ARomatherapy for Cognitive Trajectory in Chinese After Percutaneous Coronary Intervention (ARCTIC-PCI)

The ARCTIC-PCI trial has two objectives. The primary objective is to evaluate the efficacy of aromatherapy (70% menthol and 30% propanediol) in improving cognitive functions in Chinese post-PCI patients. The secondary objective is to evaluate the safety of aromatherapy. We hypothesize that the aromatherapy will result in improved 6- month cognitive functions compared to the placebo (10% menthol and 90% propanediol) among patients accepted a PCI.

Patient recruitment:

The study will be conducted at Beijing Anzhen Hospital. All eligible patients plan to undergo their PCI will be screened for eligibility, written informed consent need to be provided. For patients who meet all inclusion and exclusion criteria, baseline assessment will be carried out 1 to 3 days prior to the PCI.

Randomization and allocation concealment:

Randomization will be conducted after PCI and before hospital discharge. To ensure concealment of the treatment allocation, randomization will be performed by a web-based IT system. All eligible participants will be randomly assigned in a 1:1 ratio to receive aromatherapy (70% menthol and 30% propanediol) or placebo (10% menthol and 90% propanediol). Each sniffin' stick of aromatherapy or placebo will be labeled according to the pre-determined random code by an independent agency that does not involve any persons associated with the trial.

Masking:

Participants, investigators, physicians, and outcomes assessors will be blinded to treatment allocation. The sticks of aromatherapy and placebo are the same, and the smell of them is similar.

Interventions:

Intervention will last for 6 months. All participants will receive the standard inhalation method training before hospital discharge. For both arms, the aromatherapy/placebo will be given twice daily (morning and evening), each time training for 4 times with deep inhalation for 10 seconds.

Supervisory management will be carried out through WeChat app, each day all participants will receive reminders via WeChat through the "group assistant". By the end of the intervention, we will collect all the rest of the medications (menthol/placebo) and the total amount of the rest medication will be assessed to evaluate patients' adherence.

Measurement:

Baseline measurement including the following aspects:

1. Laboratory data including: myocardial enzyme, fasting blood glucose, glycosylated hemoglobin, total cholesterol, low-density cholesterol, high-density cholesterol, triglyceride, high-sensitivity c-reactive protein, creatinine, uric acid, liver function indicators, etc.
2. Genetic testing: APOE genotype.
3. Physical examination: height, weight, blood pressure, heart rate.
4. Clinical data including: left ventricular ejection fraction, heart failure classification, GRACE score, shock, thrombolytic therapy, myocardial infarction classification, type of MI (ST elevation or non-ST elevation), vascular stenosis, coronary artery calcification score, etc.
5. Assessment of olfactory function: collection of prior history of dysosmia or using Sniffin' Sticks test to assess olfactory function.
6. Assessment of cognitive function: The Chinese version of the Montreal Cognitive Assessment (MoCA) will be used, which is translated from the original English version and has been reviewed and authorized by the author of the original edition (Dr. Ziad Nasreddine). The Chinese version of MoCA has been verified in the elderly population in China, with good reliability and validity in screening for MCI and Alzheimer's disease. In addition, we will use internationally recognized scales to evaluate memory, executive function and orientation. All researchers involved in the cognitive function assessment are from the clinical research institute of Peking University, independent of the study sponsor. All cognitive assessors have received MoCA training and obtained official certification.
7. Assessment of depression symptom: The Center for Epidemiologic Studies Depression Scale (CES-D) will be used to measure depression symptoms severity.
8. Surgery information: methods of anesthesia, anesthetic drugs and dosage, duration of PCI, stent type, number of stents, etc.
9. Other information: length of stay in ICU, length of stay in general ward, discharge medications.

Follow-up Assessment： All participants will be invited back to hospital twice at 3- and 6- month after PCI. Cognitive functions will be assessed by the same assessors using the same methods as baseline.

Adverse events:

During the 6-month follow-up period will be recorded, which are defined as any of the unexpected signs (such as abnormal lab values), symptoms, or diseases, whether or not associated with aromatherapy.

Study-related adverse reactions including 1) respiratory allergy and 2) sneeze. Severe adverse events (SAE) during follow-up are defined as any of the following:1) all-cause mortality, 2) hospitalization for cardiovascular disease, 3) re-myocardial infarction and 4) stroke.

Sample Size Calculation:

The total number of subjects required for this study is 330:330 patients per group. This number was determined on the basis of the following hypotheses, with reference obtained from the FINGER trial (Lancet 2015;385:2255-2263), Xie et.al (JACC 2019;73: 3041-3050) and other related observational studies.

1. A decrease of 0.2 Z-score with a standard deviation of 0.3 at 6-month post-PCI in the control group
2. Intervention will reduce the overall cognitive decline by 40%, that is a decrease of 0.12 Z-score at 6-month post-PCI in the intervention group.
3. α risk of 5% and β risk of 10%
4. the maximum lost to follow-up rate:10%

Statistical Analysis:

The principal analysis will be a modified intention-to-treat (ITT) analysis on patients with at least one follow-up included in the study. The primary and continuous secondary outcomes are repeated measures, and linear mixed models will be used for analysis. All continuous outcomes will be standardized according to the mean and standard deviation of their baseline values, and z-score of each variable will be obtained. Modified Poisson regression analysis will be used for binary secondary outcomes.

Sensitivity analyses include: 1) ITT analysis including all participants, with missing data being imputed by using multiple imputation method. 2) Only include patients with both follow-up measurements. 3) For the primary outcome, we will also test if the intervention effect is modified by baseline characteristics.

Statistical analyses will be carried out using the SAS Enterprise Guide 7.13 (SAS Institute Inc, Cary, NC)