Riacutizzazione di BPCO

Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper Riacutizzazioni: definizione La riacutizzazione della BPCO è un evento, che si verifica nel corso della storia naturale della malattia, caratterizzato da un cambiamento rispetto al basale di dispnea e/o dell’espettorato, che eccede la variabilità quotidiana ed è tale da richiedere modifiche del trattamento Celli B. ERJ 2004

Costi delle AECB In generale, solo una minima parte della spesa sanitaria pro capite è generata da pazienti con BPCO lieve o moderata La malattia grave e molto grave, di competenza prevalentemente specialistica, spiega l’elevatissimo consumo di risorse sanitarie Poiché la bronchite cronica è responsabile dell’85% dei casi di BPCO, una rilevante porzione della spesa sanitaria pro capite per questi pazienti è generata dalle riacutizzazioni, indipendentemente dalla gravità della malattia di base Sethi S, File TM. Curr Med Res Opin. 2004;20:1511-21

Diagnosis of Chronic Bronchitis and AECB Definition EXACERBATION Defined as an increase in the baseline symptoms of the disease in the absence of an identifiable cause. Diagnosis of Chronic Bronchitis and AECB Chronic obstructive pulmonary disease is a vague term that is used to characterize a syndrome of progressive, irreversible airflow limitation. Similarly, the criteria used to diagnose COPD are vague (Barnes, 2000). By definition, any person who presents with sputum production on most days for at least 3 consecutive months each year for 2 consecutive years suffers from chronic bronchitis or COPD (Barnes, 2000; American Thoracic Society, 1995) . The majority of patients diagnosed with COPD have chronic bronchitis. During the natural course of the disease, patients with chronic bronchitis can experience periods of acute respiratory decompensation. These episodes are known as acute exacerbations of chronic bronchitis. The diagnosis of acute exacerbations of chronic bronchitis is also subjective and not facilitated by a single definition. It is often a diagnosis by exclusion, based on an increase in baseline symptoms (eg, dyspnea, sputum production, sputum purulence, and cough) in the absence of other causes (Sethi, 1999): ATS/ERS Statement ERJ 2004; 23:932-946

Cause di RIACUTIZZAZIONI Infezioni Batteriche Virali Allergie RIACUTIZZAZIONE Inquinamento Anidride solforosa Polveri industriali Clima Inverno *TENERE Ball P. Chest. 1995;108:43S-52S. Gump DW, et al. Am Rev Respir Dis. 1976;113:465-74.

ALL EXACERBATIONS BY MONTH OF STUDY: from East London COPD cohort

Modifiable risk factors in patients with COPD exacerbation (EFRAM study)  No influenza vaccination: 28 %  No rehabilitation program: 86 %  No home O2 in pts with PaO2 < 55 mm Hg: 28 %  Failed in inhaler maneuvers: 43 %  Current smokers: 26 % García Aymerich J et al. ERJ 2000; 16: 1037-1042

AECB ETIOLOGY Papi A et al. AJRCCM 2006

RESPIRATORY VIRUSES AND EXACERBATIONS Coinfection Coronavirus Chlamydia Pneumoniae RSV Serology Adenovirus Parainfluenza Influenza B Influenza A Rhinovirus Seemungal et al Am J Respir Crit Care Med 2001

RSV found in 26% of exacerbations RSV (PCR) IN STABLE COPD AND AT EXACERBATION Seemungal et al Am J Respir Crit Care Med 2001 EXACERBATIONS RSV found in 26% of exacerbations Detection of RSV not related to exacerbation parameters STABLE RSV found in 24% of stable samples

CHANGES IN BACTERIAL LOAD n=57 *p=0.0001 Bacterial Load Log cfu/ml 40 million cfu/ml to 102 miilion cfu/ml

Bacterial infection and COPD 10 20 30 40 50 60 70 27 55 64 4,2 2,2 5,5 Healthy subjects Stable COPD Exacerb. COPD Bacterial index Culture + Rosell et al. Arch Intern Med 2005; 165: 891-897

The “fall & rise” of bacterial AECB Modifying factors Clinical threshold Bacterial load (CFU/ml) AB1 AB2 AB3 Time (days) AE AB Cure Cure Cure Stop AB Time to relapse Miravitlles et al. Eur Respir J 2002: 20 (Suppl 36): 9s-19s

AECB Etiology The usual suspects Chlamydia pneumoniae

Persistent colonisation During a 7-year study, 122 instances of gaps in sputum cultures for H.influenzae were observed. 17 periods of prolonged periods of negative sputum cultures preceded and followed by an identical strain of H.influenzae. H.influenzae DNA present in negative sputum samples. Sputum cultures underestimate the frequency of colonisation by H.influenzae in COPD. Sethi et al. AJRCCM 2004;170:266-272

RELATIVE RISK OF EXACERBATION AND BACTERIAL STRAIN CHANGE Exacerbation visits % 33% of exacerbation visits were assoaciated with a new strain, compared to 15% of visits when no new strain was found P<0.001 For H Influenzae, S pneumoniae, M Catarrhalis Sethi et al NEJM 2002

INTERACTION OF BACTERIAL AND VIRAL INFECTION Wilkinson et al Chest 2006; 129:317-324

Rapporti tra infiammazione e infezione nei pazienti con BPCO

BACTERIAL ERADICATION AND INFLAMMATION White et al Thorax 2003

OSTRUZIONE BRONCHIALE ALTERAZIONI STRUTTURALI VIE AEREE-PARENCHIMA COLONIZZAZIONE BATTERICA OSTRUZIONE BRONCHIALE INSUFFLAZIONE RIACUTIZZAZIONI DISPNEA LIMITAZIONE SFORZO PEGGIORAMENTO Q of L

Circolo vizioso del declino funzionale nei pazienti con BPCO

39 (72.2%) of patients had bronchiectasis on HRCT Median score was 3/24 (range 1-14) Patel et al AJRCCM2004 Upper lobes 43.6% Middle lobe/lingula 46.2% Lower lobes 76.9%

NATURAL HISTORY OF COPD Never smoked Exacerbation Lung Function Smoker Exacerbation Exacerbation Time (Years) Fletcher C. BMJ 1977;1:1645-1648.

Day-to-day variability of a patient with COPD Normal variation of clinical state Exacerbation threshold Function Time Rodriguez-Roisin, R. Chest 2000;117:398S-401S

Relationship between lung function and exacerbations Exacerbations increase as lung function declines.

Lung function shows a small decline in the days immediately preceding an exacerbation FSC 50/500mcg bd Fluticasone propionate 500mcg bd 270 Salmeterol 50mcg bd Placebo 260 250 240 Mean PEF (L/min) 230 220 210 Onset of exacerbation -14 -12 -10 -8 -6 -4 -2 2 4 6 8 10 12 14 Day Pauwels et al. Am J Respir Crit Care Med 2003; 167(7): A949

INTERACTION OF BACTERIAL AND VIRAL INFECTION Wilkinson et al, Chest 2006; 129:317-324

Time Course and Recovery of COPD Exacerbations 101 patients - F/up 2.5 years FEV1 41.9% Pred Daily Symptoms and PEFR FEV1 (34) Recovery 75.2% No recovery 7.1% (90 d.) Seemungal TAR et al, AJRCCM 2000; 161: 1608

Impatto delle infezioni delle basse vie respiratorie sul declino annuale del FEV1 (ml/anno) Ex fumatori Fumatori intermittenti 70 Fumatori 60 50 40 30 Questo studio, che ha seguito per 5 anni soggetti con funzionalità respiratoria conservata al basale, ha dimostrato che il numero di riacutizzazioni e il declino della funzionalità respiratoria correlano con l’abitudine tabagica. 20 10 0-0.24 0.25-0.49 0.50-0.99 1.00-1.49 >1.50 Kanner RE et al. AJRCCM 2001 indice

Decline in FEV1 Over 12 Months in Patients with COPD Pauwels et al. AJRCCM 2001;163:A770

Variazione percentuale del FEV1 in 4 anni 0,95 Infrequente Frequente 0,9 0,85 Questo studio dimostra l’associazione tra frequenza delle riacutizzazioni infettive e declino della funzionalità respiratoria nei pazienti con BPCO moderata-grave. Più è elevato il numero di riacutizzazioni, più è rapido il declino del FEV1. 0,8 0,75 1 2 3 4 Anni Donaldson GC et al. Thorax 2002;57:847-852 indice

The risk of an exacerbation increases as lung function declines 100 Percentage of patients remaining 80 60 ATS stage 40 Mild Moderate 20 Severe 100 200 300 400 Exacerbation-free time (days) Hauber et al. Am J Respir Crit Care Med 2002; 165(8): A271.

Exacerbation Rate by FEV1 Donaldson & Wedzicha Thorax 2006;61:164

Relationship between symptoms and exacerbations Symptoms worsen before and during an exacerbation, prompting presentation to a physician, but their resolution is not sufficient for recovery.

Breathlessness increases during an exacerbation FSC 50/500mcg bd 2.4 Salmeterol 50mcg bd Fluticasone propionate 500mcg bd 2.2 Placebo 2.0 Mean breathlessness score 1.8 1.6 Onset of exacerbation 1.4 -14 -12 -10 -8 -6 -4 -2 2 4 6 8 10 12 14 Days Pauwels et al. Am J Respir Crit Care Med 2003; 167(7): A949.

Symptoms worsen during the 2 days preceding an exacerbation % patients with worsening of one or two symptoms Breathlessness score Cough score Sputum colour Sputum production 25% 11% 12% 30% 17% 20% 34% 19% 28% Pauwels et al. Am J Respir Crit Care Med 2003; 167(7): A949

INTERACTION OF BACTERIAL AND VIRAL INFECTION Wilkinson et al Chest 2006; 129:317-324

Relationship between exacerbations and health status Exacerbations have a pronounced detrimental impact on health status, while low health status is linked with increased probability of exacerbations

Recovery of health status after an exacerbation is prolonged, particularly if another exacerbation occurs during the recovery period Experiencing an exacerbation during the follow-up period Experiencing no further exacerbation n =133 Improved health status SGRQ total score 60 55 n =133 n =115 n =116 50 n =299 45 40 n =280 35 n =233 30 n =221 4 12 26 Time after presentation with an exacerbation (weeks) Spencer & Jones. Thorax 2003; 58: 589-93.

Exacerbations and quality of life P < 0.0005 SGRQ Score 3 - 8 Exacerbations/year Seemungal TAR et al, AJRCCM 1998; 157: 1418

Improved health status A higher frequency of exacerbations is related to greater impairment of health status 0-2 exacerbations per year (n=32) 3-8 exacerbations per year (n=38) Improved health status Mean SGRQ score 100 p=0.001 p<0.0005 80 p<0.0005 80,9 77,0 60 67,7 p=0.002 64,1 53,2 48,9 50,4 40 36,3 20 Total Activity Impacts Symptoms Seemungal et al. Am J Respir Crit Care Med 1998; 157: 1418-22

COPD exacerbations: Health status 613 mod. to severe COPD pts. followed for a maximum of 3 yrs * * p<0.0001 (Worse) # 3.0 # p<0.004 235 2.0 285 SGRQ slope (units/year) 91 1.0 None in 3 years Infrequent <1.65/year Frequent >1.65/year Exacerbation category Spencer S et al. Eur Respir J. 2004;23:698-702

Relationship between exacerbations and mortality Exacerbations increase the risk of death in patients with COPD.

Outcome delle AECB Mortalità Pazienti in UTI Mortalità ospedaliera 24% Mortalità ospedaliera 11-49% Pazienti ospedalizzati La mortalità ospedaliera dei pazienti con riacutizzazione della BPCO è simile a quella riportata dagli studi condotti nella polmonite. Seneff MG, et al. JAMA. 1995;274:852-1857; Connors et al. Am J Respir Crit Care Med. 1996 Oct;154 (4 Pt 1):959-67. Murata GM, et al. Ann Emerg Med. 1991 Feb;20(2):125-9; Adams SG, et al. Chest. 2000;117:1345-1352 indice

Sopravvivenza associata a AECB grave 100 80 60 Sopravvivenza (%) 40 La BPCO è, quindi, generalmente considerata una malattia poco grave, il cui sviluppo ha invece conseguenze drammatiche per i pazienti. 20 100 300 350 Giorni Connors et al. Am J Respir Crit Care Med 1996;154:959 indice

COPD Exacerbations : Mortality 1016 pts with severe COPD exacerbation (PaCO2 > 50 mm Hg) 60 49% 50 43% 40 33% Mortality (%) 30 20% 20 11% 10 Hospital stay 60 days 180 days 1 year 2 years Connors AF Jr et al. Am J Respir Crit Care Med. 1996;154:959-67

COPD exacerbations: Survival 1.0 0.8 No exacerbation 0.6 p<0.001 Probability of surviving 1–2 exacerbations p<0.0001 0.4 p=0.07 3–4 exacerbations 0.2 0.0 10 20 30 40 50 60 Time (months) Soler-Cataluña JJ et al. Thorax. 2005;64:925-31

COPD exacerbations: Survival 1.0 0.8 No exacerbation NS 0.6 ER visits p<0.0001 Probability of surviving p<0.01 0.4 1 hospitalization p<0.0001 NS 0.2 Readmission 0.0 10 20 30 40 50 60 Time (months) Soler-Cataluña JJ et al. Thorax. 2005;64:925-31

Airway inflammation and aetiology of COPD exacerbations Sethi et al Chest 2000

SPUTUM IL-8 AT EXACERBATION AND MORAXELLA CATTARHALIS Powrie et al ERS 2005

EFFECT OF CHLAMYDIA INFECTION ON INDUCED SPUTUM IL-6 Seemungal et al Thorax 2002

Microbial patterns in outpatients with COPD exacerbations and risk factors for a complicated course 777 isolates of 673 patients Inclusion criteria: age > 40 years  3 exacerb./year  3 comorbidities treatment failure or high prevalence of resistant pathogens % Anzueto et al., Clin Ther, 1998

Fattori associati indipendentemente con l’isolamento dei più comuni patogeni Germi Variabile dipendente Rapporto di LC 95% probabilità Non- ed ex-fumatori H. influenzae 8,16 1,9-43,0 vs fumatori FEV1 6,85 1,6-52,6 > 50% vs <50% P. aeruginosa FEV1 > 50% vs <50% 6,62 1,21-123,6 S. pneumoniae Mesi dall’ultima 5,02 1,12-35,7 riacutizzazione <2 vs >2 M. catarrhalis ------ ------ ------ Miravilles et al, 1999

Predictors of pathogens in hospitalized patients with COPD exacerbations % Eller et al., Chest 1998

Predictors of pathogens in patients with COPD exacerbations treated in the ICU %

Heterogeneity of COPD exacerbations The cause of an exacerbation can include acute viral bronchitis, environmental pollutants, and allergic responses as well as bacterial infections. Patients with similar degree of airflow limitation may have different rates of exacerbations, with a minority of the patients presenting with more than two exacerbations per year (frequent exacerbators).

Le manifestazioni cliniche non permettono di identificare le cause della riacutizzazione, perché virus e atipici sono associati con gli stessi sintomi e grado di risposta infiammatoria. Solo la presenza di escreato purulento è stata associata ad elevata carica batterica nelle secrezioni respiratorie durante le riacutizzazioni

CLASSIFICAZIONE DELLE RIACUTIZZAZIONI DELLA BRONCHITE CRONICA BASATA SUI SINTOMI Esacerbazioni Sintomi cardinali Tipo I • Tutti: Aumento dispnea Aumento volume escreato Aumento escreato purulento Tipo II • Due dei sintomi sopra citati Tipo III • Uno dei sintomi del Tipo I + uno tra i seguenti: Infezione delle vie respiratorie superiori nei 5 giorni precedenti Febbre senza altre cause Incremento del “wheezing” Incremento della tosse Incremento della frequenza respiratoria o cardiaca Anthonisen 1987

Possibile classificazione della severità delle riacutizzazioni di BPCO

Operational Classification of Severity of Exacerbations The Operational Classification of Severity is as follows: ambulatory (Level I), requiring hospitalisation (Level II) and acute respiratory failure (Level III). Level I Level II Level III Clinical history Co-morbid conditions History of frequent exacerbations Severity of COPD + Mild/moderate +++ Moderate/severe Severe Physical findings Haemodynamic evaluation Use accessory respiratory muscles, tachypnoea Persistent symptoms after initial therapy Stable Not present No ++ Stable/unstable Diagnostic procedures Oxygen saturation Arterial blood gases Chest radiograph Blood tests Serum drug concentrations Sputum gram stain and culture Electrocardiogram Yes If applicable +: unlikely to be present; ++: likely to be present; +++: very likely to be present ERS-ATS COPD Guidelines

Meta-analyses of typical study demographics showed that there was significant overlap in 95% CI and study data distributions for the three exacerbation severity levels Franciosi et al, Respir Res 2006; 7:74

Fixed Effect Meta-Analysis Results of Selected Spirometry Variables P < 0.017 is indicated for statistical comparisons of Level I versus II (*), II versus III (†), and I versus III (#) as well as P < 0.05 for comparison of out- versus in-patient setting (*)

Fixed Effect Meta-Analysis Results of Selected Clinical Variables P < 0.017 is indicated for statistical comparisons of Level I versus II (*), II versus III (†), and I versus III (#) as well as P < 0.05 for comparison of out- versus in-patient setting (*)

Fixed Effect Meta-Analysis Results of Selected Clinical Variables only arterial carbon dioxide tension (PaCO2) showed a statistically significant increase with increasing exacerbation severity Only arterial carbon dioxide tension (PaCO2) showed a statistically significant increase with increasing exacerbation severity P < 0.017 is indicated for statistical comparisons of Level I versus II (*), II versus III (†), and I versus III (#) as well as P < 0.05 for comparison of out- versus in-patient setting (*)

The current management and treatment of COPD exacerbations is primarily dependent on the evaluation of the symptoms rather than the signs related to the exacerbation event. Arterial carbon dioxide tension and breathing rate consistently varied with the severity of COPD exacerbations and with in- versus out-patients. Other commonly-accepted measures and suggested biomarkers for exacerbations failed to show consistent trends or lacked sufficient data to permit any meta-analysis. Franciosi et al, Respir Res 2006; 7:74

PLASMA FIBRINOGEN AT EXACERBATION Wedzicha et al Thrombosis and Hemostasis 2000 Seemungal et al Am J Respir Crit Care Med 2001 N = 120 Exacerbations Increased fibrinogen with colds P = 0.02 Increased fibrinogen with sputum purulence P = 0.03 Rise 0.56 g/l during viral Exs Rise in 0.27 g/l during non-viral Exs P = 0.056 P<0.001 P<0.001 4.3 4.2 4.1 4 Fibrinogen g/l 3.9 3.8 3.7 3.6 3.5 3.4 Stable Exacerbation Convalescence Mean ± SEM

AE-COPD: Procalcitonin Patient & Prescriber factors Standard group ProCT guided-group p-value Age, male gender (%) 71 y, 48 (53%) 70 y, 48 (53%) ns Antibiotics at admission (%) 19 (21%) 20 (22%) Anthonisen Typ I (%) 43 (48%) 49 (54%) Positive bacteriology 31/45 (67%) 28/57 (49%) GOLD III + IV % 68% 83% 0.039 FEV1 mean (L) (%) 0.99 ± 0.48 (44.9%) 0.85 ± 0.32 (38.4%) Antibiotic use (%) 62 (68.8%) 35 (38.8%) 0.0001 Antibiotic use (days) 7 ± 5 4 ± 5 Procalcitonin-guided antibiotic therapy in acute exacerbations of COPD: a randomised trial - The ProCOLD Study: D. Stolz, M. Christ-Crain, R. Bingisser, M. Gencay, J. Leuppi, D. Miedinger, C. Müller, P. Huber, B. Müller, M. Tamm. ERS Copenhagen, 2005

Evidence in favor: Stockley Prescriber factors Evidence in favor: Stockley Stockley RA, O'Brien C, Pye A, Hill SL. Relationship of sputum color to nature and outpatient management of acute exacerbations of COPD. Chest 2000; 117(6):1638-1645.

Consequence: Stockley data Prescriber factors Consequence: Stockley data Bronko Test Chart Cut-off color Stockley RA, O'Brien C, Pye A, Hill SL. Relationship of sputum color to nature and outpatient management of acute exacerbations of COPD. Chest 2000; 117(6):1638-1645.

severity of COPD and acute exacerbation Relation of severity of COPD and acute exacerbation COPD mild moderate severe acute exacerbation mild moderate severe

COPD exacerbations: Early therapy and recovery 24 0.42 d/d-delay (p<0.001) 18 12 Symptom recovery time (days) 6 7 14 Delay between onset and treatment (days) Wilkinson TMA et al. Am J Respir Crit Care Med. 2004;169:1298-303

Bacterial Eradication vs Failure Rate y= 0.5785x + 5.7679 r=0.91 Clinical failure rate (%) Eradication failure rate (%) Pechere JC et al. J Antimicrob Chemo 2000;45:19-24

Criteri per decidere se trattare una riacutizzazione di BPCO a casa o in ospedale. I. (BTS guidelines 1997)

Criteri per decidere se trattare una riacutizzazione di BPCO a casa o in ospedale. II. (BTS guidelines 1997)

Criteri per decidere se trattare una riacutizzazione di BPCO a casa o in ospedale. III. Da valutare con l’ausilio ospedaliero (BTS guidelines 1997)

Criteria for hospitalization ATS standards of care 1995 ERS / ATS guidelines 2004 ATS 1995 ERS / ATS 2004 severe dyspnea marked increase in dyspnea worsening hypoxemia / hypercapnia inability to eat or to sleep due to symptoms new onset of immobility significant, potentially unstable comorbidity presence of high risk comorbid conditions confusion changes in mental status inadequate response to outpatient management uncertain diagnosis inadequate home care

INDICAZIONI PER L’AMMISSIONE A REPARTI SPECIALIZZATI O DI TERAPIA INTENSIVA Presenza di gravi disfunzioni respiratorie Ammissione nel reparto di terapia intensiva INDICAZIONI PER RICOVERO IN ICU: insufficienza respiratoria presenza di altre disfunzioni di end-organ shock disturbi renali, epatici o neurologici instabilità emodinamica

Criteria for ICU admission ATS standards of care 1995 ERS / ATS guidelines 2004 ATS 1995 ERS / ATS 2004 severe dyspnea, not improved after 2 h impending or actual respiratory failure respiratory acidosis (pH < 7.3) despite oxagen supplementation signs of ventilatory fatigue confusion presence of other end-organ dysfunction neurological disturbance hemodynamic instability

Quanto maggiore è la presenza dei succitati indicatori, tanto più pressante è la necessità di ospedalizzare il paziente

Outcome delle AECB: insuccesso terapeutico Pazienti ospedalizzati Recidiva (ripetute visite di emergenza) 19% Pazienti ambulatoriali Tasso di insuccesso terapeutico 19-32% Circa un terzo dei pazienti trattati per riacutizzazioni della BPCO va incontro a fallimento terapeutico, evidenziato dalla necessità di nuovi ricoveri e visite mediche. Seneff MG, et al. JAMA. 1995;274:852-1857; Connors et al. Am J Respir Crit Care Med. 1996 Oct;154 (4 Pt 1):959-67. Murata GM, et al. Ann Emerg Med. 1991 Feb;20(2):125-9; Adams SG, et al. Chest. 2000;117:1345-1352 indice

in outpatients with acute COPD exacerbations Predictors of outcome in outpatients with acute COPD exacerbations Odds of failure in relation to home oxygen therapy and number of exacerbations over 24 months Variables Odds of failure Home oxygen and one exacerbation 0,311 Home oxygen and two exacerbations 1,008 Home oxygen and three exacerbations 3,274 Home oxygen and four exacerbations 10,627 Home oxygen and five exacerbations 34,707 Dewan NA et al., Chest 2000

in hospitalized patients with acute COPD exacerbations Predictors of outcome in hospitalized patients with acute COPD exacerbations Predictors of LOS Age > 65 Low FEV1 Poor performance status Predictors of death Acidosis Presence of leg edema Predictors of readmission Previous admission Readmission with > 4 medications 1400 admissions from 38 hospitals 14 % died within 3 months However: variation between hospitals 0-50% Roberts CM et al., Thorax 2002

LOWER LOBE BRONCHIECTASIS AND EXACERBATION RECOVERY Patel et al AJRCCM 2004 Patients with lower lobe score 0 or 1/8 time to recovery of symptoms = 10 days Patients with lower lobe score >/=2/8 time to recovery of symptoms = 12 days p = 0.001

Predictors of outcome (mortality) in hospitalized patients with acute COPD exacerbations 590 patients hospitalized in a university hospital Mortality rate 14,4 % OR 95% CI p Age 1,07 1,04 – 1,11 0.0001 PA-aO2 > 41 mm Hg 2,33 1,39 – 3,9 0.001 Ventricular arrhythmias 1,91 1,1 – 3,31 0.0022 Atrial fibrillation 2,27 1,14 – 4,51 0.019 Fuso L et al., Am J Med 1995