Adenosine sestamibi SPECT post-infarction evaluation (INSPIRE) trial: A randomized, prospective multicenter trial evaluating the role of adenosine Tc-99m sestamibi SPECT for assessing risk and therapeutic outcomes in survivors of acute myocardial infarction

Adenosine sestamibi SPECT post-infarction evaluation (INSPIRE) trial: A randomized, prospective multicenter trial evaluating the role of adenosine Tc-99m sestamibi SPECT for assessing risk and therapeutic outcomes in survivors of acute myocardial infarction John J. Mahmarian, MD,a Leslee J. Shaw, PhD,b Gerald H. Olszewski,c Bradley K. Pounds,d Maria E. Frias,a and Craig M. Pratt, MD,a for the INSPIRE Investigators Background. Preliminary studies indicate that adenosine myocardial perfusion single photon tomography (SPECT) can safely and accurately stratify patients into low and high risk groups early after acute myocardial infarction (AMI). Methods and Results. INSPIRE is a prospective, randomized multicenter trial which enrolled 728 clinically stable survivors of AMI. Following baseline adenosine sestamibi gated SPECT, patients were classified as low, intermediate or high risk based on the quantified total and ischemic left ventricular (LV) perfusion defect size (PDS). A subset of high risk patients with a LV ejection fraction >35% were randomized to a strategy of either intensive medical therapy or coronary revascularization. Adenosine SPECT was repeated at 6-8 weeks to determine the relative effects of anti-ischemic therapies on total and ischemic PDS (primary endpoint). All patients were followed for one year. The baseline demographic, clinical and scintigraphic characteristics of the study population are presented. Adenosine SPECT was performed within 1 day of admission in 12% of patients and in 64% by Day 4. Conclusion. The unique study design features of INSPIRE will further clarify the role of adenosine sestamibi SPECT in defining initial patient risk after AMI and in monitoring the benefits of intensive anti-ischemic therapies. (J Nucl Cardiol 2004;11:458-69.) Key Words: Single photon tomography • risk stratification • adenosine The management of patients with acute myocardial infarction (AMI) has undergone considerable evolution over the last decade. Coronary angiography with primary percutaneous coronary intervention (PCI) is currently regarded as the diagnostic and therapeutic modality of choice for patients who have acute ST-segment elevation

From the The Methodist DeBakey Heart Center and Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, Tex;a American Cardiovascular Research Institute,b Atlanta, Ga, Fujisawa Healthcare, Inc, Deerfield, Ill,c and BristolMyers Squibb Medical Imaging, North Billerica, Mass.d Supported by Bristol-Myers Squibb Medical Imaging, Fujisawa Healthcare, Inc, and Schering Plough Research Institute. Received for publication May 18, 2004; final revision accepted May 18, 2004. Reprint requests: John J. Mahmarian, MD, Professor of Medicine, Baylor College of Medicine, Section of Cardiology, 6550 Fannin St, SM-1256, Houston, TX 77030-2717; [email protected]. 1071-3581/$30.00 Copyright © 2004 by the American Society of Nuclear Cardiology. doi:10.1016/j.nuclcard.2004.05.003 458

AMI1-3 and in those in whom clinical instability develops manifested by progressive congestive heart failure, cardiogenic shock, or ongoing chest pain refractory to intensive anti-ischemic medications.4,5 Although an invasive management strategy is appropriate in these subgroups, the majority of patients after AMI are clinically stable6,7 and have not undergone initial PCI.8 The widespread acceptance of a routine invasive strategy as the community standard of care for evaluating and treating patients and improving patient outcome after uncomplicated AMI has developed despite the lack of definitive support from controlled clinical trials.9-14 In fact, intensive medical therapy has been independently shown to significantly reduce myocardial ischemia in patients after AMI15 and improve patient outcome.15-22 In this regard, a stratification strategy of noninvasive testing performed very early after AMI capable of identifying low- and high-risk groups for the development of cardiac events is desirable. Ideally, this testing strategy could guide appropriate medical and/or interventional patient management.

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Study Population

Figure 1. INSPIRE trial study design. MI, Myocardial infarction; Rx, therapy; IPDS, ischemic perfusion defect size.

Adenosine myocardial perfusion gated single photon emission computed tomography (SPECT) is a noninvasive test that fits this profile well. Preliminary studies indicate that adenosine SPECT can accurately stratify patients very early after AMI into low-, intermediate-, and high-risk groups based on the quantified total and ischemic left ventricular (LV) perfusion defect size (PDS) and the LV ejection fraction (EF)23-25 and also accurately monitor the relative benefit of medical and interventional anti-ischemic therapies.15 It is within this context that the adenosine sestamibi post-infarction evaluation (INSPIRE) trial was conceived. INSPIRE is a prospective, randomized multicenter trial designed to further clarify the role of adenosine technetium-99m sestamibi SPECT in defining initial patient risk after uncomplicated AMI and in assessing subsequent patient outcome after intensive prespecified anti-ischemic therapies. Furthermore, INSPIRE prospectively compares the relative temporal benefit of intensive medical therapy versus coronary revascularization for suppressing myocardial ischemia in stable but scintigraphically high-risk survivors of AMI. The purpose of this report is to discuss the details and implications of the INSPIRE trial design. METHODS The organizational structure of the INSPIRE trial, including principal investigators and coinvestigators at participating centers and by-center recruitment, is contained in Appendix 1. A graphic representation of the INSPIRE study design is depicted in Figure 1. Over a 36-month period (December 1999 through December 2002), 728 patients were enrolled at 16 sites, with a 1-year subsequent follow-up.

Inclusion criteria. The study population consisted of patients aged 18 years or older admitted to each coronary care unit with documented AMI defined as chest pain of at least 30 minutes’ duration associated with either (1) ST-segment elevation or depression (ⱖ0.1 mV) in 2 or more consecutive electrocardiographic leads and a rise in cardiac enzyme levels (creatine kinase MB or troponin T/I) twice the upper limit of normal or greater or (2) ST-segment elevation (ⱖ0.1 mV) in 2 or more consecutive electrocardiographic leads with development of new Q waves diagnostic of AMI. Exclusion criteria. Patients were excluded from study enrollment for (1) cardiogenic shock (systolic blood pressure ⬍90 mm Hg and pulmonary edema); (2) recurrent chest pain unresponsive to anti-ischemic medications requiring emergent coronary revascularization; (3) uncompensated congestive heart failure (New York Heart Association class III or IV); (4) sustained ventricular tachycardia or ventricular fibrillation after the first 24 hours; (5) acute coronary angiography with PCI; (6) left bundle branch block on the initial resting 12-lead electrocardiogram; (7) an absolute contraindication to adenosine defined as ongoing wheezing, greater than first-degree atrioventricular block without a pacemaker, systolic blood pressure lower than 90 mm Hg, or recent (⬍24 hours) use of dipyridamole or xanthines (eg, aminophylline, caffeine); or (8) a concomitant noncardiac illness that would limit follow-up for at least 1 year. Also excluded were premenopausal women, unless it could be documented that they were not pregnant, and any patients unable to provide signed informed consent.

Details of Study Design Timing of baseline adenosine Tc-99m sestamibi SPECT. The details of the adenosine Tc-99m sestamibi SPECT imaging protocol are contained in Appendix 2. Patients admitted to the coronary care unit with a diagnosis of AMI were evaluated as to their clinical stability. Those meeting all entry criteria and having no exclusion criteria were enrolled and asked to sign an informed consent form. Patients underwent nitrate-enhanced rest followed by adenosine stress SPECT imaging within 1 to 10 days of AMI (Figure 2). To expedite patient evaluation, SPECT was performed as early as clinically feasible as judged by the principal investigator at each site and only after intravenous nitroglycerin and inotropic agents (ie, dobutamine, milronone, amrinone) had been discontinued for at least 12 hours. For the purposes of this trial, oral anti-ischemic medications were defined as long-acting nitrates, calcium antagonists, and ␤-blockers. Oral anti-ischemic medications were held for at least 12 hours before initial SPECT imaging. From a practical standpoint, this was accomplished by holding anti-ischemic medications the morning of SPECT imaging. Therapeutic strategies based on adenosine SPECT results. Decisions regarding patient risk and subsequent management were determined based on the total adenosine-induced LV PDS, the quantified extent of scintigraphic ischemia, and the LVEF (Figure 1). Lowest-risk group. Patients with a small (⬍20%) LV PDS only had initial coronary angiography if clinical instability

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Figure 2. Rest-stress adenosine Tc-99m sestamibi SPECT imaging protocol. In patients weighing more than 250 lb, a 2-day rest-stress protocol was used, with injection of 25 to 30 mCi Tc-99m sestamibi each day. Dagger, A minimum time interval of 1.5 to 2 hours between Tc-99m sestamibi injection and cardiac imaging was used to allow for liver clearance of the radioisotope. SL NTG, Sublingual nitroglycerin.

developed. On the basis of previous studies, the infarct-free survival rate in this group at 1 year was anticipated to be greater than 95%.23-25 Patients were placed on standard medical therapy (see “Adjuvant Care” section), which included antiischemic medications to treat any residual scintigraphic evidence of ischemia. Subsequent clinical follow-up was continued for up to at least 1 year. Intermediate-risk group. Patients with a large (ⱖ20%) predominantly nonischemic (⬍10%) LV PDS were treated as outlined in the “Adjuvant Care” section. The decision to perform coronary angiography and subsequent revascularization in these patients was made at the discretion of the principal investigator at each site. Highest-risk revascularized group (LVEF ⬍35%). Patients who had a large (ⱖ20%) and ischemic (ⱖ10%) LV PDS and an LVEF lower than 35% were encouraged to undergo coronary angiography with the intent to revascularize.26 Coronary artery bypass graft surgery (CABG) was recommended over PCI in patients who had (1) greater than 50% left main stenosis,27 (2) triple-vessel coronary artery disease (CAD),28 or (3) diabetes mellitus and multivessel CAD.29 Patients considered poor revascularization candidates were managed medically with titration of therapy as tolerated. Highest-risk randomized group (LVEF ⱖ35%). Patients with a large (ⱖ20%) and ischemic (ⱖ10%) LV PDS who had an LVEF of 35% or greater were randomized to either (1) intensive anti-ischemic medical therapy (strategy 1) or (2) coronary angiography with the intent to revascularize (strategy 2). Only patients randomized to strategy 2 had routine (protocol-directed) coronary angiography.

Treatment Algorithm in Randomized Patients Medical therapy group (strategy 1). Patients randomized to strategy 1 did not undergo initial coronary angiography unless clinical instability developed. The prespecified medical treatment algorithm is shown in Appendix 3. Patient received these or comparable alternative medications at similar doses.

Medical therapy was titrated to maximally tolerated doses over a period of 4 to 8 weeks. All patients were encouraged to receive a long-acting mononitrate at doses of 60 mg and up to 120 mg/d. In patients with an LVEF lower than 40%, atenolol was recommended (maximal dose, 200 mg/d), whereas in those with an LVEF of 40% or greater, both long-acting diltiazem (maximal dose, 300 mg/d) and atenolol were recommended as clinically tolerated. In patients in whom asymptomatic bradycardia (heart rate ⬍50 beats/min) developed and/or systolic blood pressure was lower than 110 mm Hg, medications were not titrated to higher doses. A 12-lead electrocardiogram and/or rhythm strip was obtained during medication titration as clinically indicated. To ensure that several classes of anti-ischemic medications were used in combination and at high doses, amlodipine (10 mg/d) could be substituted for diltiazem in patients who had a resting heart rate of less than 50 beats/min either at baseline or after atenolol administration. Patients randomized to strategy 1 were to receive a minimal dose of at least two anti-ischemic medications (ie, ␤-blockers, calcium antagonists, long-acting nitrates) before hospital discharge. Revascularization group (strategy 2). All patients randomized to strategy 2 had coronary angiography with the intent to revascularize. PCI or CABG was performed based on the extent of CAD and technical feasibility. CABG was recommended over PCI in patients who had (1) greater than 50% left main stenosis,27 (2) triple-vessel CAD,28 or (3) diabetes mellitus and multivessel CAD.29 For patients randomized to strategy 2 who were poor revascularization candidates, optimal medical therapy was administered as proposed in patients assigned to strategy 1. Patients undergoing CABG had grafting of all arteries with significant (ⱖ50%) stenosis as deemed technically feasible. Patients undergoing PCI had dilation of the infarct-related artery and any other artery with significant (ⱖ50%) stenosis that was supplying an ischemic zone, as determined by adenosine SPECT. The decision to perform coronary artery stenting in conjunction with a glycoprotein IIb/IIIa antagonist was made at the discretion of the principal investigator at each site.

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Anti-ischemic medical therapy (as proposed in strategy 1) was encouraged in patients who either had residual angina after coronary revascularization or were judged to have had incomplete coronary revascularization.

Adjuvant Care All patients enrolled in INSPIRE were to have an assessment of LVEF by gated SPECT. Patients with an LVEF lower than 40% and those with an anterior Q-wave AMI were encouraged to receive an angiotensin-converting enzyme inhibitor as well as a ␤-blocker with doses increased as clinically tolerated (Appendix 3). All patients were treated with aspirin (325 mg/d), and those found to have hyperlipidemia (total cholesterol level ⬎200 mg/dL and low-density lipoprotein [LDL] level ⬎100 mg/dL) received dietary counseling and, if needed, lipid-lowering therapy to reduce LDL cholesterol level to less than 100 mg/dL (National Cholesterol Education Program guidelines).30 Hypertension was likewise treated to conform with current guidelines.31 Treatment of residual ischemia and/or angina in nonrandomized patients followed the same guidelines as proposed for randomized patients.

Sequential SPECT Imaging Randomized patients had adenosine sestamibi SPECT repeated approximately 6 to 8 weeks after the baseline study and after optimization of medical therapy (strategy 1) or coronary revascularization (strategy 2). All other patients with an initial SPECT PDS of 20% or greater and ischemia of 10% or greater were encouraged to undergo sequential SPECT imaging within the same time frame as randomized patients (Figure 1). The purpose of the second SPECT study in randomized patients was to determine the relative efficacy of the two treatment strategies to reduce the total and ischemic PDS. The second adenosine SPECT study was also performed to determine whether individual patients who significantly reduced their total and ischemic PDS had a lower 1-year cardiac event rate than those who did not. In this regard, the results of the second SPECT study were not communicated to the study investigators. In clear distinction to the baseline study, all patients were instructed to take their prescribed anti-ischemic medications on the morning of the second SPECT study.

Clinic Visits in Randomized and Nonrandomized Patients Randomized patients. After hospital discharge, patients assigned to strategy 1 were seen by a designated physician at each site weekly for 4 weeks; every 2 weeks for 1 month, 4 weeks later; and every 3 months thereafter for a minimum of 1 year. Frequent visits during the first 2 months allowed titration of oral anti-ischemic medications in those randomized to receive medical therapy before performing repeat adenosine SPECT. Patients randomized to strategy 2 were seen by a designated physician at each site within the first 2 weeks of hospital discharge and again at week 6. Long-term

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follow-up conformed to the same schedule of visits as for patients assigned to strategy 1. Nonrandomized patients. It was recommended that nonrandomized patients be seen once in the first month after hospital discharge and every 3 months thereafter. More frequent visits depended on the clinical stability of individual patients.

Cardiac Events The cardiac events considered in INSPIRE were as follows: (1) death (sudden or nonsudden) resulting from cardiac causes, (2) reinfarction, (3) acute coronary syndrome (defined as rest or worsening exertional chest pain requiring hospital admission and associated with ⱖ1-mm transient ST-segment depression in ⱖ2 leads but no increase in cardiac enzyme levels), and (4) signs and symptoms of severe congestive heart failure (ie, pulmonary edema) necessitating hospital admission for treatment with intravenous diuretics and/or inotropic agents. Data were also to be kept regarding the number of patients (1) in whom effort-related angina pectoris had developed and (2) who had non–protocol-directed coronary angiography and revascularization during the follow-up period. Side effects requiring down-titration of individual anti-ischemic medications were also captured on specific case report forms. The Data and Safety Monitoring Board reviewed cardiac events in the randomized treatment limbs at prospectively defined time points during the conduct of the trial and at the conclusion of study follow-up.

Crossover Between Treatment Strategies It was essential to the conduct of this trial that patients randomized to strategies 1 and 2 received their indicated therapy. A crossover was said to occur when a patient randomized to strategy 1 (medical therapy group) had coronary revascularization and when a patient randomized to strategy 2 (revascularization group) was treated with medical therapy alone. Patients randomized to strategy 1 (intensive medical therapy alone) did not undergo coronary angiography with revascularization before the second perfusion scan (6 to 8 weeks) unless clinical instability developed, defined as a recurrent nonfatal cardiac event. Patients in whom recurrent chest pain developed during the drug titration phase of the trial had their medical therapy optimized before considering coronary angiography and revascularization as a therapeutic option. After the second perfusion study, it was anticipated that most strategy 1 patients would receive similar medical therapy throughout the 1-year follow-up period. A 6- to 8-week drug titration period was included to ensure an adequate time period for maximizing medical therapy to stable, well-tolerated doses. Adjustments in medical therapy, however, might still be required during follow-up and were captured on specific case report forms. Crossover from strategy 1 (medical therapy) to strategy 2 (revascularization therapy) during the follow-up period was indicated only in patients (1) in whom a nonfatal cardiac event

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developed or (2) who were in Canadian Cardiovascular Society Functional Class II to IV despite maximally tolerated medical therapy. Crossover from strategy 1 to strategy 2 for any other non–protocol-directed reason was strongly discouraged. All protocol-directed and non–protocol-directed coronary angiographic procedures and coronary revascularizations, as well as the reasons for these procedures, were captured on specific case report forms. Patients randomized to strategy 2 (invasive therapy) had optimal coronary revascularization, as previously described. The need for repeat coronary angiography and revascularization and/or the addition or intensification of anti-ischemic medical therapy followed the same clinical guidelines as outlined for strategy 1 patients.

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Table 1. Sample size necessary per treatment arm

Mean difference in PDS change from first SPECT study to second SPECT study between randomized treatment groups Power

1

2

3

4

5

75% 80% 85% 90%

334 377 431 505

167 189 216 253

112 126 144 169

84 95 108 127

67 76 87 101

Patient Follow-up Follow-up was continued for all patients until either death or 1-year study completion. Patients rehospitalized for unstable angina or reinfarction were followed up through their intercurrent hospitalization until 1 year after study entry. All cardiac hospitalizations and major cardiac procedures were documented on specific case report forms. The INSPIRE informed consent form stated the necessity for complete participant follow-up throughout the 1-year study period. It also contained an extended statement to allow access to the patient’s hospital bill (ie, UB92). For economic follow-up, all patients completed the Patient Economic Questionnaire. Quality of life, based on the Duke Activity Status Index and Medical Outcomes Study Short Form 36, was assessed at baseline, at the second SPECT study, and at 6 and 12 months after study entry.

Statistical Analysis Study endpoints. The primary endpoint for which this study was powered was to determine the relative efficacy of intensive medical therapy (strategy 1) versus coronary revascularization (strategy 2) to reduce scintigraphic ischemia as determined by sequential adenosine Tc-99m sestamibi SPECT. The other primary emphasis in INSPIRE was to determine whether adenosine sestamibi SPECT performed early after AMI could accurately stratify patients into low- and high-risk prognostic groups. Additional secondary endpoints were to determine whether adenosine sestamibi SPECT could track patient risk based on temporal changes in the extent of scintigraphic ischemia after various anti-ischemic therapies and to determine the relative benefit of intensive medical therapy (strategy 1) versus coronary revascularization (strategy 2) for improving event-free survival. Estimates of sample size. The original intent was to recruit 1,000 patients for INSPIRE. The primary endpoint of this trial was based on a sample size of approximately 400 patients in the randomized groups who were to have a sequential adenosine SPECT study after various therapeutic interventions. Differences in SPECT PDS between baseline and 8 weeks after baseline were calculated for each patient in the trial. The estimated necessary sample size for the trial was based on the ability to detect a difference in the mean change

in total PDS between the two randomized treatment groups. An estimate of the underlying variability of the total PDS came from a published reproducibility study of these measurements, where the variance of the change in total PDS was 21.2% in a sample of 18 patients in which the measurements were taken between 3 and 10 days apart.32 Although the absolute measurements of total PDS tended to be skewed to the right, the differences between measurements tended toward a more normal distribution, and there, the general formula to detect differences between two means could be applied, as presented here: n ⱖ (2s2/⌬2)(t1-␣,v ⫹ t␤,v)2, in which n is the number of patients per treatment arm, tm,v denotes the 100(1-m) percentile point from a T distribution with v degrees of freedom, ⌬ denotes the minimal detectable difference between population means, and s2 denotes the pooled variance of the outcome. By use of a conservative estimate of that variance of 24, 200 patients per treatment arm were required to detect a 2% difference in mean PDS change between the two randomized groups at 80% power. This estimate included an expected loss–to–follow-up rate of 5.5%, or 11 patients per arm (Table 1). For the primary endpoint, a total of 205 patients were enrolled, with only 169 patients completing both SPECT studies (ie, 17.6% dropout rate). A post hoc sample size calculation with an observed SD of approximately 10% revealed that with the available sample size, the statistical power to detect a 2% change between randomized groups was in the range of 57% to 62%. For the other endpoint of primary interest, however, a post hoc sample size calculation revealed that the available sample size was necessary and sufficient to detect differences in event-free survival between the low- and high-risk SPECT subsets (␤ ⱖ .80, ␣ ⫽ .01).

Additional Statistical Considerations Primary outcome analysis. The primary endpoint of this study was a change in total PDS including the extent of ischemia as assessed by quantitative adenosine sestamibi SPECT. For the randomized portion of this study, statistical methods to compare changes in the continuous measures of myocardial perfusion included the use of a nonparametric test

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for several independent samples by use of the Kruskal-Wallis statistic. The analysis of trial data for the primary endpoint was an analysis of variance, which allowed for the control of important covariates. Baseline PDS score was an important variable to control for, as using the change score (difference from baseline) as the primary outcome did not control for potential imbalance in baseline PDS scores between treatment groups. (Because the correlation between baseline and follow-up measures is generally less than 1, there is a degree of negative correlation between baseline and change scores, and adjustment for baseline PDS in an analysis of variance removed that influence of the baseline measure in the treatment group comparison.) Site and the treatment-by-site interaction were also included in the model, and the possibility that the treatment would have a different effect on the outcome depending on the baseline value was examined by including a treatment-by-baseline interaction. Other key baseline measures included in the model were age, sex, systolic blood pressure, heart rate, prior AMI, prior CABG, diabetes mellitus, and LVEF. Analysis of PDS as a predictor of cardiac events. Secondary analysis examined rates of follow-up cardiac events at 1 year after testing. We used risk-adjusted techniques to define varying outcome differences across the varying patient strata. Risk-adjusted multivariable Cox proportional hazards models were created to determine the predictors of cardiac death or reinfarction and time to cardiac death, reinfarction, acute coronary syndromes, or new onset of heart failure. The relationships between the continuous variables (ie, quantitative perfusion measures) and each outcome were tested for linearity by use of restricted cubic spline functions. A variety of graphic techniques were used to determine any appropriate transformations needed for continuous variables that did not have a linear relationship with the outcome of interest. From the multivariable models, restricted cubic spline plots depicting these relationships were calculated as predicted probabilities with 95% confidence intervals. Predictors in each model were tested by use of the Wald ␹2 test. Time to the first cardiac event was analyzed by standard methods for the analysis of failure-time data such as KaplanMeier estimates and Cox proportional hazards regression. Cox regression models were used to estimate the degree to which PDS measures were associated with a higher hazard of cardiac event with adjustment for other important covariates such as age, LVEF, sex, diabetes mellitus, prior AMI, or prior CABG. Specific subgroups to be analyzed were based on sex, site of infarction, patient age (⬍65 years vs ⱖ65 years), LVEF (⬍40% vs ⱖ40%), and Thrombolysis in Myocardial Infarction risk score. Time since baseline was used as the time index, and both baseline PDS and change in PDS between baseline and 6-week follow-up were included in the model, the latter as a time-varying covariate. Potential nonlinear effects of continuous predictor variables were checked by use of cubic spline functions (piecewise polynomials). Two-way interactions between predictor variables were examined to assess the additivity of the factors on the log hazard of the endpoint. The validity of the assumption of proportional hazards was examined by use of residual plots and covariate-by-time interaction terms. The

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predictive accuracy of the final models was examined by use of measures of discrimination and calibration.

RESULTS The results presented are limited to the baseline demographic, clinical, and scintigraphic characteristics of the 728 patients enrolled in the INSPIRE trial according to their risk group (Table 2) and the timing of adenosine SPECT imaging after hospital admission (Figure 3). The P values in Table 2 refer to a comparison across the four designated risk groups (ie, low, intermediate, high, and randomized). The mean age across all groups was 63 years, with approximately one third of patients being women and 20% to 25% being minorities. Many risk factors were of similar frequency across all AMI groups, including family history of CAD, cholesterol profile, history of smoking, and history of hypertension. Variables known to be associated with a higher rate of recurrent cardiac events were not equally distributed among the SPECT risk groups. The SPECT risk groups varied significantly with respect to established clinical outcome variables. For example, high-risk patients classified by SPECT had a worse New York Heart Association functional class and LVEF, more diabetes, and more anterior AMIs than those in the low-risk SPECT category. Details regarding the outcome of randomized patients and those in the other SPECT risk strata will be presented separately. With regard to the timing of adenosine SPECT, 12% of patients had imaging within 1 day of admission and 68% by day 4 (Figure 3). None of the 728 patients had a cardiac event associated with adenosine administration. DISCUSSION The INSPIRE trial was designed to further define the potential role of quantitative adenosine Tc-99m sestamibi SPECT regarding two critical aspects of patient management after AMI: (1) risk stratification and (2) assessment of subsequent therapy. The INSPIRE study design included numerous features that were innovative and unique when compared with previous published trials.14,33,34 Risk Stratification: Special Design Features of INSPIRE The unique trial design features of INSPIRE begin with the imaging technique selected. In nearly all previous clinical trials comparing an invasive versus a conservative strategy for assessing patient outcome, the predischarge noninvasive study selected to detect ischemia was routine exercise treadmill testing without

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Table 2. Baseline demographic, clinical, and scintigraphic characteristics of study population by SPECT risk groups

Low Intermediate High Randomized (n ⴝ 242) (n ⴝ 213) (n ⴝ 68) (n ⴝ 205) Age (y) Women Race Black Hispanic Asian White Other Heart rate (beats/min) Hypertension (blood pressure ⱖ140/90 mm Hg) Systolic blood pressure/diastolic blood pressure Diabetes Family history Hyperlipidemia Total cholesterol LDL cholesterol HDL cholesterol Triglycerides Smoking history Prior CAD Prior AMI NYHA class I II III–IV Peak creatine kinase Peak creatine kinase MB Peak troponin T Peak troponin I Q wave AMI AMI-location Anterior Inferior Lateral Posterior Other Thrombolytic therapy TIMI risk score Low (0–2) Intermediate (3–5) High (ⱖ6) Total PDS (%) Scar PDS (%) Ischemia PDS (%) LVEF (%)

P value

All patients (N ⴝ 728)

63 ⫾ 12 42%

63 ⫾ 12 28%

64 ⫾ 12 25%

64 ⫾ 12 24%

15% 3% 5% 75% 2% 74 ⫾ 14 62%

11% 8% 8% 71% 2% 74 ⫾ 25 53%

10% 9% 1% 80% 0% 82 ⫾ 16 64%

5% 4% 6% 82% 3% 77 ⫾ 51 57%

.19 .16

10% 5% 6% 75% 4% 75 ⫾ 15 58%

134/78

127/73

127/75

129/74

.007/.007

130/75

23% 27% 60% 207 ⫾ 51 118 ⫾ 49 42 ⫾ 12 177 ⫾ 145 59% 20% 9%

36% 27% 60% 203 ⫾ 72 112 ⫾ 46 43 ⫾ 20 155 ⫾ 139 58% 31% 21%

41% 26% 73% 202 ⫾ 47 114 ⫾ 46 40 ⫾ 12 174 ⫾ 142 68% 51% 30%

28% 27% 65% 206 ⫾ 42 113 ⫾ 40 41 ⫾ 11 193 ⫾ 150 55% 28% 18%

.006 .9 .15 .82 .82 .45 .07 .29 ⬍.0001 ⬍.0001 ⬍.0001

30% 27% 62% 205 ⫾ 56 115 ⫾ 45 42 ⫾ 14 175 ⫾ 145 58% 28% 17%

89% 60% 44% 66% 10% 34% 25% 10% 1% 6% 31% 23% 652 ⫾ 612 1,423 ⫾ 1,390 1,110 ⫾ 1,069 781 ⫾ 765 46 ⫾ 62 87 ⫾ 119 96 ⫾ 122 61 ⫾ 83 1.1 ⫾ 1 19.7 ⫾ 81 4.4 ⫾ 7 1.4 ⫾ 3 22.7 ⫾ 37 39.2 ⫾ 71 29.4 ⫾ 74 22.5 ⫾ 50 39% 63% 57% 42% 22% 44% 10% 2% 23% 32% 62% 33% 5% 7.4 ⫾ 6 4.6 ⫾ 5 2.8 ⫾ 3 57 ⫾ 12

46% 34% 7% 4% 8% 45% 57% 36% 8% 36.1 ⫾ 13 32.3 ⫾ 13 3.7 ⫾ 3 37 ⫾ 13

52% 19% 13% 0% 16% 25% 62% 31% 7% 44.2 ⫾ 12 20.5 ⫾ 20 23.7 ⫾ 12 28 ⫾ 8

22% 43% 13% 2% 20% 30% 50% 38% 12% 32.6 ⫾ 10 11.3 ⫾ 11 21.3 ⫾ 9 48 ⫾ 9

.69 ⬍.0001 .007

⬍.0001 ⬍.0001 .14 .19 ⬍.0001 ⬍.0001

.002 .072

⬍.0001 ⬍.0001 ⬍.0001 ⬍.0001

63 ⫾ 12 31%

70% 18% 12% 960 ⫾ 1,032 68 ⫾ 96 6.2 ⫾ 42 28.3 ⫾ 56 48% 32% 38% 10% 2% 18% 35% 57% 35% 8% 26.3 ⫾ 17 16.1 ⫾ 15 10.2 ⫾ 11 46 ⫾ 14

LDL, Low-density lipoprotein; HDL, high-density lipoprotein; NYHA, New York Heart Association; TIMI, Thrombolysis In Myocardial Infarction.

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tion and PDS quantification was ensured through analysis of all studies by only one core laboratory investigator (J.J.M.). We have previously published studies from our laboratory establishing the degree of variability associated with sequential quantitative SPECT measurements also as interpreted by the same investigator (J.J.M.).32 Interpretation of all studies by one investigator was performed to limit variability to an absolute minimum. All of these aspects of the INSPIRE study design will facilitate an optimal assessment of the ability of adenosine SPECT to predict cardiac events in the year after AMI. Figure 3. Time from hospital admission to performance of adenosine Tc-99m sestamibi SPECT. The percentage of patients who underwent imaging on each day after admission is shown.

Assessing Post-AMI Therapy: Special Design Features of INSPIRE

myocardial perfusion imaging. This becomes a critical issue because submaximal exercise testing is insensitive for identifying myocardial ischemia,35-37 has a poor negative predictive accuracy for identifying low-risk patients,38-40 and is established as inferior to myocardial perfusion scintigraphy for assessing risk.38-40 The Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital (VANQWISH) study is the only earlier trial that selected myocardial perfusion scintigraphy as the noninvasive testing modality of choice,13 but only INSPIRE used “state-of-the-art” imaging techniques with the introduction of quantitative adenosine Tc-99m sestamibi SPECT for assessing risk and monitoring therapy. Quantitative SPECT analysis adds a new dimension to risk stratification by affording an accurate estimate of the total stress-induced LV PDS and the extent of scintigraphic ischemia. With advances in AMI therapeutics and the medical and economic desirability of earlier risk assessment, adenosine, as a substitute for treadmill exercise stress, can be administered safely even within the first days after AMI, allowing very early risk stratification based on the gated SPECT perfusion and function results and thereby expediting appropriate patient care. Another unique aspect of INSPIRE was the prospective assignment of risk based on previous adenosine SPECT pilot data.24,25 It will be interesting to compare the pilot data from which the INSPIRE risk strata were derived with the larger 1-year clinical database INSPIRE will provide. There were also numerous novel logistic features of INSPIRE. First, despite clinical centers being located in 5 countries and on 3 continents, online rapid assignment of risk group for each enrolled patient was possible through electronic transmission of SPECT data to the Methodist DeBakey Heart Center Core Nuclear Laboratory (Houston, Tex). Consistency in SPECT interpreta-

INSPIRE also had numerous study design elements that will provide unique data regarding the potential of adenosine Tc-99m sestamibi SPECT to quantitate the effect of therapies on scintigraphic ischemia and correlate therapeutic changes in quantitative ischemia defect size to subsequent cardiac events in the first year after AMI. A totally unique feature of INSPIRE and its investigators was the commitment to randomize patients with a high-risk scintigraphic study to either an invasive interventional strategy or an aggressive medical strategy. In the randomized patients, those assigned to coronary angiography and revascularization received stateof-the-art interventional approaches. In addition, the protocol encouraged medical therapy in the intervention arm. A very notable feature of the INSPIRE study design was a very aggressive algorithm to maximize medical therapy in the medical limb (Appendix 3), which included encouragement of not only high doses of multiple anti-ischemic drugs but also, when deemed appropriate, use of angiotensin-converting enzyme and angiotensin receptor blockers, as well as adherence to the National Cholesterol Education Program30 and Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines.31 Such attention to more rigorous therapy in patients randomized to medicines is a major positive departure of INSPIRE from other previously published studies (the DANish trial in Acute Myocardial Infarction [DANAMI], Fragmin and Fast Revascularisation during Instability in Coronary artery disease [FRISC], and Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy–Thrombolysis In Myocardial Infarction 18 [TACTICS]).14,33,34 For example, in both the FRISC33 and TACTICS34 trials, in patients with acute coronary syndromes, state-of-the-art interventional approaches were compared with suboptimal and poorly characterized medical therapy. This was

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also true in the DANAMI trial, which compared the relative efficacy of medical therapy versus coronary revascularization to reduce subsequent cardiac events in patients with residual ischemia after AMI.14 Medical therapy in this trial was prescribed according to local practice with no guidelines for dose titration. In this regard, only a minority of patients randomized to medical therapy received ␤-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. In contrast, the INSPIRE protocol incorporated specific design features to emphasize stateof-the-art medical therapy and ensure an objective comparison between medical and interventional anti-ischemic strategies. This important unique aspect of INSPIRE is highlighted by the recent Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT) trial, in acute coronary syndrome patients, in whom aggressive lipid reduction (mean LDL, 62 mg/dL) was associated with a lower cardiac event rate than simply “achieving guidelines” (mean LDL, 98 mg/dL).22 Other INSPIRE design details offer new, innovative approaches. The design required a second adenosine Tc-99m sestamibi SPECT study in randomized patients 6 weeks after the initial study. This sequence provides data to analyze both the short-term prognostic information provided by the initial SPECT study and the complementary value of a second SPECT study obtained after intense interventional or medical therapy. The latter study will define how SPECT tracks risk after medical or interventional therapy. This unique information and the correlation between treatment effects on scintigraphic ischemia and subsequent clinical cardiac events highlight the potential of INSPIRE to yield new and groundbreaking information. The revelations from INSPIRE may well alter clinical standards of risk stratification as well as provide pilot data from which to plan large-scale randomized trials. Throughout the United States, it is common community practice, including at our institution, to use coronary angiography to stratify risk, even in many patients without complications surviving AMI. Because of the study design features of INSPIRE, the results of this trial may offer compelling data that support more emphasis on noninvasive assessment with adenosine Tc-99m sestamibi SPECT.

Acknowledgment The authors have indicated they have no financial conflicts of interest.

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References 1. Andersen HR, Nielsen TT, Rasmussen K, et al, for DANAMI-2 Investigators. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med 2003;349:733-42. 2. Zijlstra F, de Boer MJ, Hoorntje JC, et al. A comparison of immediate coronary angioplasty with intravenous streptokinase in acute myocardial infarction. N Engl J Med 1993;328:680-4. 3. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003;361: 13-20. 4. Ryan TJ, Antman EM, Brooks NH, et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction: 1999 update: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). Available from: URL: www.acc.org. Accessed on May 15, 2004. 5. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock. N Engl J Med 1999; 341:625-34. 6. Gibson CM, Karha J, Murphy SA, et al, for TIMI Study Group. Early and long-term clinical outcomes associated with reinfarction following fibrinolytic administration in the Thrombolysis in Myocardial Infarction trials. J Am Coll Cardiol 2003;42:7-16. 7. Morrow DA, Antman EM, Charlesworth A, et al. TIMI risk score for ST-elevation myocardial infarction: a convenient, bedside, clinical score for risk assessment at presentation. An Intravenous nPA for Treatment of Infarcting Myocardium Early II trial substudy. Circulation 2000;102:2031-7. 8. Rogers WJ, Canto JG, Lambrew CT, et al. Temporal trends in the treatment of over 1.5 million patients with myocardial infarction in the US from 1990 through 1999: the National Registry of Myocardial Infarction 1, 2 and 3. J Am Coll Cardiol 2000;36:2056-63. 9. Terrin ML, Williams DO, Kleiman NS, et al. Two- and three-year results of the Thrombolysis in Myocardial Infarction (TIMI) Phase II clinical trial. J Am Coll Cardiol 1993;22:1763-72. 10. Williams DO, Braunwald E, Knatterud G, et al, and TIMI Investigators. One-year results of the Thrombolysis in Myocardial Infarction investigation (TIMI) phase II trial. Circulation 1992;85: 533-42. 11. SWIFT (Should We Intervene Following Thrombolysis?) Trial Study Group. SWIFT trial of delayed elective intervention v conservative treatment after thrombolysis with anistreplase in acute myocardial infarction. BMJ 1991;302:555-60. 12. McCullough PA, O’Neill WW, Graham M, et al. A prospective randomized trial of triage angiography in acute coronary syndromes ineligible for thrombolytic therapy. Results of the Medicine Versus Angiography in Thrombolytic Exclusion (MATE) Trial. J Am Coll Cardiol 1998;32:596-605. 13. Boden WE, O’Rourke RA, Crawford MH, et al. Outcomes in patients with acute non-Q-wave myocardial infarction randomly assigned to an invasive as compared with a conservative management strategy. Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital (VANQWISH) Trial Investigators. N Engl J Med 1998;338:1785-92. 14. Madsen JK, Grande P, Saunama¨ ki K, et al, on behalf of the DANAMI Study Group. Danish multicenter randomized study of invasive versus conservative treatment in patients with inducible

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ischemia after thrombolysis in acute myocardial infarction (DANAMI). Circulation 1997;96:748-55. 15. Dakik HA, Kleiman NS, Farmer JA, et al. Intensive medical therapy versus coronary angioplasty for suppression of myocardial ischemia in survivors of acute myocardial infarction. A prospective, randomized pilot study. Circulation 1998;98:2017-23.

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16. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001-9. 17. The MIAMI Trial Research Group. Metoprolol in Acute Myocardial Infarction (MIAMI): a randomized placebo-controlled international trial. Eur Heart J 1985;6:199-226. 18. The Norwegian Multicenter Study Group. Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med 1981;304:801-7. 19. The Danish Study Group on Verapamil in Myocardial Infarction. Effect of verapamil on mortality and major events after acute myocardial infarction (the Danish Verapamil Infarction Trial II-DAVIT II). Am J Cardiol 1990;66:779-85. 20. Gibson RS, Boden WE, Theroux P, et al, 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;315:423-9. 21. The Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med 1988;319:385-92. 22. Cannon CP, Braunwald E, McCabe CH, et al, Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-504. 23. Mahmarian JJ, Pratt CM, Nishimura S, Abreu A, Verani MS. Quantitative adenosine Tl-201 single-photon emission computed tomography for the early assessment of patients surviving acute myocardial infarction. Circulation 1993;87:1197-210. 24. 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;25:1333-40. 25. Dakik HA, Farmer JA, He Z-X, et al. Quantitative adenosine thallium-201 single photon tomography accurately predicts risk following acute myocardial infarction: the results of a prospective trial [abstract]. J Am Coll Cardiol 1997;29(Suppl A):228A. 26. Alderman EL, Fisher LD, Litwin P, et al. Results of coronary artery surgery in patients with poor left ventricular function (CASS). Circulation 1983;68:785-95. 27. Chaitman BR, Fisher LD, Bourassa MG, et al. Effect of coronary bypass surgery on survival patterns in subsets of patients with left main coronary artery disease. Report of the Collaborative Study in Coronary Artery Surgery (CASS). Am J Cardiol 1981;48:765-77. 28. Mock MB, Ringqvist I, Fisher LD, et al. Survival of medically treated patients in the coronary artery surgery study (CASS) registry. Circulation 1982;66:562-8. 29. Srinivas VS, Brooks MM, Detre KM, et al. Contemporary percutaneous coronary intervention versus balloon angioplasty for multivessel coronary artery disease: a comparison of the National Heart, Lung and Blood Institute Dynamic Registry and the Bypass Angioplasty Revascularization Investigation (BARI) study. Circulation 2002;106:1627-33. 30. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third

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Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285:2486-97. Chobanian AV, Bakris GL, Black HR, et al, National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560-72. 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;75:1116-9. FRagmin and Fast Revascularisation during InStability in Coronary artery disease (FRISC II) Investigators. Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. Lancet 1999; 354:708-15. Cannon CP, Weintraub WS, Demopoulos LA, et al. for the TACTICS—Thrombolysis in Myocardial Infarction 18 Investigators: Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001;344:187987. Dakik HA, Mahmarian JJ, Kimball KT, et al. Prognostic value of exercise thallium-201 tomography in patients treated with thrombolytic therapy during acute myocardial infarction. Circulation 1996;94:2735-42. Travin MI, Dessouki A, Cameron T, Heller GV. Use of exercise technetium-99m sestamibi SPECT imaging to detect residual ischemia and for risk stratification after acute myocardial infarction. Am J Cardiol 1995;75:665-9. Chaitman BR, McMahon RP, Terrin M, et al. Impact of treatment strategy on predischarge exercise test in the Thrombolysis in Myocardial Infarction (TIMI) II Trial. Am J Cardiol 1993;71: 131-8. Gibson RS, Watson DD, Craddock GB, et al. Prediction of cardiac events after uncomplicated myocardial infarction: a prospective study comparing predischarge exercise thallium-201 scintigraphy and coronary angiography. Circulation 1983;68:321-36. Chiamvimonvat V, Goodman SG, Langer A, Barr A, Freeman MR. Prognostic value of dipyridamole SPECT imaging in low-risk patients after myocardial infarction. J Nucl Cardiol 2001;8:136-43. Brown KA, Heller GV, Landin RS, et al. Early dipyridamole 99mTc-sestamibi single photon emission computed tomographic imaging 2 to 4 days after acute myocardial infarction predicts in-hospital and postdischarge cardiac events: comparison with submaximal exercise imaging. Circulation 1999;100: 2060-6.

APPENDIX 1: ORGANIZATIONAL STRUCTURE Steering Committee George A. Beller, MD, Kenneth A. Brown, MD, Bernard J. Gersh, MD, Raymond J. Gibbons, MD, Ami E.

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Iskandrian, MD, Neal S. Kleiman, MD, John J. Mahmarian, MD, Magnus Ohman, MD, Carl J. Pepine, MD, Craig M. Pratt, MD, Mario S. Verani, MD, and David O. Williams, MD

Data and Safety Monitoring Board Lemuel A. Moye´ , PhD, MD, David R. Holmes, MD, Robert P. Giugliano, MD, and Enrique F. Schisterman, PhD

Core Nuclear Laboratory: The Methodist DeBakey Heart Center/Baylor College of Medicine (Houston, Tex) John J. Mahmarian, MD, and Maria E. Frias

Coordinating Center: American Cardiovascular Research Institute (Atlanta, Ga) Leslee J. Shaw, PhD

Participating Clinical Centers Neil G. Filipchuk, MD, Cardiology Consultants, Calgary, Alberta, Canada (n ⫽ 156); Craig M. Pratt, MD, John J. Mahmarian, and Sherif S. Iskander, MD, Baylor College of Medicine, Houston, Tex (n ⫽ 153); Habib A. Dakik, MD, American University of Beirut, Beirut, Lebanon (n ⫽ 104); Terrence D. Ruddy, MD, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (n ⫽ 72); Sherif S. Iskander, MD, Cardiovascular Associates of East Texas, Tyler, Tex (n ⫽ 64); Milena Henzlova, MD, Mount Sinai Medical Center, New York, NY (n ⫽ 35); Felix Keng, MD, National Heart Centre, Singapore, Singapore (n ⫽ 33); Adel Allam, MD, Al-Azhar University, Cairo, Egypt (n ⫽ 32); Raymond Taillefer, MD, Centre Hospitalier de Universite, Montreal, Quebec, Canada (n ⫽ 27); Anthony Fung, MD, Vancouver General Hospital, Vancouver, British Columbia, Canada (n ⫽ 16); Richard Steingart, MD, Winthrop University Hospital, Mineola, NY (n ⫽ 12); Michael Freeman, MD, St Michael’s Hospital, Toronto, Ontario, Canada (n ⫽ 8); Vincent J. B. Robinson, MD, Medical College of Georgia, Augusta, Ga (n ⫽ 7); Charles K. Stone, MD, University of Wisconsin, Madison, Wis (n ⫽ 4); Robert C. Hendel, MD, Rush-Presbyterian, Chicago, Ill (n ⫽ 3); and Dante Graves, MD, St Thomas Heart Institute, Nashville, Tenn (n ⫽ 2).

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APPENDIX 2: ADENOSINE SESTAMIBI SPECT IMAGING PROTOCOL INSPIRE used a rest-stress Tc-99m sestamibi imaging protocol. Before receiving Tc-99m sestamibi, patients were given 1 to 2 tablets of sublingual nitroglycerin (0.4 mg) 5 minutes apart. A rest injection of 8 to 12 mCi Tc-99m sestamibi was then administered, and imaging was performed approximately 1.5 to 2 hours later. Patients then underwent adenosine stress testing approximately 3 hours after the rest study, with injection of 25 to 30 mCi Tc-99m sestamibi. Imaging was again performed approximately 1.5 to 2 hours later. Gated SPECT was performed on both the rest and stress images. In patients weighing more than 250 lb, a 2-day rest-stress sestamibi protocol was used, with injection of 25 to 30 mCi Tc-99m sestamibi on each day. Adenosine was infused into a peripheral antecubital vein via a computer-controlled pump infusion system. The infusion rate was 140 ␮g · kg⫺1 · min⫺1 for 3 minutes, after which time 25 to 30 mCi Tc-99m sestamibi was injected as a bolus and flushed with 10 mL of normal saline solution. The adenosine infusion was then maintained at 140 ␮g · kg⫺1 · min⫺1 for an additional 3 minutes, for a total infusion time of 6 minutes. Vital signs and a 12-lead electrocardiogram were obtained immediately before, every minute during, and for the first 5 minutes after the adenosine infusion. Early termination of adenosine infusion was indicated under the following conditions: (1) severe hypotension (systolic blood pressure ⬍90 mm Hg), (2) development of persistent symptomatic second-degree or complete heart block, (3) wheezing, and (4) severe chest pain and at least 2-mm ST-segment depression. Sestamibi was injected before infusion termination. For patients with a relative contraindication to adenosine, a 7-minute incremental infusion protocol was used as follows: 50 to 75 to 100 to 140 ␮g · kg⫺1 · min⫺1 at 1-minute intervals, with injection of sestamibi at the highest tolerated adenosine dose and then continued for 3 additional minutes. Sestamibi SPECT was performed by the methodology previously reported. Images were acquired by use of a single-, double-, or triple-headed rotating gamma camera with a large field of view equipped with a high-resolution parallel-hole collimator. Image acquisition was performed over a 180° anterior arc at 3° intervals and for 25 seconds per frame. Transaxial image reconstruction used a backprojection technique with a Butterworth (order, 5) high-pass filter with a low-pass window at a 40% cutoff. The reconstructed tomographic slices were then reoriented into the short, horizontal long, and vertical long axes for visual and quantitative analysis.

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Appendix 3 Table 1. LVEF lower than 40%

V1 (wk 1) ASA, 325 mg/d Long-acting nitrate, 60 mg/d Atenolol, 50 mg/d ACE inhibitor Simvastatin, 10–20 mg/d

V2 (wk 2)

V3 (wk 3)

ASA, 325 ASA, 325 mg/d mg/d Long-acting ➞ Long-acting nitrate, nitrate, 120 mg/d 120 mg/d Atenolol, ➞ Atenolol, ➞ 50 mg/d 100 mg/d ACE inhibitor ACE inhibitor ™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™3

V4 (wk 4) ASA, 325 mg/d Long-acting nitrate, 120 mg/d Atenolol, 150 mg/d ACE inhibitor Simvastatin, 20–30 mg/d

V5 (wk 6) ASA, 325 mg/d Long-acting nitrate, 120 mg/d ➞ Atenolol, 200 mg/d ➞ ACE inhibitor ➞ ™™™™™™™™™™™™™™™™™™3

SPECT 2 V6 (wk 7–8) ASA, 325 mg/d Long-acting nitrate, 120 mg/d Atenolol, 200 mg/d ACE inhibitor Simvastatin, 30–40 mg/d

Appendix 3 Table 2. LVEF of 40% or greater

V1 (wk 1) ASA, 325 mg/d Long-acting nitrate, 60 mg/d Diltiazem, 180 mg/d Atenolol, 25 mg/d Simvastatin, 10–20 mg/d

V2 (wk 2)

V3 (wk 3)

ASA, 325 ASA, 325 mg/d mg/d Long-acting Long-acting nitrate, nitrate, 120 mg/d 120 mg/d Diltiazem, ➞ Diltiazem, ➞ 180 mg/d 240 mg/d Atenolol, Atenolol, 25 mg/d 25 mg/d ™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™3

V4 (wk 4)

V5 (wk 6)

ASA, 325 mg/d Long-acting nitrate, 120 mg/d Diltiazem, 300 mg/d Atenolol, 25 mg/d Simvastatin, 20–30 mg/d

ASA, 325 mg/d Long-acting nitrate, 120 mg/d Diltiazem, 300 mg/d ➞ Atenolol, ➞ 50 mg/d ™™™™™™™™™™™™™™™™™™™3

SPECT 2 V6 (wk 7–8) ASA, 325 mg/d Long-acting nitrate, 120 mg/d Diltiazem, 300 mg/d Atenolol, 100 mg/d Simvastatin, 30–40 mg/d

V, Visit; wk, week; ASA, acetyl salisylic acid; SPECT, single photon emission computed tomography; ACE, angiotensin converting enzyme; LVEF, left ventricular ejection fraction.

Computer Quantification of Tomographic Images All SPECT images acquired by the different centers were sent directly over the Internet (generally via high-speed access lines) to the designated core laboratory at the Methodist DeBakey Heart Center/Baylor College of Medicine for quantification of the PDS and the extent of myocardial ischemia. Images were sent to the core laboratory on the day of study acquisition so as to expedite patient randomization and subsequent treatment. Results of the baseline perfusion scans were reported back to the field site within 24 hours.

APPENDIX 3: PROPOSED AGGRESSIVE MEDICATION TITRATION The patients with high-risk ischemia randomized to intensive medical therapy were to be rigorously treated. Appendix Tables 1 and 2 depict a suggested (not mandated) algorithm for aggressive medical therapy. Alternative ␤-blockers, calcium channel blockers, and statins were allowed, with these serving as examples of the proposed aggressive approach to medical therapy (see text).