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.

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.

BACKGROUND: To 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. METHODS: From 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 PlateletMappingtrade mark (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. RESULTS: There 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. CONCLUSION: This 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.

Clopidogrel "resistance": where are we now?

Antiplatelet therapy with aspirin and clopidogrel in PCI patients, though effective, is still associated with thrombotic complications. These are multifactorial in origin, but partially attributable to "clopidogrel resistance." However, how best to identify and manage "clopidogrel resistance" remains unclear. Targeting therapeutic changes specifically at those individuals with poor response to clopidogrel is likely to be a solution. A "one size fits all" approach to clopidogrel dosing is probably flawed. This review will explore (1) the definition and mechanisms of clopidogrel resistance, (2) assessment of clopidogrel resistance by (i) platelet function testing and (ii) genetic testing, (3) the management of "clopidogrel resistance," and (4) newer antiplatelet agents, and evolving stent technology. A pubmed literature review was performed using the keywords "clopidogrel", "resistance", "poor response", "adverse events", "platelet function tests", and "genetic tests". In looking at new agents, keywords "prasugrel", "cangrelor", "ticagrelor""Elinogrel", and "P2Y12 receptor antagonists" were used. Third, a search was performed looking at "stent design", "IVUS", "bioabsorbable stents", and "stent apposition". Whilst new P2Y12 receptor antagonists and improved stent technology may reduce thrombotic events in the future, there is still a need for clopidogrel. There is good evidence that poor response to clopidogrel is associated with adverse outcome. Platelet function tests probably provide more clinically useful data than genetic tests, but the question of how best to identify and manage variability in response to clopidogrel demands further research.

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.

How should I treat severe calcific coronary artery disease?

BACKGROUND: An 80-year-old man with limiting angina pectoris. INVESTIGATION: Physical examination, laboratory tests, echocardiography, exercise ECG, coronary arteriography, pressure wire assessment. DIAGNOSIS: Single severe calcific coronary artery disease. TREATMENT: Elective percutaneous coronary intervention (PCI) for calcific mid-vessel stenosis with rotational and excimer laser atherectomy.

The Potential Value of Near Patient Platelet Function Testing in PCI: Randomised Comparison of 600 mg versus 900 mg Clopidogrel Loading Doses.

Whilst poor response to clopidogrel is associated with adverse outcomes uncertainty exists as to how (a) response should be assessed and (b) poor responders managed. We utilised VerifyNow P2Y12 and short Thrombelastography (TEG) to assess 900 mg doses in (i) initial poor responders to 600 mg and (ii) in a randomised comparison with 600 mg. Blood was taken before and six hours post clopidogrel in (i) 30 volunteers receiving 600 mg (poor responders received 900 mg > two weeks later) and (ii) 60 patients randomized 1 : 1 to 600 mg or 900 mg doses. Poor response was defined as TEG %Clotting Inhibition (%CIn) or VerifyNow Platelet Response Unit (PRU) reduction <30%. (i) Poor responders to 600 mg had greater PRU reduction (45.0 versus 20.1%, P = 0.03) and greater %CIn (22.9 versus -15.1%, P = 0.01) after 900 mg but (ii) there were no significant differences between the patient groups. Near-patient assessment of response to clopidogrel is feasible and clinically useful. Whilst ineffective on a population basis 900 mg doses increase the effect of clopidogrel in initial poor responders.

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.

Malignancy: an unrecognized risk factor for coronary stent thrombosis?

Stent thrombosis is a potentially catastrophic complication of coronary artery stenting. There have been particular concerns about the incidence of stent thrombosis following insertion of drug-eluting stents. We report a series of cases in which stent thrombosis occurred in association with malignancy and describe the potential mechanisms behind such an association. We speculate that this association merits further investigation as it raises the possibility that known malignancy may be a risk factor for stent thrombosis and that unexplained stent thrombosis, particularly if recurrent, should stimulate a search for occult malignancy.

Permanent pacemaker implantation after isolated aortic valve replacement: incidence, indications, and predictors.

BACKGROUND: Conducting system defects are common in patients with aortic valve disease. Aortic valve replacement may result in further conduction abnormalities and necessitate permanent pacemaker implantation (PPM). We sought to identify the contemporary incidence and predictors for early postoperative PPM in patients undergoing isolated aortic valve replacement. METHODS: Data were analyzed from 354 consecutive patients undergoing isolated aortic valve replacement at a referral cardiac unit during a 30-month period; data were unavailable on 4 patients and a further 8 had undergone preoperative PPM. Results for the remaining 342 patients (97%; mean age, 67 +/- 14 years), of whom 212 were males, are presented. The major indications for aortic valve replacement were valvular stenosis (n = 224), regurgitation (n = 70), or infective endocarditis (n = 25). Preoperative conducting system disease was present in 26% of patients. RESULTS: In-hospital mortality was 1.8% (6 of 342 patients). Postoperatively 29 patients (8.5%) required early PPM, of which 26 were during the index admission. Patients with preoperative conducting system disease (16% versus 6%; p = 0.004) and valvular regurgitation (16% versus 7%; p = 0.01) were more likely to require PPM as opposed to those without. Preoperative conducting system disease was the only independent predictor of PPM (p < 0.01); the relative risk of PPM requirement in this group was 2.88 (95% confidence interval, 1.31 to 6.33). CONCLUSIONS: Permanent pacemaker implantation requirement after aortic valve replacement is a common occurrence, and should be discussed as part of the preoperative consent process. Preexisting conducting disease and preoperative aortic regurgitation were predictors of PPM requirement.

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.