Angiographically visible coronary artery collateral circulation improves prognosis in patients presenting with acute ST segment-elevation myocardial infarction.

BACKGROUND: Coronary collaterals are often seen supplying retrograde flow to an acutely occluded arterial territory. Whether this early collateralization offers prognostic benefit is not well established. METHODS: We analyzed data from all patients presenting to our regional cardiac unit with acute ST-elevation myocardial infarction requiring immediate angiography (years 1999-2017). Data on all patients is entered prospectively into a bespoke tailored database prior to knowledge of patient outcome. Only patients with TIMI 0 or 1 flow in the infarct-related vessel were included in the analysis. In-hospital and long-term outcome were assessed according to the presence or absence of angiographically visible collateral flow prior to treatment of the occluded vessel. RESULTS: Two thousand five hundred and forty-two patients were included in the analysis. 76% of these (n = 1944) had TIMI 0/1 flow at angiography. Angiographically-visible collateralization was seen in 17% (n = 322) and was more commonly observed in the right coronary artery (64%) than in the left anterior descending (25%) or Cx (6%). Cardiogenic shock (10.8%) and use of an intra-aortic balloon pump (5.4%) were more frequent in patients without coronary collateralisation (p = .04 and p = .02, respectively). The presence of collaterals improved long term survival (95% CI 11.4-18.7 months; p < .01). CONCLUSION: One-sixth of patients with STEMI have angiographically visible collaterals to the infarcted territory. Patients without collaterals are more likely to present in cardiogenic shock. The presence of angiographically visible collaterals at the time of STEMI is associated with an improved long-term survival.

Stent Thrombosis Patients with Hyporesponsiveness to Clopidogrel, Prasugrel, and Ticagrelor: A Case Series Using Short Thromboelastography.

Patients after percutaneous coronary intervention (PCI) with stent implantation and functional hyporesponsiveness to P2Y12 inhibitors are at higher risk of ischaemic events, particularly stent thrombosis (ST). It is currently not routine practice to assess the functional response to these agents. However, concern over functional hyporesponsiveness to clopidogrel has led to widespread uptake of prasugrel and ticagrelor as the default P2Y12 inhibitor after stent implantation in patients with acute coronary syndrome. Here we report, for the first time, 3 cases in which patients who have had ST exhibit hyporesponsiveness to clopidogrel, prasugrel, and ticagrelor.

Does the VerifyNow P2Y12 assay overestimate "therapeutic response" to clopidogrel? Insights using short thrombelastography.

In contrast to short thrombelastography (s-TEG) which utilises adenosine diphosphate (ADP) alone, the VerifyNow P2Y12 assay (VN-P2Y12) additionally uses prostaglandin E1 (PGE1) as agonist to assess response to P2Y12 inhibitors. Based upon previous observations, we hypothesised that VN-P2Y12 overestimates the therapeutic effects of clopidogrel. Simultaneous assay with s-TEG and VN-P2Y12 was performed in 43 healthy volunteers and 170 patients either on or off clopidogrel. Furthermore, in 27 patients on clopidogrel 75 mg we compared the effects of adding 22 nM PGE1 to ADP on platelet aggregation in s-TEG to ADP alone. A higher proportion of individuals had a result indicating high platelet reactivity (HPR) with s-TEG than VN-P2Y12 in (i) 43 clopidogrel naïve volunteers (95.3% vs 81.4%, p = NS); (ii) 28 volunteers loaded with clopidogrel 600 mg (39.3% vs 10.7 %, p = < 0.01); (iii) 123 clopidogrel naïve patients (93.5% vs 78%, p = < 0.0001); (iv) 47 patients on clopidogrel 75 mg (42.6% vs 4.3%, p = < 0.0001). In 59 patients loaded with clopidogrel 600 mg/900 mg, a greater proportion had a "therapeutic response" with VN-P2Y12 compared to s-TEG, regardless of the threshold for defining HPR with VN-PY12 (P2Y12 reaction units ≥ 230 or 208). Furthermore, adding PGE1 to ADP in s-TEG potentiated the anti-aggregatory effects of clopidogrel compared with ADP alone. In conclusion, VN-P2Y12 overestimates the functional effects of clopidogrel in some individuals, possibly because it utilises PGE1 in addition to ADP. This could have implications for the ability of VN-P2Y12 to stratify patients as "responders" or "non-responders" to clopidogrel.

"Aspirin resistance" in ischemic stroke: insights using short thrombelastography.

AIMS: Aspirin achieves its antithrombotic effect through inactivation of cyclo-oxygenase (COX)-1, thereby preventing generation of thromboxane (TX)A2 from arachidonic acid (AA). The reported prevalence of aspirin "resistance" varies significantly and is usually based on platelet function tests (PFTs) that use AA-induced platelet reactivity as a surrogate measure of the effect of aspirin, rather than specific assessment of its effect on its therapeutic target (ie, COX-1 inhibition). The reported rates are not only assay specific but also condition specific, with particularly high rates (up to 70%) previously reported in the stroke population. We investigated whether pharmacological responses to aspirin can be reliably determined from a functional test of AA-induced whole-blood clotting. METHODS AND RESULTS: A prospective study included 35 patients admitted with ischemic stroke and commenced on 300 mg aspirin. AA-induced whole-blood clotting was measured using short thrombelastography, a previously extensively validated near-patient PFT. Serum TXB2 and inflammatory biomarkers were also measured. The prevalence of apparent aspirin resistance measured using AA was high (range from 49% to 67%). However, serum [TXB2] was consistently low, thereby confirming adequate inhibition of COX-1 by aspirin. Mean inflammatory biomarker levels were elevated throughout. CONCLUSION: This study demonstrates that although COX-1 activity is adequately and consistently suppressed by aspirin in stroke patients, this effect is not reliably indicated by whole-blood clotting in response to AA. These data help to explain why the reported prevalence of aspirin resistance in stroke from studies employing AA-induced platelet reactivity is high and cast doubt on the veracity of such reports.

A randomized crossover study comparing the antiplatelet effect of plavix versus generic clopidogrel.

BACKGROUND: Clopidogrel exists in different salt formulations. All published data that have demonstrated its beneficial effect are based entirely on the hydrogen sulphate salt contained in the branded product Plavix, which had US sales of $6.1 billion in 2010 alone. A number of cheaper generic versions of clopidogrel are increasingly being used in Europe as an alternative to Plavix, mainly for cost reasons. However, there is insufficient evidence to show that their pharmacodynamic effect is equivalent to Plavix. METHODS: This prospective study investigated whether there is any significant difference in the antiplatelet effect of Plavix versus generic clopidogrel hydrochloride in healthy male volunteers. All participants received loading and maintenance doses of both drugs, in a crossover manner, separated by a 2-week washout period. Adenosine diphosphate (ADP)-induced platelet reactivity was measured using short thrombelastography at multiple timepoints. RESULTS: The results showed interindividual heterogeneity in responses to clopidogrel but no significant difference in ADP-induced platelet reactivity between Plavix versus generic clopidogrel hydrochloride. CONCLUSIONS: Our findings suggest comparable inhibition of ADP-induced platelet reactivity with Plavix and generic clopidogrel hydrochloride. This observation is particularly pertinent at a time when the patent for Plavix is expected to expire in the near future leading to the large-scale switch to cheaper generic preparations.

Personalised antiplatelet therapy in stent thrombosis: observations from the Clopidogrel Resistance in Stent Thrombosis (CREST) registry.

OBJECTIVE: Previous studies have demonstrated significant heterogeneity in responses to antiplatelet therapy (APT), and high residual platelet reactivity is associated with the risk of ischaemic events, including stent thrombosis (ST). The prevalence of APT hyporesponsiveness in a 'real world' registry of ST patients and the feasibility of personalising APT are reported. PATIENTS AND SETTING: 39 consecutive patients admitted to a single regional cardiothoracic centre with definite ST were prospectively evaluated. INTERVENTIONS: Response to aspirin and clopidogrel was measured following discharge using short thrombelastography (TEG), a rapid, well validated near patient platelet function test. Treatment modification in hyporesponders comprised an increase in aspirin dose and/or changing clopidogrel to prasugrel or ticagrelor. Short TEG was repeated following treatment modification to ensure an adequate response had been achieved. RESULTS: 12 (31%) patients had an adequate response to both aspirin and clopidogrel, 16 (41%) were hyporesponsive to clopidogrel alone, one (3%) was hyporesponsive to aspirin alone and 10 (26%) were hyporesponsive to both aspirin and clopidogrel. Following treatment modification, an adequate response to aspirin and P2Y12 agent was achieved in 10 (91%) and 22 (85%) patients, respectively. None has presented with a further ST episode. CONCLUSIONS: There is a high prevalence of hyporesponsiveness to APT in patients with ST. Improved APT efficacy can be achieved by tailored therapy. Short TEG is a plausible platelet function test that can be used to deliver point of care personalised APT.

Effect of clopidogrel withdrawal on platelet reactivity and vascular inflammatory biomarkers 1 year after drug-eluting stent implantation: results of the prospective, single-centre CESSATION study.

BACKGROUND: The optimal duration of clopidogrel treatment, particularly following drug-eluting stent (DES) implantation, remains contentious. Previous studies have observed a clustering of adverse events following clopidogrel cessation 1 year after DES, the aetiology of which is poorly understood. OBJECTIVE: To investigate, in the prospective CESSATION study, the effect of clopidogrel withdrawal at 1 year after DES implantation on (i) arachidonic acid (AA)- and adenosine diphosphate (ADP)-induced platelet aggregation, and (ii) biomarkers of vascular inflammation, including soluble CD40 ligand (sCD40L), high-sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL-6). METHODS AND RESULTS: The prospective CESSATION study was undertaken in 33 patients receiving aspirin and due to discontinue clopidogrel 1 year after DES. Platetet reactivity was measured using short thromboelastography, and compliance with aspirin determined from serum thromboxane B(2) (TXB(2)) levels. Venesection was performed at 4 weeks and 24 h before, and at 24 h, 48 h, 1, 2 and 4 weeks after, clopidogrel cessation. Following clopidogrel withdrawal, there was (i) a predictable increase in ADP-induced platelet aggregation (ii) an unexpected significant increase in AA-induced platelet aggregation (iii) a decline in IL-6 and hsCRP at 1 week and 4 weeks respectively; and (iv) a non-significant increase in sCD40L at 4 weeks TXB(2) levels were consistently suppressed, indicating complete inhibition of cyclo-oxygenase-1 by aspirin. CONCLUSION: An aspirin-independent, time-dependent increase in AA-induced platelet activation following clopidogrel withdrawal in patients with a DES has been described. New insights into a potential mechanism for the observed clustering of adverse events that occur early after clopidogrel cessation have been provided. These findings raise the question as to whether AA-induced clotting is an appropriate test of aspirin sensitivity.

Monitoring the effectiveness of antiplatelet therapy: opportunities and limitations.

Previous clinical studies have shown heterogeneity in individual patient responses to antiplatelet therapy and high residual platelet reactivity is associated with increased risk of adverse clinical events. Monitoring response to antiplatelet therapy and tailoring treatment accordingly is currently not recommended in routine clinical practice largely due to the lack of a standardized definition of antiplatelet therapy hyporesponse and the need for a widely accepted point-of-care platelet function test that can be reliably utilized in frontline clinical practice. Recent data have shown that titrating the dose of clopidogrel in patients undergoing percutaneous coronary intervention significantly reduces the incidence of major adverse cardiovascular events and large-scale clinical trials are currently underway to investigate whether individually tailored treatment based on results of platelet function testing leads to improved clinical outcome. Furthermore, genetic testing has demonstrated a link between CYP2C19 genetic polymorphisms, altered clopidogrel metabolite concentrations and adverse clinical events. Clinical studies are currently underway to investigate the potential clinical benefit associated with genotype-guided tailoring of antiplatelet therapy. With the advent of newer, more potent antiplatelet agents and their associated increased bleeding risks, it will become imperative in the future to select the most appropriate, safe and effective drug.

"Short" thrombelastography as a test of platelet reactivity in response to antiplatelet therapy: validation and reproducibility.

BACKGROUND: A significant proportion of patients receiving dual antiplatelet therapy following percutaneous coronary intervention experience recurrent ischaemic events despite standard doses of treatment. Although clinical studies show significant heterogeneity in antiplatelet therapy responses, routine testing is not undertaken due to (i) lack of a standardized test, and (ii) poor clarity with regards to definition of abnormal responses. Short Thrombelastography (s-TEG) is a validated test that allows rapid measurement of clotting responses to antiplatelet therapy. OBJECTIVES: This study sought to determine the reproducibility of s-TEG and to compare s-TEG with VerifyNow in assessment of responses to antiplatelet therapy. METHODS: (i) intra-individual variability was assessed using s-TEG Area Under the Curve (AUC15) and maximum amplitude (MA) in one volunteer at 20 time-points on no medication and at 10 time-points pre and post 300 mg aspirin treatment (ii) inter-individual variability was determined from a retrospective analysis of data on MA and AUC15 obtained from 56 volunteers on no medication, 25 volunteers pre and post 300 mg aspirin treatment and 28 patients pre and post 600 mg clopidogrel treatment (iii) a comparison between AUC15 arachidonic-acid (AA) channel and VerifyNow aspirin response units (VN ARU) and between AUC15 adenosine diphosphate (ADP) channel and VerifyNow P2Y12 reactivity units (VN PRU) was obtained from retrospective analysis of data at 370 and 296 time-points respectively. RESULTS: There was minimal intra-and inter-individual variability in MA and AUC15 in the AA, ADP and thrombin channels. There was a good correlation between AA AUC15 and VN ARU (r = 0.701, p < 0.001) and between ADP AUC15 and VN PRU (r = 0.609, p < 0.001). CONCLUSIONS: s-TEG is a reproducible and reliable near-patient test that correlates well with VerifyNow. Large scale studies are needed to determine its potential role in individually tailored antiplatelet therapy.

Takotsubo cardiomyopathy: a diagnostic challenge.

The frequency of the diagnosis of takotsubo cardiomyopathy has increased rapidly over the past few years, possibly due to increasing awareness among cardiologists. At initial presentation the diagnosis remains a challenge because of the close similarity between the presentation of takotsubo cardiomyopathy, and that of ST elevation myocardial infarction (STEMI). Recognition of salient aspects of the medical history at presentation are important in order to organise further appropriate investigations such as echocardiography and left ventriculography at the time of coronary angiogram. Takotsubo cardiomyopathy can be easily missed without ventriculography early after presentation because of the transient nature of left ventricular dysfunction, and in many centres left ventriculogram is not done as standard in the setting of STEMI. The authors advocate left ventriculography in all cases of ST elevation who have unobstructed coronaries. The correct diagnosis of takotsubo cardiomyopathy is very important for future advice and management of the patient. The prognosis of this condition is generally excellent with almost all patients returning to normal within a few weeks. This article examines the takotsubo cardiomyopathy literature and discusses the pathophysiology, clinical features, management, and prognosis of this condition in the context of an illustrated case.

Clopidogrel withdrawal: is there a "rebound" phenomenon?

Dual antiplatelet therapy with aspirin and clopidogrel is routinely indicated in patients with acute coronary syndromes and following percutaneous coronary intervention to reduce the risk of cardiovascular mortality and ischaemic events. Although clinical guidelines recommend aspirin lifelong and clopidogrel for between one and 12 months, depending upon the indication, the optimal duration of clopidogrel therapy actually remains contentious. Premature cessation of clopidogrel in patients receiving drug-eluting stents is a clear risk factor for stent thrombosis, but recent clinical studies have also demonstrated a link between "appropriate" cessation of clopidogrel and clustering of adverse clinical events. It has been suggested that this may be due to a "rebound" prothrombotic and/ or proinflammatory response associated with clopidogrel withdrawal. This review will examine the definition and concept of a "rebound" phenomenon associated with clopidogrel cessation as well as the likely mechanisms behind this effect. Within the context of clinical event clustering after clopidogrel cessation, we will also discuss (i) the clinical importance of clopidogrel and the increasing uncertainty surrounding optimal duration of therapy, (ii) the antiplatelet and anti-inflammatory properties of clopidogrel and, in particular, its influence on arachidonic acid pathways traditionally thought to be mediated predominantly by aspirin and (iii) the role of newer, more potent antiplatelet agents and potential changes to antiplatelet therapy prescribing guidelines in the future.

Transcatheter aortic valve implantation: the state of play.

Aortic stenosis is the most commonly acquired valvular heart disease in the Western world. Surgical aortic valve replacement is currently the gold-standard treatment for patients with severe symptomatic aortic stenosis. Without surgery, the prognosis is extremely poor, with a 3-year survival rate of less than 30%. Transcatheter aortic valve implantation (TAVI) is a rapidly evolving novel technique that was first introduced in 2002 and is currently available in Europe as an alternative to conventional aortic valve replacement for patients with severe symptomatic aortic stenosis who are deemed to be at too high a risk for open heart surgery. This article describes the TAVI technique and patient selection criteria. We explore how far we have come with advances in TAVI and analyze the short- and medium-term outcome data reported on TAVI so far. We will also look at the potential future role of TAVI and the challenges involved in setting up a TAVI service.

Multiple coronary to left ventricular fistulae.

A 39-year-old female admitted with chest pain, dyspnoea and abnormal electrocardiograph (anterior T wave inversion) was referred for cardiac investigation. Cardiac catheterization demonstrated separate origins of the left anterior descending and circumflex arteries with multiple fistulae passing directly into the left ventricular cavity. There was no evidence of atheromatous coronary disease. The right coronary artery was normal. Left ventricular function appeared preserved, but end diastolic pressure was elevated. In view of progressive symptoms, she underwent stress echocardiography. Baseline study showed normal left ventricular systolic function without wall motion abnormalities. At peak-dose dobutamine, there was dilatation of the left ventricular cavity with marked hypokinesis of the left ventricular apex, mid and apical inferoseptum and mid and apical anterior wall. The patient developed chest tightness at peak-dose dobutamine. Coronary artery fistula is an extremely rare presentation. Stress echocardiogram confirmed a marked inducible ischaemic response. The mechanism is likely to involve a 'steal phenomenon' with blood following a low-pressure route to the left ventricle with subsequent elevation in end diastolic pressure. The net result is inducible ischaemia. In this case, the patient was intolerant of all beta blockers due to asthma and calcium channel antagonists were found to be ineffective. Ivabradine resulted in symptomatic improvement.