STOP-CA: Atorvastatin Curbs Heart Function Decline During Chemotherapy

NEW ORLEANS, LA—In lymphoma patients receiving chemotherapy with anthracyclines, statins may be cardioprotective, according to the STOP-CA trial.

Among the 300 patients studied, those assigned to 40 mg of atorvastatin daily were less likely to experience a 10% or greater decline in LVEF at 12 months than those assigned to a placebo (9% vs 22%; P = 0.002). Women, individuals over age 52, those who were obese, and those who received doses of anthracyclines greater than 250 mg/m² saw the greatest benefit.

Video Interview

Beyond the Data: STOP-CA: A Role for Statins against Anthracyclines?

March 5, 2023

“These data support the use of atorvastatin among patients with lymphoma being treated with anthracyclines, where prevention of cardiac systolic dysfunction is important,” said Tomas G. Neilan, MD (Massachusetts General Hospital, Boston), in his presentation here at the American College of Cardiology/World Congress of Cardiology (ACC/WCC) 2023 meeting.

Anthracyclines are commonly used to treat lymphoma and other types of cancers, but are known to increase the risk of cardiac dysfunction and heart failure (HF) starting with the first cycle of chemotherapy. A recent study of nearly 2,200 breast cancer and lymphoma patients found that the cumulative incidence of HF after treatment with anthracyclines was more than twofold higher at 15 years compared with patients who did not have cancer. However, at least one other study showed no difference between atorvastatin and placebo for LVEF at 24 months.

A range of studies have hinted that statins might be cardioprotective in the setting of chemotherapy, but prospective studies in patients not already taking a statin for primary or secondary CVD prevention have been lacking.

Ana Barac, MD, PhD (MedStar Heart and Vascular Institute, Washington, DC), who served as a panelist during the session, noted that patients like those enrolled in the trial face significant challenges in addition to being frequently overlooked for CV prevention.

“The study suggests that one could consider atorvastatin for primary prevention in patients receiving anthracyclines for lymphoma,” she told TCTMD. But she added that the most important message to take from the trial is to get patients who are already eligible for statins and who have lymphoma on atorvastatin.

One limitation of the study is that it was not powered to assess the impact of atorvastatin on HF and the  LVEF changes can’t necessarily be extrapolated to HF prevention. Despite this, said Anita Deswal, MD (MD Anderson Cancer Center, Houston, TX), commenting on STOP-CA during a press conference, the study is useful because lymphoma patients typically receive higher doses of anthracyclines than used in other cancers like those of the breast.

Deswal noted that while the cardiotoxicity associated with anthracyclines has been known since the late 1960s or early 1970s, few options exist to combat it.

Currently, dexrazoxane is the only agent approved by the US Food and Drug Administration to reduce anthracycline-associated cardiotoxicity, but its use is limited due to increased risk of second malignant neoplasm. Neurohormonal blockade also has been tested but has shown only modest effects.

Small Absolute Difference Seen

STOP-CA was conducted at nine centers in the US and Canada. Enrolled patients (mean age 50 years; 47% female; baseline LVEF 63%) were scheduled to undergo treatment with anthracyclines. Approximately 70% had B-cell lymphoma, 27% had Hodgkin’s, and 14% had T-cell lymphoma. There were no differences in cholesterol levels between groups at baseline.

Half were assigned to take 40 mg of atorvastatin (n = 150) and half took a placebo daily (n = 150), starting before their first dose of anthracyclines and continuing for 1 year. The mean cumulative anthracycline dose was 268 mg/m² in the atorvastatin group and 260 mg/m² in the placebo group.

Atorvastatin adherence throughout the trial was high at greater than 90%. Overall, 15% of the entire cohort had a decline in LVEF between baseline and 1 year that was greater than 10%. For the placebo group, the likelihood of experiencing that degree of decline was significantly greater than the atorvastatin group (OR 2.9; 95% CI 1.4-6.4).

LVEF decline of 5% or greater from baseline to 1 year was a secondary endpoint that occurred in 21% of the entire cohort. Again, this degree of decline was far more common in the placebo group compared with atorvastatin users (29% vs 13%; P = 0.001).

Looking at exploratory endpoints, the investigators found that that the atorvastatin group had an average mean decrease in LVEF of 4% over the study period (from 63% to 59%), while the placebo group had an average mean decrease of 5% (from 63% to 57%), a small but statistically significant difference. Overall, 11 patients had HF events, with a similar number of these in the two groups (P = 0.77). However, the study was not powered to assess incident HF.

Additionally, a similar number in each group had their LVEF measured at both time points by cardiac MRI, for a total of 77% of the study population. There was no difference in the primary endpoint results when analyzed by patients who had MRI follow-up.

Among the adverse events reported, similar numbers of patients in both groups experienced muscle pain and elevated renal enzymes. Three patients in the placebo group developed renal failure, as did one patient in the atorvastatin group (P = 0.68).

Compared with placebo, patients assigned to atorvastatin had an average decline in LDL cholesterol of approximately 37%.

Future Research Needs

The investigators say more research is needed to determine the optimal timing and duration of statin therapy in cancer patients undergoing chemotherapy and to determine if the results in lymphoma patients can be extrapolated to other types of cancer.

Although STOP-CA participants had a high rate of adherence to atorvastatin, statin therapies pose known challenges, with some patients unable to tolerate them. To TCTMD, co-PI Marielle Scherrer-Crosbie, MD, PhD (Hospital of the University of Pennsylvania, Philadelphia), said the trialists closely followed the atorvastatin group, calling them regularly, and were able to convince most patients who had statin-related complaints to continue.

“We did have a given a protocol—if they had some muscle pain, for example—to decrease the dose and really question them, and measure some muscle enzymes, and then restart the drug,” she added. “So, we were very aware that this is a clinical trial environment, if you will, and that we may have some of those issues in real life.”

The investigators acknowledged that longer studies are needed, since it is unclear if the difference in LVEF between the groups would have been more pronounced beyond 12 months.