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Taltz ® (ixekizumab)
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Cardiovascular Events with Taltz® (ixekizumab)
In clinical trials, major adverse cerebrocardiovascular events were uncommon with ixekizumab treatment.
Table of contents
MACE - Major adverse cerebrocardiovascular events with Taltz
- Clinical trials in moderate-to-severe psoriasis
- Clinical trials in psoriatic arthritis
- Clinical trials in axial spondyloarthritis
Appendix: Major adverse cerebrovascular events in ixekizumab trials
MACE - Major adverse cerebrocardiovascular events with Taltz
Ixekizumab exposure has not been found to be associated with an increased risk of major adverse cerebrocardiovascular events (MACE).1-4
In ixekizumab clinical trials, all reported MACE were independently adjudicated by a sponsor-independent external adjudication committee.1,2,4-8
Appendix: Major adverse cerebrovascular events in ixekizumab trials includes the types of MACE events reported across all trials of ixekizumab in adult patients, including psoriasis, psoriatic arthritis, and axial spondyloarthritis (axSpA) trials in a post hoc analysis of end of study program data.9
Clinical trials in moderate-to-severe psoriasis
Patients with moderate-to-severe psoriasis are reported to be at an increased risk of cardiovascular mortality compared with the general population and patients with mild psoriasis.10-13
In an integrated analysis of the UNCOVER clinical trial data, MACE were uncommon, balanced across treatment groups, and exposure-adjusted incidence rates (EAIRs) per 100 patient-years (PY) remained stable over time.1,14
The most common MACE were
As of March 2022 in the psoriasis clinical trials, 91 patients experienced MACE (70 were severe, and 19 were moderate). Major adverse cerebrocardiovascular events outcomes were (N)
Most of the patients (59%) had preexisting risk factors including
- hypertension
- dyslipidemia
- type 2 diabetes mellitus
- hypercholesterolemia
- obesity, and
- cardiac disorders.8
shows total MACE incidence and EAIRs integrated across all ixekizumab psoriasis exposures in adult patients as of March 2022.
Total adjudicated MACE, n (%) [IR] |
91b (1.3) [0.5] |
Vascular deathc |
20 (0.3) [0.1] |
Nonfatal MI |
49 (0.7) [0.3] |
Nonfatal stroked |
23 (0.3) [0.1] |
Abbreviations: IR = incidence rate (per 100 patient-years); IXE = ixekizumab; MACE = major adverse cerebrocardiovascular events; MI = myocardial infarction; PY = patient-years.
aData as of March 2022.
bOne patient experienced both a nonfatal stroke and vascular death.
cIncluding cardiovascular and cerebrovascular causes excluding hemorrhagic deaths outside of the central nervous system.
dNonfatal stroke includes ischemic, hemorrhagic, and undetermined stroke type.
Clinical trials in psoriatic arthritis
In the psoriatic arthritis clinical trials, 12 patients experienced serious MACE (9 were severe, and 3 were moderate). Two of the events were fatal, and 10 were resolved or recovered.7,16,17
Nine of the 12 patients who experienced MACE had cardiovascular risk factors including
- hypertension
- Raynaud’s phenomenon
- hypercholesterolemia
- dyslipidemia, and
- obesity.7
shows total MACE incidence and EAIRs integrated across all ixekizumab PsA exposures as of March 2022.
|
All IXE-Treated Patients |
Total adjudicated MACE, n (%) [IR] |
12 (0.9) [0.5] |
Vascular deathb |
2 (0.1) [0.1] |
Nonfatal MI |
6 (0.4) [0.3] |
Nonfatal strokec |
4 (0.3) [0.2] |
Abbreviations: IR = incidence rate (per 100 patient-years); IXE = ixekizumab; MACE = major adverse cerebrocardiovascular events; MI = myocardial infarction; PY = patient-years.
aData as of March 2022.
bIncluding cardiovascular and cerebrovascular causes excluding hemorrhagic deaths outside of the central nervous system.
cNonfatal stroke includes ischemic, hemorrhagic, and undetermined stroke type.
Rates of MACE were similar in psoriasis and psoriatic arthritis clinical trials. There was no pattern of increased risk of MACE with longer exposures to ixekizumab, and rates of MACE were consistent over time and consistent with the overall background rates among patients with psoriatic arthritis.7,15,19
There is no evidence that treatment with ixekizumab in patients with psoriatic arthritis modifies the underlying risk for adverse cerebrocardiovascular events such as MI or stroke.15
Clinical trials in axial spondyloarthritis
In the axial spondyloarthritis (axSpA) clinical trials which included ankylosing spondylitis/radiographic axial spondyloarthritis (AS/r-axSpA) and nonradiographic axial spondyloarthritis (nr-axSpA) (N=932 patients accounting for 2097.7 PYs of exposure), 6 patients experienced MACE. None of the events were fatal, and 6 were resolved or recovered.9
shows total MACE incidence and EAIRs integrated across all ixekizumab axSpA exposures (including ankylosing spondylitis/radiographic axial spondyloarthritis and nonradiographic axial spondyloarthritis patients) as of March 2022.
All IXE-Treated Patients |
|
Total adjudicated MACE, n (%) [IR] |
6 (0.6) [0.3] |
Vascular deathb |
0 [0.0] |
Nonfatal MI |
6 (0.6) [0.3] |
Nonfatal strokec |
0 [0.0] |
Abbreviations: IR = incidence rate; IXE = ixekizumab; MACE = major adverse cerebrocardiovascular events; MI = myocardial infarction; PY = patient-years.
aData as of March 2022.
bIncluding cardiovascular and cerebrovascular causes excluding hemorrhagic deaths outside of the central nervous system.
cNonfatal stroke includes ischemic, hemorrhagic, and undetermined stroke type.
The incidence rate of MACE did not increase with longer ixekizumab exposure, up to 3 years.18
References
1Papp K, Bissonette R, Ohtsuki M, et al. Ixekizumab shows no association with major adverse cardiac events (MACE) in patients with moderate-to-severe psoriasis: an integrated safety analysis of clinical trials. Poster presented at: 74th Annual Meeting of the American Academy of Dermatology; March 4-8, 2016; Washington, DC.
2Deodhar A, Poddubnyy D, Pacheco-Tena C, et al; COAST-W Study Group. Efficacy and safety of ixekizumab in the treatment of radiographic axial spondyloarthritis: sixteen-week results from a phase III randomized, double-blind, placebo-controlled trial in patients with prior inadequate response to or intolerance of tumor necrosis factor inhibitors. Arthritis Rheumatol. 2019;71(4):599-611. http://dx.doi.org/10.1002/art.40753
3Mease PJ, van der Heijde D, Ritchlin CT, et al; SPIRIT-P1 Study Group. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Ann Rheum Dis. 2017;76(1):79-87. http://dx.doi.org/10.1136/annrheumdis-2016-209709
4van der Heijde D, Cheng-Chung Wei J, Dougados M, et al; COAST-V Study Group. Ixekizumab, an interleukin-17A antagonist in the treatment of ankylosing spondylitis or radiographic axial spondyloarthritis in patients previously untreated with biological disease-modifying anti-rheumatic drugs (COAST-V): 16 week results of a phase 3 randomised, double-blind, active-controlled and placebo-controlled trial. Lancet. 2018;392(10163):2441-2451. http://dx.doi.org/10.1016/s0140-6736(18)31946-9
5Gottlieb A, Papp K, Xu W, et al. Long-term safety of ixekizumab with over 18,000 patient years of exposure: analysis from 13 moderate-to-severe plaque psoriasis studies and 3 psoriatic arthritis studies. Poster presented at: 77th Annual Meeting of the American Academy of Dermatology; March 1-5, 2019; Washington, DC.
6Deodhar A, van der Heijde D, Gensler LS, et al; COAST-X Study Group. Ixekizumab for patients with non-radiographic axial spondyloarthritis (COAST-X): a randomised, placebo-controlled trial. Lancet. 2020;395(10217):53-64. http://dx.doi.org/10.1016/S0140-6736(19)32971-X
7Deodhar AA, Combe B, Accioly AP, et al. Safety of ixekizumab in patients with psoriatic arthritis: data from four clinical trials with over 2000 patient-years of exposure. Ann Rheum Dis. 2022;81(7):944-950. https://doi.org/10.1136/annrheumdis-2021-222027
8Griffiths CEM, Gooderham M, Colombel JF, et al. Safety of ixekizumab in adult patients with moderate-to-severe psoriasis: data from 17 clinical trials with over 18,000 patient-years of exposure. Dermatol Ther (Heidelb). 2022;12(6):1431-1446. https://doi.org/10.1007/s13555-022-00743-9
9Lebwohl M, Deodhar A, Schwartzman S, et al. Long-term safety of ixekizumab treatment in adult patients with psoriasis, psoriatic arthritis, or axial spondyloarthritis: a post-hoc analysis of end-of-study program data relating to major adverse cardiovascular events. Poster presented at: American Academy of Dermatology (AAD); New Orleans, LA. March 17-21, 2023.
10Gelfand JM, Troxel AB, Lewis JD, et al. The risk of mortality in patients with psoriasis: results from a population-based study. Arch Dermatol. 2007;143(12):1493-1499. http://dx.doi.org/10.1001/archderm.143.12.1493
11Gulliver W. Long-term prognosis in patients with psoriasis. Br J Dermatol. 2008;159(suppl 2):2-9. http://dx.doi.org/10.1111/j.1365-2133.2008.08779.x
12Mehta NN, Yu Y, Pinnelas R, et al. Attributable risk estimate of severe psoriasis on major cardiovascular events. Am J Med. 2011;124(8):775.e1-775.e6. https://doi.org/10.1016/j.amjmed.2011.03.028
13Edson-Heredia E, Zhu B, Lefevre C, et al. Prevalence and incidence rates of cardiovascular, autoimmune, and other diseases in patients with psoriatic or psoriatic arthritis: a retrospective study using Clinical Practice Research Datalink. J Eur Acad Dermatol Venereol. 2015;29(5):955-963. http://dx.doi.org/10.1111/jdv.12742
14Griffiths CEM, Gooderham M, Colombel JF, et al. Safety of ixekizumab in adult patients with moderate-to-severe psoriasis: data from 17 clinical trials with over 18,000 patient-years of exposure. Poster presented at: Annual Meeting of the American Academy of Dermatology (AAD); March 25-29, 2022; Boston, MA.
15Data on file, Eli Lilly and Company and/or one of its subsidiaries.
16Deodhar A, Blauvelt A, Schwartzman S, et al. Long-term safety of ixekizumab in adult patients with psoriasis, psoriatic arthritis, and axial spondyloarthritis. Poster presented at: American College of Rheumatology/ARP - 2022 Annual Scientific Meeting; November 10-14, 2022; Philadelphia, Pennsylvania.
17Deodhar A, Blauvelt A, Lebwohl M, et al. Long-term safety of Ixekizumab in adults with psoriasis, psoriatic arthritis, or axial spondyloarthritis: a post-hoc analysis of final safety data from 25 randomized clinical trials. Arthritis Res Ther. 2024;26(1):49. https://doi.org/10.1186/s13075-023-03257-7
18Schwartzman S, Deodhar A, Combe B, et al. Safety profile of ixekizumab for the treatment of psoriatic arthritis and axial spondyloarthritis up to 3 years: an updated integrated safety analysis. Poster presented at: Annual Meeting of the America College of Rheumatology (ACR Convergence Virtual); November 1-10, 2021.
19Genovese MC, Kameda H, Rahman P, et al. Safety profile of ixekizumab in patients with moderate-to-severe plaque psoriasis and psoriatic arthritis: integrated analysis of 18 clinical trials. Poster presented at: American College of Rheumatology/ARP; November 8-13, 2019; Atlanta, GA.
20Deodhar A, Poddubnyy D, Rahman P, et al. Long-term safety and efficacy of ixekizumab in patients with axial spondyloarthritis: 3-year data from the COAST program. J Rheum. Published online March 1, 2023. https://www.jrheum.org/content/early/2023/02/23/jrheum.221022.long
Appendix: Major adverse cerebrovascular events in ixekizumab trials
Pooled IXE PsO |
Pooled IXE PsA |
Pooled IXE axSpA |
|
Patients with ≥1 TEAE of MACE |
91 (1.4) [0.5]b |
12 (0.9) [0.5]b |
6 (0.6) [0.3]b |
Vascular death |
20 (0.3) [0.1] |
2 (0.1) [0.1] |
0 (0.0) [0.0] |
Death |
4 (0.1) [0.0] |
0 |
0 |
Cardiorespiratory arrest |
2 (0.0) [0.0] |
1 (0.1) [0.0] |
0 |
Cerebrovascular accident |
0 |
1 (0.1) [0.0] |
0 |
Myocardial infarction |
3 (0.0) [0.0] |
0 |
0 |
Cardiac arrest |
2 (0.0) [0.0] |
0 |
0 |
Acute myocardial infarction |
1 (0.0) [0.0] |
0 |
0 |
Cardiac failure |
1 (0.0) [0.0] |
0 |
0 |
Cardiac failure congestive |
1 (0.0) [0.0] |
0 |
0 |
Cardiogenic shock |
1 (0.0) [0.0] |
0 |
0 |
Chronic obstructive pulmonary disease |
1 (0.0) [0.0] |
0 |
0 |
Coronary artery disease |
1 (0.0) [0.0] |
0 |
0 |
Hemorrhagic cerebral infarction |
1 (0.0) [0.0] |
0 |
0 |
Respiratory failure |
1 (0.0) [0.0] |
0 |
0 |
Septic shock |
1 (0.0) [0.0] |
0 |
0 |
Nonfatal myocardial infarction |
49 (0.7) [0.3] |
6 (0.4) [0.3] |
6 (0.6) [0.3] |
Myocardial infarction |
22 (0.3) [0.1] |
1 (0.1) [0.0] |
3 (0.3) [0.1] |
Acute myocardial infarction |
16 (0.2) [0.1] |
2 (0.1) [0.1] |
3 (0.3) [0.1] |
Acute coronary syndrome |
3 (0.0) [0.0] |
1 (0.1) [0.0] |
0 |
Angina unstable |
3 (0.0) [0.0] |
0 (0.0) [0.0] |
0 |
Angina pectoris |
2 (0.0) [0.0] |
0 |
0 |
Arteriospasm coronary |
1 (0.0) [0.0] |
0 |
0 |
Coronary artery thrombosis |
0 |
1 (0.1) [0.0] |
0 |
Coronary artery disease |
1 (0.0) [0.0] |
1 (0.1) [0.0] |
0 |
Stress cardiomyopathy |
1 (0.0) [0.0] |
0 |
0 |
Nonfatal stroke |
23 (0.3) [0.1] |
4 (0.3) [0.2] |
0 |
Ischemic stroke |
20 (0.3) [0.1] |
3 (0.2) [0.1] |
0 |
Hemorrhagic stroke |
3 (0.0) [0.0] |
1 (0.1) [0.0] |
0 |
Abbreviations: axSpA = axial spondyloarthritis; IR = incidence rate; IXE = ixekizumab; MACE = major adverse cardiovascular events; PsA = psoriatic arthritis; PsO = psoriasis; PY = patient-year; TEAE = treatment-emergent adverse events.
aIncludes only clinical trials where MACE cases were adjudicated.
bIRs for MACE were within the ranges reported for patients in the general psoriasis, psoriatic arthritis, and axial spondyloarthritis populations.
Date of Last Review: 01 April 2024