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Aims: There is currently no consensus on whether atrial fibrillation (AF) patients at low risk for stroke (one non-sex-related CHA2DS2-VASc point) should be treated with an oral anticoagulant., Methods and Results: We conducted a multi-country cohort study in Sweden, Denmark, Norway, and Scotland. In total, 59 076 patients diagnosed with AF at low stroke risk were included. We assessed the rates of stroke or major bleeding during treatment with a non-vitamin K antagonist oral anticoagulant (NOAC), a vitamin K antagonist (VKA), or no treatment, using inverse probability of treatment weighted (IPTW) Cox regression. In untreated patients, the rate for ischaemic stroke was 0.70 per 100 person-years and the rate for a bleed was also 0.70 per 100 person-years. Comparing NOAC with no treatment, the stroke rate was lower [hazard ratio (HR) 0.72; 95% confidence interval (CI) 0.56-0.94], and the rate for intracranial haemorrhage (ICH) was not increased (HR 0.84; 95% CI 0.54-1.30). Comparing VKA with no treatment, the rate for stroke tended to be lower (HR 0.81; 95% CI 0.59-1.09), and the rate for ICH tended to be higher during VKA treatment (HR 1.37; 95% CI 0.88-2.14). Comparing NOAC with VKA treatment, the rate for stroke was similar (HR 0.92; 95% CI 0.70-1.22), but the rate for ICH was lower during NOAC treatment (HR 0.63; 95% CI 0.42-0.94)., Conclusion: These observational data suggest that NOAC treatment may be associated with a positive net clinical benefit compared with no treatment or VKA treatment in patients at low stroke risk, a question that can be tested through a randomized controlled trial., Competing Interests: Conflict of interest: J.J.K. is currently employed by Daiichi-Sankyo, but not during the conduct of this study, and reports personal fees from Boehringer Ingelheim, outside the submitted work; A.P. reports grants from Alcon, grants from Almirall, grants from Astellas, grants from Astra-Zeneca, grants from Boehringer Ingelheim, grants from Novo Nordisk, grants from Servier, grants from LEO Pharma, outside the submitted work; Ø.K. reports participation in imposed Post-Authorization Safety Studies on an antidiabetic and an anti-psoriasis drug. The studies are funded by Leo Pharma and Novo Nordisk, with funds paid to the institution where he is employed (no personal fees) and with no relation to the work reported in this paper; L.J.K. was supported by the Research Council of Norway as part of the International Pregnancy Drug Safety Studies (InPreSS, Project No. 273366) during the conduct of the study. All other authors have nothing to declare., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Aims: To assess persistence and adherence to non-vitamin K antagonist oral anticoagulant (NOAC) treatment in patients with atrial fibrillation (AF) in five Western European healthcare settings., Methods and Results: We conducted a multi-country observational cohort study, including 559 445 AF patients initiating NOAC therapy from Stockholm (Sweden), Denmark, Scotland, Norway, and Germany between 2011 and 2018. Patients were followed from their first prescription until they switched to a vitamin K antagonist, emigrated, died, or the end of follow-up. We measured persistence and adherence over time and defined adequate adherence as medication possession rate ≥90% among persistent patients only., Results: Overall, persistence declined to 82% after 1 year and to 63% after 5 years. When including restarters of NOAC treatment, 85% of the patients were treated with NOACs after 5 years. The proportion of patients with adequate adherence remained above 80% throughout follow-up. Persistence and adherence were similar between countries and was higher in patients starting treatment in later years. Both first year persistence and adherence were lower with dabigatran (persistence: 77%, adherence: 65%) compared with apixaban (86% and 75%) and rivaroxaban (83% and 75%) and were statistically lower after adjusting for patient characteristics. Adherence and persistence with dabigatran remained lower throughout follow-up., Conclusion: Persistence and adherence were high among NOAC users in five Western European healthcare settings and increased in later years. Dabigatran use was associated with slightly lower persistence and adherence compared with apixaban and rivaroxaban., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Studies on adherence and persistence with non-vitamin K oral anticoagulant (NOAC) treatment have relied on data from the early years of NOAC availability. We aimed to study long-term adherence and persistence with NOACs and their association with stroke risk., Methods and Results: From the Stockholm Healthcare database, we included 21 028 atrial fibrillation patients claiming a first NOAC prescription from July 2011 until October 2018, with more than 1000 patients having more than 5 years of follow-up (median: 2.0, interquartile range: 1.0-3.2). Persistence rates, defined as continuing to claim NOAC prescriptions within a 90-day gap, decreased to 70% at the end of follow-up. However, 85% of the patients were treated at the end of the study due to reinitiations. Adherence, calculated as medication possession rate (MPR) in 3 and 6-month intervals among persistent users, remained stable at 90%, with 75% of patients having an MPR >95% throughout the study period. Using a case-control design, we calculated associations of persistence and adherence with stroke risk, adjusting for potential confounders. The outcome was a composite of ischaemic or unspecified stroke and transient ischaemic attack. Non-persistence and poor adherence were both associated with increased stroke risk [non-persistence adjusted odds ratio (aOR): 2.05; 95% confidence interval (CI): 1.49-2.82, 1% reduction MPR aOR: 1.03; CI: 1.01-1.05]. There was no association between non-persistence or poor adherence and the falsification endpoints; fractions and respiratory infections, indicating no 'healthy-adherer' effect., Conclusion: Persistence rates decreased slowly over time, but persistent patients had high adherence rates. Both non-persistence and poor adherence were associated with an increased stroke risk., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: To analyse 90-day mortality in atrial fibrillation (AF) patients after a stroke or a severe bleed and assess associations with the type of antithrombotic treatment at the event., Methods and Results: From the Stockholm Healthcare database, we selected 6017 patients with a known history of AF who were diagnosed with ischaemic stroke, 3006 with intracranial haemorrhage, and 4291 with a severe gastrointestinal bleed (GIB). The 90-day mortality rates were 25.1% after ischaemic stroke, 31.6% after intracranial haemorrhage, and 16.2% after severe GIB. We used Cox regression and propensity score-matched analyses to test the association between antithrombotic treatment at the event and 90-day mortality. After intracranial haemorrhage, there was a significantly higher mortality rate in warfarin compared to non-vitamin K oral anticoagulant (NOAC)-treated patients [adjusted hazard ratio (aHR) 1.36, 95% confidence interval (CI) 1.04-1.78]. After an ischaemic stroke and a severe GIB, patients receiving antiplatelets or no antithrombotic treatment had significantly higher mortality rates compared to patients on NOACs, but there was no difference comparing warfarin to NOACs (aHR 0.84, CI 0.63-1.12 after ischaemic stroke, aHR 0.91, CI 0.66-1.25 after severe GIB). Propensity score-matched analysis yielded similar results., Conclusion: Mortality rates were high in AF patients suffering from an ischaemic stroke, an intracranial haemorrhage, or a severe GIB. NOAC treatment was associated with a lower 90-day mortality after intracranial haemorrhage than warfarin., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Oral anticoagulants (OACs) effectively reduce the risk of stroke in atrial fibrillation (AF). Three non-vitamin K antagonist OACs (NOACs) are introduced in regular care based on promising results compared with warfarin in randomized trials. This study compares outcomes with NOAC vs. warfarin treatment in OAC naïve AF patients in routine care, including primary care, in a large region with decentralized anticoagulant treatment., Methods and Results: Population-based cohort study. Individuals with non-valvular AF who initiated treatment with NOAC (n = 9279) or warfarin (n = 12 919) from 2012 to 2015 were identified in the Stockholm administrative health data register (population 2.2 million). Adjusted Cox regression analyses were performed to evaluate TIA/ischaemic or unspecified stroke/death, and severe bleeds (co-primary endpoints); and secondarily for components of the composites. NOAC patients were younger (72.9 vs. 74.1 years) and had lower CHA2DS2VASc scores (3.42 vs. 3.68) than warfarin patients. NOAC vs. warfarin treatment was associated with similar risks for TIA/ischaemic or unspecified stroke/death [hazard ratio (HR) 0.94; 0.85-1.05] and severe bleeds (HR 1.02; 0.88-1.19); lower risks of intracranial bleeds (HR 0.72; 0.53-0.97) or haemorrhagic stroke (HR 0.56; 0.34-0.93), but a higher risk for gastrointestinal bleeds (HR 1.28; 1.04-1.59). The advantages with NOAC treatment were most pronounced with standard dose in patients below 80 years, and with dose reduction in patients aged 80 and above., Conclusion: This population-based cohort study of routine care indicates similar or better effectiveness and safety with NOAC compared with warfarin treatment. NOACs were associated with fewer intracranial bleeds, but more gastrointestinal bleeds., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Background: Elevated levels of circulating microparticles (MPs) may contribute to the high cardiovascular risk in diabetes mellitus (DM) and chronic kidney disease (CKD). Therefore, we investigated the effects of lipid-lowering treatment (LLT) with simvastatin alone (S) or with ezetimibe (S+E) on MPs in DM patients with or without CKD., Methods: After a placebo run-in period, 18 DM patients with an estimated glomerular filtration rate (eGFR) of 15-59 mL/min (CKD stages 3-4) (DM-CKD) and 21 DM patients with eGFR >75 mL/min (DM-only) were treated with S and S+E in a randomized, double-blind, crossover study. MPs from platelets, monocytes and endothelial cells (PMPs, MMPs and EMPs), and their expression of phosphatidylserine (PS), P-selectin, CD40 ligand (CD40L) and tissue factor (TF) were measured by flow cytometry., Results: At baseline, all types of MPs, except TF-positive MMPs, were elevated in DM-CKD compared with DM-only patients. All MPs, regardless of origin and phenotype, were inversely correlated with eGFR. S reduced the expression of P-selectin, TF and CD40L on PMPs and of TF on MMPs in both patient groups. S+E had no further effect. S also reduced total PS-positive procoagulant MPs, PMPs and MMPs in DM-CKD but not in DM-only patients., Conclusions: DM patients with CKD stages 3-4 had elevated PMPs, EMPs and MMPs compared with DM patients with normal GFR. Simvastatin reduced procoagulant MPs, MMPs and PMPs in DM-CKD patients, suggesting a beneficial reduction of hypercoagulability in this high-risk patient group. Differences between DM-CKD and DM-only patients were counteracted by LLT., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Diabetes mellitus (DM) is associated with hyperreactive platelets and increased platelet-leukocyte aggregation (PLA), but the impact of concomitant chronic kidney disease (CKD) has been much less studied. Lipid-lowering treatment (LLT) may have favorable effects on platelet activation and inflammation. The objective of this mechanistic study was to investigate the impact of CKD on platelet function and inflammatory parameters in patients with DM and the effects of LLT., Methods: After a placebo run-in period, the effects of simvastatin alone (S) or simvastatin + ezetimibe (S + E) were compared in a randomized, double-blind, cross-over study on platelet reactivity, PLA formation and inflammatory parameters. Eighteen DM patients with estimated glomerular filtration rate (eGFR) 15-59 mL/min × 1.73 m(2) (CKD stages 3-4) (DM-CKD) and 21 DM patients with eGFR >75 mL/min (DM-only) were included., Results: PLAs were elevated at baseline in DM-CKD compared with DM-only (P = 0.04). S + E reduced PLAs among total leukocytes and neutrophils in DM-CKD patients (P = 0.01 for both) but not in the DM-only group. Platelet reactivity did not differ between patient groups or with LLT. Plasma levels of sCD40L (P < 0.001), elastase (P < 0.01) and von Willebrand factor (VWF) (P < 0.001) were elevated in DM-CKD compared with DM-only. S + E reduced sCD40L in DM-CKD patients (P = 0.01), but LLT did not influence VWF or elastase., Conclusions: DM patients with CKD stages 3-4 had increased PLA and inflammatory activity compared with DM patients with normal GFR. Simvastatin + ezetimbe decreased PLAs and plasma sCD40L in DM patients with concomitant CKD. Clinical Trial registration http://www.clinicaltrials.gov. Identifier NCT01035320.

Background: Ultrasonographic assessments of intima-media thickness and plaques in the carotid artery are widely used as surrogate markers for coronary atherosclerosis, but prospective evaluations are scarce and appear to be lacking in patients with coronary artery disease. Ultrasonographic evaluations of femoral vascular changes have not been studied prospectively., Methods and Results: In the Angina Prognosis Study in Stockholm (APSIS), 809 patients with stable angina pectoris were studied prospectively during double-blind treatment with verapamil or metoprolol. Ultrasonographic assessments of intima-media thickness, lumen diameter and plaques in the carotid and femoral arteries were evaluated in a subgroup of 558 patients (182 females) with a mean age of 60 +/-7 years, and related to the risk of cardiovascular death (n = 18) or non-fatal myocardial infarction (n = 26), or revascularization (n = 70) during follow-up (median 3.0 years). Univariate Cox regression analyses showed that carotid intima-media thickness and plaques were related to the risk of cardiovascular death or myocardial infarction. Femoral intima-media thickness was related to cardiovascular death or myocardial infarction, as well as to revascularization, whereas femoral plaques were only related to the latter. After adjustment for age, sex, smoking, previous cardiovascular disease and lipid status, carotid intima-media thickness failed to predict any cardiovascular event, whereas carotid plaques tended (P = 0.056) to predict the risk of cardiovascular death or myocardial infarction. Femoral intima-media thickness (P < 0.01) and plaques (P < 0.05) were also related to the risk of revascularization after adjustments., Conclusions: Carotid and femoral vascular changes were differently related to cardiovascular events. Carotid intima-media thickness was a weak predictor of events, whereas femoral intima-media thickness predicted revascularization. Plaques in the carotid artery were related to cardiovascular death or non-fatal myocardial infarction, whereas plaques in the femoral artery were related to revascularization. Evaluations of plaques provided better prediction than assessments of intima-media thickness in patients with stable angina., (Copyright 2001 The European Society of Cardiology.)

Aims: To evaluate the prognostic implications of results from exercise testing, and of antianginal treatment among patients with chronic stable angina pectoris., Material and Methods: Out of 809 patients in the Angina Prognosis Study In Stockholm (APSIS), 731 (511 men) performed evaluable exercise tests before and after 1 month on double-blind treatment with metoprolol or verapamil. During a median follow-up of 40 months, 32 patients suffered a cardiovascular death and 29 a non-fatal myocardial infarction., Results: Prognostic implications of results from exercise tests were assessed in a multivariate Cox model which included sex, previous myocardial infarction, hypertension and diabetes mellitus. Maximal ST-segment depression, especially if >/=2 mm and occurring after exercise, as well as exercise duration independently predicted cardiovascular death. Similar results were obtained for the combined end-point of cardiovascular death+myocardial infarction. Among patients with a positive exercise test at baseline, verapamil reduced the maximal ST-depression more markedly than metoprolol (P<0. 01). However, when the treatment given and treatment effects on ST-segment depression were added to the Cox model, no impact on prognosis could be detected for either cardiovascular death alone or combined with myocardial infarction. Anginal pain carried no prognostic information., Conclusion: Marked ST-segment depression during and after exercise, and a low exercise capacity independently predicted an adverse outcome in patients with stable angina pectoris, whereas anginal symptoms had no predictive value. Short-term treatment effects on ischaemia did not seem to influence prognosis. Post-exercise ischaemia should be examined carefully when evaluating patients with stable angina pectoris., (Copyright 2000 The European Society of Cardiology.)

Aims: Inflammatory mechanisms have been implicated in the pathogenesis of atherosclerosis. Cell adhesion molecules, expressed on endothelial cells and leukocytes, mediate transendothelial migration of leukocytes into the vessel wall, but also circulate in soluble forms. In the present study we related soluble cell adhesion molecules to the risk of suffering a cardiovascular death or a non-fatal myocardial infarction (cardiovascular death/myocardial infarction) in a substudy to the Angina Prognosis Study in Stockholm (APSIS)., Methods and Results: Soluble intercellular adhesion molecule-1, vascular adhesion molecule-1 and E-selectin were measured in serum collected on inclusion in the APSIS study. During follow-up, seven patients suffered non-fatal myocardial infarction or cardiovascular death, whereas 86 patients were event-free. Cardiovascular death/myocardial infarction was associated with elevated intercellular adhesion molecule-1 (354+/-142 vs 282+/-62ng x ml-1;P<0.01) and vascular adhesion molecule-1 (538+/-138 vs 433+/-135ng x ml-1;P =0.05), and E-selectin levels tended to be higher (72+/-54 vs 49+/-20ng x ml-1). Clinical risk factors (history of hypertension, previous myocardial infarction, diabetes and smoking) were more abundant in the event group. Subgroup analyses showed that hypertension, smoking or male sex were associated with elevated intercellular adhesion molecule-1, whereas previous myocardial infarction or male sex were associated with elevated vascular adhesion molecule-1., Conclusion: Patients with stable angina pectoris who developed cardiovascular death/myocardial infarction had elevated serum levels of soluble cell adhesion molecules, indicating increased inflammatory activity. The value of soluble cell adhesion molecules as prognostic markers in patients with stable ischaemic heart disease merits further study., (Copyright 1999 The European Society of Cardiology.)

Aim: To investigate the influence on plasma fibrin gel structure of low and intermediate doses of acetylsalicylic acid in healthy individuals. The influence of acetylsalicylic acid on thrombin formation, fibrinolytic capacity and plasminogen inhibitor-1 in plasma was also investigated., Methods: Nineteen subjects were treated with 75 mg and 11 with 320 mg acetylsalicylic acid daily; eight subjects received both doses. Fibrin gel structure was determined by a permeability technique yielding a porosity constant (Ks), and the thromboxane metabolite 11-dehydro-thromboxane B2 (TxM) was determined by an ELISA., Results: Acetylsalicylic acid increased fibrin porosity by 65% at 75 mg (P<0.001, n=19), whereas lower increases were found at 320 mg (+22%, P<0.05, n=11). One week after withdrawal Ks had essentially returned to baseline (ns). Urinary thromboxane metabolites were suppressed during treatment (-61%, P<0.001 at 75 mg, n=19; -46%, P<0.01 at 320 mg, n=11). The intra-individual comparison showed similar results (Ks +92%, TxM -62% at 75 mg; Ks +5%, TxM -52% at 320 mg). Fibrinolytic capacity, plasminogen inhibitor-1 levels and thrombin generation (in platelet-poor citrated plasma) were not influenced., Conclusion: Low dose acetylsalicylic acid causes the greatest increase in fibrin gel porosity; this may well be of therapeutic importance.

In this randomized controlled crossover study essential hypertensive men (n = 13) and matched normotensive controls (n = 18) were examined before and during cigarette and sham smoking to assess the acute effects of smoking on platelets and plasma catecholamines. Platelet activity in vivo was determined by measurements of the released alpha-granule constituent beta-thromboglobulin (beta-TG) in plasma and in urine. Urinary high molecular weight beta-TG and venous plasma epinephrine increased significantly during smoking in the hypertensive group, but not among the normotensive men. Thus, cigarette smoking induces a mild platelet release reaction and also elicits a significantly higher epinephrine response in hypertensive men compared to normotensive controls.

Aims: To evaluate signs of ischaemia and ventricular arrhythmias in relation to gender and sympathoadrenal activity in patients with stable angina pectoris and healthy controls., Material and Methods: 809 patients (248 females) with stable angina pectoris, and 50 matched healthy controls performed an exercise test and an ambulatory ECG recording. Catecholamines were measured in plasma before and immediately after exercise, and in urine during ambulatory ECG., Results: Male and female patients showed similar frequencies of ST-depression, similar blood pressure and catecholamine responses on exercise testing. Females had higher heart rates and were more prone towards silent ischaemia. The healthy controls exercised longer and showed greater adrenaline responses. During ambulatory ECG, the two genders had similar duration of ST-depression, but males had more premature ventricular complexes. Females excreted more noradrenaline, and had higher minimal and maximal heart rates. Premature ventricular complexes were equally common among patients and controls, but controls had greater catecholamine excretion. Maximal ST-depression during exercise was positively related to the duration of ST-depression during ambulatory ECG for both genders. Exercise time until ST-depression was inversely related to the duration of ST-depression during ambulatory ECG among male patients only. Catecholamine responses during exercise testing were more closely correlated to time until chest pain than to signs of ischaemia., Conclusion: Mechanisms behind myocardial ischaemia and arrhythmias may differ in male and female patients, as females seem to be more prone towards silent ischaemia. Ischaemia on exercise correlated to ambulatory ischaemia among males only.

Three commercial immunoassay systems (EMIT, EPIA, Online) for the screening of benzodiazepines in urine were evaluated using authentic patient samples with gas chromatography-mass spectrometry (GC-MS) as the reference method. The Online system (kinetic interaction of microparticles in solution) gained in performance by applying a 100-ng/mL cutoff limit and by incorporating beta-glucuronidase treatment, which could be automated on the Cobas Mira Plus instrument. When using enzymatic hydrolysis, all three immunoassay systems had high levels of sensitivity, including samples containing only flunitrazepam and nitrazepam metabolites. A high degree of concordance was observed between the Online and FPIA (fluorescence polarization immunoassay) systems when analyzing 138 randomly selected patient samples. The EMIT II and EMIT d.a.u. (enzyme multiplied immuno technique) systems gave a higher number of positive results, but the presence of benzodiazepines could not be verified by GC-MS in a substantial number of these cases. The rate of unconfirmed positive results was increased when enzyme hydrolysis was incorporated in the EMIT II assay. Although differences in the performances of the investigated assay systems were observed, they all seem appropriate for clinical use in detecting benzodiazepine intake in drug abusers when enzymatic hydrolysis is included.

Aim: This study was set up to evaluate psychosocial risk factors in patients with stable angina pectoris, with particular attention to gender differences, as this has previously been studied mainly in relation to myocardial infarction in males., Material: Seven hundred and sixty-seven patients (236 women) were studied. They were selected from the 809 patients included in the Angina Prognosis Study in Stockholm (APSIS), and 50 matched healthy subjects., Method: Data were gathered by structured psychosocial interviews on inclusion into the APSIS study., Results: Patients with stable angina pectoris experienced significantly more stressful events, and suffered more frequently from disturbed and psychosomatic symptoms than healthy controls. At work they experienced less skill discretion and less control. The patients had higher rating scores for hostility and lower levels of self-rated overall well-being. With regard to gender differences, women were more likely to suffer from the strain of work, psychosomatic symptoms, disturbed sleep and stressful events than male patients. Females rated less type A-behaviour and hostility than males., Conclusions: These findings suggest that previously known psychosocial risk factors for acute myocardial infarction are more common in patients with stable angina pectoris than in controls, and differ between female and male patients.

The effects of mental and physical stress on platelet function in patients with stable angina pectoris and healthy controls were investigated. Platelet function was studied at rest, and during mental stress (colour word test), or after exercise (bicycle ergometry), in 113 angina patients (21 on aspirin) and 50 matched controls. Platelet function was assessed by filtragometry ex vivo (reflecting platelet aggregability), by measuring platelet secretion (beta-thromboglobulin and platelet factor 4 levels in plasma), and by Born aggregometry in vitro. At rest, platelet function did not differ between patients and controls. Exercise increased platelet aggregability and secretion similarly in both groups. Aspirin did not attenuate the platelet activating effect of exercise despite inhibition at rest. Mental stress increased heart rate, blood pressure and plasma catecholamines, but platelet responses were highly variable. However, mental stress tended to shorten filtragometry readings in patients but not in controls (P < 0.05 between the groups); plasma beta-thromboglobulin showed a similar difference between patients and controls (P < 0.05 between the groups; aspirin-treated patients included). Physical exercise activates platelets in patients with stable angina pectoris and healthy controls. Aspirin is not an effective inhibitor of exercise-induced platelet aggregation. Platelet responses to mental stress are variable, but more pronounced in angina patients.

Calcium antagonists are a heterogeneous class of drugs, with different influences on neuro-hormonal activity and platelet function. Sympathetic nerves and platelets lack L-type calcium channels--calcium antagonist effects are thus related to indirect effects (cardiovascular and neurohormonal adaptation) and/or other actions on cellular mechanisms. Vascularly selective dihydropyridines usually elicit increases in heart rate, sympathetic counterregulation and renin release in the short term. In the long term, heart rate returns to basal levels, but sympathetic activity remains elevated in most studies. Heart-rate reducing calcium antagonists yield different results, with normal or reduced sympathetic activity on verapamil, and normal or elevated activity on diltiazem. Studies have mainly concerned venous plasma noradrenaline levels. There is therefore a need for more detailed studies to evaluate overall and regional sympathetic activity, and for heart rate variability studies. Antiplatelet effects of calcium antagonists are extensively documented in vitro, but such studies may reflect treatment effects poorly, and often involve high concentrations of the drugs. Clinical studies of platelet function also suggest antiplatelet effects, but the methods used have not always been optimal, and results have not been entirely consistent. More detailed and better controlled studies with in vivo-related techniques and fewer artefact influences from sampling, for example, are needed to fully evaluate calcium antagonists' effects on platelet function. Verapamil is most documented with regard to antiplatelet effects, but is also the calcium antagonist with the most varied possible mechanisms of action. Due to the heterogeneity of this class of drugs, documentation for one calcium antagonist cannot be generalized to also represent another with regard to neuro-hormonal or antiplatelet effects, especially when considering that these effects are not directly related to inhibition of Ca2+ influx via L-type calcium channels.

Objective: To study long-term treatment effects of metoprolol or verapamil on combined cardiovascular end points and psychological variables in patients with stable angina pectoris., Design: Randomized, double-blind, double-dummy trial., Patients: The study included 809 patients under 70 years of age with stable angina pectoris. The mean age of the patients was 59 +/- 7 years and 31% were women. Exclusion criteria were myocardial infarction within the previous 3 years and contraindications to beta-blockers and calcium antagonists. The patients were followed between 6 and 75 months (median 3.4 years and a total of 2887 patient years)., Intervention: The patients were treated with either metoprolol (Seloken ZOC 200 mg o.d.) or verapamil (Isoptin Retard 240 b.i.d.). Acetylsalicylic acid, ACE inhibitors, lipid lowering drugs and long acting nitrates were allowed in the study., End Points: Death, non-fatal cardiovascular events including acute myocardial infarction, incapacitating or unstable angina, cerebrovascular or peripheral vascular events. Psychological variables reflecting quality of life i.e. psychosomatic symptoms, sleep disturbances and an evaluation of overall life satisfaction., Results: Combined cardiovascular events did not differ and occurred in 30.8% and 29.3% of metoprolol and verapamil treated patients respectively. Total mortality in metoprolol and verapamil treated patients was 5.4 and 6.2%, respectively. Cardiovascular mortality was 4.7% in both groups. Non-fatal cardiovascular events occurred in 26.1 and 24.3% of metoprolol and verapamil-treated patients, respectively. Psychosomatic symptoms and sleep disturbances were significantly improved in both treatment groups. The magnitudes of change were small and did not differ between treatments. Life satisfaction did not change on either drug. Withdrawals due to side effects occurred in 11.1 and 14.6% respectively., Conclusion: This long term study indicates that both drugs are well tolerated and that no difference was shown on the effect on mortality, cardiovascular end points and measures of quality of life.

Increased plasma levels of beta-thromboglobulin, a platelet activation marker, are observed in coronary artery disease. Urinary albumin excretion, a marker of endothelial cell perturbation, is related to cardiovascular disease in diabetes. To test the value of these markers in predicting forthcoming coronary disease, the relations between urinary excretions of high molecular weight beta-thromboglobulin (HMW-beta TGf) and albumin and subsequent coronary disease in a cohort of 15,484 middle-aged women were investigated in a nested case-control study. Baseline questionnaire data and urine samples were available from a breast cancer screening program in Utrecht during 1982-1985. Cases were Utrecht hospital admissions for myocardial infarction (n = 50) or angiographically confirmed coronary disease (n = 28) from 1982-1985 to 1990-1991. Classifying events occurred a median of 5.1 years after baseline. Controls were a random sample from the cohort, individually case matched for baseline examination date and age, at a 1:2 ratio. HMW-beta TG/creatinine ratios (ng/mmol, mean +/- standard error) were 5.3 +/- 0.3 in cases and 4.7 +/- 0.3 in controls; albumin/creatinine ratios (mg/mmol, median) were, respectively, 0.37 and 0.22. Crude odds ratios for classification in the highest compared with the lowest tertiles of HMW-beta TG/creatinine and albumin/creatinine distributions were elevated for cases compared with controls: HMW-beta TG/creatinine odds ratio = 2.4, 95% confidence interval 1.1-5.0; albumin/creatinine odds ratio = 2.1, 95% confidence interval 1.0-4.1. These relations persisted after adjustment for smoking, hypertension, Quetelet index, and menopausal status. Both urinary HMW-beta TG and albumin excretion are markers of coronary disease risk in middle-aged women, indicating that increased platelet activation and endothelial cell perturbation precede coronary heart disease events in women.

We investigated cardiovascular and coronary responses to intravenous infusions of adrenaline, which raised arterial concentrations in a stepwise fashion from basal to about 5-6 nmol.l-1, in 11 non-rejecting heart transplanted patients, and in eight intact innervated subjects. Cardiac adrenaline extraction and noradrenaline release rate were also measured. The transplanted patients showed larger increases in heart rate (36 +/- 11% vs 16 +/- 6%, P < 0.0001) and cardiac index (80 +/- 30% vs 56 +/- 19%, P < 0.05), while stroke volume increments were similar in the two groups (32 +/- 17% vs 35 +/- 13%). The study groups did not differ with respect to changes in arterial pressure, cardiac work or peripheral resistances. Coronary sinus blood flow increased to a greater extent in the transplanted group (75 +/- 35% vs 48 +/- 31%, P < 0.05) and myocardial oxygen consumption also tended to increase more in these patients (78 +/- 42% vs 48 +/- 34%, NS). Myocardial adrenaline extraction was greatly reduced in the transplant patients (-6 +/- 25% vs 64 +/- 18%, P < 0.001), while forearm adrenaline extraction was similar in the two groups (41 +/- 22% vs 40 +/- 23%, NS). Cardiac noradrenaline overflow tended to be lower in the transplanted group (12 +/- 62 vs 48 +/- 43 pmol.min-1, NS). There was a wide range of noradrenaline overflow values (-64 to 147 pmol.min-1) and definite high values in three patients. Cardiac noradrenaline overflow was not correlated to heart rate responsiveness to adrenaline. We conclude that patients with cardiac transplantation respond to adrenaline with exaggerated increases in heart rate and thus in cardiac output. High values of cardiac noradrenaline overflow are seen in some transplant recipients and may suggest reinnervation. Signs of reinnervation are not associated with consistently lower heart rate responses to beta-adrenergic stimulation.

We evaluated the EMIT (enzyme-multiplied immuno technique) and FPIA (fluorescence polarization immunoassay) urine screening systems for detection of benzodiazepine intake. Healthy male volunteers were given single oral therapeutic doses of alprazolam (2 mg), chlordiazepoxide (25 mg), flunitrazepam (1 mg), lorazepam (3.75 mg), nitrazepam (5 mg), and triazolam (0.25 mg), after which urine was collected for the next 32 h. The EMIT method failed to detect the intake of flunitrazepam, lorazepam, and nitrazepam. FPIA did not detect the intake of chlordiazepoxide, flunitrazepam, lorazepam, nitrazepam, and triazolam. Modification of the EMIT method to include enzymatic hydrolysis did not significantly alter the results obtained with this method. A modification of the FPIA method to include enzymatic hydrolysis and a lower cutoff value improved the results considerably, so that we reliably detected all studied substances but flunitrazepam. We conclude that (a) both EMIT and FPIA techniques, when used as intended by the manufacturers, are unreliable for the detection of intake of therapeutic doses of these benzodiazepines, and (b) the described modification of the FPIA should provide a much improved tool for detection of benzodiazepine intake.

We report here a simple method involving urine creatine measurements for testing authenticity and reducing false-negative results in urine testing for drugs of abuse. Urinary creatinine in consecutive patient samples (n = 176) ranged between 0.1 and 31.9 mmol/L (mean 9.8 +/- SD 6.2) and the osmolality in these urines ranged between 49 and 1183 mOsm/kg (mean 595 +/- SD 276). With other consecutive samples in which creatinine was (arbitrarily chosen) less than 4.3 mmol/L (n = 85), the correlation with osmolality was lower. In 10 randomly selected urine samples from different patients, all "clean" for all drugs of abuse in initial immunological drug testing with approved methodology (in which creatinine was less than 4.3 mmol/L and osmolality was less than 200 mOsm/kg), five patients turned out to be drug positive after a simple concentration by volume. In a formerly heavy smoker of cannabis, the excretion of cannabinoids and creatinine was monitored for 93 days. The substances showed very good correlation throughout this period (r = 0.93, P less than 0.001), whereas simple measurements of cannabinoid concentrations would have falsely indicated several relapses of cannabis abuse. Urine samples used in drug-abuse testing should be tested for creatinine; if creatinine is less than 4.0 mmol/L, negative results for drugs may not be valid.

Haemodynamics and plasma catecholamine responses to isometric exercise were evaluated invasively in 11 orthotopic heart transplant recipients and seven control subjects. Differences in haemodynamic responses between the two groups were already apparent after one min of handgrip at 30% of maximal voluntary contraction, and very pronounced at the end of the fourth minute. At this point transplanted patients showed smaller increments in heart rate (4.8 +/- 3.2 vs 20.4 +/- 14.1 beats.min-1, P less than 0.001), mean arterial pressure (13.7 +/- 7.2 vs 31.5 +/- 12.2 mmHg, P less than 0.001) and cardiac index (0.51 +/- 0.22 vs 1.02 +/- 0.53 L.min-1.m-2, P less than 0.01), whereas left ventricular end-diastolic pressure increased to a greater extent (8.8 +/- 4.9 vs 2.2 +/- 1.8 mmHg, P less than 0.01). Stroke volume index increased similarly (3.8 +/- 1.8 vs 2.0 +/- 3.5 ml beat-1.m-2, NS) and systemic vascular resistance remained unchanged in both groups. The slopes of the left ventricular function curves (ratio of change in left ventricular work to change in left ventricular end-diastolic pressure) indicated depressed left ventricular function in the transplanted patients. The two groups showed similar increments in mixed venous plasma norepinephrine and epinephrine indicating normal sympathoadrenal activation in the transplanted patients. In conclusion, transplanted hearts respond to handgrip with attenuated increases in heart rate, cardiac output and arterial pressure and by increasing left ventricular filling pressure, suggesting a poor contractile reserve probably due to denervation. Circulating catecholamines, especially epinephrine, probably contribute to the cardiac responses to isometric exercise.

The effects of mental stress and dynamic exercise on central haemodynamic variables and cardiac sympathetic nerve activity were studied in 15 patients during both fixed rate ventricular-inhibited (VVI) and QT interval-sensing rate-responsive (TX) pacing. Haemodynamic measurements were made at rest, during a mental stress test and during supine exercise at 30 W. Cardiac sympathetic nerve activity was assessed by measuring the arterial and coronary sinus plasma concentrations of noradrenaline (NA) and adrenaline (ADR), the NA kinetics in arterial plasma (radiotracer infusion) and the overflow of NA into the coronary sinus. During exercise the paced ventricular rate increased by 47% with TX. TX provided a higher cardiac output than VVI despite a similar myocardial oxygen consumption and a lower level of cardiac sympathetic activity. Cardiac NA overflow based on 3H-NA extraction over the heart increased from 182 to 1046 pmol min-1 in the VVI mode (P less than 0.01) and from 178 to 793 pmol min-1 in the TX mode (P less than 0.001). The difference in cardiac NA overflow in response to exercise (P less than 0.05 by ANOVA) was not reflected in similar differences in arterial NA concentrations or spill over rates. During mental stress the ventricular rate increased in 12/14 patients. Noradrenaline overflow increased similarly in the two modes. Changes in cardiac NA overflow during mental stress and exercise were correlated with increases in TX pacing rate. This study confirms that both mental and physical stress cause significant changes in cardiac sympathetic nerve activity and central haemodynamic variables, and that the TX pacemaker responds by increasing its pacing rate in a physiological manner.

In 34 patients on double-blind postinfarction treatment with metoprolol 100-200 mg daily (N = 20) or matching placebo, the study treatment was gradually withdrawn during one week. The patients were subjected to mental stress (a modified version of Stroop's colour word conflict test) before and 1 and 12 weeks after the completion of double-blind withdrawal. This stress increased heart rate (P less than 0.001), blood pressures (P less than 0.001) and adrenaline (P = 0.003), but not noradrenaline in venous plasma. In the placebo group similar responses were evoked on all three occasions. In the metoprolol group, heart rate responses were reduced while on treatment. Following withdrawal there was no rebound increase in the heart rate response. Rather, some blockade persisted one week after withdrawal. Twelve weeks after withdrawal heart rate and blood pressure responses to mental stress were normalized. During treatment the metoprolol group had fewer ventricular arrhythmias than the placebo group. Following withdrawal, ventricular arrhythmias during stress increased in 4 patients in the metoprolol group. Plasma adrenaline levels were reduced one week after withdrawal of metoprolol treatment. Plasma noradrenaline levels did not change within either group during the follow-up period. Thus, no rebound increase in cardiovascular reactivity to mental stress was found, in contrast to our previous findings with physical stressors in similar patients participating in this study. These differences in responsiveness after metoprolol withdrawal may be related to different clearance rates for metoprolol in different tissues. Our results indicate that central, presumably supramedullary, cardiovascular control mechanisms involving beta-adrenoceptors recover at a slow rate following withdrawal.