serum inflammatory markers such as C-reactive protein (CRP) represent independent risk factors for further cardiovascular events. Recent evidence indicates that in addition to lowering cholesterol levels, statins also decrease levels of inflammatory markers. Previous controlled clinical trials reporting the positive effects of statins in participants with ACS were designed for very early secondary prevention. To our knowledge, no controlled trials have evaluated the potential benefits of statin therapy, beginning immediately at the time of hospital admission. A previous pilot study performed by our group focused on early initiation of cerivastatin therapy. We demonstrated a highly significant reduction in levels of inflammatory markers (CRP and interleukin-6). Based on these preliminary findings, we are conducting a clinical trial to evaluate the efficacy of another statin, fluvastatin, as an early intervention in patients with ACS. METHODS: The FACS-trial (Fluvastatin in the therapy of Acute Coronary Syndrome) is a multicenter, randomized, double-blind, placebo-controlled study evaluating the effects of fluvastatin therapy initiated at the time of hospital admission. The study will enroll 1,000 participants admitted to hospital for ACS (both with and without ST elevation). The primary endpoint for the study is the influence of fluvastatin therapy on levels of inflammatory markers (CRP and interleukin-6) and on pregnancy associated plasma protein A (PAPP-A). A combined secondary endpoint is 30-day and one-year occurrence of death, nonfatal myocardial infarction, recurrent symptomatic ischemia, urgent revascularization, and cardiac arrest. CONCLUSION: The primary objective of the FACS trial is to demonstrate that statin therapy, when started immediately after hospital admission for ACS, results in reduction of inflammation and improvement of prognosis. This study may contribute to new knowledge regarding therapeutic strategies for patients suffering from ACS and may offer additional clinical indications for the use of statins.