Use of a Chinese medicine composition in preparing medicaments for treating secondary prevention of myocardial infarction

This application is a U.S. national stage of International Patent Application No. PCT/CN2011/076499, filed Jun. 28, 2011, which claims priority of Chinese Patent Application No. 201010219730.2, filed on Jun. 28, 2010, the contents of which are each incorporated herein by reference in its entirety.

The present invention relates to the field of medicine, in particular to a use of Chinese medicine composition in preparing medicaments for treating secondary prevention of myocardial infarction.

Cardiovascular disease is a common and frequent disease, threatening human life and health seriously. Annually, there are about 20 million persons dying of acute cardiovascular events worldwide, and more than half of them died of acute myocardial infarction (AMI). With population aging in China, the incidence of AMI showed a clear upward trend, which has been already close to the international average level. In recent years, raised monitoring and treating level has lowered the mortality of myocardial infarction. But the survivals are still at a high risk of reoccurrence of acute cardiovascular events, e.g. the myocardial infarction, congestive heart failure and sudden death etc. Accordingly, except active treatment in acute phase, the secondary prevention of myocardial infarction should be strengthened.

The secondary prevention of myocardial infarction refers to the prevention of cardiovascular events and improvement patients' life quality after occurrence of myocardial infarction. As shown by many studies, there are a lot of drugs reported to have an active and positive effect on long-term secondary prevention of myocardial infarction, e.g. platelet inhibitors (aspirine), β-receptor blockers, statins and angiotensin converting enzyme inhibitors (ACEI) etc. In addition, efficacy of these drugs are not influenced by patients' other conditions, such as age and gender etc.

As confirmed by a large-scale medicine clinical trial results, although afore-mentioned drugs, e.g. platelet inhibitors (aspirine), β-receptor blockers, statins and angiotensin converting enzyme inhibitors (ACEI) etc can significantly decrease the mortality rate caused by AMI, a great many survivals are usually led to disability or death due to the cardiovascular events, such as re-infarction, severe arrhythmia and heart failure etc. Moreover, these drugs more or less have some adverse reactions, some of which are even very serious. In addition to this, some westerners became gradually aware of that the effect of single drug on secondary prevention may not be as good as that of combined drugs, and developed a series of compound western medicine preparations for secondary prevention of myocardial infarction. In fact, herbal prescriptions have been mainly used for treating disease in Traditional Chinese Medicine (TCM) for thousands of years. Even a single herb medicine can be considered as a small compound prescription, because it contains complicated ingredients. Besides, the TCM prescriptions have the advantages of eased efficacy, attenuated toxicity and increased effect by drug compatibility and reduced side effect, which is accordingly suitable for long-term administration as secondary prevention medicine.

Objective of present invention is to provide a use of Chinese medicine composition in preparing medicaments for treating secondary prevention of myocardial infarction. Said Chinese medicine composition is prepared from a formula comprising the crude drugs by the following weight percentages:

According to the present invention, said Chinese medicine composition has effects of decreasing the occurrence of cardiovascular events in patients after acute myocardial infarction. Said cardiovascular events include following diseases: a). re-infarction; b). severe arrhythmia; c). heart failure; d). Cardiogenic shock; e). revascularization (interventional therapy and coronary artery bypass grafting).

According to the present invention, said Chinese medicine composition has effects of decreasing the occurrence of non-cardiovascular events in patients after acute myocardial infarction. Said non-cardiovascular events include following diseases: a). stroke; b) pulmonary embolism; c). peripheral vascular events; d). tumor.

According to the present invention, said Chinese medicine composition has effects of decreasing the occurrence of death events in patients after acute myocardial infarction. Said death events include following ones: a). coronary heart disease (CHD) death; b). other cardiovascular death; c). non-cardiovascular disease death.

According to the present invention, said Chinese medicine composition can alleviate the attack of angina pectoris in patients after acute cardiovascular infarction, e.g. reducing the frequency of attack, shortening the duration, relieving pain degree, decreasing the dose of nitroglycerin and improving the symptoms of chest pain, chest tightness, short breath, fatigue, palpitation, spontaneous perspiration as well as pale complexion.

According to the present invention, said Chinese medicine composition can improve life quality in patients after acute myocardial infarction. After use of said Chinese medicine composition, the limitation degree of physical activity, steady status of angina pectoris and attack frequency of angina pectoris are significantly ameliorated.

According to the present invention, said Chinese medicine composition is preferably prepared from a formula comprising the crude drugs by weight percentages:

According to the present invention, said Chinese medicine composition can be prepared by extracting the individual crude drug in accordance with conventional extraction methods or the ones known in the prior art and mixing. Preferably, said Chinese medicine composition is prepared by a method comprising: extracting pulverized Sanqi and Danshen with water, filtering, properly concentrating the filtrate, performing alcohol precipitation, recovering the obtained supernatant and concentrating continuously to give an extract, namely Danshen & Sanqi extract; extracting pulverized Huangqi with water, filtering, properly concentrating the filtrate, performing alcohol precipitation, recovering the obtained supernatant and concentrating continuously to give an extract, namely Huangqi extract; reflux extracting Jiangxiang with water and collecting volatile oil; mixing well aforesaid two extracts, volatile oil and excipients to prepare into any one of pharmaceutically acceptable dosage forms, preferably dripping pill. Furthermore, the dripping pill is prepared by following steps: providing aforesaid Danshen & Sanqi extract, Huangqi extract and PEG-6000 with 2˜5 times the total weight of extracts, dissolving on water bath to mix well, adding the Jiangxiang volatile oil and harmonizing to prepare the dripping pills by a conventional method. Likewise, the tablet can be obtained by a conventional method.

In order to better understand the present invention, a multi-center, randomized, double-blind, double-dummy and positive drug controlled trial had been conducted. 3508 patients who were in accordance with the diagnostic standards of AMI for 28 days to 2 years and differentiated as Qi deficiency and blood stagnation syndrome by TCM were studied. 0.5 g Chinese medicine composition prepared by the method of EXAMPLE 1 (Coded as QSYQ) was administrated half an hour after meal, 3 times per day. Aspirine was used as a positive drug. The patients were treated for 1 year and observed for 6 months. As shown in the results, there was no statistical difference in non-fatal re-infarction, non-fatal stroke, cardiovascular deaths in patients after acute myocardial infarction between the Qi Shen Yi Qi dripping pill (prepared in accordance with the present invention) and aspirine (log-rank test used for inter-group comparison). Moreover, as compared with the aspirine, no statistical difference had been found in decreasing the incidence of end point of death, reducing the severity score, frequency and duration of angina pectoris, lowering nitroglycerin dose, improving a series of TCM symptoms, e.g. chest tightness, palpitation, spontaneous perspiration, pale complexion as well life quality (Seattle Angina Questionnaire (SAQ) used). It is illustrated that the Chinese medicine composition of present invention has a similar effect with the aspirine on secondary prevention in patients after acute myocardial infarction.

AE Adverse Event

FAS Full Analysis Set

SS Safety Set

PP Per-Protocol, PP

LOCF Last Observation Carried Forward

PP Per Protocol

Mean Mean number

SD Standard Deviation

Median Median value

Min Minimum value

Max Maximum value

CI Confidence Interval

HR Hazard Ratio

Aim of Study

First of all, the aim of this trial was to investigate whether there was an effect on decreasing the hazard ratio (HR) of non-fatal re-infarction, cardiovascular deaths and non-fatal stroke after long-term administration of QSYQ, and whether there was non-inferiority, as compared with the aspirine. The second was to understand the effect of QSYQ on other clinical events and the life quality in patients.

General Design

A multi-center, double blind, double dummy, randomized and positive drug controlled clinical study was carried out.

A large-scale randomized controlled trials (RCT) method was used. The trial was carried out simultaneously in 16 sub-centers (grade class III hospitals) of clinical trial in 5 regions of East, West, South, North and central China and 84 hospitals.

Randomized Method: Centralized Randomization

According to the ready-made Random Sequence Table (that was generated by the computer), the subjects were randomly assigned into any one of two treating groups in a ratio of 1:1 via an Interactive Voice Response System (IVRS).

When the subjects met inclusion/exclusion criteria, researchers called the IVRS, and the IVRS would assign a subject with a specific identification code and random number. The specific identification code and random number assigned by IVRS were unique. They were used to represent the subjects' identification and which drug the subjects received.

In order to achieve the purpose of double blind in this trial, a placebo of QSYQ had been developed. It was required that it should have the same packaging and essentially consistent appearance, shape and color with the QSYQ. Likewise, the placebo of aspirine tablet had the same packaging and essentially consistent appearance, shape and color with the aspirine. For each subject, one-month dosage was packaged into a small box, containing QSYQ and the placebo of aspirine or aspirine and the placebo of QSYQ. Three-month dosage was packaged into a large box and each medicine had a same number.

The unique numbers were pre-printed on the study medicine labels. Through the IVRS, the medicines were randomly assigned to the subjects who met the requirements. Said labels were divided into two parts: the part that was pasted on the box was to describe how to use the medicine and other information; the removable part was torn off and pasted on the Drug Distribution Table. In addition, the drug assigners should record the medicine number of each observation on the Drug Distribution Diary.

Positive Control Drug

The aspirine (AS) was used as a routine drug for secondary prevention of myocardial infarction.

Administration Method

1. QSYQ treating group: QSYQ 0.5 g, tid, administrated half an hour post meal, taken 100 mg placebo of enteric coated aspirine tablet (4 tablets) at the same time, once a day.

2. Aspirine control group: 100 mg enteric coated aspirine tablet (4 tablets), administrated half an hour post meal, once a day, taken 0.5 g placebo of QSYQ at the same time, tid.

Calculation of Sample Size

Sample size was calculated on the following assumptions. According to the previous clinical experience, the incidence of MI (myocardial infarction) within 1 year was about 5%. Assuming that the treatment could reduce the death risk to 50% (namely the HR was 0.5), the dropping rate 20%, at least total number of 3000 study subjects were required (trial group: 1800 cases, power=90%, bilateral alpha=0.05). The research time was 18 months, the first 12 months of which was the treatment period and later 6 months the follow-up period.

Evaluation Index

I.1 Definition of Index

I.1.1 Endpoint Events

(1) Cardiovascular events include a. Re-infarction, b. Severe arrhythmia, c. Heart failure, d. Cardiogenic shock, e. Revascularization (Interventional Therapy and coronary artery bypass grafting).

(2) Non-cardiovascular events include a. Stroke, b Pulmonary Embolism, c. Peripheral Vascular events, d. tumor.

(3) Death events include a. Coronary heart disease death, b. other cardiovascular death, c. non-cardiovascular death.

I.1.2 Score of Angina Pectoris and TCM Symptom

Standard of symptom score Angina pectoris Frequency 0 score: None; 2 score: 2~6 times a week; 4 score: 1~3 times a day; 6 score: 4 times or more a day. Duration 0 score: None; 2 score: duration of pain for each time ≦5 min; 4 score: 5-10 min; 6 score: ≧10 min. Pain degree 0 score: none; 2 score: attack was ameliorated after rest, and daily life not affected; 4 score: attack was treated with drug, and normal activity continued after remission; 6 score: daily activity was affected by frequent attacks (onset of symptoms could be induced by e.g. dressing, eating, walking, stool). Dose of 0 score: none; 2 score: 1~4 tablets a week; 4 score: 5~9 tablets a week; 6 score: 10 nitroglycerin tablets or more a week. TCM symptoms Chest pain 0score: none; 3 score: attack was ameliorated after rest, and daily life not affected; 6 score: attack was treated with drug, and normal activity continued after remission; 9 score: daily activity was affected by frequent attacks (onset of symptoms could be induced by e.g. dressing, eating, walking, stool). Chest 0 score: none; 3 score: chest tightness was felt occasionally, which could be self tightness relieved; 6 score: chest tightness attacked frequently, but didn't affect the nomal life and work; 9 score: chest tightness could not be relieved, and affected the normal life and work. Short breath 0 score: none; 2 score: short breath after activity; 4 score: short breath after slight activity; 6 score: short breath felt usually. Fatigue 0 score: none; 2 score: fatigue was felt after severe activity; 4 score: fatigue was felt after middle activity; 6 score: fatigue was felt after slight activity. Palpitation 0 score: none; 1 score: sporadic palpitation could be self relieved; 2 score: palpitation frequently attacked, but could continue working; 3 score: sustained palpitation could not be relieved, and affected the life and work. spontaneous 0 score: none; 1 score: occasional perspiration after activity; 2 score: apparent perspiration perspiration after activity; 3 score: often perspiration when taking rest. pale 0 score: none; 1 score: pale complexion. complexion

I.1.3 Life Quality

There were 19 questions in the Seattle angina questionnaire (SAQ), including 5 parts: physical limitation (PL), anginal stability (AS), anginal frequency (AF), treatment satisfaction (TS) and disease perception (DP). After being given necessary explanation by doctors, the questions were answered independently by patients.

I.2 Treatment Standard

Treatment standard was divided into 4 grades. The first grade standard belonged to the primary endpoint event, and the second, third and fourth grades to the secondary endpoint event.

The 1 st grade included the non-fatal re-infarction, non-fatal stroke and cardiovascular deaths.

The 2 nd grade included the severe arrhythmia, heart failure, cardiogenic shock and revascularization.

The 3 rd grade included the peripheral vascular events, pulmonary embolism and non-cardiovascular deaths.

The 4 th grade included the angina pectoris, TCM symptoms and SAQ.

The primary endpoint of this study was the incidence of endpoint events within 1 year from the first administration of medicine. The dropout subjects (e.g. revoked informed consent or out of follow-up) were removed in the last assessment. The endpoint of the study was 1 year after the last subject was randomly assigned into group (12 months).

I.2.1 Main Indexes for Therapeutic Effects

Incidence of Main Endpoint Events

The main endpoint events were defined as the first grade endpoint events, including non-fatal re-infarction, non-fatal stroke and cardiovascular death. As long as any one of the events occurred, it was regarded as occurrence of the main endpoint event. Other cases could be deleted.

The main endpoint events time was calculated in accordance with the following method. If the endpoint events occurred, the time was defined as the duration from the first administration of drug to the time when any one of aforesaid events occurred (e.g. if there were plural endpoint events in a same disease, the most recent time when event occurred was deemed as the main endpoint events time.). If the subjects dropped out of the trial or lost follow-up for any reason before the end of study, the time was calculated on the basis of withdrawal or out of follow-up time. If the subjects survived to the last observation, the time was calculated on the basis of the last observation time.

I.2.2 Secondary Indexes for Therapeutic Effects

The secondary indexes included the overall survival time, angina pectoris score, TCM symptom score and SAQ.

Overall Survival Time

Death endpoint referred to the death caused by any reason during the period of study. Other cases were defined as censorship.

Death endpoint time was calculated in accordance with following method. The time referred to the duration from the first administration of drug to the time when the endpoint events occurred, and non-endpoint time was defined with reference to method of the main endpoint event.

I.3 Safety Indexes Mainly Include:

Adverse event referred to any adverse medical events that happened from the time when patients signed the Informed consent form (ICF) and were enrolled in trial to the end of treatment, whether having a relationship with the test drug or not.

Severe adverse event included death and other cases threatening life, events leading to hospitalization treatment, prolonged hospitalization treatment, permanently or severely causing disability or malformation.

Statistical Population

1. Full Analysis Set (FAS) Population

Ideal cases set was established as possible as in accordance with the intentional treatment principle, which was obtained from the randomized subjects, to the exclusion of the least or unreasonable cases.

Missing Data Processing

(1). Endpoint events were processed in accordance with the survival data analysis. See the main indexes for therapeutic effects in section of statistical analysis.

(2). Other treatment indexes included angina pectoris score, TCM symptom score and various evaluation results that were recorded in the SAQ. The missing value for aforesaid indexes was estimated on the basis of the closest last observation carried forward (LOCF) estimation method.

2. Per-Protocol (PP) Population

Also, the PP population was called as valid cases, valid samples or evaluable cases. Full compliance with the trial program made it ensure that the data set was generated by the valid case subset shown by scientific model.

3. Safety Set (SS) Population

The SS population of this trial consisted of the subjects who received at least one treatment after randomization.

Division of the statistical analysis population was determined jointly by clinical researchers, data managers and statistical analysis experts on blind review meeting.

Statistical Analysis Method

I.4 General Principle

Two-sided test was used in all statistical tests. It was believed to have statistical significance (p≦0.05, unless otherwise indicated).

Quantitative indexes were expressed as mean value, standard deviation, median value, minimum value and maximum value.

Classification indexes were expressed as number of samples and its percentage.

I.5 Evaluation of Therapeutic Effect

1.5.1 Baseline

The baseline was defined as observation #1 of patients who entered the group before administration. The baseline evaluation was carried out in FAS population.

Either t-test or Wilcoxon rank sum test could be used for inter-group baseline comparison by total and single scores of angina pectoris, total and single scores of TCM symptom and the score of each question recorded in the SAQ.

I.5.2 Evaluation of Main Therapeutic Effects

Main therapeutic effects referred to the survival rate of main endpoint events.

Kaplan-Meier method was used to estimate the survival rate of main endpoint events in both trial and control group. The survival curve was established after calculating onset time at 25%, 50% and 75% quantile. Log-rank test was used for inter-group comparison.

Cox proportional hazard model was used to test the risk of endpoint events occurring in trial group in comparison with the control group to calculate its 95% confidence interval.

About the definition and calculation method of main endpoint events, see the relevant section of indexes of therapeutic effects.

I.5.3 Evaluation of Secondary Therapeutic Effects

They included the overall survival time, angina pectoris score, TCM symptom score and life quality score, where angina pectoris score, TCM symptom score and life quality score were evaluated at randomization, in 1 st , 3 rd , 6 th , 9 th , 12 th month after treatment and 18 th month after follow-up.

I.5.3.1 Overall Survival Time

Analysis method referred to the survival rate of main endpoint events. About the definition and calculation method of overall survival time, see the relevant section of indexes of therapeutic effects.

I.5.3.2 Angina Pectoris Score

Total angina pectoris score was described on every observation period and the change of observation in comparison with baseline. T-test or Wilcoxon rank sum test were used for inter-group comparison. Grade of total score was evaluated on every observation and Wilcoxon rank sum test was used for inter-group comparison. T-test and Pairing signed rank sum test were used for analyzing the change of total score on every observation between groups in comparison with the baseline.

Single angina pectoris score was depicted on every observation time-point and the change of observation in comparison with baseline. Wilcoxon rank sum test was used for inter-group comparison. Pairing signed rank sum test was used for analyzing the change of total score on every observation between groups in comparison with the baseline.

I.5.3.3 TCM Symptom Score

The analysis method referred to the angina pectoris score.

I.5.3.4 SAQ

All evaluation results of SAQ were described during the period of observation, and Wilcoxon rank sum test was used for inter-group comparison.

I.6 Evaluation of Safety

I.6.1 Patients' Exposure Time in Study

Observation time (day)=(ending date-starting date)+1

Medication time (day)=(last date-initial date)+1

I.6.2 Indexes for Evaluation of Safety

Adverse events were evaluated at any time after enrollment. Safety population was used for the indexes for evaluation of safety.

I.6.3 Safety Evaluation Method

Occurrence, proportion and number of the adverse events were described group by group in each treatment group. The patients who were aborted from trial by adverse events, and the ones of related adverse events and severe adverse events were described in list.

Results of Statistical Analysis

In this study, the data were for blind review and then locked.

After opening the blind on the spot, the results were divided into two groups of #A and #B for the first time and the main indexes for therapeutic effect was evaluated. After opening blind for the second time, #A group was trial group and #B group control group.

Total 3508 patients were enrolled in this study, 1748 patients in trial group and 1760 patients in control group respectively. There were 3505 patients entering the FAS population, respectively 1746 patients in trial group and 1759 patients in control group. There were 2956 patients entering the PP population, respectively 1456 patients in trial group and 1500 patients in control group. There were 3507 patients entering the SS population, respectively 1747 patients in trial group and 1760 patients in control group.

Indexes for Therapeutic Effect

Baseline:

Except there was statistically significant difference in fatigue indexes of TCM symptom between the groups (P<0.05), no statistically significant difference was found in other indexes (P>0.05).

Main Indexes for Therapeutic Effect:

Occurrence of Main Endpoint Events

I.6.4.2 Angina Pectoris Score

Total angina pectoris score was described on every observation period and the change of observation in comparison with the baseline. T-test or Wilcoxon rank sum test were used for inter-group comparison. Grade of total score was evaluated on every observation and Wilcoxon rank sum test was used for inter-group comparison. T-test and Pairing signed rank sum test were used for analyzing the change of total score on every observation between groups in comparison with the baseline.

Single angina pectoris score was described on every observation time-point and the change of observation in comparison with baseline. Wilcoxon rank sum test was used for inter-group comparison. Pairing signed rank sum test was used for analyzing the change of total score on every observation between groups in comparison with the baseline.

I.6.4.4 Seattle Angina Questionnaire (SAQ)

The evaluation results in the SAQ were depicted in different observations, and inter-group comparison was tested by Wilcoxon Rank-sum test.

I.7 Safety Evaluation

No severe adverse events were observed.

FIG. 1 was the Kaplan-Meier curve of main endpoint event time (FAS).

FIG. 2 was the Kaplan-Meier curve of main endpoint event time (FAS).

FIG. 3 was the Kaplan-Meier curve of main endpoint event time (PP).

FIG. 4 was the Kaplan-Meier curve of main endpoint event time (PP).

FIG. 5 was the Kaplan-Meier curve of death endpoint event time (FAS).

FIG. 6 was the Kaplan-Meier curve of death endpoint event time (FAS).

FIG. 7 was the Kaplan-Meier curve of death endpoint event time (PP).

FIG. 8 was the Kaplan-Meier curve of death endpoint event time (PP).

The medicaments of the present invention will be further described with reference to the following examples, which are solely used to illustrate the present invention without limitation.