Antiplatelet effects of licking an aspirin tablet can be detected by thrombelastography.

Aspirin is a cornerstone of treatment in cardiovascular disease. However, individual responses vary and hyporesponsiveness has been associated with poor outcomes following percutaneous intervention. Point of care assays for detecting the effects of aspirin in individual patients would therefore be useful. Thrombelastography has been shown to correlate with optical aggregation in the assessment of antiplatelet therapies and is suitable for use as a point of care assay. We demonstrate the ability of thrombelastography to detect the profound effects of even the tiny doses of aspirin obtained by licking an aspirin tablet.

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.

Thromboelastography: potential bedside tool to assess the effects of antiplatelet therapy?

Modified thrombelastography (TEG) is a simple point of care test that provides an overall assessment of ex vivo clot formation and currently has limited clinical application. We evaluated the ability of TEG to assess the effects of antiplatelet therapy on clot formation using a novel assessment parameter (the area under curve). Forty healthy volunteers were divided into four groups of 10. Group A took aspirin 75 mg once daily for 7 days followed by aspirin 75 mg and clopidogrel 75 mg once daily in combination for 7 more days. Blood samples were taken for analysis at day 0 and days 7 and 14. Group B took a single 300 mg dose of aspirin. Group C took 600 mg of clopidogrel only. Group D took 300 mg of aspirin and 600 mg of clopidogrel at the same time. For groups B, C and D blood was taken prior to drug administration and at 2, 6 and 24 h afterwards. Each sample was tested by TEG in four channels following activation using (1) kaolin, (2) activator F (Act F), a direct activator of fibrin, (3) Act F + arachidonic acid (AA) and (4) Act F + adenosine diphosphate (ADP). Parameters measured included the maximum amplitude (MA) of the clot and the area under the TEG-generated curve at 1 h. Significant, time-dependent reductions in MA and area were seen in the AA-activated samples following administration of aspirin in all groups as compared to baseline. By contrast, there were no significant differences in MA or area in the AA-activated samples with clopidogrel alone. Significant reductions were also seen in MA and area in ADP-activated samples from volunteers treated with clopidogrel as compared to baseline. Three out of 10 subjects receiving 600 mg clopidogrel had a reduction in their responses of 30% or less, thus identifying them as relatively resistant to the drug. This study identifies a rapid, reliable method for assessing the time-dependent effects of antiplatelet therapy on clotting using a novel parameter of area of the TEG trace, which could have an important clinical application as a point of care test of efficacy, particularly in the context of acute coronary syndromes and percutaneous coronary intervention.

Percutaneous coronary intervention: recommendations for good practice and training.

Cardiologists undertaking percutaneous coronary intervention (PCI) are excited by the combination of patient and physician satisfaction and technological advance occurring on the background of the necessary manual dexterity. Progress and applicability of percutaneous techniques since their inception in 1977 have been remarkable; a sound evidence base coupled with the enthusiasm and ingenuity of the medical device industry has resulted in a sea change in the treatment of coronary heart disease (CHD), which continues to evolve at breakneck speed. This is the third set of guidelines produced by the British Cardiovascular Intervention Society and the British Cardiac Society. Following the last set of guidelines published in 2000, we have seen PCI activity in the UK increase from 33,652 to 62,780 (87% in four years) such that the PCI to coronary artery bypass grafting ratio has increased to 2.5:1. The impact of drug eluting stents has been profound, and the Department of Health is investigating the feasibility of primary PCI for acute myocardial infarction. Nevertheless, the changes in the structure of National Health Service funding are likely to focus our attention on cost effective treatments and will require physician engagement and sensitive handling if we are to continue the rapid and appropriate growth in our chosen field. It is important with this burgeoning development now occurring on a broad front (in both regional centres and district general hospitals) that we maintain our vigilance on audit and outcome measures so that standards are maintained for both operators and institutions alike. This set of guidelines includes new sections on training, informed consent, and a core evidence base, which we hope you will find useful and informative.

Improving the positive predictive value of exercise testing in women.

OBJECTIVE: To identify exercise test variables that can improve the positive predictive value of exercise testing in women. DESIGN: Cohort study. SETTING: Regional cardiothoracic centre. SUBJECTS: 1286 women and 1801 men referred by primary care physicians to a rapid access chest pain clinic, of whom 160 women and 406 men had ST depression of at least 1 mm during exercise testing. The results for 136 women and 124 men with positive exercise tests were analysed. MAIN OUTCOME MEASURES: The proportion of women with a positive exercise test who could be identified as being at low risk for prognostic coronary heart disease and the resulting improvement in the positive predictive value. RESULTS: Independently of age, an exercise time of more than six minutes, a maximum heart rate of more than 150 beats/min, and an ST recovery time of less than one minute were the variables that best identified women at low risk. One to three of these variables identified between 11.8% and 41.2% of women as being at low risk, with a risk for prognostic disease of between 0-11.5%. The positive predictive value for the remaining women was improved from 47.8% up to 61.5%, and the number of normal angiograms was potentially reducible by between 21.1-54.9%. By the same criteria, men had higher risks for prognostic disease. CONCLUSIONS: A strategy of discriminating true from false positive exercise tests is worthwhile in women but less successful in men.

The association between deaths from myocardial infarction and household size in England and Wales.

BACKGROUND: Chronic infection with organisms such as Chlamydia pneumoniae is thought to cause coronary heart disease. We investigated whether myocardial infarction deaths are associated with large household size and overcrowding, as these are factors that may facilitate the transmission of infection. DESIGN: Ecological study of England and Wales. METHODS: Population data were obtained from the 1991 National Census and mortality data were obtained from the Office of National Statistics. For various categories of household size and overcrowding, we calculated mortality rates standardized for age, sex and deprivation. RESULTS: Standardized mortality rates for acute respiratory infections were associated with household size and overcrowding, while rates for myocardial infarction and gastric carcinoma, both putatively associated with chronic infection, were associated with household size. For combined deaths from causes other than myocardial infarction, there were small associations with household size and overcrowding. In the case of myocardial infarction, the association was generally strongest in the age group 45-54.9 years. For this age group, the standardized mortality rate ratio for the category of largest size household was 2.7 in the year 1991. CONCLUSIONS: There is an association between household size and mortality from myocardial infarction. Chronic infection is a possible cause.

Clopidogrel for prevention of major cardiac events after coronary stent implantation: 30-day and 6-month results in patients with smaller stents.

OBJECTIVES: We developed this study to assess the procedural outcome, complications, and clinical follow-up in patients treated with different antiplatelet regimens after intracoronary stent implantation with small stents. Three hundred sixty-one consecutive patients, in whom at least one 3.0-mm intracoronary stent was implanted, were studied. METHODS: The study was a prospective, observational registry of unselected consecutive patients treated in our institution. Patients who underwent stent implantation between December 1997 and July 1998 were treated with aspirin and ticlopidine; those who received stents between August 1998 and February 1999 were treated with aspirin and clopidogrel. RESULTS: In the group treated with ticlopidine, there were 190 patients who had 253 lesions treated with 274 stents. Mean age was 59.1 years, 72% were male, 31% had unstable angina, 64% had 1 stent, 36% had >1 stent, and 23% had multivessel intervention. In the group treated with clopidogrel, there were 171 patients who had 226 lesions treated with 245 stents. Mean age was 60.4 years, 79% were male, 26% had unstable angina, 70% had 1 stent, 30% had >1 stent, and 26% had multivessel intervention. Complications at 30 days in the ticlopidine group were death in 1 (0.5%), stent occlusion in 3 (1. 6%; all reopened with repeat angioplasty), non-Q-wave myocardial infarction in 2 (1%), and urgent revascularization in 4 (2%). Complications at 30 days in the clopidogrel group were noncardiac death in 1 (1.2%), cardiac death in 1 (1.2%), stent occlusion in 0, non-Q-wave myocardial infarction in 3 (1.8%), and urgent revascularization in 0. Follow-up was available in 100% of patients in both groups (mean 253 +/- 75 days in the ticlopidine group, 198 +/- 53 days in the clopidogrel group). Complications at >30 days in the ticlopidine group were death in 1 and clinical restenosis in 11 (5.8%); 1 additional patient had an admission with unstable angina to the local hospital. Hence, recurrent angina as a consequence of target lesion restenosis occurred in 5.8%. Complications at >30 days in the clopidogrel group were death in 0 and clinical restenosis in 8 (4.7%); 2 additional patients were admitted with unstable angina to the local hospital, and 1 patient had a myocardial infarction 164 days after stent implantation. Hence, recurrent angina as a consequence of target lesion restenosis occurred in 4.7%. There were no significant differences in complications between the 2 groups. CONCLUSIONS: Our observations suggest that clopidogrel can be used instead of ticlopidine in patients treated with stents with a diameter of

Circulating Chlamydia pneumoniae DNA as a predictor of coronary artery disease.

OBJECTIVE: To determine whether current vascular Chlamydia pneumoniae (CPn) infection as diagnosed by circulating CPn DNA is more common in subjects with coronary artery disease (CAD). BACKGROUND: Serological, pathological and animal studies have associated CPn with CAD and preliminary trials suggest antibiotics may prevent adverse coronary events. C. pneumoniae is thought to disseminate systemically within macrophages. We therefore detected CPn DNA in blood to determine whether its presence was a predictor of CAD. METHODS: One thousand, two hundred and five subjects attending for diagnostic and interventional coronary arteriography were recruited. The mononuclear cell layer and platelets were separated from collected blood and the polymerase chain reaction (PCR) was used to detect CPn DNA. RESULTS: Circulating CPn DNA was found in 8.8% of 669 men with CAD compared with 2.9% of 135 men with normal coronary arteries (odds ratio [OR] 3.2, 95% confidence interval [CI] 1.1-8.9). In men with CAD, those with CPn DNA had higher mean platelet counts than those without CPn DNA. Monocyte counts and indirect fibrinogen levels were also raised but not significantly so. By contrast, no association of circulating CPn DNA and CAD was seen in women. CONCLUSIONS: Circulating CPn DNA is a predictor of CAD in men. Unlike serology, it is a specific indicator of current infection and is a means of identifying subjects who may potentially benefit from antichlamydial therapy.

Does angiography six months after coronary intervention influence management and outcome? Benestent II Investigators.

OBJECTIVES: This study was performed to assess whether angiography six months after coronary balloon angioplasty or stent implantation has an influence on clinical management and one-year outcome. BACKGROUND: The Benestent II study randomized 827 patients to balloon angioplasty or stent implantation. A subrandomization was undertaken allocating patients to six-month clinical follow-up (CF) or clinical and angiographic follow-up (AF). METHODS: Seven hundred and six patients (349 CF and 357 AF) had no intercurrent angiography, so that restenosis and disease progression elsewhere remained unknown until the time of six-month follow-up. These two groups, which were well matched at enrolment, were compared with respect to symptoms, medication and major cardiac events defined as death, myocardial infarction and need for revascularization at six and 12 months. RESULTS: At six-month follow-up, 53 (15%) of the CF and 76 (21%) of the AF patients had stable angina (p = 0.041), while 5 (1%) and 4 (1%) had symptoms of unstable angina. At 12-month follow-up, 44 (13%) patients in both groups had stable angina, and only 1 patient in the CF group had unstable angina. Seventy-seven patients (27 CF and 50 AF; p < 0.01) had major cardiac events between 6 and 12 months. Of the 349 patients in the CF group, 21 underwent repeat percutaneous transluminal coronary angioplasty or coronary artery bypass graft surgery between 6 and 12 months, compared with 44 of the 357 patients in the AF group (relative risk 2.05 [1.24 to 3.37], p = 0.003). CONCLUSIONS: Patients who had AF six months after balloon angioplasty or stent implantation experienced more repeat revascularization procedures than those who had CF. They also had significantly more angina at six-month follow-up but this may be due to bias.

Intracoronary Multi-link stents: experience in 218 patients using aspirin alone.

OBJECTIVES: To assess procedural outcome, complications, and clinical follow up in 218 patients who underwent treatment with 297 Multi-link (Guidant) stents implanted without the use of intravascular ultrasound (IVUS) or quantitative coronary angiography (QCA), and using aspirin alone as antiplatelet therapy. METHODS: The case records and angiograms were reviewed and the patients were contacted by telephone to determine their symptoms and any adverse events at follow up. Data were analysed using Fisher's exact test. RESULTS: Of the 218 patients included in the study, 45 had multivessel intracoronary intervention, and 55 had unstable angina. The mean (SD) length of hospital stay following the procedure was 2.0 (2.1) days. There were two early deaths at less than 30 days, and two deaths during follow up at more than 100 days. Ten patients suffered complications during the first 30 days: four had subacute stent thrombosis, of whom two died and two were treated successfully with coronary artery bypass grafting; five had a non-Q wave myocardial infarction; and one had a femoral false aneurysm. Patient outcome was analysed according to stent diameter (3.0 mm or less, or 3.5 mm or more) and by angina status (stable or unstable). In patients in whom at least one stent was 3.0 mm diameter, four of 86 patients suffered acute stent occlusion, whereas in the 132 patients in whom all stents were at least 3.5 mm diameter there were no cases of stent occlusion (p = 0.02). In the unstable angina group two of 55 patients suffered acute stent occlusion compared to two of 163 patients in the stable angina group (NS). In patients with unstable angina and at least one stent of 3.0 mm diameter, the acute occlusion rate was 7.1% (two of 28 patients). Three of the four patients with stent occlusion had undergone complex procedures. Twenty eight patients were restudied for recurrent symptoms during the follow up period. Of these, eight patients had restenosis within their stent. In seven of these patients the stent size was 3.0 mm diameter, and in the remaining patient the stent size was 4.0 mm diameter. Three of the 28 patients restudied had developed new disease remote from the stented site, and 17 had patent stents and no significant other coronary lesion. CONCLUSIONS: This study suggests that coronary intervention using the Multi-link stent is safe and effective using aspirin alone, without IVUS or QCA, when stent diameter is greater than 3.0 mm. All cases of stent occlusion in this series occurred in patients in whom at least one stent was 3.0 mm diameter, with stent occlusion being higher in patients with unstable angina compared to those with stable angina. Additional antiplatelet therapy may be beneficial in those patients in whom Multi-link stent diameter is less than 3.5 mm, particularly in those with unstable angina, but is not necessary for patients receiving Multi-link stents of 3.5 mm diameter or greater.

Normal right ventricular systolic and diastolic function assessed by krypton-81m equilibrium ventriculography.

Krypton-81m equilibrium ventriculography was used to study right ventricular function in 23 healthy male volunteers. Technetium-99m lung perfusion scintigraphy was employed to subtract radionuclide activity within lung during image analysis thereby enhancing image quality. The imaging technique was used to generate a time-activity curve for the right ventricle allowing the definition of indices of normal systolic and diastolic function for the right ventricle. At rest, indices of systolic ejection and diastolic filling were comparable to those previously reported for the left ventricle. Using the imaging technique, movement artifact during exercise reduces image quality and limits accurate measurement of these indices to resting studies.

Late functional results after surgical closure of acquired ventricular septal defect.

To assess the longer term outlook for patients who have undergone surgery for acquired (postinfarction) ventricular septal defect, we interviewed and studied 60 survivors from a single regional cardiac center between 3 and 144 months after the operation. Including the patients who died within 1 month of the operation, the 5-, 10-, and 14-year survivals (with standard errors) were 69% (65% to 74%), 50% (44% to 57%), and 37% (27% to 46%). Eighty-two percent of patients were in New York Heart Association class I or II. Ten patients (17%) had a persisting but not hemodynamically significant ventricular septal defect. Mean left ventricular ejection fraction was reduced at 0.39 (standard deviation 0.15), but this did not correlate with either New York Heart Association class or exercise tolerance. Twenty-eight patients (47%) had asymptomatic arrhythmias (17 with ventricular premature beats). Angina and other medical problems were not prevalent.

A comparison of the acute haemodynamic effects of nisoldipine and nifedipine during treatment with atenolol in patients with coronary artery disease.

1. The acute haemodynamic effects of intravenous nisoldipine (1, 2, 4 microg kg(-1)) and nifedipine (2.5, 5, 10 microg kg(-1)) were compared in a randomised, within-patient crossover study. Fifteen male patients with stable angina pectoris treated with atenolol were studied after undergoing routine cardiac catheterisation. 2. Nisoldipine caused a dose-related fall in systemic vascular resistance (maximum 22%) associated with an increase in heart rate and cardiac index (18%) and a fall in mean arterial pressure (7%). 3. By contrast, nifedipine was associated with a significant increase in heart rate but systemic vascular resistance, cardiac index and mean arterial pressure remained unaltered. 4. At doses with equivalent effects on heart rate (2 microg kg(-1) nisoldipine; 10 microg kg(-1) nifedipine) acute dosing with nisoldipine caused a significantly greater fall in systemic vascular resistance and increase in cardiac index, whilst nifedipine caused a greater reduction in stroke volume index and left ventricular stroke work index. 5. The results suggest that, when combined with atenolol, acute dosing with nisoldipine may have a more complementary haemodynamic profile than nifedipine. The implications of this finding for chronic oral dosing in patients with impaired left ventricular function should be evaluated.

A comparison of nisoldipine and nifedipine, in combination with atenolol, in the management of myocardial ischaemia.

The effects of the addition of slow-release nifedipine 20 mg twice daily and nisoldipine 10 mg twice daily to atenolol monotherapy were compared in a double-blind placebo-controlled study of 24 patients with chronic stable angina pectoris. Neither nisoldipine nor nifedipine was associated with significant subjective benefit at these doses. Two hours post-dosing, exercise capacity improved after both nisoldipine (duration + 37 s, P < 0.01; time to angina + 67 s, P < 0.01; time to significant ST depression + 60 s, P < 0.01) and nifedipine (duration + 21 s, ns; time to angina + 56 s, P < 0.05; time to significant ST depression + 49 s P < 0.05). However, this improvement was not maintained 12 h post-dosing. Ambulatory monitoring did not demonstrate a significant reduction in the amount of silent or total ischaemia following the addition of either nifedipine or nisoldipine to atenolol monotherapy. There was no significant difference between nifedipine and nisoldipine in any parameter tested. In conclusion, like slow-release nifedipine 20 mg, the effective duration of anti-ischaemic action of nisoldipine 10 mg is less than 12 h. Since several patients experienced vasodilatory unwanted effects, more frequent administration rather than larger individual doses may be desirable to achieve a clinical response.

Right ventricular function at rest and during submaximal exercise assessed by 81Krm equilibrium ventriculography in normal subjects.

81Krm equilibrium ventriculography was used to study right ventricular function in 37 healthy male volunteers. 'Anatomical' lung subtraction using 99Tcm lung perfusion scintigraphy was compared with conventional background correction in the calculation of resting right ventricular ejection fraction (RVEF). Resting RVEF was significantly greater following 'anatomical' lung subtraction than that using background correction (0.59 +/- 0.06 versus 0.55 +/- 0.05). The exercise response of the normal right ventricle was defined in 23 subjects during exercise. Right ventricular ejection fraction showed a progressive increase during graded submaximal exercise (0.55 +/- 0.05 at rest, 0.60 +/- 0.05 at 50 W and 0.66 +/- 0.05 at 100 W). Right heart 81Krm equilibrium ventriculography is well suited to the evaluation of right ventricular function at rest and during exercise. The absolute value of RVEF will however be dependent upon the method of image analysis.