Comprehensive rehabilitation with integrative medicine for subacute stroke: A multicenter randomized controlled trial

To determine whether integrative medicine rehabilitation (IMR) that combines conventional rehabilitation (CR) with acupuncture and Chinese herbal medicine has better effects for subacute stroke than CR alone, we conducted a multicenter randomized controlled trial that involved three hospitals in China. Three hundred sixty patients with subacute stroke were randomized into IMR and CR groups. The primary outcome was the Modified Barthel Index (MBI). The secondary outcomes were the National Institutes of Health Stroke Scale (NIHSS), the Fugl-Meyer Assessment (FMA), the mini-mental state examination (MMSE), the Montreal Cognitive Assessment (MoCA), Hamilton’s Depression Scale (HAMD), and the Self-Rating Depression Scale (SDS). All variables were evaluated at week 0 (baseline), week 4 (half-way of intervention), week 8 (after treatment) and week 20 (follow-up). In comparison with the CR group, the IMR group had significantly better improvements (P < 0.01 or P < 0.05) in all the primary and secondary outcomes. There were also significantly better changes from baseline in theses outcomes in the IMR group than in the CR group (P < 0.01). A low incidence of adverse events with mild symptoms was observed in the IMR group. We conclude that conventional rehabilitation combined with integrative medicine is safe and more effective for subacute stroke rehabilitation.

Scientific RepoRts | 6:25850 | DOI: 10.1038/srep25850 We conducted a prospective, two-group, randomized, controlled, assessor-blinded trial across three centers. In this trial, we designed prescriptions of Chinese herbal medicine and acupuncture for subacute stroke according to four common types of pattern differentiation recommended as a standard treatment for stroke in China. With a holistic view of the human body, we conducted a combined treatment of acupuncture and Chinese herbal medicine to regulate the overall and delicate harmony and balance of the body. This study aimed to determine whether integrative medicine rehabilitation (which combines conventional rehabilitation with the complex treatment of acupuncture and Chinese herbal medication based on syndrome differentiation) is more effective than conventional rehabilitation in improving activities of daily living (ADL) and neurologic deficits of stroke (motor dysfunction, cognitive impairment, and post-stroke depression) during the subacute stage.

Results
Study Participants. We  Approximately 864 evaluations yielded the desired sample size of 360 randomized participants (Fig. 1). Of the 360 subjects, 131 (36.39%) passed a screening for cognitive impairment and 153 (42.50%) passed a screening for post-stroke depression (PSD). Of the twelve subjects who dropped out, three were lost to follow-up in two groups; two failed to complete treatment, and one in the IMR group suffered from aspiration pneumonia. Two subjects withdrew because of recurrent stroke and four subjects in the CR group were excluded because of their violations of the treatment restriction (receiving additional TCM treatment). In total, 176 participants of the IMR group and 172 participants of the CR group completed all of the treatments and measurements, and were included in the per-protocol set (PPS), which indicated very good compliance and tolerability of our intervention. No participants died during the study period. A total of 180 subjects of each group were included in the full-analysis set (FAS). The efficacy results of the PPS and FAS were consistent, so we presented efficacy results here only from the PPS. The two groups did not differ in pretreatment demographic and clinical variables at baseline, as shown in Table 1.
The Fugl-Meyer Assessment (FMA), with a total possible score of 100 points, was included as another secondary outcome to assess motor function 13 . There was a significant improvement in FMA in the IMR group ( Post-stroke depression (PSD) is also a common symptom after stroke. A total of 76 cases in the IMR group and 77 cases in the CR group were diagnosed to have PSD according to a 24-item HAMD score ≥ 8 15 . The baselines of HAMD and SDS in the two groups were comparable (P = 0.919; P = 0.305) ( Table 1). The means of both variables were significantly different between the two groups (Interaction effect: HAMD: F (3, 149) = 9.77, P < 0.001; SDS: F (3, 149) = 8.08, P = 0.029) ( Table 2), and the changes from baseline were also significantly bigger in IMR compared with CR (HAMD: − 7.20 ± 3.08 vs.  Table 3). Figure 2e shows that there were significant differences in means with HAMD at week 20 (

Table 3. Value Changes from Baseline (week 20-week 0) of Variables Compared by Independent Samples t-test (PPS).
reactions to Chinese medicines were monitored by lab tests (liver and kidney function tests and three routine tests of blood, urine and stool) and documentation of allergies and symptoms of gastrointestinal discomfort. Table 4 shows mild symptoms with low incidence and rare adverse events in the IMR group during the study period (Please see Supplemental Table S2. Adverse Events Reported in Study).

Discussion
This trial demonstrated that integrative medicine rehabilitation had better effects than conventional rehabilitation alone in improving ADL, neurological impairment, motor function, cognitive impairment and PSD as long-term (a) MBI score for the IMR and CR at four testing time points (mean ± SEM; IMR n = 176, CR n = 172). **P < 0.01, compared to CR group. (b) NIHSS score for the IMR and CR at four time points (mean ± SEM; IMR n = 176, CR n = 172). **P < 0.01, compared to CR group. (c) FMA score for the IMR and CR at four testing time points (mean ± SEM; IMR n = 176, CR n = 172). **P < 0.01, compared to CR group. (d) MMSE score for the IMR and CR at four testing time points (mean ± SEM; IMR n = 62, CR n = 69). *P < 0.05, compared to CR group. (e) HAMD score means for the IMR and CR at four testing time points (mean ± SEM; IMR n = 76, CR n = 77). *P < 0.05, compared to CR group.
outcomes. The beneficial results on all outcome measurements during the follow-up period indicated that this comprehensive rehabilitation focused on the adjustment of overall function may contribute to many aspects of stroke recovery. The ultimate goal of stroke rehabilitation should always be focused on improving ADL of patients so that they could achieve greater independence 16 , which was the primary outcome measured by MBI and was considerably improved in this trial. The NIHSS is a neurologic severity scale developed mainly for use in acute-stroke therapy trials and early prediction of functional abilities 17 , but we found it sensitive in our subacute stroke trial. We used the FMA motor subscale to measure motor function of upper and lower extremities, and observed positive improvements. The results of multivariate ANOVA indicated that the mean MBI and FMA both significantly improved at week 8, which were earlier than improvement in cognitive function and PSD at week 20. These findings suggested that the improvement of limb function may greatly contribute to the recovery of ADL, which is consistent with the view that motor function is particularly important in carrying out ADL 18 . Cognitive impairment and depression are two common sequelae after stroke that require early diagnosis and treatment. We used the MMSE, MoCA, HAMD, and SDS as assessment tools. The HAMD has been the "gold standard" in antidepressant clinical trials 19 . The SDS is a self-reported instrument that is usually used to screen for depression in clinical practice. We applied both scales to measure PSD and used the HAMD as a diagnostic item. In the MoCA test for evaluating cognitive impairment, many patients in our trial could not name a rhinoceros because they had never seen this animal. In contrast, the MMSE seemed more applicable in our trial, particularly for uneducated or older participants, which was consistent with previous studies 20 . The results of multivariate ANOVA for comparing means at each testing time point indicated that IMR improved cognitive function and depression at the same time point (week 20).
In terms of the safety of acupuncture and Chinese medication, a very low incidence of mild symptoms and low incidence of adverse events were observed in this trial. As long as acupuncture is performed by trained practitioners using the clean needle technique, it is usually a safe procedure 21 . Prescription of Chinese herbs under pattern identification principles, excluding the use of any toxic herbs, may provide maximum safety. In the hands of experienced practitioners, Chinese herbs are very safe 22 .
Pattern identification (or called syndrome differentiation and treatment) and holistic assessment and diagnosis are two key elements in traditional Chinese medicine. TCM "syndromes" reflect the pathogenesis and pathophysiology of a given case and provide a basis for prevention and treatment 23,24 . We designed the prescriptions of acupoints and Chinese herbs under the principles of these two key elements. The use and modification of acupoints and herbs in all subjects were all made according to the differentiation and treatment of their specific syndromes. The combined use of acupuncture and Chinese herbal medicine could more comprehensively regulate organs and meridians. Furthermore, they may overcome each other's disadvantages.  The scalp is a site dense with capillaries, and scalp acupuncture can result in a small amount of bleeding from a drop of blood to several drops of blood at the local site, which stops quickly upon applying pressure for a few seconds to a few minutes.
Although there have been a large number of randomized controlled trials on acupuncture or Chinese herbal medicine over the past twenty years, most of them were dedicated to revealing the effects of a single modality or only for one particular dysfunction after stroke. Because acupuncture and Chinese herbal medicine may have beneficial effects on many different stroke sequelae, why not use their combination to treat these disorders simultaneously? In reality, patients with stroke not only suffer from motor disorders but also experience PSD, cognitive impairment, or other dysfunctions at the same time. Integrative medicine rehabilitation for stroke patients may have beneficial effects on all dysfunctions that are responsive to personalized treatment of acupuncture and Chinese herbs. In fact, this kind of integrative approach is consistent with common clinical practice in China. Treatment with acupuncture and Chinese medication with multiple goals may produce better and more comprehensive results. Our trial treated patients with hemiplegia, cognitive disorders and PSD simultaneously. The results provide strong evidence that comprehensive rehabilitation approach has multiple effects on ischemic stroke during the subacute stage.
There are several limitations that should be acknowledged. During the trial, one patient with dysphagia suffered aspiration pneumonia caused by taking the herbal decoction orally. We used decoctions (herbs boiled with water) because it is the most common method of applying herbal therapy and is generally regarded as fast and strong in action. However, not all of the patients with dysphagia received nasogastric tube feeding, and many of them were fed orally. To avoid the occurrence of this treatment-related adverse event, we were required to remove dysphagia from the protocol. Another limitation is that we did not use sham acupuncture or placebo herbal medicine in the control group. Without controlling placebo effect, the results of the study may include a potential placebo bias. Because many Chinese patients have previous experience with acupuncture and herbal medicine or know about them, it was impractical to blind them with sham treatments. Moreover, the literature on sham acupuncture is extremely heterogeneous in design and implementation, with highly variable methods 25 . This area of study is quite specialized and is out of the scope of this project. Instead, we paid close attention to reducing bias by minimizing interaction during treatments in the IMR group and communication among participants of the two groups.

Conclusions
In conclusion, the method of integrative medicine rehabilitation in our study features the following two aspects: 1. The diagnosis, treatment and care, conventional rehabilitation, efficacy assessment and safety detection based on Western medicine; 2. The application of a unique way of diagnosing syndrome differentiation and treatment with acupuncture and Chinese herbal medicine. These combined techniques constitute a comprehensive rehabilitation strategy. Our trial demonstrated that treating subacute stroke with the combination of Western medicine and complex TCM treatments (including acupuncture and Chinese herbal medication) improved overall outcomes of stroke rehabilitation.

Study design and ethics. This 20-week clinical trial was conducted in accordance with the Declaration of
Helsinki, registered at Chictr.org (number: ChiCTR-TRC-12001972; date: March 1, 2012), and reported according to CONSORT guidelines. The details of the trial protocol have been published previously 26 . This study was approved as appropriate by the ethics committees of the Third Affiliated Hospital of Zhejiang Traditional Chinese Medical University, Hangzhou Hospital of Traditional Chinese Medicine and Jiaxing Hospital of Traditional Chinese Medicine. We recruited participants by advertising in local newspapers, health-related TV programs, Internet, and posters in the above three hospitals and communities in Hangzhou city and Jiaxing city. All participants were assigned to treatment only after they had signed their informed consent.
Participants. Patients aged 35-80 years old with a recent (30-40 days) ischemic stroke, an NIHSS score of 5-15, and a modified Rankin Scale (mRS) score of 2-5 were included. Patients who had the first incidence of stroke or patients who had a history of stroke but without disability (mRS ≤ 1) were potential candidates for inclusion.
The exclusion criteria eliminated patients with serious heart, liver, kidney, or hematopoietic system-related diseases, or serious psychiatric disorders. Any patients who had received thrombolytic therapy or TCM treatment, participated in other clinical trials in last three months, were pregnant or breast-feeding, or had been born with congenital disabilities were also excluded. Patients who could not receive acupuncture and Chinese medicine treatment were excluded from this study. At the beginning of the study, a patient with dysphagia suffered aspiration pneumonia after taking Chinese herbal decoction orally. To eliminate such treatment-related adverse events, patients with swallowing disorders, which was originally designed as one of the secondary outcomes, were excluded from our trial. We also excluded subjects with minor or severe stroke (the NIHSS score was between 4 and 24 in our original protocol) after the trial commencement, because of the more frequent and intensive care required in severe stroke patients that was beyond our treatment program, and the early discharge in minor stroke patients.
Randomization and Blinding. Subjects were randomly assigned to receive either IMR or CR at a 1:1 ratio using an Excel generated random number list. The randomization sequence was placed into sequentially numbered, opaque, sealed envelopes, which were saved by special screeners. All of the rehabilitation therapists, outcome assessors, and data analysts were blinded to group assignments.

Interventions and comparison. Both groups received conventional stroke rehabilitation treatment dur-
ing the entire 20-week study period. To examine the impact of Chinese integrative medicine on the treatment group, the conventional rehabilitation therapy was similarly applied in both groups. All rehabilitation therapists were blinded to the group assignment of the participants. Rehabilitation treatments were conducted by certified In the depression distal and anterior to the acromion, between the clavicular and acromial portions of the deltoid muscle.

LI11 (Quchi)
With the elbow flexed, on the lateral end of the elbow crease, in a depression between the end of the crease and the lateral epicondyle of the humerus, on the extensor carpi radialis longus muscle.

LI4 (Hegu)
On the radial aspect of the hand, between the 1st and 2nd metacarpal bones, closer to the 2nd metacarpal bone and approximately at its midpoint.
Basic prescription (Body acupuncture for the affected side of lower limb.)

ST32 (Biguan)
Inferior to the anterior superior iliac spine and lateral to the sartorius muscle, at the level of the lower border of the pubic symphysis.
ST36 (Zusanli) 3 cun distal to ST-35 ('lateral eye of the knee') and 1 fingerbreadth lateral to the anterior crest of the tibia, on the tibialis anterior muscle.

GB34 (Yanglingquan)
In the depression anterior and inferior to the head of the fibula, between the peroneus longus and extensor digitorum longus muscles.
GB39 (Xuanzhong) 3 cun proximal to the highest prominence of the lateral malleolus, on the anterior border of the fibula.

BL60 (Kunlun)
In the depression on the line connecting the Achilles tendon and the highest prominence of the lateral malleolus.
For CI

GV20 (Baihui)
At the junction of a line connecting the apices of the ears and the midline, 5 cun from the anterior or 7 cun from the posterior hairline respectively.

Temple-Three-Needles (Niesanzhen)
In the temple area, on the opposite side of the hemiplaegia, the first needle is located in 2 cun straight above ear apex, then the second and third needles are separately located at the lateral 1 cun of the first needle.
For PSD LR3 (Taichong) 1st and 2nd metatarsal bones, in the depression proximal to the metatarsophalangeal joints and the proximal angle between the two bones.

PC6 (Neiguan)
2 cun proximal to the anterior wrist joint space ('most distal wrist crease'), between the tendons of the palmaris longus and flexor carpi radialis muscles.

GV20 (Baihui)
At the junction of a line connecting the apices of the ears and the midline, 5 cun from the anterior or 7 cun from the posterior hairline respectively.
For Type 1 LR2 (Xingjian) Between the 1st and 2nd toes, proximal to the margin of the interdigital web.

LR3 (Taichong)
On the dorsum of the foot, between the 1st and 2nd metatarsal bones, in the depression proximal to the metatarsophalangeal joints and the proximal angle between the two bones.

LR14 (Qimen)
In the 6th intercostal space, on the mamillary line or 4 cun lateral to the midline.

KI3 (Taixi)
In the depression between the highest prominence of the medial malleolus and the Achilles tendon.

LR3 (Taichong)
On the dorsum of the foot, between the 1st and 2nd metatarsal bones, in the depression proximal to the metatarsophalangeal joints and the proximal angle between the two bones.
Continued therapists with more than five years of experience with stroke patients specifically, and were trained according to the investigator's brochure. The program was designed according to the Chinese stroke rehabilitation treatment guidelines 27 . For motor disorder, Bobath techniques and traditional rehabilitation treatments (includes normal limb posture, ROM exercises, muscle strengthening exercises) were used. Bobath concept: theory and clinical practice in neurological rehabilitation describes the major techniques used 28 . Among the above therapies, the selection of specific treatment items and intensity varied according to patients' individual conditions. Participants in both groups who met the criteria for cognitive impairment received an additional one-hour cognitive training conducted by a speech therapist. Participants in both groups who met the criteria for post-stroke depression received an additional one-hour psychological therapy conducted by a psychologist. The conventional rehabilitation program was performed five days per week for 20 weeks. All participants of both groups were recommended to be hospitalized to receive the 20-week free conventional rehabilitation treatment. Each subject had a therapy card that recorded his/her name, randomized number and rehabilitation program (included contents and time). The therapists signed their names after every treatment, but were blinded to the group information as well the assessors. The IMR group received 30 additional minutes of acupuncture therapy as a bedside treatment in a supine position once a day six days per week for eight weeks, and a Chinese herbal decoction twice a day for eight weeks.
Acupuncture treatment. The acupuncture program was performed by certified acupuncturists with more than five years of clinical experience using filiform steel needles (size 0.25 mm × 40 mm, Huatuo brand, manufactured by Suzhou Medical Appliance in Suzhou, Jiangsu Province China). The basic prescription of acupoints (including scalp acupuncture and body acupuncture) and modifications according to different sequelae and pattern identifications are detailed in Table 5. Electro-acupuncture was applied to LI15 (Jianyu), LI11 (Quchi), ST36 (Zusanli), and GB39 (Xuanzhong) points using GB6805-2 Electro-Acu Stimulators (Huayi Medical Supply & Equipment Co., Ltd, Shanghai, China). The parameter was a 2-Hz intermittent wave at an intensity within the patients' tolerance. To minimize social interaction between the acupuncturists and subjects, needles were inserted in 5-7 minutes and the subjects were left alone to rest for 30 minutes, with no additional attention, training, or interaction. Needles were removed quickly within 3-5 minutes, and social interaction during the acupuncture session was minimal.
Chinese medication. The prescription of Chinese herbs was carried out by TCM doctors, which was based on the same four types of pattern identification as acupuncture (contents of Chinese herbal medicine detailed in Table 5). This "syndrome differentiation" for sub-acute stroke treatment is clearly outlined in For PSD -Chai Hu 9 g, Yu Jin 9 g, Bai He 9 g made regarding the registration platform in our final study protocol: swallowing disorder was excluded at the very beginning of the trial to avoid treatment-related aspiration pneumonia; MBI was added as the primary outcome to measure the daily living ability of patients toward greater independence; and the follow-up period was prolonged from sixty days to 12 weeks.
Statistical analysis. Sample size calculations were based on our preliminary test and previous studies 29 and detailed in our study protocol 26 . All analyses were conducted by a statistician blinded to group allocation at the Clinical Research Institute of Zhejiang Provincial Hospital of Traditional Chinese Medicine using the SPSS (Version17.0) statistical package. A P-value (two sided) of less than 0.05 was considered to represent statistical significance. The analysis of MBI, HINSS, FMA and safety were conducted in the full analysis set (FAS) according to the intention-to-treat (ITT) principle. The per protocol set (PPS) was also conducted in the sensitivity analysis for all of variables. The analysis of cognitive impairment and PSD was made among the defined population of corresponding dysfunction (Table 1, legend c). Missing values were handled by the mixed model for repeated measurements (MMRM). Continuous variables in this trial, which were all tested with normal distribution, were expressed as mean ± SD. Categorical variables were expressed as numbers (%). Repeated-measure ANOVA was used to compare differences in all variable means across time by group and time. Multivariate ANOVA was used to compare the means of the two groups at each testing time point. A two-tailed unpaired Student's t-test was used to compare the differences in value changes (follow-up minus baseline) between the two groups. A χ 2 test was used in the statistical analysis for categorical variables of entry.