An update of the Italian Stroke Organization-Stroke Prevention Awareness Diffusion Group guidelines on carotid endarterectomy and stenting: a personalized medicine approach

Although proof-based medicine has generated much valid evidence for the drawing up of guidelines and recommendations for best clinical practice in symptomatic and asymptomatic carotid stenosis, whether and when it is better to employ endarterectomy or stenting as the intervention of choice still remain matters of debate. Moreover, guidelines have been targeted up to now to the 'representative' patient, as resulting from the statistical analyses of the studies conducted on the safety and efficacy of both interventions as well as on medical therapy alone. The Italian Stroke Organization (ISO) and Stroke Prevention and Awareness Diffusion (SPREAD) group has thus decided to update its statements for an 8th edition. To this end, a multidisciplinary team of authors representing Italian scientific societies in the neurology, neuroradiology, vascular and endovascular surgery, interventional cardiology, and general medicine fields re-examined the literature available on stroke. Analyses and considerations on patient subgroups have allowed to model the risks/benefits of endarterectomy and stenting in the individual. Accordingly, the guideline's original methodology has been revised to follow the new SIGN (Scottish Intercollegiate Guideline Network) Grade-like approach, integrating it with new considerations on Precision, or Personalized Medicine. Therefore, this guideline offers recommendations on precision medicine for the single patient, and can be followed in addition to the more standard guidelines.

SPREAD Italian Guidelines for stroke. Indications for carotid endarterectomy and stenting.

This multidisciplinary guideline provides an overview of the current evidence on the benefits obtained by endoarterectomy and stenting for the surgical treatment of patients with symptomatic and asymptomatic carotid stenosis. A hundred forty-six authors, 37 Italian scientific societies and two Italian patients' associations participated in drafting the Stroke Prevention and Educational Awareness Diffusion (SPREAD) document, which has become the national guideline for the prevention and treatment of stroke in Italy. For the surgical therapy section of this document, the main trials on carotid endoarterectomy and stenting were critically reviewed following The Scottish Intercollegiate Guideline Network Oxford Centre for Evidence-Based Medicine methodology in order to formulate recommendations and syntheses for these procedures. The final document was peer reviewed and approved by all the participants. Recommendations and syntheses are presented for the referral of patients to either carotid endoarterectomy or stenting on the basis of whether carotid stenosis is symptomatic or asymptomatic, on the presence of various risk factors such as degree of arterial narrowing, and on concomitant pathology (cardiopathy and acute stroke).

Italian SPREAD Guidelines: from past to future.

The development of the Italian Guidelines on Stroke involved a multidisciplinary working group, named the "SPREAD Collaboration" (Stroke PREvention and Awareness Diffusion), composed at present of different professional organisations and two patients' associations. The group was organised into operative subcommittees. Each subcommittee dealt with a different area covered by the guidelines and was composed of 5-10 experts in the specific field. A "scientific task force" and an editorial board were responsible for coordinating and reviewing the texts progressively processed and produced.

The Stroke in Italy and Related Impact on Outcome (SIRIO) study: design and baseline data.

The SIRIO study collected detailed information on the stroke care of patients treated in neurological departments in Italy. This report refers to the baseline profile of patients. Each centre recorded the incident cases of ischaemic and haemorrhagic stroke, excluding SAH, for 1-4 months. Baseline data include demographics, risk factors, comorbidities, pre-event medications, social conditions, NIHSS and Rankin scale on entry, Barthel Index pre-event, diagnostic tests and treatments applied on entry. Overall, 3018 patients (56.7% men; mean age 72.1+/-12.2 years) with ischaemic (85.3%) or haemorrhagic stroke were hospitalised in 103 centres; 51% arrived by ambulance. Median time to hospital was 140 min (RIQ: 60-615). TOAST classification of the 2573 ischaemic strokes was: 29.4% large-artery atherosclerosis, 24.6% cardioembolic, 26.2% small vessels occlusion, 6.5% other determined causes and 13.3% undetermined. CT and/or MR were performed in all patients. Total Greenfield's comorbidity score was 5.4+/-3.5. Mean Barthel Index pre-event was 93+/-17; Rankin score on entry was 4-5 in 48% of the patients and 0-1 in 25%. Mean NIHSS on entry was 7.1+/-5.4; 52% of the patients had a NHISS <6 and 1% >22. SIRIO began giving the expected insights on the in-hospital management of stroke in Italy. Further information will be provided by the longitudinal phase of the study, which is in progress. Pre-event patient management and mode of reporting call for additional educational actions.

Upper gastrointestinal symptoms and therapies in elderly out-patients, users of non-selective NSAIDs or coxibs.

BACKGROUND: The association between coxib or non-steroidal anti-inflammatory drug use with gastrointestinal symptoms and drug prescriptions in ambulatory elderly patients is not well defined. AIM: To evaluate the association between non-steroidal anti-inflammatory drug NSAID and coxib use with gastrointestinal symptoms and therapies in elderly subjects managed by their general practitioner. MATERIALS: The study was carried out by 133 general practitioners in Italy. By using a structured interview, sex, age, physical function, current medications, new drug prescriptions and upper gastrointestinal symptoms were registered from all elderly subjects who were referred to their general practitioners during a 2-week period. The numbers of hospitalizations, gastrointestinal bleeding events and gastrointestinal diagnostic procedures occurring during the last 6-month period were recorded. RESULTS: Included in this study were 5515 elderly subjects. The overall prevalence of drug use was 92%. Musculo-skeletal drugs were taken by 15% of patients; NSAIDs were taken by 6%, and coxibs by 3% of patients. A significantly higher prevalence of upper gastrointestinal symptoms was observed in elderly NSAID users compared with coxib users and non-users of musculo-skeletal drugs (44% vs. 33% vs. 32% respectively, P = 0.001). The prescriptions of drugs for acid-related disorders were significantly higher in patients who were concomitantly taking NSAID rather than coxibs (13% vs. 6%, P < 0.01). The prescriptions of drugs for acid-related disorders were significantly associated with the presence of upper gastrointestinal symptoms (OR = 1.7, 95% CI = 1.6-1.9), previous gastrointestinal disorders (OR = 1.1, 95% CI = 1.0-1.3) and NSAID use (OR = 1.5, 95% CI = 1.0-2.2), but no coxib use. CONCLUSION: In this elderly population, upper gastrointestinal symptoms and prescriptions for gastroenterological drugs were higher in non-steroidal anti-inflammatory drug users than coxib users and non-users of musculo-skeletal drugs.

Detected atrial fibrillation in north Italy: rates, calculated stroke risk and proportion of patients receiving thrombo-prophylaxis.

BACKGROUND: Atrial fibrillation (AF) is a major risk factor in the development of ischaemic stroke. The rate of embolic events can be reduced significantly by appropriate therapy. Epidemiological data and information about the attitude of physicians towards prophylaxis of thromboembolism are crucial to determine future strategies to decrease strokes in patients with AF. Unfortunately, these data are unknown in Italy. OBJECTIVES: The aims of this study were to study the prevalence of diagnosed AF in northern Italy, to estimate the percentage of high, moderate and low risk patients and to investigate the pattern of embolic prophylaxis among GPs. METHODS: Fifty-one GPs reviewed all the clinical records of subjects aged >/=40 years and identified those patients with chronic or paroxysmal AF. RESULTS: Among 41 050 patients, 719 [1.75%; 95% confidence interval (CI) 1.59-1.91] had AF (70% chronic, 30% paroxysmal). Only 4% were at low risk for ischaemic stroke, whereas 32% were at moderate and 64% at high risk. Contraindications to antiplatelet or anticoagulant therapy were present in 11% of AF patients. Antithrombotic prophylaxis was underused among the 51 GPs. CONCLUSIONS: Detection of AF could be 30-40% lower than real prevalence and, therefore, adequate evaluation and treatment aimed at avoiding ischaemic stroke could be denied to a great number of Italian patients. AF detection and prophylaxis of thromboembolic risk can be improved among GPs in northern Italy.

Ventricular arrhythmias in normotensive subjects and in mild hypertensive patients.

Twenty-five normotensive subjects (14 men, 11 women) aged from 25 to 60 years (mean 36) and 30 untreated patients with mild hypertension (stages 1 and 2, JNC V) without target organ damage (16 men, 14 women), aged 26-59 years (mean 35.8) underwent continuous 24-hour ECG Holter monitoring with a Fukuda Denshi SM-40 ambulatory recorder and SCM-400 ECG analyzer. During 24-hour ambulatory ECG recording, mean heart rate was slightly but not significantly higher in hypertensive patients (73.3 +/- 10 beats per minute [bpm]) in comparison with normotensive subjects (71.2 +/- 12 bpm). The prevalence of premature atrial contractions was similar in the two groups. Total ventricular arrhythmias were more prevalent in the group of mild hypertensive patients (P < 0.05), who also had a higher prevalence in complex forms of ectopy (r = 0.81 for bigeminy; r = 0.83 for trigeminy; r = 0.83 for couplets). Holter recordings did not show abnormalities of ST-T wave or episodes of silent ischemia.

Ambulatory-determined 24-hour blood pressure in mild hypertensives and in normotensives.

Noninvasive ambulatory twenty-four-hour blood pressure (BP) monitoring was carried out in 30 normotensive subjects (16 women, 14 men), aged twenty-five to sixty years (mean thirty-eight) and in 29 mild essential hypertensive patients without target organ damage (14 women, 15 men), aged twenty-three to sixty-one years (mean thirty-nine). Hypertensive patients were not treated, and they discontinued any antihypertensive treatment at least four weeks before the study. During the daytime period (6 AM-10 PM) BP was monitored every fifteen minutes, and during the night (10 PM-6 AM), every thirty minutes. Obviously, mean twenty-four-hour systolic blood pressure (SBP) and diastolic blood pressure (DBP) were higher in hypertensive patients (P < 0.001). There was a persistent correlation in the group of mild hypertensives between successive BP hourly mean readings (r ranged from 0.61 to 0.93 for SBP and from 0.45 to 0.82 for DBP). In normotensive subjects these correlations failed in particular periods: 8 AM-9 AM, r = 0.30 for SBP and 0.45 for DBP; 1 PM-3 PM, r = 0.17-0.49 for SBP and 0.28-0.37 for DBP; 9 PM to midnight, r = 0.21-0.57 for SBP and 0.23-0.38 for DBP.

[Ambulatory monitoring of blood pressure profiles in in hypertensive patients 26-65 years of age]. / Monitoraggio ambulatoriale dei profili della pressione arteriosa nei pazienti ipertesi di età da 26 a 65 anni.

We evaluated blood pressure profile in a population of 380 untreated hypertensives (210 males, 170 females, stage 1 and 2 JNC 1993) observed consecutively. A 24-hour ambulatory blood pressure monitoring was performed using and A&D TM 2420 model 6 device programmed to measure systolic and diastolic blood pressure every 15 min from 7 am to 10 pm (daytime) and every 30 min from 10 pm to 7 am (night-time). Statistical analysis was carried out by dividing the patients into four groups on the basis of age: Group I, from 26 to 35 years (26 males, 14 females); Group II, from 36 to 45 years (48 males, 39 females); Group III, from 46 to 55 years (85 males, 72 females); Group IV, from 56 to 65 years (51 males, 45 females). Systolic blood pressure was higher in older male hypertensives (56 to 65 years) who also had a persistent systolic blood pressure elevation during night-time (non-dippers); diastolic blood pressure was significantly higher in male hypertensives aged 36 to 55 years.

[Elevated cardiovascular mortality in subjects over 75 with low values of arterial pressure]. / Elevata mortalità cardiovascolare in soggetti ultrasettantacinquenni con bassi valori di pressione arteriosa.

PURPOSE: The purpose of this study was to extend the observations from recent studies that have shown an increased mortality in elderly people with low blood pressure. METHODS: In 1982 we enrolled 88 subjects, 30 males, 58 females, aged 75-90 years, divided into 3 groups, according to their blood pressure and matched for sex, serum cholesterol, smoking and body mass index: Group I: 20 people with blood pressure equal or less than 120/75 mmHg; Group II: 46 subjects with blood pressure level ranging from 130/80 to 145/90 mmHg; Group III: 22 patients with hypertension (blood pressure equal or more than 160/95 mmHg). These three groups were followed for 6 years (1983-1988) to evaluate the mortality from cardiovascular diseases. During this period, no antihypertensive drugs were given, nor did any other treatment significantly modify the value of blood pressure. No patient changed starting group. RESULTS: Mortality from cardiovascular diseases was as follows: Group I: 14 deaths (mean age 82 +/- 5, 8 for heart failure, 2 for myocardial infarction, 4 for stroke); Group II: 8 (p < 0.001 versus Group I, mean age 81 +/- 3, 6 for heart failure, 1 for myocardial infarction, 1 for stroke); Group III: 4 (p < 0.001 versus Group I, mean age 80 +/- 2, 1 for heart failure, 1 for myocardial infarction, 1 for stroke and 1 for sudden death). CONCLUSIONS: This study adds further observations indicating an increase of mortality for cardiovascular diseases in subjects over 75 years with low levels of blood pressure, which could be more dangerous than moderately high levels in older people.

Snoring and risk of cardiovascular disease.

In order to evaluate the possible role played by snoring as a risk factor for cardiovascular disease, we studied 400 patients aged 30-80 years, divided into 4 groups matched for age, sex and body mass index. The first group consisted of 100 patients who snored, having risk factors (hypertension, diabetes, obesity, smoking, high serum cholesterol level) for cardiovascular disease. The second group consisted of 100 non-snoring patients with risk factors. The third and fourth groups were formed by 100 snoring and 100 non-snoring patients without risk factors. We investigated the morbidity and the mortality from cardiovascular disease over a period of five years (1982-1987). An increase in morbidity and mortality was found for snorers with risk factors (36 and 17 respectively) compared to non-snorers with risk factors (10 and 4, P less than 0.001), and also to both snorers and non-snorers without risk factors (7 and 3, P less than 0.001; 3 and 1, P less than 0.001 respectively). No difference was noted between snorers and non-snorers without risk factors. A higher morbidity and mortality for cardiovascular disease was found in snorers with risk factors as compared with non-snorers having risk factors. Furthermore, the morbidity and mortality in patients without risk factors was found to be lower compared with that found in snorers with risk factors. In conclusion, snoring worsened the prognosis of patients with risk factors for cardiovascular disease, but did not represent an independent or predictive risk factor in itself.

Extended release felodipine in essential hypertension. Variations in blood pressure during whole-day continuous ambulatory recording.

Intraarterial blood pressure (BP) monitoring during free ambulation (Oxford technique) was carried out in 12 essential mild-to-moderate hypertensive patients undergoing 4 weeks treatment with felodipine, 10 mg given once daily in an extended release formulation. Compared to placebo, felodipine significantly reduced systolic and diastolic blood pressure throughout 24 h. The greatest reduction was observed at 10 AM, 3 h after drug administration (-32 +/- 6/-24 +/- 5 mm Hg for systolic and diastolic BP, respectively, P less than .001). Hourly BP values remained significantly lower up to and including the 24th hour during felodipine extended release treatment (-18 +/- 5/-11 +/- 3 mm Hg, P less than .001). Felodipine extended release also reduced 24 h blood pressure variability, evaluated on the standard deviation of each hourly mean (from 16.3 +/- 0.9/12.6 +/- 0.6 to 13.4 +/- 0.6/10.4 +/- 0.6 mm Hg, P less than .01). Furthermore, absolute BP values dropped significantly at the peaks of dynamic exercise (bicycle ergometer: from 248 +/- 13/123 +/- 11 to 204 +/- 24/102 +/- 13 mm Hg, P less than .001), isometric exercise (hand grip: from 232 +/- 18/133 +/- 16 to 180 +/- 20/101 +/- 16 mm Hg, P less than .001), and cold pressor test (from 229 +/- 20/127 +/- 14 to 178 +/- 22/99 +/- 15 mm Hg, P less than .001). In conclusion, felodipine extended release exerts a good antihypertensive effect which is maintained for 24 h and reduces the level of blood pressure peaks reached under different physical stresses.

[Circadian pressure variability and pressure peaks during treatment of mild to moderate essential hypertension with felodipine]. / Variabilità pressoria circadiana e picchi di pressione durante il trattamento con felodipina nell'ipertensione essenziale di grado lieve-moderato.

It is not yet known how blood pressure variability contributes to the vascular changes associated with hypertension, but 2 possibly relevant factors are mean blood pressure levels over time and pressure peaks. It has been observed that patients in whom the variability in 24-hour blood pressure is low have a lower prevalence and severity of target organ damage. We carried out a whole-day continuous intraarterial blood pressure recording (Oxford method) in 12 essential hypertensive patients after a 2-week placebo period and after a 4-week felodipine treatment, administered in an extended release formulation, 10 mg once daily at 7 am. Felodipine significantly lowered systolic and diastolic blood pressure values throughout the 24 hours (p less than 0.005 to 0.001). Also, hourly variabilities of systolic and diastolic blood pressure during whole-day monitoring were significantly reduced (p less than 0.05 to 0.001), evaluated on the basis of the hourly means of standard deviation of systolic and diastolic blood pressure. In addition, felodipine significantly lowered the values of blood pressure reached during both dynamic exercise (bicycle ergometer, p less than 0.001) and isometric exercise (handgrip, p less than 0.001).

Effect of enalapril on parasympathetic activity.

To evaluate the effect of converting enzyme inhibition induced by enalapril on parasympathetic activity, we studied ten essential hypertensive patients, age range 38-58 years, WHO I-II. Parasympathetic evaluation was obtained by measuring the variation of heart period (VHP) during at least 1 minute of steady-state, regular respiration. VHP was derived from the difference between the mean of all maximum and the mean of all minimum heart periods. The higher the VHP, the higher the parasympathetic control of heart rate and vice versa. VHP was measured supine and with tilting (30 degrees, 60 degrees, 85 degrees). Blood pressure was reduced after 1 month of enalapril treatment, while the heart rate did not change. VHP increased at the end of enalapril treatment compared with placebo: in the supine position it increased from 36 +/- 3.2 ms to 44 +/- 3.5 ms, p less than 0.01. VHP was also increased by enalapril at 30 degrees (p less than 0.05) and 60 degrees (p less than 0.05), while no difference was observed at 85 degrees between placebo and enalapril. A positive correlation was found between supine enalapril changes of VHP and those of systolic and diastolic BP. In conclusion, enalapril seems to increase parasympathetic cardiovascular control in essential hypertensive patients. This result might explain the lack of increase in heart rate that would be expected as a result of the vasodilating effect of enalapril.

Angiotensin converting enzyme inhibition, parasympathetic activity and exercise in essential hypertension.

Reduced parasympathetic activity has been reported in essential hypertension. Converting enzyme inhibition seems to increase parasympathetic tone. In order to evaluate the effects of enalapril on parasympathetic control of heart rate, the authors studied ten mild-to-moderate essential hypertensive patients (7 F, 3 M), treated for 2 weeks with placebo and for 1 month with enalapril. Compared to placebo, enalapril significantly reduced blood pressure (p less than 0.005 at least, both systolic and diastolic), without any change in heart rate. Enalapril enhanced parasympathetic activity as judged by the increased variation of heart period (VHP) during regular breathing. VHP was derived during continuous ECG recording by the difference between the mean of all maximum and minimum R-R intervals, taken as a measure of respiratory sinus arrhythmia: the higher the VHP, the higher the parasympathetic cardiac influence and vice versa. The response to exercise, used as an index of sympathetic stimulation, was not modified by enalapril: the heart rate peak reached during either static (hand grip) or dynamic (bicycle ergometer) exercise and the slope of the increase in blood pressure were unchanged. Therefore, enalapril appears to increase parasympathetic tone in essential hypertension, without any interference with sympathetic adaptation to stress.

Effect of enalapril at rest and during isometric and dynamic exercise in essential hypertensive patients.

Vasodilator drugs reduce peripheral vascular resistance but lead to a secondary baroreflex-mediated chronotropic effect. After angiotensin-converting enzyme inhibition, blood pressure falls without associated tachycardia. In a previous study it was observed that enalapril increased vagal tone in essential hypertensive patients. In order to evaluate the effect of enalapril on sympathetic stimulation 10 mild to moderate hypertensive patients were studied during static (hand grip) and dynamic exercise (bicycle ergometer), after 2 weeks of placebo and after 1 month of treatment with 20-40 mg enalapril once daily. Enalapril significantly reduced blood pressure and the rate-pressure product at rest and at peak dynamic exercise. There was no effect on supine and maximal heart rate. Enalapril also significantly reduced blood pressure during hand grip, but did not interfere with the rate of the increase. Thus, enalapril does not seem to interfere with sympathetic adaptation to stress.

Ibopamine vs. digoxin in chronic heart failure: a double-blind, crossover study.

Ibopamine, a dopamine derivative suitable for oral administration, is reported to improve cardiac function in patients with chronic heart failure. In order to evaluate the inotropic effect of ibopamine and to compare it with that of digoxin, we studied 10 patients with chronic heart failure (NYHA II-III). All patients were in sinus rhythm. After a washout period of 5 days, when the patients received a constant diuretic dosage and a placebo, ibopamine 100 mg t.i.d. or digoxin 0.25 mg o.d. was randomly given double-blind. The active treatment was continued for a 10-day period, and was followed by a second washout period of 5 days. Subsequently, the patients received digoxin if previously on ibopamine or ibopamine if previously on digoxin for 10 days. Diuretic was continued at the same dosage throughout the study. At the end of the two washout periods, all patients performed a static (hand grip) and a dynamic exercise (bicycle ergometer). Both ibopamine and digoxin improved cardiac response to both types of exercise compared to the washout periods. In particular, PEP/LVET decreased (p less than 0.001 for both drugs) and O2 consumption improved (from 586 +/- 48 to 716 +/- 35 ml/min for ibopamine and from 585 +/- 38 to 713 +/- 52 ml/min for digoxin). No difference was noted between the two drugs in the improvement of exercise tolerance. No side effects were noted with the two drugs. These data indicate that ibopamine could be a valid alternative to digoxin in heart failure patients in sinus rhythm when given for 10 days. More data are needed to evaluate the long-term efficacy of ibopamine.

Calcium entry blockade, autonomic activity and exercise performance in essential hypertensive patients.

Vasodilator drugs lead to secondary baroreflex mediated chronotropic effects. The aim of the present study was to evaluate long term therapy with nicardipine, a calcium antagonist, on exercise performance and autonomic nervous system activity. Nicardipine was administered to 10 untreated mild-moderate essential hypertensive patients. Isometric (hand grip) and dynamic (bicycle ergometer) exercise, and parasympathetic activity evaluated on the basis of Variation of Heart Period (VHP) during regular breathing were determined. Blood pressure was significantly lowered by nicardipine both supine and standing (p less than 0.001). Heart rate did not change. The increase of blood pressure during isometric and dynamic exercise was similar both before and during nicardipine. The increase of heart rate during dynamic exercise was lowered by nicardipine. The lack of basal supine and standing chronotropic activation and the smaller increase of heart rate during bicycle ergometer could be explained by the observed increase in parasympathetic activity, as indicated by the rise of VHP.