Alex Hobson

Does Routine Pressure Wire Assessment Influence Management Strategy at Coronary Angiography for Diagnosis of Chest Pain? The RIPCORD Study

Background—The use of coronary angiography (CA) for diagnosis and management of chest pain (CP) has several flaws. The assessment of coronary artery disease using fractional flow reserve (FFR) is a well-validated technique for describing lesion-level ischemia and improves clinical outcome in the context of percutaneous coronary intervention. The impact of routine FFR at the time of diagnostic CA on patient management has not been determined. Methods and Results—Two hundred patients with stable CP underwent CA for clinical indications. The supervising cardiologist (S.C.) made a management plan based on CA (optimal medical therapy alone, percutaneous coronary intervention, coronary artery bypass grafting, or more information required) and also recorded which stenoses were significant. An interventional cardiologist then measured FFR in all patent coronary arteries of stentable diameter (≥2.25 mm). S.C. was then asked to make a second management plan when FFR results were disclosed. Overall, after disclosure of FFR data, management plan based on CA alone was changed in 26% of patients, and the number and localization of functional stenoses changed in 32%. Specifically, of 72 cases in which optimal medical therapy was recommended after CA, 9 (13%) were actually referred for revascularization with FFR data. By contrast, of 89 cases in whom management plan was optimal medical therapy based on FFR, revascularization would have been recommended in 25 (28%) based on CA. Conclusions—Routine measurement of FFR at CA has important influence both on which coronary arteries have significant stenoses and on patient management. These findings could have important implications for clinical practice. Clinical Trial Registration—URL: http://www.clinicaltrial.gov. Unique identifier: NCT01070771.

Thrombelastography: current clinical applications and its potential role in interventional cardiology

Thrombelastography is a bedside blood test used to assess patients’ haemostatic status. It has a well-established role in hepatobiliary and cardiac surgery and is also used in obstetrics and trauma medicine to assess coagulation and identify the causes of post-operative bleeding. It is not routinely used in the diagnosis or treatment of thrombosis although recently it has been shown to predict thrombotic events post-operatively and after percutaneous intervention (PCI). In cardiovascular medicine the importance of the platelet in the pathophysiology of vascular events is increasingly apparent. As a result antiplatelet therapy is a cornerstone of the treatment for coronary disease, particularly in the setting of acute coronary syndromes. The increasing utilization of stents, particularly drug-eluting devices, in PCI has also necessitated widespread use of antiplatelet agents to minimize the risk of stent thrombosis. A quick, accurate and reliable test to measure the effect of platelet inhibition by antiplatelet agents on clotting in an individual patient would be of profound clinical value. The results from such a test could provide prognostic information, allow treatment with antiplatelet agents to be tailored to the individual and identify resistance to one or more of these agents. Optimization and tailoring of anti-platelet therapy in patients with cardiovascular disease, particularly those undergoing PCI, using such a test may reduce morbidity and mortality from thrombotic and haemorrhagic complications. Current methods of assessing platelet activity measure platelet count and function in isolation. Optical aggregation is the most widely used method for assessing platelet function but it is relatively time consuming, measures platelet function in isolation rather than in the context of clot formation and is not a bedside test. By contrast the modified thrombelastograph platelet mapping kit marketed by Haemoscope can be used to assess the effects of antiplatelet agents on ex vivo blood clotting, thus giving a measurement more relevant to in vivo responses. This represents a potentially powerful tool to assess response of individual patients to antiplatelet therapy, particularly in the context of PCI.

A novel fifteen minute test for assessment of individual time-dependent clotting responses to aspirin and clopidogrel using modified thrombelastography

Background: A rapid, reliable, point of care test reflecting patient specific responses to antiplatelet therapy would be of great clinical value in percutaneous coronary intervention (PCI). The aim of this study was to establish whether modified thrombelastography (TEG) can be employed as a 15 minute test of individual patient responses to aspirin and clopidogrel using a novel parameter, percentage clotting inhibition (%CIn). Methods and results: Thirty healthy volunteers and 10 patients undergoing elective PCI were recruited into four groups: 10 volunteers received a single 300 mg dose of aspirin [A1]: 10 volunteers received aspirin 75 mg daily for 7 days [A2]: 10 volunteers received a 600 mg dose of clopidogrel [C1]: 10 patients received a 600 mg loading dose of clopidogrel prior to elective PCI [C2]. In all cases the area under the clotting response curve was measured at 15 minutes (AUC15) and used to calculate a novel parameter, percentage clotting inhibition (%CIn). Large differences were demonstrated in both aspirin and clopidogrel groups in response to therapy as assessed by both the area under the curve at 15 minutes and %CIn. Furthermore, the technique demonstrated important heterogeneity of time-dependent responses between individuals. Conclusion: Modified TEG, employing AUC15 and %CIn, is a promising tool for assessing responses to aspirin and clopidogrel. Further data are now required to assess the potential of this test to optimise individual therapy in PCI patients in order to detect and treat those patients with relative hypo-responsiveness to anti-platelet drugs.

Beyond the balloon: excimer coronary laser atherectomy used alone or in combination with rotational atherectomy in the treatment of chronic total occlusions, non-crossable and non-expansible coronary lesions.

AIMS To establish success and complication rates of excimer laser coronary atherectomy (ELCA) in a contemporary series of patients with balloon failure during percutaneous coronary intervention (PCI) of both chronic total occlusions (CTO) and lesions with distal TIMI 3 flow. METHODS AND RESULTS We identified 58 cases of balloon failure treated with ELCA±rotational atherectomy (RA) over four years, representing 0.84% of all PCI performed in our centre during this period. Balloon failures were classified according to: (i) mechanism of balloon failure; and (ii) whether this occurred in the context of treating a CTO. ELCA was performed following balloon failure using the CVX-300 Excimer Laser System and a 0.9 mm catheter with saline flush. For the entire cohort, procedure success was achieved in 91% (with ELCA successful: alone in 76.1%, after RA failure in 6.8% and in combination with RA for 8.6%). Only in one case did RA succeed where ELCA had failed. There were four procedure-related complications, including transient no-reflow, side branch occlusion and two coronary perforations, of which one was directly attributable to ELCA and led to subsequent mortality. CONCLUSIONS ELCA provides safe and effective adjunctive therapy in contemporary PCI to treat lesions associated with balloon failure due to an inability either to cross the lesion or to expand a balloon sufficiently to permit stenting. ELCA was successful in the majority of these selected cases when used independently with further effectiveness achieved when combined with RA or after RA failure.

Gender and Responses to Aspirin and Clopidogrel: Insights Using Short Thrombelastography

There is significant variability in both baseline clotting tendency and response to antiplatelet therapy. Responses are associated with outcome. We have investigated whether differences could explain the increased risk observed in women presenting with coronary artery disease. We have utilized short thrombelastography to assess (i) baseline clotting responses, (ii) response to aspirin and clopidogrel, and (iii) post-treatment platelet reactivity in 48 young volunteers, 22 older patients and 18 patients with previous stent thrombosis. Baseline responses were significantly higher in young women than in men. While there was no difference in response to aspirin, platelet reactivity on aspirin remained higher in women (area under curve at 15 min [AUC15] of arachidonic acid channel 332 +/- 122 vs. 172 +/- 80, P= 0.04). Young women had less response to clopidogrel (% reduction in AUC15 with adenosine diphosphate [ADP] 36.4 +/- 12.4 vs. 64.0 +/- 13.2, P < 0.01) in addition to higher post-treatment reactivity (AUC15 of ADP 714 +/- 161 vs. 311 +/- 146, P < 0.01) compared to men. There were no such differences between male and female patients over 50. However, young women with previous stent thrombosis had among the highest platelet reactivity observed. Compared to men, young women have greater baseline clotting tendency, reduced response to clopidogrel, and greater post-treatment reactivity while on both aspirin and clopidogrel. Differences in clotting tendency and response to antiplatelet therapy may contribute to the excess risk observed in young women but are not observed in older female patients.

Point-of-care platelet function assays demonstrate reduced responsiveness to clopidogrel, but not aspirin, in patients with Drug-Eluting Stent Thrombosis whilst on dual antiplatelet therapy

BackgroundTo test the hypothesis that point-of-care assays of platelet reactivity would demonstrate reduced response to antiplatelet therapy in patients who experienced Drug Eluting Stent (DES) ST whilst on dual antiplatelet therapy compared to matched DES controls. Whilst the aetiology of stent thrombosis (ST) is multifactorial there is increasing evidence from laboratory-based assays that hyporesponsiveness to antiplatelet therapy is a factor in some cases.MethodsFrom 3004 PCI patients, seven survivors of DES ST whilst on dual antiplatelet therapy were identified and each matched with two patients without ST. Analysis was performed using (a) short Thrombelastogram PlateletMapping™ (TEG) and (b) VerifyNow Aspirin and P2Y12 assays. TEG analysis was performed using the Area Under the Curve at 15 minutes (AUC15) as previously described.ResultsThere were no differences in responses to aspirin. There was significantly greater platelet reactivity on clopidogrel in the ST group using the Accumetrics P2Y12 assay (183 ± 51 vs. 108 ± 31, p = 0.02) and a trend towards greater reactivity using TEG AUC15 (910 ± 328 vs. 618 ± 129, p = 0.07). 57% of the ST group by TEG and 43% of the ST cases by Accumetrics PRU had results > two standard deviations above the expected mean in the control group.ConclusionThis study demonstrates reduced platelet response to clopidogrel in some patients with DES ST compared to matched controls. The availability of point-of-care assays that can detect these responses raises the possibility of prospectively identifying DES patients at risk of ST and manipulating their subsequent risk.

Effects of clopidogrel on "aspirin specific" pathways of platelet inhibition

The most widely accepted methods of assessing response to clopidogrel involve isolated ADP-induced platelet aggregation. Whilst poor response determined by these assays correlates with adverse clinical events, the number of “poor responders” is far higher than the number of events attributed to treatment failure. Clopidogrel may have effects that cannot be assessed using isolated ADP-induced aggregation. We have investigated the effect of clopidogrel on Arachidonic Acid (AA) induced platelet activation–an “aspirin specific” pathway using a novel near patient assay. Thirty four volunteers on no medication and 36 patients, on maintenance therapy with aspirin 75 mg daily, were recruited. Blood tests for Thrombelastogram PlateletMapping were taken immediately prior to and 6 hours after administration of a 600 mg clopidogrel loading dose. Changes in the area under the response curve at 15 minutes (AUC15) with both ADP- and AA-stimulation were calculated as were the corresponding percentage platelet and percentage clotting inhibition (%PIn and %CIn). There were predictable and significant changes in the AUC15 of the ADP channel in response to clopidogrel and the corresponding %PIn and %CIn in both volunteers and patients. There were also significant reductions in the AUC15 of the AA channel (presented as Mean +/− 95%CI), by 27.2 +/− 11.8%, p = 0.005 in volunteers and 35.0 +/− 8.2%, p < 0.001 in patients) and increases in the %PIn and %CIn calculated using the AA channel in volunteers (by 20.0 +/− 11.4%, p + 0.02 and 32.3 +/− 12.8%, p < 0.001 respectively) and patients (by 24.2 +/− 8.6%, p < 0.001 and by 18.0 +/− 8.6, p < 0.001 respectively). Clopidogrel has both independent and aspirin-synergistic effects on AA-induced platelet activation suggesting potentiation of the antiplatelet activity of aspirin. This effect may be clinically important and is not detected by current “gold standard” methods of assessing response to clopidogrel.

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.

Individualised Assessment of Response to Clopidogrel in Patients Presenting with Acute Coronary Syndromes: A Role for Short Thrombelastography?

INTRODUCTION There is considerable interindividual variation in response to the antiplatelet agent clopidogrel. Hyporesponse predicts negative outcomes in patients presenting with a variety of ischemic cardiac conditions and following intracoronary stent placement. Many tests of clopidogrel activity are time consuming and complex. Short thromboelastography (s-TEG) allows rapid measurement of platelet clopidogrel response. AIMS We initiated this study to investigate the utility of s-TEG in assessing the response to clopidogrel in patients presenting with acute coronary syndromes (ACS) and to compare these results with established clopidogrel monitoring techniques. METHODS Patients admitted with unstable angina (UA) or Non ST elevation myocardial infarction (NSTEMI) undergoing coronary angiography were recruited. After routine loading with clopidogrel, all patients were tested with s-TEG and Accumetrics Verify-Now rapid platelet function analyzer (VN-RPFA). We used the modified TEG technique of measuring area under the curve at 15 min (AUC15), which allows a rapid estimation of antiplatelet response. Vasodilator-stimulated phosphoprotein phosphorylation (VASP) was also tested in a subgroup of patients. Clinical follow-up was obtained at 1 year. s-TEG results were correlated with VN-RPFA and VASP findings. RESULTS A total of 49 patients (33 male, mean age 63) were recruited and tested with s-TEG and VN-RPFA and a total of 39 patients were also assessed with VASP. s-TEG readings correlated well with VN-RPFA (r(2)= 0.54, P < 0.0001) and VASP (r(2)= 0.26, P= 0.001). CONCLUSION s-TEG provides timely results which compare to current tests of clopidogrel activity. This technique can also be used to measure a variety of other clotting parameters and as such could develop into a valuable near patient test for the interventional cardiologist.

Coronary spasm induced by capecitabine mimicks ST elevation myocardial infarction

Capecitabine is a chemotherapeutic prodrug that is metabolised to 5-fluorouracil. Supported by the National Institute for Health and Clinical Excellence guidance it is now first-line adjuvant treatment for metastatic colorectal cancer in the UK. Although cardiac chest pain and myocardial ischaemia are well recognised side effects of 5-fluorouracil, their association with capecitabine is not widely appreciated. Two cases are described of coronary spasm secondary to capecitabine in patients referred for emergency invasive treatment of presumed ST elevation myocardial infarction (STEMI). The contemporary treatment of acute coronary syndromes involves aggressive antiplatelet therapy, anticoagulation and cardiac catheterisation. This treatment, although beneficial in most patients, is associated with a small but significant risk of bleeding complications. A wider appreciation of the potential for capecitabine to induce spasm mimicking STEMI is important in order to reduce the risk of the administration of thrombolytics and other potentially dangerous drugs and have a higher threshold for referral for emergency angiography.