This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dakik, H. A. Articles by Mahmarian, J. J. Search for Related Content PubMed PubMed Citation Articles by Dakik, H. A. Articles by Mahmarian, J. J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Angioplasty Heart Attack Hazardous Substances DB DILTIAZEM ISOSORBIDE DINITRATE METOPROLOL

(Circulation. 1998;98:2017-2023.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Intensive Medical Therapy Versus Coronary Angioplasty for Suppression of Myocardial Ischemia in Survivors of Acute Myocardial Infarction

A Prospective, Randomized Pilot Study

Presented in part at the 46th Scientific Sessions of the American College of Cardiology, Anaheim, Calif, March 17, 1997 and published in abstract form (J Am Coll Cardiol. 1997;29(suppl A):53A.

Habib A. Dakik, MD; Neal S. Kleiman, MD; John A. Farmer, MD; Zuo-Xiang He, MD; Juliet A. Wendt, MD; Craig M. Pratt, MD; Mario S. Verani, MD; ; John J. Mahmarian, MD

From the Section of Cardiology, Baylor College of Medicine, Houston, Tex.

Correspondence to John J. Mahmarian, MD, 6550 Fannin St, SM-1246, Houston, TX 77030-2716. E-mail johnj{at}bcm.tmc.edu

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background—Patients who have inducible ischemia after acute myocardial infarction (AMI) generally undergo coronary angiography with the intent to revascularize. Whether this approach is superior to intensive treatment with anti-ischemic medications is unknown.

Methods and Results—We performed a prospective, randomized pilot study comparing intensive medical therapy with coronary angioplasty (PTCA) for suppression of myocardial ischemia in 44 stable survivors of AMI. Myocardial ischemia was quantified with adenosine ²⁰¹Tl tomography (SPECT) performed 4.5±2.9 days after AMI. All patients at baseline had a large total (20%) and ischemic (10%) left ventricular perfusion defect size (PDS). SPECT was repeated at 43±26 days after therapy was optimized. The total stress-induced PDS was comparably reduced with medical therapy (from 38±13% to 26±16%; P<0.0001) and PTCA (from 35±12% to 20±16%; P<0.0001). The reduction in ischemic PDS was also similar (P=NS) in both groups. Cardiac events occurred in 7 of 44 patients over 12±5 months. Patients who remained clinically stable had a greater reduction in ischemic PDS (-13±9%) than those who had a recurrent cardiac event (-5±7%; P<0.02). Event-free survival was superior in the 24 patients who had a significant (9%) reduction in PDS (96%) compared with those who did not (65%; P=0.009).

Conclusions—In this small pilot study, intensive medical therapy and PTCA were comparable at suppressing ischemia in stable patients after AMI. Sequential imaging with adenosine SPECT can track changes in PDS after anti-ischemic therapies and thereby predict subsequent outcome. Corroboration of these preliminary findings in a larger cardiac-event trial is warranted.

Key Words: myocardial infarction • tomography • ischemia

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Patients recovering from acute myocardial infarction (AMI) who have residual ischemia are at high risk for subsequent cardiac events.^{1 2} Although aspirin,³ lipid-lowering agents,⁴ ß-blockers,⁵ and heart rate–lowering calcium antagonists^{6 7} improve event-free survival after AMI, patients with residual ischemia generally undergo coronary revascularization as the preferred approach. This therapeutic strategy is assumed to be optimal and is used in most large clinical trials,^{8 9} as well as in clinical practice.^{10 11}

The purpose of this pilot study was to determine the relative efficacy of intensive anti-ischemic medical therapy versus coronary angioplasty (PTCA) for suppression of ischemia in high-risk but stable survivors of AMI. This study was not designed to determine differences in cardiac event rates between the 2 treatment strategies. Ischemia suppression was assessed with sequential adenosine ²⁰¹Tl single-photon emission computed tomography (SPECT).

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Study Population
Between February 1995 and June 1996, 167 consecutive patients (aged 18 years) were admitted to our coronary care unit with the diagnosis of AMI based on standard criteria.^{7 12} Thirty-four patients with initial clinical instability (ie, cardiogenic shock [n=5], need for emergent coronary revascularization [n=10], or concomitant serious noncardiac illnesses [n=9]), death of ventricular fibrillation (n=2), or a contraindication to adenosine (n=8) were excluded. The remaining 133 patients (80%) had adenosine SPECT performed 4.5±2.9 days after AMI.

Sixty-three (47%) of 133 patients had a large total (20%) and ischemic (10%) left ventricular (LV) perfusion defect size (PDS) and were considered for study entry pending coronary angiography. This scintigraphic profile defines a population at high risk for recurrent cardiac events after AMI.² Patients with significant (50%) left main stenosis, 3-vessel coronary artery disease (CAD) and an LV ejection fraction (EF) <35%,^{13 14} and CAD not amenable to PTCA were excluded. Forty-five of 63 patients met all entry criteria; 1 patient randomized to PTCA had CABG and was excluded. Thus, 44 patients constituted the study population.

Study Design
This was a prospective, randomized pilot study of a larger trial evaluating the clinical utility of adenosine SPECT early after AMI. The protocol was approved by the Baylor Institutional Review Board, and all patients signed informed consent forms.

Patients meeting entry criteria were randomized to either PTCA (n=21) or intensive anti-ischemic medical therapy (n=23); the latter combined isosorbide dinitrate (ISDN) with metoprolol (Lopressor) and diltiazem (Cardizem CD). After therapy was optimized, 22 of 23 patients randomized to medical therapy and 19 of 21 randomized to PTCA had repeat adenosine SPECT 43±26 days after their baseline study. All 44 patients were prospectively followed up for 6 months (mean, 12±5 months).

Medical Therapy Group
Anti-ischemic medications were titrated to maximally tolerated doses over 4 to 8 weeks. In patients with asymptomatic bradycardia and/or a systolic blood pressure <110 mm Hg, medications were not titrated to higher doses. All patients were to receive ISDN up to the target dose of 120 mg/d. In patients with an LVEF 40%, metoprolol was administered (maximal dose, 200 mg/d), whereas in those with an LVEF >40%, both diltiazem (maximal dose, 300 mg/d) and metoprolol were given as clinically tolerated. Metoprolol was initially chosen for patients with an LVEF 40% because of the known survival advantage with ß-blockers in this population.^{5 15} Diltiazem was chosen for patients with an LVEF >40% on the basis of trials demonstrating a significant reduction in early reinfarction⁷ and late cardiac events¹⁶ with this medication and no excess risk of heart failure.¹⁷ All patients received aspirin, and lipid-lowering agents were given to treat hypercholesterolemia. Patients continued the same anti-ischemic dosing regimen throughout the study.

Coronary Angioplasty Group
All patients had PTCA of the infarct-related artery and any other artery with significant (50%) stenosis that was supplying an ischemic zone as determined by adenosine SPECT. Anti-ischemic medications were given to treat residual angina, and ß-blocker use was empirically encouraged. Aspirin and lipid-lowering agents were administered as in the medical treatment group.

Adenosine ²⁰¹Tl SPECT
Adenosine SPECT was performed as previously reported by our laboratory.² Adenosine was administered intravenously with a standard 6-minute protocol, with injection of ²⁰¹Tl at minute 3. Initial and 4-hour-delayed images were acquired.

SPECT quantification was performed by 1 experienced investigator (J.J.M.) who was blinded to patient randomization. The initial and 4-hour-delay polar maps were independently computer generated and normalized with circumferential profile analysis.² Raw data polar maps for each patient were compared statistically with a corresponding normal data bank to determine total LV PDS and the extent of scarring and ischemia. Anti-ischemic medications were withheld 12 hours before SPECT 1 was performed but were given on the morning of SPECT 2.

Cardiac Events
All patients were closely monitored after hospital discharge in the outpatient clinic: weekly for the first 2 months, monthly for 3 months, and once every 3 months thereafter. Cardiac events were prospectively defined as (1) cardiac death, (2) nonfatal reinfarction (ie, rise in creatine kinase-MB in a patient with new ST changes and/or chest pain), and (3) unstable angina (ie, rest or worsening exertional chest pain requiring hospital admission, with transient ST changes but no rise in cardiac enzymes).²

Statistical Analysis
The primary study goal was to determine the extent to which each treatment strategy reduced the mean total LV PDS. Secondary goals were to compare reductions in mean ischemic PDS with each strategy and determine the relationship between changes in PDS and patient outcome. A 9% reduction in PDS with SPECT defines the 95% CI for a significant change beyond technique variability.¹⁸ With a sample size of 40 patients, at an of .05, this study had 80% power to detect a >4% absolute difference in total and ischemic PDS between strategies. Baseline characteristics and changes in SPECT variables between groups were compared with unpaired t tests. Differences in medication doses and SPECT variables over time were assessed by paired t tests. ² analysis compared discrete data variables. Kaplan-Meier analysis compared event rates based on a change in PDS dichotomized at 9%. Data are presented as mean±SD. A P value <0.05 was considered significant.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Baseline Characteristics
The majority of patients had multivessel disease, and 51% had anterior infarction. No significant difference in any baseline variable was observed between the 2 groups (Table 1).

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics

Anti-Ischemic Medical Therapy
Patients randomized to medical therapy had a marked increase in the number and doses of medications administered during the titration phase of the study (Figure 1). The dose of ISDN increased from 58±14 mg/d in 14 patients to 113±23 mg/d in 21 patients, whereas the dose of metoprolol doubled and that of diltiazem tripled. After therapy was optimized, all patients in the medical limb were taking either 2 (73%) or 3 (27%) drugs (Table 2). Furthermore, 95% and 59% of patients were taking maximal doses of at least 1 or 2 medications, respectively.

View larger version (60K): [in this window] [in a new window]   Figure 1. Anti-ischemic medication usage and doses in the 2 randomized groups.

View this table: [in this window] [in a new window]   Table 2. Number and Doses of Anti-Ischemic Medical Therapy (SPECT 2)

In the PTCA group, the number and doses of anti-ischemic medications did not significantly differ between SPECT 1 and 2 (Figure 1). These patients were ultimately taking 1 (42%) or at most 2 (58%) medications (Table 2). Only 3 patients (16%) were taking maximal doses of any medication, and in 2 this was for treatment of hypertension. Thus, at the time of SPECT 2, patients assigned to medical therapy were (1) taking significantly higher doses of metoprolol and ISDN and (2) taking a greater number of anti-ischemic medications (2.3±0.5 versus 1.5±0.6; P<0.0001) at maximal dosages (95% versus 16%; P<0.0001) than those assigned to PTCA. Ten patients in each treatment strategy were taking lipid-lowering medications (P=NS).

Coronary Angioplasty
No patient randomized to medical therapy had coronary revascularization before SPECT 2. Patients randomized to PTCA had revascularization performed in either 1 (n=17) or 2 (n=2) arteries: 12 left anterior descending, 4 circumflex, and 5 right coronary arteries. Stents were deployed in 6 patients. PTCA was successfully performed in 19 (79%) of 24 coronary arteries with >50% stenosis and scintigraphic ischemia within their vascular territory.

Side Effects With Medical Therapy
In patients randomized to medical therapy, ISDN was discontinued (n=1) or titrated downward (n=2) in 3 patients owing to headaches, but 19 of 22 were maintained on maximal doses (Table 3). Metoprolol was discontinued or titrated downward in 4 of 22 patients because of intolerable side effects. Nine additional patients did not achieve maximal doses because of asymptomatic bradycardia or hypotension or because of fatigue; 6 of these 9 patients were already taking high-dose diltiazem. Metoprolol was not added in 4 others who were taking maximal doses of ISDN and diltiazem. Diltiazem was discontinued in only 1 patient owing to tremor but was not started in 8 patients who had either an LVEF 40% (n=6) or asymptomatic bradycardia while taking high-dose metoprolol (n=2). Ten patients were taking maximal doses of diltiazem. Overall, 8 (36%) of 22 patients had 1 of their medications discontinued or titrated downward owing to side effects (Table 3).

View this table: [in this window] [in a new window]   Table 3. Side Effects and Dose Adjustments in Medical Therapy Group

In patients randomized to PTCA, ISDN was discontinued in 1 because of headaches, and metoprolol was titrated downward in another owing to fatigue.

SPECT Results
In the 41 patients studied with sequential SPECT, the total LV PDS significantly decreased from 37±13% at baseline to 23±16% after anti-ischemic therapy (P<0.0001). The reduction in ischemic PDS from 20±10% to 8±9% (P<0.0001) accounted entirely for the decrease observed in total PDS. The scar size did not significantly change with therapy.

Total and ischemic PDS were significantly reduced in patients randomized to either medical therapy or PTCA (Figure 2). The magnitude of the absolute reduction in total (-12±11% versus -15±14%) and ischemic (-12±10% versus -12±9%) PDS was similar (P=NS) in both groups. A significant (9%) reduction in total PDS was observed in an equal number of patients randomized to either strategy (n=12) (Figure 3).

View larger version (60K): [in this window] [in a new window]   Figure 2. Tomographic (SPECT) results in the 2 randomized groups.

View larger version (26K): [in this window] [in a new window]   Figure 3. Mean and individual patient changes in PDS from SPECT 1 to 2. Bold lines indicate patients who reduced their PDS by 9%. Circled dots indicate patients who had a recurrent event.

Cardiac Events
Cardiac events occurred in 7 of 44 patients. In the medical therapy group, 1 patient died, and 3 developed unstable angina; 2 had CABG, but this occurred after SPECT 2. In the PTCA group, 1 patient died, and 2 had nonfatal reinfarction. One patient in each group continued to have intermittent exertional angina. Cardiac event rates were similar between patients treated medically (17%) and those who underwent PTCA (14%; P=NS).

Cardiac Events Based on Changes in Ischemia
Sequential adenosine SPECT assessed the relationship between ischemia suppression and patient outcome. Baseline total PDS (35±11% versus 37±13%) and ischemic PDS (18±12% versus 20±9%) were similar (P=NS) in patients who did (n=7) or did not (n=34) have a recurrent event. Patients who were clinically stable at follow-up had a greater reduction in their total PDS (-15±13% versus -6±7%; P<0.02) and ischemic PDS (-13±9% versus -5±7%; P<0.02) than those who had an event, respectively. Only 1 (4%) of 24 patients who had a significant (9%) reduction in PDS with anti-ischemic therapy returned to the hospital with a subsequent event versus 6 (35%) of 17 patients who had persistent defects (P=0.009) (Figure 4). The sequential SPECT images of a patient randomized to medical therapy are shown in Figure 5.

View larger version (15K): [in this window] [in a new window]   Figure 4. Kaplan-Meier curves depicting event-free survival based on changes in PDS after anti-ischemic therapy.

View larger version (120K): [in this window] [in a new window]   Figure 5. Sequential SPECT images of a patient randomized to medical therapy. Short-axis stress and redistribution images (left) are shown at baseline (SPECT 1) and after therapy (SPECT 2) with corresponding polar plots (right). SPECT 1 demonstrates a large and predominantly ischemic defect (34%) that dramatically improves after triple anti-ischemic medical therapy (SPECT 2) (11%). This patient was still clinically stable at 1-year follow-up.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The treatment of ischemia in stable survivors of AMI has been the subject of multiple large clinical trials. Patients without residual ischemia have a comparably low subsequent cardiac event rate whether they are treated medically or with PTCA.¹⁹ However, in patients with ischemia, coronary revascularization is frequently the preferred therapeutic approach. The widespread acceptance of an invasive strategy as the "community standard" has occurred despite the lack of definitive clinical trials supporting this strategy over medical therapy. In fact, subgroup analysis from the SAVE²⁰ and GUSTO I¹¹ trials report a comparable infarct-free survival among patients treated in the United States and Canada despite a 2- to 3-fold higher rate of coronary revascularization in the United States.

The present study is the first randomized, prospective trial to directly compare the anti-ischemic effects of intensive medical therapy and PTCA in clinically stable patients who had "high-risk" scintigraphic ischemia demonstrated early after AMI. By study design, patients with an LVEF <35% were excluded because CABG is preferable in this group of patients who also have ischemia.¹³ To avoid potential treatment bias, patients were only randomized after they were deemed amenable to PTCA. Our results indicate that intensive medical therapy suppresses myocardial ischemia to a degree comparable to that achieved by a combination of PTCA and low-dose background medical therapy. The sequential SPECT results suggest that ischemia suppression with either strategy results in a favorable event-free survival at 1 year.

Ischemia Suppression With Medical Therapy
Our results with medical therapy in patients surviving AMI are directionally similar to those reported in trials evaluating patients with stable CAD.^{21 22 23 24 25 26} Various nitrate preparations,^{23 24 25} ß-blockers,²⁶ and calcium antagonists²⁵ can effectively reduce stress-induced scintigraphic ischemia. The Asymptomatic Cardiac Ischemia Pilot (ACIP) study likewise demonstrated that ischemia suppression is achievable with combination medical therapy.^{27 28} In ACIP, coronary revascularization was superior to medical therapy in suppressing ambulatory ECG ischemia, but the latter was less aggressively administered than in the present study. In fact, most patients in ACIP were only taking low doses of 1 or, at most, 2 medications.²⁸

The Danish trial in Acute Myocardial Infarction (DANAMI)²⁹ compared the relative efficacy of medical therapy versus coronary revascularization in patients surviving AMI. Although mortality rates were similar over 2.4 years, infarct-free survival was significantly better in patients randomized to revascularization (90.8%) than in those who received medical therapy (85.1%). However, medical therapy was prescribed only according to local practice, with no guidelines for dose titration, so that a minority of patients were taking ß-blockers (40%), calcium antagonists (41%), or long-acting nitrates (25%). No data were reported as to the number or doses of medications that patients received.

To ensure an objective comparison between medical therapy and PTCA, the present study titrated medical therapy over 4 to 8 weeks until protocol-directed dosing end points were achieved. Accordingly, all of our patients randomized to medical therapy were ultimately taking maximally tolerated doses of 2 (73%) or 3 (27%) drugs. These differences in study design may help explain the apparent disparity between our results and those reported by the ACIP and DANAMI investigators.

Tracking Ischemia Suppression With Adenosine SPECT
Exercise SPECT is an accurate and reproducible technique for the evaluation of ischemia suppression.^{23 24 30} The present study and others^{26 31} demonstrate that SPECT, when combined with pharmacological stressors, can also track changes in myocardial ischemia after medical therapy. The mechanisms underlying these changes may relate to the effects of medications on resting coronary flow reserve. Nitrates improve resting myocardial blood flow in patients with CAD³² through direct vasodilation of epicardial³³ or collateral vessels.²³ The improved detection of tissue viability in underperfused myocardium after nitroglycerin-augmented ²⁰¹Tl reinjection imaging further supports this finding.³⁴ ß-Blockers reduce resting myocardial oxygen demands in normal subjects and thereby increase coronary blood flow during dipyridamole-induced hyperemia.³⁵ Anti-ischemic medications, by improving resting coronary flow reserve, may allow a more homogeneous increase in myocardial blood flow during pharmacologically induced hyperemia, thereby reducing perfusion defects.

Ischemia Suppression and Subsequent Outcome
The presence and extent of residual myocardial ischemia after AMI predict subsequent risk for cardiac events.^{1 2} Mounting evidence supports the concept that ischemia suppression in patients with CAD may reduce risk and improve long-term outcome.^{36 37 38} In both the ACIP and Atenolol Silent Ischemia Study, suppression of ambulatory ECG ischemia predicted an improved event-free survival.^{36 37} In the Angioplasty Compared to Medicine study, survival was improved if medical therapy or PTCA suppressed exercise-induced scintigraphic ischemia.³⁸ Our results are in agreement with these findings. Patients who remained clinically stable had a significantly greater reduction in ischemic PDS after therapy than those who had a subsequent event. In fact, event-free survival was 96% in patients who had a significant (9%) reduction in PDS compared with only 65% in those who did not. These preliminary data all indicate that ischemia suppression, by whatever means, may improve patient outcome. Our results support the role of adenosine SPECT for tracking patient risk on the basis of changes in the extent of inducible myocardial ischemia.

Study Limitations
The small sample size of this single-center pilot study precludes direct comparison of cardiac event rates between treatment groups. This is precisely why SPECT parameters were chosen as a surrogate end point for events. The high reproducibility of SPECT¹⁸ affords evaluation of anti-ischemic therapies with relatively small sample sizes.^{23 24 30}

Although anti-ischemic medications and PTCA were comparable at suppressing ischemia, neither therapy accomplished this in all patients. It is possible that more complete coronary revascularization, as achieved with CABG, might have more effectively reduced ischemia than either medical therapy or PTCA.³⁹

Conclusions
This prospective, randomized study demonstrates that medical therapy and PTCA are comparable at suppressing myocardial ischemia in stable but high-risk survivors of AMI. The sequential imaging results further strengthen the concept that future outcome is closely linked to the degree of ischemia suppression. Adequately powered clinical event trials are needed to better define the independent and combined roles of medical and revascularization strategies in suppressing ischemia. Such trials will ultimately have profound implications for both the management of patients after AMI and the proper allocation of healthcare resources.

	Acknowledgments

 
The authors wish to acknowledge the assistance of Maria E. Frias.

	Footnotes

 
Guest editor for this article was Carl J. Pepine, MD, University of Florida, Gainesville, Fla.

Received January 6, 1998; revision received May 4, 1998; accepted July 16, 1998.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Mahmarian JJ. Prediction of myocardium at risk: clinical significance during acute infarction and in evaluating subsequent prognosis. Cardiol Clin. 1995;13:355–378.[Medline] [Order article via Infotrieve]

2. Mahmarian JJ, Mahmarian AC, Marks GF, Pratt CM, Verani MS. Role of adenosine thallium-201 tomography for defining long-term risk in patients after acute myocardial infarction. J Am Coll Cardiol. 1995;25:1333–1340.[Abstract]

3. The Persantine-Aspirin Reinfarction Study (PARIS) Research Group. The Persantine-Aspirin Reinfarction Study. Circulation.. 1980;62:V85–V88.

4. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001–1009.[Abstract/Free Full Text]

5. Teo KK, Yusuf S, Furberg CD. Effects of prophylactic antiarrhythmic drug therapy in acute myocardial infarction: an overview of results from randomized controlled trials. JAMA. 1993;270:1589–1595.[Abstract/Free Full Text]

6. The Danish Study Group on Verapamil in Myocardial Infarction. Effect of verapamil on mortality and major events after myocardial infarction (the Danish Verapamil Infarction Trial II: DAVIT II). Am J Cardiol. 1990;66:779–785.[Medline] [Order article via Infotrieve]

7. Gibson RS, Boden WE, Theroux P, Strauss HD, Pratt CM, Gheorghiade M, Capone RJ, Crawford MJ, Schlant RC, Kleiger RE, Young PM, Schechtman K, Perryman B, Roberts R, and the Diltiazem Reinfarction Study Group. Diltiazem and reinfarction in patients with non-Q-wave myocardial infarction: results of a double-blind, randomized, multicenter trial. N Engl J Med. 1986;315:423–429.[Abstract]

8. Williams DO, Braunwald E, Knatterud G, Babb J, Bresnahan J, Greenberg MA, Raizner A, Wasserman A, Robertson T, Ross R, and TIMI Investigators. One-year results of the Thrombolysis In Myocardial Infarction investigation (TIMI) phase II trial. Circulation. 1992;85:533–542.[Abstract/Free Full Text]

9. The SWIFT Investigators. SWIFT trial of delayed elective intervention vs conservative treatment after thrombolysis with anistreplase in acute myocardial infarction: SWIFT (Should We Intervene Following Thrombolysis?) Trial Study Group. BMJ. 1991;302:555–560.

10. Pilote L, Miller DP, Califf RM, Rao JS, Weaver WD, Topol EJ. Determinants of the use of coronary angiography and revascularization after thrombolysis for acute myocardial infarction. N Engl J Med. 1996;335:1198–1205.[Abstract/Free Full Text]

11. Mark DB, Naylor CD, Hlatky MA, Califf RM, Topol EJ, Granger CB, Knight JD, Nelson CL, Lee KL, Clapp-Channing NE, Sutherland W, Pilote L, Armstrong PW. Use of medical resources and quality of life after acute myocardial infarction in Canada and the United States. N Engl J Med. 1994;331:1130–1135.[Abstract/Free Full Text]

12. Mahmarian JJ, Pratt CM, Borges-Neto S, Cashion WR, Roberts R, Verani MS. Quantification of infarct size by Tl-201 single-photon emission computed tomography during acute myocardial infarction in humans: comparison with enzymatic estimates. Circulation. 1988;78:831–839.[Abstract/Free Full Text]

13. Alderman EL, Fisher LD, Litwin P, Kaiser GC, Myers WO, Maynard C, Levine F, Schloss M. Results of coronary artery surgery in patients with poor left ventricular function (CASS). Circulation. 1983;68:785–795.[Abstract/Free Full Text]

14. Takaro T, Hultgren HN, Lipton MJ, Detre KM. The VA cooperative randomized study of surgery for coronary arterial occlusive disease, II: subgroup with significant left main lesions. Circulation. 1976;54(suppl):III-107–III-117.

15. The MIAMI Trial Research Group. Metoprolol In Acute Myocardial Infarction (MIAMI): mortality. Am J Cardiol. 1985;56:15G–22G.[Medline] [Order article via Infotrieve]

16. Boden WE, Krone RJ, Kleiger RE, Oakes D, Greenberg H, Dwyer EJ Jr, Miller JP, Abrams J, Coromilas J, Goldstein R, Moss AJ, and the Multicenter Diltiazem Post-Infarction Trial Research Group. Electrocardiographic subset analysis of diltiazem administration on long-term outcome after acute myocardial infarction. Am J Cardiol. 1991;67:335–342.[Medline] [Order article via Infotrieve]

17. Goldstein RE, Boccuzzi SJ, Cruess D, Nattel S. Diltiazem increases late-onset congestive heart failure in postinfarction patients with early reduction in ejection fraction: the Adverse Experience Committee; and the Multicenter Diltiazem Postinfarction Research Group. Circulation. 1991;83:52–60.[Abstract/Free Full Text]

18. Mahmarian JJ, Moye LA, Verani MS, Bloom MF, Pratt CM. High reproducibility of myocardial perfusion defects in patients undergoing serial exercise thallium-201 tomography. Am J Cardiol. 1995;75:1116–1119.[Medline] [Order article via Infotrieve]

19. Ellis SG, Mooney MR, George BS, da Silva EE, Talley JD, Flanagan WH, Topol EJ. Randomized trial of late elective angioplasty versus conservative management for patients with residual stenoses after thrombolytic treatment of myocardial infarction: Treatment of Post Thrombolytic Stenoses (TOPS) Study Group. Circulation. 1992;86:1400–1406.[Abstract/Free Full Text]

20. Rouleau JL, Moyé LA, Pfeffer MA, Arnold JMO, Bernstein V, Cuddy TE, Dagenais GR, Geltman EM, Goldman S, Gordon D, Hamm P, Klein M, Lamas GA, McCans J, McEwan P, Menapace FJ, Parker JO, Sestier F, Sussex B, Braunwald E, for the SAVE Investigators. A comparison of management patterns after acute myocardial infarction in Canada and the United States. N Engl J Med. 1993;328:779–784.[Abstract/Free Full Text]

21. Frishman W, Charlap S, Kimmel B, Teicher M, Cinnamon J, Allen L, Strom J. Diltiazem, nifedipine, and their combination in patients with stable angina pectoris: effects on angina, exercise tolerance, and the ambulatory electrocardiographic ST segment. Circulation. 1988;77:774–786.[Abstract/Free Full Text]

22. Subramanian VB, Bowles MJ, Khurmi NS, Davies AB, Raftery EB. Rationale for the choice of calcium antagonists in chronic stable angina: an objective double-blind placebo-controlled comparison of nifedipine and verapamil. Am J Cardiol. 1982;50:1173–1179.[Medline] [Order article via Infotrieve]

23. Aoki M, Sakai K, Koyanagi S, Takeshita A, Nakamura M. Effect of nitroglycerin on coronary collateral function during exercise evaluated by quantitative analysis of thallium-201 single photon emission computed tomography. Am Heart J. 1991;121:1361–1366.[Medline] [Order article via Infotrieve]

24. Mahmarian JJ, Fenimore NL, Marks GF, Francis MJ, Morales-Ballejo H, Verani MS, Pratt CM. Transdermal nitroglycerin patch therapy reduces the extent of exercise-induced myocardial ischemia: results of a double-blind, placebo-controlled trial using quantitative thallium-201 tomography. J Am Coll Cardiol. 1994;24:25–32.[Abstract]

25. Stegaru B, Loose R, Keller H, Buss J, Wetzel E. Effects of long-term treatment with 120 mg of sustained-release isosorbide dinitrate and 60 mg of sustained-release nifedipine on myocardial perfusion. Am J Cardiol. 1988;61:74E–77E.[Medline] [Order article via Infotrieve]

26. Shehata AR, Gillam LD, Mascitelli VA, Herman SD, Ahlberg AW, White MP, Chen C, Waters DD, Heller GV. Impact of acute propranolol administration on dobutamine-induced myocardial ischemia as evaluated by myocardial perfusion imaging and echocardiography. Am J Cardiol. 1997;80:268–272.[Medline] [Order article via Infotrieve]

27. Knatterud GL, Bourassa MG, Pepine CJ, Geller NL, Sopko G, Chaitman BR, Pratt C, Stone PH, Davies RF, Rogers WJ, Deanfield JE, Goldberg AD, Ouyang P, Mueller H, Sharaf B, Day P, Selwyn AP, Conti CR, for the ACIP Investigators. Effects of treatment strategies to suppress ischemia in patients with coronary artery disease: 12-week results of the Asymptomatic Cardiac Ischemia Pilot (ACIP) study. J Am Coll Cardiol. 1994;24:11–20.[Abstract]

28. Pratt CM, McMahon RP, Goldstein S, Pepine CJ, Andrews TC, Dyrda I, Frishman WH, Geller NL, Hill JA, Morgan NA, Stone PH, Knatterud GL, Sopko G, Conti CR, for the ACIP Investigators. Comparison of subgroups assigned to medical regimens used to suppress cardiac ischemia (the Asymptomatic Cardiac Ischemia Pilot [ACIP] study). Am J Cardiol. 1996;77:1302–1309.[Medline] [Order article via Infotrieve]

29. Madsen JK, Grande P, Saunamäki K, Thayssen P, Kassis E, Eriksen U, Rasmussen K, Haunsø S, Nielsen TT, Haghfelt T, Fritz-Hansen P, Hjelms E, Paulsen PK, Alstrup P, Arendrup H, Niebuhr-Jørgensen U, Andersen LI, on behalf of the DANAMI Study Group. Danish multicenter randomized study of invasive versus conservative treatment in patients with inducible ischemia after thrombolysis in acute myocardial infarction (DANAMI). Circulation. 1997;96:748–755.[Abstract/Free Full Text]

30. Mahmarian JJ, Moye LA, Nasser GA, Nagueh SF, Bloom MF, Benowitz NL, Byrd WG, Pratt CM. Nicotine patch therapy in smoking cessation reduces the extent of exercise-induced myocardial ischemia. J Am Coll Cardiol. 1997;30:125–130.[Abstract]

31. Sharir T, Livschitz S, Rabinowitz B, Chouraqui P. Anti-ischemic drugs reduce size of reversible defects in dipyridamole/submaximal exercise Tl-201 SPECT imaging. J Nucl Cardiol. 1997;4:S71. Abstract.

32. Fallen EL, Nahmias C, Scheffel A, Coates G, Beanlands R, Garnett ES. Redistribution of myocardial blood flow with topical nitroglycerin in patients with coronary artery disease. Circulation. 1995;91:1381–1388.[Abstract/Free Full Text]

33. Brown BG, Bolson E, Petersen RB, Pierce CD, Dodge HT. The mechanisms of nitroglycerin action: stenosis vasodilatation as a major component of the drug response. Circulation. 1981;64:1089–1097.[Abstract/Free Full Text]

34. He ZX, Medrano R, Hays JT, Mahmarian JJ, Verani MS. Nitroglycerin-augmented Tl-201 reinjection enhances detection of reversible myocardial hypoperfusion: a randomized, double-blind, parallel, placebo-controlled trial. Circulation. 1997;95:1799–1805.[Abstract/Free Full Text]

35. Bottcher M, Czernin J, Sun K, Phelps ME, Schelbert HR. Effect of B1 adrenergic receptor blockade on myocardial blood flow and vasodilatory capacity. J Nucl Med. 1997;38:442–446.[Abstract/Free Full Text]

36. Rogers WJ, Bourassa MG, Andrews TC, Bertolet BD, Blumenthal RS, Chaitman BR, Forman SA, Geller NL, Goldberg AD, Habib GB, Masters RG, Moisa RB, Mueller H, Pearce DJ, Pepine CJ, Sopko G, Steingart RM, Stone PH, Knatterud GL, Conti CR, for the ACIP Investigators. Outcome at 1 year for patients with asymptomatic cardiac ischemia randomized to medical therapy or revascularization. J Am Coll Cardiol. 1995;26:594–605.[Abstract]

37. Pepine CJ, Cohn PF, Deedwania PC, Gibson RS, Handberg E, Hill JA, Miller E, Marks RG, Thadani U, for the ASIST Study Group. Effects of treatment on outcome in mildly symptomatic patients with ischemia during daily life: the Atenolol Silent Ischemia Study (ASIST). Circulation. 1994;90:762–768.[Abstract/Free Full Text]

38. Parisi AF, Hartigan PM, Folland ED, for the ACME Investigators. Evaluation of exercise thallium scintigraphy versus exercise electrocardiography in predicting survival outcomes and morbid cardiac events in patients with single- and double-vessel disease: findings from the Angioplasty Compared to Medicine (ACME) study. J Am Coll Cardiol. 1997;30:1256–1263.[Abstract]

39. Bourassa MG, Pepine CJ, Forman SA, Rogers WJ, Dyrda I, Stone PH, Chaitman BR, Sharaf B, Mahmarian J, Davies RF, Knatterud GL, Terrin M, Sopko G, Conti R, for the ACIP Investigators. Effects of coronary angioplasty and coronary artery bypass graft surgery on recurrent angina and ischemia. J Am Coll Cardiol. 1995;26:606–614.[Abstract]

This article has been cited by other articles:

				D. G. Katritsis and B. Meier Percutaneous Coronary Intervention for Stable Coronary Artery Disease J. Am. Coll. Cardiol., September 9, 2008; 52(11): 889 - 893. [Abstract] [Full Text] [PDF]

				A. Schomig, J. Mehilli, A. de Waha, M. Seyfarth, J. Pache, and A. Kastrati A Meta-Analysis of 17 Randomized Trials of a Percutaneous Coronary Intervention-Based Strategy in Patients With Stable Coronary Artery Disease J. Am. Coll. Cardiol., September 9, 2008; 52(11): 894 - 904. [Abstract] [Full Text] [PDF]

				G. J. Zoghbi, T. A. Dorfman, and A. E. Iskandrian The Effects of Medications on Myocardial Perfusion J. Am. Coll. Cardiol., August 5, 2008; 52(6): 401 - 416. [Abstract] [Full Text] [PDF]

				P. Erne, A. W. Schoenenberger, D. Burckhardt, M. Zuber, W. Kiowski, P. T. Buser, P. Dubach, T. J. Resink, and M. Pfisterer Effects of Percutaneous Coronary Interventions in Silent Ischemia After Myocardial Infarction: The SWISSI II Randomized Controlled Trial JAMA, May 9, 2007; 297(18): 1985 - 1991. [Abstract] [Full Text] [PDF]

				D J Rakhit, T H Marwick, K A Armstrong, D W Johnson, R Leano, and N M Isbel Effect of aggressive risk factor modification on cardiac events and myocardial ischaemia in patients with chronic kidney disease Heart, October 1, 2006; 92(10): 1402 - 1408. [Abstract] [Full Text] [PDF]

				T. F. Christian Positively Magnetic North J. Am. Coll. Cardiol., April 18, 2006; 47(8): 1646 - 1648. [Full Text] [PDF]

				D. G. Katritsis and J. P.A. Ioannidis Percutaneous Coronary Intervention Versus Conservative Therapy in Nonacute Coronary Artery Disease: A Meta-Analysis Circulation, June 7, 2005; 111(22): 2906 - 2912. [Abstract] [Full Text] [PDF]

				J E Udelson and E J Flint Radionuclide imaging in risk assessment after acute coronary syndromes Heart, August 1, 2004; 90(suppl_5): v16 - v25. [Full Text] [PDF]

				C. L. Grines, M. W. Watkins, J. J. Mahmarian, A. E. Iskandrian, J. J. Rade, P. Marrott, C. Pratt, N. Kleiman, and for the Angiogenic GENe Therapy (AGENT-2) Study Gr A randomized, double-blind, placebo-controlled trial of Ad5FGF-4 gene therapy and its effect on myocardial perfusion in patients with stable angina J. Am. Coll. Cardiol., October 15, 2003; 42(8): 1339 - 1347. [Abstract] [Full Text] [PDF]

				R. A. Henderson, S. J. Pocock, T. C. Clayton, R. Knight, K. A. A. Fox, D. G. Julian, D. A. Chamberlain, and Second Randomized Intervention Treatment of Angina Seven-year outcome in the RITA-2 trial: coronary angioplasty versus medical therapy J. Am. Coll. Cardiol., October 1, 2003; 42(7): 1161 - 1170. [Abstract] [Full Text] [PDF]

				W. S. Weintraub and S. Sadanandan Percutaneous Coronary Intervention in Stable Patients After Acute Myocardial Infarction Circulation, September 16, 2003; 108(11): 1292 - 1294. [Full Text] [PDF]

				U. Zeymer, R. Uebis, A. Vogt, H.-G. Glunz, H.-F. Vohringer, D. Harmjanz, and K.-L. Neuhaus Randomized Comparison of Percutaneous Transluminal Coronary Angioplasty and Medical Therapy in Stable Survivors of Acute Myocardial Infarction With Single Vessel Disease: A Study of the Arbeitsgemeinschaft Leitende Kardiologische Krankenhausarzte Circulation, September 16, 2003; 108(11): 1324 - 1328. [Abstract] [Full Text] [PDF]

				R. G. Schwartz, T. A. Pearson, V. G. Kalaria, M. L. Mackin, D. J. Williford, A. Awasthi, A. Shah, A. Rains, and J. J. Guido Prospective serial evaluation of myocardial perfusion and lipids during the first six months of pravastatin therapy: Coronary artery disease regression single photon emission computed tomography monitoring trial J. Am. Coll. Cardiol., August 20, 2003; 42(4): 600 - 610. [Abstract] [Full Text] [PDF]

				T. H. Marwick Safe Sex for Men With Coronary Artery Disease: Exercise, Sildenafil, and Risk of Cardiac Events JAMA, February 13, 2002; 287(6): 766 - 767. [Full Text] [PDF]

				S. C. Smith Jr, J. T. Dove, A. K. Jacobs, J. Ward Kennedy, D. Kereiakes, M. J. Kern, R. E. Kuntz, J. J. Popma, H. V. Schaff, D. O. Williams, et al. ACC/AHA guidelines for percutaneous coronary intervention (revision of the 1993 PTCA guidelines): A report of the American College of Cardiology/ American Heart Association Task Force on practice guidelines (Committee to revise the 1993 guidelines for percutaneous transluminal coronary angioplasty) endorsed by the Society for Cardiac Angiography and Interventions J. Am. Coll. Cardiol., June 15, 2001; 37(8): 2239 - 2239. [Full Text] [PDF]

				S. T. Mast, L. K. Shaw, G. C. Ravizzini, M. Chambless, P. Joski, R. E. Coleman, and S. Borges-Neto Incremental Prognostic Value of RNA Ejection Fraction Measurements During Pharmacologic Stress Testing: A Comparison with Clinical and Perfusion Variables J. Nucl. Med., June 1, 2001; 42(6): 871 - 877. [Abstract] [Full Text] [PDF]

				R. C. Becker, M. Burns, N. Every, C. Maynard, P. Frederick, F. A. Spencer, J. M. Gore, C. Lambrew, and for the National Registry of Myocardial Infarction Early Clinical Outcomes and Routine Management of Patients With Non-ST-Segment Elevation Myocardial Infarction: A Nationwide Perspective Arch Intern Med, February 26, 2001; 161(4): 601 - 607. [Abstract] [Full Text] [PDF]

				Intensive Medical Therapy Suppresses Ischemia After MI as Well as PTCA Journal Watch (General), December 8, 1998; 1998(1208): 2 - 2. [Full Text]

				C. J. Pepine and P. C. Deedwania How Do We Best Treat Patients With Ischemic Heart Disease? Circulation, November 10, 1998; 98(19): 1985 - 1986. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dakik, H. A. Articles by Mahmarian, J. J. Search for Related Content PubMed PubMed Citation Articles by Dakik, H. A. Articles by Mahmarian, J. J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Angioplasty Heart Attack Hazardous Substances DB DILTIAZEM ISOSORBIDE DINITRATE METOPROLOL