UMIN-CTR Clinical Trial

Public title

Real-World Evidence Retrospective Cardiovascular Outcome Study among Users of Heated Tobacco Products (HTPs) Compared to Smokers of Cigarettes (CIG), Former Smokers, and Never Smokers in Japan

Acronym

RWE Retrospective Cardiovascular Outcome Study in Users of HTPs in Japan

Scientific Title

Real-World Evidence Retrospective Cardiovascular Outcome Study among Users of Heated Tobacco Products (HTPs) Compared to Smokers of Cigarettes (CIG), Former Smokers, and Never Smokers in Japan

Scientific Title:Acronym

RWE Retrospective Cardiovascular Outcome Study in Users of HTPs in Japan

Region

Japan

Condition

Non-fatal myocardial infarction, unstable angina

Classification by specialty

Cardiology

Classification by malignancy

Others

Genomic information

NO

Narrative objectives1

The purpose of the study is to retrospectively evaluate the impact of having switched from CIG to exclusive use of HTPs (hereafter, exclusive HTP use) on time to first subsequent major adverse cardiovascular event (hereafter, MACE) compared with continued smoking of CIG (hereafter, exclusive CIG smoking), dual use of CIG and HTP, quitting of CIG (hereafter, former smoking), and never smoking in patients who have already experienced a first-ever (defined as first identified or first recorded in the Tokushukai Medical Database) cardiovascular event of non-fatal myocardial infarction (MI), unstable angina, or urgent coronary revascularization procedure (Index Event), after adjusting for sociodemographic and other risk factors.

Basic objectives2

Others

Basic objectives -Others

The primary outcome is about comparative effectiveness.

Trial characteristics_1

Trial characteristics_2

Developmental phase

Not applicable

Primary outcomes

To compare the time from Index Event to a first subsequent MACE between comparable groups of exclusive HTP users and exclusive CIG smokers.
-Index Event will be defined as first-ever (defined as first identified or first recorded in the Tokushukai Medical Database) of any of the following: non-fatal MI, unstable angina, or urgent coronary revascularization procedure.
-MACE (called hereafter as Broad Modified MACE, defined as a 6-point composite endpoint of any of the following):
->Non-fatal MI,
->Non-fatal stroke,
->Hospitalization for angina,
->Hospitalization for heart failure,
->Urgent revascularization for angina, or
->All-cause mortality

Key secondary outcomes

1.To compare the time from Index Event to all-cause mortality between comparable groups of (i) exclusive HTP users versus exclusive CIG smokers, (ii) exclusive HTP users versus dual users of CIG and HTP, (iii) exclusive HTP users versus former smokers, and (iv) exclusive HTP users versus never smokers.
Endpoint:
-All-cause morality

2.To compare the time from Index Event to a first subsequent Broad Modified MACE defined above between comparable groups of (i) exclusive HTP users versus former smokers, (ii) exclusive HTP users versus dual users of CIG and HTP, and (iii) exclusive HTP users versus and never smokers.

3. To compare the number and frequency of first subsequent CVD-related hospitalizations (defined as hospitalizations due to MI, unstable angina, or stroke) by comparable tobacco exposure groups (never smokers, former smokers, dual users of CIG and HTP, exclusive CIG smokers, and exclusive HTP users).
Endpoint:
-Annual numbers and frequency of first subsequent hospitalizations due to MI, unstable angina, or stroke as a composite endpoint.

4. To evaluate whether the time from Index Event to a first subsequent MACE for exclusive HTP users vs. exclusive CIG smokers as defined above varies for exclusive HTP users by:
-The number of years of HTP use (<1 year, 1-3 years, >3 years).
-Age at Index Event
-Sex
-History of other CVD prior to the Index Event (e.g., stroke, hypertension, peripheral vascular disease [PVD])

Study type

Observational

Basic design

Randomization

Randomization unit

Blinding

Control

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

No. of arms

Purpose of intervention

Type of intervention

Interventions/Control_1

Interventions/Control_2

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

30

years-old

<=

Age-upper limit

Not applicable

Gender

Male and Female

Key inclusion criteria

-Patients with any healthcare encounter records in the Tokushukai Medical Database
-Patients with first record of Index Event (first-ever [defined as first identified or first recorded in the Tokushukai Medical Database] of any of the following: non-fatal MI, unstable angina, or urgent coronary revascularization procedure) from 1st May 2016 to 31st December 2020
-Age 30 years or older at the time of the Index Event
-Patients of any gender
-Patients or relatives who are able to understand the information provided in the ICF and have signed it

Key exclusion criteria

-Employees of Tobacco industries or their families such as their parents
-Employees of Philip Morris International (PMI) and its affiliate companies, Tokushukai Medical Corporation, 3H Medi Solution, or Syneos Health Clinical K.K.

Target sample size

5490

Name of lead principal investigator

1st name	Makoto
Middle name
Last name	Hibino

Organization

Tokushukai Medical Corporation Shonan-Fujisawa Tokushukai Hospital

Division name

Respiratory Medicine

Zip code

251-0041

Address

1-5-1 Tsujidokandai, Fujisawa-shi, Kanagawa, Japan

TEL

0466-35-1177

Email

m-hibino@ctmc.jp

Name of contact person

1st name	Takashi
Middle name
Last name	Sato

Organization

Syneos Health Clinical K.K.

Division name

Clinical Operations/Real World and Late Phase

Zip code

100-7012

Address

12F JP Tower, 2-7-2 Marunouchi, Chiyoda-ku, Tokyo, Japan

TEL

03-6733-9690

Homepage URL

Email

takashi.sato@syneoshealth.com

Institute

Philip Morris Products S.A.

Institute

Department

Personal name

Organization

Philip Morris Products S.A.

Organization

Division

Category of Funding Organization

Profit organization

Nationality of Funding Organization

Switzerland

Co-sponsor

Name of secondary funder(s)

Organization

The Tokushukai Group Ethics Committee

Address

Tokyodo Chiyoda Bldg. 15F, 1-3-1, Kudan-minami, Chiyoda-ku, Tokyo, Japan

Tel

03-3263-4801

Email

mirai-ec1@mirai-iryo.com

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

徳洲会グループ/ Tokushukai Group

Date of disclosure of the study information

2025

Year

05

Month

09

Day

URL releasing protocol

Not applicable.

Publication of results

Unpublished

URL related to results and publications

Not applicable.

Number of participants that the trial has enrolled

6791

Results

Of the 6,791 patients who signed the informed consent form, 6,174 met all eligibility criteria to be included in the study. Among patients included in the study, 88 were exclusive HTP users, 486 were exclusive CIG smokers, 43 were dual users of CIG and HTPs, 2,927 were former smokers, and 2,630 were never smokers at the time of the Index Event (defined as first myocardial infarction, unstable angina, or urgent coronary revascularization).

Results date posted

2026

Year

09

Month

07

Day

Results Delayed

Results Delay Reason

Not applicable. There were no delays in result reporting.

Date of the first journal publication of results

Baseline Characteristics

Among the 6,174 patients included in the study, 486 (7.9%) were exclusive CIG smokers, 88 (1.4%) were exclusive HTP users, 43 (0.7%) were dual users of CIG and HTPs, 2,927 (47.4%) were former smokers, and 2,630 (42.6%) were never smokers. The median age at the time of Index Event (all exposure groups combined) was 70.0 years (Q1: 62.0, Q3: 77.0). By exposure group, the median age was 66.0 years (Q1: 57.0, Q3: 71.0) for exclusive CIG smokers, 60.0 years (Q1: 51.0, Q3: 65.0) for exclusive HTP users, 61.0 years (Q1: 53.0, Q3: 66.0) for dual users of CIG and HTPs, 69.0 years (Q1: 62.0, Q3: 75.0) for former smokers, and 73.0 years (Q1: 65.0, Q3: 80.0) for never smokers in the unadjusted (unweighted) analysis.

The majority of the patients were males (73.9%, all exposure groups combined). By exposure groups, most patients were males in all the exposure groups (over 87%), except in never smokers where males were approximately half (48.5%) in the unadjusted analysis. The median pack-years of CIG smoking prior to the Index Event for all exposure groups combined (excluding never smokers) was 33.0 (Q1: 18.4, Q3: 57.0). Among the exposure groups, the median pack-years of prior CIG smoking was 37.7 (Q1: 27.6, Q3: 63.0) in the exclusive CIG smokers, 43.5 (Q1: 25.4, Q3: 60.0) in the exclusive HTP users, 49.5 (Q1: 29.7, Q3: 69.0) in the dual users of HTPs and CIG, and 31.9 (Q1: 16.7, Q3: 55.5) in the former smokers in the unadjusted analysis.

Comorbidities prior to the Index Event were ascertained from the Tokushukai Medical Database. They included diagnosis of hypertension, stroke, dyslipidemia, diabetes, chronic obstructive pulmonary disease, etc. In all exposure groups combined, the most common comorbidities were hypertension (36.4%), dyslipidemia (32.3%), and diabetes (21.6%). Comorbidities were more common in the enrolled exclusive HTP users than in exclusive CIG smokers in the unadjusted analysis.

Participant flow

A total of 48,613 potentially eligible patients (including those deceased) were identified in the Tokushukai Medical Database. They were contacted by post to probe their interest in participating in the study. Of those, 6,791 patients consented (either personally or through a relative / legal guardian) to participate in the study. Of those providing consent, 6,174 met all eligibility criteria and were included in the study. A total of 617 patients were excluded from the study because of the following reasons:
3 patients had informed consent form details that did not match the questionnaire type they answered (e.g., patients completing the Relatives` Questionnaire),
27 patients had date of the Index Event that did not align with the first healthcare encounter recorded in the Tokushukai Medical Database (date of Index Event was earlier than the date of first healthcare encounter), and
587 patients could not be assigned to any tobacco exposure group due to missing information from the questionnaires.

Adverse events

Not applicable. This was a retrospective cohort study, with no active follow-up of patients. Therefore, no information on adverse events was collected.

Outcome measures

Primary (Main) Outcome: time until next cardiovascular event (Broad Modified MACE)
Of the 6,791 patients who signed the informed consent form, 6,174 met all eligibility criteria to be included in the study. Among patients included in the study, 88 were exclusive HTP users and 486 were exclusive CIG smokers at the time of the Index Event (defined as first myocardial infarction, unstable angina, or urgent coronary revascularization). The estimated sample size (prior to patient recruitment) required for the primary outcome comparison between exclusive HTP users and exclusive CIG smokers was 5,490 (3,660 exclusive CIG smokers and 1,830 exclusive HTP users). No hypothesis testing was performed due to the low number of exclusive HTP users and exclusive CIG smokers enrolled in the study.

Patients who were exclusive HTP users at the time of the Index Event had used HTPs for a median duration of 1.6 years prior to the Index Event and had smoked CIG a median of 43.5 pack-years before switching to HTPs. Patients who were exclusive CIG smokers at the time of the Index Event had smoked CIG for a median of 37.7 pack-years before the Index Event.

The median follow-up time was 1.00 year (first quartile [Q1]: 0.12, third quartile [Q3]: 4.14) usive HTP users and 0.52 years (Q1: 0.08, Q3: 2.48) for the exclusive CIG smokers. The median time to first subsequent Broad Modified MACE event [unadjusted] was 0.65 years for the exclusive HTP users and 0.24 years for the exclusive CIG smokers.

Propensity score weighting was applied to adjust for age, sex, type of Index Event, and pack-years of prior CIG smoking between the populations of exclusive HTP users and exclusive CIG smokers. These variables were appraised to be the most relevant for statistical adjustment based on knowledge of the risk factors for cardiovascular outcomes in the literature.

The weighted median time during which patients had no Broad Modified MACE was 3.6 years (95% confidence interval 1.0-5.2) among the exclusive HTP users and 1.1 years (95% CI: 0.8-2.0) among the exclusive CIG smokers. In the weighted Cox proportional hazards model, the hazard ratio of first subsequent Broad Modified MACE for exclusive HTP users versus exclusive CIG smokers was 0.85 (95% CI: 0.57-1.29).


Secondary Outcomes
Time until the next cardiovascular event: Broad Modified MACE
The median follow-up time for Broad Modified MACE was 0.77 years (Q1: 0.09, Q3: 4.27) among exclusive HTP users, 0.54 years (Q1: 0.09, Q3: 1.50) among dual users of CIG and HTPs, 0.72 years (Q1: 0.10, Q3: 4.28) among former smokers, and 0.88 years (Q1: 0.10, Q3: 4.45) among never smokers. Propensity score weighting was applied to adjust for age, sex, type of Index Event, and pack-years of prior CIG smoking (except for never smoker comparison) between the populations of exclusive HTP users and each of the other exposure groups (dual users of CIG and HTPs, former smokers, and never smokers).

By the fifth year of follow up, the percentage of patients with no occurrence of Broad Modified MACE was 39.7% among the exclusive HTP users, 17.4% among dual users of CIG and HTPs (two-sided log-rank for exclusive HTP users and dual users for the entire follow-up period, p = 0.287), 37.5% among former smokers (two-sided log-rank for exclusive HTP users and former smokers for the entire follow-up period, p = 0.415), and 40.6% among never smokers (two-sided log-rank for exclusive HTP users and never smokers for the entire follow-up period, p = 0.816) in the weighted analysis.

Time until all-cause mortality
The median follow-up time was 4.83 years (Q1: 1.63, Q3: 6.32) among the exclusive CIG smokers, 5.61 years (Q1: 4.27, Q3: 6.98) among the exclusive HTP users, 4.08 years (Q1: 0.54, Q3: 5.86) among dual users of CIG and HTPs, 6.20 years (Q1: 5.03, Q3: 7.45) among former smokers, and 6.07 years (Q1: 4.94, Q3: 7.31) among never smokers. Propensity score weighting was applied to adjust for age, sex, type of Index Event, and pack-years of prior CIG smoking (except for never smoker comparison) between the populations of exclusive HTP users and the other exposure groups (exclusive CIG smokers, dual users of CIG and HTPs, former smokers, and never smokers).

By the fifth year of follow up, the percentage of patients who were alive (free from all-cause mortality) was 97.4% among the exclusive HTP users, 93.9% among the exclusive CIG smokers (two-sided log-rank for exclusive HTP users and exclusive CIG smokers for the entire follow-up period, p = 0.204), 98.0% among former smokers (two-sided log-rank for exclusive HTP users and former smokers for the entire follow-up period, p = 0.839), and 96.9% among never smokers (two-sided log-rank for exclusive HTP users and never smokers for the entire follow-up period, p = 0.707) in the weighted analysis. No mortality event occurred among dual users of CIG and HTPs in the weighted dataset (1 mortality event occurred among dual users of CIG and HTPs in the unweighted dataset).

Time until next cardiovascular event: CVD-related hospitalizations
The median follow-up time was 1.62 years (Q1: 0.21, Q3: 4.91) among the exclusive CIG smokers, 2.90 years (Q1: 0.46, Q3: 5.73) among the exclusive HTP users, 1.03 years (Q1: 0.16, Q3: 4.10) among dual users of CIG and HTPs, 4.27 years (Q1: 0.57, Q3: 6.12) among former smokers, and 3.97 years (Q1: 0.51, Q3: 5.94) among never smokers. Propensity score weighting was applied to adjust for age, sex, type of Index Event, and pack-years of prior CIG smoking (except for never smoker comparison) between the populations of exclusive HTP users and the other exposure groups (exclusive CIG smokers, dual users of CIG and HTPs, former smokers, and never smokers).

The weighted incidence rate ratio of CVD-related hospitalizations was 0.84 (95% CI: 0.46-1.56) for exclusive HTP users versus exclusive CIG smokers, 0.62 (95% CI: 0.35-1.11) for exclusive HTP users versus dual users of CIG and HTPs, 1.16 (95% CI: 0.64-2.09) for exclusive HTP users versus former smokers, and 1.30 (95% CI: 0.70-2.39) for exclusive HTP users versus never smokers. None of the differences were statistically significant.

The analysis on whether the time from Index Event to a first subsequent Broad Modified MACE for exclusive HTP users versus exclusive CIG smokers varies by the number of years of HTP use prior to the Index Event, age at the time of the Index Event, or history of CVD prior to the Index Event could not be performed due to the low number of enrolled exclusive HTP users and exclusive CIG smokers.

Plan to share IPD

The study sponsor is committed to transparency and will consider any requests for underlying data, provided that such data may be shared under applicable laws.

IPD sharing Plan description

Refer to the section "Plan to share IPD."

Recruitment status

No longer recruiting

Date of protocol fixation

2024

Year

08

Month

06

Day

Date of IRB

2024

Year

08

Month

13

Day

Anticipated trial start date

2024

Year

12

Month

09

Day

Last follow-up date

2025

Year

04

Month

30

Day

Date of closure to data entry

2025

Year

06

Month

30

Day

Date trial data considered complete

2025

Year

08

Month

31

Day

Date analysis concluded

2025

Year

12

Month

29

Day

Other related information

It is expected that there will be a difference in the time from Index Event to a first subsequent Broad Modified MACE between smokers who switched to exclusive use of HTP and those that continued to smoke CIG exclusively. The findings on the time from Index Event to a first subsequent Broad Modified MACE in exclusive HTP users compared to dual users of CIG and HTP, former smokers, or never smokers will also be reported. The results of the study will be released in the first quarter of 2026.

Registered date

2025

Year

05

Month

08

Day

Last modified on

2026

Year

09

Month

07

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000065853