Does Honghua (Carthamus tinctorius) extract injection have the benefits for angina pectoris?

Does Honghua (Carthamus tinctorius) extract injection often have adverse effects and events for treating angina pectoris?

A comprehensive and exhaustive search strategy will be formulated in an attempt to identify all relevant studies regardless of language or publication status (published, unpublished, in press or in progress).

The following electronic databases will be searched:

1.Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (Issue 3,2012);

2.MEDLINE(January 1966 - September 2012);

3.CBMdisc(Chinese biomedical literature database,1979 to 2012);

4.China National Knowledge Infrastructure(CNKI,1979 - 2012);

5.Chinese VIP Information (1989 - 2012);

6.WanFang Data(1985-2012).

The following databases of ongoing trials will be also searched:

1.The Chinese Clinical Trial Register;

2.The ISRCTN Register;

3.The Clinical Trials;

4.National Research Register and Current Controlled Trials;

5.The WHO ICTRP Search Portal.

Randomized controlled trials will be included in this systematic review. We will contact all the included study authors for the details of randomized methods.

Angina pectoris

Ischemic heart disease is a leading cause of death in the Western countries, where it amounts to almost 33% of overall mortality (Braunwald 1992) and the "first clinical sign" in over half of patients is angina pectoris (Gibbons 1999). Angina pectoris, generally described as a discomfort within or adjacent to the chest, is the most common clinical manifestation of myocardial ischemia caused by imbalance of myocardial blood supply and metabolic demand due to narrowed or blocked atheromatous coronary arteries in coronary heart disease. Angina often occurs during exercise, strong emotions or extreme temperatures, alleviated by rest. Some people, even when at rest, may also have angina due to coronary artery spasm. Angina is a sign that someone is at increased risk of heart attack, cardiac arrest and sudden cardiac death (Bernard 1979; KAU 2004). In China, a study showed that incidence of coronary heart disease would increase by 26.1% for male and 19.0% for female from 1998 to 2008 (Wu 2001).

The Canadian Cardiovascular Society Classification is used for grading angina (CCSC 2004):

Class I - Patients with angina only during strenuous or prolonged physical activity;

Class II - Slight limitation with angina only during vigorous physical activity;

Class III - Symptoms with everyday living activities, i.e. moderate limitation;

Class IV - Inability to perform any activity or angina at rest, i.e. severe limitation.

Stable angina is defined as chest pain or discomfort that follows a consistent pattern and does not change in severity, duration, time of appearance, or the setting in which it occurs. It typically lasts one to five minutes and may be caused by periods of exertion or emotional stress. It is relieved by rest and the episodes are usually predictable (Gill 1999). Unstable angina is defined as having three possible presentations:

(1) symptoms of angina at rest, usually prolonged >20 minutes;

(2) new onset (within 2 months) exertional angina of at least CCSC (CCSC 2004) class III in severity;and

(3) within recent 2 months acceleration of angina as reflected by an increase in severity of at least CCSC class I to at least CCSC class III.

Variant angina, non-Q-wave myocardial infarction (MI), and post-MI (>24 hours) angina are part of the spectrum of unstable angina (KAU 2004).

Honghua extract injection's pharmacological action is the rationale of this review. Chinese herbal medicine Honghua (safflower) is the tubiform floret of composite Carthamus tinctorius. The main chemical active components are Safflor yellow and Carthamin. The main action of Honghua is activating blood circulation and stimulating meridians as well as scattering blood stasis and relieving pain under Traditional Chinese Medicine theory (Huang 2000). In the fields of cardiovascular systems, modern pharmacological studies found Honghua extract injection can decrease blood viscosity, increase coronary artery blood flow, inhibiting platelet aggregation, dilate the blood vessels, improve microcirculation, protect the myocardial ischemia and antioxidant action (Wang1995) .Safflor yellow can restrain ADP or acid originally induced platelet aggregation, which can protect the formulation of thrombosis as well as promote the thrombosis (Xie 2001). Because of these functions, Honghua injection or other forms of product of Honghua are widely used alone or combined with other drugs for treating cardiac-cerebral vascular diseases in China. A number of clinical trials about Honghua in the treatment of these diseases are carried out annually and many have reported good results. There are types of classic drugs for angina pectoris, but they may not be suitable for every patients, as aspirin is not used for patients with hypersensitivity or active bleeding (KAU 2004) and nitrate tolerance may develop by long-term use of nitroglycerin and use of long-acting nitrates (Raymond 1999), some Chinese herbal medicines were recommended to be potential drugs, such as Huangqi, Danshen etc. Honghua as an important common herbal medicine had been systematically reviewed once (Wu 2010), however, the study only looked at unstable angina and Honghua injection. Meanwhile, adverse events of Honghua such as anaphylaxis shock have been frequently noticed recently (Han 2003). The therapeutic effectiveness and safety of using this herbal medicine need to be reviewed systematically to inform the current practice.

References

Braunwald E (ed). Heart Disease: A Textbook of Cardiovascular Medicine. 4th Edition. Philadelphia/ London: Saunders, 1992.

Braunwald 1994 Braunwald E, Mark DB, Jones RH. Clinical Practice Guideline. AHCPR Publication, 1994.

Bernard R, Corday E, Eliasch H, Gonin A, Hiait R, Nikolaeva LF, et al. Nomenclature and Criteria for Diagnosis of Ischemic Heart Disease, The Joint International Society and Federation of Cardiology/World Health Organization Task Force on Standardization of Clinical Nomenclature. Circulation 1979;59(3):607-9.

KAU (AHCPR guidelines revised by KAU 1/96). Unstable Angina: Diagnosis and Management. http://www.medana.unibas.ch/eng/internt/angina.htm accessed at 5 July, 2004.

Gill D, Mayou R, Dawes M, Mant D. Presentation, management and course of angina and suspected angina in primary care. Journal of Psychosomatic Research 1999;46(4):349-58.

Canadian Cardiovascular Society Classification. Grading scale for classification of severity of angina. http://indian heart journal.com/Sept October2001/abstact/565-589/17_Canadian cardiovascular Society. Htm [accessed 6 July 2004].

Yang Y, Feng WS, Chemical constituents of traditional Chinese medicine extraction and separation manual. Beijing, China Press of Traditional Chinese Medicine,1998:127.

Huang TK, Ding ZZ, Zhao SX,etc. Modern compendium of materia medica. Beijing: China Medical Scientific Press. 2000:1171-1731.

Wang XP, Qiao J, Qian ZX,etc. Experimental study on the protective and antioxidation on effects of Safflower Yellow on ischemic myocardium. Chinese Journal of Thoracic and Cardiovascular Surgery,1995,11(3):176-177.

Xie RJ, Teng XP, Shen QL.Research on the stability of Honghua injection. Li Shi Zhen Medical and Materia Medica Research.2001,1(6):490.

Gibbons RJ. ACC/AHA/ACP-ASIM Guidelines for the Management of Patients with Chronic Stable Angina. Journal of the American College of Cardiology 1999;33:2143-4

Wu FB, Xu T, Li J, Tang Y,Meta Analysis on Efficacy and Safety of Safflower Injection in Treating Unstable Angina Pectoris,2010,19(17):4-5.

Han YB. 1 case of anaphylaxis shock caused intravenous drip of Safflower injection.Journal of HuaiHai Medicine 2003,21(6):534.

Patients of both sexes who have stable angina pectoris(SAP) or unstable angina pectoris(UAP), regardless of age, gender race or educational and economic status will be included. Participants with myocardial infarction, heart failure, hepatic failure and renal failure were excluded. The diagnostic criteria of SAP and UAP are explicit according to the domestic or international acknowledged diagnostic criteria(e.g: The 2007 ACC/AHA guidelines for SAP,The 2011 ACC/AHA guidelines for UAP).

For interventions, we will include any trials in which Honghua extract injection (containing Honghua injection and safflower yellow injection) was used for treating angina pectoris. Any current western drugs may also be used for the interventions which are combined with Honghua extract injection. Three specific comparisons will be made as follows:

1 Honghua extract injection combined with any current western drugs compared with the same western drugs alone;

2 Honghua extract injection combined with any current western drugs compared with placebo plus the same western drugs;

3 Honghua extract injection compared with any current western drugs.

In the event that participants were to experience angina pectoris during treatment, nitroglycerin could be used and the dosage recorded as an outcome measure.

For control,any current western drugs and placebo are allowed in the control.

Any specific herbs extract injection and Chinese medicine are not allowed in the controls.

No setting restictions.

Primary outcomes

1.all-cause mortality.

2.Cardiovascular events including AMI, PTCA or CABG.

3.Improvement of angina symptoms(e.g.: frequency of acute attacks of angina duration of angina, severity of chest pain and breathlessness).

Secondary outcomes

1. ECG changes

2. DCG changes

3. Readmission to hospital

4. Consumption of short-acting nitroglycerin

5. Heart rate and blood pressure

6. Levels of haemodynamics index

7. Health-related quality of life

8. Adverse event(e.g.:mortality,life-threatening events, any event that results in the discontinuation of treatment)

9. Adverse effects(e.g.:toxic responses,anaphylaxis,any problems with veins used for intravenous administration)

Two reviewers (Zhang F and Chen ZH) will independently screen the titles and abstracts for the clinical studies trials by using pre-specified selection criteria. Full texts of the screened articles will be retrieved and further assessed in the same manner according to the inclusion criteria. Any disagreement will be resolved by discussion or by consultation with a third author (Yang GL). Publication authors will be contacted if any clarification is needed regarding study eligibility. In cases of author non-response, a consensus judgment will be made based on available information.

Data will be independently extracted by two reviewers using a piloted data extraction form (Zhang F and Chen ZH). We will extract data on study characteristics including general information, trail characteristics, participants, interventions, outcomes and results. The data extraction form will include the following items :

General information:

Study ID, published/unpublished, title, authors, reference/source, contact address, country, start and end dates, language of publication, year of publication, sponsor, setting.

Trial characteristics:

Design, duration of treatment and follow up, method of randomization, allocation concealment, blinding (patients, people administering treatment, outcome assessors).

Intervention(s):

Treatment group (injection, dosage, duration, co-medications);control group (injection, dosage, duration, co-medications).

Patients:

Diagnostic criteria, inclusion criteria, exclusion criteria, total number and number in groups, age, baseline characteristics, similarity of groups at baseline (including any co-morbidity),assessment of compliance, withdrawals/losses to follow-up (reasons/description).

Outcomes:

Outcomes specified above, any other outcomes assessed, adverse effects, adverse events, quality of reporting of outcomes; for each outcome, the number of participants randomized and the number of participants analyzed will be recorded for each treatment group. For dichotomous outcomes, we will record the number experiencing events and the number of patients in each treatment group. For continuous outcomes, we will record the arithmetic mean and standard deviation and the numbers of patients in each group.

Results:

For outcomes and times of assessment (including a measure of variation),if necessary converted to measures of effect specified below, selective reporting outcomes and intention-to-treat analysis will be used.

We will resolve any disagreements by referring to the trial report and through discussion, or by consulting another reviewer (Yang GL). If data from the trial reports are insufficient or missing, we will attempt to contact the authors for additional information. Where possible we will extract data to allow an intention-to-treat analysis (the analysis should include all the participants in the groups to which they were originally randomly assigned). If the number randomized and the numbers analyzed are inconsistent, we will calculate the percentage loss to follow-up and report this information in a table. We will record the number of participants experiencing the event in each group of the trial.

According to the Cochrane Handbook of Systematic Reviews of Interventions, the risk of bias will be assessed to evaluate the methodological quality of the included studies (Higgins 2011).The following domains will be evaluated for methodological quality: sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, incomplete outcome data and selective outcome reporting. The evaluated domains will be judged as "low risk"," high risk" or "moderate risk" according to the criteria.

Sequence generation

• Low risk: investigators described a random component in the sequence generation process, such as the use of random number table, coin tossing, card or envelope shuffling, etc.

• High risk: investigators described a nonrandom component in the sequence generation process, such as the use of odd or even date of birth, algorithm based on the day or date of birth, hospital, or clinic record number.

• Unclear risk: insufficient information to permit judgment of the sequence generation process.

Allocation concealment

• Low risk: participants and the investigators enrolling participants cannot foresee assignment (e.g., central allocation; or sequentially numbered, opaque, sealed envelopes).

• High risk: participants and investigators enrolling participants can foresee upcoming assignment (e.g., an open random allocation schedule, date of birth, alternation or rotation, case record number and any other explicitly unconcealed procedure); or envelopes were unsealed or non-opaque or not sequentially numbered.

• Unclear risk: insufficient information to permit judgment of the allocation concealment or the method not described.

Blinding of participants and personnel

• Low risk: blinding of the participants and key study personnel, and unlikely that the blinding could have been broken. No blinding in the situation where non-blinding is not likely to introduce bias.

• High risk: no blinding or incomplete blinding when the outcome is likely to be influenced by lack of blinding.

• Unclear risk: insufficient information to permit judgment of ‘Low risk’ or ‘High risk’.

Blinding of outcome assessment

• Low risk: blinding of the outcome assessment and unlikely that the blinding could have been broken. No blinding in the situation where nonblinding is not likely to introduce bias.

• High risk: no blinding or incomplete blinding when the outcome is likely to be influenced by lack of blinding.

• Unclear risk: insufficient information to permit judgment of ‘Low risk’ or ‘High risk’.

Incomplete outcome data

• Low risk: no missing outcome data, reasons for missing outcome data unlikely to be related to true outcome, or missing outcome data balanced in number across groups.

• High risk: reason for missing outcome data likely to be related to true outcome, with either imbalance in number across groups or reasons for missing data.

• Unclear risk: insufficient reporting of attrition or exclusions.

Selective reporting

• Low risk: a protocol is available which clearly states the primary outcome as the same as in the final trial report.

• High risk: the primary outcome differs between the protocol and final trial report.

• Unclear risk: no trial protocol is available or there is insufficient reporting to determine if selective reporting is present.

Other forms of bias

• Low risk: there is no evidence of bias from other sources.

• High risk: there is potential bias present from other sources (e.g. early stopping of trial, fraudulent activity, extreme baseline imbalance, or bias related to specific study design).

• Unclear risk: insufficient information to permit judgment of adequacy or otherwise of other forms of bias.

Based on these criteria, studies will be broadly subdivided into the following three categories.

Low risk of bias for all key domains: low risk of bias.

Unclear risk of bias for one or more key domains: moderate risk of bias.

High risk of bias for one or more key domains: high risk of bias.

Higgins JPT, Altman DG, Sterne JAC: Chapter 8: Assessing risk of bias in included studies. In Cochrane Handbook for Systematic Reviews of Interventions Version 5.10 (updated March 2011). Edited by: Higgins JPT, GreenS. The Cochrane Collaboration, 2011

We expect both event (dichotomous) data and continuous data. Different comparisons will be analyzed separately. Risk ratios (RR) with 95% confidence intervals (CI) and control events rates will be used for reporting dichotomous data. Other binary data will be changed into the RR form.

Continuous data will be expressed as mean differences (MD) with 95% CI. Other forms of data will be converted into MD. In the case of outcome of continuous data with different scales, we will use standardized mean difference (SMD) with 95% CI.

Only simple, parallel-group designed trials will be included for meta-analysis. If there are any studies that have multiple observations for outcome variables, the time frames of included studies will be classified as short-term (within 2 weeks) and long-term (over 2 weeks) follow-up and the meta-analysis will be conducted accordingly.

Tests for homogeneity will be carried out using chi-squared test with significance being set at P > 0.1 and I-squared will be used to estimate total variation across studies (Higgins 2003). If levels of heterogeneity (I-squared < 50%) are seen for the outcomes, we will perform a fixed-effect meta-analysis. If levels of heterogeneity (I-squared > 50%) are seen for the outcomes, we will explore possible sources of heterogeneity using sensitivity and subgroup analyses as described below. If considered appropriate, pooled results in these circumstances will be estimated using a random-effects model. If high levels of heterogeneity (I-squared > 80%) are seen for the primary or secondary outcomes, we will just take the descriptive analyses.

Potential publication bias will be assessed using the funnel plot or other corrective analytical methods depending on the number of included studies (usually n>10) (Egger 1997).

Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327(7414):557-60.

Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple graphical test. BMJ 1997;315(7109):629-34.

Subgroup analyses will be performed in order to explore effect size differences as follows:

1 Patients with stable angina, unstable angina and coronary heart disease angina pectoris.

2 Duration of treatment lasts two weeks and longer than two weeks

3 Patients were treated by Honghua injection or safflower yellow injection

Sensitivity will be repeating the analysis excluding unpublished studies, lower methodological quality, sample size fewer and equal to 40 and different statistical approaches (e.g. using a random effects model instead of a fixed effect model or vice versa);

Fan Zhang

Chongshandonglu Road 79,Huanggu District, Shenyang City, Liaoning Province, China

514917451@qq.com

Liaoning University of traditional Chinese medicine

Mr Fan Zhang, Traditional Chinese medicine blood and vascular institute,Liaoning University of traditional Chinese medicine
Miss Zhi-Hui Chen, Traditional Chinese medicine blood and vascular institute, Liaoning University of traditional Chinese medicine
Dr Hui-Juan Cao, Center for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine
Professor Zhe Zhang, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine
Professor Guan-Lin Yang, Liaoning University of traditional Chinese medicine

09 October 2012

09 January 2013

No funding sources

None known

English

China

Subject indexing assigned by CRD

Angina Pectoris; Carthamus tinctorius; Drugs, Chinese Herbal; Humans;

10 October 2012

10 October 2012