RANDOMIZED CLINICAL TRIAL TO EVALUATE THE EFFICACY OF GOMUTRA HARITAKI RASAYANA WITH AND WITHOUT VIRECHANA KARMA IN THE MANAGEMENT OF KAPHAJ HRUDROGA [CORONARY ARTERY DISEASE]

Title

Randomized Clinical Trial to Evaluate the efficacy of Gomutra Haritaki Rasyanawith and without Virechana Karma in the Management of Kaphaj Hrudroga (Coronary Artery Disease).**

Research question:

What is the efficacy of Gomutra Haritaki Rasyana, both with and without Virechana Karma, in the management of Kaphaj Hrudroga (coronary artery disease)

Hypothesis

**Null hypothesis:**There is no significant difference in the efficacy of Gomutra Haritaki Rasyana with Virechana Karma compared to Gomutra Haritaki Rasyana without Virechana Karma in the management of Kaphaj Hrudroga (Coronary Artery Disease).

**Alternative hypothesis:**There would be significant difference in the efficacy of Gomutra Haritaki Rasyana with Virechana Karma compared to Gomutra Haritaki without Virechana Karma in the management of Kaphaj Hrudroga(Coronary Artery Disease ).

According to world health organization cardiovascular diseases are the leading cause of death globally. Coronary artery disease (CAD) also known as atherosclerotic heart disease is the most common type of heart disease and a frequent cause of cardiac events. The World Health Organization reported that, In 2022, there were 315 million people with CAD globally, with an age-standardized prevalence of 3,605 per 100,000[1]. In urban India, the prevalence of CAD has increased from 1.1% to about 7.5% over the last three decades. In rural India, the prevalence has increased from 2.1% to 3.7%[2]. This disease has been proved to be the major cause of death in both the developed and developing countries. Lifestyle, environmental factors, and genetic factors pose as risk factors for the development of cardiovascular disease. The risk factors of CAD include diabetes mellitus, hypertension, smoking, hyperlipidemia, obesity, homocystinuria, and psychosocial stress. The implementation and maintenance of healthy lifestyle behaviours are considered the rate limiting step in cardiovascular disease prevention. The epidemiological transition views the period of mid nineteen century as the period of transition from infectious to non infectious disease and increase in lifestyle diseases such as cardiovascular diseases.Coronary artery disease (CAD) presents with a wide range of symptoms, reflecting its impact on multiple organ systems. The primary symptoms of CAD often include fatigue and shortness of breath, which arise from the heart’s decreased ability to pump blood effectively. As the disease progresses, patients may experience orthopnea, or difficulty breathing while lying flat, and paroxysmal nocturnal dyspnea (PND), characterized by sudden episodes of breathlessness at night.

Effective management of coronary artery disease requires a holistic approach addressing primary cardiac issues and secondary effects on other organs. This includes lifestyle changes, medications, and interventions, alongside monitoring for complications like kidney dysfunction and cognitive decline. A multidisciplinary team and patient education are essential for optimal outcomes.

Cardiovascular disorders are discussed under Hrudroga in ayurveda. As ayurveda is recognized as a foremost life science and describes way to prevent and manage lifestyle disorders, the world is being attracted towards its potential. Ayurveda provides better solution in the form of Hrudya regime which includes proper dietary management, lifestyle advices, Panchakarma like detoxification and biopurification procedures, medicaments and rejuvenation therapy.

Need of the study

Despite important advancements in the pharmacotherapy of coronary artery disease (CAD), the actual percent reduction in mortality associated with the use of modern pharmacological agents has been relatively unpretentious. Moreover, the available pharmacological agents are also not free from various adverse effects. In the current epidemiological shift of diseases in a global perspective, where the life style diseases, degenerative diseases and mutagenic diseases are over extended, for which the current practises in medicines are proving to be inadequate and thus the need for an evidence-based approach of medicine is needed. Hence there is an immense requirement of certain Ayurvedic drugs which can increase efficiency and performance of compromised heart for healthy living in a natural way with least possible adverse effects. Ayurveda is having such prepatent ability for correcting that inadequacy in managing these diseases, which can be managed and prevented with proper assessment and intervention.

Drug review:

Details of study drug

1.    Gomutra Haritaki

Classical categorisation

**Charaka:**Mentioned in Pandu Roga and Kaphaj Sotha

2.     Trikatu Churna

(Su. sutra 38/58)

Table 2

S. No

Drug Name

Scientific Name

Properties

Part used

Proprotion

|1.

Pippali

Piper longumLinn

Rasa-Katu. Guna-Laghu Virya-Ushna Vipaka-Madhura

Fruit

1

|2.

Sunthi

Zingiber officinaleRoscoe

Rasa-Katu. Guna-Laghu. Virya-Ushna Vipaka-Madhur. Dosha karma-Kapha, Vata Samak

Fruit

1

|3.

Maricha

Piper nigrumLinn

Rasa-Katu

Guna-Tikshna, Laghu.

Virya-Ushna. Vipaka-Katu Doshakarma-Kaphavatahara

Fruit

1

       PREVIOUS RESEARCH WORKS:

Previous research work has been conducted on Coronary Artery Disease globally with Ayurvedicintervention. The important database related to the proposed clinical trial are listed in Table  3.

 Study Design

Type of Study:                             Interventional

No. of Groups:                              2

Parallel assignment of subjects

Sample size:                                  130 (65 in each group)

Method of Randomization:           Random table number

Masking:                                       Open label

Primary Purpose:                          Treatment

Timing:                                          Prospective

 Sample Size:

Study aims to measure the effect of Gomutra Haritaki Rasyana with and without Virechana karma on Coronary Artery Disease patients, it is assumed that the Virechana Karma will have  15% better result than those without Virechana Karma on change in volume and percentage occlusion of soft and hard plaques in CCT angiography. Assuming equal allocation (1:1), 80% power, 5% level of significance and 2-sided test and using the below said formula -

sample size = 65, assuming 10 percent dropout/non-response.

Considering the time constraints and financial budget, the sample size can be 30 per group.

Inclusion

Both Male and Female.

Age group 20-65 years

Class I, II and IIa (III) as per Canadian Cardiovascular Society grading of angina pectoris.

CAC Scoring< 400 or less than 90 percentile

ECG- T wave inverted without Q wave / ST elevation

Stress TMT- Positive

Troponin T test- Negative

Angiography- < 60% occlusion in any of the coronary artery

Brain Natriuritric Peptide < 400pg/ml

Those are able to give written consent

Exclusion criteria

Age group> 65 year

Renal insufficiency (S. Creatinine> 2 mg/dl, Blood Urea> 40 mg/dl)

ECG finding S/O

ST Elevation

LBBB

Q wave

2D ECHO showing presence of any valvular heart disease

Tachycardia/ Ventricular arrhythmia

Low Left Ventricular Ejection Fraction (LVEF< 40%)

Positive Troponin Test

CT Angiography lesion > 60%

CPK-MB> 5%

Prolonged or traumatic cardiovascular resuscitation

Previous Coronary Intervention (within 6-12 months) or any bypass surgery

Prolonged chest pain (> 30mints) associated with vomiting and syncope

Chest pain with vagotonia (bradycardia, pallor and syncope)

Recorded Blood Pressure >180/100mmHg

Raised Prothombin time, Activated Partial Thromboplastin Time

Heart failure (Brain Natriuritric Peptide > 2 times)

BMI<25

Grouping and Drug Delivery Regimen (drug, dose, duration, follow-up, withdrawal criteria, rescue medication)

A.    For this study, clinically diagnosed and confirmed patient of Coronary Artery Disease will be divided into two groups

§  Group 1  Registered patients of Coronary Artery Disease will be given Virechana therapy followed by Gomutra Haritaki  (3g) and Trikatu churna (2g) twice in a day with luke warm water, empty stomach for three months.

§  Group 2 registered patients of Coronary Artery Disease will be given Gomutra Haritaki (3g) and Trikatu churna (2g) twice in a day with luke warm water, empty stomach for three months.

B.    Preparation of Drug and Standardization:

All the drugs will be procured from the genuine source and identified and standardized as per API from the Govt. approved laboratory.

Study Protocol

Step 1  Deepan- Pachan (Musta Churna (3g) plus Trikatuchurna (3g) twice in a day with luke warm water)

Step 2  Snehapana with GugguluTiktak Ghrita as per the dose decided by physician

Step 3  Virechana by PhalatrikadiKwath (50ml) plus Kutakichurna  (5g)

Samsarjana Karma

GomutraHaritakiRasayana

ü Gomutra bhavita haritaki churna (3g) and trikatu churna (2g) given twice in a day with water as vehicle (12h apart) for 90 days.

Medicines use in different stages of Virechana are-

 

S. No.

Stage of Virechana

Medicine with dose and timing

|1.

Deepana- Pachana

Musta churna- 3g plus Trikatu churna 3g twice in a day with lukewarm water

|2.

Snehapana

Guggulu Tiktak Ghrita

|3.

Bahya Abhyanga and Svedana (external massage and sudation)

Mahanaryan Taila for external massage and Dashamula Kwath for fomentation.

|4.

Virechana

Phalatriakdi Kwath (50ml) plus Kutaki Churna (5g).

·       Virechana karma will not be done in patients having BMI less than 15, uncontrolled blood pressure and patients having uncontolled cardiac markers like NT-ProBNP, CK-MB etc.

DIET PLAN DURING RESEARCH TRIAL

1.     Deepan-Pachana

Regular diet with Dhanyaka- Shunthi Jala (water processed with Coriander and ginger powder).

2.     Snehapana

Luke warm water whole day as and when required.

Moong dal soup – Soup of green gram.

Roti + boiled green vegetables with spices. Whenever required.

The above food item should be taken only when patient feel excessive hunger.

3.     Abhyanga- Svedana(External massage and sudation):

Khichadi (Polenta)- Prepared by moong dal (green gram) plus rice plus ginger powder plus turmeric powder and Saindhavalavan.

Moong dal soup – Soup of green gram with spices – Pepper, ginger etc.

Roti and  boiled green vegetables with spices.

 4.     **During *Virechana-***Virechana should be given empty stomach and during purgation hot water is allowed to drink. After completion of Virechana diet is planned according to the number of Vega (number of stool pass).

5.     **After Virechana:**Protocol of diet after Virechana is very specifically defined in Ayurveda and termed as **Samsarjana Krama.**This dietary regulation advocates the restoration of normal diet in sequential manner starting from very light liquid diet. The dietary module given after Virechana is as followed-

 

Day

Annakala**(Timing)**

PravaraShudhi

MadhyamaShudhi

Avara or HinaShudhi

|1

1

M

|E

Shali Peya(thin gruel)

Shali Peya (thin gruel)

Shali Peya (thin gruel)

|2

2

M

Shali Peya

Shali Peya

ShaliVilepi(thick gruel)

|3

E

Shali Peya

Shali Vilepi

Krita/akritaYusha (green gram soup)

|3

4

M

ShaliVilepi(thick gruel)

ShaliVilepi(thick gruel)

Krita/akritaMamsa rasa (processed/ unprocessed meat soup)

|5

E

ShaliVilepi

AkritaYusha

Normal diet

|4

6

M

ShaliVilepi

KritaYusha

|7

E

AkritaYusha

Akrita Mamsarasa

|5

8

M

KritaYusha

KritaMamsarasa

|9

E

KritaYusha

Normal diet

|6

10

M

AkritaMamsarasa

|11

E

KritaMamsarasa

|7

12

M

Krita Mamsarasa

|E

Normal diet

M=morning, E=evening; Pravara Shuddhi= Nu. of stool> 20; Madhyam Suddhi- Nu. of stool> 10; Avara Suddhi- Nu. of stool < 10

Shali – The official botanical name is Oryza sativa but is commonly referred to in English as Asian rice, Paddy or simply (rice).

Peya- Thin gruel, Vilepi= Thick gruel, Akrut Yusha= Unprocessed green gram soup, Krut Yusha isProcessed green gram soup, Krut Mamsa rasa= Processed meat juice, Akruta mamsa rasa- Unprocessed meat juice.

Manda, Peya, Vilepi, Yavagu, Odana in Samsarjana krama are prepared by using rice.

Manda is very thin gruel prepared by boiling rice in water, the watery portion is manda.

Peya is liquid rice gruel prepared by boiling rice until it becomes very soft and thin.

Vilepi is thick gruel with more of boiled rice in it.

Yavagu is semi solid food with much rice and very little of fluid in it.

According to Sharangdhara four Pala rice (1 Pal= 48g) boiled in 14 times water, the watery portion is mandaand the thick rice is madhura and laghu that is odana. According to Shushrut, Odan is cooked rice prepared from washed rice, dirt free rice, pleasing to mind, pleasant odour, it should be well cooked, hot or warm, drained off fluid, vishada (non-slimy), easily digestible. That prepared from unwashed rice, not drained off its fluid, not well boiled, and which has become cold is hard for digestion. That prepared from bhrushta tandula (fried rice) are laghu sugandhi, migitates kapha.

Yusha According to Sharangdhara, 1 Pal dravya kalka (48 g of paste) , sunthi and pippali half karsha and drava bhaga one prastha should be taken and boiled till it reduce to half the quantity of drava bhaga, that is yusha.

Yushais prepared by Shimbi dhanya (pulses) like mudga (green gram), masoor (red lentils), chana (split Bengal gram), kulattha (horse gram), etc. But preferably for Samsarjana kramamudga is used. There are two types of yusha-akrut yusha (unprocessed)krut yusha (processed with spices, oil and salt).

According to Sushruta, akrut yusha (unprocessed) is liquid diet which is not added with sneha (oil)lavana (salt) and katu rasa and krut yusha is liquid diet which is medicated with sneha lavanaand katu rasa (green gram soup processed with oil, salt and spices).

Medication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or during the trial.

No concomitant medicine or treatment will be allowed during trial period except the rescue medicine if any adverse reaction appears.

OBJECTIVES OF THE RESEARCH PROJECT:

Primary Change in volume and percentage occlusion of soft and hard plaques in CCT angiography.

Secondary

To evaluate the effectiveness of Gomutra Haritaki Rasayana therapy and Virechanatherapy on S. osteocalcin level and intra-coronary calcium deposition.

To evaluate the effectiveness of Gomutra Haritaki Rasayana therapy and Virechanatherapy on soft vs hard intra-coronary plaque deposition.

To evaluate the effectiveness of Gomutra Haritaki Rasayana therapy and Virechanatherapy on coronary artery stenosis.

(B) Duration of Trial

Total duration of trial(clinical trial duration + Follow up duration)- 16 weeks  more or less 5 days due to variability in duration of Virechana Karma) + 30 days =20 weeks.

Duration for Virechanatherapy (including deepan-pachan, ghritapana, virechana and samsarsaj karma)  for 3 weeks (maximum)

Duration of Rasayana therapy for  12 weeks.

Follow-up duration after completion of therapeutic interventions for 4 weeks.

(C) Follow up studies

Subject receiving the Ayurvedic treatment will be daily observed during Virechana Karmaand Samarjana Karma after which they will be regularly followed-up after 4 weeks and 12 weeks whereas the subject receiving only Gomutra Haritaki Rasayana therapy will be followed after 4 weeeks, 8 weeks and 12 weeks.

Subjects of both group will be followed-up after 4 weeks of completion of trial.

All the patient’s will be planned to undergo following laboratory investigations before and after the treatment-

Cardiac computed tomography angiography (CCTA)

Coronary artery calcium scoring

Stress TMT

S. osteocalcin

S. Homocystein

ECG

Lipid profile

CT & BT

CBC

After completion of follow-up duration: Stress TMT, Vit D and ECG will be done.

(E) Criteria for Selection or Diagnosis:

1)    Subjective:

Based on Screening Proforma having CAD Assessment Test (CAT), Canadian Cardiovascular Society Grading Scale and HRUDROGA as per Ayurveda.

2)     Objective-

S. osteocalcin.

Coronary artery calcium scoring

CRITERIA FOR ASSESSMENT

1.     Subjective

Various symptoms based on Ayurvedic text will be assessed before, during and after the treatment for any improvement. The symptoms which will be looked into specifically and rated in each case included Hrudshula, Murccha, Vaivarna, Shwasa, Kasa, etc. For the assessment of improvement, the standard symptom rating scale will be used.

Canadian Cardiovascular Society Grading Scale questionnaires[10].

SF-36 questionnaires for (CAD).

2.     Objective

Laboratory Parameter

Cardiac computed tomography angiography (CCTA)

Coronary artery calcium scoring

Stress TMT

ECG

S. Osteocalcin

S. Homocystein

PARAMETER FOR ASSESSMENT OF STUDY OUTCOMES

Primary Endpoint

Change in volume and percentage occlusion of soft and hard plaques in  CCT angiography.

Secondary Endpoint

Change in followings-

Change in coronary artery calcium scoring.

Change in stress TMT.

Change in Chest Pain/ Discomfort Questionnaires.

SF-36

BODE Index.

STATISTICAL METHODS

The data will be presented in the form of Descriptive statistics such as Mean SD, SEM or Range, etc., and Median with 25 and 75 Percentile, Qualitative variables will be presented as counts and percentages.

Data sets-Efficacy assessment as per protocol set and safety assessment with Intent to treat set. The data generated would be subjected to a normality test with the Shapiro-Wilk test. If the normality test is passed, a parametric test would be employed otherwise non-parametric test is employed.

For objective data, the paired t test will be employed to assess before and after treatment differences within the groups and Repeated measures of ANOVA(R-M Anova) will be employed to assess the differences between the groups. This will apply to hematological parameters and calcium scoring during the trial.

For subjective data, the Wilcoxon signed rank test will be employed to assess before and after treatment differences within the groups, Mann Whitney test will be employed for assessing the difference between the groups.

The changes observed with a p value less than 0.05 will be considered significant and less than 0.001 to be highly significant.

IBM SPSS Statistics for Windows, version 26 will be used for the statistical analysis. Also, the standardized effect size will be calculated to ascertain the significant difference observed in the clinical evaluation.