Highlight
– In a secondary, prespecified imaging analysis of the randomized STOP‑CA trial, pretreatment with atorvastatin 40 mg daily prevented the anthracycline‑associated rise in aortic pulse wave velocity (PWV) over 12 months.
– A ≥1 SD rise in PWV occurred in 5% of atorvastatin‑treated patients versus 50% of placebo (OR 0.05; 95% CI, 0.02–0.16; P < .001).
– Increasing PWV was associated with a small but statistically significant decline in LVEF, supporting the clinical relevance of vascular stiffening during chemotherapy.
Background
Anthracycline chemotherapy (eg, doxorubicin) remains central to curative regimens for many hematologic and solid tumors but carries a well‑recognized risk of cardiovascular toxicity. Cardiotoxic effects include left ventricular (LV) systolic dysfunction and heart failure, and accumulating evidence implicates vascular injury—especially increases in arterial stiffness—as an important contributor to anthracycline‑related cardiovascular risk. Aortic stiffness, commonly quantified by pulse wave velocity (PWV), is a potent predictor of cardiovascular events and mortality in the general population and may be an early marker of treatment‑related cardiovascular injury in cancer patients.
Study Design
This report is a secondary analysis of the Statins to Prevent the Cardiotoxicity From Anthracyclines (STOP‑CA) randomized, double‑blind, placebo‑controlled trial (ClinicalTrials.gov NCT02943590). STOP‑CA enrolled patients with newly diagnosed lymphoma who were planned to receive anthracycline‑based chemotherapy and who had no existing indication for statin therapy. Participants were randomized 1:1 to atorvastatin 40 mg once daily or matched placebo, started before chemotherapy and continued for 12 months.
The subanalysis focused on cardiac magnetic resonance (CMR) imaging‑derived vascular end points: aortic arch pulse wave velocity (PWV) and aortic distensibility (AD). Investigators used an intention‑to‑treat approach. Outcomes reported here are post hoc but prespecified imaging end points within the trial protocol. Key comparisons included the change in PWV and ascending aortic distensibility (AAD) over 12 months, the proportion of participants with ≥1 SD worsening (increase in PWV or decrease in AAD), and associations between PWV change and LV ejection fraction (LVEF) changes.
Results
Enrollment and imaging completeness: Of 300 randomized participants (150 atorvastatin, 150 placebo), paired PWV data were available for 152 participants (mean age 51 ± 17 years; 47% female): 82 in the atorvastatin arm and 70 in placebo. Paired aortic distensibility data were available for 168 participants.
PWV and Aortic Distensibility Changes
Atorvastatin group: mean aortic arch PWV remained essentially unchanged over 12 months (6.5 ± 1.9 m/s at baseline vs 6.5 ± 2.0 m/s at 12 months).
Placebo group: PWV increased from 5.7 ± 1.8 m/s at baseline to 6.8 ± 2.0 m/s at 12 months, a group‑level rise consistent with anthracycline‑associated vascular stiffening.
Proportions Reaching Threshold Worsening
A rise in PWV of ≥1 SD (0.8 m/s) occurred in 4 of 82 patients (5%) randomized to atorvastatin compared with 35 of 70 patients (50%) randomized to placebo. This translated to an odds ratio of 0.05 (95% CI, 0.02–0.16; P < .001), favoring atorvastatin for prevention of PWV worsening.
A ≥1 SD decrease in AAD (1.8 × 10−3 mm Hg−1) was observed in 6 of 88 patients (7%) with atorvastatin and in 14 of 80 patients (18%) with placebo, suggesting a similar direction of benefit for distensibility measures though with smaller absolute event counts.
Association with Cardiac Function
Participants who experienced a ≥1 SD increase in PWV had a mean decline in LVEF of 2.70% (95% CI, −4.65% to −0.81%; P = .006) compared with those who did not, linking vascular stiffening with subclinical LV systolic deterioration during anthracycline therapy.
Other End Points and Safety
The investigators also examined a previously defined minimal annual PWV increment of 0.15 m/s seen in age‑matched populations, but the most clinically salient and statistically robust findings were evident using the 1 SD thresholds. The parent trial’s primary cardiac outcomes and safety data have been published separately; this analysis did not identify new safety signals specific to short‑term atorvastatin exposure in this population.
Interpretation and Clinical Implications
This secondary analysis provides randomized evidence that atorvastatin 40 mg daily, when started before anthracycline exposure and continued for 12 months, preserves aortic elastic properties as measured by CMR PWV and aortic distensibility. The magnitude of the effect was large for the PWV threshold analysis: a tenfold relative reduction in the proportion of patients with marked PWV worsening (5% vs 50%).
Mechanistically, statins have well‑described pleiotropic effects beyond LDL lowering, including improvement of endothelial function, reduction of oxidative stress and inflammation, and favorable effects on vascular remodeling—pathways implicated in anthracycline vascular injury. Anthracyclines induce endothelial dysfunction and oxidative damage, which may accelerate arterial stiffening. By interrupting those processes, statins could plausibly attenuate vascular remodeling and thereby mitigate a contributor to downstream LV afterload and cardiomyopathy.
From a practical standpoint, these data raise the possibility that prophylactic statin therapy could be considered as part of a cardio‑protection strategy for patients receiving anthracyclines, even in the absence of an a priori lipid indication. Preservation of arterial compliance may translate into less LV afterload, reduced myocardial stress, and potentially lower long‑term cardiovascular morbidity. However, the current analysis does not provide hard evidence of reductions in clinical events (eg, symptomatic heart failure, myocardial infarction, or cardiovascular death), so the findings should be interpreted as hypothesis‑generating for outcomes trials.
Strengths and Limitations
Strengths: randomized, double‑blind, placebo‑controlled design of the parent trial; objective CMR‑based measurement of vascular stiffness; biologically plausible mechanism backed by association between PWV worsening and LVEF decline.
Limitations: this is a secondary, post hoc imaging analysis and not the primary prespecified clinical endpoint of STOP‑CA; imaging data were available for a subset of participants (~50% for PWV), which raises potential selection bias; follow‑up was limited to 12 months—longer‑term vascular and clinical outcomes are unknown; the study population consisted of patients with lymphoma and mean age 51 years, which may limit generalizability to older patients and to those receiving other cancer regimens; the trial was not powered for clinical cardiovascular events, and the relationship to long‑term clinical outcomes requires confirmation in larger, dedicated trials.
Expert Commentary and Guideline Context
Current cardio‑oncology guidelines emphasize risk assessment, surveillance, and management of cardiotoxicity, including consideration of cardioprotective strategies (ACE inhibitors, beta‑blockers) in high‑risk patients. Randomized evidence for routine statin prophylaxis in patients without a conventional indication has been limited. The STOP‑CA vascular subanalysis provides an important randomized signal supporting the vascular protective properties of statins in the anthracycline setting. Nonetheless, guideline incorporation will require confirmation of benefit on patient‑centered clinical outcomes and safety across diverse cancer populations.
Practical Considerations for Clinicians
Clinicians considering statin prophylaxis for patients receiving anthracyclines should weigh the following:
- Patient baseline cardiovascular risk and competing indications for statin therapy.
- Potential drug‑drug interactions between statins (particularly those metabolized by CYP3A4, like atorvastatin) and specific chemotherapeutic or supportive agents.
- Monitoring for statin‑associated adverse effects (eg, transaminitis, myopathy) during combined therapy.
- The current evidence supports vascular protection but not yet proven reductions in heart failure or mortality related specifically to anthracycline cardiotoxicity.
Conclusion
In this secondary analysis of STOP‑CA, atorvastatin 40 mg daily started before anthracycline therapy was associated with preservation of aortic elastic function over 12 months compared with placebo. The magnitude and consistency of the PWV findings, together with the observed association between PWV worsening and modest LVEF decline, support a role for statins in mitigating anthracycline‑related vascular injury. These data are hypothesis‑generating and justify confirmatory trials powered for clinical cardiovascular outcomes and exploration in broader cancer populations.
Funding and trial registration
ClinicalTrials.gov Identifier: NCT02943590. Funding sources and detailed trial sponsorship are reported in the primary STOP‑CA publications and trial record.
References
1. Juhasz V, Drobni ZD, Quinaglia T, et al. Atorvastatin and Aortic Stiffness During Anthracycline‑Based Chemotherapy: A Secondary Analysis of a Randomized Clinical Trial. JAMA Cardiol. 2025 Nov 8:e254548. doi: 10.1001/jamacardio.2025.4548.
2. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity. Pharmacol Rev. 2004 Jun;56(2):185–229.
3. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of Cardiovascular Events and All‑Cause Mortality With Arterial Stiffness: A Systematic Review and Meta‑Analysis. J Am Coll Cardiol. 2010 Mar 9;55(13):1318–1327.
4. STOP‑CA Trial record. ClinicalTrials.gov Identifier: NCT02943590. https://clinicaltrials.gov/ct2/show/NCT02943590
AI thumbnail prompt
A realistic clinical thumbnail: a female patient in her 50s seated at an outpatient oncology infusion center, an MRI image of the aortic arch floating beside her with colorized flow vectors, a prescription bottle labeled ‘Atorvastatin 40 mg’ on a clipboard, soft clinical lighting, a sense of cautious optimism; photorealistic, 3:2 aspect ratio.
