Author + information
- Received January 19, 2000
- Revision received July 24, 2000
- Accepted September 13, 2000
- Published online January 1, 2001.
- Laura F. Wexler, MD, FACC∗,* (, )
- Alvin S. Blaustein, MD†,
- Philip W. Lavori, PhD‡,
- Kenneth G. Lehmann, MD§,
- Michael Wade, MS∥,
- William E. Boden, MD∥∗∗,
- for the Veterans Affairs Non–Q-Wave Infarction Strategies in Hospital (VANQWISH) Trial Investigators¶
- ↵*Reprint requests and correspondence:
Dr. Laura F. Wexler, Cardiology Section, Department of Veterans Affairs Medical Center, 3200 Vine Street, Cincinnati, Ohio 45220
We wished to determine the effect of post-infarct management strategy on event rates (death or recurrent nonfatal myocardial infarction [MI]) in patients who evolved non–Q-wave MI (NQMI) following thrombolytic therapy.
Patients who evolve NQMI following thrombolytic therapy are often considered to be at high risk and are frequently managed with routine early invasive testing despite a lack of data supporting improved outcome.
The Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) study included 115 patients who evolved NQMI following thrombolytic therapy. We compared the event rates in patients randomized to routine early coronary angiography with those in patients randomized to a conservative strategy of noninvasive functional assessment, with angiography reserved for patients with spontaneous or induced ischemia.
During an average follow-up of 23 months, 19 of 58 patients (33%) randomized to the invasive management strategy died or suffered recurrent nonfatal MI, compared with 11 of 57 patients (19%) randomized to the conservative strategy (p = 0.152). Equivalent numbers of patients were subjected to revascularization (percutaneous transluminal coronary angioplasty or coronary artery bypass graft). There were more deaths in the invasive management group than in the conservative management group (11 vs. 2). Excess deaths could not be attributed to periprocedural mortality.
Overall event rates (death or recurrent nonfatal MI) are comparable with conservative and invasive strategies in patients who evolve NQMI following thrombolytic therapy. Mortality rate in patients managed conservatively is low (3.5%), and routine invasive management may be associated with an increased risk of death.
The natural history of non–Q-wave myocardial infarction (NQMI) following thrombolytic therapy is thought to be similar to that of spontaneously occurring NQMI (1). Post hoc analyses suggest that the prognosis of patients who develop NQMI following lytic therapy is similar to that of lytic treated patients overall and is not influenced by early angiography and intervention. However, many centers routinely manage post-lytic NQMI patients with early coronary angiography in the absence of data clearly supporting improved outcomes with this invasive approach (2,3). This strategy is usually based on the assumption that evolution of a NQMI following lytic therapy represents an incomplete infarction, leaving myocardium in jeopardy that would be protected by revascularization (4).
The Veterans Affairs Non–Q-Wave Infarction Strategies In-Hospital (VANQWISH) trial (3)compared clinical outcomes in a cohort of 920 NQMI patients randomized to either a conservative post-myocardial infarction (MI) risk assessment strategy (noninvasive stress testing with coronary angiography reserved for patients with spontaneous or induced ischemia) or to routine predischarge coronary angiography. Overall mortality during follow-up did not differ significantly.
By study design, thrombolytic therapy was a predefined stratifying variable for the randomization of NQMI patients to the conservative (CON) or invasive (INV) management strategy. In this report, we compare the clinical characteristics and outcomes after randomization of the subgroup of 115 patients who developed NQMI after receiving thrombolytic therapy with those of the remaining 805 VANQWISH patients with spontaneously occurring NQMI. Based on previously reported similarities between patients with post-lytic NQMI and spontaneously occurring NQMI, we hypothesized that the CON and INV management strategies would produce equivalent outcomes in the subgroup of post lytic NQMI patients, as had been noted in the overall VANQWISH cohort (3).
Details of the VANQWISH trial design and methodology have been published previously (5). Eligible patients had a clinical presentation consistent with evolving acute MI, MB-CK isoenzyme levels >1.5 times the hospital upper limit of normal, and absence of new abnormal Q waves (or R-waves for posterior infarction) on serial electrocardiograms. At least one electrocardiogram was obtained 48 h after admission to exclude late development of Q waves, most of which (80%) occur within that time period (6). Patients were excluded if they exhibited significant co-morbidity or “very high risk” complications in the coronary care unit (i.e., cardiogenic shock or severe heart failure that persisted despite intravenous diuretics and/or vasodilators; persistent or recurrent ischemia at rest despite intensive medical therapy; symptomatic ventricular tachyarrhythmia) that posed clinical and/or ethical concerns for inclusion in a randomized controlled trial.
Patients who met study entry criteria and gave informed, written consent were randomized with the adaptive allocation (biased coin) procedure (7), which maximized the probability of balance between strategies by center and for each of five prognostic (stratifying) variables: age (<60 years/>60 years), prior MI, infarct location by electrocardiogram (anterior/nonanterior), entry ST-segment depression and use of thrombolytic therapy. Randomization typically occurred within 24 to 48 h after infarct onset.
For patients assigned to the INV strategy, coronary angiography was performed as the initial diagnostic test soon after randomization. Subsequent decisions regarding medical or revascularization therapy were not dictated by the study but were made by the individual investigator.
Patients randomized to the CON strategy had a radionuclide ventriculogram to assess left ventricular function as the initial noninvasive test, followed by a predischarge symptom-limited (standard Bruce protocol) treadmill exercise test with thallium scintigraphy. Patients who were unable to achieve ≥5 METS of exercise underwent thallium scintigraphy following standard protocol infusion of 0.56 mg/kg dipyridamole.
Coronary angiography with or without myocardial revascularization was performed in patients randomized to the CON strategy only if one or more of the following criteria were met: 1) clinical criterion:recurrent postinfarction angina with ischemic electrocardiographic changes (>0.1 mV ST-segment deviation and/or T-wave inversion in two or more contiguous leads); 2) exercise electrocardiographic criterion:≥2 mm ST-segment depression during peak exercise; and 3) “high-risk” thallium pattern:redistribution defects in two or more different vascular regions, or one redistribution defect with increased lung-to-heart ratio of thallium uptake.
Decisions to perform myocardial revascularization in patients with objective evidence of ischemia were made by the site investigator.
Whenever safe and appropriate, all study patients received enteric-coated aspirin 325 mg/day and long-acting Diltiazem 180 mg/day to 300 mg/day, based on reports supporting this therapy as secondary prevention following NQMI (8). Patients could also receive any other medical therapy considered to be standard care during the early course of hospitalization, including nitroglycerin, angiotensin converting-enzyme inhibitors, beta-blockers or dose-adjusted intravenous heparin.
Follow-up and end points
Patients were seen one month following discharge, and at three-month intervals until trial termination. The primary end point of the trial was all-cause mortality or recurrent nonfatal MI during a minimal 12-month follow-up period. All-cause mortality was a secondary end point. Patients were followed for a mean of 23 months.
Categorical baseline characteristics between groups were analyzed using Pearson’s chi-square test, whereas continuous outcomes were tested with Student t- test. Kaplan-Meier (9)curves were used to describe the event and mortality distributions between the thrombolytic therapy groups. Where appropriate, hazard ratios were adjusted for imbalanced baseline covariates using the Cox proportional-hazards regression model (10).
Characteristics of the study population and comparison of post-lytic to spontaneous NQMI patient subgroups
Of the 920 randomized patients from the 17 study sites, 115 (12.5%) received thrombolytic therapy. Their clinical characteristics are compared with those of the remaining 805 spontaneously occurring NQMI patients in Table 1. The post-lytic patients were slightly younger and had a lower prevalence of diabetes mellitus, hypertension, peripheral vascular disease and current smoking than the patients with spontaneously occurring NQMI.
Table 2compares results of noninvasive and invasive studies performed in patients with post-thrombolytic and spontaneous NQMI. Left ventricular ejection fraction (LVEF) was slightly higher in the post-lytic patients; and a smaller percent had LVEF <35%. Post-infarct thallium studies, performed primarily in patients randomized to the CON arm, showed a similar prevalence of high-risk patterns (as described in the Methods section).
A similar percentage of patients in the post-lytic and spontaneous NQMI subgroups underwent coronary angiography before discharge. In addition to those randomized to the INV arm, 18% of the post-lytic and 25% of the spontaneous NQMI patients randomized to the CON arm underwent protocol-based coronary angiography during the index hospitalization because of high-risk clinical or noninvasive test indicators. Distribution of coronary artery lesions was similar in the two groups, although there was a trend toward less severe disease in the post-lytic group, which had a higher prevalence of single-vessel disease and a lower prevalence of three-vessel disease.
Patients were equally likely to undergo revascularization following post-lytic or spontaneous NQMI, but post-lytic patients were more likely to undergo PTCA and less likely to undergo CABG, probably in concert with their higher prevalence of single-vessel disease.
Comparison of outcomes in post-lytic versus spontaneous NQMI subgroups
Figures 1 and 2⇓⇓show Kaplan–Meier analyses of the probability of event-free survival (Fig. 1)and survival (Fig. 2)in post-lytic and spontaneously occurring NQMI during the 12 to 44 month follow-up period. Neither the survival rate nor the event-free survival rate differed significantly over the 23-month follow-up period. The proportion of patients with combined end points and the proportion of patients who died were similar (Table 3).
Comparison of outcomes in post-lytic NQMI patients randomized to CON or INV management strategy
Table 4compares the clinical characteristics of the 115 post-lytic NQMI patients randomized to the CON or the INV management strategy, indicating they were closely matched with respect to age, risk factors, and ECG variables.
Figures 3 and 4⇓⇓compare outcomes in the 115 post-lytic NQMI patients randomized to the CON or INV strategy. The difference between the cumulative rates of death or recurrent MI during long-term follow-up did not reach statistical significance. However, cumulative rate of death was significantly lower in the CON group than in the INV group (p = 0.014).
Comparison of outcomes in patients according to management strategy
Table 5compares clinical outcomes according to assigned management strategy in the post-lytic and spontaneous NQMI patients. Among all four subgroups, the most strikingly different outcome was the low (3.5%) mortality rate in the post-lytic NQMI patients randomized to the CON strategy.
Table 6shows the revascularization procedures performed during follow-up in the post-lytic NQMI patients randomized to the two strategies. More revascularization procedures were performed in patients randomized to the INV strategy, primarily because of a significantly greater number of patients undergoing PTCA.
The reported causes of death and procedures performed in the post-lytic NQMI patients are shown in Table 7. Approximately half the deaths in the INV group occurred within six months of NQMI. In contrast, the two deaths in the CON group (both noncardiac) occurred more than six months after NQMI. Two patients in the INV group died prior to angiography. None died within 24 h of coronary angiography. None of the patients who died underwent PTCA. Of three patients who had CABG, none were recorded as postoperative deaths.
As we have reported elsewhere, the VANQWISH study demonstrated no benefit associated with an early invasive as compared with a conservative, ischemia-guided post infarct management strategy in a large (n = 920) cohort of patients with NQMI, the majority of whom had spontaneously occurring infarcts (3). The subgroup of 115 post-lytic NQMI patients also showed no benefit from invasive as compared with conservative management. Of particular note is the very low mortality rate in the post-lytic patients treated conservatively (3.5%).
The increased number of deaths associated with the INV management strategy (11 vs. 2) is of uncertain significance given the small number of events (Table 7). The apparent excess deaths in the INV group occurred largely in the first six months after randomization but could not be attributed to different clinical characteristics or ECG variables or to an increased surgical or procedural mortality rate. Differences in severity of underlying disease cannot be excluded; the number of patients in the CON group who underwent protocol-based coronary angiography (10/57) was too small too allow meaningful comparisons of the distribution of coronary lesions between the INV and CON groups.
Our study showed no significant outcome differences between patients whose NQMI followed thrombolytic therapy and those with spontaneously occurring NQMI. This was also implied in the TIMI IIIB study (11), in which event rates at one year were similar in the post-lytic and placebo-treated NQMI groups, the latter group being comparable to the spontaneously occurring NQMI patients in our study.
Few major trials have specifically addressed the issue of appropriate management strategies in NQMI following thrombolytic therapy. The TIMI II trial provided a post hoc analysis of patients who evolved NQMI following thrombolytic therapy (12). At 42 days follow-up, event rates were not significantly different in those treated conservatively or invasively. The TIMI IIIB trial also compared the outcomes of invasive and conservative strategies similar to those used in the present study (2,11). Of the 477 patients with NQMI, neither mortality rate nor rate of recurrent nonfatal MI were different among patients randomized to each strategy.
A significant difference between the TIMI IIIB trial and the present study is that the crossover rate from the CON to the INV arm was much higher in TIMI IIIB (64%). The relatively low rate of protocol-driven angiography in the CON group (23%), which signified that the majority of patients remained within their assigned treatment group, supports the validity of the comparison between the two treatment arms and strengthens our conclusion that there is no benefit to a routine early invasive strategy in this subgroup of patients.
By study design, patients with obvious indications for early revascularization, such as hemodynamic instability or ongoing medically refractory chest pain, were excluded from randomization. As such, the study population consisted of NQMI patients who did not have obvious urgent indications for invasive study within the first 24 to 48 h after diagnosis of NQMI. However, this represented only 10% of the protocol-eligible patients in the overall VANQWISH cohort (3). Because we did not exclude patients with anterior location of MI, age >60 years or low left ventricular ejection fraction, this study included a representative sample of NQMI patients, many of whom had features known to confer increased risk of poor outcome and considered to be indications for early invasive management.
In summary, a strategy of conservative, ischemia-guided management of patients who evolve NQMI following thrombolytic therapy appears to be safe and effective.
The following persons and institutions participated in the VANQWISH trial: Study Chairman’s Office (Hartford, Connecticut): W. Boden (chairman), H. Dai and D. Joyce (project coordinators), and P. Crawford (program assistant); Veterans Affairs Medical Centers: Albuquerque—M. Crawford, M. Holland, K. Wagoner; Cincinnati—L. Wexler, V. Thomas; Fresno, California—P. Deedwania, F. Carbajal, R. Kanefield; Gainesville, Florida—C. Pepine, J. Green, Jr., M. Limacher, E. Handberg Thurmond, N. Davis; Hines, Illinois—M. Hwang, S. Lemoine; Houston—A. Blaustein, C. Rowe; Lexington, Kentucky—C. Chasen, P. Frazier; Little Rock, Arkansas—M. Murphy, J. Doherty, E. Smith, III, J. Calkins, Jr., A. Bierle; Loma Linda, California—D. Ferry, A. Jacobson, G. Frivold, K. Okubo; Nashville—R. Smith, S. Levine, R. Bruce; Palo Alto, California—J. Giacomini, C. Stepp; Richmond, Virginia—R. Jesse, A. Minisi, C. Murphy; San Antonio, Texas—R. O’Rourke, A. Jain, C. Patterson; San Diego, California—A. Maisel; Seattle—K. Lehmann, J. Caldwell, S. Ferris; St. Louis—H. Stratmann, L. Younis, L. Conwill; Tampa, Florida—R. Zoble, G. Cintron, J. Sullebarger, J. Umberger; Cooperative Studies Program Coordinating Center (Palo Alto, California): P. Lavori (chief), D. Bloch, B. Chow, M. Iwane, R. Thomas, A. Busette, L. Sheridan, R. Yezzi, S. Jones, J. King, K. Small; Cooperative Studies Program Clinical Research Pharmacy Coordinating Center (Albuquerque): C. Haakenson, M. Miller, L. Guidarelli, L. Vasquez, F. Chacon, C. Tripp, G. Garcia, J. Price; Cooperative Studies Program Central Office: P. Huang, Washington, D.C., and J. Gold, Boston; Planning Committee: J. Abrams, University of New Mexico, Albuquerque; T. Bigger, Columbia University, New York; P. Carson, Georgetown University, Washington, D.C.; R. Kleiger, Jewish Hospital of St. Louis; J. Leppo, University of Massachusetts, Worcester; M. Moskowitz, Boston University; M. Smith Veterans Affairs Medical Center, Manchester, New Hampshire: M. Hlatky, Stanford University, Stanford, California; R. Thomas Veterans Affairs Medical Center, Palo Alto, California; End-Points Committee: C. Cannon (chairman), Brigham and Women’s Hospital, Boston; K. Eagle, University of Michigan Medical Center, Ann Arbor; D. Losordo, St. Elizabeth’s Hospital, Boston; Data Monitoring Board: B. Pitt (chairman), University of Michigan Medical Center, Ann Arbor; M. Moskowitz, University Hospital, Boston; A. Moss, University of Rochester Medical Center, Rochester, New York; R. DeBusk, Stanford University School of Medicine, Palo Alto, California; S. Azen, University of Southern California, Los Angeles; R. Schlant, Emory University School of Medicine, Atlanta; J. Wittes, Statistics Collaborative, Washington, D.C.; Core Laboratories: R. Kleiger, Electrocardiography Core Laboratory, Jewish Hospital, Washington University School of Medicine, St. Louis; J. Leppo, Nuclear Cardiology Quality Assessment Laboratory, University of Massachusetts Medical Center, Worcester; R. Kerensky, Coronary Angiography Quality Assessment Laboratory, University of Florida, Gainesville.
↵¶ The study sites, investigators and study personnel participating in the VANQWISH Trial are listed in the .
☆ Supported by a research grant from the Department of Veterans Affairs Cooperative Studies Program, and by an unrestricted research grant from Hoechst Marion Roussel.
- coronary artery bypass graft
- conservative management strategy
- invasive management strategy
- left ventricular ejection fraction
- myocardial infarction
- non-Q wave myocardial infarction
- percutaneous transluminal coronary angioplasty
- Thrombolysis In Myocardial Infarction
- Veterans Affairs Non–Q-Wave Infarction Strategy In-Hospital
- Received January 19, 2000.
- Revision received July 24, 2000.
- Accepted September 13, 2000.
- American College of Cardiology
- Boden W.E.,
- Roberts R.
- TIMI IIIB Investigators
- Ferry D.R.,
- O’Rourke R.A.,
- Blaustein A.S.,
- et al.
- Goodman S.G.,
- Langer A.,
- Ross A.M.,
- et al.
- Cox D.R.
- Anderson H.V.,
- Cannon C.P.,
- Stone P.H.,
- et al.
- Aguirre F.V.,
- Younis L.T.,
- Chaitman B.R.,
- et al.