2022 ACR Blockbuster: Who is at better risk of MACE from tofacitinib or TNF inhibitors in patients with rheumatoid arthritis?

Background and Purpose:

A post-grant safety study of oral monitoring (NCT 02092467; tofacitinib 5 and 10 mg twice daily [BID] versus TNF inhibitors [TNFi] found that tofacitinib was associated with a higher
risk of major adverse cardiovascular events (CV) (MACE) and venous thromboembolism (VTE) compared with TNFi 。 Post-hoc analysis of ORAL monitoring found that in patients with a history of atherosclerotic cardiovascular disease (ASCVD) (pts), tofacitinib was at higher risk of developing MACE than TNFi; In patients without a history of ASCVD, there appears to be no difference in the risk of tofacitinib 5 mg of BID and TNFi
.
By assessing the risk of all identified CV events, this study extends part of the MACE endpoint with tofacitinib versus TNFi oral monitoring
.

Method:

Patients with RA aged ≥ 50 years with ≥ 1 additional CV risk factor are treated with tofacitinib 5 mg (N = 1455) or 10 mg (N = 1456) BID or TNFi (N = 1451
).
。 The extended MACE endpoint is based on MACE-3 and sequentially adds identified ischemic CV events (i.
e.
, hospitalization for unstable angina [MACE-4], coronary revascularization surgery [MACE-5], transient ischemic attack [MACE-6], and peripheral vascular disease [MACE-7]), heart failure hospitalization (HF; MACE-8) and VTE (MACE-8 + VTE).

Risk ratio (HR; Tofacitinib vs TNFi assessed
the extended MACE endpoint (the first event from risk period to cumulative CV event) and the single component endpoint (risk period to the first event of a single CV event), respectively.
Subgroup analysis
was performed by history of ASCVD.

Outcome:

For the extended endpoint of the identified ischemic CV event (i.
e.
, MACE-4 to -7), the HR of tofacitinib with TNFi is similar to that of MACE-3 (Figure 1).

The risk of MACE-8 in combination with tofacitinib was similar to TNFi (HR [95% confidence interval (CI)] 1.
08 [0.
81 to 1.
44]).

The risk of MACE-8 + VTE was similar to that of tofacitinib 5 mg BID vs TNFi (hazard ratio 1.
12 [0.
82 to 1.
52]), but tofacitinib 10 mg BID vs TNFi had a higher risk (hazard ratio 1.
38 [1.
02 to 1.
85]) (Figure 1).

Tofacitinib was associated with a higher risk of myocardial infarction (MI) compared with TNFi (hazard ratio 1.
74 [0.
89 to 3.
41], combined dose), but the risk of CV events identified by other individuals was broadly similar (Figure 2).

Looking at the extended MACE definition (e.
g.
, MACE-8), tofacitinib is at higher risk than TNFi in patients with a history of ASCVD (Figure 3).

Fig.
1 Risk of tofacitinib and TNFi prolonging the MACE endpoint

Fig.
2 Tofacitinib and TNFi on the risk of CV events identified by individuals

Figure 3 Tofacitinib versus TNFi prolongs the risk of MACE endpoints in patients with or without a history of ASCVD

Conclusion:

In ORAL monitoring, the composite risk of all ischemic CV events and HF (i.
e.
, MACE-8) was not different
from tofacitinib and TNFi.
However, in patients with a history of ASCVD, the risk of tofacitinib across the extended MACE endpoint was numerically higher than TNFi
.
The total CV risk (i.
e.
, MACE-8 + VTE) was higher in the tofacitinib 10 mg BID group compared to TNFi, driven by an increase in VTE events
.
Limitations include the small number of individual CV events and the lack of consideration for the severity/frequency
of multiple events.
These data underscore the need to better understand the risk of
cardiovascular events in individual patients with rheumatoid arthritis.

Original source:

Maya H.
Buch, Deepak L.
Bhatt, et al.
Risk of Extended Major Adverse Cardiovascular Event Endpoints with Tofacitinib vs TNF Inhibitors in Patients with Rheumatoid Arthritis: A Post Hoc Analysis of a Phase 3b/4 Randomized Safety Study.
ACR Convergence 2022.
October 18, 2022.