Cardiovascular safety of tocilizumab: A systematic review and network meta-analysis

Abstract

Objectives: Our objective was to compare the cardiovascular safety of tocilizumab and other biological disease-modifying antirheumatic drugs (bDMARD) in rheumatoid arthritis using a network meta-analysis (NMA).

Methods: A systematic literature search through May 2018 identified randomized controlled trials (RCT) or observational studies (cohort only) reporting cardiovascular outcomes of tocilizumab (TCZ) and/or abatacept (ABA) and/or rituximab (RTX) and/or tumor necrosis factor inhibitors (TNFi) in rheumatoid arthritis patients. The composite primary outcome was the rate of major adverse cardiovascular outcomes (MACE, myocardial infarction (MI), peripheral artery disease (PAD) and cardiac heart failure (CHF)).

Results: 19 studies were included in the NMA, including 11 RCTs and 8 cohort studies. We found less events with RTX (5.41 [1.70;17.26]. We found no difference between TCZ and other treatments. Concerning MI, we found no difference between TCZ and csDMARD (4.23 [0.22;80.64]), no difference between TCZ and TNFi (2.00 [0.18;21.84]). There was no difference between TCZ and csDMARD (1.51[0.02;103.50] and between TCZ and TNFi (1.00 [0.06;15.85]) for stroke event. With cohorts and RCT NMA, we found no difference between TCZ and other treatments for MACE (0.66 [0.42;1.03] with ABA, 1.04 [0.60;1.81] with RTX, 0.78[0.53;1.16] and 0.91 [0.54;1.51] with csDMARD), but the risk of myocardial infarction was lower with TCZ compared to ABA (0.67 [0.47;0.97]). We lacked data to compare TCZ and other bDMARD for stoke and MI. Not enough data was available to perform a NMA for CHF and PAD.

Conclusions: Despite an increase in cholesterol levels, TCZ has safe cardiovascular outcomes compared to other bDMARD.

Fig 1. Flow chart of the systematic literature review.

PubMed/Medline, Web of science, Cochrane library, Science direct and ACR, Annual College of Rheumatology; EULAR, European League Against Rheumatism databases.

Fig 2. NMA with RCT on major adverse cardiac events, myocardial infarction and stroke with TCZ vs other treatments.

comparison—Treatment comparison, k—Number of studies providing direct evidence, prop—Direct evidence proportion, nma—Estimated treatment effect (RR) in network meta-analysis, direct—Estimated treatment effect (RR) derived from direct evidence, indirect—Estimated treatment effect (RR) derived from indirect evidence, RoR—Ratio of Ratios (direct versus indirect), p-value—p-value of test for disagreement (direct versus indirect), TCZ—tocilizumab; csDMARDs—conventional synthetic disease-modifying antirheumatic drugs; TNFi—tumor necrosis factor inhibitor; ABA—abatacept; RTX—rituximab.

Fig 3. NMA with cohort studies on major adverse cardiac events, myocardial infarction and stroke with TCZ vs other treatments.

comparison—Treatment comparison, k—Number of studies providing direct evidence, prop—Direct evidence proportion, nma—Estimated treatment effect (RR) in network meta-analysis, direct—Estimated treatment effect (RR) derived from direct evidence, indirect—Estimated treatment effect (RR) derived from indirect evidence, RoR—Ratio of Ratios (direct versus indirect), p-value—p-value of test for disagreement (direct versus indirect), TCZ—tocilizumab; csDMARDs—conventional synthetic disease-modifying antirheumatic drugs; TNFi—tumor necrosis factor inhibitor; ABA—abatacept; RTX—rituximab.

Fig 4. NMA with both designs (RCT and cohorts) on major adverse cardiac events, myocardial infarction and stroke with TCZ vs other treatments.

comparison—Treatment comparison, k—Number of studies providing direct evidence, prop—Direct evidence proportion, nma—Estimated treatment effect (RR) in network meta-analysis, direct—Estimated treatment effect (RR) derived from direct evidence, indirect—Estimated treatment effect (RR) derived from indirect evidence, RoR—Ratio of Ratios (direct versus indirect), p-value—p-value of test for disagreement (direct versus indirect), TCZ—tocilizumab; csDMARDs—conventional synthetic disease-modifying antirheumatic drugs; TNFi—tumor necrosis factor inhibitor; ABA—abatacept; RTX—rituximab.