Association Between 2-Dose vs 3-Dose Hepatitis B Vaccine and Acute Myocardial Infarction

Katia Bruxvoort; Jeff Slezak; Lei Qian; Lina S Sy; Bradley Ackerson; Kristi Reynolds; Runxin Huang; Zendi Solano; William Towner; Cheryl Mercado; Steven J Jacobsen

doi:10.1001/jama.2022.2540

. 2022 Mar 25;327(13):1260–1268. doi: 10.1001/jama.2022.2540

Association Between 2-Dose vs 3-Dose Hepatitis B Vaccine and Acute Myocardial Infarction

Katia Bruxvoort ^1,^2,^✉, Jeff Slezak ², Lei Qian ², Lina S Sy ², Bradley Ackerson ², Kristi Reynolds ², Runxin Huang ², Zendi Solano ², William Towner ², Cheryl Mercado ², Steven J Jacobsen ^2,³

¹Department of Epidemiology, School of Public Health, University of Alabama at Birmingham

²Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena

³Marshfield Clinic Research Institute, Marshfield, Wisconsin

^✉

Corresponding Author: Katia Bruxvoort, PhD, MPH, Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, 1665 University Blvd, Birmingham, AL 35233 (kbruxvoort@uab.edu).

Accepted for Publication: February 9, 2022.

Published Online: March 25, 2022. doi:10.1001/jama.2022.2540

Author Contributions: Dr Bruxvoort had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Bruxvoort, Slezak, Qian, Sy, Ackerson, Reynolds, Towner, Jacobsen.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Bruxvoort.

Critical revision of the manuscript for important intellectual content: Slezak, Qian, Sy, Ackerson, Reynolds, Huang, Solano, Towner, Mercado, Jacobsen.

Statistical analysis: Slezak, Qian, Huang.

Obtained funding: Mercado, Jacobsen.

Administrative, technical, or material support: Ackerson, Solano, Mercado, Jacobsen.

Supervision: Ackerson, Reynolds, Towner, Mercado, Jacobsen.

Conflict of Interest Disclosures: Dr Bruxvoort reported receiving research support from Gilead, GlaxoSmithKline, Moderna, Pfizer, and Seqirus. Mr Slezak reported receiving research support from Pfizer, Novavax, and ALK. Dr Qian reported receiving research support from GlaxoSmithKline and Moderna. Ms Sy reported receiving research support from GlaxoSmithKline, Moderna, Novavax, and Seqirus. Dr Ackerson reported receiving research support from Genentech, GlaxoSmithKline, Novavax, Moderna, Pfizer, and Seqirus. Dr Reynolds reported receiving research support from Amgen, Merck, and Novartis. Ms Huang reported receiving grants from the Centers for Disease Control and Prevention. Ms Solano reported receiving support from Gilead, GlaxoSmithKline, and Novavax. Dr Towner reported receiving research support from Gilead, Merck, Moderna, Pfizer, and ViiV Healthcare. No other disclosures were reported.

Funding/Support: This work was funded by Dynavax Technologies, manufacturers of HEPLISAV-B.

Role of the Funder/Sponsor: Dynavax Technologies had the right to comment on the study design, interpretation of data, and manuscript content. However, it had no role in the conduct of the study; collection, management, and analysis of the data; preparation of the manuscript; and decision to submit the manuscript for publication, nor did it have the right to veto publication or to decide to which journal the manuscript was submitted.

Meeting Presentation: This work was presented in part at the meeting of the Advisory Committee on Immunization Practices; September 29, 2021; and interim results from this study at the Annual Conference on Vaccinology Research; April 27, 2021, both held virtually.

Additional Contributions: The authors would also like to thank Robert Janssen, MD, Randall Hyer, MD, and Kimberly Erby, BS, who were employed at Dynavax Inc during the study; Jennifer Nelson, PhD, Arthur Reingold, MD, and Veronique Roger, MD, who were compensated for serving on the data monitoring committee; Mingsum Lee, MD, Nigel Gupta, MD, and Albert Shen, MD, who were employed by KPSC and were compensated for adjudicating potential acute MI cases; and Brittany Brown, MPH, Bianca Cheung, MS, Nidia Golla, Chika Okonkwo, MPH, Lia Pallivathucal, MPH, Claire Park, MPH, Karen Schenk, BA, Sarah Simmons, MPH, and Katherine Wong, MPH, who were employed by KPSC and provided research support.

^✉

Corresponding author.

PMCID: PMC8957040 PMID: 35333303

Key Points

Question

Do recipients of 2-dose hepatitis B vaccine with a cytosine phosphoguanine adjuvant (HepB-CpG) have a higher rate of acute myocardial infarction (MI) than recipients of a 3-dose hepatitis B vaccine with an aluminum hydroxide adjuvant (HepB-alum)?

Findings

In this prospective cohort noninferiority study of 31 183 recipients of HepB-CpG vaccine and 38 442 recipients of HepB-alum vaccine, rates of acute MI per 1000 person-years were 1.67 and 1.86, respectively. The upper confidence limit for the adjusted hazard ratio was 1.32, which was less than the noninferiority margin of 2.

Meaning

Receipt of HepB-CpG compared with HepB-alum was not significantly associated with an increased risk of acute myocardial infarction.

Abstract

Importance

The 2-dose hepatitis B vaccine with a cytosine phosphoguanine adjuvant (HepB-CpG vaccine; Heplisav-B) generated higher seroprotection in prelicensure trials than did a 3-dose hepatitis B vaccine with an aluminum hydroxide adjuvant (HepB-alum vaccine; Engerix-B). However, in 1 trial, a higher number of acute myocardial infarction (MI) events were observed among those who received the HepB-CpG vaccine than among those who received the HepB-alum vaccine, an outcome requiring further study.

Objective

To compare the rate of acute MI between recipients of HepB-CpG vaccine and HepB-alum vaccine.

Design, Setting, and Participants

This prospective cohort noninferiority study was conducted at Kaiser Permanente Southern California (KPSC), an integrated health care system with 15 medical centers and approximately 4.7 million members. The study included 69 625 adults not undergoing dialysis who received at least 1 dose of a hepatitis B vaccine in either family medicine or internal medicine departments at KPSC from August 7, 2018, to October 31, 2019 (November 30, 2020, final follow-up).

Exposures

Receipt of HepB-CpG vaccine vs HepB-alum vaccine. The first dose during the study period was the index dose.

Main Outcomes and Measures

Individuals were followed up for 13 months after the index dose for occurrence of type 1 acute MI. Potential events were identified using diagnosis codes and adjudicated by cardiologists. The adjusted hazard ratio (HR) of acute MI was estimated comparing recipients of HepB-CpG vaccine with recipients of HepB-alum vaccine, with inverse probability of treatment weighting (IPTW) to adjust for demographic and clinical characteristics. The upper limit of the 1-sided 97.5% CI was compared with a noninferiority margin of 2.

Results

Of the 31 183 recipients of HepB-CpG vaccine (median age, 49 years; IQR, 38-56 years), 51.2% (n = 15 965) were men, and 52.7% (n = 16 423) were Hispanic. Of the 38 442 recipients of HepB-alum (median age, 49 years; IQR, 39-56 years), 50.8% (19 533) were men, and 47.1% (n = 18 125) were Hispanic. Characteristics were well-balanced between vaccine groups after IPTW. Fifty-two type 1 acute MI events were confirmed among recipients of HepB-CpG vaccine for a rate of 1.67 per 1000-person-years, and 71 type 1 acute MI events were confirmed among recipients of HepB-alum vaccine for a rate of 1.86 per 1000 person-years (absolute rate difference, −0.19 [95% CI, −0.82 to 0.44]; adjusted HR, 0.92 [1-sided 97.5% CI, ∞ to 1.32], which was below the noninferiority margin; P < .001 for noninferiority).

Conclusions and Relevance

In this cohort study, receipt of HepB-CpG vaccine compared with HepB-alum vaccine did not meet the statistical criterion for increased risk of acute myocardial infarction.

This large prospective cohort study compares the rates of acute myocardial infarction between recipients of a 2-dose hepatitis B vaccine and recipients of a 3-dose hepatitis B vaccine.

Introduction

Hepatitis B is a vaccine–preventable viral disease that continues to cause substantial morbidity and mortality.^1,2,3 In the US, most new hepatitis B virus (HBV) infections occur in persons 30 years or older because universal hepatitis B vaccination of infants and catch-up vaccination of older children have been recommended since 1991.⁴ Hepatitis B vaccination of adults, recommended for those at risk of HBV infection,⁵ has remained low; in 2018, only 30% of adults had received 3 or more doses of the vaccine.^6,7

Hepatitis B vaccine with a cytosine phosphoguanine adjuvant (HepB-CpG vaccine, Heplisav-B) is a 2-dose (at 0 and 1 month) vaccine composed of hepatitis B surface antigen (HBsAg) and a toll-like receptor 9 agonist adjuvant, CpG 1018. In clinical trials, the HepB-CpG vaccine elicited significantly greater and earlier seroprotection than did a 3-dose (0, 1, and 6 months) hepatitis B vaccine with an aluminum hydroxide adjuvant (HepB-alum vaccine, Engerix-B).^8,9 Adverse events were generally mild, infrequent, and similar between the 2 vaccines.

However, a single clinical trial reported a numerical imbalance in acute myocardial infarction (MI): 14 participants (0.25%) receiving HepB-CpG vaccine and 1 (0.04%) receiving HepB-alum vaccine. The acute MI events occurred in participants with high prevalence of baseline cardiovascular risk factors, occurred randomly with no temporal relationship to vaccination, occurred at lower-than-expected incidence rates, and were not related to persistent inflammatory or autoimmune conditions.¹⁰

Based on the totality of prelicensure efficacy and safety data, the US Food and Drug Administration licensed HepB-CpG vaccine in November 2017, requiring a postmarketing study of acute MI risk.¹¹ In April 2018, the Advisory Committee on Immunization Practices (ACIP) recommended HepB-CpG vaccine for at-risk adults.¹² Thus, a large prospective cohort study was conducted at Kaiser Permanente Southern California (KPSC) to compare rates of acute MI among recipients of HepB-CpG vaccine and HepB-alum vaccine.

Methods

Study Setting

KPSC is an integrated health care system serving more than 4.7 million members, with diverse racial and ethnic and socioeconomic backgrounds similar to the underlying population.¹³ KPSC comprises 15 medical centers across Southern California, each with a hospital and associated medical office buildings. A comprehensive electronic health record (EHR) system records all details of care, including diagnoses, vaccinations, laboratory tests, procedures, and pharmacy records. Members are proactively offered recommended vaccines free of charge at any health care visit or walk-in vaccination clinic; this is facilitated by electronic alerts and reminders for hepatitis B vaccination, including for adults who are ordered tests for sexually transmitted infections and for adults with diabetes. Vaccinations received outside of the KPSC system are entered into the EHR with appropriate documentation. Claims data capture medical care received outside of the system because documentation is required for reimbursement. The study was approved by the KPSC Institutional Review Board, which waived the requirement for informed consent due to minimal risk to participants. The study protocol is available in Supplement 1.

Study Design and Participants

This pragmatic, prospective cohort, noninferiority study used a nonrandomized cluster design to distribute vaccines as part of routine care, such that HepB-CpG vaccine became the only hepatitis B vaccine available in 7 of the 15 KPSC medical centers in family medicine and internal medicine departments, while the other 8 medical centers continued to use HepB-alum vaccine. The rationale for the study design has been described previously.¹⁴ In brief, the nonrandomized cluster design was optimal because EHR order sets for hepatitis B vaccines could be modified for groups of medical centers. Moreover, KPSC medical centers prefer to stock 1 vaccine product at a time to reduce administration and documentation errors. We included KPSC members who were 18 years or older if they received at least 1 dose of hepatitis B vaccine from August 7, 2018, to October 31, 2019, during family medicine or internal medicine department visits, where more than 90% of hepatitis B vaccines are administered. Individuals undergoing dialysis were excluded (Figure 1).

Figure 1. — ^aMedian number of individuals per medical center, 4920 (IQR, 3574-5952).

^bMedian number of individuals per medical center, 4834 (IQR, 2988-5605).

^cMedian number of individuals per medical center, 5235.5 (IQR, 4070.5-10 317.5).

^dExclusions were not mutually exclusive; recipients could have multiple reasons for exclusion.

^eMedian number of individuals per medical center, 4755 (IQR, 2881-5572).

^fMedian number of individuals per medical center, 4169.5 (IQR, 1856-8125).

HepB-alum indicates hepatitis B vaccine with an aluminum hydroxide adjuvant; HepB-CpG, hepatitis B vaccine with a cytosine phosphoguanine adjuvant; KPSC, Kaiser Permanente Southern California.

Exposure

The exposure for this study was receipt of HepB-CpG vaccine vs HepB-alum vaccine. The first dose received during the study accrual period was considered the index dose (index date), and individuals were included in the study even if the index dose was not their first-ever dose of a hepatitis B vaccine. Individuals were followed up through the EHR from their index date until the first occurrence of the outcome, disenrollment from KPSC, death, or 13 months, whichever occurred first. The 13-month duration of follow-up was selected for comparability with the HepB-CpG clinical trial in which imbalance of the acute MI was observed.¹⁴

Outcome

The outcome was confirmed type 1 acute MI (definite or probable), based on the Fourth Universal Definition of Myocardial Infarction.¹⁵ Potential acute MI events were identified from the EHR and claims using the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes I21.x or I22.x. Medical records for potential events were independently adjudicated by 2 cardiologists, masked to the hepatitis B vaccine exposure. The cardiologists determined if each potential event was a definite acute MI, a probable acute MI, not an acute MI, or had insufficient information; for a definite and probable acute MI, they further determined the acute MI type. Disagreements were resolved by a third cardiology adjudicator. Cases with disagreement from all 3 cardiologists were considered indeterminate.

Covariates

We extracted covariates from the EHR, using membership data, ICD-10 codes, laboratory values, medications dispensed, procedures, and immunization records. These included sociodemographic characteristics at index date (age; sex; race and ethnicity, reported categorically by participants and included due to association with acute MI¹⁶; and neighborhood median household income), duration of KPSC membership prior to the index date, clinical characteristics in the year prior to the index date (diabetes, acute MI, dyslipidemia, depression, obesity, coronary artery disease, chronic kidney disease, Charlson Comorbidity Index,¹⁷ smoking, hypertension, most recent hemoglobin A_1c value, most recent low-density lipoprotein cholesterol value, cardiovascular disease medications, cardiac revascularization, health care utilization—number of hospitalization, emergency department visits, and outpatient visits—and hepatitis B vaccination), and vaccines administered concomitantly with the index dose (Tables 1 and 2).

Table 1. Demographic Characteristics of Recipients of Hepatitis B Vaccines.

	Before inverse probability of treatment weighting			After inverse probability of treatment weighting^a
	HepB-CpG vaccine, No. (%) (n = 31 183)	HepB-alum vaccine, No. (%) (n = 38 442)	Standardized difference^b	HepB-CpG vaccine, % (n = 31 183)	HepB-alum vaccine, % (n = 38 442)	Standardized difference^b
Age at index dose, median (IQR), y	49 (38-56)	49 (39-56)	−0.059	49 (39-56)	49 (39-56)	−0.002
Sex
Men	15 965 (51.2)	19 533 (50.8)	0.008	51.1	51.0	0.002
Women	15 218 (48.8)	18 909 (49.2)	0.008	48.9	49.0	0.002
Race and ethnicity^c
Asian	4893 (15.7)	3987 (10.4)	0.323	12.8	12.8	0.001
Black	2696 (8.6)	2768 (7.2)		7.9	7.9
Hispanic	16 423 (52.7)	18 125 (47.1)		49.6	49.6
White	5126 (16.4)	11 188 (29.1)		23.4	23.4
Other	1018 (3.3)	1266 (3.3)		3.3	3.3
Unknown	1027 (3.3)	1108 (2.9)		3.1	3.1
Neighborhood median household income, $
<40 000	3102 (9.9)	3198 (8.3)	0.096	8.9	9.0	0.009
40 000-59 999	8676 (27.8)	9958 (25.9)		26.4	26.6
60 000-79 999	8425 (27.0)	10 184 (26.5)		26.5	26.6
80 000-99 999	5228 (16.8)	7440 (19.4)		18.3	18.3
≥100 000	5700 (18.3)	7585 (19.7)		19.6	19.3
Missing^d	52 (0.2)	77 (0.2)		0.2	0.2
Enrollment duration prior to index dose, median (IQR), y	3.7 (1.3-10.9)	3.9 (1.3-11.2)	−0.025	3.8 (1.3-11.0)	3.8 (1.3-11.0)	0.005

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Abbreviations: HepB-alum, hepatitis B vaccine with an aluminum hydroxide adjuvant; HepB-CpG, hepatitis B vaccine with a cytosine phosphoguanine adjuvant.

^{^a}

All variables were used in inverse probability of treatment weighting (IPTW) except dyslipidemia, obesity, depression, mild liver disease, coronary artery disease, congestive heart failure, cancer, cerebrovascular disease, connective tissue or rheumatic disease, acute myocardial infarction, metastatic carcinoma, peptic ulcer disease, paraplegia and hemiplegia, dementia, insulin, antiarrhythmic medication, digoxin, and number of emergency department visits. See Table 2 for listing of clinical variables.

^{^b}

The standardized difference is a measure of balance between groups in the distribution of covariates, with a value of less than 0.1 considered a negligible difference.

^{^c}

Hispanic includes Hispanic of all races; the “other” race category includes American Indian or Alaska Native, Pacific Islander or Native Hawaiian, multiple races, and other unspecified races. The “unknown” category was included with the “other” category in IPTW.

^{^d}

Missing household income data were included in IPTW.

Table 2. Clinical Characteristics of Recipients of Hepatitis B Vaccines.

	Before inverse probability of treatment weighting			After inverse probability of treatment weighting^a
	HepB-CpG vaccine, No. (%) (n = 31 183)	HepB-alum vaccine, No. (%) (n = 38 442)	Standardized difference^b	HepB-CpG vaccine, % (n = 31 183)	HepB-alum vaccine, % (n = 38 442)	Standardized difference^b
Charlson Comorbidity Index in year prior to index dose^c
0	10 432 (33.5)	12 505 (32.5)	0.081	33.1	32.9	0.018
1	13 690 (43.9)	16 103 (41.9)		42.8	42.8
2	4475 (14.4)	5821 (15.1)		14.8	14.8
3	1053 (3.4)	1618 (4.2)		3.7	4.0
≥4	1533 (4.9)	2395 (6.2)		5.7	5.6
Comorbidities in year prior to index dose
Diabetes	18 521 (59.4)	22 432 (58.4)	0.021	58.9	58.9	0.001
Without complications^d	15 204 (48.8)	17 981 (46.8)	0.040	47.8	47.6	0.003
With complications^d	3317 (10.6)	4451 (11.6)	−0.030	11.1	11.2	−0.003
Dyslipidemia	12 904 (41.4)	16 067 (41.8)	−0.008	41.6	41.5	0.003
Obesity	7387 (23.7)	9549 (24.8)	−0.027	24.3	24.2	0.003
COPD^d	2754 (8.8)	4206 (10.9)	−0.071	9.9	10.0	−0.001
Depression	2270 (7.3)	3466 (9.0)	−0.064	8.1	8.3	−0.007
Mild liver disease^d	1816 (5.8)	2532 (6.6)	−0.032	6.0	6.3	−0.013
Kidney disease^d	1019 (3.3)	1676 (4.4)	−0.057	3.9	3.9	0
Peripheral vascular disease^d	1005 (3.2)	1506 (3.9)	−0.037	3.6	3.6	0
Coronary artery disease	813 (2.6)	1257 (3.3)	−0.039	2.9	3.0	−0.010
Congestive heart failure^d	512 (1.6)	757 (2.0)	−0.025	1.8	1.8	0.001
Cancer^d	447 (1.4)	665 (1.7)	−0.024	1.6	1.6	0.005
Cerebrovascular disease^d	388 (1.2)	579 (1.5)	−0.023	1.3	1.4	−0.012
Connective tissue or rheumatic disease^d	240 (0.8)	382 (1.0)	−0.024	0.9	0.9	−0.008
Moderate or severe liver disease^d	128 (0.4)	304 (0.8)	−0.049	0.6	0.6	−0.004
Acute MI	121 (0.4)	177 (0.5)	0.011	0.4	0.4	−0.003
Metastatic carcinoma^d	103 (0.3)	137 (0.4)	−0.005	0.4	0.3	0.007
Peptic ulcer disease^d	94 (0.3)	141 (0.4)	−0.011	0.3	0.3	0.002
Paraplegia and hemiplegia^d	92 (0.3)	141 (0.4)	−0.013	0.3	0.3	−0.010
AIDS/HIV^d	82 (0.3)	160 (0.4)	−0.026	0.3	0.3	−0.001
Dementia^d	36 (0.1)	59 (0.2)	−0.010	0.1	0.1	−0.006
CVD risk factors in year prior to index dose^e
Smoking	8670 (27.8)	11 676 (30.4)	−0.057	29.1	29.2	−0.002
Hypertension	9565 (30.7)	12 235 (31.8)	−0.025	31.2	31.3	−0.001
CVD medication use in year prior to index dose
Any of CVD medications	19 273 (61.8)	24 553 (63.9)	−0.043	63.0	63.0	0
Antihyperglycemic	13 974 (44.8)	17 676 (46.0)	−0.024	45.6	45.5	0.001
Antihypertensive^f	11 945 (38.3)	15 748 (41.0)	−0.054	39.8	39.8	0.001
Statin	11 897 (38.2)	15 185 (39.5)	−0.028	38.9	38.9	0.000
Insulin	3021 (9.7)	4163 (10.8)	−0.038	10.2	10.5	−0.009
Antiplatelet agent	1674 (5.4)	2080 (5.4)	−0.002	5.4	5.4	−0.000
Other CVD medications	647 (2.1)	1088 (2.8)	−0.049	2.5	2.5	0.001
Other lipid-lowering medication	537 (1.7)	853 (2.2)	−0.036	2.0	2.0	0
Anticoagulant	433 (1.4)	619 (1.6)	−0.018	1.5	1.5	−0.000
Antiarrhythmic^f	344 (1.1)	568 (1.5)	−0.033	1.3	1.3	0
Nitrate	244 (0.8)	439 (1.1)	−0.037	1.0	1.0	−0.001
Digoxin	55 (0.2)	90 (0.2)	−0.013	0.2	0.2	−0.005
HbA_1c levels in year prior to index dose, %
<6.5	10 701 (34.3)	13 615 (35.4)	0.068	34.9	34.9	0.001
≥6.5	14 327 (45.9)	16 450 (42.8)		44.3	44.2
Not tested^g	6155 (19.7)	8377 (21.8)		20.9	20.9
LDL levels in year prior to index dose, mg/dL
<100	9874 (31.7)	11 353 (29.5)	0.088	30.5	30.5	0.002
≥100	9990 (32.0)	11 501 (29.9)		30.9	30.9
Not tested^h	11 319 (36.3)	15 588 (40.5)		38.6	38.7
Cardiac revascularizationⁱ	42 (0.1)	36 (0.1)	0.012	0.1	0.1	0
Health care use in year prior to index date
No. of inpatient visits
0	29 780 (95.5)	36 218 (94.2)	0.059	94.8	94.8	0.001
1	1064 (3.4)	1721 (4.5)		4.0	4.0
≥2	339 (1.1)	503 (1.3)		1.2	1.2
No. of outpatient visits
0	2945 (9.4)	3187 (8.3)	0.117	8.8	8.8	0.001
1	3723 (11.9)	3986 (10.4)		11.0	11.0
2-4	10 254 (32.9)	11 663 (30.3)		31.5	31.5
5-9	7989 (25.6)	10 346 (26.9)		26.4	26.4
≥10	6272 (20.1)	9260 (24.1)		22.3	22.3
No. of ED visits
0	25 733 (82.5)	31 283 (81.4)	0.032	81.7	82.0	0.007
1	3727 (12.0)	4823 (12.5)		12.3	12.2
2-4	1519 (4.9)	2032 (5.3)		5.2	5.1
≥5	204 (0.7)	304 (0.8)		0.8	0.7
Hepatitis B vaccine in year prior to index dose^j
1	4659 (14.9)	5595 (14.6)	0.018	14.8	14.7	0.007
2	2449 (7.9)	3185 (8.3)	0.018	8.0	8.2	0.007
Other vaccines on same day as index dose^k	14 609 (46.8)	18 787 (48.9)	−0.041	48.1	47.8	0.006

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Abbreviations: ED, emergency department; MI, myocardial infarction; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular disease; HbA_1c, hemoglobin A_1c; HepB-alum, hepatitis B vaccine with an aluminum hydroxide adjuvant; HepB-CpG, hepatitis B vaccine with a cytosine phosphoguanine adjuvant; LDL, low-density lipoprotein.

SI conversion factor: To convert LDL from mg/dL to mmol/L, multiply by 0.0259.

^{^a}

See Table 1 footnotes for inverse probability of treatment weighting variables.

^{^b}

See Table 1 footnotes for standardized difference definition.

^{^c}

The Charlson Comorbidity Index predicts mortality by weighting certain comorbidities. In this study, the Quan et al¹⁷ algorithm was used to calculate the index (range, 0-15; higher values represent greater morbidity).

^{^d}

Individual Charlson comorbidities.

^{^e}

Smoking was defined as any history of smoking; hypertension, 2 or more outpatient diagnosis codes within 1 year or 1 or more outpatient diagnosis codes plus a hypertension medication within 1 year.

^{^f}

β-Blockers were included in both antihypertensive and antiarrhythmic medications.

^{^g}

Missing HbA_1c testing results were included in probability weighting.

^{^h}

Missing test results were included in the inverse probability of treatment weighting analysis.

^ⁱ

Cardiac revascularization included percutaneous coronary intervention and coronary artery bypass graft surgery.

^{^j}

Mostly hepatitis B-alum vaccine with a small number of HepA-HepB vaccines.

^{^k}

The most common concomitant vaccinations (eTable 2 in Supplement 2) were influenza vaccine without a novel adjuvant (approximately 23% of all hepatitis B vaccine recipients); pneumococcal vaccines (16%); tetanus, diphtheria, pertussis vaccine (5.7%); measles, mumps, and rubella vaccine (4.7%); and hepatitis A vaccine (4.6%).

Statistical Analyses

We described the distribution of these characteristics among recipients of HepB-CpG vaccine and recipients of HepB-alum vaccine and applied inverse probability of treatment weighting (IPTW) by computing stabilized weights inversely proportional to cohort members’ probability of HepB-CpG vaccine exposure. Because P value magnitude is highly related to sample size, we used standardized differences to assess whether IPTW achieved balance in the distribution of characteristics between recipients of HepB-CpG vaccine and HepB-alum vaccine, with an absolute value of less than 0.10 considered a negligible difference. The missing indicator method was used for covariates with missing data.¹⁸

We calculated rates of confirmed type 1 acute MI during the follow-up period for recipients of the HepB-CpG and HepB-alum vaccines by dividing the number of acute MI events by the number of person-years, and we calculated the absolute rate difference (RD) and 95% CI. Next, we used Kaplan-Meier analysis with the log-rank test to compare the cumulative incidence of acute MI between the recipients of HepB-CpG vaccine and recipients of HepB-alum vaccine (Figure 2). Because the proportional hazards assumption was met with no significant correlation of Schoenfeld residuals, we used Cox proportional hazards regression to estimate the hazard ratio (HR) and 1-sided 97.5% CI for acute MI by comparing recipients of HepB-CpG vaccine with recipients of HepB-alum vaccine, adjusting for potential confounders using IPTW.

Figure 2. — ^aThe mean (SD) observation time was 365 (86) days for hepatitis B vaccine with a cytosine phosphoguanine adjuvant (HepB-CpG) vaccine and 363 (88) days for hepatitis B vaccine with an aluminum hydroxide adjuvant (HepB-alum) vaccine; the median observation time was 365 days (IQR, 365-365 days).

Potential acute myocardial infarction (MI) events identified through diagnosis codes were reviewed by cardiologists who determined occurrence of type 1 acute MI. Details of acute myocardial infarction adjudication results are presented in eTable 3 in Supplement 2.

The primary analysis was a noninferiority design to test the null hypothesis that the HR would be 2 or higher, such that the null hypothesis would be rejected if the upper limit of the 95% CI (ie, the 1-sided 97.5% CI) for the adjusted HR was less than 2. The noninferiority margin was determined by what would be considered clinically acceptable to regulators.¹⁴ Based on an estimated sample size of approximately 30 000 recipients of HepB-CpG vaccine and 30 000 recipients of HepB-alum vaccine, follow-up of 13 months after the index date, 10% loss to follow-up, and a confirmed type 1 acute MI event rate of 1.5 per 1000 person-years, the study had approximately 92% power to exclude an HR of 2 or higher. Clustering by medical center was considered through random-effects variables in the analysis.

We repeated the analyses using separate IPTW models in a priori–defined subgroups including individuals younger than 50 years, individuals 50 years or older, individuals with diabetes, individuals with hypertension, individuals who received the index dose with concomitant vaccine(s), individuals who received the index dose as their first-ever dose of hepatitis B vaccine, and individuals who received the index dose as a subsequent dose of hepatitis B vaccine. Because of the potential for type I error due to multiple comparisons, findings for subgroup analyses should be interpreted as exploratory.

We also conducted sensitivity analyses. First, we examined 3 alternative analytic approaches: (1) a multivariable-adjusted Cox model, (2) a propensity score–adjusted Cox model, and (3) a propensity score–stratified Cox model. Second, to address potential misclassification of type 1 and type 2 acute MI,^19,20 we conducted sensitivity analyses using 2 alternative outcomes: all acute MI events and confirmed type 1 acute MI events plus indeterminate events. In addition, we plotted confirmed type 1 acute MI events by days since the index dose. All analyses were conducted using SAS Enterprise Guide version 7.1 (SAS Institute Inc).

Results

During the study accrual period, 31 183 recipients were included in the HepB-CpG vaccine group and 38 442 recipients, in the HepB-alum vaccine group (Figure 1; eTable 1 in Supplement 2). The median age was 49 years (IQR, 38-56 years) in the HepB-CpG vaccine group and 49 years (IQR, 39-56 years) in the HepB-alum vaccine group (standardized difference, −0.002); 51.2% and 50.8% were men (standardized difference, 0.008), respectively; and 52.7% and 47.1% were Hispanic (standardized difference, 0.323), respectively (Table 1). Prior year comorbidities, cardiovascular disease risk factors, cardiovascular medications, and health care utilization were well-balanced between groups before IPTW, and further balanced after IPTW (eFigure 1 in Supplement 2). A total of 14 609 recipients (46.8%) in the HepB-CpG vaccine group and 18 787 recipients (48.9%) in the HepB-alum vaccine group received other vaccines concomitantly with the index dose (Table 2); the majority of concomitant vaccines were influenza vaccines or pneumococcal vaccines, and very few had a novel adjuvant (eTable 2 in Supplement 2).

During the follow-up period, 74 potential acute MI events occurred in the HepB-CpG vaccine group and 128 in the HepB-alum vaccine group, of which 52 (70.3%) and 71 (55.5%), respectively, were confirmed to be type 1 acute MIs (eTable 3 in Supplement 2). A higher proportion of events in the HepB-alum vaccine group came from claims, and a lower proportion of claims cases were adjudicated as type 1 acute MI. Similar proportions of events for the HepB-CpG vaccine group and HepB-alum vaccine group were adjudicated as type 2 acute MIs. There were no events that had insufficient information for adjudication, and 7 events among the HepB-alum vaccine group were considered indeterminate due to reviewer disagreement. The rate per 1000 person-years of type 1 acute MI was 1.67 among the HepB-CpG vaccine group and 1.86 among the HepB-alum vaccine group (absolute RD, −0.09 [95% CI, −0.82 to 0.44]; Table 3). By Kaplan-Meier analysis, cumulative incidence of type 1 acute MI was similar between groups (P = .56) (Figure 2). There was no evidence of temporal clustering of acute MI events relative to the index dose or a dose response for either vaccine type (eFigure 2 and 3 in Supplement 2).

Table 3. Primary Weighted Analysis of Confirmed Type 1 Acute Myocardial Infarction Comparing Recipients of HepB-CpG Vaccine With Recipients of HepB-Alum Vaccine.

HepB-CpG vaccine			HepB-alum vaccine			Absolute rate difference (95% CI)	Hazard ratio (1-sided 97.5% CI)				P value for noninferiority
HepB-CpG vaccine			HepB-alum vaccine				HepB-CpG vaccine		HepB-alum vaccine
Confirmed type 1 acute MI^a	Follow-up time in person-years	Rate per 1000 person-years	Confirmed type 1 acute MI^a	Follow-up time in person-years	Rate per 1000 person-years		Unadjusted	Adjusted^b	Unadjusted	Adjusted^b
52	31 139	1.67	71	38 200	1.86	−0.19 (−0.82 to 0.44)	0.90 (−∞ to 1.29)	0.92 (−∞ to 1.32)	1 [Reference]	1 [Reference]	<.001

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Abbreviations: HepB-alum, hepatitis B vaccine with an aluminum hydroxide adjuvant; HepB-CpG, hepatitis B vaccine with a cytosine phosphoguanine adjuvant; MI, myocardial infarction.

^{^a}

Potential acute MI events identified through diagnosis codes were reviewed by cardiologists who determined occurrence of type 1 acute MI. Details of acute MI adjudication results are presented in eTable 3 in Supplement 2.

^{^b}

The adjusted hazard ratio (primary result) was estimated using Cox proportional hazards models with inverse probability treatment weighting.

In the primary analysis using a Cox proportional hazards model with IPTW, the adjusted HR was 0.92 (1-sided 97.5% CI, ∞ to 1.32; Table 3). The upper bound of the 97.5% CI was less than the noninferiority margin of 2, ruling out a doubling of the type 1 acute MI rate and supporting rejection of the null hypothesis (P < .001 for noninferiority). Sensitivity analyses using alternative analytic approaches and outcome definitions yielded consistent results (eTable 4 in Supplement 2). In subgroup analyses, characteristics of HepB-CpG vaccine and HepB-alum vaccine groups were well-balanced after IPTW in each subgroup (eTables 5-11 in Supplement 2), and adjusted HRs ranged from 0.71 to 1.00, with 95% CIs all overlapping 1 (Figure 3).

Figure 3. — ^aSubgroups were prespecified in the study protocol (age group at index dose, index dose as first or subsequent hepatitis B vaccination) or were requested by the study’s independent data monitoring committee (concomitant vaccine recipients, diabetes, or hypertension).

^bPotential acute myocardial infarction (MI) events identified through diagnosis codes were reviewed by cardiologists, who determined occurrence of type 1 acute MI. Details of acute MI adjudication results are presented in eTable 3 in Supplement 2.

^cAdjusted hazard ratios (HRs) were estimated using Cox proportional hazards models with inverse probability of treatment weighting, numbers and details of which are presented in eTables 5 through 11 in Supplement 2.

HepB-alum indicates hepatitis B vaccine with an aluminum hydroxide adjuvant; HepB-CpG, hepatitis B vaccine with a cytosine phosphoguanine adjuvant.

Discussion

In this large study in a clinical setting, receipt of HepB-CpG vaccine compared with HepB-alum vaccine was not significantly associated with an increased risk of acute MI. These findings were consistent across subgroups defined by age group, diabetes, hypertension, and receipt of concomitant vaccines and by whether the index dose was the first or subsequent hepatitis B vaccine dose. Similar results from sensitivity analyses using different analytic approaches and outcome definitions, as well as lack of temporal clustering or a dose response, combine to provide strong evidence that the HepB-CpG vaccine was not associated with acute MI.

Hepatitis B vaccination is the most effective strategy for prevention of HBV and is a critical component of global hepatitis elimination efforts, including the US Department of Health and Human Services’ Viral Hepatitis National Strategic Plan: 2021-2025. However, only 30% of adults overall have received a full hepatitis B vaccine series, and coverage among those with HBV risk factors such as individuals with diabetes, travelers to HBV-endemic countries, and health care workers is suboptimal. In addition, disparities in vaccine uptake among racial and ethnic groups persist, with Black and Hispanic individuals less likely to receive hepatitis B vaccine than Asian and White individuals. Among individuals who receive an initial dose of a 3-dose hepatitis B vaccine, 31% complete the series.²¹ Prior work has shown that the shorter HepB-CpG vaccine schedule (2 doses at 0 and 1 month vs 3 doses at 0, 1, and 6 months for HepB-alum vaccine) was associated with increased series completion.²² Further research is needed to determine if individuals would be more likely to initiate a shorter 2-dose series than a longer 3-dose series, as well as to address vaccine hesitancy and other barriers to hepatitis B vaccine uptake among adults.²³

A strength of this study was the prospective cohort design in which hepatitis B vaccines were administered as part of routine health care delivery. Because only 1 adult hepatitis B vaccine product was available per facility, the study design inherently minimized selection bias associated with choice of hepatitis B vaccine product based on a patient’s risk profile. Although there is potential for measured and unmeasured confounding in all observational studies, sociodemographic and clinical characteristics were balanced at baseline using IPTW in this pragmatic nonrandomized cluster design. This approach mimicked a randomized clinical trial for a primary outcome of safety, providing a robust sample size while avoiding the individual selection bias present in registries created for safety studies. A priori stratified and subgroup analyses were conducted, as well as sensitivity analyses using alternative analytic approaches and outcome definitions, for which consistent results were observed. In addition, generalizability of results was strengthened by the large and diverse study population, in contrast to the largely White demographics of prelicensure trials.

Limitations

This study had several limitations. First, misclassification of the vaccine exposure was possible, but manufacturer and lot number descriptions were checked against the brand name, and chart review of doses with potential discrepancies was conducted. Second, misclassification of the acute MI outcome was also possible. However, all potential events were adjudicated by at least 2 cardiologist reviewers. Third, there were more events from claims (outside the KPSC health system) among HepB-alum vaccine recipients, with a lower proportion adjudicated as definite or probable type 1 acute MI; the HR for acute MI comparing HepB-CpG vaccine and HepB-alum vaccine recipients would have been even lower if some events adjudicated as not acute MI were instead true acute MI.

Conclusions

In this cohort study, receipt of HepB-CpG vaccine compared with HepB-alum vaccine did not meet the statistical criterion for increased risk of acute myocardial infarction.

Supplement 1.

Trial Protocol

Click here for additional data file.^{(365.6KB, pdf)}

Supplement 2.

eTable 1. Uptake of HepB-CpG vaccine and HepB-alum vaccine

eTable 2. Distribution of concomitant vaccines among HepB-CpG vaccine and HepB-alum vaccine recipients comparing standardized differences before and after IPTW

eTable 3. Results of acute MI adjudication

eTable 4. Hazard ratios for acute MI comparing HepB-CpG vaccine and HepC-alum vaccine recipients in sensitivity analysis

eTable 5. Demographic and clinical characteristics of HepB-CpG vaccine recipients among age <50 years comparing standardized differences before and after IPTW

eTable 6. Demographic and clinical characteristics of HepB-CpG vaccine and HepB-alum vaccine recipients among individuals age ≥50 years comparing standardized differences before and after IPTW

eTable 7. Demographic and clinical characteristics of HepB-CpG vaccine and HepB-alum vaccine recipients among individuals with diabetes comparing standardized differences before and after IPTW

eTable 8. Demographic and clinical characteristics of HepB-CpG vaccine and HepB-alum vaccine recipients among individuals with hypertension comparing standardized differences before and after IPTW

eTable 9. Demographic and clinical characteristics of individuals who received HepB-CpG vaccine and HepB-alum vaccine with a concomitant vaccine comparing standardized differences before and after IPTW

eTable 10. Demographic and clinical characteristics of individuals who received their index dose of HepB-CpG vaccine and HepB-alum vaccine as their first ever dose of hepatitis B vaccine, comparing standardized differences before and after IPTW

eTable 11. Demographic and clinical characteristics of individuals who received their index dose of HepB-CpG vaccine and HepB-alum vaccine as a subsequent dose of hepatitis B vaccine, comparing standardized differences before and after IPTW

eFigure 1. Comparison of standardized differences for distribution of characteristics of HepB-CpG vaccine and HepB-alum vaccine recipients before and after IPTW

eFigure 2. Distribution of confirmed type 1 acute MI and HepB-CpG vaccine doses

eFigure 3. Distribution of confirmed type 1 acute MI and HepB-alum vaccine doses

Click here for additional data file.^{(1.9MB, pdf)}

References

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11.US Food and Drug Administration . Summary basis for regulatory action: HEPLISAV-B. Accessed February 10, 2020. https://www.fda.gov/media/109808/download
12.Schillie S, Harris A, Link-Gelles R, Romero J, Ward J, Nelson N. Recommendations of the Advisory Committee on Immunization Practices for use of a hepatitis B vaccine with a novel adjuvant. MMWR Morb Mortal Wkly Rep. 2018;67(15):455-458. doi: 10.15585/mmwr.mm6715a5 [DOI] [PMC free article] [PubMed] [Google Scholar]
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16.Chi GC, Kanter MH, Li BH, et al. Trends in acute myocardial infarction by race and ethnicity. J Am Heart Assoc. 2020;9(5):e013542. doi: 10.1161/JAHA.119.013542 [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Quan H, Sundararajan V, Halfon P, et al. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care. 2005;43(11):1130-1139. doi: 10.1097/01.mlr.0000182534.19832.83 [DOI] [PubMed] [Google Scholar]
18.Miettinen O. Theoretical Epidemiology: Principles of Occurrence Research. John Wiley & Sons; 1985. [Google Scholar]
19.Raphael CE, Roger VL, Sandoval Y, et al. Incidence, trends, and outcomes of type 2 myocardial infarction in a community cohort. Circulation. 2020;141(6):454-463. doi: 10.1161/CIRCULATIONAHA.119.043100 [DOI] [PMC free article] [PubMed] [Google Scholar]
20.McCarthy C, Murphy S, Cohen JA, et al. Misclassification of myocardial injury as myocardial infarction: implications for assessing outcomes in value-based programs. JAMA Cardiol. 2019;4(5):460-464. doi: 10.1001/jamacardio.2019.0716 [DOI] [PMC free article] [PubMed] [Google Scholar]
21.Trantham L, Kurosky SK, Zhang D, Johnson KD. Adherence with and completion of recommended hepatitis vaccination schedules among adults in the United States. Vaccine. 2018;36(35):5333-5339. doi: 10.1016/j.vaccine.2018.05.111 [DOI] [PubMed] [Google Scholar]
22.Bruxvoort K, Slezak J, Huang R, et al. Association of number of doses with hepatitis b vaccine series completion in US adults. JAMA Netw Open. 2020;3(11):e2027577. doi: 10.1001/jamanetworkopen.2020.27577 [DOI] [PMC free article] [PubMed] [Google Scholar]
23.Lazarus JV, Picchio CA, Nayagam S, Ratzan S, Thursz M. Strengthening vaccine confidence during the COVID-19 pandemic: a new opportunity for global hepatitis B virus elimination. J Hepatol. 2020;73(3):490-492. doi: 10.1016/j.jhep.2020.06.008 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

Trial Protocol

Click here for additional data file.^{(365.6KB, pdf)}

Supplement 2.

eTable 1. Uptake of HepB-CpG vaccine and HepB-alum vaccine

eTable 2. Distribution of concomitant vaccines among HepB-CpG vaccine and HepB-alum vaccine recipients comparing standardized differences before and after IPTW

eTable 3. Results of acute MI adjudication

eTable 4. Hazard ratios for acute MI comparing HepB-CpG vaccine and HepC-alum vaccine recipients in sensitivity analysis

eTable 5. Demographic and clinical characteristics of HepB-CpG vaccine recipients among age <50 years comparing standardized differences before and after IPTW

eTable 6. Demographic and clinical characteristics of HepB-CpG vaccine and HepB-alum vaccine recipients among individuals age ≥50 years comparing standardized differences before and after IPTW

eTable 7. Demographic and clinical characteristics of HepB-CpG vaccine and HepB-alum vaccine recipients among individuals with diabetes comparing standardized differences before and after IPTW

eFigure 1. Comparison of standardized differences for distribution of characteristics of HepB-CpG vaccine and HepB-alum vaccine recipients before and after IPTW

eFigure 2. Distribution of confirmed type 1 acute MI and HepB-CpG vaccine doses

eFigure 3. Distribution of confirmed type 1 acute MI and HepB-alum vaccine doses

Click here for additional data file.^{(1.9MB, pdf)}

[joi220022r1] 1.Centers for Disease Control and Prevention . Viral hepatitis surveillance United States, 2018. Accessed September 4, 2020. https://www.cdc.gov/hepatitis/statistics/2018surveillance/pdfs/2018HepSurveillanceRpt.pdf

[joi220022r2] 2.Lim JK, Nguyen MH, Kim WR, Gish R, Perumalswami P, Jacobson IM. Prevalence of chronic hepatitis B virus infection in the United States. Am J Gastroenterol. 2020;115(9):1429-1438. doi: 10.14309/ajg.0000000000000651 [DOI] [PubMed] [Google Scholar]

[joi220022r3] 3.Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45(2):507-539. doi: 10.1002/hep.21513 [DOI] [PubMed] [Google Scholar]

[joi220022r4] 4.Mast EE, Margolis HS, Fiore AE, et al. ; Advisory Committee on Immunization Practices (ACIP) . A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP), 1: immunization of infants, children, and adolescents. MMWR Recomm Rep. 2005;54(RR-16):1-31. [PubMed] [Google Scholar]

[joi220022r5] 5.Schillie S, Vellozzi C, Reingold A, et al. Prevention of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2018;67(1):1-31. doi: 10.15585/mmwr.rr6701a1 [DOI] [PMC free article] [PubMed] [Google Scholar]

[joi220022r6] 6.Lu PJ, Hung MC, Srivastav A, et al. Surveillance of vaccination coverage among adult populations—United States, 2018. MMWR Surveill Summ. 2021;70(3):1-26. doi: 10.15585/mmwr.ss7003a1 [DOI] [PMC free article] [PubMed] [Google Scholar]

[joi220022r7] 7.Lu PJ, Byrd KK, Murphy TV, Weinbaum C. Hepatitis B vaccination coverage among high-risk adults 18-49 years, US, 2009. Vaccine. 2011;29(40):7049-7057. doi: 10.1016/j.vaccine.2011.07.030 [DOI] [PubMed] [Google Scholar]

[joi220022r8] 8.Heyward WL, Kyle M, Blumenau J, et al. Immunogenicity and safety of an investigational hepatitis B vaccine with a toll-like receptor 9 agonist adjuvant (HBsAg-1018) compared to a licensed hepatitis B vaccine in healthy adults 40-70 years of age. Vaccine. 2013;31(46):5300-5305. doi: 10.1016/j.vaccine.2013.05.068 [DOI] [PubMed] [Google Scholar]

[joi220022r9] 9.Jackson S, Lentino J, Kopp J, et al. ; HBV-23 Study Group . Immunogenicity of a two-dose investigational hepatitis B vaccine, HBsAg-1018, using a toll-like receptor 9 agonist adjuvant compared with a licensed hepatitis B vaccine in adults. Vaccine. 2018;36(5):668-674. doi: 10.1016/j.vaccine.2017.12.038 [DOI] [PubMed] [Google Scholar]

[joi220022r10] 10.Vaccines and Related Biological Products Advisory Committee Meeting . July 28, 2017. Accessed February 10, 2020. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/VaccinesandRelatedBiologicalProductsAdvisoryCommittee/UCM568492.pdf

[joi220022r11] 11.US Food and Drug Administration . Summary basis for regulatory action: HEPLISAV-B. Accessed February 10, 2020. https://www.fda.gov/media/109808/download

[joi220022r12] 12.Schillie S, Harris A, Link-Gelles R, Romero J, Ward J, Nelson N. Recommendations of the Advisory Committee on Immunization Practices for use of a hepatitis B vaccine with a novel adjuvant. MMWR Morb Mortal Wkly Rep. 2018;67(15):455-458. doi: 10.15585/mmwr.mm6715a5 [DOI] [PMC free article] [PubMed] [Google Scholar]

[joi220022r13] 13.Koebnick C, Langer-Gould AM, Gould MK, et al. Sociodemographic characteristics of members of a large, integrated health care system: comparison with US Census Bureau data. Perm J. 2012;16(3):37-41. doi: 10.7812/TPP/12-031 [DOI] [PMC free article] [PubMed] [Google Scholar]

[joi220022r14] 14.Bruxvoort K, Sy LS, Ackerson BK, et al. Challenges in phase 4 post-licensure safety studies using real world data in the United States: hepatitis B vaccine example. Vaccine X. 2021;8:100101. doi: 10.1016/j.jvacx.2021.100101 [DOI] [PMC free article] [PubMed] [Google Scholar]

[joi220022r15] 15.Thygesen K, Alpert JS, Jaffe AS, et al. ; Executive Group on behalf of the Joint European Society of Cardiology (ESC)/American College of Cardiology (ACC)/American Heart Association (AHA)/World Heart Federation (WHF) Task Force for the Universal Definition of Myocardial Infarction . Fourth Universal Definition of Myocardial Infarction (2018). Circulation. 2018;138(20):e618-e651. doi: 10.1161/CIR.0000000000000617 [DOI] [PubMed] [Google Scholar]

[joi220022r16] 16.Chi GC, Kanter MH, Li BH, et al. Trends in acute myocardial infarction by race and ethnicity. J Am Heart Assoc. 2020;9(5):e013542. doi: 10.1161/JAHA.119.013542 [DOI] [PMC free article] [PubMed] [Google Scholar]

[joi220022r17] 17.Quan H, Sundararajan V, Halfon P, et al. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care. 2005;43(11):1130-1139. doi: 10.1097/01.mlr.0000182534.19832.83 [DOI] [PubMed] [Google Scholar]

[joi220022r18] 18.Miettinen O. Theoretical Epidemiology: Principles of Occurrence Research. John Wiley & Sons; 1985. [Google Scholar]

[joi220022r19] 19.Raphael CE, Roger VL, Sandoval Y, et al. Incidence, trends, and outcomes of type 2 myocardial infarction in a community cohort. Circulation. 2020;141(6):454-463. doi: 10.1161/CIRCULATIONAHA.119.043100 [DOI] [PMC free article] [PubMed] [Google Scholar]

[joi220022r20] 20.McCarthy C, Murphy S, Cohen JA, et al. Misclassification of myocardial injury as myocardial infarction: implications for assessing outcomes in value-based programs. JAMA Cardiol. 2019;4(5):460-464. doi: 10.1001/jamacardio.2019.0716 [DOI] [PMC free article] [PubMed] [Google Scholar]

[joi220022r21] 21.Trantham L, Kurosky SK, Zhang D, Johnson KD. Adherence with and completion of recommended hepatitis vaccination schedules among adults in the United States. Vaccine. 2018;36(35):5333-5339. doi: 10.1016/j.vaccine.2018.05.111 [DOI] [PubMed] [Google Scholar]

[joi220022r22] 22.Bruxvoort K, Slezak J, Huang R, et al. Association of number of doses with hepatitis b vaccine series completion in US adults. JAMA Netw Open. 2020;3(11):e2027577. doi: 10.1001/jamanetworkopen.2020.27577 [DOI] [PMC free article] [PubMed] [Google Scholar]

[joi220022r23] 23.Lazarus JV, Picchio CA, Nayagam S, Ratzan S, Thursz M. Strengthening vaccine confidence during the COVID-19 pandemic: a new opportunity for global hepatitis B virus elimination. J Hepatol. 2020;73(3):490-492. doi: 10.1016/j.jhep.2020.06.008 [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Association Between 2-Dose vs 3-Dose Hepatitis B Vaccine and Acute Myocardial Infarction

Katia Bruxvoort, PhD

Jeff Slezak, MS

Lei Qian, PhD

Lina S Sy, MPH

Bradley Ackerson, MD

Kristi Reynolds, PhD

Runxin Huang, MS

Zendi Solano, BS

William Towner, MD

Cheryl Mercado, MPH

Steven J Jacobsen, MD, PhD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Exposures

Main Outcomes and Measures

Results

Conclusions and Relevance

Introduction

Methods

Study Setting

Study Design and Participants

Figure 1. Flow of Recipients of Hepatitis B Vaccines .

Exposure

Outcome

Covariates

Table 1. Demographic Characteristics of Recipients of Hepatitis B Vaccines.

Table 2. Clinical Characteristics of Recipients of Hepatitis B Vaccines.

Statistical Analyses

Figure 2. Cumulative Incidence of Confirmed Type 1 Acute Myocardial Infarction Among Recipients of Hepatitis B Vaccinesa.

Results

Table 3. Primary Weighted Analysis of Confirmed Type 1 Acute Myocardial Infarction Comparing Recipients of HepB-CpG Vaccine With Recipients of HepB-Alum Vaccine.

Figure 3. Subgroup Analyses of Confirmed Type 1 Acute Myocardial Infarction Comparing Recipients of HepB-CpG Vaccine With Recipients of HepB-Alum Vaccinea,b.

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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Figure 2. Cumulative Incidence of Confirmed Type 1 Acute Myocardial Infarction Among Recipients of Hepatitis B Vaccines^a.

Figure 3. Subgroup Analyses of Confirmed Type 1 Acute Myocardial Infarction Comparing Recipients of HepB-CpG Vaccine With Recipients of HepB-Alum Vaccine^a,b.