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Clonal hematopoiesis, cardiovascular events and treatment benefit in 63,700 individuals from five TIMI randomized trials

Nature Medicine volume 30, pages 2641–2647 (2024)Cite this article

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Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with an increased risk of cardiovascular (CV) disease in the general population. Currently, it is unclear whether this association is observed in large clinical trial cohorts with a high burden of existing CV disease or whether CV therapies can mitigate CHIP-associated CV risk. To address these questions, we studied 63,700 patients from five randomized trials that tested established therapies for CV disease, including treatments targeting the proteins PCSK9, SGLT2, P2Y12 and FXa. During a median follow-up of 2.5 years, 7,453 patients had at least one CV event (CV death, myocardial infarction (MI), ischemic stroke or coronary revascularization). The adjusted hazard ratio (aHR) for CV events for CHIP+ patients was 1.07 (95% CI: 0.99–1.16, P = 0.08), with consistent risk estimates across each component of CV risk. Significant heterogeneity in the risk of MI was observed, such that CHIP+ patients had a 30% increased risk of first MI (aHR = 1.31 (1.05–1.64), P = 0.02) but no increased risk of recurrent MI (aHR = 0.94 (0.79–1.13), Pint = 0.008), as compared to CHIP− patients. Moreover, no significant heterogeneity in treatment effect between individuals with and without CHIP was observed for any of the therapies studied in the five trials. These results indicate that in clinical trial populations, CHIP is associated with incident but not recurrent coronary events and that the presence of CHIP does not appear to identify patients who will derive greater benefit from commonly used CV therapies.

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Fig. 1: Distribution of CHIP over the lifetime and by gene.
Fig. 2: Association between CHIP and major CV events and cause of death.
Fig. 3: Association between CHIP burden and major CV events in patients with and without prior MI.
Fig. 4: Associations between CHIP and the cumulative risk of first versus recurrent MI and coronary revascularization.

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Data availability

Due to contractual agreements with the sponsors of the clinical trials, trial data cannot be made publicly available.

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Acknowledgements

N.A.M. receives funding from the National Institutes of Health (NIH) under grant K08HL153950. J.P.P. is supported by NIH under grant K08HL159346. M.P.B. receives support from the AHA SFRN under awards 18SFRN3390085 (BWH-DH SFRN Center) and 18SFRN33960262 (BWH-DH Clinical Project). A.G.B. is supported by NIH grant DP5 OD029586.

Author information

Author notes

  1. These authors contributed equally: Nicholas A. Marston, James P. Pirruccello.

  2. These authors jointly supervised this work: Alexander G. Bick, Marc S. Sabatine, Christian T. Ruff.

Authors and Affiliations

  1. TIMI Study Group, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Nicholas A. Marston, Giorgio E. M. Melloni, Frederick Kamanu, Robert P. Giugliano, Benjamin M. Scirica, Stephen D. Wiviott, Eugene Braunwald, Marc S. Sabatine & Christian T. Ruff

  2. Division of Cardiology, Institute for Human Genetics and Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA

    James P. Pirruccello

  3. CPC Clinical Research, Aurora, CO, USA

    Marc P. Bonaca

  4. Mount Sinai Heart, Icahn School of Medicine at Mount Sinai Health System, New York City, NY, USA

    Deepak L. Bhatt

  5. Division of Cardiology, Assistance Publique-Hopitaux de Paris, Universite de Paris, Paris, France

    Philippe Gabriel Steg

  6. Department of Endocrinology and Metabolism, Hadassah Hebrew University Hospital, Jerusalem, Israel

    Itamar Raz

  7. Cardiovascular Medicine Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Peter Libby

  8. Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA

    Patrick T. Ellinor

  9. Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Patrick T. Ellinor

  10. Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

    Patrick T. Ellinor

  11. Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Alexander G. Bick

Authors
  1. Nicholas A. Marston
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  2. James P. Pirruccello
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  15. Alexander G. Bick
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  16. Marc S. Sabatine
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  17. Christian T. Ruff
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Contributions

N.A.M. developed the analysis plan, oversaw the analyses, interpreted the results and drafted the paper. J.P.P. led the CHIP calling and data preparation and contributed to the initial draft of the paper. G.E.M.M. led the statistical analyses and contributed to the initial and subsequent drafts of the paper. F.K. provided additional statistical and analytical support and provided critical review of the paper. M.P.B., R.P.G., B.M.S., S.D.W., D.L.B., P.G.S., I.R. and E.B. contributed to data collection and reviewed the paper. P.L., P.T.E., A.G.B., M.S.S. and C.T.R. provided oversight and guidance throughout the analysis, including critical review and revisions of the paper.

Corresponding author

Correspondence to Nicholas A. Marston.

Ethics declarations

Competing interests

P.L. has a financial interest in TenSixteen Bio (a company targeting somatic mosaicism and CHIP to discover and develop new therapeutics to treat age-related diseases). A.G.B. is on the scientific advisory board of TenSixteen Bio. The other authors declare no competing interests.

Peer review

Peer review information

Nature Medicine thanks Alan Tall and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Michael Basson, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Fig. 1 The association between specific CHIP driver mutations and major cardiovascular events in patients with and without history of MI (n = 63,700).

DNA damage genes: TP53 and PPM1D, spliceosome genes: SF3B1, SRSF2, U2AF1. HRs and 95% CI are reported adjusted for age, age2, sex, BMI, current smoking, history of hypercholesterolemia, systolic blood pressure, history of diabetes, statin use, ancestry (PC 1–10), prior MI, stroke, AF, malignancy, eGFR, PAD, CHF, and trial. Two-sided p-values were obtained via Wald test.

Extended Data Fig. 2 Association of CHIP subgroups with major cardiovascular events.

The association between CHIP (a) and TET2 (b) and major cardiovascular events stratified by IL6R Asp358Ala genotypes (n = 53,298). HRs and 95% CI are reported adjusted for age, age2, sex, BMI, current smoking, history of hypercholesterolemia, systolic blood pressure, history of diabetes, statin use, ancestry (PC 1–10), prior MI, stroke, AF, malignancy, eGFR, PAD, CHF, and trial. Two-sided p-values were obtained via Wald test.

Extended Data Fig. 3 Association between TET2+ and major adverse cardiovascular events as a function of LDL-C level.

Hazard ratio estimates are derived from an interaction model between TET2 status and a 3-knot restricted cubic spline of LDL-C. 95% CI bands (in gray) were obtained via bootstrap. The model is adjusted for age, age2, sex, BMI, current smoking, history of hypercholesterolemia, systolic blood pressure, history of diabetes, statin use, ancestry (PC 1–10), prior MI, stroke, AF, malignancy, eGFR, PAD, CHF, and trial. P-interaction = 0.26. PEGASUS LDL-C values were approximated by transformed ApoB values. LDL-C values were not available in ENGAGE.

Extended Data Table 1 Baseline characteristics by trial
Full size table
Extended Data Table 2 Unadjusted and adjusted hazard ratios for study endpoints in CHIP+ patients compared to CHIP−
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Extended Data Table 3 Sensitivity analysis of the association between CHIP and major cardiovascular events using leave one trial out (N-1) approach
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Extended Data Table 4 Competing risk analysis using Fine–Gray model to evaluate the association between CHIP and (a) major vascular events and (b) MACE stratified by trial
Full size table
Extended Data Table 5 Association between CHIP+ and TET2+ and major cardiovascular events stratified by statin use
Full size table

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Marston, N.A., Pirruccello, J.P., Melloni, G.E.M. et al. Clonal hematopoiesis, cardiovascular events and treatment benefit in 63,700 individuals from five TIMI randomized trials. Nat Med 30, 2641–2647 (2024). https://doi.org/10.1038/s41591-024-03188-z

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