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Clinical Trial
Received: July 17, 2003Accepted after revision: September 2, 2003 Early Drug Therapy and In-Hospital
Mortality following Acute Myocardial
Infarction
Paul Ernea Dragana Radovanovic b Philip Urband Jean-Christophe Stauffere Osmund Bertelc Felix Gutzwillerb aDivision of Cardiology, Kantonsspital, Luzern, bAMIS Plus Data Center, Institute for Social andPreventive Medicine, University Zürich, cDivision of Cardiology, Stadtspital Triemli, Zürich, dDivision of Cardiology,Hôpital La Tour, Genève, eDivision of Cardiology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland Key Words
pating hospitals between 1997 and 2002 were analyzed, Drug therapy W Acute myocardial infarction W In-hospital and the effect of factors and drug therapies on in-hospital mortality was assessed by logistic regression analysis.
Results: Age and diabetes were identified as factors
associated with a higher likelihood of in-hospital mortali-
Abstract
ty, while a significant and important reduction of in-hos- Background: Early drug therapy in patients with ST-ele-
pital mortality was due to the use of thrombolytic thera- vation infarction is essential for improved short- and py or primary percutaneous coronary intervention (PCI) long-term outcomes. Most of the drugs used currently [relative risk reduction (RRR) of 31%, odds ratio (OR) and have been extensively studied in the era prior to reperfu- 95% confidence interval: 0.69; 0.54–0.87; p = 0.002 for sion therapies, and thus it is important to assess the val- thrombolysis, RRR of 34%; OR 0.66; 0.44–0.99; p = 0.044 ue of these drugs in today’s clinical practice and com- for PCI]. Early administration of aspirin or ADP antago- pare the results with those of randomized trials. Objec-
nists is associated with a risk reduction of in-hospital tives: The study assessed the effects of age, gender, risk
mortality by 36% (OR 0.63; 0.45–0.89; p = 0.009) and 50% factors, reperfusion therapy and early drug therapy in (OR 0.49; 0.35–0.70; p ! 0.001), respectively. The use of patients with acute myocardial infarction with ST eleva- unfractionated heparin did not reduce in-hospital mortal- tion or new left bundle-branch block on in-hospital mor- ity. Administration of ACE inhibitors, nitrates or beta- tality. Methods: The analysis of drug administration and
blockers reduced the relative risk of in-hospital death by in-hospital mortality is based on the AMIS Plus project, a 40% (OR 0.60; 0.49–0.75; p = 0.009), 42% (OR 0.58; 0.46– registry of acute coronary syndromes in Switzerland 0.72; p ! 0.001) and 54% (OR 0.46; 0.37–0.57; p ! 0.001), since 1997. Data from 7,279 patients admitted to partici- respectively. Less frequent use of reperfusion therapies
and beta-blockers was documented for older patients.
Gender was not a determining factor for in-hospital sur-
vival. Conclusion: Early administration of aspirin or ADP
Acute Myocardial Infarction and Unstable Angina in Switzerland (AMIS Plus). List of participating hospitals in the ‘Appendix’.
inhibition with ticlopidine or clopidogrel as well as the Tel. +41 41 205 51 06, Fax +41 41 205 51 09, E-Mail Paul.Erne@KSL.ch early use of beta-blockers, nitrates and ACE inhibitors Registries of defined populations have some important had a beneficial effect on in-hospital mortality in the limitations. However, they do offer the opportunity to reperfusion era with either thrombolytics or PCI. The study the impact of new evidence, to evaluate adherence association of a beneficial effect of ADP inhibition was to guidelines and to assess the impact of therapies in an more pronounced than that found in randomized trials unselected group of patients [2]. They also offer the possi- for non-ST-elevation infarction. However, it cannot be bility of improving compliance to therapy as shown for excluded that patients with a lower risk for in-hospital the use of aspirin [13–15] and beta-blockers [16, 17] fol- death who were selected for early invasive assessment lowing MI. In Switzerland, we initiated a registry on acute received more frequently ADP inhibitors and that this MI in 1997 and we now report on the impact of early drug influenced this beneficial effect. Diabetes and age had therapy on in-hospital mortality in patients with acute negative effects on in-hospital mortality, and both reper- fusion therapy and beta-blockers were much less fre-quently used in elderly patients.
The AMIS Plus RegistryIn 1997 the Swiss Societies of Cardiology, Internal Medicine and Introduction
Intensive Care initiated a registry to assess the diagnostic and thera-peutic measures in patients with acute MI in Switzerland (AMIS).
The management of acute myocardial infarction (MI) Participating hospitals provide blinded data on these patients to a in patients with ST elevation was recently reviewed by the Data Center through an Internet- and paper-based questionnaire of140 questions. The Data Center checks the data for plausibility and Task Force on the Management of Acute Myocardial cross-checks in case of queries. In 2000, unstable angina was added to Infarction of the European Society of Cardiology [1].
this Registry and the Data Center was transferred from Geneva to Many drug therapies such as aspirin, beta-blockers, hepa- Zurich (AMIS Plus). The project is led by a Steering Committee com- rins and nitrates, once cornerstones of therapy and her- prised of members of the founding societies. The Registry was alded as major advances in the treatment of patients with approved by the Above-Regional Ethical Committee for ClinicalStudies and the Swiss Board for Data Security.
MI, need to be reassessed in the context of thrombolysisand percutaneous coronary interventions (PCI) as revas- cularization strategies. The treatment of acute MI under- The AMIS Plus Registry documented data from 11,845 patients went a remarkable evolution over the past decade [2]. The admitted to hospital for acute coronary syndrome between 1997 and effectiveness of aspirin was convincingly evidenced by the 2002. In the present analysis, data from 7,279 patients with ST eleva-tion or new left bundle-branch block (LBBB) were analyzed. The ISIS-2 trial [3] and its clinical value documented in large characteristics of these patients are summarized in table 1. The most meta-analyses [4, 5]. The beneficial use of heparins in dominant risk factors were overweight, dyslipidemia and hyperten- addition to aspirin was documented by the ISIS-3 trial [6].
sion. We analyzed the drugs administered within 48 h of symptom Although there is substantial evidence that starting thera- onset and their impact on in-hospital mortality. Reinfarction, cere- py with ACE inhibitors on the 1st day of MI can reduce brovascular insult and death were defined as major cardiac events.
mortality by a small but significant amount [7, 8], other studies failed to show a benefit [9]. A large number of Data are presented as percentages for discrete variables and as trials carried out in the prethrombolytic era demonstrated mean B SD and median for continuous variables. The nonparamet- a reduction in mortality and reinfarction by beta-block- ric Mann-Whitney rank sum test was used for group comparisons. A ers. The beneficial effects of beta-blockade were docu- p value of ! 0.05 was considered significant.
To predict hospital mortality, a multivariate logistic regression mented in subgroups [10], but careful meta-analysis indi- analysis was conducted using the following variables: age, gender, cated that early administration of beta-blockers has a pos- Killip class admission (Killip class 1 as a reference category with an itive effect on both short- and long-term outcomes after odds ratio, OR, of 1.0), history of hypertension, diabetes, drugs MI [11]. A significant reduction of mortality due to administered within 48 h after symptom onset (aspirin, beta-blocker, nitrates was shown in a meta-analysis [12], but this posi- ticlopidine or clopidogrel, standard heparin, ACE inhibitor, andnitrates). Angiotensin II antagonists, low-molecular-weight heparin tive effect could not be demonstrated in large randomized and statins were excluded from analysis in order to increase the sam- ple size in the multivariate analysis.
Prospective, randomized trials do not necessarily re- SPSS (Chicago, Ill., USA) for Windows XP (version 11.5) was flect the wider-range patient population, nor do they nec- essarily reflect a transfer of findings to clinical practice.
Fig. 1. Reperfusion therapies in patients
with ST elevation and/or LBBB.
Table 1. Characteristics of the study population (n = 7,279)
Reperfusion Therapy in Patients with ST Elevation orNew LBBB In most patients, reperfusion therapy was carried out, although this therapy did not exceed 80% in any of the patient groups and was less frequently used in patients older than 60 years (fig. 1). Primary PCI was the preferred therapeutic strategy in the very young patient group, and the older the patient the less this therapy was applied.
There is a definitely increasing temporal trend for PCI, this strategy being used in 8% of patients in 1997 and in Early Drug Therapy in Patients with ST Elevation or Early drug therapy was defined as the administration of drugs within 48 h of symptom onset. In table 2, the fre- quency of administration within the various age groups is summarized. Aspirin, unfractionated heparin and ni- trates were most frequently administered in all age groups. Beta-blockers were more frequently used in youn-ger age groups and ACE inhibitors in elderly patients.
Inhibitors of ADP-induced platelet aggregation, ticlopid-ine and clopidogrel, were administered in those agegroups with more frequent PCIs. ADP inhibitors wereapplied to 1,839 patients (25.6%), 968 of these patientsunderwent primary PCI, while in 871 patients with ADPinhibitors PCI was not performed as the primary revascu- Erne/Radovanovic/Urban/Stauffer/Bertel/Gutzwiller Fig. 2. Outcome in patients with ST eleva-
tion and/or LBBB.
Table 2. Early drug therapy in patients with ST elevation and/or LBBB (%)
larization strategy. Calcium channel blockers and the years are shown. In table 3, the result of the logistic regres- more recent angiotensin II antagonists were infrequently sion analysis, odds ratios, and confidence limit with used in acute MI (less than 5% of patients) and were thus regard to in-hospital mortality in this patient population, is summarized. Age and the Killip class were the impor-tant determinants of increased mortality, while gender In-Hospital Mortality and Major Adverse Cardiac had no significant association and effect on in-hospital mortality. In-hospital mortality increased by 6% per year An overall hospital mortality of 9.9% (n = 717) and an of age. While diabetes had a negative effect, hypertension incidence of major adverse cardiac events (MACE) of had no significant effect on in-hospital mortality. Both 13.5% (n = 949) were documented. In figure 2, the age- thrombolysis and PCI reperfusion strategies reduced the associated increases in in-hospital mortality and inci- risk of in-hospital mortality by more than 30%. The use of dence of MACE, as well as maximal mortality (26.6%) unfractionated heparin did not affect in-hospital mortali- and incidence of MACE (30.5%) in patients older than 80 ty, whereas the use of aspirin, inhibition of ADP-platelet Table 3. Multivariate logistic regression model for predicting in-hos-
Discussion
The AMIS Plus project is a registry of patients admit- ted with unstable angina or acute MI in Switzerland. Its purpose is to enable assessment of temporal changes in the epidemiology of patients, and in diagnostic and thera- peutic measures. Another purpose is to facilitate the con- trol of compliance of evidence from randomized trials and the evolution of guidelines [1, 18] in the treatment of MI and unstable angina. Registries are valuable means of documenting potential under- or overuse of diagnostic procedures, of defining how new information from evi- dence-based medicine is transferred to clinical practice, and also of documenting effects not addressed in clinical This study focused on the in-hospital mortality of patients with ST-elevation MI as a strong outcome mea- sure and confirms the already documented importance of age and diabetes for higher in-hospital mortality. Further- more, as documented in other registries [2] and studies[19], we report a reduced reperfusion therapy in older Medication within 48 h after chest pain began (including emer- patients. Moreover, this study has found that reperfusion therapy is highly effective and provides a relative overallrisk reduction of more than 30% on in-hospital mortality.
As in studies on patients with severe coronary artery dis-ease [20], but in contrast to the present investigation in aggregation, beta-blockers and ACE inhibitors was associ- MI, beta-blockers were more widely used in a younger ated with a risk reduction of in-hospital death by 37, 50, patient population while ACE inhibitors were more fre- quently used in older patients. Based on this result, itmight be concluded that elderly patients are less likely to receive guideline-indicated therapies. The less frequent The number of participating hospitals during the time use of therapies is most obvious for acute reperfusion for of this data collection varied, ranging from 18 to 52 (from both thrombolytic therapy and primary angioplasty, rural to university) of the 106 hospitals treating acute MI while aspirin is evenly administered to patients of all age in Switzerland. Therefore, the participating hospitals may not be representative of all Swiss hospitals. However, no The administration of aspirin in the acute phase of MI differences were documented on early drug treatments resulted in a 34% reduction of in-hospital mortality and it between the different categories of hospitals with the was postulated that it is of utmost importance to give aspi- exception of the use of GP IIb/IIIa antagonists, which rin to all patients as soon as the diagnosis of acute MI is were more frequently applied early in hospitals with deemed probable [1]. This is clearly taken into account by direct cath lab facilities (data not shown). On-site valida- the participating hospitals. We cannot exclude a bias in tion of data collection was only periodic and there were no the sense that patients with MI who did not receive aspi- checks for consistency between data-base entries and rin suffered from other serious conditions such as bleed- medical chart notes. There were no assessments of clinical ing disorders or recent surgery, which did not allow eligibility for each medication, and thus failure in the use administration of aspirin, and that these conditions might of certain medications may reflect contraindication to have influenced the incidence of MACE and in-hospital their use. Furthermore, there was no follow-up after hos- deaths. In patients who were treated by ADP inhibition, a pital discharge since the Ethical Committee and Board for similar but more pronounced association of risk reduc- Data Security restricted the registry to the collection of tion (50%) has been documented irrespective of whether the patients underwent angioplasty as a primary treat- Erne/Radovanovic/Urban/Stauffer/Bertel/Gutzwiller ment strategy. However, it cannot be excluded that ADP antagonism on in-hospital mortality were even larger than inhibition was more frequently used in patients who were in studies on patients with non-ST elevation. Overall, we managed with the option of early percutaneous interven- documented a high rate of mortality in association with tion. This association of ADP inhibition was also greater age and diabetes but also a very low rate of reperfusion than the relative risk reduction (31%) found with clopido- therapy provision to older patients.
grel in the CURE trial, in which patients with non-ST ele-vation were treated [21]. Although the beneficial effect ofheparin was documented in a large randomized trial [6], Appendix
this study found the use of unfractionated heparin to beassociated with a trend, albeit not significant, toward increased in-hospital mortality. We do not know if the The AMIS Plus Registry is funded by grants from (in alphabetical participating hospitals monitored the effect of heparin order): Astra-Zeneca, Switzerland, Biotronik, Switzerland, Bristol-Myers Squibb, Switzerland, Guidant AG, Switzerland, Johnson & and adjusted the dose to values for partial thromboplastin Johnson, Switzerland, Jomed AG, Switzerland, Medtronic AG, Swit- time, since values over 70 s increase the likelihood of mor- zerland, A. Menarini AG, Switzerland, Merck Sharp Dohme Chi- bret, Switzerland, Pfizer AG, Switzerland, Rahn Foundation, Swit- Apart from hypotension, renal failure and angioneu- zerland, Roche Pharma, Switzerland, Swiss Heart Foundation. Their rotic edema, it is now generally agreed that there are no support is gratefully acknowledged. The supporting institutions didnot play any role in the design of the Registry, Data Collection, Anal- major contraindications for starting ACE inhibitors early, in particular in patients with impaired ejection fraction or Steering Committee: P. Erne, President, Luzern, F.W. Amann, patients who experienced heart failure in the early phase Zürich, W. Angehrn, St. Gallen, O. Bertel, Zürich, J.-M. Gaspoz, [23]. However, in an unselected patient population of Genève, S. Dehler, Zürich, F.R. Eberli, Zürich, F. Gutzwiller, variable reduction of ejection fraction, the overall effect Zürich, P. Hunziker, Basel, M. Maggiorini, Zürich, B. Quartenoud,Fribourg, J. Schilling, Zürich, P. Siegrist, Zollikerberg, J.-Ch. Stauf- might be small but nevertheless significant. In this trial of fer, Lausanne, P. Urban, Genève and S. Windecker, Bern.
patients cared for in daily routine practice, we could docu- The following hospitals participated in the AMIS Registry on ment an important 39% relative risk reduction on in-hos- which this report is based from 1997–2002 (in alphabetical order): pital mortality. A similarly unexpected and important Kantonsspital, Altdorf (Dr. R. Simon), Kantonales Spital Altstätten, association with reduced in-hospital mortality for early Altstätten (Dr. P.-J. Hangartner), Kantonsspital Basel, Basel (PD Dr.
P. Hunziker), St. Claraspital, Basel (Dr. C. Grädel), Inselspital, Bern use of nitrates was also documented in this trial. How- (Prof. B. Meier), Spitalzentrum Biel, Biel (Dr. H. Schläpfer), Ober- ever, this positive association may emerge from a more walliser Kreisspital, Brig-Glis (Dr. D. Evéquoz), Spital Bülach, Bü- common use of nitrates to reduce ischemic burden, which lach (Dr. R. Pampaluchi/Dr. A. Ciurea), Rätisches Kantons- und would contrast with randomized studies in which nitrates Regionalspital Chur, Chur (Dr. P. Müller), Kreuzspital, Chur (Dr. V.
were administered independently of chest pain [7].
Wüscher), Spital Davos, Davos Platz (Dr. G. Niedermaier), Hôpitalcantonal Fribourg, Fribourg (Dr. B. Quartenoud), Spital Frutigen, Early intravenous administration of beta-blockers was Frutigen (Dr. S. Moser), HUG, Genève (Dr. J.-M. Gaspoz), Kantons- convincingly documented prior to the use of fibrinolytic spital Glarus, Glarus (Dr. W. Wojtyna), Spital Grenchen, Grenchen agents or PCI [24]. However, a post hoc analysis of the (Dr. P. Schlup/Dr. A. Oestmann), Bezirksspital Grosshöchstetten, GUSTO-I trial [25] did not support the routine early Grosshöchstetten (Dr. C. Simonin), Kantonales Spital, Heiden (Dr.
intravenous use of beta-blockers in today’s care of pa- R. Waldburger), Kantonales Spital, Herisau (Dr. P. Staub), SpitalInterlaken, Interlaken (Dr. P. Sula), Spital Jegensdorf, Jegenstorf tients by revascularizations. On the other hand, it is wide- (Dr. H. Marty), Hôpital La Chaux-de-Fonds, La Chaux-de-Fonds ly agreed that early oral administration of beta-blockers is (Dr. H. Zender), Spital Lachen, Lachen (Dr. I. Poepping), Kantons- beneficial for both short- and long-term outcome of MI, spital, Luzern (Prof. P. Erne), Hôpital régional, Martigny (Dr. B. Jor- and this study documented an impressive association to dan), Hôpital de la Tour, Meyrin (PD Dr. P. Urban), Hôpital du relative risk reduction of 54% on in-hospital mortality.
Chablis, Monthey (Dr. P. Feraud), Hôpital de Zone, Montreux (Dr.
E. Beretta), Hôpital du Jura bernois, Moutier (Dr. Ch. Stettler), In summary, this study based on a large patient popu- Regionales Spital Zentrum, Münsingen (Dr. F. Repond), Kreisspital lation in a registry of acute coronary syndromes demon- für das Freiamt, Muri (Dr. A. Spillmann), Group Hosp. Ouest strates an outstanding association for the early adminis- lémanique, Nyon (Dr. R. Polikar), Gesundheitszentrum Fricktal, tration of beta-blockers, ACE inhibitors and nitrates in Regionalspital Rheinfelden, Rheinfelden (Dr. H.-U. Iselin), Kanto- patients with ST elevation in an era where drug or inter- nales Spital, Rorschach (Dr. M. Pfister), Kantonsspital Obwalden,Sarnen (Dr. T. Kaeslin), Kantonsspital Schaffhausen, Schaffhausen ventional revascularization was frequently used. These (Dr. R. Frey), Spital Limmattal, Schlieren (Dr. B. Risti), Spital results suggest that under these circumstances, the benefi- Schwyz, Schwyz (Dr. P. Eichhorn), Ospidal d’Engiadina Bassa, Scuol cial effects of platelet inhibition by aspirin and ADP (Dr. G. Flury/Dr. C. Neumeier), Bürgerspital, Solothurn (Dr. P. Hil- ti), Kantonsspital, St. Gallen (Dr. W. Angehrn), Thusis Kranken- tal Sursee-Wolhusen, Wolhusen (Dr. M. Peter), Spital Zofingen, haus, Thusis (Dr. U.-P. Veragut), Spital Uster, Uster (Dr. D. Maurer/ Zofingen (Dr. H.J. Vonesch), Spital Zollikerberg, Zollikerberg (Dr. P.
Dr. S. Heinbuch), Kantonales Spital Uznach, Uznach (Dr. A. We- Siegrist), Zuger Kantonsspital, Zug (Prof. M. Vogt), Universitätsspi- ber), Spital Zimmerberg, Wädenswil (Dr. G. Garzoli), Spital Wald, tal, Zürich (PD Dr. F. Eberli/PD Dr. M. Maggiorini), Stadtspital Wald (Dr. M. Schneider), GZO Spital Wetzikon, Wetzikon (Dr. M.
Triemli, Zürich (Prof. O. Bertel) and Stadtspital Waid/Medizinische Graber), Kantonsspital, Winterthur (Dr. A. Haller), Kantonales Spi- Klinik, Zürich (Dr. M. Brabetz/Dr. S. Christen).
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