Sanqi Panax Notoginseng Injection for Angina Pectoris

Objective. To evaluate the clinical curative effects of SPN injection on AP. Methods. Six databases were systematically searched including Cochrane Central, PubMed, EMBASE, CBM, Chinese National Knowledge Infrastructure (CNKI), and VIP to identify randomized controlled trials (RCTs). We assessed the quality of included studies, extracted valid data, and undertook meta-analysis following the steps of systematic review recommended by the Cochrane group. Results. Ten moderate-to-low quality randomized controlled trials involving 969 patients were included. There was no evidence that SPN alone had better or worse effects than conventional drugs on improving clinical symptoms (RR 1.09, 95% CI 0.85 to 1.39) and ECG (RR 1.17, 95% CI 0.84 to 1.63). However, there was an evidence that SPN combined with western medications was a better treatment option than conventional drugs alone in improving clinical symptoms (RR 1.28, 95% CI 1.19 to 1.33) and ECG (RR 1.27, 95% CI 1.12 to 1.45). No serious adverse effects were reported. Conclusion. Compared with conventional treatment, SPN may show the potential of optimizing symptomatic outcomes. As a kind of alternative and complementary medicine, SPN may provide another choice for AP patients and further large-scale high-quality trials are needed to confirm this efficacy.


Introduction
Ischemic heart disease (IHD) is characterized by an imbalance of the coronary blood flow and myocardial requirement [1], usually with symptomatic discomfort in the chest, that is, angina pectoris (AP) [2]. AP, especially unstable angina pectoris (UAP), may represent the first clinical manifestation of IHD, and it can follow an acute coronary syndrome (ACS) [3]. Meanwhile, IHD can lead to acute myocardial infarction (AMI) or fatal arrhythmia or cause a number of chronic sequelae, mostly prominently stable angina pectoris (SAP) or heart failure [4]. According to a survey of a community in Beijing, the incidence of AP and myocardial infarction is 30.7% (male 26.2%, female 33.7%) and 2.9% (male 4.8%, female 1.7%), respectively [5]. Conventional medicines for reducing ischemic symptoms and improving prognosis of angina pectoris include nitrates, beta blockers, calcium antagonists, aspirin, and ACE inhibitors. However, all these drugs can have undesirable effects. For example, the abuse of nitrates carries the risks of tolerance and rebound, and can cause headaches, flushed cheeks, and other adverse reactions [6].
In clinical practice, the available PNS agent, which is approved by State Food and Drug Administration of China, includes Sanqi Panax Notoginseng (SPN) injection for intravenous treatment and Xuesaitong soft capsule for oral treatment. PNS, which including notoginsenoside R1, ginsenoside Rb1, Rg1, are extracted from the raw root of Sanqi and then chemically derivatized into water-soluble PNS for the preparation of injection. The common dosage for administration of SPN is 200-400 mg per day. SPN injection is given diluted at the point of treatment in 250-500 mL 5% glucose injection for intravenous administration. It is widely used in Chinese hospitals for cardiovascular diseases.
This study aimed to systematically and objectively evaluate the clinical curative effect and safety of SPN for AP based on a general understanding of previous research and metaanalysis of randomized controlled trials (RCTs) on AP. Yang and X. Xiong). The English searching terms were used individually or combined including "angina pectoris", "Sanqi Panax Notoginseng injection, " "randomized controlled trial", "controlled clinical trial", "randomly", "trial", "randomized, " and "randomized". The Chinese searching terms were used individually or combined including those for the generic name of angina pectoris ("Xian jiao tong"), Sanqi Panax Notoginseng injection ("Xue sai tong zhu she ye"), and randomized ("sui ji").

Study Selection.
Both the titles and abstracts of potentially relevant studies were identified through searching and reviewed independently by 2 reviewers (X. Yang, and X. Xiong). The randomized controlled trials that evaluated the cardiovascular effects of SPN for AP were included: (a) participants were suffering from and being treated for angina pectoris; (b) the study was claimed to be an RCT; (c) the study compared SPN with western medicine in efficacy; (d) duration of treatment was at least four weeks. Duplicated or redundant studies were excluded. If there were discrepancies in the process of selection, whether to include or exclude a study was resolved by a third author (J. Wang).

Inclusion Criteria of Interventions and Participants.
The trials include intervention and comparison of any of the following: (1) SPN plus routine treatment versus routine treatment; (2) SPN plus routine treatment versus routine treatment + placebo; (3) SPN versus routine treatment. The participants who were suffering from and had been diagnosed as UA should be included regardless of the severity. The Diagnosis of AP [18] was according to "the International Society and Federation of Cardiology/World Health Organization (ISFC/WHO). "

Inclusion Criteria of Outcome
Measures. The primary outcome measure was mortality due to ischemic heart disease or incidence of heart events, for instance, AMI, severity arrhythmia, heart failure, and revascularization. The secondary outcome measure was symptomatic and ECG improvements. Effective symptomatic improvements should achieve at least 50% (basic) or 80% (significant) reduction of angina symptoms (RAS). Effective ECG improvements should achieve at least 0.05 mV lowering at ST segment in ECG (basic) or nearly normal (significant) ECG during an exercise test as suggested in the ACC/AHA guideline [19]. Other outcomes like frequency of angina attack (FAA), duration of angina attack (DAA), follow-up, and adverse events were also measured.

Methodological Quality Assessment.
Six specific domains were used to assess the qualities of included RCTs including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome data, incomplete outcome data, and selective reporting. Two authors (X. Xiong and X. Yang) independently assessed the methodological quality of included RCTs using RevMan 5.1.0. This judgment on the risk of bias is categorized by three levels: "high risk, " "unclear risk, " and "low risk. " Trials which met all criteria were judged as having a low risk of bias, trials which met none of the criteria were judged as having a high risk of bias, and trials with insufficient information to judge were classified as unclear risk of bias.

Statistical Analysis.
Two authors (X. Yang and X. Xiong) used RevMan 5.1.0 provided by Cochrane Collaboration to perform a meta-analysis of RCTs if the intervention, control, and outcome were the same or similar [20]. Dichotomous data were expressed as risk ratio (RR) and continuous outcomes as weighted mean difference (WMD), with their 95% confidence intervals (CI), respectively. The statistical heterogeneity was examined with the 2 -test. In the absence of significant heterogeneity ( 2 < 50%), a fixed-effect model was used; otherwise random-effects model was used for pooling data ( 2 > 50%).

Result
A total of 1442 studies were identified through searching 6 electronic databases. After screening and examining the titles and abstracts of studies, 125 of them were included for further assessment. We excluded the duplicates, animal Evidence-Based Complementary and Alternative Medicine 3 experiments, reviews, case reports, and so on for not meeting the inclusion criteria. The full texts of all 125 articles were reviewed carefully by two authors (X. Xiong and X. Yang) and other ineligible studies were excluded. Finally, 10 RCTs [21][22][23][24][25][26][27][28][29][30] were included which had been conducted and published in Chinese (see Figure 1).  [25] reported follow-up data and adopted mortality as primary outcome. The daily dosages of SPN were 400 mg in four studies [21,26,29,30] and 500 mg in the other six studies [22-25, 27, 28]. SPN injection was given diluted at the point of treatment in 20 mL 25% glucose injection for intramuscular administration or in 250-500 mL 5% glucose injection for intravenous administration. The symptomatic and ECG improvements were reported in all ten studies, while two studies [21,27] also reported changes of frequency of angina attack and duration of angina attack, respectively. The other outcomes included blood lipid, C-reactive protein (CRP), and adverse effects. There were two comparisons: (I) SPN versus conventional medicines; (II) SPN plus conventional medicines versus conventional medicines.

Quality Assessment of the Included Studies.
Cochrane risk of bias tool was used to assess of risk bias. All 10 RCTs mentioned the word "randomization, " but none of them described it in details. Only one study [24] mentioned the performance of single blinding. None mentioned allocation concealment or intention-to-treat analysis. Because the protocols of all the 10 included trials were not accessible, selective reporting was generally unclear (Figures 2 and 3).   ? ? treatment group reported angina and ECG improvement. No statistical heterogeneity was found among these studies in angina improvement ( = 0.09 > 0.05, 2 = 43%); however, heterogeneity was found in ECG improvement ( = 0.05, 2 = 50%) (see Figures 4 and 5). The results showed that SPN plus conventional drugs achieved statistically significant improvement of clinical symptoms than conventional drugs alone (RR 1.28, 95% CI 1.19 to 1.33, Figure 4) and improvement of ECG (RR 1.27, 95% CI 1.12 to 1.45, Figure 5).  ( = 0.004, 2 = 77%) and in ECG improvement ( = 0.006, 2 = 76%) (see Figures 6 and 7). The results showed that SPN achieved no significant improvement of clinical symptoms than conventional drugs alone (RR 1.09, 95% CI 0.85 to 1.39, Figure 6) and improvement of ECG (RR 1.17, 95% CI 0.84 to 1.63, Figure 7).

Other Outcomes (Frequency and Duration of Angina
Attack, BL, and CRP). Compared with conventional medicine, one trial [21] indicated that duration of angina attack decreased 8.9 ± 3.5 min to 6.5 ± 2.4 min favoring SPN plus conventional medicine. The other trial [27] indicated that frequency of angina attack decreased 4.21 ± 2.05 times to 2.47 ± 1.57 times favoring SPN plus conventional medicine. Four trials [22,23,26,28] showed that, after treatment, the level of BL decreased significantly ( < 0.05) in SPN group compared to control group. Two trials [26,30] showed that after treatment, the level of CRP decreased significantly ( < 0.05) in SPN plus conventional drugs group compared to control group.

Publication Bias.
We failed to perform funnel plot to detect publication bias because of insufficient number of trials.

Discussion
According to our results, SPN appeared to be an effective and safe treatment option for the treatment of AP, and SPN plus conventional drugs appeared to be more effective than conventional drugs alone. A total of 10 randomized trials including one with 969 participants were included in our review for AP. Improving patient outcomes is one of the primary goals of AP  management. Several evidences have proved that traditional Chinese medicine (TCM) is a holistic system of medicine and have unique theories of the treatment, especially for relieving symptoms [32][33][34]. Compared with conventional drugs, SPN has the potential of being more effective on the improvement of clinical symptoms and ECG; however, these advantages have been obvious based on the low-level evidences collected so far. The results in Groups I and II show that SPN with or without routine conventional drugs could improve the degree of angina and reduce the frequency of angina attacks after 2-4 weeks of treatment. Besides these presenting symptoms of the patients, objective measurements such as ECG also provided evidence. However, several limitations should be considered before accepting the findings of this paper.
Although all 10 RCTs claimed that the positive effect of SPN combined with conventional drugs was better than conventional drugs alone. We still cannot make firm conclusions due to poor methodological quality. All trials reported randomization but lacked details on the method of randomization. They failed to provide enough information for judging whether the randomization procedures had been carried out properly. No multicenter, large-scale RCTs were identified. No dropouts and withdrawals were described. No placebo control was used and none of the trials were described as double blind. All of the conventional drugs therapies varied from trial to trial. It should also be pointed out that the different measurements of outcome were all short-term outcomes, such as symptoms relief before and after treatment. The durations of treatment were various, and reported methods were diverse in included trials. The longterm effects of SPN on patients with AP and its role in the prognosis were scarcely discussed.
None of the included trials reported severe adverse events possibly related to XST, and the adverse effects included 7 cases of headache 1.53% (7/456) and 3 cases of rash 0.65% (3/456) only. We cannot draw firm conclusions about the safety of XST since 3 of 10 trials did report information on safety.
Since all of the trials were of small size with positive results and were conducted in China, geographic biases may be induced. The 10 trials included in this review were of moderate-to-low quality. As a result, the evidences need to be interpreted with caution. While SPN is a widely used therapy for AP in China, the results of the present review suggest that high-quality controlled trials are required for assessing longterm safety by designing a longer duration of treatment and a long-term follow-up.

Conclusion
To the best of our knowledge, this review is the first to systematically evaluate the effects of SPN in the treatment of AP, addressing the lack of this type of research. In conclusion, SPN shows potential in treating AP; however, the findings should be interpreted with caution due to the low quality of included trials. Rigorous multicenter, large-scale clinical trials must be carried out to reveal the exact effectiveness in the future.

Conflicts of Interests
All authors declare that they have no conflicts of interests.