Changes in Drug Clinical Trials of Thyroid Diseases in China, 2009-2022.

Objective: The incidence rate of thyroid diseases increased worldwide. This study aims to overview the changing landscape of drug clinical trials on thyroid disease during 2009-2022. Methods: The detailed information of thyroid disease drug trials registered on the National Medical Products Administration (NMPA) Registration and Information Disclosure Platform for Drug Clinical Studies was searched and collected. The thyroid drug clinical trials were analyzed by the characteristics, time trends, indications, and geographical distribution. Results: Sixty-five thyroid disease drug clinical trials were launched from 2009 to 2022 in China, which included 21 trials in nontumorous thyroid disease and 44 trials in thyroid carcinoma. The number of registered trials of thyroid diseases including thyroid carcinoma and nontumorous thyroid disease increased steadily from 2009 to 2020. Bioequivalence studies accounted for the largest proportion (32[49.2%]), while phase I and Phase II studies both only accounted for 18.5% (12/65). A significant difference was observed in the trials phase, and randomization between thyroid carcinoma and nontumorous thyroid disease. In terms of clinical indications and drug mechanisms, the number of trials in multi-target tyrosine kinase inhibitors for thyroid carcinoma (n=35) ranked first, followed by thyroid hormone for hypothyroidism (n=7), thyrotropin for thyroid carcinoma (n=6). Sixty-five trials were led by 36 principal investigator (PI) units, and more than 30% of PI-leading units were located in Shanghai (n=7) and Beijing (n=4). Conclusion: During the past 13 years, the development of thyroid diseases drugs trials has achieved certain progress in thyroid carcinoma, especially the molecular targeted therapy, yet the development of drug trials on nontumorous thyroid disease was very slow.

Level of evidence supporting the Chinese cardiovascular disease clinical practice guidelines and its evolution in the past two decades.

Background: Clinical practice is guided by guidelines in the era of evidence-based medicine to improve healthcare. The consistency between the strength of recommendations and the underlying quality of evidence in clinical guidelines and its evolution dynamically reflects the status of medical practice in important aspects. This study aimed to evaluate the levels of evidence (LOEs) supporting different classes of recommendations (CORs) in Chinese cardiovascular disease (CVD) guidelines between 2003 and 2021, and changes over time. Methods: Clinical guideline documents on cardiovascular topics issued by leading professional organizations were retrieved in the Databases of SinoMed and Wanfang Med Online from inception to June 2021. All guidelines were screened through abstract and full-text reading, and included if satisfying the pre-specified criteria. 79 Chinese guideline documents on 12 sub-topics including a total of 5195 recommendations and the designated CORs/LOEs, were abstracted. The number of recommendations of Class Ⅰ, Class Ⅱ, Class Ⅲ, LOE A, LOE B, and LOE C were identified for each guideline document. The proportion of CORs, LOEs, and COR-LOE combinations in guidelines and the changes among those with ≥2 versions. Findings: A total of 79 guidelines were included in the analysis. When examining the status of current guidelines, among the 3325 recommendations derived from 59 documents during 2011-2021, 735 recommendations (22.1%) were classified as LOE A, 1280 (38.5%) as LOE B, and 1310 (39.4%) as LOE C. 596 recommendations (17.9%) were characterized as Class Ⅰ-LOE A, accounting for the majority of LOE A recommendations but only one-third of Class I recommendations. Evidence levels varied greatly across different sub-topics and individual guidelines. There are 9 guidelines on 5 sub-topics having ≥2 versions. When analyzing the changes over time, although an increase was observed in the total number of recommendations, the proportion of recommendations designated as Class Ⅰ-LOE A did not significantly improve (19.1% [current] vs 19.0% [prior], p = 0.97). Interpretation: In current Chinese CVD guidelines, the high level of evidence lacks, and its alignment with strong recommendations is deficient. Although it shows moderate improvements in certain major topics (e.g., coronary artery disease, interventional therapy, surgery) in the past two decades, the overall proportion of Class I-LOE A recommendations remains small, suggesting that conduction, and particularly translation, of high-quality studies like RCTs addressing CVDs-related questions are still essential and demanded, especially for areas with less attention. Funding: This study was supported by Beijing Nova Program from Beijing Municipal Science & Technology Commission (Z211100002121063, Z201100006820002); Fundamental Research Funds for the Central Universities (3332022023); National Key R&D Program of China (2020YFC2004705); CAMS Innovation Fund for Medical Sciences (2021-I2M-5-003); National Natural Science Foundation of China (81825003, 91957123, 82270376).

The triglyceride-glucose index as a potential protective factor for hypertrophic obstructive cardiomyopathy without diabetes: evidence from a two-center study.

OBJECTIVE: This study aimed to investigate the relationship between the TyG (Triglyceride-glucose index) and the prognosis of patients with HOCM (hypertrophic obstructive cardiomyopathy) without diabetes. RESEARCH DESIGN AND METHODS: A total of 713 eligible patients with HOCM were enrolled in this study and divided into two groups based on treatment: an invasive treatment group (n = 461) and a non-invasive treatment group (n = 252). The patients in both two groups were then divided into three groups based on their TyG index levels. The primary endpoints of this study were Cardiogenic death during long-term follow-up. Kaplan-Meier analysis was used to study the cumulative survival of different groups. Restricted cubic spline was used to model nonlinear relationships between the TyG index and primary endpoints. Myocardial perfusion imaging/Myocardial metabolic imaging examinations were performed to assess glucose metabolism in the ventricular septum of the HOCM patients. RESULTS: The follow-up time of this study was 41.47 ± 17.63 months. The results showed that patients with higher TyG index levels had better clinical outcomes (HR, 0.215; 95% CI 0.051,0.902; P = 0.036, invasive treatment group; HR, 0.179; 95% CI 0.063,0.508; P = 0.001, non-invasive treatment group). Further analysis showed that glucose metabolism in the ventricular septum was enhanced in HOCM patients. CONCLUSIONS: The findings of this study suggest that the TyG index may serve as a potential protective factor for patients with HOCM without diabetes. The enhanced glucose metabolism in the ventricular septum of HOCM patients may provide a potential explanation for the relationship between the TyG index and HOCM prognosis.

The changing landscape of drug clinical trials on cardiometabolic diseases in China, 2009-2021.

BACKGROUND: Cardiometabolic disease is a clinical syndrome characterized by multiple metabolic disorders, with atherosclerosis as the core and cardiovascular and cerebrovascular events as the outcome. Drug research and development (R&D) in cardiometabolic diseases has grown rapidly worldwide. However, the development of cardiometabolic drug clinical trials in China remains unclear. This study aims to depict the changing landscape of drug clinical trials for cardiometabolic diseases in China during 2009-2021. METHODS: The detailed information of drug trials on cardiometabolic diseases registered in the National Medical Products Administration (NMPA) Registration and Information Disclosure Platform was collected between January 1, 2009, and July 1, 2021. The landscape of cardiometabolic drug clinical trials was analyzed by the characteristics, time trends, indications, pharmacological mechanisms, and geographical distribution. RESULTS: A total of 2466 drug clinical trials on cardiometabolic diseases were extracted and analyzed. The annual number of drug trials increased rapidly in the past twelve years. Among all the trials, the bioequivalence trials (1428; 58.3%) accounted for the largest proportion, followed by phase I (555; 22.5%), phase III (278; 11.3%), phase II (169; 6.9%), and phase IV (26; 1.1%). Of 2466 trials, 2133 (86.5%) trials were monomer drugs, only 236 (9.6%) trials were polypills and 97 (3.9%) were traditional Chinese medicine (TCM) compounds. In terms of pharmacological mechanisms, the number of trials in dihydropyridine (DHP) calcium antagonists 321 (11.9%) ranked first, while trials in angiotensin receptor blocker (ARB) 289 (10.7%) and dipeptidyl peptidase-4 (DPP-4) inhibitor 205 (7.6%) ranked second and third place respectively. Of 236 chemical polypills trials, 23 (9.7%) polypills were the combination of DHP calcium antagonists and statins, while others were the combination of two same pharmacological effect agents. As for the geographical distribution of leading units, 36 trials were led by principal investigators (PI) units from Beijing, followed by Jiangsu (n = 29), Shanghai (n = 19), Guangdong (n = 19), and Hunan (n = 19), showing an uneven regional distribution. CONCLUSIONS: Great progress has been made in drug clinical trials on cardiometabolic diseases, especially in antihypertensive agents, hypoglycemic agents, and hypolipidemic agents. However, the insufficient innovation of first-in-class drugs and polypills should be carefully considered by all stakeholders in drug trials.

Elevated HsCRP in Chronic Obstructive Pulmonary Disease: A Prospective Study of Long-Term Outcomes After Percutaneous Coronary Intervention.

Objective: Anti-inflammatory therapies are reported to have additional benefits beyond lipid control for patients with cardiovascular disease. However, no study has focused on the relationship between inflammation status and long-term outcomes for chronic obstructive pulmonary disease (COPD) patients, after percutaneous coronary intervention (PCI). Methods: 277 COPD-PCI patients were divided into two groups according to hsCRP status upon admission. Major adverse cardiac events (MACE) in high hsCRP patients were compared to patients with low hsCRP. Restricted cubic spline (RCS) analysis was performed using MACE hazard ratios (HR) to investigate interrelations with hsCRP, as a continuous variable. Results: Patients in the high hsCRP group incurred more inflammation activation, in terms of higher white blood cell counts, neutrophil, lymphocytes, and had higher smoking rates, compared to those with lower hsCRPs. A significant increase in MACEs was observed in hsCRP high group, compared to the low hsCRP group (HR: 2.47, 95% CI: 1.22-5.00; p = 0.012). RCS curves suggest that HRs rise beyond 1.0, after the 0.24 juncture for Lg HsCRP (base 10 logarithm with hsCRP), HR per SD: 1.19 (95% CI: 0.96-1.48). Further subgroup analysis implies that elevated hsCRP is associated with a higher risk of MACEs across the sub-groups tested. Conclusion: HsCRP could be a useful indicator for COPD-CAD patient prognosis, after PCI. This is because hsCRP highlights inflammation activation. More multi-center research, designed for COPD-CAD patients should be conducted to more accurately determine the cut-off value for hsCRP.

Association Between Thyroid Dysfunction and Incidence of Atrial Fibrillation in Patients With Hypertrophic Obstructive Cardiomyopathy.

Objective: To explore the correlation between the incidence of atrial fibrillation (AF) and thyroid dysfunction in patients with hypertrophic obstructive cardiomyopathy (HOCM). Methods: Thyroid function testing in 755 consecutive patients with HOCM were examined at the National Center for Cardiovascular Diseases (China) from October 2009 to December 2013. Patients were divided into four groups according to the TSH levels: TSH<0.55 mIU/L(n=37)、0.55~2.49 mIU/L (n=490)、2.50~9.9 mIU/L (n=211) and >10.00mIU/L(n=17). Results: A total of 107 patients were diagnosed with AF (14%).(1) Compared to HOCM patients without AF,HOCM patients with AF have older age (P<0.001), higher NT-proBNP (P=0.002), higher Cr (P=0.005), larger left atrial diameter(P=0.001), lower FT3 (P=0.046), higher FT4 (P=0.004).(2) In the four groups according to the TSH levels: TSH<0.55 mIU/L, 0.55~2.49mIU/L, 2.50~9.9mIU/L and ≥10.00mIU/L, the incidence of AF was 27.02%(10/37),10.20%(50/490), 19.43%(41/211), and 35.29%(6/17), respectively. Both high and low TSH levels were associated with an increased incidence of AF. After adjusting for the common risk factor (age, NT-proBNP, and so on), stepwise multiple logistic regression analysis revealed that TSH levels were significantly related to AF incidence.Compared to patients with TSH 0.55~2.49 mlU/L, the adjusted odds ratio of AF for TSH<0.55, 2.50~9.99, ≥10.00 mIU/L were 1.481 (95% CI 0.485~4.518,P=0.490), 1.977 (95%CI 1.115~3.506, p=0.02), 4.301 (95%CI 1.059~17.476, P=0.041), respectively. Conclusion: Our results suggested that thyroid dysfunction was associated with an increased risk of AF in patients with HOCM.

The Association Between High-Sensitivity C-Reactive Protein/Albumin Ratio and Cardiovascular Prognosis in Patients Undergoing Percutaneous Coronary Intervention.

Limited studies have focused on the impact of high-sensitivity C-reactive protein (hsCRP) to albumin ratio (CAR) on cardiovascular outcomes in patients undergoing percutaneous coronary intervention (PCI). Hence, the present study evaluates the association between CAR and cardiovascular outcomes in patients undergoing drug-eluting stent (DES) implantation. We consecutively enrolled 9375 CHD patients undergoing DES implantation. All patients were divided into 3 groups according to their CAR: tertile 1 (CAR ≤.02, n=3125), tertile 2 (.02.06, n = 3125). The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE). Kaplan-Meier analysis indicated that the incidences of MACCE and MI increased with high tertiles of the CAR (MACCE: 8.7 vs 10.5 vs 12.3%, log-rank P < .001; MI: 3.3 vs 4.0 vs 4.7%, long-rank P = .015). Cox regression analysis suggested that CAR was an independent risk factors for MACCE (HR per standard deviation (SD) increase: 1.07, 95% CI, 1.01-1.14, P = .024), and MI (HR per SD increase: 1.11, 95% CI, 1.01-1.22, P = .028). In conclusion, the CAR is an independent predictor of MACCE and MI in CHD patients.

Long-Term Outcomes for Chinese COPD Patients After PCI: A Propensity Score Matched, Double-Cohort Study.

Objectives: The aim of this study was to analyze long-term outcomes of Chinese coronary artery disease (CAD) patients with (and without) chronic obstructive pulmonary disease (COPD) after percutaneous coronary intervention (PCI). Background: Chronic obstructive pulmonary disease is a chronic condition which often develops in conjunction with CAD. PCI is a core therapy for CAD, although we still need to understand CAD-COPD outcomes and to identify factors that influence prognoses, across ethnicities. Methods: This double-cohort study involved 12,343 Chinese CAD patients who received PCI. Baseline characteristics were collected in two independent, specialty centers. Propensity-score matching was performed to control confounding factors, using a nearest neighbor matching method within a 0.02 caliper and on a propensity score scale of 0.1 for each center. Comorbid CAD-COPD cases were compared to non-COPD patients in terms of major adverse cardiac events (MACEs). Results: Patients with COPD were generally older than those without COPD (65.4 ± 9.2 vs. 58.2 ± 10.3, p < 0.001). There were no significant differences in the end points between COPD and non-COPD groups after PCI (All p > 0.05); however, the incidence of MACEs increased after 450 days. Further subgroup analysis suggests that COPD is approximately four times more prevalent among those aged over 75 years (HR, 3.818; 95%CI, 1.10-13.29; p = 0.027) and those aged below 55 years (HR = 4.254; 95% CI, 1.55-11.72; p = 0.003). Conclusion: Having COPD does not appear to have a significant impact on CAD outcomes 2 years after PCI, and beyond. However, an increasing number of MACEs was observed after 450 days, which suggests that there may be a double-stage effect of COPD on PCI prognosis. There is a need for focused comorbidity management, specifically for those aged below 55 years and above 75 years.

Atherogenic index of plasma for non-diabetic, coronary artery disease patients after percutaneous coronary intervention: a prospective study of the long-term outcomes in China.

BACKGROUND: Non-diabetic coronary artery disease (CAD) patients are thought to encounter metabolic dysfunction and while these changes may be imperceptible to the patient they probably influence outcomes. At present, there is no system to support patients sensing these subtle changes, nor is there an established model for prognoses. The Atherogenic Index of Plasma (AIP) index has already proven useful for atherosclerosis although further research is needed, especially for those without hyperglycemia. METHODS: This is a prospective study of 5538 non-diabetic CAD patients who had received percutaneous coronary intervention (PCI). Participants were assigned to one of three groups according to their AIP index. High AIP index cases were then compared to low index patients according to major adverse cardiac events (MACE). Restricted cubic spline (RCS) analysis was also conducted to investigate interrelations between AIP index levels and hazard ratios (HR) for MACEs. RESULTS: Patients with a high AIP index encountered metabolic dysfunction compared to those with a low AIP index i.e., higher Body Mass Index (BMI), Total Cholesterol (TC), Triglycerides (TG), and uric acid as well as lower HDL-C. Each of the aforementioned interrelations were significant with p values of less than 0.001. There was also a significant increase in the number of MACEs in the high AIP index group compared to the low AIP index group (HR: 1.37, 95% CI 1.04-1.81; p = 0.025). A J-shaped RCS curve highlighted a change in the HR after the 0.18 juncture (HR per SD: 1.20, 95% CI 0.96-1.50). Further subgroup analysis supported the main findings, all with HRs greater than one. CONCLUSION: The AIP index could be used in prognostics for non-diabetic CAD patients 2 years after PCI. The relationship between hazard ratio and the AIP index appears to be J-shaped. Although, further multi-center studies designed for non-diabetic patients with potential metabolic dysfunction should be conducted to determine the value of the AIP index.

The Impact of the Stress Hyperglycemia Ratio on Short-term and Long-term Poor Prognosis in Patients With Acute Coronary Syndrome: Insight From a Large Cohort Study in Asia.

OBJECTIVE: In recent years, some studies have indicated that a novel marker described as the stress hyperglycemia ratio (SHR) can reflect true acute hyperglycemic status and is associated with the short-term poor prognosis in patients with acute myocardial infarction. In the current study we evaluated the association of SHR with adverse cardiovascular events among patients with acute coronary syndrome (ACS). RESEARCH DESIGN AND METHODS: We consecutively enrolled 5,562 ACS patients who underwent drug-eluting stent (DES) implantation. All subjects were divided into five groups according to SHR, which was determined by the following formula: ABG / [(28.7 × HbA1c %) - 46.7], where ABG is admission blood glucose level. The primary end point was major adverse cardiovascular and cerebrovascular events (MACCE) at the 2-year follow-up, and the secondary end point included major adverse cardiovascular events (MACE) at 2-year follow-up, cardiac death, and nonfatal myocardial infarction (MI) at 2-year follow-up and in-hospital cardiac death and nonfatal MI. RESULTS: A total of 643 MACCE were recorded during a median follow-up of 28.3 months. Kaplan-Meier survival analysis showed the lowest MACCE incidence in quintile 3 (P < 0.001). Moreover, the outcomes of restricted cubic spline analysis suggested that there was a U-shaped or J-shaped association between the SHR and early and late cardiovascular outcomes even after adjustment for other confounding factors. CONCLUSIONS: There were U-shaped associations of SHR with MACCE rate and MACE rate at 2-year follow-ups and J-shaped associations of SHR with in-hospital cardiac death and MI and that at 2-year follow-up in ACS patients who underwent DES implantation, and the inflection point of SHR for poor prognosis was 0.78.

The Impact of Subclinical Hyperthyroidism on Cardiovascular Prognosis in Patients Undergoing Percutaneous Coronary Intervention.

CONTEXT: Limited studies have focused on the impact of subclinical hyperthyroidism (SHyper) on poor prognosis in patients with known coronary artery disease (CAD). OBJECTIVE: We implemented the present study to explore the association between SHyper and adverse cardiovascular events in CAD patients who underwent drug-eluting stent implantation. METHODS: We consecutively recruited 8283 CAD patients undergoing percutaneous coronary intervention (PCI). All subjects were divided into 2 groups according to their thyroid function: group 1 (euthyroidism group, n = 7942) and group 2 (SHyper group, n = 341). After 1:4 propensity score (PS) matching, 1603 patients (332 SHyper group and 1271 euthyroidism group) were selected. The primary endpoint was major adverse cardiovascular events (MACEs), a composite of cardiac mortality, nonfatal myocardial infarction (MI), and target vessel revascularization (TVR). RESULTS: Kaplan-Meier (K-M) survival analyses suggested that there was no significant difference in the primary endpoint and secondary endpoints (MACE: 11.4% vs 8.8%, log-rank P = .124; cardiac death: 1.2% vs 0.9%, log-rank P = .540; nonfatal MI: 5.7% vs 4%, log-rank P = .177; and TVR: 6% vs 4.7%, log-rank P = .303) in the PS-matched population. Cox regression analysis indicated that SHyper was not an independent risk factor for MACEs (HR 1.33, 95% CI 0.92-1.92, P = .127). CONCLUSION: SHyper is not independently associated with adverse cardiovascular events in CAD patients undergoing PCI. More studies should be implemented in the future to assess the long-term predictive value of SHyper with thyrotropin levels <0.1 mIU/L for CAD patients undergoing PCI.

The Impact of the Triglyceride-Glucose Index on Poor Prognosis in NonDiabetic Patients Undergoing Percutaneous Coronary Intervention.

Background: The triglyceride-glucose index (TyG index) is a valuable marker for predicting adverse cardiovascular events in diabetic patients. However, for nondiabetic patients, whether the TyG index is independently related to poor prognosis remains unclear. This cohort study assessed the association of the TyG index with future cardiovascular risk in nondiabetic subjects who received percutaneous coronary intervention (PCI). Methods: We consecutively enrolled 5,489 nondiabetic patients who underwent PCI. All experimental subjects were divided into three groups based on their TyG index, which was determined by the equation ln (fasting triglyceride (mg/dl) × fasting blood glucose (mg/dl)/2). The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE), including all-cause death, nonfatal myocardial infarction (MI), nonfatal stroke, and target vessel revascularization (TVR). Results: A total of 386 MACCE were documented during a median 29-month follow-up. The Kaplan-Meier survival results indicated that among the three groups, there was no obvious difference in any endpoints. Further Cox regression analyses suggested that the TyG index was not independently related to adverse cardiovascular outcomes for nondiabetic patients who underwent PCI (HR: 0.77, 95% CI 0.56-1.16, P = 0.210 for MACCE). Subgroup analysis suggested that the TyG index was independently relevant to MACCE for patients with low-density lipoprotein cholesterol (LDL-C) lower than 1.8 mmol/L. Conclusion: The TyG index is not an effective predictive factor for adverse cardiovascular prognosis in nondiabetic patients who underwent PCI. However, in subjects with LDL-C lower than 1.8mmol/L, it may predict future cardiovascular risk.

mTOR and Beclin1: Two key autophagy-related molecules and their roles in myocardial ischemia/reperfusion injury.

Autophagy is the general term of lysosomal degradation of substances in cells, which is considered the key to maintaining the normal structure and function of the heart. It also has a correlation with several heart diseases, in particular, myocardial ischemia/reperfusion (I/R) injury. At the stage of myocardial ischemia, autophagy degrades nonfunctional cytoplasmic proteins providing the critical nutrients for the critical life activities, thereby suppressing cell apoptosis and necrosis. However, autophagy is likely to affect the heart negatively in the reperfusion stage. Mammalian target of rapamycin (mTOR) and Beclin1 are two vital autophagy-related molecules in myocardial I/R injury playing significant roles in different stages. In the ischemia stage, mTOR plays its roles through AMPK/mTOR and phosphoinositide 3-kinase/Akt/mTOR pathway, whereas Beclin1 plays its roles through its upregulation in the reperfusion stage. A possible interaction between mTOR and Beclin1 has been reported recently, and further studies need to be done to find the underlying interaction between the two molecules in myocardial I/R injury.

The novel relationship between Sirt3 and autophagy in myocardial ischemia-reperfusion.

Class III histone deacetylases (HDACs) belong to the proteasome family, comprising seven family members identified in mammalian cells, identified Sirt1-Sirt7. As an important member of HDACs, Sirt3 is hotly debated for its multiple functions. It was reported that Sirt3 got involved in the alleviation of multiple diseases, including myocardial infarction, neuron ischemia, hypertrophy, and diabetic myopathy. Through regulating many cellular mechanisms, such as apoptosis, autophagy, and clearance of reactive oxygen species (ROS), Sirt3 played an important role in the alleviation of myocardial ischemia-reperfusion injury. Nowadays Sirt3-induced autophagy was indicated to be involved in the process of the development of myocardial ischemia-reperfusion injury. Sirt3 could both activate and inhibit autophagy process by activating different downstream signal pathways, such as Sirt3-AMP-activated protein kinase pathway, Sirt3-Foxo3a pathway, and Sirt3-superoxide dismutase-mitochondrial ROS pathway. Whereas the Sirt3-induced autophagy in different phases of myocardial ischemia-reperfusion has not been systematically illustrated. In this review, we summarized the regulated mechanisms found in these years and listed the updated research about the relationship between Sirt3 and autophagy which are both positive and negative during myocardial ischemia-reperfusion phase. We anticipated that we may controlled the activation of autophagy by regulating the concentration of Sirt3 in myocyte. By maintaining a proper expression of autophagy in different phases of myocardial ischemia-reperfusion, we could reduce the morbidity of patients with myocardial infarction apparently in the future.