Risk Stratification

Abstract

The present invention relates to a method of in vivo imaging with meta-[.sup.123I]iodobenzylguanidine ([.sup.123I]mIBG) and more particularly wherein said method is used to stratify a defined subset of subjects with heart failure into particular treatment regimens.

Claims

1. A method comprising: (i) obtaining an in vivo image with meta-[.sup.123I]iodobenzylguanidine ([.sup.123I]mIBG) of a human subject wherein said subject has a left ventricular ejection fraction (LVEF) of >35% and New York Heart Association (NYHA) symptoms of class II or above; (ii) measuring [.sup.123I]mIBG uptake in said subject wherein said measuring comprises defining in said in vivo image a heart region of interest (ROI) and a mediastinum ROI; (iii) calculating the ratio of [.sup.123I]mIBG uptake between said heart ROI and said mediastinum ROI (H/M ratio); (iv) making a clinical decision based on whether or not H/M is less than 1.6 wherein said clinical decision is to implant a cardioverter-defibrillator (ICD) where said H/M ratio is less than 1.6.

2. The method as defined in claim 1 wherein step (i) comprises intravenous injection of a radiopharmaceutical composition comprising [.sup.123I]mIBG.

3. The method as defined in claim 1 wherein step (i) comprises planar scintigraphy.

4. The method as defined in claim 1 wherein step (i) comprises obtaining early and late anterior planar scintigraphic images.

5. The method as defined in claim 4 wherein said early anterior planar scintigraphic image is obtained at 15 minutes following injection of said radiopharmaceutical composition comprising [.sup.123I]mIBG.

6. The method as defined in claim 4 wherein said late planar scintigraphic image is obtained at 3 hours and 50 minutes following injection of said radiopharmaceutical composition comprising [.sup.123I]mIBG.

7. The method as defined in claim 1 wherein said heart can be visualised in said in vivo image and said heart ROI is defined by the epicardial border of the heart.

8. The method as defined in claim 1 wherein said heart cannot be visualised in said in vivo image and said heart ROI is defined by the presumed location of the heart.

9. The method of claim 1 wherein said mediastinum ROI is defined within the superior mediastinum.

10. The method as defined in claim 1 wherein a mean count density is obtained for each of said heart ROI and said mediastinum ROI.

11. The method as defined in claim 1 wherein said human subjects have NYHA symptoms of class III or above.

12. The method as defined in claim 1 wherein said clinical decision is selection of subjects for a clinical trial.

13. Use of [.sup.123I]mIBG in a method for guiding ICD therapy in a group of patients having LVEF of >35% and NYHA symptoms of class II or above wherein said method is as defined in claim 1.

14. The use as defined in claim 14 wherein said patients have NYHA symptoms of class III or above.

15. A composition comprising [.sup.123I]mIBG for use in the method as defined in claim 1.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0021] FIG. 1 is a Kaplan Meier curve for all-cause mortality at 5 years follow up comparing patients with AdreView H/M ratio <1.6 and 1.6 in the LVEF strata of >35%.

[0022] FIG. 2 is a Kaplan Meier curve for cardiac mortality at 5 years follow up comparing patients with AdreView H/M ratio <1.6 and 1.6 in the LVEF strata of >35%.

[0023] FIG. 3 is a Kaplan Meier curve for time to first arrhythmic event based on the on-site LVEF categorization (>35-58%) and AdreView uptake H/M ratio (<1.60 vs. >=1.60).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] To more clearly and concisely describe and point out the subject matter of the claimed invention, definitions and particular embodiments are provided hereinbelow for the terms used throughout the present specification and claims. Any exemplification of specific terms herein should be considered as a non-limiting example.

[0025] Meta-iodobenzylguanidine (mIBG) is a synthetic guanethidine analogue similar to norepinephrine (NE). The .sup.123I-labelled version ([.sup.123I]mIBG) has the following structure:

##STR00001##

[0026] Imaging with [.sup.123I]mIBG is an established test to evaluate innervation of the cardiac sympathetic nervous system. As a structural and functional analogue of NE, [.sup.123I]mIBG is subject to the same uptake and accumulation pathways. [.sup.123I]mIBG is primarily taken up from the extracellular environment into the pre-synaptic sympathetic nerve terminals by the NE transporter (NET). Similar to NE, [.sup.123I]mIBG is subsequently stored in pre-synaptic vesicles, but in contrast to NE it does not undergo metabolism. This accumulation of [.sup.123I]mIBG enables the in vivo imaging of sympathetic innervation of adrenergic nerves such as those of the heart. [.sup.123I]mIBG is commercially-available from GE Healthcare as the radiopharmaceutical formulation AdreView.

[0027] Left ventricular ejection fraction (LVEF) is the fraction of blood pumped out of the left heart with each heartbeat. A normal value for LVEF is over 50% but in patients with heart failure, the LVEF is typically below 40% and in many cases below 30%.

[0028] New York Heart Association (NYHA) class is a well-established measure of the extent of heart failure in patients. Classes I-IV can be understood as follows:

TABLE-US-00001 NYHA Class Symptoms I Cardiac disease, but no symptoms and no limitation in ordinary physical activity, e.g. no shortness of breath when walking, climbing stairs etc. II Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary activity. III Marked limitation in activity due to symptoms, even during less- than-ordinary activity, e.g. walking short distances (20-100 m). Comfortable only at rest. IV Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients.

[0029] In one embodiment, said NYHA class is present while the subject is receiving guideline-directed medical therapy (GDMT). In one embodiment said NYHA class is III or above. In one embodiment said NYHA class is IV.

[0030] The term [.sup.123I]mIBG uptake refers to the amount of [.sup.123I]mIBG retained in tissues of the subject at a defined time following its administration to said subject. [.sup.123I]mIBG uptake can be understood to be the actual uptake in said subject as well as uptake as illustrated in the in vivo image obtained in step (i) of the method of the invention.

[0031] The term defining with respect to defining a region of interest (ROI) refers to the process comprising drawing an area on the in vivo image corresponding to that ROI. In one embodiment the in vivo image is a digital image represented on a computer screen and drawing is achieved by means of a suitable software package.

[0032] The step of making a clinical decision based on whether or not H/M is less than 1.6 can encompass a range of clinical decisions, e.g. in clinical trials for stratification of subjects or in clinical treatment of patients. In one embodiment, said clinical decision is selection of subjects for a clinical trial. The statistics in clinical trials are dependent on the patient cohort in the treated and untreated arms having cardiac events (e.g. potentially fatal arrest) and by using the method of the present invention high risk patients can be identified and placed into the trial, which increases the event rate and reduces the number of subjects required to demonstrate efficacy in the trial. In one embodiment, said is clinical decision is to implant a cardioverter-defibrillator (ICD) where said H/M ratio is less than 1.6. The term implantable cardioverter-defibrillator (ICD) refers to a medical device used in the treatment of heart failure that comprises a generator placed under the skin of the left upper chest and wires connected to the generator that are passed through a vein to the right chambers of the heart. The device is configured to perform cardioversion, defibrillation and pacing of the heart. ICDs can also have an anti-tachycardia pacing function which refers to the use of pacing stimulation techniques for termination of tachyarrhythmias like ventricular tachycardia (VT). It is a painless way to terminate VT rather than using an electric shock. Sub-cutaneous ICDs (5-ICDs) are also now available, i.e. for which leads and wires are not inserted into the veins but rather are sub-cutaneous. These are easier to implant and less subject to complications. However by design these cannot have the antipacing function as leads/wires are sub-cutaneous.

[0033] In one embodiment of the method of the invention step (i) comprises intravenous injection of a radiopharmaceutical composition comprising [.sup.123I]mIBG. The term intravenous injection refers to administration of a substance directly into the vein of a subject, typically using a hypodermic needle.

[0034] A radiopharmaceutical composition comprising [.sup.123I]mIBG is a composition comprising [.sup.123I]mIBG in a form suitable for human administration. In one embodiment said radiopharmaceutical composition comprises a biocompatible carrier. By the term biocompatible carrier is meant a fluid, especially a liquid, such that the composition is physiologically tolerable, i.e. can be administered to the mammalian body without toxicity or undue discomfort. The biocompatible carrier is suitably an injectable carrier liquid such as sterile, pyrogen-free water for injection; an aqueous solution such as saline (which may advantageously be balanced so that the final product for injection is isotonic); an aqueous buffer solution comprising a biocompatible buffering agent (e.g. phosphate buffer); an aqueous solution of one or more tonicity-adjusting substances (e.g. salts of plasma cations with biocompatible counterions), sugars (e.g. glucose or sucrose), sugar alcohols (e.g. sorbitol or mannitol), glycols (e.g. glycerol), or other non-ionic polyol materials (e.g. polyethyleneglycols, propylene glycols and the like). Preferably the biocompatible carrier is pyrogen-free water for injection, isotonic saline or phosphate buffer. Hence the aqueous suspension suitably excludes water-immiscible organic solvents.

[0035] In one embodiment of the method of the present invention step (i) comprises planar scintigraphy. The term planar scintigraphy images the distribution of an injected gamma-emitting isotope bound to a biologically active molecule (e.g. [.sup.123I]mIBG) in a single two-dimensional image, analogous to a planar X-ray scan. The term anterior planar scintigraphic image will be well understood by those of skill in the art of in vivo imaging as an image taken from the front of the subject.

[0036] In one embodiment of the method of the present invention step (i) comprises obtaining early and late anterior planar scintigraphic images. The terms early and late in the context of anterior planar scintigraphic images of the present invention refer to those images taken following administration of [.sup.123I]mIBG respectively before and after wash-out of [.sup.123I]mIBG. The term wash-out refers to the elimination from organs and tissues of the subject of [.sup.123I]mIBG that has not specifically been taken up by sympathetic neurons. In one embodiment said early anterior planar scintigraphic image is obtained at 15 minutes following injection of said radiopharmaceutical composition comprising [.sup.123I]mIBG. In one embodiment said late planar scintigraphic image is obtained at 4 hours following injection of said radiopharmaceutical composition comprising [.sup.123I]mIBG.

[0037] In one embodiment of the method of the invention wherein said heart can be visualised in said in vivo image, said heart ROI is defined by the epicardial border of the heart. The epicardial border of the heart refers to the innermost layer of the pericardium, in direct contact with the heart and thereby defining the outer border of the heart.

[0038] In one embodiment of the method of the invention wherein said heart cannot be visualised in said in vivo image, said heart ROI is defined by the presumed location of the heart. A person of skill in the art of cardiac in vivo imaging will be able to find in a straightforward manner the presumed location of the heart in those cases where the heart cannot be visualised in said in vivo image.

[0039] The mediastinum is the central compartment of the thoracic cavity surrounded by loose connective tissue. In one embodiment said mediastinum ROI is defined within the superior mediastinum. The superior mediastinum refers to that area of the mediastinum below the lung apices. In one embodiment, the mediastinum ROI is a defined section of the in vivo image within said superior mediastinum equidistant from the medial aspects of the right and left lung.

[0040] Defined methods of calculating the H/M ratio are known in the art. For example, the prescribing information for AdreView sets out in detail the steps that should be carried out using an in vivo image obtained by planar scintigraphy using AdreView (GE Healthcare AdreView |obenguane|123 Injection prescribing information March 2013).

[0041] In one embodiment of the method of the invention a mean count density is obtained for each of said heart ROI and said mediastinum ROI. The term mean count density refers to the mean counts per pixel of a particular ROI.

[0042] In one embodiment of the method of the invention said [.sup.123I]mIBG imaging comprises single-photon emission tomography (SPECT) imaging. SPECT imaging can be defined as a method of imagine that produces a series of contiguous two-dimensional images of the distribution of the radiotracer using the same agents as planar scintigraphy as defined above.

[0043] In an extension of ADMIRE-HF study ( (Jacobson et al. 2010 J Am Col Cardiol; 55(20): 2212-2221)), Example 1 below describes patients that were followed-up for 5 years after the initial administration of Adreview. In the sub-group of patients having a LVEF >35% the 5-year all-cause mortality was 46.5% for the patients with an H/M ratio <1.6 and only 19.6% for the patients with an H/M ratio 1.6. Moreover, in the same sub-group, cardiac mortality was 16% for the patients with an H/M ratio <1.6 and only 3.3% for the patients with an H/M ratio 1.6. This later finding is important because it is on the reduction of cardiac mortality that ICDs can demonstrate their main benefit. The present invention therefore can identify within HF patients having a LVEF >35% those at higher risk for cardiac death and therefore requiring an ICD implantation. Current guidelines for the management of heart failure (HF) patients stipulate that an ICD must be implanted in NYHA class II HF patients where LVEF is less or equal than 35%. Therefore, the present invention is contrary to these established guidelines, and demonstrates utility in patients with LVEF above 35%, i.e. the present invention demonstrates that the [.sup.123I]mIBG H/M ratio serves to identify patients having LVEF above 35% who would benefit from having an ICD.

[0044] The definitions and embodiments as defined for the first aspect of the invention as defined herein are equally applicable to the second aspect of the invention.

Brief Description of the Examples

[0045] Example 1 describes a study to evaluate the ability of [.sup.123I]mIBG imaging to predict risk of cardiac death in subjects having LVEF >35%.

List of Abbreviations Used in the Examples

NYHA: New York Heart Association

[0046] LVEF: left ventricular ejection fraction

IRB: Institutional Review Board

IEC: Independent Ethics Committee

SSDI: Social Security Death Index

[0047] CRF: case report form
HF: heart failure
LVAD: left-ventricular assist device
ICD: implantable cardioverter defibrillator
H/M: heart to mediastinum ratio
ROI: region of interest

CI: Confidence Interval

EXAMPLES

Example 1: Evaluation of [.SUP.123.I]mIBG Imaging to Predict Risk of Cardiac Death in Subjects Having LVEF >35%

Study Design & Subjects

[0048] A Phase 4, open-label, multicenter trial was carried out to investigate the prognostic usefulness of AdreView imaging to identify those subjects with New York Heart Association (NYHA) Class II or III HF who would die during 60 months of follow-up from the date of administration of AdreView. HF subjects enrolled and dosed with AdreView in the ADMIRE-HF study (Jacobson et al. 2010 J Am Col Cardiol; 55(20): 2212-2221) were eligible to participate.

[0049] All subjects completed the informed consent form before collection of any study information. However, waiver of informed consent was requested from the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) for subjects who could not be located; for those who, in the course of attempts to contact them, were determined to have died; and for those who were determined to be alive but declined to provide informed consent. For deceased subjects and those who could not be located, the IRB/IEC was requested to allow the recording of survival status and information from medical institution records and publicly available sources (death certificates, media reports, Social Security Death Index [SSDI], etc.) on the case report form (CRF). For subjects who declined to provide informed consent, the IRB/IEC was requested to allow recording on the CRF that the subject was alive.

[0050] Subject status was determined at a single point in time, specifically the date on which the subject or another individual with knowledge of the subject's survival status was contacted. As per protocol, in-person visits were required only to verify details of a life-saving intervention.

Collection of Follow-Up Information

[0051] If the subject was determined to be deceased, information was sought from a designated medical care provider, as well as from publicly available sources such as the SSDI, depending upon the provisions of the approved informed consent form or the IRB/IEC waiver. For subjects confirmed to have died subsequent to last follow-up in the ADMIRE-HF study, the investigator endeavored to determine date and cause of death in order to categorize the death as cardiac (due to HF, sudden death, myocardial infarction, or other causes) or non-cardiac.

[0052] If the subject was alive at the date of last contact in the ADMIRE-HF study, the investigator indicated if either of the following categories of events occurred subsequent to the subject's latest follow-up:

Category 1: Change in Cardiac Physiology

[0053] Cardiac transplant [0054] Insertion of left-ventricular assist device (LVAD)

Category 2: Potentially Life-threatening Arrhythmic Event

[0055] Resuscitated cardiac arrest. [0056] Appropriate implantable cardioverter defibrillator (ICD) discharge (anti-tachycardia pacing or defibrillation).

[0057] The efficacy population included all subjects who received an administration of AdreView, were successfully scanned in the ADMIRE-HF study, were not withdrawn because of protocol violations, and met all entrance criteria for the present study.

[0058] The primary analysis tested the prognostic value of the numerical H/M ratio on planar AdreView imaging, dichotomized as either 1.60 or <1.60, for death in HF subjects during 60 months of follow-up. The relative hazard at time t was assessed for these subjects to assess the prognostic value of the numerical H/M ratio on planar AdreView imaging by a proportional hazards model as described below. A univariate Cox proportional hazards model was fitted to the time to death for each subject. The time to death was the response variable of interest and was measured in days. The Cox proportional hazards model was used to assess relative hazard for death at time t for the subjects in the 2 groups based on the H/M ratio (<1.60 and 1.60), denoted as low and high.

[0059] The efficacy analyses using planar scintigraphy used the derived consensus reader interpretation for the H/M ratio. This single interpretation was based upon the 3-hour, 50-minute H/M ratio accepted by at least 2 of the readers. If a different H/M ratio was accepted by each reader, then the mean value was used in the analyses. If 2 readers judged an image as non-diagnostic, the subject was considered non-diagnostic and was excluded from the analyses.

[0060] For each planar image, myocardial and mediastinum regions of interest (ROls) were drawn and the H/M ratio calculated as per the methodology provided by the sponsor and as described below: [0061] (1) Draw an irregular ROI defining the epicardial border of the heart. If the epicardial border cannot be defined because all or the majority of the myocardium is not visualized, draw the ROI based upon the presumed location of the heart, using the medial aspects of the left and right lower lung for anatomical guidance. [0062] (2) Draw a horizontal line to mark the estimated location of the lung apices. If the most superior aspect of the image does not include the lung apices (because of limited field of view for a small gamma camera), draw this line at the top of the image display. [0063] (3) Draw a vertical line approximately equidistant from the medial aspects of the right and left lung. [0064] (4) Examine the counts for the 12 pixels along the vertical line starting 4 pixels below the intersection point with the horizontal line determined in step 2, and identify the pixel with the lowest counts. If more than one pixel has this same number of counts, choose the most superiorly located pixel. [0065] (5) Using the pixel defined in step 4 as the center, draw a square ROI of 77 dimensions. [0066] (6) Calculate the H/M ratio by dividing the counts/pixel in the total myocardium ROI determined in step 1 by the counts/pixel in the 77 pixel mediastinal ROI determined in step 5.

Results

[0067] Confidence Interval (CI) was calculated using the exact Clopper-Pearson method for binomial proportion.

TABLE-US-00002 TABLE 1 Summary of All-Cause Mortality Based on Core Lab Left Ventricular Ejection Fraction Categorization and the AdreView Uptake H/M Ratio at 3 Hours 50 Minutes Post Dose on Planar Scintigraphy. H/M (<1.60) H/M (>=1.60) Number of Subjects 213 92 Number of Deaths 99 18 Mortality Rate 46.5% 19.6% Mortality Rate 95% CI 39.6, 53.4 12.0, 29.1

TABLE-US-00003 TABLE 2 Summary of Cardiac Mortality Based on Core Lab Left Ventricular Ejection Fraction Categorization and the AdreView Uptake H/M Ratio at 3 Hours 50 Minutes Post Dose on Planar Scintigraphy. H/M H/M (<1.60) (>=1.60) Number of Subjects 213 92 Number of Cardiac Deaths 34 3 Cardiac Mortality Rate 16% 3.3% Cardiac Mortality Rate 95% CI 11.3, 21.6 0.7, 9.2

[0068] Additionally, Kaplan Meier curves for all cause and cardiac mortality at 5 years follow up showed significant differences between patients with H/M ratio <1.6 and those with ratios 1.6 in the LVEF strata of >35% by core lab readings. This is illustrated in FIGS. 1 (all-cause mortality), 2 (cardiac death), and 3 (first arrhythmic event).