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Poststress Left Ventricular Ejection Fraction is an Independent Predictor of Major Cardiac Events in Patients With Coronary Artery Disease and Impaired Left Ventricular Function

September 13, 2008

By De Winter, O Van De Veire, N; De Bondt, P; Van De Wiele, C; De Buyzere, M; De Backer, G; Gillebert, T C; Dierckx, R A; De Sutter, J

Aim. The aim of this study was to investigate the prognostic value of myocardial perfusion and function SPECT imaging in patients with coronary artery disease (CAD) and poor left ventricular (LV) function. Methods. We studied 261 patients (231 men, age 66+-10 years) with CAD and a resting LV ejection fraction (LVEF) =40% assessed during myocardial gated SPECT. Perfusion defect extent was calculated using 4D-MSPECT(R) software (Michigan University). Ischemia scoring was performed visually. Considered end points were: 1) major adverse cardiac events (MACE) (cardiac death, non-fatal myocardial infarction or late revascularization), 2) MACE or the need for hospitalization due to heart failure (MACE-HF) and 3) cardiac death or non-fatal myocardial infarction.

Results. During a median follow-up of 31 months, 52 patients (20%) died (35 cardiac deaths), 50 (19%) developed a MACE and 69 (26%) a MACE-HF. In a clinical model, diabetes and angina status were the only predictors of MACE (chi^sup 2^=19.3; P

Conclusion. In patients with impaired LV function and CAD, poststress LVEF is an independent predictor of future cardiac events.

KEY WORDS: Prognosis – Single photon emission tomography – Ischemia – Coronary artery disease – Heart failure, congestive.

Coronary artery disease (CAD) is the most common cause of heart failure in the Western world, accounting for 60-70% of the cases.1 Incidence and prevalence of congestive heart failure due to CAD are increasing worldwide as a result of increasing life expectancy in general and the longer survival of patients with CAD in particular.2 Although rates of death from most cardiovascular diseases are stable or declining, mortality data from heart failure are less clear.3 Patients with CAD and impaired left ventricular (LV) function are at very high risk for cardiac death and future cardiac events.4

Myocardial ischemia assessed by nuclear myocardial perfusion imaging is a well-known risk factor for future cardiac events in patients with known or suspected CAD.59 It is less clear whether ischemia is of prognostic importance in patients with depressed LV function. Revascularization procedures have shown to improve prognosis in patients with CAD and a depressed LV function,10 but some studies suggest no prognostic value for the presence of ischemia in patients with a poor systolic LV function.11 The favorable imaging characteristics of ^sup 99m^T/c bound ligands make it possible to perform electrocardiogram (ECG) gated cardiac single photon emission computed tomography (SPECT) during the acquisition of myocardial perfusion,12 which not only improves the specificity for detection of CAD 1^ but also permits the assessment of global LV functional parameters, including LV ejection fraction (LVEF) and LV volumes.14, 15 The predictive value of global LV functional parameters can be assessed using different imaging modalities and have shown predictive value in patients with known or suspected CAD. 16-21 The aim of this study was to investigate the predictive value of combined perfusion and function assessment during gated SPECT in patients with CAD and impaired LV function for prediction of future cardiac events.

Materials and methods

Study population

All patients with ischemic heart disease and a resting LVEF =40% determined by gated SPECT were prospectively evaluated (n=285) among 2 168 consecutive patients referred for a 2 day stress-rest gated myocardial perfusion SPECT imaging in the period from October 1998 until December 2001. The diagnosis of ischemic heart disease was based on a history of myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting or angiographic significant CAD (at least one vessel with ?75% stenosis). Follow-up was achieved in 273 patients (95%). Twelve patients were excluded because they had an early revascularization procedure within 3 months following the myocardial SPECT.8 Therefore 261 patients (231 males) formed the study population.

STRESS TESTING

Bicycle stress testing was used in patients able to perform maximal physical stress (n=130, 50%). Each subject underwent maximal exercise testing on a computer-driven bicycle ergometer (Ergoselect, Ergoline GmbH, Bitz, Germany) using a ramp protocol starting at 50 Watts with gradual increase of 25 or 10 Watts according to the general condition of the patient. A standard 12-lead ECG was continuously recorded and the heart rate was followed. Blood pressure was measured by means of a mercury sphygmomanometer at each stage and at the peak of exercise. Subjects were exercised to their self-determined maximal capacity or until the physician stopped the test becau.se of significant symptoms, such as chest pain or dizziness, potential dangerous arrhythmias or ST-segment deviations, or marked systolic hypotension or hypertension.

When a patient was not able to perform maximal bicycle stress (n=27, 10%), an additional intravenous infusion of dipyridamole was given (infusion over a 4 min period, 0.142 mg/kg/min).

In patients who were not able to perform bicycle stress at all (n=104, 40%), only dipyridamole was given (infusion over a 4 min period, 0.142 mg/kg/min).

Patients were informed not to consume caffeinecontaining products for 24 h before testing. At peak stress 900 MegaBecquerel (MBq) Technetium-99m tetrofosmin was injected.

Gated SPECT acquisition and reconstruction

Stress and rest studies were performed in a 2-day protocol as described previously.22 In both stress and rest studies, 900 MBq (25 mCi) of technetium-99m tetrofosmin was injected intravenously. Imaging was started between 30-60 min after injection in the resting state and 15-30 min after injection at peak stress. A gated SPECT acquisition was performed over 360[degrees] in step-and-shoot mode (120 sectors of 3[degrees], 30 s/step, matrix size 64 x 64) using a triple-headed camera (Picker Prism 3000, Marconi, Philips, Cleveland, OH, USA) equipped with low energy all-purpose collimators. Acquisitions were gated for 8 frames per cardiac cycle. There was a 20% acceptance window around the 140 keV photon peak. Attenuation correction, background subtraction and beat rejection were not performed. The raw gated SPECT data were ungated and reconstructed using filtered back projection (ramp filter) and postfiltered using a low pass filter (order 5, cut-off frequency 0.21). The left ventricle was reoriented manually to obtain short axis gated and ungated images. The gated images were processed using Quantified Gated SPECT software (QGS*, CedarsSinai, Los Angeles, CA, USA) to obtain resting and poststress LVEF and LV volumes.

Scoring of the perfusion images

The ungated short axis images were used for semiquantitative detennination of myocardial defect extent on stress and rest myocardial perfusion images using 4D-MSPECT(R) software (University of Michigan, Ann Arbor, MI, USA) by comparison with a gender specific normal perfusion database generated at our institution. These stress and rest normal database files were made out of patients with a low cardiac risk (

Clinical data and follow-up

Demographic data at study entrance were collected by reviewing hospital records. Hypertension was defined as a blood pressure 140/ 90 mmHg or treatment with antihypertensive medication. Diabetes mellitus was defined as a fasting blood glucose level >140 mg/dL or the need for insulin or oral antidiabetic agents. Follow-up data were collected in 2003. One author (ODW) contacted patients’ general practitioners and reviewed hospital records. The author was blinded to scanning results at the time of follow-up. A standard questionnaire was used for follow-up interviews. The following cardiac events were taken into account: nonfatal acute myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting, and the need for hospitalization because of heart failure, death and cause of death. Cardiac death was defined as death caused by acute myocardial infarction, refractory congestive heart failure, clinically important cardiac arrhythmias and sudden death without another explanation. The need for cardiac transplantation (n=2) was also considered as cardiac death. Myocardial infarction was defined according to the Joint European Society of Cardiology/American College of Cardiology Committee criteria.24 Patients who died from non-cardiac causes were censored on the day of their death. The time of the last patient contact was used to determine the end of the follow-up period in patients without events. Follow-up was limited to 36 months. Three combined cardiac end points were defined in advance and used for further analysis:

1) major adverse cardiac events (MACE): cardiac death, non-fatal myocardial infarction, percutaneous coronary intervention or coronary artery bypass grafting;

2) MACE-HF: MACE or the need for hospitalization due to heart failure-,

3) cardiac death or non-fatal myocardial infarction.

If a patient died from a cardiac cause, only cardiac death was considered. If there were 2 or more nonfatal events in one patient, only the event that came first in time was considered.

The study was approved by the local Ethics Committee of the Ghent University Hospital.

Statistical analysis

Statistical analyses were performed using SPSS 11.0.1 statistical software (SPSS Inc., Chicago, IL, USA). Data are shown as median (25th-75th percentile) or number (%). Non-parametric Mann- Whitney U testing or chi^sup 2^ testing was used to assess differences in clinical and SPECT variables between patients with and without events. Kruskal-Wallis testing was used to investigate trends in event rates between groups. Cumulative event free survival rates as a function over time were obtained by the Kaplan-Meier method. Differences in survival were analysed by log-rank testing. Clinical parameters significant by univariate analysis were forced into a stepwise multivariate Cox proportional hazards regression model to identify SPECT variables (functional parameters at rest and poststress, stress and rest defect extent and presence of reversibility) predicting cardiac events independently and incrementally above clinical parameters. Significance was set at

Results

Clinical characteristics of patients with and without events

Patients’ characteristics are summarized in Table I. Median age was 67 years. Of the 261 patients 231 (89%) were male. At the time of myocardial SPECT imaging 174 patients (67%) had a history of myocardial infarction, 45 patients (17%) a history of percutaneous coronary intervention and 58 patients (22%) previously underwent coronary artery bypass grafting. At the start of the follow-up period, 133 patients (51%) were taking ss-blockers and 188 (72%) angiotensinconverting enzyme inhibitors or angiotensin-II receptor blockers as medical treatment (Table I).

TABLE I. – Clinical characteristics of all patients and comparison between patients with and without MACE.

Gated SPECT variables inpatients with and without events

During a median follow-up of 31 months (interquartile range 21- 36 months), 52 patients (20%) died of which 35 deaths (13% of the total population) were considered cardiac. This means that 67% of the death causes in this population were cardiac. There were 50 patients (19%) who developed a MACE and 69 (26%) a MACE-HF. In the whole population, the annual event rate was 8.4% for MACE and 12.1% for MACEHF. Patients who developed a MACE during follow-up were more likely to be diabetic and to have angina complaints (Table I). When considering MACE-HF, the presence of diabetes mellitus was the only significant clinical variable in the univariate analysis (P

TABLE II. – Gated SPECT variables of all patients and comparison between patients with and without major cardiac events. Data are presented as median (25th- 73th percentile) or number (%).

TABLE III. – Annual cardiac event rate according to the presence of ischemia on myocardial perfusion imaging.

Multivariate predictors of cardiac events

With diabetes and the angina status as the major clinical variables included into the stepwise multivariate Cox regression model for MACE, adding of poststress LVEF provided a chi^sup 2^ gain of 6.4 (P=0.008). When the ischemia detection was added to this model, there was an additional chi^sup 2^ gain of 5.8 (P=0.018) (Figure 5).

In the clinical model of MACE-HF, only diabetes was significant and was forced in the multivariate analysis. Adding of poststress LVEF provided a ?2 gain of 5.5 (P=0.0 19) and ischemia detection on perfusion imaging an additive chi^sup 2^ gain of 4.3 (P=0.044) in this model (Figure 5).

Uni- and multivariate predictors of cardiac death or non-fatal myocardial infarction

Univariate predictors of cardiac death or non-fatal myocardial infarction were diabetes mellitus (P

Discussion

The results of this study indicate that the combined assessment of function and perfusion using technetium-99m tetrofosmin gated SPECT provides significant and independent predictive information regarding the subsequent risk of major cardiac events in patients with CAD and systolic LV dysfunction.

Figure 1. – Kaplan-Meier curves for MACE free survival according to the presence or absence of ischemia detected by myocardial perfusion imaging. MACE: major adverse cardiac event.

Figure 2. – Kaplan-Meier curves for MACE-HF free survival according to the presence or absence of ischemia. MACE-HF: major adverse cardiac event or hospitalization for heart failure.

Prognostic value of myocardial perfusion assessment

Multiple studies investigated the prognostic value of myocardial perfusion imaging in subjects with known or suspected CAD for predicting cardiac events and mortality.7, 9, 25-29 However, these prognostic data were all collected in patient populations with known or suspected CAD and only few data are available regarding the prognostic value of myocardial perfusion imaging in patients with impaired LV function and known CAD. The risk for subsequent cardiac events is much higher in this population than in the generally investigated populations.30 Therefore, results and risk factors found in other populations may not be extrapolated.31

Figure 3. – Kaplan-Meier curves for MACE free survival according to the poststress LVEF (in tertiles). LVEF: left ventricular ejection fraction; MACE: major adverse cardiac event.

Data on the prognostic value of myocardial perfusion imaging in patients with CAD and LV dysfunction are scarce. In concordance with our data, Miller et al. found a higher revascularization rate, but no difference in survival between patients with large ischemic defects versus patients with large fixed defects in 214 patients with a LVEF

Prognostic value of LV functional parameters

One of the most powerful prognostic parameters in patients with CAD is the LVEF. Multiple studies have demonstrated the important prognostic value of this parameter assessed using planar radionuclide angiography l921 or using other imaging modalities 16- 18 in patients with known or suspected CAD. Our data demonstrated that even in this population in which all patients had a depressed LVEF and the spreading of LVEF values was narrow, poststress LVEF was highly predictive for future cardiac events.

Figure 4. – Kaplan-Meier curves for MACE-HF free survival according to the poststress LVEF (in tertiles). LVEF: left ventricular ejection fraction; MACE-HF: major adverse cardiac event or hospitalization for heart failure.

Figure 5. – Chi-squares obtained by stepwise multivariate Cox regression analysis for MACE and MACE-HF. MACE: major cardiac event; MACE-HF: major cardiac event or the need for hospitalization due to heart failure; LVEF: left ventricular ejection fraction.

Importance of combined perfusion and function assessment in patients with CAD and poor LV function using gated SPECT

The addition of LV ventricular functional data to myocardial perfusion imaging has shown benefit in diagnostic settings by increasing specificity and decreasing the number of borderline interpretations.13- 33, 34 Another potential diagnostic use is in identifying patients with multivessel disease who might be otherwise missed by myocardial perfusion imaging.35

There are however limited data on the prognostic value of LVEF as assessed by gated SPECT in patients with impaired LV function. As part of a larger study, Sharir et al.36 investigated a subgroup of 277 patients with suspected CAD and a LVEF /=70 mL. In our study group, there was a trend towards a higher resting (P=0.084) and poststress (P=0.010) LV end systolic volume in patients with a subsequent hard event (cardiac death or non-fatal myocardial infarction). However, once the poststress LVEF was added to the model, there was no further predictive value for LV volumes. Since myocardial perfusion imaging is used in daily clinical practice for diagnosis and follow-up of patients with CAD and LV dysfunction and ECG gating during the acquisition of myocardial SPECT can be easily performed in daily practice, gated SPECT could be an ideal tool for risk stratification in this patient population.

Limitations of the study

Because only 130 (50%) of the 261 patients were able to perform maximal bicycle exercise stress, a possible incremental prognostic value of nuclear imaging variables above parameters obtained during bicycle stress (stress electrocardiography changes, maximum workload or blood pressure change) could not be assessed.

Conclusions

This study showed the significant incremental power of nuclear imaging data over clinical data in predicting cardiac events in patients with a depressed systolic LV function due to CAD. A lower poststress LVEF is an independent predictor of future cardiac events in patients with CAD and impaired systolic LV function.

This work was made possible by a Special Research Grant of the Ghent University and the Flemish Government (BOZF 01100400). J. De Sutter is a senior clinical investigator and N. Van de Veire is a research fellow of the Fund for Scientific Research – Flanders (Belgium) (FWO – Vlaanderen).

Received on June 14, 2005.

Accepted for publication on 9 February, 2006.

Epub ahead of print on January 15, 2007.

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O. DE WINTER1, N. VAN DE VEIRE2, P. DE BONDT1, C. VAN DE WIELE L M. DE BUYZERE2, G. DE BACKER3 T. C. GILLEBERT2, R. A. DIERCKX1, J. DE SUTTER2

1Nuclear Medicine Division

Ghent University Hospital Ghent, Belgium

2Department of Cardiovascular Diseases

Ghent University Hospital. Ghent, Belgium

3Cardiac Rehabilitation Center

Ghent University Hospital. Ghent. Belgium

Address reprint requests to: O. De Winter, MD. Nuclear Medicine Division, Ghent University Hospital. De Fintelaan 185, 9000 Ghent. Belgium. E-mail: olivier.dewinter@UGent.be

Copyright Edizioni Minerva Medica Sep 2008

(c) 2008 Quarterly Journal of Nuclear Medicine, The. Provided by ProQuest LLC. All rights Reserved.




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