Two trials reported mortality and progression to severe complications after a 1-year follow-up.46,66 BP was assessed in all included trials. The treatment durations of 5 trials was >6 months.42,46,50,66,89 The QOL was reported in 5 trials,33,36,42,76,92 of which 4 trials33,36,42,76 used the Croog Scale,94 and 1 trial92 used the SF-36 Scale.95 The AEs of 33 trials have been described in detail.21–23,28–30,33,35,38–40,43,45–50,53,60,68–71,74,77,79,84,85,88–91
Risk of Bias in Individual Studies
The risk of bias in the included trials was assessed as unclear and high according to the predefined Cochrane criteria. No randomized, double-blind, and placebo-controlled trial was identified. Only 4 trials on Song ling xue mai kang capsules,21,23,28,44 1 trial on Yang xue qing nao granules,51 1 trial on Liu wei dihuang pills,65 2 trials on Xin ke shu,70,71 2 trials on Tianma gouteng granules,76,77 1 trial on Qiang li tianma duzhong capsules,80 1 trial on Zhen ju jiang ya tablets,87 and 1 trial on Qiang li ding xuan tablets88 reported methods for randomization. The remaining 50 trials simply declared that patients with EH were randomized into treatment and control groups without a description of the specific method. No detailed information was provided to judge whether the study was conducted properly. One trial reported the blinding of participants and personnel.28 Allocation concealment and the blinding of the outcome assessment were not mentioned in all included trials. Six trials reported drop-outs or withdrawals.21,37,46,56,60,79 A pre-trial estimation of sample size was not reported in all trials. We attempted to contact the corresponding authors via telephone, fax, and email for inadequate information; however, most studies did not provide detailed contact information, and no additional information could be obtained to date.
Mortality and Progression to Severe Complications
The effects of TCPM on mortality and the progression to severe complications were only reported in 2 trials.46,66 One trial on Yang xue qing nao granules (130 patients) assessed the incidence of mortality and progression to severe complications at 1 year after treatment compared with antihypertensive drugs (with no detailed information regarding the classification or dosage).46 No deaths or severe complications occurred in the Yang xue qing nao granules group. However, 5 cases of coronary heart disease and 2 cases of transient ischemic attack were identified in the antihypertensive drugs group. A meta-analysis indicated that there was no significant difference between Yang xue qing nao granules and antihypertensive drugs regarding the incidence of coronary heart disease (RR: 0.09; 95% CI: 0.00–1.60; P = 0.10) or a transient ischemic attack (RR: 0.20; 95% CI: 0.01–4.25; P = 0.30).
Another trial also evaluated the effects of quan tianma capsules (500 patients) on the incidence of mortality and the progression to severe complications compared with nifedipine sustained-release tablets (10 mg, bid).66 The meta-analysis indicated that there was no significant difference between quan tianma capsules and nifedipine sustained-release tablets for the incidence of coronary heart disease (RR: 0.84; 95% CI: 0.54–1.29; P = 0.43), myocardial infarction (RR: 0.57; 95% CI: 0.24–1.36; P = 0.21), heart failure (RR: 0.42; 95% CI: 0.11–1.57; P = 0.20), cerebral infarction (RR: 1.04; 95% CI: 0.66–1.62; P = 0.87), cerebral hemorrhage (RR: 0.43; 95% CI: 0.13–1.44; P = 0.17), transient ischemic attack (RR: 1.15; 95% CI: 0.76–1.72; P = 0.51), renal failure (RR: 0.91; 95% CI: 0.42–1.96; P = 0.81), retinopathy (RR: 1.06; 95% CI: 0.49–2.32; P = 0.88), or death (RR: 0.26; 95% CI: 0.06–1.04; P = 0.06).
AE monitoring was reported in 33 trials on 13 TCPMs,21–23,28–30,33,35,38–40,43,45–50,53,60,68–71,74,77,79,84,85,88–91 whereas it is not mentioned in the remaining 40 trials. The 13 included TCPMs were Liu wei dihuang pills, Niuhuang jiang ya pills, Qiang li ding xuan tablets, Qiang li tianma duzhong capsules, Qing gan jiang ya capsules, Qing nao jiang ya tablets, Qing xuan jiang ya tablets, Quan tianma capsules, Song ling xue mai kang capsules, Tianma gouteng granules, Tianma shouwu tablets, Xin ke shu, and Yang xue qing nao granules. Of the 33 trials, no AEs were reported in 10 trials and with Qing xuan jiang ya tablets. The AEs of the other 12 TCPMs included orthostatic hypotension, headache, dizziness, facial flushing, palpitations, nasal congestion, drowsiness, rash, pruritus, dry mouth, cough, nausea, abdominal discomfort, diarrhea, constipation, and ankle edema. No serious AEs were identified, and all AEs disappeared without special treatment. There were 1087 patients in the TPAD group and 1083 patients in the antihypertensive drugs group. Because significant heterogeneity among the trials on every TCPM existed (chi-square = 28.21, P = 0.003; I2
= 61%), a random-effects model was applied. A meta-analysis of all 12 TCPMs indicated that there was no significant difference regarding the AEs between TPAD and antihypertensive drugs (RR: 0.57; 95% CI: 0.32–1.00; P = 0.05), with the exception of Xin ke shu (RR: 0.11; 95% CI: 0.04–0.29; P < 0.0001), Yang xue qing nao granules (RR: 0.18; 95% CI: 0.05–0.60; P = 0.005), and Qing nao jiang ya tablets (RR: 22.05; 95% CI: 1.34–363.98; P = 0.03) (Figure 2).
All 73 included trials evaluated the effects of TCPMs on BP in individuals with EH. Fourteen trials used the categorical BP to evaluate the efficacy of 8 TCPMs, the evaluation criteria of which were authoritatively recommended by the CFDA and the Guidelines of Clinical Research of New Drugs of Traditional Chinese Medicine. The effects were described as follows: “significant improvement” (DBP decreased by 10 mmHg and reached the normal range or DBP did not return to normal but decreased by more than 20 mmHg), “improvement” (DBP decreased by <10 mmHg but reached the normal range, DBP decreased by 10–19 mmHg but did not reach the normal range, or SBP decreased by >30 mmHg), and “no improvement” (did not meet the previously discussed standards).96 To permit at least some overall analysis, these outcomes were converted into dichotomous data. Therefore, we grouped together “significant improvement” and “improvement” as “effective” and “no improvement” as “ineffective.” The 8 TCPMs that were included were Liu wei dihuang pills, Niuhuang jiang ya pills, Qi ju dihuang pills, Quan tianma capsules, Song ling xue mai kang capsules, Tianma gouteng granules, Tianma shouwu tablets, and Yang xue qing nao granules. There were 809 patients in the TPAD group and 787 individuals in the antihypertensive drugs group. Fixed-effects model was used because no significant heterogeneity of the trials was identified (chi-square = 5.29, P = 0.62; I2
= 0%). A meta-analysis of the 14 trials on the 8 TCPMs identified a significant BP-lowering effect of TPAD (RR: 1.15; 95% CI: 1.10–1.20; P < 0.00001) compared with antihypertensive drugs alone (Figure 3).
Fifty-nine trials used continuous BP to evaluate the treatment effects of 16 TCPMs in hypertensive patients, with the exception of Tianma shouwu tablets. The combined results suggested that 13 TCPMs (13/16, 81.25%) used as complementary therapy to antihypertensive drugs significantly decreased SBP by 3.94–13.50 mmHg; however, the other 3 TCPMs (3/16, 18.75%) decreased SBP by 1.00–5.00 mmHg, with no significant difference compared with antihypertensive drugs alone. The meta-analysis also indicated that 9 TCPMs (9/16, 56.25%) used as complementary therapy to antihypertensive drugs significantly decreased DBP by 2.28–11.25 mmHg; however, the other 7 TCPMs (7/16, 43.75%) decreased DBP by -1.00–9.41 mmHg with no significant difference compared with antihypertensive drugs alone. The detailed effect sizes of TPAD compared with antihypertensive drugs are summarized in Table 3. Two TCPMs, Song ling xue mai kang capsules (854 vs 835) and Yang xue qing nao granules (882 vs. 879), had more studies and >1000 patients, respectively.
Quality of Life
Both the Croog and SF-36 scales were used to assess the QOL in 5 trials regarding Song ling xue mai kang capsules,33,36,42 Tianma gouteng granules,76 and Tian shu capsules.92 All 5 trials reported a significant improvement in the QOL of the TPAD group compared with the antihypertensive drug group at the end of treatment. One trial on Song ling xue mai kang capsules33 demonstrated that the Croog Scale increased with the total score (WMD = 26.10; 95% CI: 25.88–26.32; P < 0.00001).
The other 2 trials on song ling xue mai kang capsules36,42 all reported a significant improvement in the sense of well-being (WMD = 7.70; 95% CI: 7.54–7.87; P < 0.00001), physical symptoms (WMD = 2.56; 95% CI: 2.28–2.84; P < 0.00001), work performance and satisfaction (WMD = 2.54; 95% CI: 2.37–2.72; P < 0.00001), and life satisfaction (WMD = 3.48; 95% CI: 3.28–3.68; P < 0.00001) compared with the antihypertensive drug group. One trial on Tianma gouteng granules76 demonstrated a significant improvement on the Croog Scale (WMD = 13.93; 95% CI: 8.10–19.76; P < 0.00001). One trial on tian shu capsules92 exhibited a significant reduction in the total score of the SF-36 Scale (WMD = −27.56; 95% CI: -28.67 to -26.45; P < 0.00001).
Summary of Evidence
The previous decade has witnessed an unprecedented expansion of the field of antihypertensive treatment and drug discovery and development. Thus, Western medicine became the dominant medical treatment worldwide. However, it has been increasingly realized that Western medicine may sometimes fail to treat cardiovascular diseases (CVDs), especially in patients with a history of conventional medicine-related AEs, whereas CAM is becoming increasingly popular and frequently used among patients with CVDs.97,98 As a result of the different theoretical systems and control methods, Western physicians often find CAM difficult to understand. TCM has continued to hold an important position in primary healthcare both in China and other Asian countries.99 Additionally, there is one important characteristic of China's national medical system that facilitates CAM, that is, integrative medicine, which combines TCM and Western medicine together in the clinic and is responsible for health care.100,101 Therefore, as an adjunctive treatment to antihypertensive drugs, TCPM is a popular natural product for EH.102 Because of its health-enhancing qualities, TCPM has been developed and used in China for >30 years. Currently, there are 82 TCPMs approved by the CFDA for the treatment of EH. However, few TCPMs have been evaluated regarding their effectiveness and safety according to current scientific standards; furthermore, few relevant articles on TCPMs for EH have been published in English-language medical journals. There is a lack of studies that assess the majority of the commonly used TCPMs for EH, which has limited their clinical use and weakened the credibility of the study of TCPM internationally. In this article, although many TCPMs did not meet our selection criteria, the findings provided the current status of the clinical evidence regarding the approved TCPMs for EH in China. The methodological quality of most included trials was evaluated as generally “poor” because of inadequate reporting of their methods in detail. However, we did not arbitrarily exclude them because we sought to report on the overall quality. As the first systematic review, this study aimed to assess the quantity, quality, and overall strength of the evidence regarding the most commonly used and government-recommended TCPMs for EH.
There are several strengths in this study. Previous studies have demonstrated that antihypertensive medicine treatment is associated with a substantial reduction of cardiovascular events and mortality.103 There is the possibility that TCPM could, as a complementary therapy to antihypertensive drugs, more significantly lower the incidence rate of major cardiovascular events. In this review, the first finding was the evidence regarding the efficacy of the evaluated TCPMs on primary outcomes. There was inadequate reporting of primary outcome measures. Only 2 trials on Yang xue qing nao granules and Quan tianma capsules assessed the long-term outcomes of mortality and progression to severe complications after treatment. No significant difference between the treatment and control groups was identified. Therefore, no convincing evidence of the beneficial effects that support the routine use of TCPM as an adjunctive therapy for EH could be drawn because of the very limited numbers of RCTs and the patients in these 2 trials. Nonetheless, the findings demonstrated that long-term outcomes of TCPM could be evaluated with RCTs.
Another valuable finding of this review was the estimation on the incidence of AEs. There was a lack of knowledge regarding the significance of reporting the frequency of AEs in the RCTs. TCPM appeared to be free of major AEs. The reported AEs were not severe and required no additional special treatment. Although the aggregated results indicated that there was no difference regarding the AEs between the 2 groups, the safety of TCPMs must still be rigorously monitored and appropriately reported in future clinical trials.
The most striking finding in this systematic review was the estimation of the therapeutic effects of TCPM on secondary outcomes. We also evaluated the effectiveness of TCPM in lowering BP in individuals with EH. The BP outcomes were reported in all included trials. The meta-analysis indicated that 13 TCPMs (81.25%) possess a better BP-lowering effect as complementary therapies, with a SBP decrease of 3.94 to 13.50 mmHg and a DBP decrease of 2.28 to 11.25 mmHg. For example, a significant BP-lowering effect of the most commonly used 2 TCPMs, song Ling xue mai kang capsules (SBP decreased by 7.30 mmHg and DBP decreased by 6.74 mmHg) and Yang xue qing nao granules (SBP decreased by 8.11 mmHg and DBP decreased by 4.91 mmHg), was identified. However, confirmation regarding BP was limited because of the poor methodological quality, the lack of placebo-controlled trials, and the significant heterogeneity of the included trials (Figure 4). Therefore, more evidence is required to confirm these conclusions. If the beneficial effects on BP were confirmed by rigorously designed trials with high methodological quality, it could lead to the identification and use of many valuable treatments for EH.
The fourth finding was the evaluation of the effects of TCPM on QOL. In this review, the data regarding QOL were insufficient. Only 5 trials on 3 TCPMs (Song ling xue mai kang capsules, Tianma gouteng granules, and Tian shu capsules) assessed the QOL in hypertensive patients using the Croog and SF-36 scales. Although the QOL in the treatment groups was generally higher than in the control groups for 3 TCPMs, more rigorously designed RCTs are warranted to confirm these results.
Our study has several limitations. First, all included trials were of poor methodological quality. In our review, in fact, it was impossible to identify well-designed trials to evaluate the efficacy of TCPM for the management of EH. All the included trials were shown to have a high or unclear risk of bias due to design, reporting, and methodology. Inadequate reports of the study design, allocation sequence, allocation concealment, blinding, intention-to-treat analysis, and drop outs were identified in the majority of the trials. There were no definite randomized, double-blind, placebo-controlled trials with clear methodologies. Only 10 trials reported methods for randomization. Allocation concealment was not mentioned in any of the trials. Therefore, the “alleged” trials may not actually represent real RCTs, which could weaken the strength of the clinical evidence and lead to a potential selection bias. No trials were double-blinded. Only 1 trial reported the blinding of participants and personnel. Blinding of the outcome assessment was not mentioned. This would directly lead to performance and detection biases. Additionally, there was a lack of placebo control use. All trials included in the review used an “A + B versus B” design, in which patients with EH are randomized to receive treatment (A) combined with treatment (B) versus treatment (B) alone. This type of add-on design is quite popular in TCM studies in which TCM therapy is added to conventional therapy. Nevertheless, without a rigorous control for a placebo effect, this approach may exaggerate the effects of TCPM and is prone to generate false-positive results and significant systemic errors in the assessment of outcomes. We understood that such bias is a common problem in all TCM studies. Perhaps certain physical features associated with TCPMs, such as aromas, colors, and appearances, limited clinical placebo use. Unfortunately, none of the RCTs utilized a placebo control in the trials. Only a few trials reported drop-outs or withdrawals. Most of the trials did not report details of the intention-to-treat analysis. No trials had a pre-trial estimation of sample size. Thus, whether a sample size met the requirements of a given trial remains unknown.
Second, publication bias is another major cause of bias that should also be considered. We have made efforts to avoid language and location biases; however, only trials conducted in China and published in Chinese could be included for further analysis after comprehensive searches. Therefore, we cannot completely rule out the potential publication bias.
Furthermore, other systematic reviews regarding CAM have encountered similar problems.104 Recently, through huge investments in scientific research and the economical exploitation of TCM, the Chinese government has undertaken enormous efforts to modernize TCM and aims to prove the efficacy of TCM according to international standards. However, in our review, only 1 of the 73 selected articles declared their sources of funding.51
Overall, the results of the trials included in this systematic review are likely to be biased by many factors because of the poor methodological qualities of these studies. The reported beneficial effect of TCPM in lowering BP in hypertensive patients should be interpreted cautiously. Additionally, 2 TCPMs, Song ling xue mai kang capsules and Yang xue qing nao granules, had more studies and greater patient numbers (>1000 patients) and may be worthy of further research.
In summary, this systematic review provided the first limited piece of clinical evidence regarding the effectiveness of TCPMs as a complementary therapy in improving mortality, the progression to severe complications, AEs, BP, and QOL. According to the Oxford Center for Evidence-Based Medicine 2011 Levels of Evidence, the usage of TCPMs for EH was supported by evidence of class level III. However, because of the negative results on primary outcomes, insufficient clinical data, poor methodological quality, small sample sizes, limited numbers of each trial, and the high heterogeneity of the studies, the current evidence is insufficient to support a recommendation for wide TCPM use.
Therefore, future studies should overcome the limitations of the trials included in this systematic review. The following methodological issues should be cautiously addressed: adequate generation of allocation sequences and the concealment of allocation; appropriate methods of double-blinding (blinding of participants and personnel and blinding of outcome assessment); wider use of placebo controls; strict reporting regarding drop-outs and the use of intention-to-treat analysis; a specifically focus on mortality and cardiovascular events with long-term follow-up; and comprehensive reporting of the trials according to the recommendations of the CONSORT Statement.105,106 We also suggest that Song ling xue mai kang capsules and Yang xue qing nao granules, which were evaluated to be with the evidence of class level III, should be prioritized for further research. We hope that this systematic review will pave the way for the generation of evidence-based TCPMs for the treatment of EH.
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