Relationship of Therapeutic Improvements and 28-Day Case Fatality in Patients Hospitalized With Acute Myocardial Infarction Between 1978 and 1993 in the REGICOR Study, Gerona, Spain
Background—The aim of this study was to analyze 28-day case fatality trends between 1978 and 1993 among hospitalized acute myocardial infarction (AMI) patients in the REGICOR registry, Gerona, Spain, and relate them to thrombolytic and antiplatelet drug use and changes in patient characteristics.
Methods and Results—A total of 2053 consecutive patients 25 to 74 years of age with a first Q-wave AMI admitted to the reference hospital between 1978 and 1993 were registered. Clinical characteristics and patient management were recorded. Four 4-year periods were considered: 1978 to 1981, 1982 to 1985 (prethrombolytic therapy), 1986 to 1989 (thrombolytic and antiplatelet drugs introduced), and 1990 to 1993 (thrombolytic and antiplatelet drugs used routinely). The end point was death at 28 days. Case fatality at 28 days decreased 6% per year between 1978 and 1993. A logistic model adjusted for comorbidity and severity showed the last 3 periods to present a steep decrease in the OR of death at 28 days: 0.86 (95% CI, 0.52 to 1.41), 0.59 (95% CI, 0.35 to 0.99), and 0.40 (95% CI, 0.24 to 0.69), respectively, compared with the first period. After 1986, 85.7% of the 112 lives saved could be attributed to the use of antiplatelet and thrombolytic drugs. Adjusted relative risk reduction was 56.0% for antiplatelet drugs, 34.1% for thrombolytic drugs, and 77.9% for the 2 combined.
Conclusions—Our results strongly suggest that new therapies introduced since 1986 have contributed to the decrease in 28-day case fatality of patients admitted with a first Q-wave AMI. This decrease could be attributable mainly to the use of antiplatelet and thrombolytic drugs. These findings should encourage the routine use of thrombolytic and antiplatelet drugs and particularly their combination in the acute phase of AMI.
Coronary heart disease (CHD) mortality has been declining since 1970 in most developed countries,1 accounting for 10.7% of deaths in Spain in 1993.2 This decline has been more evident in countries in which mortality was initially higher.1 Primary prevention interventions, particularly reduction in mean population cholesterol levels, cigarette smoking, and arterial blood pressure levels, have been judged to be principally responsible for this decline before the mid-1980s.3 4 Since then, improved medical care appears to have contributed greatly to the decrease in CHD mortality.5 6 Furthermore, these improvements should result in lower short-term mortality in hospitalized acute myocardial infarction (AMI) patients. In fact, a decline in case fatality has been observed in recent decades.7 The introduction of different pharmacological treatments and particularly thrombolytic therapy and the widespread use of antiplatelet drugs, anticoagulant drugs, β-blockers, and the advent of coronary angioplasty in the 1980s reduced in-hospital mortality to 13% to 16%.8 Therapeutic improvements such as fibrinolytic and antiplatelet agents9 have proved to reduce early mortality in clinical trial settings in selected groups of patients who do not necessarily reflect a real-life hospital patient case mix.10 11
More extensive evaluation of effectiveness in a general setting such as population-based registries is required to ascertain the effect of these therapeutic modalities on short-term AMI mortality.
The aim of this study was to analyze 28-day case fatality trends between 1978 and 1993 among hospitalized first Q-wave AMI patients in Gerona, Spain, and to relate them to the introduction and use of thrombolytic and antiplatelet drugs and to changes in patient characteristics (age, sex, AMI severity, or comorbidity).
The hospital under study is the only reference teaching center with a coronary care unit (CCU) in the area. There are 6 community hospitals that refer their AMI patients to that hospital after emergency treatment.
Most AMI patients initially admitted to community hospitals have been transferred to the reference center by medically attended ambulances since 1988. Since then, emergency treatment in community hospitals has been coordinated by CCU staff from the reference center using guidelines for early AMI management.
This setting provides the population-based Registre Gironí del COR11 (REGICOR) registry of hospitalized AMI patients in a northeastern region of Spain that covers 591 060 km2 and has 509 628 inhabitants (1991 census).
All patients 25 to 74 years of age who were residents of Gerona and were admitted to the reference hospital with a definite diagnosis of first Q-wave AMI between 1978 and 1993 were included in the study. Diagnosis of Q-wave AMI was based on a definite ECG, ie, new Q or QS waves, and at least 1 of the following: increased AMI enzymes (at least twice the upper normal value) and typical pain, ie, located in the anterior chest wall, lasting ≥20 minutes for which no cause other than CHD was found.
The following data were recorded: age, sex, cardiovascular risk factors or comorbidity (smoking status, hypertension, and diabetes), history of angina, and ECG AMI location. Disease severity was established by the clinical degree of ventricular dysfunction (acute pulmonary edema or cardiogenic shock) and the presence of ventricular arrhythmias (fibrillation or tachycardia) requiring immediate treatment. Management variables, including thrombolytic and antiplatelet drugs, coronary angiogram, PTCA, and CABG surgery, were also recorded.
Follow-Up and End Points
Vital status at 28 days was verified by personal or telephone contact and by linkage of our database with the Catalonia Mortality Registry, which collects all death certificates (updated to December 1995).
AMI Management From 1978 to 1993
The 16-year study was divided into 4 inclusive 4-year periods. The first 4-year period was considered to be the CCU “running-in” period (1978 to 1981). The period from 1982 to 1985 may be considered prethrombolytic. In the next period, 1986 to 1989, thrombolytic and antiplatelet drugs were progressively introduced into clinical practice after the publication of trial results. In the last period, 1990–1993, these drugs were routinely used at the reference and community hospitals. The proportion of patients receiving each of the above-mentioned treatments in each period is shown in Table 1⇓.
The χ2 test was used to assess the association between categorical variables. Trends among periods were analyzed with the Mantel-Haenszel χ2 test for linear trends. Age-adjusted annual decrease in mortality was assessed by logistic regression.
For analysis purposes, a 4-category variable was created, with each category corresponding to the periods described above. Each patient was allocated to the category covering the date he or she entered the study. This permitted ecological analysis of the effect of entering the study in each period on 28-day mortality of hospitalized AMI patients.
Adjusted OR of 28-day mortality in the different study periods was estimated by including the period of enrollment variable in a logistic model, together with demographic, comorbidity, clinical, and severity factors that statistically differed with a P<0.05 in bivariate analysis among the 4 periods studied and were further associated with 28-day mortality as potential confounders. The influence of the 2 major therapeutic improvements (thrombolytic and antiplatelet drugs) on the effect of the periods studied was measured by adding the corresponding treatment variable to the former model.
Assessment of Relative Risk Reduction and Number of Lives Saved by New Treatments
In an observational cohort study such as that presented here, treatments are provided on a clinical indication basis according to current knowledge of their efficacy. Because randomization is not applied, a favorable outcome cannot be attributed solely to the beneficial effects of the drug. Thus, risk estimates require previous adjustment for the factors that may differ between treated and untreated patients (ie, age, smoking, comorbidity, and severity).
The crude odds of dying in patients receiving each treatment were calculated and divided by the adjusted OR of treated patients and thus gave the odds of death in the treated group if the treated patients’ characteristics had been the same as among the untreated. Converting these odds to a probability resulted in an adjusted estimation of death probability if they had not received treatment (IOA). The number of lives saved with each treatment was calculated as the difference between the expected number of deaths in each treatment group on the basis of the above probability minus the observed deaths in that treatment.12 The same method was used to calculate the number of lives saved in each period. These results are presented with their 95% CIs.
An estimation of the adjusted relative risk reduction (ARRR) of the different treatments was then obtained with the following formula: ARRR=(IOA−It)/IOA, where It is the event incidence among treated patients.
Between February 1978 and December 1993, 2053 consecutive patients (1702 men, 351 women) 25 to 74 years of age admitted with a first Q-wave AMI were prospectively registered. Overall mean age was 59.9±9.8 years (mean±SD): 65.1±7.9 years in women and 59.4±9.9 years in men. No patient was lost to follow-up.
Overall 28-day case fatality rate was 12.3%. Mortality decreased from 25.3% in 1978 to 11.6% in 1993. Age-adjusted mortality decreased 6% (95% CI, 3% to 9%) per year from 1978 to 1993: 7% (95% CI, 4% to 11%) in men and 3% (95% CI, −3.5% to 9%) in women. Four-year proportion of patients with clinically severe ventricular dysfunction (pulmonary edema or cardiogenic shock) decreased from the 1978 to 1981 period (16.8%) to the 1986 to 1989 period (9.9%) but increased thereafter up to 17.0% in 1990 to 1993. The proportion of patients with severe arrhythmias paralleled the ventricular dysfunction pattern. Despite these changes, 28-day mortality decreased until 1986 to 1989 to stabilize in the following years (Table 2⇓).
Period Effect on 28-Day Mortality
Demographic, comorbidity, and clinical characteristics and 28-day mortality in the different periods are shown in Table 2⇑. A statistically significant increase was observed in the proportion of older patients and diabetics and a decreasing proportion of smokers throughout the study periods. A marginally significant trend toward a higher proportion of women was observed (P=0.06). The proportion of severe arrhythmias significantly increased, whereas that of anterior AMI decreased. However, all variables but sex showed differences among periods in a χ2 test (Table 2⇑).
Regarding patient characteristics according to vital status, survivors were younger and predominantly men; there were a lower proportion of hypertensives and diabetics and a higher proportion of smokers. Fatal cases presented a higher proportion of severe ventricular dysfunction, severe arrhythmias, and anterior AMI location but a lower use rate of thrombolytic and antiplatelet drugs. Although the use rate of coronary angiograms was similar in both groups, that of revascularization procedures was higher among fatal cases (Table 3⇓).
Crude and adjusted ORs for 28-day case fatality of the 4 study periods are shown in Table 4⇓. The adjusted OR was higher than the crude OR in the 1990 to 1993 period but lower in the 1982 to 1985 and 1986 to 1989 periods. Compared with 1978 to 1981, a steep decrease in adjusted 28-day mortality risk was found throughout the study periods (see the Figure⇓ and period effect model in Table 4⇓). Mortality risk reduction was statistically significant after 1986, when most management improvements were introduced, and the lowest risk corresponded to the more recent period, when the use of the new therapies had become routine.
Thrombolytic and antiplatelet drugs were introduced in the 1986 to 1989 period and were routinely used in the last period analyzed (Table 1⇑). Acetylsalicylic acid was used in 99.7% of cases, and streptokinase was the thrombolytic drug of choice in 95.5%. When these treatments were included in an adjusted logistic model (period effect model in Table 4⇑), the 1986 to 1989 period effect was attenuated and became statistically non–significant, and the 1990 to 1993 period effect disappeared (therapeutic effect model in Table 4⇑). Furthermore, 112 lives were saved in the last 2 periods when new treatments were used (35 in the 1986 to 1989 and 77 in the 1990 to 1993 periods) compared with the case fatality expected if patients had been treated in the 1978 to 1981 period (Table 5⇓).
The number of lives saved by antiplatelet and thrombolytic drugs was 96 (63 by antiplatelet drugs, 2 by thrombolytic drugs, and 31 by both treatments combined, as shown in Table 6⇓). This represents 85.7% of the 112 lives saved after 1986.
Compared with patients treated with neither antiplatelet nor thrombolytic drugs, adjusted relative risk reduction was 56.0% for patients treated with antiplatelet drugs, 34.1% with thrombolytic drugs, and 77.9% with both drugs administered together.
In the present study, 28-day mortality significantly decreased from 1978 to 1993 despite dramatic increases in disease severity of patients admitted in the last 4 years studied. A risk reduction was conclusively established in appropriately adjusted logistic models. Most of the decrease in risk from 1986 to 1993 might be explained by thrombolytic and antiplatelet drug use. Their individual and combined effectiveness has also been established in terms of the number of lives saved in all consecutive patients registered for a first AMI from 1978 to 1993.
Decrease in Case Fatality at 28 Days
Crude case fatality rates declined from 1978 to 1989, which might be explained in part by the progressively increasing referral of patients with AMI to the new CCU that opened in 1978. It is reasonable to assume that more severe cases were referred to the CCU in the earlier period. Over the years, it is logical to suppose that fewer selected cases of AMI were sent to the reference CCU. The fact that the decline stopped after 1989 is surprising, considering that the use of improved therapies increased in the last 4 years (Table 1⇑). This apparent paradox can be explained by the admission after 1989 of older patients and those with greater disease severity and comorbidity. In fact, the only crude OR that decreased after adjustment was that corresponding to the last period (Table 4⇑). Moreover, the adjusted OR of the period variable was statistically significant in the last 2 periods, when most management improvements were introduced, and the lowest risk corresponded to the last period, when they were routinely used.
The increase in severity of AMI patients admitted to the reference hospital in the last period could be related to faster access to improved emergency management in community hospitals. In this period, emergency care for AMI patients in community hospitals was provided according to standard guidelines that were periodically updated and coordinated by the reference CCU medical staff. Furthermore, medically attended transportation began in 1988 and has been routinely used since 1990. These changes may have resulted in an increasing admission of patients who, without the described facilities, might have died in the emergency departments of community hospitals. However, the impact of these factors on the increasing severity of AMI patients admitted to the reference hospital cannot be precisely measured. Some studies have reported an increasing trend of early care that may result in more severe AMI patients being admitted to hospitals.12
Our results concur with those of most studies analyzing trends in short-term case fatality in the 1980s and 1990s that found a decline in short-term mortality of hospitalized patients in most industrialized countries in the last few decades.6 7 8 13 14 15 Only 1 study analyzing similar periods of time did not find a decrease in in-hospital case fatality.16
Interestingly, declining trends in early mortality did not appear to correlate with variations in disease severity or comorbidity of admitted patients in other studies as they did in ours.17
Despite this, results of different studies that examined changes over time in short-term case fatality must be compared with caution, given the potential differences in sociodemographic and clinical characteristics of patients, diagnostic criteria for AMI (especially non–Q-wave AMI), period of time studied (which determines the treatments available), follow-up considered (in-hospital versus 28-day or similar), and inclusion of recurrent AMIs.
The introduction of new diagnostic procedures and new treatments appears to account for the decrease in in-hospital case fatality observed between 1979 and 19907 12 ; in particular, 20% of the improvement between 1985 and 1990 could be related to the use of thrombolytic drugs.14 Moreover, if the benefit of antiplatelet drugs is as described in ISIS 2,9 it might explain as much as 50% of the decrease in early case fatality after AMI between 1985 and 1990.6
In our study, the fact that the 1986 to 1989 and 1990 to 1993 period protective effects disappeared with the inclusion of therapeutic variables in the logistic models suggests that thrombolytic and antiplatelet drugs were largely responsible for the decreasing adjusted mortality observed. In fact, 85.7% of lives saved from 1986 to 1993 can be attributed to these treatments. Similar results were obtained by other authors.6
Adjusted relative risk reduction with both types of treatments in this observational study is higher than that reported in clinical trials and highest when the drugs are administered together, which concurs with current knowledge.18 Some studies have already highlighted the differences between AMI patients enrolled in clinical trials and an unselected general AMI population,12 15 16 resulting in the exclusion of high-risk patients from clinical trials.10 The explanation for the discrepancy could be related to these and other differences in case mix; ie, we included only first Q-wave AMIs and our age limit was set at 74 years, whereas in clinical trials, there is no upper limit. Other hypotheses that cannot be tested with our design refer to the effect of the lower population AMI case fatality in our region compared with that of other industrialized countries.19 20 Although protective, the effect of thrombolytic therapy was not statistically significant owing to the low number of patients receiving this drug alone; most received it combined with antiplatelet drugs, as shown in Table 6⇑.
Study Characteristics and Limitations
The large sample size provides this population-based hospital registry study with a highly representative, statistically powered group of myocardial infarction patients.
Less than 10% of the all-area patients hospitalized with a myocardial infarction were treated in community hospitals after 1988, which indicates that a selection bias is unlikely. Prehospital case fatality represented 62.4% of total 28-day case fatality in Gerona between 1988 and 1993.19 This figure is similar to that reported in most community myocardial infarction registries in the world.20 Incidence and mortality in Gerona are low and did not vary substantially between 1988 and 1993.19
This is an observational study, and no cause-effect relationship should be drawn from our findings that, however, convincingly support the effectiveness of thrombolytic and antiplatelet drugs in daily clinical practice because (1) they are biologically plausible, (2) an increasing protective effect emerges in the last 2 periods studied (when the drugs were used), (3) they are consistent with those of other studies,6 9 14 (4) the combination of both treatments has been found to provide an optimum additive benefit, and (5) the strength of the relationship between drug use and case fatality reduction is great in terms of OR magnitude. The effect of improvements in primary care and prehospital emergency care, changes in primary prevention, and better lifestyles cannot be readily ascertained. Nevertheless, the variable “period of inclusion” would contain the impact of all the unmeasurable effects described, and the models are properly adjusted to obtain the intrinsic effect of thrombolytic and antiplatelet drugs.
Characteristics of the study patients were homogeneous because patients with previous AMI and those ≥75 years of age, in whom prognosis is worse, were excluded. These differential characteristics may have been counteracted in part by the worse prognosis of Q-wave compared with non–Q-wave AMI that were also excluded from our study. This selection, however, provides homogeneity and requires less mathematical adjustment than when all cases are included.
β-Blocker use rate in our study was low (19.5% after 1988), as in the rest of Spain.21 Their use was recorded only after 1988, whereas information on their administration route was not. Moreover, β-blockers were given on discharge in most cases. This use of β-blockers provides no benefit in 28-day case fatality, which is the end point of our study. Inclusion of this variable in our models would produce distortions in risk estimators, ie, a large, illusory protective effect. A model further adjusted for coronary angiography and revascularization use did not change the effect of periods or the drugs analyzed (results not shown).
Conclusions and Clinical Implications
Although patients with increasing disease severity were admitted during the last 4 years of the register, 28-day case fatality risk adjusted for age, disease severity, and comorbidity steadily decreased. Our results convincingly suggest that most of the case fatality reduction was related to thrombolytic and antiplatelet treatments, which contributed to counteracting the effect of the higher risk profile of the more recently admitted patients. These findings should encourage the routine use of thrombolytic and antiplatelet drugs and particularly their combination in the treatment of AMI patients.
The REGICOR investigators were C. Aubó, M. Bosch, M. Cardona, M.I. Covas, R. Elosua, M. Gil, J.M. Manresa, J. Marrugat, S. Martín, M. Pavesi, A. Pena, G. Pérez, P. Roset, M. Sentí, J. Vila (Institut Municipal d’Investigació Mèdica), X. Albert, R. Masiá, and J. Sala (Hospital Universitari “Josep Trueta”).
This work was funded by grants FIS-90/0672 and FIS-93/0568 and grant CIRIT/1997 SGR 00218. We appreciate the English revision made by Christine O’Hara; the statistical advice of Dave McFarlane, Aurelio Tobías, and Rosa Lamarca; and the comments on the manuscript by Drs Gaietà Permanyer and Carles Brotons.
See the “Appendix” for a list of REGICOR investigators.
- Copyright © 1999 by American Heart Association
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