Determinants of treatment strategies and survival in acute myocardial infarction: a population-based study in the Florence district, Italy

Results of the acute myocardial infarction Florence registry (AMI-Florence)1,,2

Eva Buiattia, Alessandro Barchiellib,*, Niccolò Marchionnic, Daniela Balzib, Nazario Carrabbad, Serafina Valentee, Iacopo Olivottof, Cristina Landinig, Maurizio Filiceh, Marco Torrii, Giuseppe Regolij and Giovanni M. Santorod

a Epidemiology Unit, Agenzia Regionale di Sanità della Toscana, via Vittorio Emanuele II 64, 50134 Florence, Italy
b Epidemiology Unit, Azienda Sanitaria di Firenze, via san Salvi 12 41, 50100 Florence, Italy
c Department of Critical Care Medicine and Surgery, Unit of Gerontology and Geriatric Medicine, University of Florence, and Azienda Ospedaliera Careggi, Via delle Oblate 4, 50141 Florence, Italy
d Cardiology Unit 1, Azienda Ospedaliera Careggi, Viale Pieraccini 17, 50139 Florence, Italy
e Department of Critical Care Medicine and Surgery, Unit of Internal Medicine and Cardiology, University of Florence, and Azienda Ospedaliera Careggi, Viale Morgagni 85, 50139 Florence, Italy
f Emergency Department, Azienda Ospedaliera Careggi, Viale Pieraccini 17, 50139 Florence, Italy
g Cardiology Unit, Santa Maria Nuova Hospital Azienda Sanitaria di Firenze, P.zza Santa Maria Nuova 1, 50122 Florence, Italy
h Cardiology Unit, Nuovo San Giovanni di Dio Hospital, Azienda Sanitaria di Firenze, via di Torregalli 3, 50100 Florence, Italy
i Medicine Unit 1, Santa Maria Annunziata Hospital, Azienda Sanitaria di Firenze, via dell‘Antella 58, 50011 Bagno a Ripoli, Italy
j Medicine Unit 2, Santa Maria Annunziata Hospital, Azienda Sanitaria di Firenze, via dell‘Antella 58, 50011 Bagno a Ripoli, Italy

* Corresponding author: Dr A. Barchielli, Azienda Sanitaria di Firenze, Epidemiology Unit, via S. Salvi 12, 50135 Florence, Italy. Tel.: +39-556263307; fax: +39-556263375.
E-mail address: epidemiologia{at}asf.toscana.it

Received 29 October 2002; revised 10 February 2003; accepted 3 April 2003


    Abstract
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Aims The Florence Acute Myocardial Infarction Registry is a prospective, observational study aimed at identifying the determinants of use of primary PCI and of prognosis in patients with STE-AMI, in an unselected population-based setting.

Methods and results Nine hundred and thirty cases of STE-AMI (mean age: 70.5 years) were prospectively recorded. Factors associated with use of revascularization, or influencing survival were identified through multivariate analyses (respectively: logistic and Cox regression). Primary PCI was the preferred reperfusion therapy in the study district, with 50% of STE-AMI cases admitted within 24h, and 58% of those admitted within 12h from symptom onset treated; about 5% of patients undergone fibrinolysis (overall revascularization being 55% and 63%, respectively). Availability of PCI facilities at admission hospital was the strongest independent positive predictor of subsequent primary PCI. Advanced age, comorbidities, Killip class 3, delayed hospitalisation and other factors independently reduced the probability of receiving reperfusion. In the whole series, in-hospital mortality was 6.6% for revascularization and 15.6% for conservative therapy, 6-month mortality was 10.1% and 26.0% respectively. The independent, protective effect of primary PCI persisted at the multivariate analysis, being 44% the reduction in the risk of death at 6 months.

Conclusion In this unselected series of patients, primary PCI, routinely performed in high volume centres, achieved good results in terms of survival even outside the setting of a randomised clinical trial. However, the relatively high number of untreated subjects and the tendency to select less severe cases of AMI for reperfusion treatment confirm the need for an accurate reassessment of behavioural patterns in selecting patients for revascularization.

Key Words: STE-AMI • PCI • Population-based • Registry • Prognosis • Determinants of use


    1. Introduction
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Early coronary reperfusion by fibrinolysis or primary percutaneous coronary intervention (PCI) is suggested as the standard treatment for Acute Myocardial Infarction (AMI) by European and US guidelines, since the late 1990s.1,2Meta-analysis of several prospective randomised trials3have reported a nearly 25% reduction in mortality with early fibrinolysis in AMI. Even more favourable results have been reported with early PCI in AMI presenting with ST-segment elevation (STE-AMI).4–8However, such excellent results were obtained within clinical trials and by experienced interventionists, and a recent editorial raised the question as to what may happen in the ‘real world’.9Indeed, while the Atlantic Cardiovascular Patients Outcome Research Team (C-PORT), a study carried out in community hospitals, confirmed that primary PCI during AMI is associated with better clinical 6-month outcomes than fibrinolysis,5other studies suggested that, at a population level, a substantial proportion of patients eligible for reperfusion do not receive it.10–12

The Florence health district (about 800 000 inhabitants) comprises five community and one teaching hospital (Azienda Ospedaliera Careggi), the latter with two cardiology and one geriatric departments running three coronary care units and implementing high-volume programs for PCI (24h/day, 7 days/week; about 2600 PCI carried-out in 2001, 600 of which primary or rescue procedures). As a rule, patients with AMI admitted to the Careggi Hospital are treated with urgent PCI. Patients referred to the community hospitals without PCI facilities who are considered eligible for revascularization, are usually transferred to Careggi hospital for primary PCI or, less frequently, receive fibrinolytic therapy onsite. Therefore, primary PCI represents the most common reperfusion strategy for AMI in the Florence area. Although the eligibility criteria for urgent coronary reperfusion were substantially uniform for all participating institutions, the indication to urgent PCI or fibrinolysis was left to the attending physician of the emergency room or CCU. The referral pattern and transportation of patients with AMI has developed over several years, and is fully integrated by a centralised emergency service providing physician-assisted ambulance transportation over the whole area.

We describe here the results of the Florence Acute Myocardial Infarction (AMI-Florence) Registry, a prospective observational study carried-out in an unselected population-based setting, which was aimed at identifying the determinants of use of primary PCI and of early and late prognosis in patients with STE-AMI.


    2. Methods
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
2.1. Patients
The study involved all emergency, cardiology and internal medicine departments located in the 6 hospitals, and the medical emergency transportation service in the area. The distance between the teaching hospital, equipped with PCI facilities, and the community hospitals ranges between 5 and 33 Kilometres (3–20 miles; transportation time: about 10 to 35min).

All cases of myocardial infarction (MI) diagnosed among residents in the Florence area between March 2000 and February 2001 who arrived alive at one of the six study hospitals were prospectively identified and recorded, with no exclusion criteria. AMI was diagnosed by at least two of the following criteria: typical chest pain lasting >30min, rise in serum creatine phosphokinase activity at least twice above the normal upper limit within 72h, and evidence of MI on first ECG (ST-segment elevation ≥0.1mV in two or more adjacent leads or new onset of LBBB). Other signs of myocardial necrosis (i.e. scintigraphic, echocardiographic or angiographic) were also taken into account for diagnosing sub-acute MI.13Based on both admission and discharge ECG, AMI was classified as Q-waves anterior, Q-waves other location, or non-Q-waves.

A standard case-report form was used to collect information on demographics, medical history, presenting symptoms, clinical and ECG features of MI, treatment and outcome during hospitalization. Time interval from onset of symptoms to hospital admission and revascularization, when applicable, was also collected. A local investigator at each department periodically sent the case-report forms to the AMI Florence Co-ordinating Centre for database entry. Data were checked for inconsistency and, in case of need, referred back to local investigators for further check or correction before processing. The completeness of enrolment was periodically checked through a hospital discharge system recording all admissions to regional public and private hospitals. The discharge diagnosis of AMI (ICD-9 410.*) for patients residing in the Florence district and admitted alive to the study hospitals was matched with the database ofenrolled patients and, for unmatched cases, the original clinical record was checked. When enrolment criteria were met, the case was included in the study. Therefore, the series of MI cases in the study is population-based and fully representative of the incident cases in the area over the study period.

A follow-up study was carried out by consulting the Registry Office of the municipality of residence, to assess all participants life status at 6 months.

2.2. Statistical analysis
Differences across subgroups (revascularization vs conservative therapy; non-survivors vs survivors) were evaluated with the {chi}2test for categorical variables, and with the Student’s t test for continuous variables. All tests were two-sided. Variables with significant effects at univariate analysis were tested in bivariate models with inclusion of age. Separate, stepwise multivariate regression analyses (forward method, significance level for addition to the model: p<0.05) were carried out to identify factors associated with use of revascularization and survival. Logistic regression was used to identify determinants of use of revascularization. The goodness-of-fit of the model was checked through the Hosmer-Lemeshow test. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated. In addition, Cox regression was used to assess the prognostic effect of treatment and of clinical and demographic variables on the 6-month survival. To this purpose, hazard ratios (HR) and 95% CI were calculated. The proportional hazard assumption was checked through the test proposed by Grambsch and Therneau, and the goodness-of-fit of the model through the test proposed by May and Hosmer.12Patients with multiple episodes of AMI during the study period were included only once in survival analysis, with follow-up observation starting from the first episode.

Analyses were carried out using STATA statistical package (version 6.0, Stata Corporation, College Station, Texas, 1999).


    3. Results
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
3.1. Patients presentation and revascularization therapy
Over the study period, 930 cases of STE-AMI were admitted to hospital within 24h of symptoms onset. Over the same period, 128 additional patients with subacute MI were also hospitalised, who were significantly older than the patients with STE-AMI (mean age: 73.1 vs 70.5, p=0.036). Of 930 STE-AMI cases, 390 (42%) were admitted directly to the hospital with PCI facilities, and 540 (58%) to the community hospitals: of these, 163 were transferred for urgent PCI. Overall, about 50% of the enrolled patients were treated with primary PCI, while 5% received fibrinolysis and 45% conservative therapy (Fig. 1). Primary PCI was the most common reperfusion strategy at any age, ranging from 66% at age 50–59 to 29% at age ≥80 years, while the maximum use of fibrinolysis raised to 7% at age 50–59. The proportion of revascularization was stable among cases admitted up to 6h after onset of symptoms (≤3h: 64% vs 4–6h: 66%), but decreased substantially among those admitted after 7–9h (55%), 10–12h (41%) and >12h (33%) from onset of symptoms. Use of revascularization was even lower (11%) among patients with unknown interval between onset of symptoms and hospital arrival (even if within 24h), suggesting that diagnostic uncertainty or delayed hospital presentation characterised this group of patients. Among 746 patients admitted within 12h of onset of symptoms, the proportion of cases undergoing revascularization was 63% and primary PCI 58%. The median time interval between onset of symptoms and hospital admission was 140min (interquartile range: 90–250). The median door-to-balloon time for primary PCI was 45min (interquartile range: 20–110min). At least one stent was implanted in 96% and TIMI3 flow was restored in 94% of cases. Six cases initially treated with fibrinolysis underwent rescue PCI, and 72 cases initially treated with conservative therapy (7.7% of the whole series) underwent PCI 24h after onset of symptoms.



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Fig. 1 Cases enrolled in the study, by subgroup.

 
3.2. Factors influencing the use of primary PCI
Demographic and clinical characteristics of patients receiving primary PCI or conservative therapy are compared in Table 1. Females, older patients, and cases with previous cardiovascular diseases, or other chronic conditions (such as MI, angina with onset >1 month, atrial fibrillation, cardiac conduction disorders, congestive heart failure, previous stroke, depression, renal failure, obstructive pulmonary disease, anaemia, diabetes) were less likely to receive revascularization. Controversially, primary PCI was more likely in patients affected by recent angina (≤1 month), and in those directly admitted to the hospital equipped with PCI facilities, during office hours, and with a shorter time between symptom onset and hospital admission. Furthermore, cases treated with conservative therapy had higher Killip scores, and lower peak CPK. Primary PCI rate was higher in cases of anterior AMI, while it was very low in non-Q AMI. Previous PCI or coronary bypass surgery, and the modality of referral to the hospital, did not differ between the two groups.


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Table 1 Demographic and clinical characteristics by type of therapy*

 
The multivariate analysis (Table 2) showed that availability of PCI facilities in the first admission hospital had the strongest positive, independent association with subsequent primary PCI. Age ≥80, previous congestive heart failure or stroke, a history of depression, chronic renal failure, onset of AMI during hospitalisation, admission outside office hours or ≥13h from onset of symptoms, non-anterior or non-Q waves MI, and Killip class 3 were all variables negatively associated with the probability of undergoing primary PCI. On the other hand, the probability of primary PCI was about twice among cases with recent onset of angina. Moreover, the multivariate analysis showed a remarkable, though non-significant, reduction in the probability of primary PCI among patients with previous MI (OR: 0.61, 95%CI: 0.35–1.03), active cancer (OR: 0.35, 95%CI: 0.11–1.12), and admitted to hospital 7–9h (OR: 0.45, 95%CI: 0.20–1.02) and 10–12h (OR: 0.46, 95%CI: 0.15–1.38) from onset of symptoms.


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Table 2 Variables multivariately (logistic analysis) associated with use of primary PCI

 
Of note, the differences in baseline clinical characteristics and the results of the multivariate analysis were virtually unchanged when patients receiving different types of revascularization (i.e. PCI or thrombolysis), rather than PCI alone, were compared to conservative treatment (data not shown).

3.3. Revascularization therapy and outcomes
Of 930 cases of STE-AMI diagnosed over the study period, 10 were recurrent episodes of AMI occurring in the same patient. Therefore, the overall number of subjects included in the follow-up analysis was 920. In the whole series, in-hospital and 6-month all-causes mortality were 10.7% (98/920) and 17.3% (159/920), respectively. The probability of in-hospital and 6-month death was 2.4 and 2.6 times greater in patients treated with conservative therapy compared to revascularization (respectively: 15.6% vs 6.6% and 26.0% vs 10.1%, P<.001). This difference was similar when only the 740 subjects admitted within 12h were taken into account, with an in-hospital and 6-month mortality of 5.7% and 9.2% in patients treated with revascularization, versus 14.5% and 24.4% for those treated with conservative therapy. Prognosis was similar inpatients treated with primary PCI or fibrinolysis (log rank test, P=0.7), their 6-month mortality being 10.2% (47/461) and 8.9% (4/45), respectively (Fig. 2). The independent, protective effect of primary PCI persisted after adjusting for demographic and clinical variables at Cox multivariate analysis (Table 3), which showed that primary PCI was associated with a 44% lower risk of death at 6 months. Such an apparent benefit was significant, and even more evident, when patients undergoing any type of revascularization were pooled (HR: 0.53, 95%CI: 0.36–0.77, P<0.001), while fibrinolysis alone failed to reach statistical significance (HR: 0.46, 95%CI: 0.16–1.25, P: 0.13). Advanced age, angina with onset >1 month, previous stroke or active cancer, and Killip class on hospital admission, were all additional independent predictors of the risk of death. In particular, the risk of death was 6.7 times higher in Killip class 4 than in class 1. On the other hand, non-Q waves MI was associated with a 41% lower probability of death at 6 months.



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Fig. 2 Probability of survival at 6 months, by treatment. Kaplan–Meier curves.

 

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Table 3 Variables independently (multivariate Cox analysis) associated with the risk of death at 6 months

 
Finally, we focused the analysis on patients admitted within 12h, with chest pain and without significant comorbidities (i.e., significant renal failure, previous stoke, cancer, etc.), for which the greatest benefit from early reperfusion therapy is expected. In this subgroup of patients, about 30% (190/624, 20% of the whole series) were treated with conservative therapy. Six-month mortality was 7.8% for reperfusion therapy and 19.0% for conservative therapy (P<001; multivariate HR: 0.64, 95%CI: 0.39–1.06, P=0.08).


    4. Discussion
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
The AMI-Florence Registry is a prospective, observational study designed to identify at a population level the determinants of the use of coronary reperfusive strategies and of related outcomes in STE-AMI, in an health district with a strongly preferential use of primary PCI. All cases of AMI in the target population that were hospitalised during the recruitment period were included in the study and, to exclude selection biases, completeness of recruitment was systematically checked. These characteristics distinguish the AMI-Florence from most of the other observational studies on treatment and outcomes of AMI, which were carried out in a single hospital,15,16or in large sets of hospitals that were not representative of a whole area,17with the exclusion of some patients,18or with retrospective collection of data.19Furthermore, follow-up has sometimes been limited to the hospitalisation period,17while in the present study patients have been followed-up for 6 months after hospital discharge.

Primary PCI was confirmed as the preferred reperfusion therapy in the study area, with 50% of STE-AMI cases admitted within 24h and 58% of those admitted within 12h from symptom onset receiving PCI. These proportions are substantially larger than in previous reports. During the late ‘90s, for example, 7.3% of cases enrolled in the National Registry of Myocardial Infarction 3, US, underwent PCI while 20.8% received thrombolytic therapy; these proportions raised to less than 20% and about 55% respectively in patients with STE-AMI admitted 12h from symptom onset.17In the GRACE Registry surveying USA, Brazil, Argentina andEurope, the proportions of patients with STE-AMI admitted to hospital within 12h who underwent primary PCI or thrombolytic therapy ranged from 14% to18% and from 31% to 53%, respectively.11In general, fibrinolysis represent the most widely used coronary reperfusion therapy,11,17and it has recently been suggested that it is likely to remain the dominant reperfusion therapy globally for the foreseeable future’.18However, several studies have shown that primary PCI is associated with better clinical outcomes at hospital discharge and after 6 months of follow-up than thrombolytic therapy.4–7

Many authors have pointed out that, to the present time, coronary reperfusion therapy remains underused in AMI.11,12,17,18The NRMI data showed that in the US, in spite of a growing use of primary PCI, the proportion of eligible patients who did not receive reperfusion (over 25%) remained stable between 1994 and 1999.17The GRACE results suggest that about one third of presumably eligible patients still are not actively reperfused.11In our area, the proportion of patients with STE-AMI admitted within 12h who were treated with every type of reperfusion therapy was 63%, which is somewhat lower than in other studies. This could be partially explained by patient enrolment without exclusion criteria, and by the inclusion of all the hospitals in the area. As previously reported,17the rather large proportion of untreated patients in spite of an unusually wide diffusion of primary PCI, together with the very low frequency of fibrinolysis, suggest that in this area primary PCI is used as an ‘alternative’ reperfusion strategy, rather than as an ‘additional’ strategy for patients ineligible for thrombolysis. The proportion of patients not treated with reperfusive therapy is also high (about 20% of the whole series) among the subgroups of patients for which the greatest benefit from early reperfusion therapy is expected.

We identified several factors independently associated with the likelihood of receiving reperfusion therapy. Availability of PCI facilities at admission hospitals was the strongest independent positive predictor of subsequent primary PCI. Several other independent factors reduced the probability of receiving reperfusion (i.e.: advanced age, some comorbidities, Killip class 3, delay in hospitalisation, etc.). This finding is in keeping with results from the GRACE registry11and may be related to the variable perception by attending physicians of indications to reperfusion, as well as to the implicit practice of the Medical Emergency Transport Service when choosing the referral hospital for patients with different clinical presentation.

The probability of reperfusion decreased progressively for hospital admissions delayed more than 6h from onset of symptoms. Furthermore, 128 cases (about 12% of all MI cases hospitalised during the study period) were hospitalised with a delay of 24h or more. This reinforces the importance of a timely hospitalisation for the proper management of AMI. The length of pre-hospital delay is a well known problem,16,18–20which is influenced by a wide range of factors (i.e.: patient’s awareness, age, skill of primary health care etc.).

Specific subgroups of patients were particularly unlikely to receive reperfusion therapy, i.e. those aged ≥80 years, as well as those with previous cardiovascular or other chronic diseases (i.e.: congestive heart failure, MI or stroke, chronic renal failure, depression, active cancer). These findings are consistent with other reports. In the GRACE registry, reperfusion was less likely in older patients, in those with previous congestive heart failure or coronary artery bypass surgery, and in those presenting without chest pain but with other ischaemic symptoms.11Other studies confirmed a lower use of thrombolysis in olderpatients,12,19,21,22despite the fact that many authors have claimed that, in this subgroup at high-risk of death, the absolute benefit of coronary reperfusion may be even larger than in the general population,11and that an inadequately frequent use of reperfusion therapy in these patients is not consistent with available guidelines.21

Since fibrinolysis was rarely used in the Florence district, our data did not allow a reliable comparison of the two reperfusion strategies. In fact, subjects undergoing fibrinolysis were a highly selected group and the statistical power for the comparison was low. Therefore, our analysis compared the effects of primary PCI to those of conservative treatment. In this setting, we were able to show that patients who received primary PCI had a 44% lower risk of death at 6 months, and that this observed benefit was maintained after adjusting for relevant prognostic variables. As previously specified, our data was derived from an observational study. This is at the same time the main reason of interest for the results, but also the cause of their limits. Indeed, the study describes what happened in the current clinical practice. On the other hand, the benefit of PCI over conservative therapy, assessed outside a randomised trial, cannot be completely adjusted for all baseline characteristics of patients and for other comorbidities not adequately recorded in the study. From a general point of view, non-randomised studies tend to show a larger treatment effect than randomised ones.23Therefore, the observed PCI benefit should be cautiously interpreted.

In conclusion, in this unselected series ofpatients, primary PCI, routinely carried out in high volume centres, achieved good results in terms of survival even outside the setting of a randomized clinical trial. However, the relatively high number of untreated subjects and the tendency to select less severe cases of AMI for reperfusion treatment, confirm the need for an accurate reassessment of behavioural patterns in selecting patients for coronary reperfusion therapy.14


    Footnotes
 
1 Work was performed at: Agenzia Regionale di Sanità della Toscana, Azienda Sanitaria di Firenze, Azienda Ospedaliera Careggi Back

2 AMI-Florence Working Group: Azienda Ospedaliera Careggi: G. M. Santoro, N. Carrabba (Cardiology Unit 1), G. Santoro, G. Corti (Cardiology Unit 2), M. Margheri, S. Valente (Department of Critical Care Medicine and Surgery, Unit of Internal Medicine and Cardiology), F. Ferrante (Medicine Unit 1), V. Verdiani (Medicine Unit 2), I. Olivotto (Medicine Unit 3), N. Marchionni, M. Monami (Department of Critical Care Medicine and Surgery, Unit of Gerontology and Geriatric Medicine). Azienda Sanitaria di Firenze: A. Barchielli, D. Balzi, V. Lazzeri, P. Naldoni, C. Melani, M. Maci (Epidemiology Unit); R. Vergassola, L. Fratoni (Emergency ambulance transport 118 service); Santa Maria Annunziata Hospital: A. Fantini (Coronary Care Unit), M. Torri (Medicine Unit 1), G. Regoli, C. Mugnaini (Medicine Unit 2); Santa Maria Nuova Hospital: M. C. Landini (Coronary Care Unit), M. Granelli (Medicine Unit 1); Nuovo San Giovanni di Dio Hospital: M. Filice (Coronary Care Unit), P. Fabiani (Medicine Unit 1); Mugello Hospital: F. Miglietta (Int. Therapy Unit), L. Scarti, I. Berni ( Medicine Unit); Figline Hospital: G. Fabrizi de Biani, F. A. Tarmun (Medicine Unit). Agenzia Regionale di Sanità della Toscana: E. Buiatti, S. Arniani, S. Bartolacci (Epidemiology Unit) Back


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 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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