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Background: The contribution of atrial fibrillation (AF) to the etiology and burden of stroke may vary by country income level., Aims: We examined differences in the prevalence of AF and described variations in the magnitude of the association between AF and ischemic stroke by country income level., Methods: In the INTERSTROKE case-control study, participants with acute first ischemic stroke were recruited across 32 countries. We included 10,363 ischemic stroke cases and 10,333 community or hospital controls who were matched for age, sex, and center. Participants were grouped into high-income (HIC), upper-middle-income (subdivided into two groups-UMIC-1 and UMIC-2), and lower-middle-income (LMIC) countries, based on gross national income. We evaluated the risk factors for AF overall and by country income level, and evaluated the association of AF with ischemic stroke., Results: AF was documented in 11.9% (n = 1235) of cases and 3.2% (n = 328) of controls. Compared to HIC, the prevalence of AF was significantly lower in UMIC-2 (aOR 0.35, 95% CI 0.29-0.41) and LMIC (aOR 0.50, 95% CI 0.41-0.60) on multivariable analysis. Hypertension, female sex, valvular heart disease, and alcohol intake were stronger risk factors for AF in lower-income countries, and obesity a stronger risk factor in higher-income countries. The magnitude of association between AF and ischemic stroke was significantly higher in lower-income countries compared to higher-income countries. The population attributable fraction for AF and stroke varied by region and was 15.7% (95% CI 13.7-17.8) in HIC, 14.6% (95% CI 12.3-17.1) in UMIC-1, 5.7% (95% CI 4.9-6.7) in UMIC-2, and 6.3% (95% CI 5.3-7.3) in LMIC., Conclusion: Risk factors for AF vary by country income level. AF contributes to stroke burden to a greater extent in higher-income countries than in lower-income countries, due to a higher prevalence and despite a lower magnitude of odds ratio., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Smoking is a major risk factor for the global burden of stroke. We have previously reported a global population attributable risk (PAR) of stroke of 12.4% associated with current smoking. In this study we aimed to explore the association of current tobacco use with different types of tobacco exposure and environmental tobacco smoke (ETS) exposure on the risk of stroke and stroke subtypes, and by regions and country income levels., Methods: The INTERSTROKE study is a case-control study of acute first stroke and was undertaken with 13,462 stroke cases and 13,488 controls recruited between January 11, 2007 and August 8, 2015 in 32 countries worldwide. Association of risk of tobacco use and ETS exposure were analysed with overall stroke, ischemic and intracerebral hemorrhage (ICH), and with TOAST etiological stroke subtypes (large vessel, small vessel, cardioembolism, and undetermined)., Findings: Current smoking was associated with an increased risk of all stroke (odds ratio [OR] 1.64, 95% CI 1.46-1.84), and had a stronger association with ischemic stroke (OR 1.85, 95% CI 1.61-2.11) than ICH (OR 1.19 95% CI 1.00-1.41). The OR and PAR of stroke among current smokers varied significantly between regions and income levels with high income countries (HIC) having the highest odds (OR 3.02 95% CI 2.24-4.10) and PAR (18.6%, 15.1-22.8%). Among etiological subtypes of ischemic stroke, the strongest association of current smoking was seen for large vessel stroke (OR 2.16, 95% CI 1.63-2.87) and undetermined cause (OR 1.97, 95% CI 1.55-2.50). Both filtered (OR 1.73, 95% CI 1.50-1.99) and non-filtered (OR 2.59, 95% CI 1.79-3.77) cigarettes were associated with stroke risk. ETS exposure increased the risk of stroke in a dose-dependent manner, exposure for more than 10 h per week increased risk for all stroke (OR 1.95, 95% CI 1.69-2.27), ischemic stroke (OR 1.89, 95% CI 1.59-2.24) and ICH (OR 2.00, 95% CI 1.60-2.50)., Interpretation: There are significant variations in the magnitude of risk and PAR of stroke according to the types of tobacco used, active and ETS exposure, and countries with different income levels. Specific strategies to discourage tobacco use by any form and to build a smoke free environment should be implemented to ease the global burden of stroke., Funding: The Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland, and through unrestricted grants from several pharmaceutical companies with major contributions from Astra Zeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MERCK, Sharp and Dohme, Swedish Heart and Lung Foundation, UK Chest, and UK Heart and Stroke., Competing Interests: We declare no competing interests. Dr. Hans-Christoph Diener has reported receiving fees from Pfizer, Abbott, and Daiichi Sankyo. Dr. Denis Xavier reported receiving grants from Population Health Research Institute, Hamilton Health Science, Boehringer Ingelheim, Bristol Myers Squibb, Coco cola India, Indian Council of Medical Research, Pfizer, United Kingdom Medical Research Council and Welcome Trust., (© 2024 The Authors.)

Background and Purpose: The association of dyslipidemia with stroke has been inconsistent, which may be due to differing associations within etiological stroke subtypes. We sought to determine the association of lipoproteins and apolipoproteins within stroke subtypes., Methods: Standardized incident case-control STROKE study in 32 countries. Cases were patients with acute hospitalized first stroke, and matched by age, sex and site to controls. Concentrations of total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (apoA1), and apoB were measured. Non-HDL-C was calculated. We estimated multivariable odds ratio (OR) and population attributable risk percentage (PAR%). Outcome measures were all stroke, ischemic stroke (and subtypes), and intracerebral hemorrhage (ICH)., Results: Our analysis included 11,898 matched case-control pairs; 77.3% with ischemic stroke and 22.7% with ICH. Increasing apoB (OR, 1.10; 95% confidence interval [CI], 1.06 to 1.14 per standard deviation [SD]) and LDL-C (OR, 1.06; 95% CI, 1.02 to 1.10 per SD) were associated with an increase in risk of ischemic stroke, but a reduced risk of ICH. Increased apoB was significantly associated with large vessel stroke (PAR 13.4%; 95% CI, 5.6 to 28.4) and stroke of undetermined cause. Higher HDL-C (OR, 0.75; 95% CI, 0.72 to 0.78 per SD) and apoA1 (OR, 0.63; 95% CI, 0.61 to 0.66 per SD) were associated with ischemic stroke (and subtypes). While increasing HDL-C was associated with an increased risk of ICH (OR, 1.20; 95% CI, 1.14 to 1.27 per SD), apoA1 was associated with a reduced risk (OR, 0.80; 95% CI, 0.75 to 0.85 per SD). ApoB/A1 (OR, 1.38; 95% CI, 1.32 to 1.44 per SD) had a stronger magnitude of association than the ratio of LDL-C/HDL-C (OR, 1.26; 95% CI, 1.21 to 1.31 per SD) with ischemic stroke (P<0.0001)., Conclusions: The pattern and magnitude of association of lipoproteins and apolipoproteins with stroke varies by etiological stroke subtype. While the directions of association for LDL, HDL, and apoB were opposing for ischemic stroke and ICH, apoA1 was associated with a reduction in both ischemic stroke and ICH. The ratio of apoB/A1 was the best lipid predictor of ischemic stroke risk.

Background: Although low sodium intake (<2 g/day) and high potassium intake (>3.5 g/day) are proposed as public health interventions to reduce stroke risk, there is uncertainty about the benefit and feasibility of this combined recommendation on prevention of stroke., Methods: We obtained random urine samples from 9,275 cases of acute first stroke and 9,726 matched controls from 27 countries and estimated the 24-hour sodium and potassium excretion, a surrogate for intake, using the Tanaka formula. Using multivariable conditional logistic regression, we determined the associations of estimated 24-hour urinary sodium and potassium excretion with stroke and its subtypes., Results: Compared with an estimated urinary sodium excretion of 2.8-3.5 g/day (reference), higher (>4.26 g/day) (odds ratio [OR] 1.81; 95% confidence interval [CI], 1.65-2.00) and lower (<2.8 g/day) sodium excretion (OR 1.39; 95% CI, 1.26-1.53) were significantly associated with increased risk of stroke. The stroke risk associated with the highest quartile of sodium intake (sodium excretion >4.26 g/day) was significantly greater (P < 0.001) for intracerebral hemorrhage (ICH) (OR 2.38; 95% CI, 1.93-2.92) than for ischemic stroke (OR 1.67; 95% CI, 1.50-1.87). Urinary potassium was inversely and linearly associated with risk of stroke, and stronger for ischemic stroke than ICH (P = 0.026). In an analysis of combined sodium and potassium excretion, the combination of high potassium intake (>1.58 g/day) and moderate sodium intake (2.8-3.5 g/day) was associated with the lowest risk of stroke., Conclusions: The association of sodium intake and stroke is J-shaped, with high sodium intake a stronger risk factor for ICH than ischemic stroke. Our data suggest that moderate sodium intake-rather than low sodium intake-combined with high potassium intake may be associated with the lowest risk of stroke and expected to be a more feasible combined dietary target., (© The Author(s) 2020. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd.)

Background: Studies show that hyperuricemia is an element of the pathophysiology of many conditions. Therefore, the aim of this study was to assess primary care physicians' knowledge and attitudes toward asymptomatic hyperuricemia and gout management., Methods: A survey-based cross-sectional study was conducted to assess the primary physicians' attitudes, knowledge, and patient management regarding hyperuricemia and gout., Results: A total of 336 primary care physicians were included. Physicians who read at least one scientific paper covering the topic of hyperuricemia in the past year scored significantly higher in knowledge questions (N = 152, 6.5 ± 2.05 vs. N = 183, 7.04 ± 2.14, p = 0.019). Only around half of physicians correctly identified drugs that can lower or elevate serum uric acid levels. Furthermore, the analysis of correct answers to specific questions showed poor understanding of the pathophysiology of hyperuricemia and possible risk factors., Conclusions: This study identified gaps in primary care physicians' knowledge essential for the adequate management of patients with asymptomatic hyperuricemia and gout. As hyperuricemia and gout are among the fastest rising non-communicable diseases, greater awareness of the available guidelines and more education about the causes and risks of hyperuricemia among primary care physicians may reduce the development of diseases that have hyperuricemia as risk factors.

Objective: Hypertension is the most important modifiable risk factor for stroke globally. We hypothesised that country-income level variations in knowledge, detection and treatment of hypertension may contribute to variations in the association of blood pressure with stroke., Methods: We undertook a standardised case-control study in 32 countries (INTERSTROKE). Cases were patients with acute first stroke (n=13 462) who were matched by age, sex and site to controls (n=13 483). We evaluated the associations of knowledge, awareness and treatment of hypertension with risk of stroke and its subtypes and whether this varied by gross national income (GNI) of country. We estimated OR and population attributable risk (PAR) associated with treated and untreated hypertension., Results: Hypertension was associated with a graded increase in OR by reducing GNI, ranging from OR 1.92 (99% CI 1.48 to 2.49) to OR 3.27 (2.72 to 3.93) for highest to lowest country-level GNI (p-heterogeneity<0.0001). Untreated hypertension was associated with a higher OR for stroke (OR 5.25; 4.53 to 6.10) than treated hypertension (OR 2.60; 2.32 to 2.91) and younger age of first stroke (61.4 vs 65.4 years; p<0.01). Untreated hypertension was associated with a greater risk of intracerebral haemorrhage (OR 6.95; 5.61 to 8.60) than ischaemic stroke (OR 4.76; 3.99 to 5.68). The PAR associated with untreated hypertension was higher in lower-income regions, PAR 36.3%, 26.3%, 19.8% to 10.4% by increasing GNI of countries. Lifetime non-measurement of blood pressure was associated with stroke (OR 1.80; 1.32 to 2.46)., Conclusions: Deficits in knowledge, detection and treatment of hypertension contribute to higher risk of stroke, younger age of onset and larger proportion of intracerebral haemorrhage in lower-income countries., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Stroke disproportionately affects people in low-income and middle-income countries. Although improvements in stroke care and outcomes have been reported in high-income countries, little is known about practice and outcomes in low and middle-income countries. We aimed to compare patterns of care available and their association with patient outcomes across countries at different economic levels., Methods: We studied the patterns and effect of practice variations (ie, treatments used and access to services) among participants in the INTERSTROKE study, an international observational study that enrolled 13 447 stroke patients from 142 clinical sites in 32 countries between Jan 11, 2007, and Aug 8, 2015. We supplemented patient data with a questionnaire about health-care and stroke service facilities at all participating hospitals. Using univariate and multivariate regression analyses to account for patient casemix and service clustering, we estimated the association between services available, treatments given, and patient outcomes (death or dependency) at 1 month., Findings: We obtained full information for 12 342 (92%) of 13 447 INTERSTROKE patients, from 108 hospitals in 28 countries; 2576 from 38 hospitals in ten high-income countries and 9766 from 70 hospitals in 18 low and middle-income countries. Patients in low-income and middle-income countries more often had severe strokes, intracerebral haemorrhage, poorer access to services, and used fewer investigations and treatments (p<0·0001) than those in high-income countries, although only differences in patient characteristics explained the poorer clinical outcomes in low and middle-income countries. However across all countries, irrespective of economic level, access to a stroke unit was associated with improved use of investigations and treatments, access to other rehabilitation services, and improved survival without severe dependency (odds ratio [OR] 1·29; 95% CI 1·14-1·44; all p<0·0001), which was independent of patient casemix characteristics and other measures of care. Use of acute antiplatelet treatment was associated with improved survival (1·39; 1·12-1·72) irrespective of other patient and service characteristics., Interpretation: Evidence-based treatments, diagnostics, and stroke units were less commonly available or used in low and middle-income countries. Access to stroke units and appropriate use of antiplatelet treatment were associated with improved recovery. Improved care and facilities in low-income and middle-income countries are essential to improve outcomes., Funding: Chest, Heart and Stroke Scotland., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Stroke is a leading cause of death and disability, especially in low-income and middle-income countries. We sought to quantify the importance of potentially modifiable risk factors for stroke in different regions of the world, and in key populations and primary pathological subtypes of stroke., Methods: We completed a standardised international case-control study in 32 countries in Asia, America, Europe, Australia, the Middle East, and Africa. Cases were patients with acute first stroke (within 5 days of symptom onset and 72 h of hospital admission). Controls were hospital-based or community-based individuals with no history of stroke, and were matched with cases, recruited in a 1:1 ratio, for age and sex. All participants completed a clinical assessment and were requested to provide blood and urine samples. Odds ratios (OR) and their population attributable risks (PARs) were calculated, with 99% confidence intervals., Findings: Between Jan 11, 2007, and Aug 8, 2015, 26 919 participants were recruited from 32 countries (13 447 cases [10 388 with ischaemic stroke and 3059 intracerebral haemorrhage] and 13 472 controls). Previous history of hypertension or blood pressure of 140/90 mm Hg or higher (OR 2·98, 99% CI 2·72-3·28; PAR 47·9%, 99% CI 45·1-50·6), regular physical activity (0·60, 0·52-0·70; 35·8%, 27·7-44·7), apolipoprotein (Apo)B/ApoA1 ratio (1·84, 1·65-2·06 for highest vs lowest tertile; 26·8%, 22·2-31·9 for top two tertiles vs lowest tertile), diet (0·60, 0·53-0·67 for highest vs lowest tertile of modified Alternative Healthy Eating Index [mAHEI]; 23·2%, 18·2-28·9 for lowest two tertiles vs highest tertile of mAHEI), waist-to-hip ratio (1·44, 1·27-1·64 for highest vs lowest tertile; 18·6%, 13·3-25·3 for top two tertiles vs lowest), psychosocial factors (2·20, 1·78-2·72; 17·4%, 13·1-22·6), current smoking (1·67, 1·49-1·87; 12·4%, 10·2-14·9), cardiac causes (3·17, 2·68-3·75; 9·1%, 8·0-10·2), alcohol consumption (2·09, 1·64-2·67 for high or heavy episodic intake vs never or former drinker; 5·8%, 3·4-9·7 for current alcohol drinker vs never or former drinker), and diabetes mellitus (1·16, 1·05-1·30; 3·9%, 1·9-7·6) were associated with all stroke. Collectively, these risk factors accounted for 90·7% of the PAR for all stroke worldwide (91·5% for ischaemic stroke, 87·1% for intracerebral haemorrhage), and were consistent across regions (ranging from 82·7% in Africa to 97·4% in southeast Asia), sex (90·6% in men and in women), and age groups (92·2% in patients aged ≤55 years, 90·0% in patients aged >55 years). We observed regional variations in the importance of individual risk factors, which were related to variations in the magnitude of ORs (rather than direction, which we observed for diet) and differences in prevalence of risk factors among regions. Hypertension was more associated with intracerebral haemorrhage than with ischaemic stroke, whereas current smoking, diabetes, apolipoproteins, and cardiac causes were more associated with ischaemic stroke (p<0·0001)., Interpretation: Ten potentially modifiable risk factors are collectively associated with about 90% of the PAR of stroke in each major region of the world, among ethnic groups, in men and women, and in all ages. However, we found important regional variations in the relative importance of most individual risk factors for stroke, which could contribute to worldwide variations in frequency and case-mix of stroke. Our findings support developing both global and region-specific programmes to prevent stroke., Funding: Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Health Research Board Ireland, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland (Sweden), AstraZeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MSD, Chest, Heart and Stroke Scotland, and The Stroke Association, with support from The UK Stroke Research Network., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aim: White coat hypertension (WCH) is hard to differentiate from sustained hypertension without the use of 24-h ambulatory blood pressure monitoring (ABPM). This invaluable procedure is nevertheless cumbersome and expensive. A simple test of deep breathing over 30 s (DBT) was proposed as a method to unveil WCH., Methods: Two hundred and fourteen outpatients referred for the evaluation of uncontrolled hypertension (blood pressure, BP > 140/90 mmHg despite therapy) were enrolled in a controlled clinical trial. The examinees were randomly divided in two groups: control (n = 108; sequential standard BP measurement only) and intervention (n = 106; the same+DBT), using ABPM as the reference standard., Results: The relative decrease in BP was significantly larger in the intervention group than in the control group, by 15/4 mmHg (p = 0.005). The best detection of WCH was obtained at ≥ 15% systolic BP reduction following DBT, with a positive predictive value of 94.0% (95% CI 72.0-100.0). BP reduction of ≤ 8% may rule WCH out with a negative predictive value of 78.4% (95% CI 64.0 - 85.9)., Conclusion: DBT is a reliable, inexpensive and fast test for the detection of WCH in primary care.

Excessive salt intake is a major cardiovascular risk factor. At variance to the developed countries, the main source of sodium in transitional and developing countries is salt added while cooking and/or at the table. The objective of this trial was to examine the impact of warning labels placed on home salt containers on daily salt intake.A sample of treated hypertensives (n = 150) was randomized in two subgroups, one receiving just a leaflet about the harmful effects of excessive salt intake (control; n = 74), and the other one receiving in addition warning stickers for household salt containers (intervention; n = 76). Arterial blood pressure (BP) and 24-hour urinary sodium excretion (Na24) were measured in all the subjects at the start of the trial, and 1 month and 2 months later. The average starting Na24 was 207 ± 71 mmol in the control group and 211 ± 85 mmol in the intervention group (P = .745). One month and 2 months later, a significant decrease was observed in the intervention group (to 183 ± 63 mmol and 176 ± 55 mmol; P < .0001), as opposed to the control group (203 ± 60 mmol and 200 ± 58 mmol; P = .1466). Initial BP was 143.7/84.1 mm Hg in the control, and 142.9/84.7 mm Hg in the intervention group (P = .667). One month and 2 months later, a significant drop in BP, by 5.3/2.9 mm Hg, was observed in the intervention group as opposed to the control group (0.4/0.9 mm Hg). Decrease in Na24 positively correlated to BP lowering (r(2) = 0.5989; P < .0001). A significant reduction in 24Na and BP is achieved with warning labels on harmful effects of excessive salt intake. Decreasing daily salt input by 35 mmol may result in an extra BP lowering by some 5-6/2-3 mm Hg., (Copyright © 2015 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Previous studies have shown a paradoxical increase in early mortality in older patients (>70 years) with acute STEMI treated with fibrinolytic therapy (FT), which has been attributed to the development of free wall rupture (FWR). Our aim was to assess occurrence of FWR in STEMI patients receiving FT. In this 7-year prospective study, data from 1701 consecutive patients were obtained. We analyzed predictors of the in-hospital mortality in patients>70 years old. The independent contribution of several variables to overall mortality and FWR development was assessed using multiple logistic regression analyses. The mortality of entire cohort was 18% (306/1701). Diabetes mellitus, anterior infarction, smoking, female gender and hypercholesterolemia were independent predictors of in-hospital mortality. FT was given to 18% of all patients (304/1701) of which 13% died (39/304). FWR was 18.4-times more often in patients who received FT. Among patients younger than 70 years who received FT there was no FWR, while in patients ≥ 70 years of age FWR was found in almost half of the deceased (30/68; 44%). Application of FT in STEMI patients is not associated with higher mortality, but significantly increases number of FWR, especially in patients over 70 years of age., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Salt intake contributes to the rise in blood pressure and prevalence of hypertension. In this interventional trial on 110 treated hypertensives over three months a permanently elevated sodium excretion was found, averaging 187.9 +/- 81.5 mmol/day (range 103-297), because of inappropriate salt intake. The treated hypertensives, despite opposite claims, consume large amounts of salt, which, in addition to noncompliance, is the leading cause of poor hypertension control. Dietary education is an important part of preventive care in family medicine, and legal measures to enforce salt labeling on alimentary products are mandatory.

Diuretics, particularly thiazides and thiazide-like drugs, are antihypertensives of first choice. A prominent role in this group is reserved to chlorthalidone because of several pharmacological (e.g. longer biological half-life) and clinical advantages (e.g. superior reduction in cardiovascular events). Nevertheless, favored is hydrochlorothiazide, especially in fixed drug combinations, revealing a poor policy.

Non-steroidal anti-inflammatory drugs (NSAIDs) have prohypertensive effects and blunt the effects of many antihypertensives. The mechanism of this interaction is still not understood enough. The objective of this investigation was to determine the level of prohypertensive effects of two NSAIDs (ibuprofen, piroxicam) and paracetamol, co-prescribed with two antihypertensive drugs (lisinopril + hydrochlorothiazide, amlodipine), and to improve the understanding of this interaction. A prospective clinical trial, conducted in a Croatian family practice, included 110 already treated hypertensive patients, aged 56-85 years; 50 control patients and 60 patients who were also taking NSAIDs for osteoarthritis treatment. The antihypertensive regimens remained the same during this study, while NSAIDs and paracetamol were crossed-over in three monthly periods. Blood pressure, body weight, serum creatinine, potassium, sodium, diuresis and 24 h urinary sodium excretion were followed-up. In the lisinopril/hydrochlorothiazide subgroup, both ibuprofen and piroxicam elevated mean arterial pressure by 8.9-9.5% (p < 0.001). Body weight increased significantly in the lisinopril/ hydrochlorothiazide + piroxicam subgroup only, while creatinine, urinary output and electrolyte values did not change appreciably in any of the subgroups. NSAID's prohypertensive effects seem to be mostly due to vasoconstriction and, to a minor degree, to volume expansion, since no marked changes in body weight, urinary output, serum creatinine or serum/urinary electrolyte profile were observed.

Aims: Summating risk factor burden is a useful approach in the assessment of cardiovascular risk among apparently healthy individuals. We aimed to derive and validate a new score for myocardial infarction (MI) risk using modifiable risk factors, derived from the INTERHEART case-control study (n = 19 470)., Methods and Results: Multiple logistic regression was used to create the INTERHEART Modifiable Risk Score (IHMRS). Internal validation was performed using split-sample methods. External validation was performed in an international prospective cohort study. A risk model including apolipoproteins, smoking, second-hand smoke exposure, hypertension, and diabetes was developed. Addition of further modifiable risk factors did not improve score discrimination in an external cohort. Split-sample validation studies showed an area under the receiver-operating characteristic (ROC) curve c-statistic of 0.71 [95% confidence interval (CI): 0.70, 0.72]. The IHMRS was positively associated with incident MI in a large cohort of people at low risk for cardiovascular disease [12% increase in MI risk (95% CI: 8, 16%) with a 1-point increase in score] and showed appropriate discrimination in this cohort (ROC c-statistic 0.69, 95% CI: 0.64, 0.74). Results were consistent across ethnic groups and geographic regions. A non-laboratory-based score is also supplied., Conclusions: Using multiple modifiable risk factors from the INTERHEART case-control study, we have developed and validated a simple score for MI risk which is applicable to an international population.

Background: Nonsteroidal anti-inflammatory drug (NSAID) side effects can impair quality of life in patients with osteoarthritis. Due to its particular mechanism of action, paracetamol might bypass these negative effects., Objectives: To determine both the role of paracetamol in the treatment of osteoarthritis patients and optimal combination of antihypertensives and antirheumatics for these patients., Methods: A prospective clinical trial in a family practice included 110 treated hypertensives aged over 55 years: 50 controls and 60 also taking NSAIDs for osteoarthritis. This 3-month study compared two antihypertensives, lisinopril/hydrochlorothiazide fixed combination and amlodipine, with two NSAIDs, ibuprofen and piroxicam, and with paracetamol. Following clinical work-up and NSAID discontinuation for at least 3 days (run-in period of only 3-7 days), osteoarthritis subjects were randomized to 1-month periods of ibuprofen (400-600 mg t.i.d.) or piroxicam (10-20 mg o.d.) with one month of paracetamol (1000 mg t.i.d.) in the middle as a "wash-out" interval, continuing the prescribed amlodipine (5-10 mg o.d.) or lisinopril/hydrochlorothiazide fixed drug combination (10/6.25-20/12.5 mg o.d.), while control subjects (hypertensives with no osteoarthritis) were just keeping their antihypertensive therapy. Blood pressure was measured with standard mercury sphygmomanometer and with an automatic device, in standing, sitting and supine position. The intensity of arthritic pain (on a visual analogue scale from 1 to 10, where 0 means "no pain" and 10 "the worst pain you may imagine") and the patient's quality of life estimate (on a visual analogue scale from 1 to 10, where 0 means "general condition excellent" and 10 "the worst possible") were recorded., Results: Blood pressure control was unchanged in the amiodipine group across the study periods and impaired in the lisinopril/ hydrochlorothiazide group during either ibuprofen or piroxicam, but not during paracetamol. In the amlodipine +/- ibuprofen subgroup, the reduction of the average pain intensity score throughout the study was significant (chi2 = 8.250; df 3; P = 0.037). In the lisinopril/hydrochlorothiazide +/- piroxicam subgroup, the assessed quality of life differed significantly (chi2 = 9.716; df 3; P = 0.018), while in the amlodipine +/- ibuprofen and amlodipine +/- piroxicam subgroups the changes were marginal (chi2 = 6.936; df 3; P = 0.072 and chi2 = 7146; df 3; P = 0.065, respectively).

The aim of study was to compare the impact of coronary risk factors on the incidence of acute myocardial infarction (MI) between Croatia, Central and Eastern Europe, and the rest of the world. As a part of the large international INTERHEART case-control study of acute MI in 52 countries (15,152 cases and 14,820 controls) we have investigated the relationship between several known risk factors (smoking, history of hypertension or diabetes, waist/hip ratio, dietary patterns, physical activity, consumption of alcohol, blood apolipoproteins, and psychosocial factors) and MI among patients without previously known coronary heart disease in Southern Croatia. The main identified MI risk factors in Southern Croatia were heavy smoking (>20 cig/day; OR 3.86; 95% CI 2.31-6.46), diabetes mellitus (OR 2.83; 95% CI 1.58-5.23), abnormal ratio of B-100 and A-1 apolipoproteins (OR 2.23; 95% CI 1.28-3.89), elevated waist to hip ratio (OR 1.96; 95% CI 1.21-3.18), and arterial hypertension (OR 1.68; 95% CI 1.15-2.45). Protective was moderate alcohol consumption (OR 0.63; 95% CI 0.40-0.99). The prevalence of major MI risk factors in Croatia is similar to that in the surrounding countries and in the world, accounting for over 90% of the population attributable risk. However, physical activity, dietary and psychosocial factors are seemingly less important in this country, while moderate alcohol consumption is more protective than regionally or globally.

Some prevalent, important ethical issues concerning the manuscript reviewing process are discussed, with special reference to the referees' irresponsibility, bias, conflict of interest, conflict of opinion, clash between rapidity of publication and careful revision, and anonymity, suggesting possible amendments.

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) may increase blood pressure (BP) and blunt the effects of many antihypertensives. It seems that NSAIDs and the antihypertensive drugs differ in their propensity to such an interaction., Objectives: To determine the extent of the interaction between two antihypertensives and three NSAIDs., Methods: A prospective clinical trial in a family practice included 88 treated hypertensives aged over 55 years; 39 controls and 49, also taking NSAIDs for osteoarthritis. During this 3-month study, two antihypertensives, lisinopril/hydrochlorothiazide and amlodipine, were compared with three NSAIDs: ibuprofen, acetaminophen, and piroxicam. BP was measured with standard mercury sphygmomanometer and with an automatic device, in standing, sitting, and supine position., Results: The average starting blood pressure in the study group was 149.3A+/-9.8/88.6A+/-6.8 mm Hg. In the lisinopril/hydrochlorothiazide subgroup, both ibuprofen and piroxicam elevated systolic BP by 7.7-9.9% (p<0.001), which, during the acetaminophen period, decreased by 6.9-9.4% to 0.3-0.9% above baseline (p<0.001), increasing again by 7.0-7.7% (p<0.001) during the second exposition to these drugs. In the amlodipine subgroup, ibuprofen or piroxicam increased BP by 1.1-1.6% (p>0.290) only, and there were no significant shifts in the follow-up periods. Analogous deviations were observed with both measurement devices, in all the examinee's positions. In the control group, BP did not change appreciably., Conclusions: Piroxicam and ibuprofen markedly blunt the effects of antihypertensive drugs while acetaminophen is almost inert. Lisinopril/hydrochlorothiazide combination is much more affected by this interaction than amlodipine (ClinicalTrials.gov #NCT00631514).

Discussed is the actual controversy concerning the role of P-adrenergic blocking agents in the treatment of arterial hypertension. The author argues that these drugs are not suitable for elderly hypertensive patients, particularly in primary stroke prevention. The diabetogenic and atherogenic potential of these agents is marginal, and there are no marked differences between the available P blockers (atenolol has possibly some slight disadvantages). However, for the time being these drugs remain in the first line antihypertensive armamentarium for the younger hypertensive patients; for compelling indications or intolerance of other antihypertensives should be prescribed to any patient, as Croatian Society of Hypertension concluded in 1999.

Objectives: In the past 30 years, an increased cardiovascular disease (CVD) mortality has been observed in both industrialized and transition countries. The latter countries, such as Croatia, are considered to be in the third stage of epidemiological transition, defined as having 35%-65% of total as CVD mortality, predominantly ischemic heart disease and cerebrovascular disease. The CVD epidemic in transition countries is due to increasing rates of hypertension, obesity, smoking and sedentary lifestyle. Among CVD diagnoses, the most important is coronary heart disease (CHD), which varies in incidence among different ethnic groups and countries. Worldwide, it is estimated that nine potentially modifiable risk factors contribute to more than 90% of myocardial infarctions. Approximately 80%-90% of patients with symptomatic CHD and more than 95% of patients who died from CHD had at least one of the four traditional risk factors (smoking, hypertension, hyperlipidemia, and diabetes)., Aim: Little research has been done to quantify the relationship between the prevalence of CHD risk factors and acute myocardial infarction (AMI) in Croatia. In south Croatia, we expected that specific dietary patterns and lifestyle would have favorable effects on CHD risk. Therefore, we have conducted a case-control study to examine the relationship between several CHD risk factors (smoking, hypertension, hyperlipidemia, diabetes, obesity, alcohol, fruit and vegetable consumption, and physical activity) in AMI patients and persons without previously known CHD in south Croatia., Methods: We took part in the INTERHEART study over 4 years (1999-2002). Cases were all eligible patients with first AMI admitted to the Coronary Care Unit, Split University Hospital. Within one month of admission at least one control was recruited and matched to every AMI case by age (+/-5 years) and sex. Exclusion criteria were the same for cases and controls. Structured questionnaires were administered and physical examinations were undertaken in the same manner in cases and controls. Relationship between the risk factors and AMI are presented by odds ratios, estimated by multivariate logistic regression., Results: During the study period 263 cases and 264 controls were enrolled. The proportion of males (74.6%) was threefold that of females. The highest relative difference between the case and control risk factors was noted for current smoking (16.6%; p<0.001), diabetes (10.5%; p<0.001), hypertension (9.0%; p=0.038) and abdominal obesity (18.5%; p<0.001). Ever smoking accounted for 75% higher AMI risk than non-smoking (OR 1.74; p=0.006), while current smoking accounted for a 2.6 time higher risk in comparison to non-smoking (OR 2.58; p<0.001). Diabetes had a threefold risk (OR 2.83; p<0.001). Hypertension accounted for a 70% higher risk (OR 1.68; p=0.007). Abdominal obesity was associated with a significantly increased AMI risk (OR 1.96; p=0.007). The highest apolipoprotein B/apolipoprotein A-1 (ApoB/ApoA-1) tertile accounted for nearly 2.5-fold risk (OR 2.23; p=0.005). Physical activity and daily consumption of fruits and vegetables did not prove to be significant factors in Croatia. Regular consumption of alcohol decreased coronary risk by approximately one third (OR 0.63; p=0.044)., Conclusions: The most important AMI risk factor in south Croatia is current smoking, followed by diabetes, abnormal ApoB/ApoA-1 ratio, abdominal obesity, and hypertension. A protective risk factor is alcohol consumption, while physical activity and fruit and vegetable consumption are less important. These results are similar to the global INTERHEART data showing that most of AMI risk could be predicted with nine simple, measurable risk factors worldwide. Protective measures for CHD, including increased daily consumption of fruits and vegetables, moderate physical activity and particularly smoking cessation should be implemented worldwide. In specific regions such as south Croatia, moderate alcohol consumption (mostly red wine) may be included among protective measures due to sociologic and cultural reasons.

Controlled clinical trial methodology includes unbiased data gathering, subject to statistical analysis, eliminating subjective and environmental influences on the results. These studies compare treatments in patients minimizing or equalizing all variables except the intervention (mostly a drug) under evaluation. The scope of this short review is to present how much recent clinical trials have improved our understanding and treatment of cardiovascular diseases.

Aim: To assess the frequency of cardiac arrest and outcomes and predictors of survival after cardiopulmonary resuscitation in hospitalized patients., Methods: We prospectively analyzed the data on all patients who experienced cardiac arrest while hospitalized at the Split University Hospital between January and December 2003. Data were collected on patients' demographic characteristics, etiology and presentation of cardiac arrest, time, site, methods, and outcomes of cardiopulmonary resuscitation., Results: Out of 120 cases of cardiac arrest among 32,861 hospitalized patients, 76.7% were witnessed. Ninety-six (80.0%) patients with cardiac arrest underwent resuscitation, and 22.5% of them were discharged alive. The survival rate was 20.0% at the Department of Internal Medicine, 29.2% in the Coronary Care Unit, and only 7.1% in other departments (P=0.058, chi2 test). Out of 92 patients with witnessed cardiac arrest, 28.3% survived to discharge, whereas only one of 28 patient with unwitnessed cardiac arrest survived to discharge (P=0.004, Fisher's exact test). More patients with cardiac arrest due to ventricular fibrillation or pulseless ventricular tachycardia survived than patients with asystole and pulseless electrical activity (47.6% vs 10.7%, respectively, P<0.001, Fisher's exact test). None of the patients with unclassified cardiac arrest survived until discharge. Cardiac arrest survivors were significantly younger (60.8+/-12.9 vs 71.1+/-11.7 years, P<0.001, Student t-test). Sex had no influence on survival. There were no significant circadian or hospital shift differences in the frequency rate of cardiac arrest, but the rate of successful resuscitation was lower during the night shift., Conclusion: The rate of successful resuscitation was higher in the coronary care unit, during the day and in younger witnessed cardiac arrest patients with ventricular fibrillation or pulseless ventricular tachycardia.

Background: Obesity is a major risk factor for cardiovascular disease, but the most predictive measure for different ethnic populations is not clear. We aimed to assess whether markers of obesity, especially waist-to-hip ratio, would be stronger indicators of myocardial infarction than body-mass index (BMI), the conventional measure., Methods: We did a standardised case-control study of acute myocardial infarction with 27 098 participants in 52 countries (12,461 cases and 14,637 controls) representing several major ethnic groups. We assessed the relation between BMI, waist and hip circumferences, and waist-to-hip ratio to myocardial infarction overall and for each group., Findings: BMI showed a modest and graded association with myocardial infarction (OR 1.44, 95% CI 1.32-1.57 top quintile vs bottom quintile before adjustment), which was substantially reduced after adjustment for waist-to-hip ratio (1.12, 1.03-1.22), and non-significant after adjustment for other risk factors (0.98, 0.88-1.09). For waist-to-hip ratio, the odds ratios for every successive quintile were significantly greater than that of the previous one (2nd quintile: 1.15, 1.05-1.26; 3rd quintile: 1.39; 1.28-1.52; 4th quintile: 1.90, 1.74-2.07; and 5th quintiles: 2.52, 2.31-2.74 [adjusted for age, sex, region, and smoking]). Waist (adjusted OR 1.77; 1.59-1.97) and hip (0.73; 0.66-0.80) circumferences were both highly significant after adjustment for BMI (p<0.0001 top vs bottom quintiles). Waist-to-hip ratio and waist and hip circumferences were closely (p<0.0001) associated with risk of myocardial infarction even after adjustment for other risk factors (ORs for top quintile vs lowest quintiles were 1.75, 1.33, and 0.76, respectively). The population-attributable risks of myocardial infarction for increased waist-to-hip ratio in the top two quintiles was 24.3% (95% CI 22.5-26.2) compared with only 7.7% (6.0-10.0) for the top two quintiles of BMI., Interpretation: Waist-to-hip ratio shows a graded and highly significant association with myocardial infarction risk worldwide. Redefinition of obesity based on waist-to-hip ratio instead of BMI increases the estimate of myocardial infarction attributable to obesity in most ethnic groups.

Interactions between antihypertensive agents and nonsteroidal anti-inflammatory drugs (NSAIDs) are often seen in clinical practice. Inhibiting the renal synthesis of vasodilatory prostaglandins and enhancing salt and water retention, NSAIDs increase blood pressure, particularly in hypertensive subjects. Not all NSAIDs are equal in this respect: the highest elevations in mean arterial pressure are reported with indomethacin, naproxen, piroxicam and rofecoxib, while low-dosed aspirin, celecoxib and ibuprofen, are less unwelcome in this respect. The same is true for the antihypertensive drugs: the most prone to the interaction (worsening of blood pressure control) are diuretics and ACE inhibitors, and the most resistant seem to be the calcium channel blockers. Although these claims must be corroborated by further clinical investigations, one of which is under way in Croatia, coprescription of antihypertensives and NSAIDs, particularly to the elderly, in addition to vigilance and care, requires operative knowledge of the therapeutic options.

Aim: To compare the effects of a selective beta-blocker atenolol and a nonselective beta-blocker propranolol on platelet aggregation., Methods: Twenty successive outpatients with moderate essential hypertension (6 women and 14 men, mean age-/+standard deviation 42.6-/+8.5 years) were randomized to either propranolol (40 mg three times a day) or atenolol (100 mg once a day) for the first two weeks, followed by a one-day washout period, and then a two-week administration of the alternative drug. Along with standard examinations and tests, circulating platelet aggregates were measured., Results: There were no significant differences in creatinine, blood glucose, potassium, total cholesterol, hemoglobin, red blood cells (RBC), or platelets in three periods: baseline, atenolol, and propranolol period. Significant and comparable reductions in systolic and diastolic arterial pressure, body weight, heart rate, and HDL-cholesterol were recorded in both patient groups. The LDL-cholesterol concentration increased significantly in propranolol compared with both baseline and atenolol period. Serum triglycerides increased significantly with both medications. The number of circulating platelet aggregates decreased significantly with propranolol (0.99-/+0.19) in comparison with both atenolol (1.41-/+0.70; P=0.004, Wilcoxon matched pairs test) and baseline (1.59-/+0.94; P=0.002, Wilcoxon matched pairs test)., Conclusion: Propranolol inhibits platelet aggregation more than atenolol and may have a favorable effect on the management of hypertension especially in patients with increased cardiovascular risk.

A small subgroup of children, whose parents have suffered a heart attack in their late thirties and early forties, may be at particularly high cardiovascular risk. University Hospital "Split" gives tertiary health care to some 700,000 people in southern Croatia and treats about 300 acute myocardial infarctions per year, with a 3-5% share in the age under 45 years. This cross-sectional, clinical and laboratory study included all the patients below the age limit of 45 years, treated for acute myocardial infarction between 1990 and 1995, complexively 55 of them, and their natural children, 97 all in all. The results were compared to those of a stratified children's sample taken from the population of the same region. The relative weight, blood pressure, and plasma cholesterol were significantly higher in these children than in the control group (p < 0.05). In 50 of these offspring (51.5%), in addition to the obviously positive family history, detected were further cardiovascular risk factors, defined as values above the 95th distribution percentile for age and gender. The average blood pressure, relative weight and cholesterol levels were even higher in these, "risky" children than in the studied sample (p < 0.05), and much more elevated than in the matching control pupils (p < 0.001). The most often detected risk factors were elevated cholesterol (in 44%), arterial hypertension (in 40%), obesity (in 32%), and smoking (in 24%). Most of the children (64%) had only one additional risk factor, while in the remaining 36% the most prevalent risk factors were overweight (in 14 out of 18) and arterial hypertension (in 11 out of 18). It is concluded that cardiovascular risk factor screening among children with a positive family history of premature atherosclerotic complications is appropriate and cost-effective.

Aim: To assess the smoking prevalence and efficacy of nicotine replacement therapy on the quitting rate after 3 weeks of therapy and after 1- and 5-year follow-up among health care workers with a smoking habit in Split, Croatia., Methods: Among 311 hospital health professionals included in the study, there were 112 (36%) smokers; 44 (39%) of them were physicians and 68 (61%) nurses. In a randomized double-blind study, 112 smokers were divided in 2 groups, applying daily either a transdermal nicotine system (TNS) or placebo patch over 3 weeks. Abstinence was evaluated via questionnaire and on the basis of carbon monoxide concentration measured in the exhaled breath., Results: The abstinence rates after the 3-week intervention period were 39% in the TNS group and almost 20% in the control group (chi-square test, p=0.038). After one year, these rates declined to 23% and 16%, respectively (p=0.476), and converged to 18% and 14% (p=0.797), respectively, at 5-year follow-up., Conclusions: Short-term TNS treatment is effective in smoking cessation, although the effects steadily wane over time and the relapse rate is high. Continuous, structured, and composite efforts are needed for the maintenance of the non-smoking behavior.

There are a lot of methods for smoking cessation but transdermal nicotine system (TNS) is one of the most popular. On a sample of more than 300 smokers we have formerly shown that TNS achieves higher abstinence rate than placebo (38%:21%). In the present study we have tested the optimal administration of TNS. 160 smokers were subdivided in 4 groups of 40, receiving either TNS or placebo, for 3 or 6 weeks. The abstinence rate was evaluated by appropriate questionnaires and measuring CO in the exhaled air. After 3 weeks of TNS 60% of the examinees were abstaining compared to 50% after 6 weeks; the abstinence rates in the placebo groups were 17.5% and 20%, respectively (p < 0.05). Short TNS treatment (3 weeks) is at least as effective as a longer one (6 weeks), which is relevant both medically and economically.

Aim: To compare the effects of four antihypertensive drugs, which have reportedly different effectiveness in reducing myocardial mass., Methods: A randomized, double-blind, prospective study included 80 hypertensive patients with left ventricular (LV) hypertrophy confirmed both electrocardiographically and echocardiographically. We investigated the effects of indapamide, nicardipine, propranolol, and chlorthalidone on arterial blood pressure and LV mass and function., Results: Sixty-four patients (34 men and 30 women) completed the 6-month study. No significant differences in antihypertensive effects of the four medications were found. The average decrease in systolic and diastolic blood pressure was 12.8% and 10.4%, respectively. All four antihypertensive medications caused pronounced reduction in LV mass, between 7.9% in the propranolol group and 10.1% in the nicardipine group, with no significant difference between the groups. In patients receiving diuretics, predominant decrease was observed in LV mass and LV mass index. In patients treated with propranolol, the thickness of both the LV wall and interventricular septum was reduced, whereas the reduction in LV mass, LV wall and interventricular septum thickness was found in patients treated with nicardipine. There was no significant correlation between the changes in LV mass and other variables (blood pressure, and systolic and diastolic function). Systolic function did not improve with the reversion of LV hypertrophy in any group of patients, but improvement was observed in some indices of diastolic function. The early and late LV filling velocity and their ratio did not improve significantly, either. Clinically relevant side effects were not observed., Conclusion: All four antihypertensive monotherapies achieved a comparable control of hypertension and reduction in LV hypertrophy.

Background: Nausea and vomiting are well-known gastrointestinal complications in chronic renal failure and are frequent indications for the commencement of dialysis. Although the administration of antiemetic drugs (metoclopramide and, recently, ondansetron) is usually mentioned, there are scanty data on their effects., Methods: A double-blind crossover study was done in 10 uremic patients. All the patients were uremic and suffered from nausea and vomiting. The drugs were randomly administered intravenously (either metoclopramide 10 mg or ondansetron 8 mg) 2 h after blood drawing for laboratory tests either on the 1st or on the 3rd study day at the same time. The outcomes were scored after 24 h of follow-up by (1) one of us (D.P.; 1-3 points: 1 = no effect; 2 = moderate effect - decreased frequency of vomiting, and 3 = good effect - no vomiting), and (2) by the patients (1-5 points)., Results: The results obtained showed that ondansetron was more effective in controlling nausea and vomiting than metoclopramide, either objectively (2.80 +/- 0.422 vs. 1.40 +/- 0.699, p < 0.005) or subjectively (4.10 +/- 0.738 vs. 2.10 +/- 0.994, p < 0.005)., Conclusions: We conclude that at the dosage level studied ondansetron is about twice as effective as metoclopramide in the symptomatic relief of uremia-induced nausea and vomiting., (Copyright 2002 S. Karger AG, Basel)