WO2008000067A1

WO2008000067A1 - Treatment of mild chronic heart failure in human patients

Info

Publication number: WO2008000067A1
Application number: PCT/CA2007/001086
Authority: WO
Inventors: David Elsley; Eldon R. Smith; Jay H. Kleiman; Anthony E. Bolton; Arkady Mandel
Original assignee: Vasogen Ireland Limited
Priority date: 2006-06-26
Filing date: 2007-06-18
Publication date: 2008-01-03
Also published as: AR061635A1

Abstract

ABSTRACT This invention provides a method for prophylaxis or treatment of patients suffering from mild chronic heart failure characterized by one or more of New York Heart Association CHF Class II, serum CRP levels not greater than 3.0 mg/mL, left ventricular ejection fraction not less than 23% and no previous myocardial infarction, which comprises administering to such a patient an aliquot of the patient's blood extracted from the patient and treated ex vivo with at least one stressor selected from the group consisting of an oxidizing agent, an electromagnetic emission and elevated temperature.

Description

TREATMENT OF MILD CHRONIC HEART FAILURE IN HUMAN PATIENTS

FIELD OF THE INVENTION This invention relates to medical treatments, compositions for use in medical treatments, diagnosis of medical conditions and assessment of suitability of patients to receive selected medical treatments and compositions. More specifically, it relates to medical treatments of a selected population of patients who have a risk or manifestation of cardiovascular disease which is different from that of the general population, and treatment of at least some of the selected population to decrease their risk of developing cardiovascular disease, or, in cases where cardiovascular disease has developed, to arrest or retard its progression.

BACKGROUND OF THE INVENTION

The New York Heart Association (NYHA) classification of heart failure is a well known and well accepted assessment used by physicians to assess the stage of heart failure in a patient, and to determine the best course of therapy. This classification system relates symptoms to everyday activities and the patient's quality of life. Class I denotes mild heart failure, with no limitation of physical activity, and in which ordinary physical activity does not cause undue fatigue, palpitation or shortness of breath. Class II, also mild, denotes patients with slight limitation of physical activity, who are comfortable at rest, but ordinary physical activity causes fatigue, palpitation or shortness of breath (dyspnea). Class III is moderate heart failure, where the patient has marked limitation of physical activity, is comfortable at rest, but less than ordinary activity causes fatigue, palpitation or dyspnea. Class IV is severe heart failure, where the patient in unable to carry out any physical activity without discomfort. The Class IV patient has symptoms of cardiac insufficiency at rest, and discomfort is increased by any undertaking of physical activity.

A known risk factor for cardiovascular disease is elevated levels of C- reactive protein, CRP, in serum. C-reactive protein is produced by the liver in response to inflammation, and is an acute phase protein produced in response to major trauma etc. Increased blood levels of C- reactive protein are present in many infections and inflammatory diseases, and measurements of CRP in blood have been used for many years to assist the diagnosis of such conditions. A highly sensitivity assay for serum CRP has recently become widely available, and, using this more sensitive assay system, it has been shown that mildly elevated serum levels of CRP correlate with increased risk of developing a number of severe pathological events, including heart attacks, stroke and other cardiovascular events. CRP levels in blood are routinely measured using a high sensitivity assay when assessing a patient's cardiovascular condition.

Tests of CRP levels in serum are used to classify patients as at low risk, average risk or high risk of developing cardiovascular disease or cardiovascular events in the future. A serum CRP level from 1 .0 - 3.0 mg/L indicates a patient at medium risk; a serum CRP level higher than 3.0 mg/L CRP indicates a patient at high risk of developing future cardiovascular disease or cardiovascular events. Patients with serum CRP levels less than 1.0 mg/L are considered to be of low risk of cardiovascular events (Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107:499-51 1 ).

It has been hypothesized that very low serum levels of CRP indicate a low risk of developing acute vascular events. Chronic inflammation on the other hand leads to excess risk of acute vascular events, see Ridker, Paul M.; Wilson, Peter W. F.; and Grundy, Scott M., "Circulation" June 15, 2004, p. 2818-2825. Elevated serum CRP levels are considered to be the strongest and most significant predictor of the risk of future cardiovascular events yet identified (Ridker PM et al, N Engl J Med 2000/342:836-43

United States Patent 6,572,895 Torre-Amione et. al. discloses a process of treating congestive (chronic) heart failure in human patients, which comprises taking an aliquot of the patient's blood, treating it extracorporeal Iy with an oxidative stressor such as ozone, and electromagnetic radiation such as UV, under carefully controlled conditions, and re-administering the treated aliquot to the patient intramuscularly.

SUMMARY OF THE INVENTION

The present invention is based upon the discovery that blood treated with at least one stressor such as ozone, upon administration to a mammalian patient, is surprisingly effective in treating patients suffering from early stage chronic heart failure, and who evidence on diagnosis New York Heart Association (NYHA) Class Il stage of heart failure, optionally in combination with at least one of the following characteristics: No prior myocardial infarction (Ml); Serum CRP levels less than about 3.0 mg/mL; and a left ventricular ejection fraction (LVEF) greater than 23%.

Thus according to a first aspect, this invention provides a method of retarding progression of chronic heart failure in a patient suffering therefrom and diagnosed to have a stage of chronic heart failure corresponding to New York Heart Association (NYHA) Class II, which comprises administering to a so-diagnosed patient an aliquot of the patient's own blood which has been treated ex vivo with at least one stressor which is an oxidizing agent, an electromagnetic emission or elevated temperature.

According to a second aspect, the invention provides a composition for retarding progression of chronic heart failure in a patient suffering therefrom and diagnosed to have a stage of chronic heart failure corresponding to New York Heart Association (NYHA) Class Il stage of heart failure, comprising an aliquot of the patient's own blood which has been treated ex vivo with at least one stressor which is an oxidizing agent, an electromagnetic emission or elevated temperature.

Another aspect of the invention provides a process of determining the appropriateness of treatment of mammalian patients to alleviate or delay the progression of chronic heart failure exhibited by the patients, and subsequently conducting the treatment on a so-determined group of such patients, which comprises conducting on patients suffering from chronic heart failure a determination of their NHYA Class of chronic heart failure and selecting from those patients a group exhibiting in NYHA Class II, and treating at least one member of said selected group with a composition as defined above (hereinafter "treated autologous blood").

According to another aspect of the invention, there is provided the use in preparation of a medicament for treatment of chronic heart failure in mammalian patients diagnosed to have at least one of (a) NYHA Class Il stage of CHF, (b) no prior myocardial infarction, (c) serum CRP not greater than about 3.0 mg/mL, or (d) left ventricular ejection fraction greater than 23%, of treated autologous blood.

According to another aspect of the invention, there is provided the use in preparation of a medicament for treatment of chronic heart failure in mammalian patients diagnosed to have at least one of (a) NYHA Class Il stage of CHF, (b) non-ischemic cardiomyopathy, (c) serum CRP not greater than about 3.0 mg/mL, or (d) left ventricular ejection fraction greater than 23%, of treated autologous blood. In a further aspect, the mammalian patients diagnosed as having non-ischemic cardiomyopathy are further diagnosed as having no prior myocardial infarction.

Cardiomyopathy is a disease of the heart muscle that decreases the heart's ability to pump blood and is a major cause of CHF. Nonischemic cardiomyopathy is not related to coronary artery disease (i.e. poor coronary artery blood supply). A preferred embodiment of the present invention is directed to CHF suffering patients who have nonischemic cardiomyopathy. In another preferred embodiment is the treatment of patients with CHF who have non-ischemic cardiomyopathy and have no prior Ml. The condition to which the process, uses and compositions according to the invention are directed may be classified as "mild chronic heart failure", defined as being characterized by one, or a combination of two or more of, (a) NYHA Class Il stage of CHF, (b) non-ischemic cardiomyopathy, (c) serum CRP not greater than about 3.0 mg/mL, (d) left ventricular ejection fraction greater than 23%, and (d) no previous history of myocardial infarction, in the patient.

The preparation of the treated autologous blood for use in the present invention preferably comprises extracting from the subject an aliquot of blood of volume about 0.01 mL to about 400 ml_, and contacting the aliquot of blood, extracorporeal^, with an immune system-stimulating effective amount of ozone gas and an electromagnetic transmission.

Following administration to the mammalian patient, the treated blood is believed to interact rapidly with the immune system which results in effects on inflammatory and anti-inflammatory cytokines.

DESCRIPTION OF PREFERRED EMBODIMENTS

According to the present invention, blood from patients selected as described above, is treated extracorporeal^, with at least one stressor such as an electromagnetic emission or ozone (including combinations of stressors). Preferably the patients have the NYHA Class Il diagnosis, in combination with one or more of the other recited diagnoses. The treated blood is then re-injected to the patient.

The left ventricle of the heart is the lower chamber which is responsible for pumping oxygen-rich blood into the arteries of the body. The ejection of blood from the left ventricle is a common, well-accepted measure of heart function. The fraction of the blood present in the left ventricle that is pumped out on each systole phase of the heartbeat cycle is the left ventricular ejection fraction, LVEF. It can vary over time, even minute by minute. A normal LVEF of a healthy human heart is from about 55 - 75%. A preferred embodiment of the present invention is directed to CHF suffering patients but with LVEF of greater than 23%. A more preferred embodiment is directed to patients having both NYHA Class Il CHF and LVEF greater than 23%.

In humans, a serum CRP level of at least 1.0 mg/L indicates that the patient is at risk of developing an adverse future cardiovascular disease or event. In some instances, serum levels of CRP as low as 0.7 mg/L can be construed as elevated particularly if there is familial history (MDS, Inside Diagnostics, April 2003; Rifai, N., and Ridker, P.M., Proposed Cardiovascular Risk Assessment Algorithm using High Sensitivity C-Reactive Protein and Lipid Screening, CHn. Chem., 2001 ; 47: 28-30. Serum tests for CRP are well known and routine. A preferred embodiment of the present invention is the use of the above procedure, namely the re-injection of extra-corporeally stressed autologous blood, to patients having CHF NYHA Class Il and serum CRP less than 3.0 mg/mL, preferably between 0.7 and 3.0 mg/mL.

Myocardial infarction (Ml), as is well known, is the loss of living heart muscle as a result of coronary artery occlusion. A survivor of an Ml evidences loss of heart muscle function and is readily diagnosed as such. The present invention is directed to treatment, in a preferred embodiment, of those patients with NYHA Class Il CHF who have not suffered an Ml. In the practice of the invention, an anti-coagulated blood aliquot from the appropriately diagnosed patient is prepared by exposing the aliquot to at least one stressor, in controlled amounts, the stressor being selected from among oxidizing agents such as ozone, ultraviolet radiation and elevated temperature. Combinations of two or all three of such stressors are also preferred. The resulting blood aliquot, after such treatment, can be re-injected into the patient.

Preferably, the stressors to which the cells in the extracted blood aliquot are subjected are a temperature stress (blood temperature above body temperature), an oxidative environment such as a mixture of ozone and oxygen bubbled through the blood aliquot, and an electromagnetic emission, individually, in any combination, simultaneously or successively, but preferably simultaneously. In general, from about 0.01 ml_ to about 400 ml_ of blood may be treated according to the invention. Preferred amounts are in the range of about 0.1 to about 200 ml_. More suitably, the aliquot for treatment has a volume of from about 0.1 to about 100 ml_s, preferably 1 to about 50 imL and most preferably 5 to 15 ml_. The method most preferably involves treating an aliquot of about 10 mLs blood with ozone gas and an electromagnetic emission, then re-administering the treated blood to the patient by intramuscular injection.

It is preferred, according to the invention, to apply a temperature stress (blood temperature above or below body temperature), in addition to the electromagnetic emission stress and the oxidative stress. Preferably, all three of the aforementioned stressors are applied simultaneously to the aliquot under treatment, in order to ensure the appropriate modification to the blood. Care must be taken to utilize an appropriate level of the stressors to thereby effectively modify the blood to alleviate the CHF condition in the subject.

The temperature stressor warms the aliquot being treated to a temperature above normal body temperature or cools the aliquot below normal body temperature. The temperature is selected so that the temperature stressor does not cause excessive hemolysis in the blood contained in the aliquot and so that, when the treated aliquot is injected into a subject, reduction of the serum CRP levels will be achieved. Preferably, the temperature stressor is applied so that the temperature of all or a part of the aliquot is up to about 55⁰C, and more preferably in the range of from about -5°C to about 55⁰C.

In some preferred embodiments of the invention, the temperature of the aliquot is raised above normal body temperature, such that the mean temperature of the aliquot does not exceed a temperature of about 55°C, more preferably from about 4O⁰C to about 50⁰C, even more preferably from about 40°C to about 44⁰C, and most preferably about 42.5±1⁰C.

In other preferred embodiments, the aliquot is cooled below normal body temperature such that the mean temperature of the aliquot is within the range of from about -5°C to about 36.5°C, even more preferably from about 10°C to about 30°C, and even more preferably from about 15⁰C to about 25°C.

Alternatively, the blood sample is heated while being subjected to an electromagnetic emission until the blood reaches a predetermined temperature (preferably about 42.5+1 ° Celsius) at which point bubbling of ozone gas through the blood is commenced. The concurrent electromagnetic emission/ozone treatment is then maintained for a predetermined period of time, preferably about 3 minutes.

Another alternative method involves subjecting the blood to electromagnetic emission/ozone while heating to a predetermined temperature (preferably about 42.5+1 ° Celsius), then either ending the treatment once the predetermined temperature is reached, or continuing electromagnetic emission/ozone treatment for a further period of time, most preferably about 3 minutes.

The oxidative environment stressor can be the application to the aliquot of solid, liquid or gaseous oxidizing agents. Chemical oxidants such as hydrogen peroxide or sodium butyrate can be used. Preferably, it involves exposing the aliquot to ozone gas. More preferably, it involves exposing the aliquot to a mixture of medical grade oxygen and ozone gas, most preferably by bubbling through the aliquot, at the aforementioned temperature range, a stream of medical grade oxygen gas having ozone as a minor component therein. The ozone content of the gas stream and the flow rate of the gas stream should be selected such that the amount of ozone introduced to the blood aliquot, either on its own or in combination with other stressors, does not give rise to excessive levels of cell damage such that the therapy is rendered ineffective. Suitably, the gas stream has an ozone content of up to about 300 μg/mL, preferably up to about 100 μg/mL, more preferably about 30 μg/mL, even more preferably up to about 20 μg/mL, particularly preferably from about 10 μg/mL to about 20 μg/mL, and most preferably about 14.5±1.0 μg/mL. The gas stream is suitably supplied to the aliquot at a rate of up to about 2.0 litres/min, preferably up to about 0.5 litres/min, more preferably up to about 0.4 litres/min, even more preferably up to about 0.33 litres/min, and most preferably about 0.24±0.024 litres/min. The lower limit of the flow rate of the gas stream is preferably not lower than 0.01 litres/min, more preferably not lower than 0.1 litres/min, and even more preferably not lower than 0.2 litres/min.

The electromagnetic emission stressor is suitably applied by irradiating the aliquot under treatment from a source of an electromagnetic emission while the aliquot is maintained at the aforementioned temperature and while the oxygen/ozone gaseous mixture is being bubbled through the aliquot. Preferred electromagnetic emissions are selected from photonic radiation, more preferably UV, visible and infrared light, and even more preferably UV light. The most preferred UV sources are UV lamps emitting primarily UV-C band wavelengths, i.e. at wavelengths shorter than about 280 nm. Such lamps may also emit amounts of visible and infrared light. Ultraviolet light corresponding to standard UV-A (wavelengths from about 315 to about 400 nm) and UV-B (wavelengths from about 280 to about 315) sources can also be used. For example, an appropriate dosage of such UV light, applied simultaneously with the aforementioned temperature and oxidative environment stressors, can be obtained from lamps with a combined power output of from about 45 - 65 mW/cm ². Up to eight such lamps surrounding the sample container holding the aliquot, with a combined output at 253.7 nm of 15 - 25 watts, operated at an intensity to deliver a total UV light energy at the surface of the blood of from about 0.025 to about 10 joules/cm², preferably from about 0.1 to about 3.0 joules/cm². Preferably, four such lamps are used.

The time for which the aliquot is subjected to the stressors can be from a few seconds to about 60 minutes. The time depends to some extent upon the chosen intensity of the electromagnetic emission, the temperature and the concentration of the rate at which the oxidizing agent is supplied to the aliquot. Some experimentation to establish optimum times may be necessary on the part of the operator, once the other stressor levels have been set. Under most stressor conditions, preferred times will be in the approximate range of from about 2 to about 5 minutes, more preferably around 3 minutes. The starting blood temperature and the rate at which it can be warmed or cooled to a predetermined temperature, tends to vary from subject to subject. Warming is suitably by use of one or more infrared lamps placed adjacent to the aliquot container. Other methods of warming can also be adopted.

In the practice of the preferred process of the present invention, the blood aliquot (or the separated cellular fractions of the blood, or mixtures of the separated cells, including platelets, these various leukocyte-combinations, along with whole blood, being referred to collectively throughout as the "aliquot") may be treated with the stressors using an apparatus of the type described in U.S. Pat. No. 4,968,483 Mueller. The aliquot is placed in a suitable, sterile, UV light- transmissive container, which is fitted into the machine. The UV lamps are switched on for a fixed period before the gas flow is applied to the aliquot providing the oxidative stress, to allow the output of the UV lamps to stabilize. The UV lamps are typically on while the temperature of the aliquot is adjusted to the predetermined value, e.g. 42.5±rc. Then the oxygen/ozone gas mixture, of known composition and controlled flow rate, is applied to the aliquot, for the predetermined duration of up to about 60 minutes, preferably 2 to 5 minutes and most preferably about 3 minutes as discussed above, so that the aliquot experiences all three stressors simultaneously. In this way, blood is appropriately modified according to the present invention to achieve the desired effects.

A subject preferably undergoes a course of treatments, each individual treatment comprising removal of a blood aliquot, treatment thereof as described above and re-administration of the treated aliquot to the subject. A course of such treatments may comprise daily administration of treated blood aliquots for a number of consecutive days, or may comprise a first course of daily treatments for a designated period of time, followed by an interval and then one or more additional courses of daily treatments.

In one preferred embodiment, the subject is given an initial course of treatments comprising the administration of 1 to 6, more preferably 4 to 6 aliquots of treated blood. In another preferred embodiment, the subject is given an initial course of therapy comprising administration of from 2 to 4 aliquots of treated blood, with the administration of any pair of consecutive aliquots being either on consecutive days, or being separated by a rest period of from 1 to 21 days on which no aliquots are administered to the patient, the rest period separating one selected pair of consecutive aliquots being from about 3 to 15 days. In a more specific, preferred embodiment, the dosage regimen of the initial course of treatments comprises a total of three aliquots, with the first and second aliquots being administered on consecutive days and a rest period of 11 days being provided between the administration of the second and third aliquots. For optimum effectiveness of the treatment, it is preferred that no more than one aliquot of modified blood be administered to the subject per day, in one or more injection sites, and that the maximum rest period between any two consecutive aliquots during the course of treatment be no greater than about 21 days. It may be preferred to subsequently administer additional courses of treatments following the initial course of treatments. Preferably, subsequent courses of treatments are administered following a rest period of several weeks or months, preferably at least about three weeks, after the end of the initial course of treatments. In one particularly preferred embodiment, the subject receives a second course of treatments comprising the administration of one aliquot of treated blood every 30 days following the end of the initial course of treatments, for a period of 6 months or longer. It may also be preferred in some circumstances to follow one or more of the above-described courses of treatment by periodic "booster" treatments, if necessary, to maintain the desired effects of the present invention. For example, it may be preferred to administer booster treatments at intervals of 3 to 4 months following the initial course of treatment. It will be appreciated that the spacing between successive courses of treatments should be such that the positive effects of the treatment of the invention are maintained, and may be determined on the basis of the observed response of individual subjects.

The prophylaxis or treatment methods described herein may be administered in combination with one or more other modalities. Examples of other preferred modalities include, but are not limited to, statin therapy. Administration in combination includes, for example, administration of the treated blood described herein, prior to, during or after administration of the other one or more modalities. One of skill in the art will be able to determine the administration schedule and dosage.

EXAMPLE 1 This example presents results from a phase III, double blind, randomized clinical trial in over 2400 patients suffering from CHF. Male and female patients 18 years of age or older were randomized through 176 sites in Canada, United States, Germany, Israel, Denmark, Poland, and Norway. Inclusion criteria included NYHA classification M-IV, left ventricular systolic dysfunction, and hospitalization for heart failure. Patients were randomly allocated between the placebo and treatment groups and were tracked in the study for a minimum of six months. A primary and a number of secondary endpoints were assessed. The primary endpoint was the combined endpoint of all-cause mortality or cardiovascular hospitalization. Some of the secondary endpoints included the combined endpoint of all-cause mortality or hospitalization for all causes, combined endpoint of all-cause mortality or hospitalization due to worsening heart failure, and individual components of the composite endpoints.

The intent-to-treat population (ITT) included all randomized subjects subjected to treatment according to the invention and subjected to placebo treatment.and all demographic and efficacy evaluations were based on the ITT group. 1207 patients were randomized in each of the placebo and treatment groups.

Protocol: Patients received multiple treatments in two phases: an induction phase and a maintenance treatment phase. The induction phase was spread over two weeks during which three treatments were administered (either treated blood or placebo) at days 1 , 2, and 14. The maintenance phase, which began four weeks after the last treatment of the induction phase, consisted of single treatments given at four-week intervals until the end of the clinical trial or patient withdrawal from the clinical trial.

Each individual treatment comprised the following steps: 1. Collection of 10 mL of a patient's venous blood into 2 mL of sodium citrate USP as an anti-coagulant to prevent the blood from clotting during the treatment.

2. Transfer of the citrated blood sample to a sterile, disposable low density polyethylene container. 3. Ex vivo treatment of the blood sample performed over a period of approximately 20 minutes by simultaneous exposure to: elevated temperature of 42.5+1.0⁰C, a gas mixture of medical grade oxygen containing 14.5+1.0 /yg/nriL of ozone, at a flow rate of 240+24 mL/minute (at STP) for 3 minutes, and ultraviolet light at a wavelength of 253.7+10 nm.

4. Transfer of treated blood from the sterile disposable container to a sterile syringe.

5. Intramuscular injection of 8-10 mL of treated blood into the gluteal muscle of the same patient, following injection with a local anaesthetic (1 mL of 2% Novocaine or equivalent)

Approximately 35 minutes after blood collection, 10 mL of saline was administered to patients in the placebo group applying the same injection procedures used for the treated blood.

The ex vivo treatment of the blood sample in step (3) above was performed with an apparatus as generally described in U.S. Patent No. 4,968,483 to Mueller et a/. Patients had blood withdrawn at the beginning of the trial and the end of their involvement in the trial to assess serum CRP levels, using known test methods in a commercial test laboratory, to determine the change in serum CRP levels over time for both treatment and placebo groups.

Appropriate statistical tests were used to analyze the data from the clinical trial including time-to-event distribution, and evaluating magnitude of effect, including Kaplan-Meier curves plotting time to event, and applying a log-rank test to determine a p-value as evaluation of statistical significance. A p value of <0.05 was taken as indicative of statistical significance. The Cox Proportional Hazards Model was applied to quantify the difference between the curves and determine relative risk reduction and hazard ratio.

There was a statistically significant difference in the primary endpoint and a number of the secondary endpoints, between the treatment group and the placebo groups, for ITT group patients classified as being in Class II, NYHA, as shown in Table 1 below. There were 693 patients in the ITT group, with 360 patients in the treatment group and 333 patients in the placebo group. TABLE 1

The data from Table 1 indicates that in the group receiving treatment according to the invention, there was a statistically significant increase in the time, for a patient classified as Class Il NYHA, to experience various deleterious events associated with CHF such as death, first cardiovascular hospitalization, or time to first hospitalization due to worsening heart failure, in comparison to the placebo group. Of the 333 patients with NYHA Class Il in the placebo group, 124 experienced a major event (hospitalization due to cardiovascular problems, or death), compared with 92 patients out of 360 in the treated group, for a hazard ratio of 0.61.

Patients classified as Class Il NYHA have not advanced to the late stage of CHF but are at risk of doing so.

EXAMPLE 2

From the clinical trial conducted as above, placebo patients (462) and treated patients (461 ) with no prior history of myocardial infarction were isolated and analyzed. 138 of these placebo patients suffered a major event, compared with 105 of the treated patients, for a hazard ratio of 0.74 and a statistical significance p = 0.02.

EXAMPLE 3

From the clinical trial conducted as above, placebo patients (574) and treated patients (555) with a serum CRP level at the start of the trial of less than 3.0 mg/mL were isolated and analyzed. 180 of these placebo patients suffered a major event, compared with 141 of the treated patients, for a hazard ratio of 0.78 and a statistical significance p = 0.03.

EXAMPLE 4

From the clinical trial conducted as above, placebo patients (566) and treated patients (573) with a left ventricular ejection fraction of greater than 23% were isolated and analyzed. 183 of the placebo patients suffered a major event, compared with 159 of the treated patients, for a hazard ratio of 0.84 trending towards statistical significance (p = 0.08).

EXAMPLE 5 From the clinical trial conducted above, placebo patients (656) and treated patients (649) who were either NYHA Class Il or had no prior myocardial infarction (which included NYHA Class Il and NYHA Class III and NYHA Class IV with no history of prior myocardial infarction) were isolated and analyzed. With respect to all cause mortality or cardiovascular hospitalization, the placebo group had 226 events in comparison to the treatment group which had 165 events, for a hazard ratio of 0.69 and a statistical significance of p=0.0003.

EXAMPLE 6 From the clinical trial conducted above, there was a significant reduction in the average days spent in hospital for cardiovascular cause for treated patients classified as New York Heart Association (NYHA) Class M-IV non-ischemic cardiomyopathy patients, characterized as having no prior history of heart attack, and Class Il patients with ischemic heart failure, in comparison to the placebo group (p=0.013).

The results from the above Examples are indicative of the utility of the present invention in retardation of the progression of CHF.

Claims

WHAT IS CLAIMED IS:

1. A method of retarding progression of mild chronic heart failure in a patient diagnosed as suffering therefrom, which comprises administering to a so-diagnosed patient an aliquot of the patient's own blood which has been treated ex vivo with at least one stressor which is an oxidizing agent, an electromagnetic emission or elevated temperature.

2. A method according to claim 1 wherein the mild congestive heart failure is NYHA Class II.

3 A method according to claim 2 wherein the patient is also diagnosed to have had no prior myocardial infarction (Ml).

4. A method according to claim 1 , claim 2 or claim 3 wherein the patient has a serum CRP level of 3.0 or less.

5. A method according to any preceding claim wherein the patient has a left ventricular ejection fraction of greater than

23%.

6. A method according to any preceding claim wherein the patient has non-ischemic cardiomyopathy.

7. Composition for retarding progression of mild chronic heart failure in a patient diagnosed as suffering therefrom comprising an aliquot of the patient's own blood which has been treated ex vivo with at least one stressor which is an

8. Composition according to claim 7 wherein the patient is diagnosed to have a stage of chronic heart failure corresponding to New York Heart Association (NYHA) Class Il stage of heart failure,

9. Composition according to claim 7 or claim 8 wherein the patient is diagnosed to have had no prior myocardial infarction (Ml).

10. Composition according to claim 7, claim 8 or claim 9 wherein the patient has a serum CRP level of 3.0 or less.

11. Composition according to any of claims 7 - 10 wherein the patient also has a left ventricular ejection fraction of greater than 23%.

12. Composition according to any of claims 7 - 11 wherein the oxidizing agent stressor is ozone/oxygen mixture.

13. Composition according to any of claims 7 - 12 wherein the electromagnetic radiation stressor is ultraviolet light.

14. Composition according to any of claims 7 - 13 wherein the temperature stressor is a temperature above body temperature.

15. Composition according to any of claims 7 - 14 wherein the blood aliquot is treated simultaneously with all three said stressors.

16. A process of determining the appropriateness of treatment of mammalian patients to alleviate or delay the progression of mild chronic heart failure exhibited by the patients, and subsequently conducting the treatment on a so-determined group of such patients, which comprises conducting on patients suffering from mild chronic heart failure a determination of their NHYA Class of chronic heart failure and selecting from those patients a group exhibiting in NYHA Class II, and treating at least one member of said selected group with a composition as claimed in any of claims 7 - 15.

17. The process of claim 15 which additionally comprises conducting on said patients a determination of serum CRP level and limiting the selected group to those patients with serum CRP less than 3.0 mg/mL, and NYHA Class Il chronic heart failure.

18. The process of claim 17 which additionally comprises conducting on said patients a determination of whether the patients have previously suffered a myocardial infarction, and limiting the selected group to those who have had no myocardial infarction and have NYHA Class Il chronic heart failure.

19. The process of claim 17 which additionally comprises conducting on said patients a determination of left ventricular ejection fraction, and limiting the selected group to those with LVEF greater than 23% and having NYHA Class Il chronic heart failure.

20. The process of claim 19 which additionally comprises conducting on said patients a determination of whether the patients have previously suffered a myocardial infarction, and limiting the selected group to those who have had no myocardial infarction, have LVEF greater than 23% and have

NYHA Class Il chronic heart failure.

21. The process of claim 19 which additionally comprises conducting on said patients a determination of serum CRP level, and limiting the selected group to those patients with serum CRP less than 3.0 mg/mL, LVEF greater than 23% and NYHA Class Il chronic heart failure.

22. The process of claim 21 which additionally comprises conducting on said patients a determination of whether the patient has previously suffered a myocardial infarction, and limiting the selected group to those who have had no myocardial infarction, have NYHA Class Il chronic heart failure, have LVEF greater than 23% and additionally have serum CRP less than 3.0 mg/mL.