Differences in Cancer Death Risk Long After ACS Among Selected Urban and Rural Areas in North Italy: The ABC-7a Study on Heart Disease

Background: An increased risk of cancer death has been demonstrated for patients
diagnosed with acute coronary syndrome (ACS). We are investigating possible
geographic risk disparities.
Methods: This prospective study included 541 ACS patients who were admitted to
hospitals and discharged alive in three provinces of Italy’s Veneto region. The patients
were classified as residing in urban or rural areas in each province.
Results: With 3 exceptions, all patients completed the 22-year follow-up or were followed
until death. Urban (46%) and rural (54%) residents shared most of their baseline
demographic and clinical characteristics. Pre-existing malignancy was noted in 15
patients, whereas 106 patients developed cancer during the follow-up period, which
represented 6232 person-years. No difference in the cancer death risk was found
between the urban and rural areas or between southern and northern provinces
(hazard ratio [HR] 1.1; 95% confidence interval [CI] 0.7–1.7; p = 0.59 and HR 1.1; 95%
CI 0.9–1.4; p = 0.29, respectively) according to the unadjusted Cox regression analysis.
Geographic areas, however, showed a strong positive interaction, with risk increasing
from the urban to rural areas from southern to northern provinces (HR 1.9; 95% CI 1.1–
3.0; p = 0.01). The fully adjusted Cox regression and Fine-Gray competing risk regression
models provided similar results. Interestingly, these results persisted, and even
strengthened, after exclusion of the 22 patients who developed malignancy and
survived to the end of follow-up. We did not observe an urban/rural difference in nonneoplastic
death risk or a significant interaction between the geographic areas.
Conclusion: Our analysis reveals that the cancer death risk among unselected ACS
patients in Italy’s Veneto region significantly differs by geography. The northern rural area
has the highest risk. These results highlight the importance of implementing a preventive
policy based on area-specific knowledge.

Albumin Excretion in Acute Myocardial Infarction: a Guide for Long-term Prognosis

Giuseppe Berton, MD, FESC, Rocco Cordiano, MD, Stefano Mazzuco, PhD, Ethan Katz, MD, Renzo De Toni, PhD, and Paolo Palatini, MD Conegliano, Adria, and Padova, Italy; and Cleveland, OH

Background Albumin excretion rate has been found to be associated with increased risk of mortality in several clinicalsettings. We assessed the relationship between urinary albumin and 7-year mortality in a cohort of patients with acutemyocardial infarction (AMI).

Methods In this prospective study, we examined 505 white patients admitted with AMI to the intensive care unit of3 hospitals. Main end points were nonearly all-cause and cardiovascular (CV) mortality. Albumin-to-creatinine ratio (ACR) was measured by radioimmunoassay on the first, third, and seventh days after admission. Risk estimates were made using Coxproportional-hazard model and relative odds. Forty patients (7.9%) died early inhospital, and 175 (34.7%) died during therest of the follow-up (nonearly mortality).

Results The ACR measured on the third day predicted the occurrence of 7-year nonearly all-cause and CV mortality.Hazard ratios for ACR≥0.97 mg/mmol were 3.0 (95% confidence limit 2.2-4.1),P< .0001, for nonearly all-cause mortalityand 3.5 (95% confidence limit 2.5-5.0),P< .0001, for CV mortality. Correspondent fully adjusted hazard ratios were1.9 (95% CI 1.4-2.6),P< .0001, and 2.2 (95% CI 1.5-3.2),P< .0001, respectively. By adding ACR to the 18-variablepredictive model, ACR improved significantly both the goodness of fitting of the model for nonearly all-cause (P< .0001) andCV mortality (P< .0001) and the C-statistic value (P< .0001 andP= .002 for nonearly all-cause and CV mortality,respectively). Similar results were obtained for ACR measured on the first day or the seventh day.

Conclusions An early increase of urinary albumin in AMI is a strong independent predictor of long-term adverse clinicaloutcome. The ACR improved clinical prediction over and above baseline traditional multivariable risk models.

(Am Heart J2008;156:760-8.)

Atrial Fibrillation during Acute Myocardial Infarction: Association with All-cause Mortality and Sudden Death after 7-year of Follow-up

G. Berton, R. Cordiano, F. Cucchini, F. Cavuto, M. Pellegrinet, P. Palatini

Aims: Atrial fibrillation⁄flutter (AF⁄FL) is a common complication of acute myocar-dial infarction (AMI). Indeed, the determinants of AF⁄FL in AMI-patients and theassociation of AF⁄FL with mortality are not well-known. The purpose of the pres-ent study was to investigate the relationship between presence of AF⁄FL and mor-tality in patients with AMI and to report on predictors of AF⁄FL.

Methods: We studied 505 patients enrolled in three intensive care units with definite AMI andfollowed up for 7 years. No patient was lost to follow-up. Patients with AF⁄FLduring the 1st week of hospitalisation were compared with those with steady sinusrhythm. End-points were all-cause mortality and modes of death.

Results: At multivariable logistic regression analysis, elderly, body mass index, congestive heartfailure (CHF), history of hypertension and plasma cholesterol (in a negative fashion)were independently associated with the presence of AF⁄FL. At survival analysis,after full adjustment, AF⁄FL was not associated with in-hospital mortality. After7 years of follow-up, AF⁄FL was found to be associated with all-cause mortality[adjusted odds ratio (OR) = 1.6; 95% confidence interval (CI) = 1.2–2.3], togetherwith age, diabetes mellitus, creatine kinase-MB isoenzyme (CK-MB) peak, CHF,estimated glomerular filtration rate and thrombolysis. At adjusted logistic polyno-mial regression analysis, AF⁄FL was found to be associated with an excess of mor-tality for reasons of sudden death (SD) (adjusted OR = 2.7; 95% CI = 1.2–6.4).No interaction was observed between AF⁄FL and medications on in-hospitalmortality. For 7-year mortality, angiotensin-converting enzyme (ACE)-inhibitors anddigitalis showed an independent negative (protective) interaction chiefly on SD(adjusted OR = 0.06; 95% CI = 0.01–0.74, and RR = 0.10; 95% CI = 0.02–0.58, respectively).

Conclusions: Patients with AMI and AF⁄FL portend a poorprognosis in the long-term chiefly because of an excess of SD. Treatment withACE-inhibitors and digitalis may have long-term beneficial effects on SD.

Acute-phase Inflammatory Markers During Myocardial Infarction: Association with Mortality and Modes of Death after 7 Years of Follow-up

Giuseppe Berton, Rosa Palmieri, Rocco Cordiano, Fiorella Cavuto, Sigismondo Pianca and Paolo Palatini

Background The relationship between acute-phase inflammatory markers in the setting of acute myocardial infarction (AMI) and long-term outcomes is largely unexplored.

Objectives The aim of the study was to investigate the predictive power of acute-phase inflammatory markers following AMI for short-term and long-term mortality separately and modes of death.

Methods In 220 unselected patients with AMI [median age 67 (interquartile range 60-74) years, women 26%], blood neutrophil granulocytes, erythrocyte sedimentation rate, C-reactive protein, and a1-acid glycoprotein were measured 1, 3 and 7 days after admission. All patients completed 7 years of follow-up. Endpoints were 1-year (short-term) and 2- to 7-vear (long-term) mortality and modes of death, classified as nonsudden cardiovascular, sudden, and noncardiovascular death.

Results The short-term mortality rate was 18%. The long- term mortality rate was 26%. The short-term mortality risk was higher in patients in whom the markers were in the upper tertile. Fully adjusted hazard ratios (and 95% confidence interval) were 3.2 (1.4-7.9), 3.5 (1.7-7.9), 3.5 (1.6-8.6), and 6.1 (2.3-19.1) for neutrophil granulocyte, erythrocyte sedimentation rate, C-reactive protein, and «i-acid glycoprotein, respectively. The excess mortality was chiefly due to nonsudden cardiovascular mortality

Conclusion The acute-phase inflammatory markers tested following AMI are independently and concordantly associated with short-term mortality and their prediction is associated only with nonsudden cardiovascular modes of death. These markers are not associated with long-term mortality.

Keywords C-reactive protein, inflammatory markers, long-term mortality, myocardial infarction, prognosis, short-term mortality

Comparison of C-reactive Protein and Albumin Excretion as Prognostic Markers for 10-Year Mortality After Myocardial Infarction

Giuseppe Berton, MD,FESC;Rocco Cordiano, MD;Rosa Palmieri, MD;Fiorella Cavuto, MD;Patrizio Buttazzi, PhD; Paolo Palatini, MD

Background: C-reactive protein (CRP) is an established prognostic marker in the setting of acute coronarysyndromes. Recently, albumin excretion rate also has been found to be associated with adverse outcomesin this clinical setting. Our aim was to compare the prognostic power of CRP and albumin excretion rate forlong-term mortality following acute myocardial infarction (AMI).

Hypothesis: To determine whether albumin excretion rate is a better predictor of long-term outcome than CRPin post-AMI patients.Methods:We prospectively studied 220 unselected patients with definite AMI (median [interquartile] age67 [60–74] y, female 26%, heart failure 39%). CRP and albumin-to-creatinine ratio (ACR) were measured onday 1, day 3, and day 7 after admission in 24-hour urine samples. Follow-up duration was 10 years for allpatients.

Results: At survival analysis, both CRP and ACR were associated with increased risk of 10-year all-causemortality, also after adjusting for age, hypertension, diabetes mellitus, prehospital time delay, creatinekinase-MB isoenzyme peak, heart failure, and creatinine clearance. CRP and ACR were associated withnonsudden cardiovascular(non-SCV) mortality but not with sudden death (SD) or noncardiovascular(non-CV)death. CRP was not associated with long-term mortality, while ACR was independently associated withoutcome both in short- and long-term analyses. At C-statistic analysis, CRP did not improve the baselineprediction model for all-cause mortality, while it did for short-term non-SCV mortality. ACR improved all-causeand non-SCV mortality prediction, both in the short and long term.

Conclusions: ACR was a better predictor of long-term mortality after AMI than CRP.

Albuminuria During Acute Myocardial Infarction and Prognosis: a Methodological Issue

To the Editor. In the recently published study by Lazzeri et al. [1], microalbuminuria and other clinical variables were evaluated in hypertensive, nondiabetic patients with ST elevation myocardial infarction [1]. "The authors concluded that microalbuminuria does not yield prognostic information about the inhospital mortality or complications and claimed an association between acute glucose dysmetabolism and outcomes. We believe that, in this study, the predictive power of microalbuminuria has been overlooked by the authors due to a series of methodological problems.

Predictors of Ten-Year Event-Free Survival in Patients With AcuteMyocardial Infarction (from the Adria, Bassano, Conegliano, andPadova Hospitals [ABC] Study on Myocardial Infarction)


The long-term event-free survival (EFS) after acute myocardial infarction (AMI) is largelyuninvestigated. We analyzed noninvasive clinical variables in association with long-termEFS after AMI. The present prospective study included 504 consecutive patients with AMIat 3 hospitals from 1995 to 1998 (Adria, Bassano, Conegliano, and Padova Hospitals [ABC]study).

Thirty-seven variables were examined, including demographics, cardiovascular riskfactors, in-hospital characteristics, and blood components. The end point was 10-year EFS.Logistic and Cox regression models were used to identify the predictive factors. Wecompared 3 predictive models according to the goodness of fit and C-statistic analyses. Atenrollment, the median age was 67 years (interquartile range 58 to 75), 29% were women,38% had Killip class>1, and the median left ventricular ejection fraction was 51%(interquartile range 43% to 60%).

The 10-year EFS rate was 19%. Both logistic and Coxanalyses identified independent predictors, including young age (hazard ratio 1.2, 95%confidence interval 1.1 to 1.3, p=0.0006), no history of angina (hazard ratio 1.4, 95%confidence interval 1.1 to 1.8, p=0.009), no previous myocardial infarction (hazard ratio1.4, 95% confidence interval 1.1 to 1.7, p0.01), high estimated glomerular filtration rate(hazard ratio 0.8, 95% confidence interval 0.7 to 0.9, p=0.001), low albumin/creatinineexcretion ratio (hazard ratio 1.2, 95% confidence interval 1.1 to 1.3, p<0.0001), andhighleft ventricular ejection fraction (hazard ratio 0.8, 95% confidence interval 0.7 to 0.9, p=0.006).These variables had greater predictive power and improved the predictive power of 2 othermodels, including Framingham cardiovascular risk factors and the recognized predictors ofacute heart damage. In conclusion, 10-year EFS was strongly associated with 4 factors (ABCmodel) typically neglected in studies of AMI survival, including estimated glomerular filtrationrate, albumin/creatinine excretion ratio, a history of angina, and previous myocardial infarc-tion. This model had greater predictive power and improved the power of 2 other models usingtraditional cardiovascular risk factors and indicators of heart damage during AMI. 

Traduzione dall’originale: Rosanna Sedran, RN, Giuseppe Berton, MD.

Predittori clinici della sopravvivenza libera da eventi per 10 anni dopo infarto miocardico acuto (da: “the Adria, Bassano, Conegliano, and Padova Hospitals [ABC] Study on Myocardial Infarction")


La sopravvivenza a lungo termine libera da eventi (EFS) dopo infarto miocardico acuto (AMI) è poco conosciuta.
Abbiamo analizzato variabili cliniche non invasive in associazione con EFS per un lungo periodo dopo un infarto miocardico acuto. Questo studio prospettico ha riguardato 504 pazienti con infarto miocardico acuto, non selezionati, arruolati consecutivamente in 3 ospedali generali dal 1995 al 1998 (the ABC study). Trentasette variabili cliniche sono state esaminate, compresi fattori demografici, fattori di rischio cardiovascolare, caratteristiche ospedaliere e componenti ematochimici.
L’obbiettivo dello studio è stato verificare l'EFS per 10 anni dopo l’AMI. Per l’analisi statistica sono stati usati modelli di regressione logistica e di Cox per identificare i fattori associati con EFS. Abbiamo confrontato 3 modelli predittivi usando analisi basate su “goodness of fit” e “C-­‐ statistic”. All'inizio dello studio l'età mediana dei pazienti era di 67 anni (interquartili 58-­‐75), il 29% donne, il 38% in classe di Killip > 1, e la mediana della frazione di eiezione ventricolare sinistra è stata del 51% (interquartili 43-­‐60%). L’EFS a 10 anni è stato del 19%. All’analisi logistica e di
Cox sono stati identificati i seguenti fattori predittivi indipendenti: giovane età (hazard ratio 1,2, intervallo di confidenza 95%, 1.1-­‐1.3, p=0,0006), non-­‐storia di angina (hazard ratio 1,4, 95% intervallo di confidenza 1,1-­‐1,8, p = 0,009), non-­‐precedente infarto miocardico (hazard ratio 1,4,  intervallo  di  confidenza  95%  1,1-­‐1,7,  p  =  0,01), elevata velocità di filtrazione glomerulare stimata (hazard ratio 0.8, intervallo di confidenza 95% 0,7-­‐0,9, p = 0.001), basso livello di escrezione di albumina/creatinina (hazard ratio 1.2, intervallo di confidenza 95% 1,1-­‐1,3, p <0,0001) ed elevata frazione di eiezione ventricolare sinistra (hazard ratio 0.8, intervallo di confidenza 95% 0,7-­‐0,9, p = 0.006). Queste variabili hanno mostrato maggiore potere predittivo di altri 2 modelli, che includono fattori di rischio cardiovascolare di Framingham e predittori di danno cardiaco acuto. In conclusione l'EFS per 10 anni dopo AMI è risultato fortemente associato a 4 fattori (the ABC model) sinora poco considerati negli studi di sopravvivenza dopo AMI, tra cui filtrazione glomerulare stimata, rapporto albumina/creatinina, storia di angina e precedente infarto miocardico. Questo modello ha maggiore capacità predittiva e risulta migliorativo rispetto ad altri due modelli tradizionali basati sui fattori di rischio cardiovascolare ed indicatori di danno cardiaco durante AMI.

Prospective History of Long-Term Mortality and Modes of Death in Patients Discharged After Acute Coronary Syndrome: The ABC-2* Study on Acute Coronary Syndrome

Background: The aim of this study was to examine the prognostic value of several clinical characteristics on long-term mortality and causes of death after acute coronary syndrome.

Methods: The   ABC-2   study   is   a   prospective   investigation   comprising  557  patients  with  acute  coronary  syndrome.  During  hospitalization,   33   clinical   variables,   including   demographics,   cardiovascular  risk  factors,  in-hospital  characteristics,  and  blood  components, were examined. “Acute models” were survival models containing  the  variables  accrued  within  72  h  from  admission,  and  “sub-acute  models”  contained  data  accrued  over  a  7-day  period.  Cox regression models were used for the survival analysis.

Results: The  12-year  follow-up  study  revealed  that  51.2%  of  the  patients  died  (15.8%  of  the  patients  died  from  coronary  artery  disease  and/or  heart  failure,  12.6%  of  the  patients  experienced  sudden death, 8.3% of the patients died from other-cardiovascular diseases, and 14.5% of the patients died from non-cardiovascular causes. The following factors were independently associated with all-cause  mortality  in  both  the  acute  and  sub-acute  models:  age,  left ventricular ejection fraction (negative), body mass index (non-linear),  previous  myocardial  infarction,  diabetes  mellitus,  blood  glucose  (non-linear),  Killip  class>1,  albumin/creatinine  ratio,  and  pre-hospital  time  delay.  The  variables  associated  with  coronary  artery  disease  and/or  heart  failure  included  age,  left  ventricular  ejection fraction (negative), body mass index (non-linear), previous myocardial   infarction,   Killip   class>1,   albumin/creatinine   ratio,   and  pre-hospital  time  delay,  while  the  variables  associated  with  sudden  death  included  age,  hypertension  (negative),  uric  acid,  left  ventricular  ejection  fraction  (negative),  and  pre-hospital  time  delay,  and  those  associated  with  other-  cardiovascular  causes  included age, hypertension, and albumin/creatinine ratio. The only variable associated with non- cardiovascular mortality was age. The C-statistic of the predictive models was 0.86 for all-cause mortality, whereas the C-statistic ranged from 0.74 to 0.80 for cardiovascular causes.

Conclusions: The  ABC-2  study  revealed  clinical  predictors  of long-term  mortality  after  acute  coronary  syndrome  that  might  help  prognostication,  patient  education,  and  risk  modification. Furthermore,  the  results  showed  that  the  modes  of  death  are  independently associated with different baseline clinical features.

Keywords: Acute coronary syndrome;  Mortality; Risk   prediction; Survival analysis

Heart Failure in Women and Men During Acute Coronary Syndrome and Long-term Cardiovascular Mortality (the ABC-3* Study on Heart Disease) (*Adria, Bassano, Conegliano, and Padova Hospitals)

Aims: We investigated the gender-based differences in the association between heart failure (HF) during acutecoronary syndrome (ACS) and post-discharge, long-term cardiovascular (CV) mortality.

Methods and results: The present study included 557 patients enrolled in three intensive coronary care units anddischarged alive. HF during ACS was evaluated by Killip class and left ventricular ejection fraction (LVEF). Inter-action between gender and HF after 15 years of follow up was studied using Cox models including a formal inter-action term. Median age was 67 (interquartile range [IQR], 59–75) years, 29% were females, 37% had non-STelevation myocardial infarction and 32% Killip classN1, and median LVEF was 53% (IQR 46–61). All butfive pa-tients were followed up to 15 years, representing 5332 person-years. Of these, 40.2% died of CV-related causes.Crude CV mortality rate was higher among women (52.2%) than men (35.3%;Pb0.0001). At a univariablelevel, a negative interaction between female gender and Killip class for CV mortality was found [hazard ratio(HR) = 0.51 (0.34–0.77),P=0.002].Infive multivariable models after controlling for age, main CV risk factors,clinical features, post-discharge medical treatment, and mechanical coronary reperfusion, the interaction wassignificant across all models [HR = 0.63 (0.42–0.95),P= 0.02 in the fully adjusted model]. LVEF showed no sig-nificant hazard associated with female gender on univariable analysis [HR = 1.4 (0.9–0.2.0),P= 0.11] but did soin all adjusted models [HR = 1.7 (1.2–2.5),P= 0.005 in the fully adjusted model].

Conclusion: Gender is a consistent, independent effect modifier in the association between HF and long-term CVmortality after ACS.

Keywords: Gender, Heart failure, Killip class, LVEF, Acute coronary syndrome, Cardiovascular mortality, Surviving analysis

Risk of malignancy long after acute coronary syndrome in selected urban and rural areas and comparison with smoking risk: the ABC-7* study on Heart Disease

Background: Increased cancer risk has been reported in patients with acute coronary syndrome (ACS).
Objectives: To investigate geographic differences in risk malignancy long after ACS.
Methods: We enrolled 586 ACS patients admitted to hospitals in three provinces in the Veneto region of Italy in this prospective study. Patient’s residency was classified into three urban and three nearby rural areas.
Results: All (except for 3) patients completed the follow-up (22 years or death) and 54 % were living in rural areas. Sixteen patients had pre-existing malignancy, and 106 developed the disease during follow-up. Cancer prevalence was 17 % and 24 % (p = 0.05) and incidence of malignancy was 16 and 21/1000 person-years for urban and rural areas, respectively. In unadjusted logistic regression analysis, cancer risk increased from urban to rural areas (odds ratio [OR] 3.4;95 % confidence interval [CI] 1.7–7.1; p = 0.001), with little change from north to south provinces (OR 1.5;95 % CI 1.0-2.2; p = 0.06). Yet, we found a strong positive interaction between urban-rural areas and provinces (OR 2.1;95 % CI 1.2–3.5; p = 0.003). These results kept true in the fully adjusted model. Unadjusted Cox regression analysis revealed increasing hazards ratios (HRs) for malignancy onset from urban to rural areas (HR 3.0;95 % CI 1.5–6.2; p = 0.02), but not among provinces (HR 1.3;95 % CI 1.0–2.0; p = 0.14). Also, we found a strong positive interaction between geographic areas (HR 2.1;95 % CI 1.3–3.5; p = 0.002), even with a fully adjusted model.
Conclusions: The results in unselected real-world patients demonstrate a significant geographic difference in malignancy risk in ACS patients, with the highest risk in the north-rural area.
Keywords: Acute coronary syndrome, Malignancy risk, Urban-Rural.