Complement use of Chinese herbal medicine after percutaneous coronary intervention: a prospective observational study

Si-Yu YAN,Wei-Xian YANG ,Pei-Pei LU,Xuan-Tong GUO,Cai-Xia GUO,Yan-Ni SU,Li-Hong MA

Chinese Academy of Medical Sciences &Peking Union Medical College Fuwai Hospital,Xicheng District,Beijing,China

ABSTRACT BACKGROUND Chinese herbal medicine is widely used as a complement or alternative treatment in coronary artery disease(CAD) patients after percutaneous coronary intervention (PCI) in China.We compared the incidence of the major adverse cardiovascular event (MACE) of CAD patients with or without the complement use of Chinese herbal medicine after PCI.METHODS In this prospective,observational study that was conducted from September 2016 to August 2019 in Fuwai Hospital(China),we followed up consecutive patients who received PCI treatment for two years.MACE was defined as the composite allcause mortality,revascularization,and myocardial infarction (MI) and was compared between those using (integrative medicine group) or those not using Chinese herbal medicine as an additional treatment to standard Western medicine,with unadjusted(Kaplan-Meier curves) and risk-adjusted (multivariable Cox regression) analyses.RESULTS A total of 5942 patients after PCI were enrolled in this study,and 5453 patients were included in the final analysis(4189 [76.8%] male;mean age: 61.9 ± 9.9% years).During the follow-ups,2932 (53.8%) patients used only Western medicine while 2521(46.2%) patients had used Chinese herbal medicine as an additional treatment to standard Western medicine.Patients in the integrative medicine group (IM group) were older than the Western medicine group (WM group),had more females and less previous MI.The incidence of MACE was 15.3% (449/2932) in WM group and 11.54% (291/2521) in IM group.Cox regression analysis showed that cumulative incidence of MACE was 27% lower in patients of the IM group than those in WM group (hazard ratio=0.73;95% CI: 0.63-0.85;P <0.0001).CONCLUSIONS For CAD patients after PCI treatment,complement use of Chinese herbal medicine is associated with a lower 2-year MACE incidence.Randomized prospective studies are warranted to provide higher levels of benefit evidence in these patients.

Coronary artery disease (CAD) is a major public challenge and the leading cause of morbidity and mortality worldwide.[1]Percutaneous coronary intervention (PCI) is the most common strategy for treating CAD.In 2018,915,256 patients underwent PCI in the Chinese mainland,[2]which increased 21.5% year over year in 2017.[3]With the development of medical,surgical and interventional treatments,the survival rate of patients with CAD is greatly increased.PCI can achieve patients’coronary artery reperfusion,but cannot change the etiology and pathogenesis of CAD,and may lead to vascular endothelial injury.In CAD patients after PCI who take conventional drugs including aspirin,clopidogrel and statins,about 5%-15% will have a major adverse cardiovascular event (MACE) within one year.[4-6]In addition,conventional drugs may not be tolerated in some patients due to allergies and severe side-effects.[7]Therefore,the secondary prevention strategy after PCI needs to be improved.

In China,traditional Chinese medicine (TCM) is widely used in patients after PCI,in addition to conventional western medicine.Several previous studies showed that for CAD patients after PCI,combined use of Chinese herbal medicine and conventional western medicine may reduce recurrence angina frequency,[8]the occurrence of adverse cardiovascular events,[9-12]improve quality of life,[13]and improve hemorheology,blood lipid,and inflammatory parameters.[14]However,all these studies were limited by small sample size,short follow-up times and inconsistent data analysis methods.[14-16]Therefore,there is a lack of reliable evidence for the efficacy and benefit of TCM in long-term management in post-PCI CAD patients.Thus,we designed this large sample,long-term follow up,observational study with the following objectives: (1) to observe the treatment effects of Chinese patients after PCI in the real-world;(2) to identify the incidence and trends in MACE after PCI;and (3) to compare the incidence of MACE within 2-year in CAD patients who have undergone PCI with and without using additional Chinese herbal medicine.

METHODS

Study Design and Patients

This study was a prospective observational study.Consecutive patients diagnosed with CAD after PCI within a week in Fuwai hospital,Chinese Academy of Medical Sciences from September 2016 to August 2017 were enrolled.Exclusion criteria include(1) age ≤ 18 years;(2) with cognitive or communication impairment;and (3) participating in other clinical studies.Follow-up was conducted by outpatient visit or telephone at 3rd,6th,12th,18th,and 24thmonths after PCI (with a time window of ± 14 days).The study was reviewed and approved by the Ethics Review Committee of Fuwai Hospital,Chinese Academy of Medical Sciences.All participants gave written informed consent.

Definition of Using Chinese Herbal Medicine

Using of Chinese herbal medicine was defined as the patients’ use of any Chinese herbal medicine prescribed by treating physician or by self-prescription for more than half a year during the 2-year follow-up.Chinese herbal medicine includes decoction,powder and Chinese patent medicine.Decoction and powder are usually composed of various herbal drugs,such as Ren Shen,San Qi,Angelica Sinensis,and the specific drug types and doses were mostly decided by clinicians according to the patients’ traditional Chinese medicine (TCM) syndrome classification.Chinese patent medicines are commercial TCM preparation approved by China Food and Drug Administration.

Outcomes

The primary endpoint was MACE,including allcause mortality,myocardial infarction (MI),and revascularization,which was a composite of PCI,percutaneous transluminal coronary angioplasty (PTCA)and coronary artery bypass grafting (CABG).The secondary endpoints were angina symptom score(ASS) and traditional Chinese medicine syndrome quantification score (TCMSS).The safety was evaluated by cardiovascular hospitalization and stroke.An independent endpoint committee adjudicated all potential events.All endpoint events of patients were evaluated by an independent endpoint committee.

Sample Size Calculation

In this study,it is expected that the data of 6000 patients who were consecutively enrolled in Fuwai Hospital after PCI will be collected during the first year.According to previous experience,the proportion of patients treated with Chinese herbal medicine can reach 1/3 level in Fuwai Hospital.Combined with the literature[17]and clinical data of our hospital,the incidence of primary endpoint events at two years after PCI was about 15%-20%.Accordingly,the number of primary endpoints by the end of the study was expected to be about 1200.As an event-driven study,based on a bilateral significant level of 2.5%and an 80% degree of confidence,a statistically significant result can be obtained when a relative reduction of 20% (HR=0.8) or more in the risk of the primary endpoint in IM group compared to WM group with the above sample size.

Statistical Analysis

Continuous variables are expressed in the form of mean ± SD,categorical variables are described in the form of frequency and percentage.According to the distribution characteristics of data,the corresponding parameter or non-parameter statistical method is selected.Baseline characteristics were compared between two groups usingt-tests orχ2tests.The primary endpoint and the safety endpoints were analyzed by the survival analysis.In addition to describing the occurrence of events in each group with the Kaplan Meier curve,Cox proportional hazard model was used to estimate the hazard ratio (HR) and its 95% confidence interval (CI).To further explore the prognostic differences between the two groups,we selected some baseline characteristics as covariables for multivariate Cox regression analysis based on previous studies and clinical significance.The secondary endpoints were analyzed byt-tests.The significance level of the statistical test was 5% on two sides.Statistical analyses were performed using SAS 9.4.

RESULTS

Study Patients and Baseline Characteristics

We screened 6000 patients after PCI,5942 of whom were included in this study.Five thousand four hundred and seventy-one patients completed the 2-year follow-up,of which 5453 (4189 male [76.8%];mean age: 61.91 ± 9.91 years) were included in the final data analysis (Figure 1).Among them,there were 2932 patients (53.77%) in Western medicine group (WM group) and 2521 patients (46.23%) in integrative medicine group (IM group).Baseline demographic and clinical characteristics of patients in two groups are shown in Table1.Patients in WM group were younger,had more males compared to those in IM group,with shorter duration,and more frequently had a history of myocardial infarction compared to those in the IM group.

Table 1 Baseline demographic and clinical characteristics of patients.

Figure 1 Study flowchart of participants.PCI: percutaneous coronary intervention.

Primary Outcome

All patients were followed up for two years.In total,740 patients experienced MACE.The incidence of MACE was 15.31% (449/2932) in WM group and 11.54% (291/2521) in IM group.Patients in IM group had a 27% lower cumulative risk of MACE than those in the WM group (HR=0.73;95% CI: 0.63-0.85;P<0.0001) (Figure 2A).Based on previous studies and clinical significance,we selected some baseline characteristics as covariables for Cox regression analysis (age,gender,the duration of CAD,history of MI,ACS,first PCI,overweight or obesity,current smoking,hypertension,hyperlipemia and diabetes).After adjusting these baseline characteristics,multivariate Cox regression analysis showed a significant difference of MACE incidence between WM group and IM group (HR=0.72;95% CI: 0.62-0.84;P<0.0001).Then,we excluded the patients with poor medication compliance during follow-up(12 patients in WM group and 33 patients in IM group),the results of multivariate Cox still showed that the risk of MACE was significantly lower in IM group than that in WM group (HR=0.71;95% CI:0.61-0.82;P<0.0001).

The incidence of the components of MACE were further investigated.The differences of two groups in all-cause mortality (HR=0.11;95% CI: 0.05-0.24;P<0.0001) and revascularization (HR=0.82;95% CI:0.70-0.96;P=0.012) were statistically significant(Figure 2B&C).Because the number of patients who experienced MI during the follow-ups was too small (6 patients in WMGvs.3 patients in IMG),we did not perform Cox regression analysis for this component.

Secondary Outcomes

After excluding 77 deaths during two years (69 patients in WM group and 8 patients in IM group),5376 survival patients were evaluated with ASS and TCMSS.We analyzed the difference value between the last follow-up and baseline.Table 2 showed that the variations of ASS (P<0.001) and TCMSS (P<0.001)were both significantly different between two groups.

Table 2 The variations of ASS and TCMSS of two groups.

Safety Outcomes

Figure 3 showed the cumulative risks of cardiovascular hospitalization and stroke between the two groups.A total of 406 patients (13.85%) in WM group and 296 patients (11.74%) in IM group were hospitalized for cardiovascular reasons during the 2-year follow up.Multivariate Cox regression analysis showed that the risk of cardiovascular hospitalization in IM group was 19.1% lower than that in the WM group(HR=0.81;95%CI: 0.70-0.94;P=0.007).Twentyfour patients (0.82%) in WM group and 23 patients(0.91%) in IM group experienced stroke.Multivariate Cox regression indicated that there was no significant difference in the incidence of stroke between the two groups (HR=1.04;95%CI: 0.58-1.86;P=0.896).

Figure 2 Two-year cumulative incidence of the primary outcomes and the components of MACE among 5453 patients after PCI.(A): MACE;(B): all-cause mortality;and (C): revascularization.MACE: major adverse cardiovascular event;PCI: percutaneous coronary intervention.

Figure 3 Two-year cumulative incidence of the safety outcomes among 5453 patients after PCI.(A): cardiovascular readmission;and (B): stroke.PCI: percutaneous coronary intervention.IMG: integrative medicine group;WMG: Western medicine group.

DISCUSSION

To our knowledge,this study is the largest prospective clinical study on the efficacy of compliment use of Chinese herbal medicine for the treatment of CAD patients after PCI with MACE as the primary outcome.The results demonstrated that in post-PCI patients with CAD,compared to conventional western medicine alone,additional use of Chinese herbal medicine is associated with significantly lower risks of MACE (especially in all-cause mortality and revascularization) and milder clinical symptoms.

Our study results were consistent with those of previous randomized controlled trials (RCTs).The 5C trial of 808 patients with acute coronary syndrome after PCI reported that combined use of traditional Chinese medicine and standard Western medicine may confer significant benefits to patients regarding the occurrence of MACE.[9]Similarly,another study[10]of 1054 patients with stable CAD showed that additional use of Chinese herbal medicine reduced the incidence of MACE,and a prospective cohort study of 334 AMI patients showed similar results.[18]Gao,et al.[19]analyzed the data of 5284 patients with CAD treated in nine Integrative Medicine hospitals in Beijing and Tianjin,China,and suggested that combined use of traditional Chinese medicine might have potential benefit in reducing MACE,but there was a great difference in sample size between the two groups,which may reduce the statistical power.However,several studies showed that additional use of Chinese herbal medicine might improve clinical symptoms in CAD patients,but not reduce cardiovascular events[12,13].The different results may be related to the sample size,follow-up time,drugs and definition of MACE.

Overall,the 2-year incidence of MACE in this study is 13.3% (15.0% in WM groupvs.11.2% in IM group),which is consistent with the incidence in recent relevant studies.[20-23]

The various Chinese herbal medicines taken by the patients in this study have been extensively utilized in clinical practice in China,some of which have been proved to have a significant effect on CAD in previous clinical research.[8,14,24]In terms of the mechanism of drug action,the previous studies showed that Shexiang Baoxin Pill can reduce myocardial infarction area and protect cardiac function through promoting angiogenesis.[25]Qishen capsules can increase angiogenesis to improve the cardiac function of rats after MI by the Akt signaling pathway.[26]Tongxinluo can alleviate myocardial ischemia/reperfusion injury by activating cardiac microvascular endothelial cells endothelial nitric oxide synthase.[27]Compound danshen dripping pills ameliorate myocardial ischemia,reverse the reprogramming of the metabolism induced by ISO and normalized the level of most myocardial substrates and the genes/enzymes associated with that metabolic changes.[28]

The strength of our present study includes a large sample size,relatively long follow-up times,and a very low rate of losing follow up.Furthermore,our study enrolled participants using various types of Chinese herbal medicine,which may better reflect the real-world efficacy of this treatment in China.According to TCM theory,patients with the same disease types may present different TCM syndromes,and the syndromes of patients will change with time,place,climate and other factors,so the herbal medicines should be adjusted accordingly.

This study has the following limitations: firstly,as a prospective,observational study,inclusion criteria were wider than the RCT study,and patient heterogeneity was greater.Although multivariate adjustment was performed in Cox analysis of endpoint events,other unknown factors that may have influenced the results may still exist.In terms of data on patients’ clinical background,there was a lack of overall assessment of patients’ atherosclerosis,STEMI risk factors and TIMI grading were not collected and evaluated comprehensively.The above confounding factors may have some influence on the results.Secondly,this study is single-center clinical research,which may limit the generalizability of the results,although it may promote consistency of treatment and evaluation.We are looking forward to relevant RCTs with large sample size and long follow-up time to verify our study.

In conclusion,our study showed that,compared to using western medicine alone,additional use of Chinese herbal medicine was associated with a significantly lower risk of 2-year MACE incidence among the CAD patients after PCI,particularly in terms of all-cause mortality and revascularization.The additional benefits of TCM based on conventional western medicines can be anticipated to further improve the second prevention of CAD in the future.

Ethics

The study was reviewed and approved by the Ethics Review Committee of Fuwai Hospital,Chinese Academy of Medical Sciences (Approval No.2016-786).All participants gave written informed consent.

Availability of Data and Materials

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

None.

Funding

This work was supported by the National Key R&D Program of China (2021ZD0111003) and the Capital Health Development Project of China grant (SHF-2016-2-4032).

Authors’ contributions

Li-Hong MA and Si-Yu YAN had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.Concept and design: Li-Hong MA,Wei-Xian YANG,Cai-Xia GUO,Pei-Pei LU.Acquisition,analysis,or interpretation of data: Si-Yu YAN,Pei-Pei LU,Xuan-Tong GUO,Yan-Ni SU.Drafting of the manuscript: Si-Yu Yan,Pei-Pei Lu,Li-Hong Ma.

Acknowledgments

We thank the Medical Statistics Division of Fuwai Hospital,Chinese Academy of Medical Sciences for data analysis.We thank Beijing Econ Medical Technology for the construction and maintenance of the data collection platform.We thank all patients who participated in this study.