Major Adverse Cardiovascular Events by Baseline Cardiovascular Risk in Patients with Ulcerative Colitis Treated with Tofacitinib: Data from the OCTAVE Clinical Programme

Abstract

Background and Aims

Patients with inflammatory bowel disease have increased risk of atherosclerotic cardiovascular [CV] disease [ASCVD]. Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis [UC]. We report major adverse CV events [MACE] in the UC OCTAVE programme, stratified by baseline CV risk.

Methods

Rates of MACE were analysed by baseline [first tofacitinib exposure] CV risk profile: prior ASCVD, or 10-year ASCVD risk categories [low, borderline, intermediate, high].

Results

Of 1157 patients [2814.4 patient-years of exposure; ≤7.8 years’ tofacitinib treatment], 4% had prior ASCVD and 83% had no prior ASCVD and low–borderline baseline 10-year ASCVD risk. Eight [0.7%] patients developed MACE; one had prior ASCVD. Incidence rates [unique patients with events/100 patient-years of exposure; 95% confidence intervals] for MACE were: 0.95 [0.02–5.27] in patients with prior ASCVD; and 1.81 [0.05–10.07], 1.54 [0.42–3.95], 0.00 [0.00–2.85], and 0.09 [0.01–0.32] in patients without prior ASCVD and with high, intermediate, ­borderline, and low baseline 10-year ASCVD risk, respectively. For the 5/7 patients with MACE and without prior ASCVD, 10-year ASCVD risk scores were numerically higher [>1%] prior to MACE versus at baseline, primarily due to increasing age.

Conclusions

Most patients receiving tofacitinib in the UC OCTAVE programme had low baseline 10-year ASCVD risk. MACE were more frequent in patients with prior ASCVD and higher baseline CV risk. This analysis demonstrates potential associations between baseline CV risk and MACE in patients with UC, suggesting CV risk should be assessed individually in clinical practice.

ClinicalTrials.gov

NCT00787202; NCT01465763; NCT01458951; NCT01458574; NCT01470612.

Graphical Abstract

Graphical Abstract.

1. Introduction

Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis [UC]. The safety of tofacitinib for the treatment of moderately to severely active UC has been evaluated in a series of clinical trials, including three 8-Week Phase 2 and Phase 3 induction studies, a 52-Week Phase 3 maintenance study, an open-label, long-term extension study, and a Phase 3B/4 study.^1–4

Patients with chronic inflammatory conditions, such as inflammatory bowel disease [IBD], rheumatoid arthritis [RA], and psoriasis, have an increased risk of atherosclerotic cardiovascular [CV] disease [ASCVD; including coronary artery disease, cerebrovascular disease, or peripheral artery disease] compared with the general population.^5–7 The increased risk of ASCVD in patients with IBD has been attributed to traditional and non-traditional CV risk factors, such as hypercoagulability, dyslipidaemia, insulin resistance, and hypertension associated with the use of glucocorticoids, local and systemic inflammation, and gut microbiome abnormalities.⁵

ORAL Surveillance [NCT02092467] was a post-authorisation safety study in patients with active RA. The study was the first to evaluate the relative risk of adjudicated major adverse CV events [MACE; including non-fatal myocardial infarction, non-fatal stroke, and CV death] and adjudicated malignancies (excluding non-melanoma skin cancer [NMSC]) with tofacitinib versus tumour necrosis factor inhibitors [TNFi] in a randomised, open-label setting of patients ≥50 years of age with RA and ≥1 additional CV risk factor. For both MACE and malignancies [excluding NMSC], noninferiority (shown if the upper limit of the two-sided 95% confidence interval [CI] for the hazard ratio was <1.8) was not shown for the combined tofacitinib doses (5 mg and 10 mg twice daily [BID]) versus TNFi in this CV risk-enriched RA population. The risk of MACE was similar with tofacitinib 5 mg versus 10 mg BID (hazard ratio 1.15 [95% CI 0.77–1.71]). The increased risk of MACE with tofacitinib versus TNFi was more prominent in patients ≥65 years of age compared with those <65 years of age.⁸ Moreover, a post hoc analysis of ORAL Surveillance showed that an increased risk of MACE with tofacitinib 5 mg and 10 mg BID versus TNFi was predominantly observed in patients with prior ASCVD at baseline.⁹

MACE were previously reported to be infrequent in the UC OCTAVE clinical programme. In a cohort of patients who received tofacitinib 5 mg or 10 mg BID in Phase 2, Phase 3, and open-label, long-term extension studies, and a Phase 3B/4 study (N = 1157; 2999.7 patient-years [PY] of exposure), the incidence rate [IR] of MACE was 0.29 [95% CI 0.13–0.55].¹⁰

Here, we evaluated the 10-year CV risk profile of patients with UC treated with tofacitinib in the Phase 2, Phase 3, and open-label, long-term extension studies, using a validated risk-prediction tool [ASCVD-PCE].¹¹ We also examined the association between baseline 10-year CV risk and incidence of MACE in patients treated with tofacitinib in the UC OCTAVE clinical programme.

2. Materials and Methods

2.1. Study design

This post hoc analysis included data from the Phase 2 ­induction study [NCT00787202], the Phase 3 induction and maintenance studies (OCTAVE Induction 1 and 2 [NCT01465763 and NCT01458951], and OCTAVE Sustain [NCT01458574]), and the open-label, long-term extension study (OCTAVE Open [NCT01470612]). Details of all studies have previously been described.^1–3 All studies received appropriate institutional review board and/or independent ethics committee approval. All patients provided written ­informed consent.

2.2. Assessments

MACE were defined as the occurrence of any myocardial infarction, stroke, or CV death [defined as death due to acute myocardial infarction, sudden cardiac death, heart failure, stroke, CV procedures, CV haemorrhage, or other CV causes, such as peripheral artery disease], and were adjudicated by an independent review committee. For patients with MACE during the UC OCTAVE clinical programme, prior medical history in patient profiles and case narratives was reviewed for CV risk-factor information, such as: a medical history of CV events, diabetes mellitus, hypercholesterolaemia, or hypertension; smoking status; and prior and concomitant medications [including lipid-lowering agents]. MACE were determined by external adjudication for patients in OCTAVE Induction 1 and 2, OCTAVE Sustain, and OCTAVE Open; data from the Phase 2 induction study were excluded, as this study took place prior to the establishment of the adjudication committee.

2.3. Evaluation of CV risk

To investigate whether the incidence of MACE was associated with baseline CV risk, IRs [unique patients with events per 100 PY of exposure] were stratified by CV risk profiles at baseline [defined as first tofacitinib exposure]. The ASCVD-PCE calculator is a validated risk-prediction tool recommended by the American College of Cardiology, and considers traditional CV risk factors to estimate 10-year risk of primary ASCVD.¹¹ Patients were first categorised by prior history of ASCVD, defined as any of the following: coronary heart disease [stable or unstable angina pectoris, coronary artery procedure, myocardial infarction], cerebrovascular disease, or peripheral artery disease. Patients without prior ASCVD were further stratified by CV risk categories [high: ≥20%; intermediate: ≥7.5%–<20%; borderline: ≥5%–<7.5%; and low: <5%], based on 10-year ASCVD risk, as calculated by the ASCVD-PCE. The ASCVD risk score assessment contains several components [including age, race, serum lipids, systolic blood pressure, hypertension treatment, history of diabetes, and smoking status], all of which were assessed and collected in the clinical trial case report forms. ASCVD risk scores were calculated at the following time points: induction baseline, induction Week 8, and maintenance Week 52 [final data cut: August 24, 2020].

Whilst the ASCVD-PCE calculator is a validated tool for patients ≥40 years of age, sensitivity analyses were performed to investigate the impact of the inclusion of patients <40 years of age. In addition, ASCVD scores were determined for patients with MACE after controlling by age at baseline.

2.4. Statistical analysis

Analyses were performed for the overall cohort, defined as all patients receiving ≥1 dose of tofacitinib 5 mg or 10 mg BID in the UC OCTAVE clinical programme. IRs of MACE, with 95% CIs, were calculated using the Exact Poisson method. IRs are based on the number of unique patients [per 100 PY of exposure] with an event, divided by the total time at risk within the risk period [from the patient’s first dose of tofacitinib to their last dose of tofacitinib plus 28 days, or to the date of the first event, whichever occurs earlier].

3. Results

3.1. Patients

Overall, 1157 patients received at least one dose of tofacitinib in the UC OCTAVE clinical programme. Total tofacitinib exposure was 2814.4 PY, with a median treatment duration of 623 [range = 1–2850] days. Of these 1157 patients, 45 [4%] had prior ASCVD, 1112 [96%] had no prior ASCVD, and 925 [80%] with no prior ASCVD were in the low 10-year ASCVD risk category at baseline [Figure 1].

Figure 1.

Proportion of patients in the tofacitinib UC OCTAVE clinical programme in each baseline 10-year CV risk category. Percentages do not add up to 100%, as ASCVD risk scores were not calculated in 48 patients due to one or more components of the ASCVD-PCE being missing, and also because remaining percentages were rounded to whole numbers. Prior ASCVD was defined as a history of any of coronary artery disease [including myocardial infarction], cerebrovascular disease [including stroke], or peripheral artery disease. Patients without prior ASCVD were categorised according to their 10-year ASCVD risk at baseline, per the ASCVD-PCE calculator, as recommended by the American College of Cardiology.¹¹ Baseline was defined as first tofacitinib exposure. Includes data from the Phase 2 induction study [NCT00787202], the Phase 3 studies (OCTAVE Induction 1 and 2 [NCT01465763; NCT01458951] and OCTAVE Sustain [NCT01458574]), and the open-label, long-term extension study (OCTAVE Open [NCT01470612]), from patients who received ≥1 dose of tofacitinib 5 mg or 10 mg BID [N = 1157]. ASCVD, atherosclerotic CV disease; ASCVD-PCE, ASCVD pooled cohort equation[s]; BID, twice daily; CV, cardiovascular; N, total number of patients included in the analysis; n, number of patients in each category; UC, ulcerative colitis.

Baseline demographics and clinical characteristics were generally similar across baseline 10-year ASCVD risk categories. However, patients’ mean age increased with increased ASCVD risk category (mean age in years [standard deviation (SD)]: low risk = 37.3 [10.9]; borderline risk = 52.3 [9.4]; intermediate risk = 62.9 [8.7]; high risk = 70.9 [6.7]). Patients with prior ASCVD, or with a high baseline 10-year ASCVD risk, were more likely to have smoked, received immunosuppressant treatment, be receiving lipid-lowering agents, and have a medical history of diabetes mellitus or hypertension, compared with patients with a low baseline 10-year ASCVD risk [Table 1]. In addition, patients with prior ASCVD were more likely to have received TNFi treatment, compared with patients without prior ASCVD.

Table 1.

Select baseline demographic and clinical characteristics in the tofacitinib UC OCTAVE clinical programme, stratified by baseline ASCVD risk.

	Prior ASCVD [N = 45]	No prior ASCVD
		ASCVD risk category
		High [N = 17]	Intermediate [N = 83]	Borderline [N = 39]	Low [N = 925]
Female, n [%]	9 [20.0]	5 [29.4]	16 [19.3]	6 [15.4]	416 [45.0]
Age [years], mean [SD]a	59.8 [11.1]	70.9 [6.7]	62.9 [8.7]	52.3 [9.4]	37.3 [10.9]
Race, n [%]
White	38 [84.4]	12 [70.6]	70 [84.3]	32 [82.1]	759 [82.1]
Black	0 [0.0]	0 [0.0]	2 [2.4]	1 [2.6]	7 [0.8]
Asian	4 [8.9]	5 [29.4]	9 [10.8]	5 [12.8]	121 [13.1]
Other	1 [2.2]	0 [0.0]	2 [2.4]	1 [2.6]	38 [4.1]
Total Mayo score, mean [SD]a	8.6 [1.7]	8.5 [1.8]	8.2 [2.2]	8.0 [2.0]	8.7 [1.9]
C-reactive protein concentration [mg/ml], mean [SD]a	8.8 [11.7]	15.6 [24.6]	10.5 [23.8]	10.6 [16.7]	10.9 [17.2]
Disease duration [years], mean [SD]a	9.0 [6.5]	10.4 [9.2]	12.1 [10.3]	10.8 [8.2]	7.6 [6.3]
Body mass index [kg/m2], mean [SD]a	28.5 [4.7]	27.0 [4.4]	26.3 [3.7]	27.2 [5.7]	24.5 [5.0]
Smoking status, n [%]b
Never smoked	18 [40.0]	5 [29.4]	31 [37.3]	13 [33.3]	650 [70.3]
Current smoker	1 [2.2]	1 [5.9]	5 [6.0]	8 [20.5]	42 [4.5]
Ex-smoker	25 [55.6]	11 [64.7]	47 [56.6]	18 [46.2]	233 [25.2]
Medical history, n [%]a
Diabetes mellitus	8 [17.8]	7 [41.2]	11 [13.3]	7 [17.9]	12 [1.3]
Hypertension	19 [42.2]	12 [70.6]	38 [45.8]	10 [25.6]	71 [7.7]
Coronary heart disease	22 [48.9]	0 [0.0]	0 [0.0]	0 [0.0]	0 [0.0]
Stroke	13 [28.9]	0 [0.0]	0 [0.0]	0 [0.0]	2 [0.2]f
Cardiac failure	3 [6.7]	0 [0.0]	0 [0.0]	0 [0.0]	0 [0.0]
Prior medication, n [%]
TNFib	29 [72.5]	9 [52.9]	40 [50.0]	19 [48.7]	483 [53.6]
Immunosuppressantsb,c	32 [80.0]	15 [88.2]	54 [67.5]	27 [69.2]	677 [75.1]
Concomitant medication, n [%]
NSAIDa,c	17 [42.5]	3 [17.6]	12 [15.0]	5 [12.8]	32 [3.6]
Lipid-lowering agentd	23 [51.1]	5 [29.4]	17 [20.5]	3 [7.7]	24 [2.6]
Corticosteroidsa	19 [42.2]	9 [52.9]	37 [44.6]	17 [43.6]	421 [45.5]
Blood pressure [mmHg], mean [SD]a
Systolic	132.0 [20.8]	141.3 [12.5]	130.0 [14.4]	127.8 [13.1]	119.2 [12.8]
Diastolic	77.6 [9.8]	79.3 [10.6]	78.0 [11.6]	80.4 [10.0]	75.2 [9.2]
Serum lipid concentrations [mg/dl], mean [SD]a,e
TC	176.8 [39.9]	182.1 [39.3]	198.4 [35.3]	197.7 [33.8]	181.6 [38.0]
HDL-c	63.4 [22.4]	52.8 [15.8]	55.5 [16.2]	54.7 [17.3]	57.9 [17.5]
LDL-c	90.2 [29.6]	101.2 [29.0]	116.2 [30.2]	118.2 [30.0]	102.2 [30.0]

Prior ASCVD was defined as a history of any of coronary artery disease [including myocardial infarction], cerebrovascular disease [including stroke], or peripheral artery disease. Patients without prior ASCVD were categorised according to their 10-year ASCVD risk at baseline, per the ASCVD-PCE calculator, as recommended by the American College of Cardiology.¹¹ Includes data from the Phase 2 induction study [NCT00787202], the Phase 3 studies (OCTAVE Induction 1 and 2 [NCT01465763; NCT01458951] and OCTAVE Sustain [NCT01458574]), and the open-label, long-term extension study (OCTAVE Open [NCT01470612]), from patients with prior ASCVD or patients for whom baseline CV risk could be determined who received ≥1 dose of tofacitinib 5 mg or 10 mg BID [N = 1109; 48 patients were excluded due to ≥1 components of the ASCVD-PCE being missing]. N is the total number of treated patients; the sum of the number of patients evaluated for each category may be fewer than N due to missing data.

ASCVD, atherosclerotic CV disease; ASCVD-PCE, ASCVD pooled cohort equation[s]; ATC, anatomical therapeutic chemical; BID, twice daily; CV, cardiovascular; HDL-c, high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol; N, number of patients treated; n, number of patients in the specified category; NSAID, non-steroidal anti-inflammatory drug; SD, standard deviation; TC, total cholesterol; TNFi, tumour necrosis factor inhibitor[s]; UC, ulcerative colitis.

^aDay 1 of active tofacitinib treatment in the UC OCTAVE clinical programme.

^bAt baseline of induction studies.

^cExcludes Phase 2 study data.

^dBased on ATC2 lipid-lowering agent, excluding fish oil preparations.

^eReference ranges: TC = 130–200 mg/dl; HDL-c = 40–80 mg/dl; and LDL-c = 0–130 mg/dl.

^fCerebral venous thrombosis and intracranial venous sinus thrombosis, which were not considered ASCVD.

3.2. Incidence of MACE and association with baseline CV risk

In patients without prior ASCVD, higher mean baseline 10-year ASCVD risk scores were observed for patients with versus without MACE [13.5% vs 2.5%, respectively]. Out of 1124 patients in whom MACE were adjudicated, MACE were reported in eight [0.7%] patients (IR = 0.28 [95% CI 0.12–0.54]). MACE IRs were 0.51 [95% CI 0.14–1.30] and 0.19 [95% CI 0.05–0.48] in patients receiving a predominant dose of tofacitinib 5 mg or 10 mg BID, respectively. There were three events each of myocardial infarction [all in patients receiving a predominant dose of tofacitinib 5 mg BID] and stroke [one in a patient receiving a predominant dose of tofacitinib 5 mg BID, and two in patients receiving a predominant dose of tofacitinib 10 mg BID], and two events of CV death [aortic dissection and cardiac arrest; both in patients receiving a predominant dose of tofacitinib 10 mg BID]. When patients without prior ASCVD were further stratified by their 10-year ASCVD risk at baseline, IRs of MACE were very low in those with a low or borderline baseline 10-year ASCVD risk (0.09 [95% CI 0.01–0.32] and 0.00 [95% CI 0.00–2.85], respectively), and were numerically lower versus patients with an intermediate or high baseline 10-year ASCVD risk (1.54 [95% CI 0.42–3.95] and 1.81 [95% CI 0.05–10.07], respectively) or prior ASCVD (0.95 [95% CI 0.02–5.27]; Figure 2). MACE IRs by ASCVD risk categories and predominant tofacitinib dose are included for reference in Table S1 [available as Supplementary data at ECCO-JCC online]. Stratifying patients by age group in a sensitivity analysis demonstrated that including patients <40 years of age had minimal impact on IRs of MACE in any of the baseline 10-year ASCVD risk categories [Table S2, available as Supplementary data at ECCO-JCC online].

Figure 2.

IRs of MACE in the tofacitinib UC OCTAVE clinical programme, stratified by baseline 10-year CV risk category. MACE were adjudicated by an independent review committee and defined as any of myocardial infarction, stroke, or CV death. Events that occurred >28 days after the last dose of study drug were excluded. Prior ASCVD was defined as a history of any of coronary artery disease [including myocardial infarction], cerebrovascular disease [including stroke], or peripheral artery disease. Patients without prior ASCVD were categorised according to their 10-year ASCVD risk at baseline, per the ASCVD-PCE calculator, as recommended by the American College of Cardiology.¹¹ Includes patients with prior ASCVD and patients for whom baseline CV risk could be determined, and excludes data from the Phase 2 study; therefore, N = 1124 for the assessment of adjudicated MACE. In addition, 47 patients were excluded due to one or more components of the ASCVD-PCE being missing. ^aUpper CI value continues beyond the axis shown [10.07]. ASCVD, atherosclerotic CV disease; ASCVD-PCE, ASCVD pooled cohort equation[s]; CI, confidence interval; CV, cardiovascular; IR, incidence rate [unique patients with events per 100 PY of exposure]; MACE, major adverse CV event[s]; N, number of patients with prior ASCVD or non-missing baseline ASCVD score; n, number of unique patients with a MACE; PY, patient-years; UC, ulcerative colitis.

Demographics and clinical characteristics for patients with MACE are presented in Table 2. Of the eight MACE, one occurred in a patient with prior ASCVD, five occurred in patients within the intermediate–high baseline 10-year ASCVD risk categories, and two occurred in patients in the low–borderline baseline 10-year ASCVD risk category. In five out of the seven [71.4%] patients without prior ASCVD, 10-year ASCVD risk scores were increased by at least 1% prior to MACE versus baseline [Table 2], resulting in a change to a higher 10-year risk category for two patients [from intermediate to high, and low to borderline; 2/7 patients; 28.6%; Table 2]. Assessment of ASCVD scores after controlling by age at baseline was carried out in order to determine if age was the primary driver of increased ASCVD scores. This sensitivity analysis indicated that none of the patients changed ASCVD risk category during treatment with tofacitinib [Table S3, available as Supplementary data at ECCO-JCC online].

Table 2.

Demographics and clinical characteristics of patients with MACE in the tofacitinib UC OCTAVE clinical programme.

MACE/ adjudicated event preferred term	Baseline CV risk category [prior ASCVD or ASCVD risk score, %]a	CV risk category prior to first MACE [prior ASCVD or ASCVD risk score, %]b	Induction baseline age, years; gender, male/female	Day of onset;c predominant tofacitinib dosed	Average partial Mayo score;e average total Mayo scoree	Induction baseline serum lipid concentrations [mg/dl]e,f	Serum lipid concentrations at last recorded study time point [mg/dl]e,f	Baseline systolic/ diastolic blood pressure [mmHg]e	Concomitant medication prior to MACE	Study drug outcome
Myocardial infarction/acute coronary syndrome	Prior ASCVD	Prior ASCVD	66; male	28;g 5 mg BID	4.0; 8.0	TC = 192 HDL-c = 112 LDL-c = 59 TG = 105	TC = 151 HDL-c = 65 LDL-c = 70 TG = 82	150/88	Acetylsalicylic acid Perindopril Verapamil Rosuvastatin	Temporary discontinuation
Myocardial infarction	Intermediate [17.9]	Intermediate [17.9]	74; male	142;h 5 mg BID	1.2; 5.5	TC = 161 HDL-c = 63 LDL-c = 71 TG = 134	TC = 172 HDL-c = 44 LDL-c = 96 TG = 159	108/66	Acetylsalicylic acid Warfarin Simvastatin	Temporary discontinuation
Myocardial infarction/acute myocardial infarction	Intermediate [9.6]	Intermediate [14.3]	64; male	1540;i 5 mg BID	1.6; 3.2	TC = 167 HDL-c = 59 LDL-c = 92 TG = 80	TC = 151 HDL-c = 51 LDL-c = 82 TG = 88	130/70	None reported	Temporary discontinuation
CV death/aortic dissection	Low [1.4]	Low [1.4]	39; male	31;g 10 mg BID	5.0; 9.0	TC = 309 HDL-c = 80 LDL-c = 189 TG = 194	Not assessed	140/90	None reported	Death
CV death/cardiac arrest	Intermediate [15.2]	High [25.7]	67; male	1725;i 10 mg BID	0.7; 3.1	TC = 172 HDL-c = 39 LDL-c = 103 TG = 150	TC = 214 HDL-c = 54 LDL-c = 128 TG = 159	128/70	Atorvastatin	Death
Stroke/ haemorrhagic stroke	Low [4.2]	Borderline [5.5]	55; female	148;h 10 mg BID	3.4; 7.5	TC = 183 HDL-c = 63 LDL-c = 94 TG = 132	TC = 205 HDL-c = 71 LDL-c = 111 TG = 117	130/80	Irbesartan Atorvastatin Insulin	Permanent discontinuation
Stroke/ cerebrovascular accident	High [36.3]	High [49.6]	56; male	857;i 10 mg BID	1.4; 4.3	TC = 230 HDL-c = 39 LDL-c = 132 TG = 297	TC = 181 HDL-c = 56 LDL-c = 73 TG = 258	140/90	Amlodipine Enalapril Metformin Glimepiride Atorvastatin	Permanent discontinuation
Stroke/ cerebellar haemorrhage	Intermediate [9.9]	Intermediate [14.0]	55; male	1438;i 5 mg BID	0.8; 2.3	TC = 216 HDL-c = 34 LDL-c = 150 TG = 161	TC = 282 HDL-c = 51 LDL-c = 191 TG = 194	140/102	None reported	Permanent discontinuation

Prior ASCVD was defined as a history of any of coronary artery disease [including myocardial infarction], cerebrovascular disease [including stroke], or peripheral artery disease.

ASCVD, atherosclerotic CV disease; ASCVD-PCE, ASCVD pooled cohort equation[s]; BID, twice daily; CV, cardiovascular; HDL-c, high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol; MACE, major adverse CV event[s]; TC, total cholesterol; TG, triglycerides; UC, ulcerative colitis.

^aPatients without prior ASCVD were categorised according to their 10-year ASCVD risk at baseline, per the ASCVD-PCE calculator, as recommended by the American College of Cardiology.¹¹ Baseline was defined as first tofacitinib exposure.

^bLatest CV risk score prior to MACE.

^cStudy onset day in relation to first day of tofacitinib exposure.

^dPatients were categorised based on the average daily dose of tofacitinib [placebo exposure was not included]: predominant dose of tofacitinib 5 mg BID [average total daily dose <15 mg] and predominant dose of tofacitinib 10 mg BID [average total daily dose ≥15 mg].

^eAt baseline of induction studies.

^fReference ranges: TC = 130–200 mg/dl; HDL-c = 40–80 mg/dl; LDL-c = 0–130 mg/dl; TG = 45–250 mg/dl.

^gEvent onset during OCTAVE Induction 1 or 2.

^hEvent onset during OCTAVE Sustain.

ⁱEvent onset during OCTAVE Open.

Further details for each of the patients with MACE are as follows: three patients experienced a myocardial infarction:

1. 1) A 66-year-old male with left-sided colitis had acute coronary syndrome while receiving tofacitinib 10 mg BID. The patient, an ex-smoker, had prior ASCVD [myocardial infarction and angina pectoris] and a medical history of arrhythmia, hypercholesterolaemia, and hypertension. At induction baseline, the patient had elevated high-density lipoprotein cholesterol [HDL-c].

2. 2) A 74-year-old male with left-sided colitis had a myocardial infarction while receiving tofacitinib 5 mg BID. The patient, an ex-smoker, had a medical history of hyperlipidaemia, hypertension, and deep vein thrombosis. At induction baseline and prior to the event, the patient had an intermediate 10-year ASCVD risk score [17.9%].

3. 3) A 64-year-old male with left-sided colitis had an acute myocardial infarction while receiving tofacitinib 5 mg BID. The patient, a non-smoker, had no significant medical history. At induction baseline and prior to the event, the patient had intermediate 10-year ASCVD risk scores of 9.6% and 14.3%, respectively.

Two patients experienced a CV death:

1. 1) A 39-year-old male with left-sided colitis had an aortic dissection while receiving tofacitinib 10 mg BID; this event resulted in death. The patient, a non-smoker, had a medical history of hyperlipidaemia (elevated total cholesterol [TC] and low-density lipoprotein cholesterol [LDL-c] at induction baseline), a low 10-year ASCVD risk score [1.4%] at baseline and prior to the event.

2. 2) A 67-year-old male with pancolitis had a cardiac arrest while receiving tofacitinib 10 mg BID; this event resulted in death. The patient, an ex-smoker, had a history of dyslipidaemia. At induction baseline, the patient had an intermediate 10-year ASCVD risk score [15.2%], which increased to 25.7% [high 10-year risk] prior to the event.

Three patients experienced a stroke:

1. 1) A 55-year-old female with pancolitis had a haemorrhagic stroke while receiving tofacitinib 10 mg BID. The patient, a non-smoker, had a medical history of hypertension, hypercholesterolaemia, and diabetes mellitus. At induction baseline, the patient had a low 10-year ASCVD risk score [4.2%], which increased to 5.5% [borderline 10-year risk] prior to the event.

2. 2) A 56-year-old male with left-sided colitis had a cerebrovascular accident while receiving tofacitinib 10 mg BID. The patient, who had been a smoker for 35 years, had a medical history of hypertension and diabetes mellitus, and had elevated serum lipid concentrations (TC, LDL-c, and triglycerides [TG]), and reduced HDL-c, at induction baseline. At induction baseline and prior to the event, the patient had high 10-year ASCVD risk scores of 36.3% and 49.6%, respectively.

3. 3) A 55-year-old male with pancolitis had a cerebellar haemorrhage while receiving tofacitinib 5 mg BID. The patient, a non-smoker, had a medical history of left ventricular hypertrophy and hypertension, and had elevated serum lipid concentrations [TC and LDL-c] and reduced HDL-c at induction baseline. At induction baseline and prior to the event, the patient had intermediate 10-year ASCVD risk scores of 9.9% and 14.0%, respectively.

4. Discussion

This post hoc analysis evaluated the occurrence of MACE, stratified by baseline CV risk in patients from the UC OCTAVE clinical programme. Baseline 10-year ASCVD risk was assessed using the ASCVD-PCE calculator, which considers traditional CV risk factors, such as age, race, serum lipids, systolic blood pressure, hypertension treatment, history of diabetes, and smoking status. At baseline, 4% of patients had prior ASCVD, and most [80%] patients without prior ASCVD had a low baseline 10-year ASCVD risk. Among tofacitinib-treated patients with UC, MACE occurred in eight patients and were more frequent in patients with prior ASCVD and those with an intermediate or high baseline 10-year ASCVD risk, versus patients with a low or borderline baseline 10-year risk.

In this analysis, baseline mean 10-year ASCVD scores were higher in patients with MACE, compared with patients without MACE [13.5% vs 2.5%, respectively]. In addition, for those patients experiencing MACE, the majority [5/7 patients; 71.4%] had a ≥1% increase in 10-year ASCVD risk scores prior to MACE in comparison with their 10-year ASCVD risk score at baseline, which resulted in a change to a higher 10-year ASCVD risk category for two patients [2/7 patients; 28.6%]. Assessment of age-controlled scores indicated that none of these patients changed ASCVD risk category during treatment with tofacitinib. Consequently, the risk increases observed in this analysis appear to be driven by the patients’ increasing age during the course of the trials, which is a known risk factor for MACE.

As expected, most patients with MACE either had prior ASCVD or an intermediate–high 10-year ASCVD risk score at baseline, and CV risk factors [such as a medical history of diabetes, hypercholesterolaemia, hypertension, and elevated serum lipid concentrations]. In a previous analysis of data from the tofacitinib UC OCTAVE clinical programme, an inverse relationship between decreased inflammation [based on C-reactive protein levels] and increased serum lipid concentrations was observed during treatment.¹² Furthermore, assessment of the 10-year risk of CV events using the Reynolds Risk Score [based on age, blood pressure, smoking status, concentrations of TC, HDL-c, and C-reactive protein, and a family history of CV events] showed that the mean Reynolds Risk Score was relatively unchanged following 8 weeks of tofacitinib treatment, suggesting that the predicted 10-year CV risk was unaffected by lipid increases in induction with reduced inflammation.

The results presented here should be interpreted in the context of ORAL Surveillance, which reported increased relative risk of MACE with tofacitinib compared with TNFi, whereas the UC OCTAVE clinical programme did not include an active comparator; therefore, this analysis describes the relationship between risk factors and the absolute risk of an outcome. Importantly, ORAL Surveillance was a long-term safety study conducted in a CV risk-enriched RA population [patients ≥50 years of age with RA and ≥1 additional CV risk factor], designed to ensure the accumulation of a sufficient number of CV events.⁸ Patients in the tofacitinib UC OCTAVE clinical programme were not enriched by CV risk, and only 12.6% of patients entering at the OCTAVE Induction studies baseline met the ORAL Surveillance inclusion criteria. Accordingly, there were major differences in the baseline CV risk between patients with UC included in this study and patients with RA included in ORAL Surveillance. In ORAL Surveillance, 15% of patients treated with tofacitinib had prior ASCVD, 52% had an intermediate–high baseline 10-year CV risk, and 32% had a low–borderline baseline 10-year CV risk,^9,13 whereas in the tofacitinib UC clinical programme, 4% of patients had prior ASCVD, 9% had an intermediate–high baseline 10-year CV risk, and 83% had a low–borderline baseline 10-year CV risk. These results highlight an important difference between these two study populations.

There are relative differences in the overall epidemiological and CV risk profiles of patients with UC versus RA, such as a generally lower age.^14,15 Importantly, all patients within ORAL Surveillance were ≥50 years of age (mean [SD] age = 61.2 [7.1] years) and were older than the patient population in the tofacitinib UC OCTAVE clinical programme (mean [SD] age = 41.3 [13.9] years).¹⁶ In addition, there may also be important differences in the background CV risk associated with UC, compared with the risk associated with RA. In a cross-sectional analysis of patients in Spain with different immune-mediated inflammatory diseases, after adjustment for demographic variables, educational level, and traditional CV risk factors, the risk of CV disease associated with UC was significantly lower than that associated with RA (odds ratio [95% CI] = 0.35 [0.16–0.75]). In addition, the prevalence of comorbidities that increased CV risk, such as hypertension, dyslipidaemia, and diabetes, was higher in patients with RA compared with those with UC.¹⁷

Associations between disease activity and increased CV risk have previously been demonstrated in patients with RA.^18–20 To account for the additional CV risk associated with RA, the European League Against Rheumatism recommends a 1.5 multiplication factor when calculating patients’ CV risk [eg, with ASCVD-PCE], which was applied in the analyses of ORAL Surveillance.²¹ Although associations between disease activity and the resulting impact on CV risk in patients with IBD have been reported,^22–24 there are currently no recommendations on CV disease prevention in patients with IBD. However, general guidelines on CV disease prevention state that immune-mediated disease should be regarded as a risk-enhancing factor.^11,25 These findings emphasise the importance of identifying, assessing, and treating risk factors for MACE in individual patients with UC, and also the need for additional analyses on CV risk in the UC patient population.

Interpretation of these data was limited by the post hoc nature of the analyses and the low number of events, which was not as high as would be predicted by evaluation of previous publications in patients with IBD.²⁶ Additionally, these analyses were performed over a relatively short median treatment duration with respect to assessment of long-latency events, such as MACE. However, MACE IRs in patients receiving tofacitinib have been previously demonstrated to remain stable for up to 7.8 years.²⁷ Further investigation, such as in large registries, is warranted. Also, as discussed above, the UC OCTAVE clinical programme did not include any active comparator and, therefore, any relative differences in risk of MACE could not be ascertained. In addition, abnormalities detected by electrocardiogram [eg, heart blockage or left-sided failure] were included as exclusion criteria for all studies included in this analysis; this could have excluded patients who had CV risk factors. The ASCVD-PCE tool used in this study to assess CV risk has been designed for use in individuals 40–75 years of age who are being evaluated for CV disease prevention, but use of the calculator in patients <40 years of age, or in those from geographical regions or racial and ethnic groups where it is not explicitly validated, could result in underestimation or overestimation of predicted CV risk.¹¹ As such, the lower age of patients in this analysis [mean age = 41.3 years] may have impacted on the high percentage of patients within the low baseline 10-year ASCVD risk score group [80%]; however, after stratifying patients by age [<40 vs ≥40 years of age], it was observed that the inclusion of patients <40 years of age had minimal impact on the IRs of MACE. In addition, the majority of patients were White, which results in a lack of generalisability to other ethnic groups. Future prospective studies should take a multi-ethnic approach and comprise large registries that would allow a distinction between the influence of pre-existing ASCVD risks from therapy-inferred changes, which may be cardioprotective in some patients.²⁸

In conclusion, MACE were infrequent in patients treated with tofacitinib in the UC OCTAVE clinical programme. At baseline, in contrast to what was observed in patients with RA in the CV risk-enriched ORAL Surveillance population, the majority of patients with UC had a low baseline 10-year ASCVD risk, which suggests that population differences make it difficult to fully generalise the results from ORAL Surveillance to the majority of the UC patient population. These results highlight the importance of performing risk assessments in individual patients in order to optimise the benefit-to-risk ratio of the available treatment, including Janus kinase inhibitors. This analysis shows that the known association of CV risk and incidence of MACE potentially occurs in patients with UC treated with tofacitinib. Our findings highlight the importance of regularly assessing CV risk in patients with UC, using validated risk-prediction tools, and also emphasise that a coordinated effort from both gastroenterologists and preventive cardiologists or endocrinologists would be necessary.

Funding

This work was supported by Pfizer. This study was sponsored by Pfizer.

Conflict of Interest

SS has received consulting fees from AbbVie, Amgen, Arena, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Dr Falk Pharma, Eli Lilly, Ferring, Fresenius, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, I-MAB Biopharma, Janssen, Merck, Novartis/Sandoz, Pfizer Inc, Protagonist, Takeda, and Theravance. DTR has received consulting fees from AbbVie, AltruBio, Arena, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene Corp/Syneos, Connect BioPharma, Eli Lilly, GalenPharma/Atlantica, Genentech/Roche, Gilead Sciences, InDex Pharmaceuticals, Iterative Scopes, Janssen, Pfizer Inc, Prometheus Biosciences, Reistone, Takeda, and Techlab; and research support from Takeda. SCN has received research support from AbbVie, Ferring, and Olympus; speaker fees from AbbVie, Ferring, Janssen, Menarini, Pfizer Inc, Takeda, and Tillotts; and holds a directorship with Microbiota I-Center. LP-B has received personal fees from AbbVie, Alimentiv, Allergan, Amgen, Arena, Biogen, Bristol-Myers Squibb, Celgene, Celltrion, Eli Lilly, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead Sciences, Gossamer Bio, InDex Pharmaceuticals, Inotrem, Janssen, MSD, Mylan, Norgine, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Pfizer Inc, Roche, Samsung Bioepis, Sandoz, Takeda, Theravance, Thermo Fisher, Tillotts, Viatris, and Vifor Pharma; research support from AbbVie, Fresenius Kabi, MSD, and Takeda; and holds stock options for CTMA. SD has received consulting fees from AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Gilead Sciences, Hospira, Janssen, Johnson & Johnson, MSD, Mundipharma, Pfizer Inc, Roche, Sandoz, Takeda, TiGenix, UCB, and Vifor Pharma. IM, XG, CS, KKK, YC, and AY are employees and shareholders of Pfizer Inc. HJ is a former employee of Syneos Health, which was a paid contractor to Pfizer Inc in connection with the development of this manuscript and related statistical analysis. WR has received research support from AbbVie, Janssen, MSD, Sandoz, Sanofi, and Takeda; lecture fees from AbbVie, Celltrion, Dr Falk Pharma, Ferring, Galapagos, Janssen, MSD, Pfizer Inc, Pharmacosmos, Roche, Shire, Takeda, and Therakos; consulting fees from AbbVie, Amgen, AM Pharma, AOP Orphan, Arena, Astellas, AstraZeneca, Bioclinica, Boehringer Ingelheim, Bristol-Myers Squibb, Calyx, Celgene, Cellerix, Dr Falk Pharma, Eli Lilly, Ferring, Galapagos, Gatehouse Bio Inc, Genentech, Gilead Sciences, Grünenthal, ICON, InDex Pharmaceuticals, iNova, Janssen, Landos Biopharma, Medahead, MedImmune, Microbiotica, Millennium, Mitsubishi Tanabe Pharma, MSD, Novartis, OMass, Otsuka, Parexel, Periconsulting, Pfizer Inc, Pharmacosmos, Protagonist, Provention, Quell Therapeutics, Sandoz, Seres Therapeutics, SetPoint Medical, Sigmoid, Sublimity, Takeda, Teva Pharma, Therakos, Theravance, and Zealand; and advisory board fees from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Galapagos, Janssen, Mitsubishi Tanabe Pharma Corporation, MSD, Pfizer Inc, Pharmacosmos, Sandoz, and Takeda. MCD has received consulting fees from AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead Sciences, Janssen, Pfizer Inc, Prometheus Laboratories, Takeda, and UCB.

Author Contributions

XG, KKK, HJ, and AY designed the post hoc analysis and contributed to the statistical analysis. All authors contributed to the interpretation of the data, the development of the manuscript, and critically reviewed/revised the manuscript for important intellectual content. All authors approved the final version of the manuscript before submission.

Conference presentation

Parts of the data in this manuscript were presented at United European Gastroenterology (UEG) Week 2022 (October 8–11, 2022; Vienna, Austria) and the American College of Gastroenterology (ACG) 2022 Annual Scientific Meeting (October 21–26, 2022; Charlotte, NC, USA).

Data Availability

Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See [https://www.pfizer.com/science/clinical-trials/trial-data-and-results] for more information.