Randomized controlled trials of acupuncture for the treatment of essential hypertension: a meta-analysis

To systematically assess the efficacy and safety of acupuncture therapy for essential hypertension. A computerized literature search of the Chinese National Knowledge Infrastructure (CNKI), Chongqing VIP Database (CQVIP), Wanfang Academic Journal Full-text Database (Wanfang), China Biology Medicine Disc (CBM), PubMed, EMBASE, and Cochrane Library was conducted to retrieve randomized controlled clinical trials on acupuncture as the main intervention for the treatment of essential hypertension published from the inception of the database to 30 January 2021. The risk-of-bias assessment was carried out for each included study according to the Cochrane Handbook. Data analysis was performed using Review Manager 5.4.1 and Stata 15.0. After the screening, 46 randomized controlled trials involving a total of 3 859 subjects were included. Primary outcomes included changes in the diastolic blood pressure after intervention [eight studies showed that the acupuncture plus antihypertensive drug group was better than the antihypertensive drug monotherapy group [mean difference (MD)=1.45, 95% confidence interval (CI) (0.48, 2.43), P=0.004, fixed effects model; I2=39%] and changes in the systolic blood pressure after intervention {11 studies showed that the acupuncture plus antihypertensive drug group was better than the antihypertensive drug monotherapy group [MD=8.60, 95%CI (7.12, 10.07), P<0.00001, fixed effects model; I2=26%]}. The secondary outcome was antihypertensive efficacy, 12 studies of acupuncture monotherapy group [risk ratio (RR)=1.20, 95%CI (1.12, 1.28), P<0.00001, fixed effects model; I2=36%] and 15 studies of acupuncture combined with antihypertensive drug group [RR=1.27, 95%CI (1.20, 1.34), P<0.00001, fixed effects model; I2=6%] showed better results than the antihypertensive drug monotherapy group in antihypertensive efficacy. In terms of the adverse events, four studies showed that the acupuncture monotherapy group had fewer adverse events than the antihypertensive drug monotherapy group [RR=0.10, 95%CI (0.04, 0.25), P<0.00001, fixed effects model; I2=0%]. Acupuncture combined with antihypertensive drugs is superior to antihypertensive drugs alone in reducing blood pressure, and acupuncture therapy is effective and safe for the treatment of essential hypertension with fewer side effects. However, there is still a lack of high-quality multicenter randomized double-blinded controlled trials in this field. Rigorous large-sample clinical trials are needed to validate these findings.

Essential hypertension is a clinical syndrome characterized by elevated arterial blood pressure in the systemic circulation. It is one of the most common cardiovascular diseases and can easily cause damage to organs such as the heart, brain, and kidney [1] . With economic progress, improvement in living standards, and lifestyle changes, the prevalence of hypertension is increasing yearly [2] . According to statistics from the World Health Organization (WHO), the global number of deaths from hypertension complications in 2012 was 9.4 million, and essential hypertension has become a significant public health problem worldwide [3] .
The treatment of essential hypertension is usually the life-long use of antihypertensive agents to maintain blood pressure in a relatively stable range. However, long-term medication use produces drug resistance and different toxic and side effects, including excessively decreased blood pressure, which can lead to dizziness and high pulse pressure due to low diastolic blood pressure (DBP) and unchanged systolic blood pressure (SBP). These can increase the possibility of cardiovascular events [4] . Therefore, how to reduce the toxic and side effects of drugs and seek safe, stable, and effective blood pressure reduction methods in treatment has gradually drawn the attention of patients and physicians.
Acupuncture is a treatment method based on the theory of meridians and collaterals of traditional Chinese medicine (TCM). It prevents and treats diseases by needling specific points on the body with needles and has achieved positive clinical effects [5] . As a TCM therapy, acupuncture has been widely accepted because of its effectiveness, tolerability, and lack of significant side effects. In particular, the effect of acupuncture in lowering blood pressure has been recognized [6] . Researchers have demonstrated that acupuncture can lower the levels of plasma endothelin [7] , adrenaline, and norepinephrine [8] to lower blood pressure. Moreover, it can increase endorphin and nitric oxide [9] to regulate blood pressure.
In clinical research, some researchers have observed acupuncture's efficacy in treating essential hypertension. Many studies have shown that acupuncture has good efficacy for essential hypertension [10] . However, some controversial voices say that acupuncture alone has no significant difference from Western medicine alone regarding the antihypertensive effects [11] . Therefore, acupuncture's clinical efficacy in treating hypertension remains debatable. To this end, this study involved a systematic review and meta-analysis of the randomized controlled clinical trials of acupuncture treatment for essential hypertension to provide further evidence for the application of acupuncture for essential hypertension.

Eligibility criteria 1.Types of studies
We included randomized controlled clinical trials of acupuncture for the treatment of essential hypertension published in formal Chinese or English journals.

Participants
We included patients diagnosed with essential hypertension according to the hypertension criteria defined by the WHO/International Society of Hypertension (WHO/ISH) [12] and the Chinese Guidelines for the Prevention and Treatment of Hypertension [1] , i.e., SBP ≥140 mmHg and/or DBP ≥90 mmHg. We excluded patients with secondary hypertension due to an identifiable cause, such as parenchymal renal disease, renovascular hypertension, primary aldosteronism, and endocrine hypertension.

Interventions
Acupuncture was the primary intervention in the observation group. Acupuncture intervention here included electroacupuncture or acupuncture therapies. We included only conventional body acupuncture, stimulating points only with metallic needles. And we excluded other point stimulation forms, such as point thread embedding, auriculotherapy, and moxibustion, as the main intervention.
Antihypertensive drugs or sham acupuncture or no treatment or lifestyle management were accepted in the control group. If acupuncture combined with Western medicine was the intervention in the observation group, the same Western medicine treatment had to be used in the control group.

Outcomes
The primary outcome measures included changes in the DBP and SBP. The secondary outcome measures included antihypertensive efficacy [13] and adverse events. Other outcomes, such as plasma neuropeptide Y (NPY) and symptomatic efficacy [13] , were accepted if studies were sufficient.

Search strategy
The database search terms were "hypertension", "essential hypertension", "high blood pressure", "blood pressure", "acupuncture", "point", "acupoint", "randomized controlled trial", "random", "randomized", "randomization", "controlled clinical trial", and "clinical trial". The retrieval team searched reviews and conference abstracts related to acupuncture treatment of essential hypertension in order to reduce the risk of missing studies. An example search of PubMed is shown in Table 1 (similar search run in other databases).

Data collection and management
According to the above inclusion criteria, two researchers (LU Yuqing and LI Lingjie) independently screened full texts to determine whether we should include the study. If disagreement existed, a third researcher (XU Jing) was consulted.
Data collection and analysis were independently completed and cross-checked by two authors (HUANG Yan and ZHONG Rui). In all included literature, valid information and data were extracted in a data extraction form, including the basic study information, sample characteristics, interventions, outcomes, follow-up, and adverse events. ZHONG Rui checked it to verify the accuracy of the data. Disagreements between the investigators were resolved by discussion.

Risk of bias assessment
The risk of bias in the included studies was assessed by two reviewers (LU Yuqing and WANG Zhaoqin) according to the bias risk assessment criteria in the Cochrane Handbook for Systematic Reviews of Interventions [14] . We resolved disagreements by discussion or with the third review author (XU Jing).

Data synthesis and analysis
We used Review Manager 5.4.1 software to measure the effect of treatment. The continuous variables were analyzed by mean difference (MD) with a 95% confidence interval (CI). The dichotomous data were analyzed by risk ratio (RR) with a 95%CI. The I 2 statistic was used to measure heterogeneity. The random effects model was used to analyze the combined effect values of the studies with high heterogeneity (P≤0.10 and/or I 2 ≥50%), and the fixed effects model was used for the studies with low heterogeneity (P>0.10 and I 2 <50%). P<0.05 was considered statistically significant. We defined the change in the blood pressure as the pre-treatment blood pressure minus the post-treatment blood pressure, and the mean and standard deviation (SD) were extracted as the continuous outcome. If the mean value and SD were missing, we calculated them according to the formula offered by the Cochrane Handbook for Systematic Reviews of Interventions (Version 5.10) [15][16] . Please see Figure 1 [17] .
Note: SDchange=Standard deviation of change-from-baseline; SD1=Standard deviation of baseline; SD2=Standard deviation of the final; Corr=Correlation coefficient.

Figure 1 Formula for calculation
Here we input the value of correlation coefficient as 0.4. The Review Manager software was used for forest plot analysis to assess study effects, and funnel plot analysis was performed to assess reporting bias if enough studies were included in the meta-analysis (n≥10).

Description of general literature
According to the search strategy, 1 803 potentially qualified studies were initially retrieved in the search. After reading the full texts carefully, 44 qualified studies were finally selected, including 36 Chinese randomized controlled trials (RCTs) and 8 English RCTs ( Figure 2 and Table 2).
A variety of outcome measures were observed in the study.

Risk of bias in the included studies
Baseline data were similar among the 44 RCTs included.

Identification of studies via databases Identification of studies via other methods
Reports sought for retrieval (n=9) Reports not retrieved (n=2)

Identification
Screening

Summary of findings
In reducing blood pressure, the antihypertensive effect of acupuncture combined with antihypertensive drugs was better than that of antihypertensive drugs alone or sham acupuncture plus antihypertensive drugs. However, the effect of acupuncture alone did not show a significant advantage over antihypertensive drugs alone in reducing SBP or DBP. Regarding the antihypertensive efficacy rate, the antihypertensive efficacy in both the acupuncture alone group and acupuncture combined with antihypertensive drug group was more significant than that in the antihypertensive drug monotherapy group.
The systematic review showed that the studies had heterogeneity in reducing blood pressure. The effect of acupuncture can be affected by many factors, including the time of needle retention, treatment course, and the interval between treatments. In the included studies, the duration of acupuncture in each treatment session ranged from 10 min to 30 min, and the course of intervention went from 14 d to 3 months. Most articles did not report the interval between treatments. The minimum frequency of interventions was twice a week, and the maximum was five times a week in the included articles. The high clinical heterogeneity regarding acupuncture intervention may blame for the considerable variation in acupuncture time. In terms of the control group, high heterogeneity is attributed partly to the selection of different antihypertensive drugs. These factors may be responsible for the high heterogeneity in the blood pressure reduction effect.
According to the meta-analysis result of the symptomatic efficacy rate, the efficacy rate of acupuncture alone was better than that of antihypertensive drugs alone. But our findings showed that the symptomatic efficacy was similar between acupuncture plus antihypertensive drugs and antihypertensive drugs alone. This contradictory result implies that the symptomatic efficacy rate may not be a reasonable or adequate outcome measure for evaluating the efficacy of treating essential hypertension. Four studies [18,26,28,49] reported adverse events after treatment compared to the acupuncture alone group and the control group. The incidence of adverse events was significantly lower in the acupuncture group than in the control group, indicating one of the advantages of acupuncture in treating essential hypertension, which is a high safety rating.
Regarding the plasma NPY, acupuncture combined with antihypertensive drugs showed a stronger effect than antihypertensive drugs alone in reducing its level, and the result showed low heterogeneity in the studies. NPY is a critical vasoactive polypeptide that can raise blood pressure levels directly or indirectly [62][63] . Therefore, this indicator indirectly reflects the antihypertensive effect of acupuncture treatment.
We found that the point used most in the included studies was Quchi (LI11), followed by Taichong (LR3), Zusanli (ST36), and Fengchi (GB20). It is suggested that Quchi (LI11) may be a key point in the treatment of essential hypertension.

Strengths and limitations of this study
As one of the meta-analyses of randomized controlled trials to assess the clinical efficacy and safety of acupuncture in treating essential hypertension, this study has preliminarily confirmed that acupuncture is safe and effective for essential hypertension.
However, although the statistical results showed that the acupuncture alone group was better than the antihypertensive drugs alone group in terms of the antihypertensive efficacy rate, the description of the severity classification of hypertension in the included RCTs was unclear, which could also result in publication biases. Besides, the risk of bias in most included RCTs was evaluated as unclear, such as selection bias, potential publication bias might exist due to the lack of methodological details, and the variable design of methodology is also a potential source of high heterogeneity in the included studies.

Conclusion
This study shows that acupuncture plus antihypertensive drugs should be better than using antihypertensive drugs alone in reducing SBP and DBP. In addition, either used alone or combined with antihypertensive drugs, acupuncture can produce a higher antihypertensive efficacy rate than antihypertensive drugs alone. Furthermore, a lower adverse effect rate was reported in acupuncture treatment of essential hypertension compared with antihypertensive drugs alone. Therefore, this study preliminarily proves the efficacy and safety of acupuncture therapy for essential hypertension, and it can be considered a supplementary combination therapy for this medical condition.