Clinical Characteristics and Mortality of Patients Screened for Entry Into the Trandolapril Cardiac Evaluation (TRACE) Study

doi:10.1016/S0002-9149(99)80791-7

The American Journal of Cardiology

Volume 76, Issues 1–2, July 1995, Pages 1-5

https://doi.org/10.1016/S0002-9149(99)80791-7 Get rights and content

In mortality studies of patients after acute myocardial infarction (AMI), exclusion of patients during selection from the screened population may be imporlant for evaluating the impact of trials, but data on patients excluded from studies are rarely presented. In the Trandolapril Cardiac Evaluation (TRACE) trial of the angiotensin-converting enzyme inhibitor trandolapril versus placebo in patients with left ventricular (LV) systolic dysfunction shortly after AMI, medical hislory, infarct complication, and survival were accounted for in all patients screened for entry. A total of 7,001 consecutive enzyme-confirmed AMls were screened for entry in 27 Danish coronory care units. The 1-year mortality of all screened AMI cases was 23% (95% confidence interval 22% to 24%). The target population of the TRACE trial were patients with LV systolic dysfunction (echocardio-graphically determined wall motion index ≤1.2, n = 2,606) within 6 days of AMI. The 1-year mortality of this group was 34 ± 2%. Patients with wall motion index >1.2 (n = 3,920) had a 1-year morlality of 12 ± 1%. Of those with wall motion index ≤1.2, 859 (33%) were excluded. A total of 1,749 were included in the study. The excluded and included groups had a 1-year mortality of 54 ± 3% and 24 ± 2%, respectively. The result of the TRACE study will be applicable to two thirds of the patients with LV systolic dysfunction; however, even with this high figure, care should be taken in extrapolating the result to the general population with reduced LV function after AMI since the group excluded from the study had a higher mortality than those who were included.

Section snippets

Methods

Patients: Details of the Trandolapril Cardiac Evaluation (TRACE) protocol have been published elsewhere.⁶ TRACE is a randomized, placebo-controlled, double-blind, parallel-group trial of the ACE inhibitor trandolapril among patients with LV systolic dysfunction shortly after an AMI. The primary end point of the trial is all-cause mortality.

In brief, consecutive patients with an enzyme confirmed AMI in 27 Danish hospitals were screened. An echocardiography and a medical history were obtained. LV

Results

A total of 7,001 enzyme-confirmed myocardial infarctions were screened for entry into the study at the 27 participating centers. The 7,001 infarctions represented 6,676 patients: 272 patients were screened twice, 19 three times, and 5 four times. Descriptive statistics of the 7,001 infarctions are listed in Table II. In this table, the numbers refer to infarctions, not patients. However, if descriptive statistics are calculated corresponding to initial infarction, the result is nearly the same:

Discussion

The 1-year mortality of patients with AMI screened for entry into TRACE and of those finally randomized were very similar, 23% and 24%. With regard to other studies attempting to randomize high-risk patients, a question is raised as to the possibility of extrapolating the result of the trial beyond those randomized.

The 7,001 AMIs screened for entry into TRACE were representative of the general population with AMI admitted alive to the hospital when 1-year mortality results are compared with

Acknowledgment

We thank Laurent Auclair, MD, and David Cole, PhD, for their helpful comments.

References (10)

J. Berning et al.
Early estimation of risk by echocardiographic determination of wall motion index in an unselected population with acute myocardial infarction
Am J Cardiol
(1990)
M.I. Charlson et al.
Applying results of randomized trials to clinical practice: impact of losses before randomization
Br Med J
(1984)
M.A. Pfeffer et al.
Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the Survival and Ventricular Enlargement trial
N Engl J Med
(1992)
The effect of ramipril on mortality and morbidity of survival of acute myocardial infarction with clinical evidence of heart failure
Lancet
(1993)
R. Stevenson et al.
Short and long term prognosis of acute myocardial infarction since introduction of thrombolysis
Br Med J
(1993)

There are more references available in the full text version of this article.

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These different modes of RAAS inhibition may explain some of the clinical differences between ACEIs, ARBs and DRIs. The evidence for ACEIs and reduced CV outcomes largely stem from the placebo-controlled trials of heart failure (HF)10 and post-MI.11 Beneficial effect of ACEIs was also seen in the placebo-controlled HOPE4 trial which included high-risk patients who had evidence of vascular disease or diabetes plus one other CV risk factor and who were not known to have HF.
The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in the pathogenesis of hypertension (HTN). Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are first line anti-HTN drug classes that are potent, effective and largely safe. Direct renin inhibitors (DRIs) have shown similar blood pressure (BP) reduction but more side effects. The efficacy of ACEIs and ARBs (for cardiovascular, cerebrovascular and renal protection) has been promoted to extend beyond what could be explained by BP reduction alone. In the current review, we will briefly discuss the (1) pathophysiology of renin-angiotensin-aldosterone system (RAAS) system, (2) clinical evidence for ACEIs, ARBs and DRIs in HTN, (3) comparison of ACEIs vs. ARBs and combination therapy, (4) role of RAAS inhibitors in specific patient populations, (5) safety profile of RAAS inhibitors, and (6) guideline recommendations and future perspectives. Closer scrutiny of outcome data shows little, if any, evidence that the efficacy of RAAS blockers in HTN extends beyond BP reduction.
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: The Trandolapril Cardiac Evaluation study was sponsored by Roussel UCLAF, Romainville, France, and Knoll AG, Ludwigshafen, Germany

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Clinical Characteristics and Mortality of Patients Screened for Entry Into the Trandolapril Cardiac Evaluation (TRACE) Study

Section snippets

Methods

Results

Discussion

Acknowledgment

Am J Cardiol

Applying results of randomized trials to clinical practice: impact of losses before randomization

Br Med J

Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the Survival and Ventricular Enlargement trial

N Engl J Med

The effect of ramipril on mortality and morbidity of survival of acute myocardial infarction with clinical evidence of heart failure

Lancet

Short and long term prognosis of acute myocardial infarction since introduction of thrombolysis

Br Med J